article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "BACKGROUND\nThe use of isavuconazole is approved for the management of invasive aspergillosis and mucormycosis, only in adults, as no paediatric pharmacology studies have been reported to date. Very few paediatric cases have been published concerning the use of isavuconazole. Amphotericin B is the only antifungal agent recommended in paediatric mucormycosis, but adverse effects and especially nephrotoxicity, even with the liposomal formulation, could be problematic. In this context, the use of other antifungal molecules active on Mucorales becomes needful.\n\n\nMETHODS\nWe describe a case of mucormycosis with rapid onset dissemination in a 3-year-old girl recently diagnosed with acute lymphocytic leukaemia. She was successfully treated with isavuconazole alone and then in combination with liposomal amphotericin B. Isavuconazole therapy was guided by therapeutic drug monitoring.\n\n\nCONCLUSIONS\nThis case offers new perspectives on the potential use of isavuconazole in children with mucormycosis, as an alternative or adjunct to liposomal amphotericin B.",
"affiliations": "Laboratoire de Parasitologie Mycologie, CHU Lille, Univ. Lille, INSERM U995 - LIRIC - Lille Inflammation Research International Centre, F-59000, Lille, France.;Service d'Onco-Hématologie Pédiatrique, CHU Lille, F-59000, Lille, France.;Laboratoire de Parasitologie Mycologie, CHU Lille, Univ. Lille, INSERM U995 - LIRIC - Lille Inflammation Research International Centre, F-59000, Lille, France.;Service d'Onco-Hématologie Pédiatrique, CHU Lille, F-59000, Lille, France.;Laboratoire de Parasitologie Mycologie, CHU Lille, Univ. Lille, INSERM U995 - LIRIC - Lille Inflammation Research International Centre, F-59000, Lille, France.;Paris Descartes University, Sorbonne Paris Cité, Infectious Diseases Unit, Necker-Enfants Malades University Hospital, AP-HP, Imagine Institute, Paris, France.;Service de Radio-pédiatrie, CHU Lille, F-59000, Lille, France.;Service des urgences et maladies infectieuses pédiatriques, CHU Lille et Univ. Lille, F-59000, Lille, France.;Service d'Onco-Hématologie Pédiatrique, CHU Lille, F-59000, Lille, France.;Laboratoire de Parasitologie Mycologie, CHU Lille, Univ. Lille, INSERM U995 - LIRIC - Lille Inflammation Research International Centre, F-59000, Lille, France. bsendid@univ-lille2.fr.",
"authors": "Cornu|Marjorie|M|;Bruno|Bénédicte|B|;Loridant|Séverine|S|;Navarin|Pauline|P|;François|Nadine|N|;Lanternier|Fanny|F|;Amzallag-Bellenger|Elisa|E|;Dubos|François|F|;Mazingue|Françoise|F|;Sendid|Boualem|B|",
"chemical_list": "D000935:Antifungal Agents; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C068538:liposomal amphotericin B; C508735:isavuconazole; D000666:Amphotericin B",
"country": "England",
"delete": false,
"doi": "10.1186/s40360-018-0273-7",
"fulltext": "\n==== Front\nBMC Pharmacol ToxicolBMC Pharmacol ToxicolBMC Pharmacology & Toxicology2050-6511BioMed Central London 27310.1186/s40360-018-0273-7Case ReportSuccessful outcome of disseminated mucormycosis in a 3-year-old child suffering from acute leukaemia: the role of isavuconazole? A case report Cornu Marjorie marjorie.cornu@univ-lille2.fr 1Bruno Bénédicte benedicte.bruno@chru-lille.fr 2Loridant Séverine severine.loridant@chru-lille.fr 1Navarin Pauline pauline.navarin@chru-lille.fr 2François Nadine nadine.francois@chru-lille.fr 1Lanternier Fanny fanny.lanternier@aphp.fr 345Amzallag-Bellenger Elisa elisa.bellenger@chru-lille.fr 6Dubos François francois.dubos@chru-lille.fr 7Mazingue Françoise francoise.mazingue@chru-lille.fr 2Sendid Boualem +33 3 20 44 55 79bsendid@univ-lille2.fr 11 0000 0004 0471 8845grid.410463.4Laboratoire de Parasitologie Mycologie, CHU Lille, Univ. Lille, INSERM U995 – LIRIC - Lille Inflammation Research International Centre, F-59000 Lille, France 2 0000 0004 0471 8845grid.410463.4Service d’Onco-Hématologie Pédiatrique, CHU Lille, F-59000 Lille, France 3 0000 0001 2175 4109grid.50550.35Paris Descartes University, Sorbonne Paris Cité, Infectious Diseases Unit, Necker-Enfants Malades University Hospital, AP-HP, Imagine Institute, Paris, France 4 0000 0001 2353 6535grid.428999.7Institut Pasteur, Unité de Mycologie Moléculaire, CNRS URA3012, Paris, France 5 0000 0001 2353 6535grid.428999.7Institut Pasteur, Centre National de Référence Mycoses Invasives et Antifongiques, Paris, France 6 0000 0004 0471 8845grid.410463.4Service de Radio-pédiatrie, CHU Lille, F-59000 Lille, France 7 0000 0004 0471 8845grid.410463.4Service des urgences et maladies infectieuses pédiatriques, CHU Lille et Univ. Lille, F-59000 Lille, France 6 12 2018 6 12 2018 2018 19 814 9 2018 21 11 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe use of isavuconazole is approved for the management of invasive aspergillosis and mucormycosis, only in adults, as no paediatric pharmacology studies have been reported to date. Very few paediatric cases have been published concerning the use of isavuconazole. Amphotericin B is the only antifungal agent recommended in paediatric mucormycosis, but adverse effects and especially nephrotoxicity, even with the liposomal formulation, could be problematic. In this context, the use of other antifungal molecules active on Mucorales becomes needful.\n\nCase presentation\nWe describe a case of mucormycosis with rapid onset dissemination in a 3-year-old girl recently diagnosed with acute lymphocytic leukaemia. She was successfully treated with isavuconazole alone and then in combination with liposomal amphotericin B. Isavuconazole therapy was guided by therapeutic drug monitoring.\n\nConclusions\nThis case offers new perspectives on the potential use of isavuconazole in children with mucormycosis, as an alternative or adjunct to liposomal amphotericin B.\n\nKeywords\nIsavuconazoleMucormycosisPaediatricsDrug-monitoringLichtheimiaCHRU de Lille-bonus Hissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nThe use of isavuconazole is approved for the management of invasive aspergillosis and mucormycosis, only in adults, as no paediatric pharmacology studies have been reported to date [1]. Very few paediatric cases have been published concerning the use of isavuconazole [2, 3]. Amphotericin B and posaconazole are the only antifungal molecules recommended in mucormycosis in patients with haematological malignancies [4]. However, posaconazole is not yet approved in paediatric population, and the availability of IV and new per os formulations is recent. Moreover adverse effects, especially nephrotoxicity, related to the use of amphotericin B, liposomal formulation included, could be problematic. In children, therapeutic options are limited and the use of other antifungal molecules active on Mucorales becomes necessary.\n\nCase presentation\nAt the end of 2015, a 3-year-old girl, with B-cell acute lymphocytic leukaemia with TEL-AML1 fusion and profound neutropenia, was started treatment with EORTC 58081 protocol (NCT01185886), medium risk AR1. After 19 days of prednisolone (60 mg/m2/day), two doses of vincristine (1.5 mg/m2), one dose of daunorubicin (30 mg/m2) and one dose of asparaginase (10,000 IU/m2), she developed febrile neutropenia with digestive problems. Procalcitonin and serum C-reactive protein (CRP) levels were 1.85 ng/mL and 91 mg/L, respectively. Chemotherapy was discontinued and antibiotherapy was started with ceftriaxone. Due to persistence of fever, ceftriaxone was switched on Day 3 to piperacillin-tazobactam for 14 days and amikacin for 3 days. At that time, neutrophil count was 0.5 × 109/L. Increasing CRP (350 mg/L) prompted the addition of caspofungin on Day 6 (70 mg/m2 day 1, followed by 50 mg/m2/day) following a local protocol established according to international guidelines [5]. Twice weekly screening for serum mannan, galactomannan (Platelia™; Bio-Rad Laboratories) and (1,3)-β-D-glucan (Fungitell™; Associates of Cape Cod, Inc.) remained negative. On Day 10 of fever, a chest computed tomography (CT) scan showed condensation in the left lower lobe associated with right pleural effusion evocative of invasive aspergillosis. Treatment with intravenous voriconazole was started (9 mg/kg bid day 1, then 8 mg/kg bid) and caspofungin was stopped. An abdominal ultrasound showed bilateral nephromegaly. Direct microscopic examination, culture, galactomannan detection and Aspergillus q-PCR in bronchoalveolar lavage were negative. All blood cultures remained sterile.\n\nOn Day 21 of fever, neutrophil count was 11.2 × 109/L. Fundoscopy was performed because of a reduction in visual acuity, revealing multiple subretinal foci suspected to be fungal in origin. Direct microscopy of vitreous humour revealed large, aseptate, ribbon-like hyphae. Among the different mycological techniques used, only Mucorales q-PCR was positive for Lichtheimia spp. (Cq 31) in vitreous humour, but was negative in serum. Magnetic resonance imaging (MRI) showed two abscess-like cerebral lesions and confirmed the kidney infiltration (Fig. 1a). A diagnosis of disseminated mucormycosis was established.Fig. 1 a Plasma trough concentration of isavuconazole after intravenous (IV) or oral dosing (arrows indicate times of pharmacokinetic study days). In parallel, cerebral MRIs on Day 21 of fever and after 6 months of antifungal treatment showing regression of a ring-enhanced cerebral lesion (from 5.5 cm in diameter to 3.2 cm) in the right frontal parietal region. b Pharmacokinetic profiles of isavuconazole. Plasma concentrations of isavuconazole during 24 h following dosing at day 7 (90 mg/d, IV), and during 12 h following dosing day 24 (90 mg bid, IV) and day 44 (100 mg bid, oral). (bid, twice a day; IV, intravenous; L-AmB, liposomal amphotericin B; po, per os)\n\n\n\nDespite limited experience in children, voriconazole was switched to isavuconazole (ISAV) (compassionate off-label use) instead of liposomal amphotericin B (L-AmB), because of renal impairment. Each dose (70 mg every 8 h for 48 h, then 70 mg/day IV) was infused over 1 h. Plasma drug monitoring was implemented from Day 3 after ISAV introduction (AISAVI) and was repeated regularly up to Day 150 (Fig. 1a). Considering a target trough plasma level (TPL) of 2000–4000 ng/mL (approximate average adult TPL observed in Phase 3 studies) [6, 7], low TPL on Day 5 AISAVI prompted an increase in dose to 90 mg/day. A pharmacokinetic profile (Fig. 1b) obtained on Day 7 AISAVI showed that TPL decreased to 1110 ng/mL at 24 h. The ISAV dosage was changed to 90 mg twice daily and L-AmB (10 mg/kg/day) was added despite renal impairment because of the cerebral lesions and difficulties in achieving the ISAV TPL target. The TPL target was reached on Day 17 AISAVI and levels were stable by Day 24. In order to facilitate home nursing care, the route of administration was changed to capsules (100 mg bid). Due to difficulties in swallowing, the capsules were opened and the contents dissolved in an acidic beverage. After 1 week, the mixture was introduced via a nasogastric tube because of vomiting. Median TPL was 4890 ng/mL from Day 66 AISAVI and remained stable over time, while the maximum concentration was obtained between 1 or 2 h after administration, with values varying between 4200 and 4690 ng/ml (Fig. 1b).\n\nWith the exception of slight nausea/vomiting during the first 2 months after initiation, no adverse effects were noted with ISAV, and liver enzymes were in the range of normal values observed in healthy subjects. The patient was in complete cytological and molecular remission and was chemotherapy-free for 7 months, until her leukaemia relapsed at 8 months. The patient was treated with the first-line CAALL-F01 protocol (NCT02716233), medium risk, and was in complete remission 4 months after relapse. Because of the risk of drug interactions, L-AmB (7 mg/kg/day) was continued alone for 4 months and was then replaced with ISAV (50 mg twice daily). Antifungal treatment was maintained during maintenance chemotherapy. The size of the cerebral abscesses decreased between the first and last MRI (at 16 months) from 55 × 37 and 45 × 38.4 mm to 23.5 × 18 and 17 × 17 mm with persistence of hypometabolism on a fluorodeoxyglucose-positron emission tomography scan (FDG PET/CT). Renal insufficiency was stable with clearance of 78 ml/min/m2 according to the Schwartz formula. The loss of left-sided vision was irreversible. After 24 months of treatment, the patient was still alive without further damage. The treatment timeline is shown in the Table 1.Table 1 Timeline of events\n\n\tClinical features\tBiology results\tAntimicrobial therapy\t\nD-19\tStart of chemotherapy\tNeutropenia\t\t\t\nD0\tFebrile neutropenia\tHigh level of CRP and PCT\tAntibiotherapy introduction\tCeftriaxone 100 mg/kg/d\t\nD3\tPersistence of fever\tRising of CRP and PCT rates\tAntibiotherapy switch\tTazobactam Piperacillin 400 mg/kg/d\nAmikacine\t\nD6\tPersistence of fever\t\tAdding antifungal therapy\tCaspofungin 70 mg/m2 day 1, then 50 mg/m2/d\t\nD10\tAbnormal chest CT scan and abdominal ultra-sound\t\tAntifungal combined therapy\tAdding voriconazole 9 mg/kg bid day 1, then 8 mg/kg bid IV\t\nD16\t\tNegative BAL\tWithdrawal Antibiotherapy and caspofungin\t\t\nD21\t\tPositive Fundoscopy\tVoriconazole intravitreal injection 50 μg/ml\t\t\nD24\tAbnormal brain MRI\nInitiation of TDM on D27\t\tSwitch antifungal therapy\tIsavuconazole 70 mg every 8 h for 48 h, then 70 mg/d IV\t\nD31\t\t\t\tIsavuconazole 90 mg/d IV\t\nD37\t\t\tAntifungal combined therapy\tIsavuconazole 90 mg bid IV\nL-AmB 10 mg/kg/d\t\nD39\tFever resolution\t\t\t\t\nD58\t\t\t\tIsavuconazole 100 mg bid p.o\t\nD63\tTPL steady state\t\t\t\t\nM6\tRegression of lesions on imagery\t\t\t\t\nM8\tLeukaemia relapse\t\tWithdrawal isavuconazole\tL-AmB 7 mg/kg/d\t\nM12\tComplete remission\t\tSwitch antifungal therapy\tIsavuconazole 50 mg bid p.o\t\nM16\tRegression of lesions on imagery\t\t\t\t\nBAL bronchoalveolar lavage, bid, twice a day, CRP C-Reactive protein, d day, IV intra-venous, L-AmB liposomal amphotericin B, PCT procalcitonin, p.o per os, TDM therapeutic drug monitoring, TPL trough plasma level\n\n\n\nDiscussion and conclusions\nThe incidence of mucormycosis in Europe is increasing [8–10]. Haematological malignancy is the prominent underlying disease, accounting for 32–38% of cases [10]. Diagnosis of mucormycosis depends on a combination of clinical, radiological and mycological criteria, and is often missed or delayed. Our patient was diagnosed 25 days after the onset of fever. The time between the first symptoms and diagnosis ranges from 0 to 30 weeks [11]. In our patient, disseminated mucormycosis appeared as an early complication of leukaemia (19 days after the start of chemotherapy). However, her fungal infection may have begun to develop before the diagnosis of leukaemia, probably in relation to the initial profound neutropenia. She rapidly presented with cerebral, ocular, pulmonary, muscular and renal lesions. Although surgery may improve survival [12, 13], the discovery of cerebral and disseminated lesions in this patient prevented surgical intervention. L-AmB is the most effective antifungal agent against Mucorales with doses up to 10 mg/kg [12, 14]. More recently, two azoles with potent activity against Mucorales have been developed as alternatives to L-AmB: posaconazole and ISAV [6, 12]. In animal models, azoles penetrate brain tissue well [15]. However, neither posaconazole nor ISAV drug are currently approved for paediatric use. Only an oral suspension posaconazole has been tested in children and this resulted in high inter- and intra-patient variability in serum concentrations [16]. An intravenous formulation was not available in France at that time. ECIL-6 guidelines recommend posaconazole with grade CIII as an alternative treatment if AmB formulations are contraindicated [4]. Recently, two trials (VITAL, SECURE) have been reported which led to the recent indication, in adults, of ISAV use in cases where L-AmB is inappropriate [17]. In view of the renal impairment in our patient, ISAV was considered as a treatment option [18].\n\nAccording to a paediatric epidemiological study based on two large international registries of mucormycosis, mortality rates range from 41.3 to 66.6% in children suffering from malignancies [13]. Although dissemination was one of two significant factors influencing mortality, our patient is still alive 24 months after the diagnosis of mucormycosis. However, an assessment of the specific contribution of ISAV to this favourable outcome remains difficult. Indeed, the early termination of chemotherapy contributing to faster aplasia recovery, the prolonged remission of leukaemia without chemotherapy and the concomitant use of L-AmB at the start of antifungal therapy may all have played an important role in the outcome. However, it should be emphasized that the fungal lesions continued to regress under ISAV alone. Moreover, tolerance of ISAV was good and this case provides interesting information about ISAV pharmacokinetics and alternative routes of administration in the paediatric population.\n\nRecently, the use of ISAV in three young children, between 4.5 and 7 years of age having developed mucormycosis, has been reported [2, 3]. For two of them, the initial dose of ISAV was lower than that in adult, 80 and 100 mg/day, respectively. The remaining one received the adult dosage (200 mg/day). In the present case, we started with the recommended dose of 70 mg/day after a loading dose. Because of the absence of data in children, initial estimation of dose was obtained via extrapolation approach based on pharmacokinetic-pharmacodynamic modelling and calculation based on body surface area. Altogether, pharmacokinetics studies obtained from these patients suggest that a lower dosage of ISAV is not appropriate for the management of paediatric patients. Indeed, higher drug clearance rate and shorter half- life of ISAV in children as compared with adults may explain lower trough levels obtained in these three cases [2]. The final dosage for two paediatric cases was 200 mg/day, the 7-year-old girl received a higher dose increased to 2 × 200 mg/day. In the three previous cases, while the infection was progressing despite surgery/debridement and lipid formulations of AmB, the clinical states improved with the addition of ISAV as salvage therapy. No side effects were reported in all of these paediatric cases, which underline the safety of isavuconazole in this population.\n\nAlthough more evidence is needed to support its paediatric use, this case offers new perspectives on the use of ISAV. Due to the current lack of an established paediatric dose, therapeutic drug monitoring of ISAV must be performed to guide therapy.\n\nAbbreviations\nAISAVIAfter isavuconazole introduction\n\nCRPC-reactive protein\n\nFDG PET/CTFluorodeoxyglucose-positron emission tomography scan\n\nISAVIsavuconazole\n\nL-AmBLiposomal amphotericin B\n\nMRIMagnetic resonance imaging\n\nTPLTrough plasma level\n\nAcknowledgements\nNot applicable.\n\nFunding\nThis work was supported by internal funding “Fonds d’aide à l’émergence et à l’excellence du CHRU de Lille-Bonus H”.\n\nAvailability of data and materials\nNot applicable\n\nAuthors’ contributions\nMC, BB, SL, PN, NF, FL, EAB, FB, FM and BS were involved in the patient care and the management of her fungal disease. MC, BB, SL, FD and BS wrote the manuscript. All authors read and approved the final version of the manuscript.\n\nEthics approval and consent to participate\nBasilea Pharmaceutica International Ltd., provided the medication for compassionate use in the context of a Temporary Authorization for Use which was granted by the French National Agency for Medicines and Health Products Safety. Its authorization has been obtained after a multidisciplinary consultation meeting.\n\nIn this context, the parents of the child were informed and gave their consent for compassionate use of isavuconazole.\n\nConsent for publication\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from the parent of the patient. A copy of the consent form is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Ullmann AJ, Aguado JM, Arikan-Akdagli S, Denning DW, Groll AH, Lagrou K, Lass-Florl C, Lewis RE, Munoz P, Verweij PE et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018. 10.1016/j.cmi.2018.01.002.\n2. Barg AA, Malkiel S, Bartuv M, Greenberg G, Toren A, Keller N. Successful treatment of invasive mucormycosis with isavuconazole in pediatric patients. Pediatr Blood Cancer. 2018. 10.1002/pbc.27281.\n3. Pomorska A, Malecka A, Jaworski R, Radon-Proskura J, Hare RK, Nielsen HV, Andersen LO, Jensen HE, Arendrup MC, Irga-Jaworska N. Isavuconazole in a successful combination treatment of disseminated mucormycosis in a child with acute lymphoblastic leukaemia and generalized haemochromatosis: a case report and review of the literature. Mycopathologia. 2018. 10.1007/s11046-018-0287-0.\n4. Tissot F, Agrawal S, Pagano L, Petrikkos G, Groll AH, Skiada A, Lass-Florl C, Calandra T, Viscoli C, Herbrecht R. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica. 2017. 10.3324/haematol.2016.152900.\n5. Groll AH, Castagnola E, Cesaro S, Dalle JH, Engelhard D, Hope W, Roilides E, Styczynski J, Warris A, Lehrnbecher T et al. Fourth European conference on infections in Leukaemia (ECIL-4): guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation. Lancet Oncol. 2014. 10.1016/S1470-2045(14)70017-8.\n6. Marty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR, Thompson GR, 3rd, Alangaden GJ, Brown JM, Fredricks DN, Heinz WJ et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis. 2016. 10.1016/S1473-3099(16)00071-2.\n7. Maertens JA, Raad, II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, Bow EJ, Rahav G, Neofytos D, Aoun M et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016. 10.1016/S0140-6736(15)01159-9.\n8. Bitar D, Van Cauteren D, Lanternier F, Dannaoui E, Che D, Dromer F, Desenclos JC, Lortholary O. Increasing incidence of zygomycosis (mucormycosis), France, 1997-2006. Emerg Infect Dis. 2009. 10.3201/eid1509.090334.\n9. Skiada A, Pagano L, Groll A, Zimmerli S, Dupont B, Lagrou K, Lass-Florl C, Bouza E, Klimko N, Gaustad P et al. Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) working group on Zygomycosis between 2005 and 2007. Clin Microbiol Infect. 2011. 10.1111/j.1469-0691.2010.03456.x.\n10. Petrikkos G, Skiada A, Drogari-Apiranthitou M. Epidemiology of mucormycosis in Europe. Clin Microbiol Infect. 2014. 10.1111/1469-0691.12563.\n11. Lanternier F, Dannaoui E, Morizot G, Elie C, Garcia-Hermoso D, Huerre M, Bitar D, Dromer F, Lortholary O, French Mycosis Study G. A global analysis of mucormycosis in France: the RetroZygo study (2005-2007). Clin Infect Dis. 2012. 10.1093/cid/cir880.\n12. Cornely OA, Arikan-Akdagli S, Dannaoui E, Groll AH, Lagrou K, Chakrabarti A, Lanternier F, Pagano L, Skiada A, Akova M et al. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect. 2014. 10.1111/1469-0691.12371.\n13. Pana ZD, Seidel D, Skiada A, Groll AH, Petrikkos G, Cornely OA, Roilides E, Collaborators of Zygomyco.net and/or FungiScope R. Invasive mucormycosis in children: an epidemiologic study in European and non-European countries based on two registries. BMC Infect Dis. 2016. 10.1186/s12879-016-2005-1.\n14. Lanternier F, Poiree S, Elie C, Garcia-Hermoso D, Bakouboula P, Sitbon K, Herbrecht R, Wolff M, Ribaud P, Lortholary O et al. Prospective pilot study of high-dose (10 mg/kg/day) liposomal amphotericin B (L-AMB) for the initial treatment of mucormycosis. J Antimicrob Chemother. 2015. 10.1093/jac/dkv236.\n15. Felton T, Troke PF, Hope WW. Tissue penetration of antifungal agents. Clin Microbiol Rev. 2014. 10.1128/CMR.00046-13.\n16. Jancel T, Shaw PA, Hallahan CW, Kim T, Freeman AF, Holland SM, Penzak SR. Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review. J Clin Pharm Ther. 2016. 10.1111/jcpt.12483.\n17. Ledoux MP, Toussaint E, Denis J, Herbrecht R. New pharmacological opportunities for the treatment of invasive mould diseases. J Antimicrob Chemother. 2017. 10.1093/jac/dkx033.\n18. Farmakiotis D, Kontoyiannis DP. Mucormycoses. Infect Dis Clin N Am. 2016. 10.1016/j.idc.2015.10.011.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-6511",
"issue": "19(1)",
"journal": "BMC pharmacology & toxicology",
"keywords": "Drug-monitoring; Isavuconazole; Lichtheimia; Mucormycosis; Paediatrics",
"medline_ta": "BMC Pharmacol Toxicol",
"mesh_terms": "D000208:Acute Disease; D000666:Amphotericin B; D000935:Antifungal Agents; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D015448:Leukemia, B-Cell; D009091:Mucormycosis; D009570:Nitriles; D011725:Pyridines; D016896:Treatment Outcome; D014230:Triazoles",
"nlm_unique_id": "101590449",
"other_id": null,
"pages": "81",
"pmc": null,
"pmid": "30522521",
"pubdate": "2018-12-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "26316385;29544767;24988936;27982447;22247443;28355467;19788806;26969258;30039238;24396137;28011902;27832748;21199154;26684607;29932282",
"title": "Successful outcome of disseminated mucormycosis in a 3-year-old child suffering from acute leukaemia: the role of isavuconazole? A case report.",
"title_normalized": "successful outcome of disseminated mucormycosis in a 3 year old child suffering from acute leukaemia the role of isavuconazole a case report"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1057367",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
"drugadditional": nul... |
{
"abstract": "OBJECTIVE\nSpitzoid lesions are a group of melanocytic tumors characterized by spindle-like or epithelioid cells with variable malignant potential. While some spitzoid lesions are classified as evidently benign or malignant by clinic and histology, others present with unclear clinical and histological characteristics and are categorized as lesions of intermediate biologic potential. These lesions represent a challenge for pathologists and clinicians alike. No consensus on ancillary diagnostics and clinical management exists. Prediction of their clinical course is difficult. The implementation of ancillary diagnostics is currently subject of extensive discussions.\n\n\nMETHODS\nWe report three cases of spitzoid lesions in three young female patients (3-, 15- and 17 years old) from a single reference center with different clinical and histological manifestations. In each case, uncertain clinical and histological presentation led to the stepwise application of additional diagnostics using immunohistochemistry and a custom next generation sequencing panel optimized for melanocytic lesions (MelArray). Combining ancillary diagnostics helped determine clinical management in all cases by characterizing the biology of these lesions.\n\n\nCONCLUSIONS\nWe illustrate how clinical, histological and molecular features contribute to an optimized management plan in these critical situations and present a possible algorithm for the assessment of spitzoid neoplasms.",
"affiliations": "Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.;Department of Dermatopediatrics, Children's Hospital Zurich, Zurich, Switzerland.;Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.;Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.;Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.;Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.",
"authors": "Hilbers|Marie-Luise|ML|;Brändli|Regula|R|;Mühleisen|Beda|B|;Freiberger|Sandra N|SN|;Mangana|Joanna|J|;Dummer|Reinhard|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.27854",
"fulltext": "\n==== Front\nOncotarget\nOncotarget\nImpact Journals LLC\nOncotarget\n1949-2553 Impact Journals LLC \n\n27854\n10.18632/oncotarget.27854\nCase Report\nStandardized diagnostic algorithm for spitzoid lesions aids clinical decision-making and management: a case series from a Swiss reference center\nHilbers Marie-Luise 1 Brändli Regula 2 Mühleisen Beda 1 Freiberger Sandra N. 3 Mangana Joanna 1 Dummer Reinhard 1 1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland\n2Department of Dermatopediatrics, Children’s Hospital Zurich, Zurich, Switzerland\n3Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland\nCorrespondence to: Reinhard Dummer, email: reinhard.dummer@usz.ch\n19 1 2021 \n19 1 2021 \n12 2 125 130\n07 7 2020 14 12 2020 Copyright: © 2021 Hilbers et al.This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Importance: Spitzoid lesions are a group of melanocytic tumors characterized by spindle-like or epithelioid cells with variable malignant potential. While some spitzoid lesions are classified as evidently benign or malignant by clinic and histology, others present with unclear clinical and histological characteristics and are categorized as lesions of intermediate biologic potential. These lesions represent a challenge for pathologists and clinicians alike. No consensus on ancillary diagnostics and clinical management exists. Prediction of their clinical course is difficult. The implementation of ancillary diagnostics is currently subject of extensive discussions.\n\nObservations: We report three cases of spitzoid lesions in three young female patients (3-, 15- and 17 years old) from a single reference center with different clinical and histological manifestations. In each case, uncertain clinical and histological presentation led to the stepwise application of additional diagnostics using immunohistochemistry and a custom next generation sequencing panel optimized for melanocytic lesions (MelArray). Combining ancillary diagnostics helped determine clinical management in all cases by characterizing the biology of these lesions.\n\nConclusions and Relevance: We illustrate how clinical, histological and molecular features contribute to an optimized management plan in these critical situations and present a possible algorithm for the assessment of spitzoid neoplasms.\n\nspitzoid nevimelanocytic lesiondermatopathologypediatric dermatologydiagnostic algorithm\n==== Body\nINTRODUCTION\nSpitzoid lesions are a diverse group of rapid-growing melanocytic tumors characterized by spindle-like or epithelioid cells. Certain spitzoid lesions show evidently benign or malignant clinic and histology, while others present with unclear characteristics and are therefore categorized as lesions of intermediate biologic potential [1]. These lesions are a challenge for pathologists and clinicians, as there is no consensus on ancillary diagnostics or clinical management [2]. As patients are typically young [2, 3], prediction of the clinical outcome is essential to determine if adjuvant treatment is necessary.\n\nThe implementation of ancillary diagnostics such as immunohistochemistry (IHC), comparative genomic hybridization (CGH) and next generation sequencing (NGS) is currently subject of extensive discussions.\n\nThe usefulness of IHC in these cases is widely accepted, although there is no consensus on which markers to apply [1, 2, 4]. Garola et al. suggest the use of a panel combining p16, HMB45 and Ki67 stainings [5]. Current research further suggests a stepwise implementation of additional diagnostics including CGH or NGS. However, for all diagnostics, no cut-offs or standardized panel recommendations exist [2].\n\nMelArray is a customized NGS panel optimized for melanocytic lesions that focuses on 190 genes previously reported in melanoma [6].\n\nWe use three cases to present the interplay between clinical presentation, pathology and molecular biology and illustrate how this currently influences clinical management.\n\nCLINICAL CASES\nPatient 1\nA 3-year-old female presented with a quickly developing lesion on the right calf. The parents had first noticed a flat, reddish macula at 29 months of age. Within 4 months, it had grown in size and elevation and developed a verrucous aspect. Due to unclear clinical features, the lesion was totally excised in April 2019. Histology, IHC and MelArray were performed (see Figure 1).\n\nFigure 1 Diagnostics in benign spitzoid lesion.\nClinical manifestation of lesion in January 2019 (A) and April 2019 (B) showing progression from small erythematous macula to verrucous papule. Histologically, the lesion showed pronounced verrucous hyperplasia of the epidermis. In the dermis there is a well demarcated dense infiltration of epitheloid cells with extensive cytoplasm presenting mild mitotic activity (H&E, original magnification 100×) (C) and (H&E, original magnification 40×) (D). p16 was homogenously positive in melanocytic cells (P16 staining, original magnification 40×) (E) and HMB45 was negative in the dermal compartment (H&E, original magnification 40×) (F). Ki67 was widely expressed in the dermal-epidermal junction in keratinocytes and some melanocytic cells (Ki67 staining, original magnification 40×) (G). Denoised copy ratio depicts the ratio of copy numbers of the tissue analyzed compared to normal tissue gained from the same FFPE block. In this case, no CNVs were seen (H). No non-synonymous mutations were detected in the genes included in the MelArray panel.\n\nConsidering atypical clinical presentation and histology with inconspicuous molecular characteristics, clinical follow-ups were recommended after total excision. The patient has been followed up for 9 months without relapse.\n\nPatient 2\nA 15-year-old female presented with a 13 × 18 mm dome-shaped, pinkish papule on the lower right back. Right inguinal lymphadenopathy was detected concomitantly. The patient reported to have first noticed the skin lesion in October 2017 and an inguinal swelling in February 2019. A biopsy of the skin was taken in March 2019. Histology, IHC and MelArray were performed (see Figure 2).\n\nFigure 2 Diagnostics in intermediate spitzoid lesion.\nClinical presentation of the lesion in March 2019 (A). Conventional histology showed a lesion with nevoid architecture with an acanthotic epithelial reaction pattern. In the dermis there are abundant preferentially spindle cell shaped melanocytic cells presenting disconcerting deep infiltration as well as pleomorphic nuclei and mitotic activity. (H&E, original magnification 40×) (B) (H&E, original magnification 100×) (C). p16 immunoreactivity was seen as far as the deep dermis (P16 staining, original magnification 40×) (D). Ki67 staining confirmed an increased fraction of cells undergoing mitotic proliferation. (Ki67 staining, original magnification 100×) (E). HMB45 staining was negative in tumor cells (HMB45 staining, original magnification 40×) (F). CNV analysis showed no alterations in MelArray genes (G). 7 non-synonymous mutations (11 mut/Mb) were detected in MelArray genes. MelArray also showed a variant in the RASA2 gene (c876_877delinsTT) (H).\n\nBased on this diagnostic constellation, a re-excision with 1 cm safety margin was carried out shortly after.\n\nFine needle aspiration of the enlarged right inguinal lymph node with a diameter of 1 cm and thereafter a modified lymphadenectomy was performed in April 2019.\n\nHistology and IHC of the lymphadenectomy sample showed locoregional spreading.\n\nA PET/CT performed before the operation showed no further manifestations of disease.\n\nThe family was informed about the uncertain prognostic outcome. We recommended a close follow-up regimen with clinical assessments every 6 weeks and imaging every 3 months, alternating ultrasound and PET/CT scans and no adjuvant therapy. After 9 months, no relapses have occurred.\n\nPatient 3\nA female was referred to our clinic in April 2017 at the age of 14. The girl initially presented with a 15 mm, asymmetrically pigmented lesion on her back. The lesion had been present for years but had increased in size and thickness. Upon biopsy, a distinctly malignant histology and IHC features were seen; MelArray was performed to assess mutational status (see Figure 3, Supplementary Figures 1 and 2).\n\nFigure 3 Diagnostics in malignant spitzoid lesion.\nClinical presentation of primary not available. Conventional histology showed a polypoid, asymmetrical lesion with irregular shouldering (H&E, original original magnification 40×). (A) Melanocytic nests and mutiple single cells, focally lining up in the junction zone present in the atrophic epidermis with slight hyperkeratosis, spindle-like cells with polymorphic nuclei and pagetoid epidermal spread and lack of maturation in the dermis lead to the diagnosis of melanoma with a Breslow depth of 1.9 mm (H&E, original magnification 100×). (B) Denoised copy ratio and CNV analysis showed a high number of CNVs (1938 CNVs). (C) 11 non-synonymous mutations (17.5 mut/Mb) were seen. A BRAF p.V600E (D) mutation as well as alterations in several other melanoma-relevant genes were detected. These included amplifications (such as CCND1 (chromosome 11)) and heterozygous losses (such as loss of CDKN2A (chromosome 9)) (see Supplementary Materials).\n\nThe clinical management followed current melanoma guidelines: a re-excision with 2 cm safety margin and sentinel lymph node biopsy (SLNB) were performed. The SLNB showed a 2.5 mm metastasis. Adjusted lymphadenectomy was carried out in a peripheral center and was tumor-free. The patient was treated with adjuvant Ipilimumab without complications from August to November 2017. Follow-ups took place every 3 months and showed no recurrence until February 2019, when multiple lymph node, lung and brain metastases were detected during routine diagnostics. The biggest brain metastasis was excised and irradiated stereotactically. Systemic immunotherapy with Ipilimumab and Nivolumab was initiated in March 2019. The patient had to discontinue immunotherapy due to progressive disease and myositis of the ocular muscles after her second and third infusions.\n\nThe patient is now undergoing targeted therapy with Dabrafenib and Trametinib since May 2019. She is followed up clinically every month, with imaging every 3 months.\n\nThe last PET/CT performed in December 2019 showed complete response of all extracranial lesions and cMRI showed stable disease.\n\nDISCUSSION AND CONCLUSIONS\nVariability of histologic classification [3, 7, 8] and the absence of standardized ancillary diagnostic or therapeutic algorithms [2] create insecurity concerning clinical management and prognosis of patients with spitzoid lesions [1, 9].\n\nIn our first patient, unremarkable IHC and molecular patterns lead us to believe that the biology of the lesion was most likely benign and a loose regimen with regular clinical follow-ups was chosen.\n\nThe lesion in our second patient showed regular nevus architecture with large cells in conventional histology. Focal Ki-67 activity raised concern. Additionally, NGS showed a variant in the RASA2 gene, a tumor-suppressor for which inactivating mutations are described in 5% of melanomas [10]. To our best knowledge, there are no published reports showing RASA2 alterations in spitzoid lesions, hence the significance of the variant documented in this lesion is unknown.\n\nThe frequency of non-synonymous coding mutations suggested an intermediate genetic instability. The constellation of clinical presentation of primary lesion, histology, IHC and NGS, lead us to postulate an intermediate biologic instability of the lesion. Although the tumor had already developed lymph node spreading, we expect a low risk of developing further metastases.\n\nIn cases like hers, where prognosis is unpredictable, counseling of patients is crucial. A close follow-up regimen was chosen in agreement with the family, with close clinical follow-ups and frequent imaging. Adjuvant immunotherapy was not recommended.\n\nIn our third patient, IHC corroborated with histology, showing distinct signs of malignancy. NGS showed BRAF (p.V600E) mutation as well as a variety of other mutations (see Supplementary Materials) and a high amount of copy number variants (CNVs) in the genes analyzed by MelArray. All technologies pointed towards high potential for malignant course of disease, supporting the clinicians’ decision to proceed according to melanoma guidelines including adjuvant immunotherapy. Our primary goal was to define the dignity of these lesions and find a suitable therapeutic strategy, rather than classify them by nomenclature. Nevertheless, we would like to note that, since Spitz nevi only rarely present BRAF (p.V600E) mutations [2, 11], whereas common melanocytic nevi often do [12], we decided to classify this lesion as spitzoid melanoma rather than Spitz melanoma. Hence, we would like to underline that, by using NGS as a part of a standardized diagnostic algorithm, we were able to differentiate between a lesion with traits typical for Spitz tumors versus other types of melanoma by analyzing it’s genetic hallmarks in a clinically and histologically malignant lesion with spitzoid traits.\n\nThe combination of specific IHC-staining and NGS gave valuable insight on lesion biology in all cases. As NGS accessibility increases, it is conceivable that it will play a role in routine assessment of biologic potential of spitzoid lesions in the near future. Although the mutational landscape of Spitz tumors differs from cutaneous melanoma [2, 4, 12], many of previously mentioned genetic alterations found in Spitz tumors [2, 11, 13] are mutations, amplifications and losses that are detectable by MelArray (as HRAS mutations, BAP1 mutations, TERTp mutations. see Supplementary Materials). A weakness of the use of this customized NGS panel for characterization of Spitz tumors is the lack of detectability of fusions, which make up a significant part of their genetic landscape [2, 11, 13].\n\nHowever, information on mutational burden and CNV analysis allows us to estimate the genomic alteration burden that might reflect malignant potential, as multiple mutations and CNVs tend to be more common in lesions with higher malignancy [4, 14, 15].\n\nWe are confident that a standardized classification system, which routinely includes IHC and NGS, will give more clarity on spitzoid lesions in the near future [2, 16].\n\nFor centers rarely confronted with spitzoid lesions and technologies such as NGS are not readily available, we suggest cases be referred to reference centers for further assessment [2].\n\nWith these cases we portray three different clinical, histological and molecular manifestations of spitzoid lesions. All the information gained impacted the clinical management plan. Here we present a possible algorithm for the classification of biologic potential of spitzoid lesions (Figure 4).\n\nFigure 4 Proposed diagnostic and therapeutic algorithm [2].\nIHC combining proliferative and melanocytic markers (for example Ki67, p16, HMB45). If lesion seems benign in histology and IHC, then further analysis might not be needed. If lesion shows unclear or malignant characteristics, MelArray should be performed. Management: probably benign lesions should be totally excised and followed up clinically, intermediate lesions should be excised with a safety margin and potentially receive SLNB, although this is still subject of fierce debate. Malignant lesions should be managed according to melanoma guidelines.\n\nLarger, multi-center validation studies and registries with long-term follow-up are needed to evaluate feasibility and clinical relevance of routine implementation.\n\n\nAuthor contributions\n\n\nRD conceived the algorithm. MLH coordinated and documented patient information. RBW and RD contributed to collecting cases. MLH wrote manuscript with input from all authors. All authors discussed and contributed to the final manuscript.\n\n\nCONFLICTS OF INTEREST\n\n\nMLH, RBW, BM and SNF have no conflicts of interests. JM has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis and Pierre Fabre and has received travel support from Ultrasun, L’Oréal, Merck Sharp & Dohme, Bristol Myers and Squibb und Pierre Fabre outside of the submitted work. RD has intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome outside the submitted work.\n\n\nFUNDING\n\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nSUPPLEMENTARY MATERIALS\n==== Refs\nREFERENCES\n1. \n\nElder \nDE \n, \nMassi \nD \n, \nScolyer \nRA \n, \nWillemze \nR \n, and International Agency for Research on Cancer . WHO classification of skin tumours\n. Lyon : International Agency for Research on Cancer ; 2018 \nhttps://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/WHO-Classification-Of-Skin-Tumours-2018.\n\n2. \n\nHillen \nLM \n, \nVan den Oord \nJ \n, \nGeybels \nMS \n, \nBecker \nJC \n, \nZur Hausen \nA \n, \nWinnepenninckx \nV \n. Genomic Landscape of Spitzoid Neoplasms Impacting Patient Management\n.\nFront Med (Lausanne) . 2018 ; 5 :344 . 10.3389/fmed.2018.00344 .\n30619857 \n3. \n\nMones \nJM \n, \nAckerman \nAB \n. “Atypical” Spitz’s nevus, “malignant” Spitz’s nevus, and “metastasizing” Spitz’s nevus: a critique in historical perspective of three concepts flawed fatally\n.\nAm J Dermatopathol . 2004 ; 26 :310 –33\n. 10.1097/00000372-200408000-00008 .\n15249862 \n4. \n\nHarms \nKL \n, \nLowe \nL \n, \nFullen \nDR \n, \nHarms \nPW \n. Atypical Spitz Tumors: A Diagnostic Challenge\n.\nArch Pathol Lab Med . 2015 ; 139 :1263 –70\n. 10.5858/arpa.2015-0207-RA .\n26414472 \n5. \n\nGarola \nR \n, \nSingh \nV \n. Utility of p16-Ki-67-HMB45 score in sorting benign from malignant Spitz tumors\n.\nPathol Res Pract . 2019 ; 215 :152550 . 10.1016/j.prp.2019.152550 .\n31351802 \n6. \n\nFreiberger \nSN \n, \nMorand \nGB \n, \nTurko \nP \n, \nWager \nU \n, \nDummer \nR \n, \nHüllner \nM \n, \nHolzmann \nD \n, \nRupp \nNJ \n, \nLevesque \nMP \n. Morpho-Molecular Assessment Indicates New Prognostic Aspects and Personalized Therapeutic Options in Sinonasal Melanoma\n.\nCancers (Basel) . 2019 ; 11 :E1329 . 10.3390/cancers11091329 .\n31500314 \n7. \n\nZedek \nDC \n, \nMcCalmont \nTH \n. Spitz nevi, atypical spitzoid neoplasms, and spitzoid melanoma\n.\nClin Lab Med . 2011 ; 31 :311 –20\n. 10.1016/j.cll.2011.03.008 .\n21549244 \n8. \n\nGerami \nP \n, \nBusam \nK \n, \nCochran \nA \n, \nCook \nMG \n, \nDuncan \nLM \n, \nElder \nDE \n, \nFullen \nDR \n, \nGuitart \nJ \n, \nLeBoit \nPE \n, \nMihm \nMC \n, \nPrieto \nVG \n, \nRabkin \nMS \n, \nScolyer \nRA \n, et al. Histomorphologic assessment and interobserver diagnostic reproducibility of atypical spitzoid melanocytic neoplasms with long-term follow-up\n.\nAm J Surg Pathol . 2014 ; 38 :934 –40\n. 10.1097/PAS.0000000000000198 .\n24618612 \n9. \n\nLallas \nA \n, \nKyrgidis \nA \n, \nFerrara \nG \n, \nKittler \nH \n, \nApalla \nZ \n, \nCastagnetti \nF \n, \nLongo \nC \n, \nMoscarella \nE \n, \nPiana \nS \n, \nZalaudek \nI \n, \nArgenziano \nG \n. Atypical Spitz tumours and sentinel lymph node biopsy: a systematic review\n.\nLancet Oncol . 2014 ; 15 :e178 –83\n. 10.1016/S1470-2045(13)70608-9 .\n24694641 \n10. \n\nArafeh \nR \n, \nQutob \nN \n, \nEmmanuel \nR \n, \nKeren-Paz \nA \n, \nMadore \nJ \n, \nElkahloun \nA \n, \nWilmott \nJS \n, \nGartner \nJJ \n, \nDi Pizio \nA \n, \nWinograd-Katz \nS \n, \nSindiri \nS \n, \nRotkopf \nR \n, \nDutton-Regester \nK \n, et al. Recurrent inactivating RASA2 mutations in melanoma\n.\nNat Genet . 2015 ; 47 :1408 –10\n. 10.1038/ng.3427 .\n26502337 \n11. \n\nRaghavan \nSS \n, \nPeternel \nS \n, \nMully \nTW \n, \nNorth \nJP \n, \nPincus \nLB \n, \nLeBoit \nPE \n, \nMcCalmont \nTH \n, \nBastian \nBC \n, \nYeh \nI \n. Spitz melanoma is a distinct subset of spitzoid melanoma\n.\nMod Pathol . 2020 ; 33 :1122 –34\n. 10.1038/s41379-019-0445-z .\n31900433 \n12. \n\nDa Forno \nPD \n, \nFletcher \nA \n, \nPringle \nJH \n, \nSaldanha \nGS \n. Understanding spitzoid tumours: new insights from molecular pathology\n.\nBr J Dermatol . 2008 ; 158 :4 –14\n. 10.1111/j.1365-2133.2007.08207.x .\n17916202 \n13. \n\nWiesner \nT \n, \nKutzner \nH \n, \nCerroni \nL \n, \nMihm \nMC \n, \nBusam \nKJ \n, \nMurali \nR \n. Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy\n.\nPathology . 2016 ; 48 :113 –31\n. 10.1016/j.pathol.2015.12.007 .\n27020384 \n14. \n\nRaskin \nL \n, \nLudgate \nM \n, \nIyer \nRK \n, \nAckley \nTE \n, \nBradford \nCR \n, \nJohnson \nTM \n, \nFullen \nDR \n. Copy number variations and clinical outcome in atypical spitz tumors\n.\nAm J Surg Pathol . 2011 ; 35 :243 –52\n. 10.1097/PAS.0b013e31820393ee .\n21263245 \n15. \n\nLazova \nR \n, \nPornputtapong \nN \n, \nHalaban \nR \n, \nBosenberg \nM \n, \nBai \nY \n, \nChai \nH \n, \nKrauthammer \nM \n. Spitz nevi and Spitzoid melanomas: exome sequencing and comparison with conventional melanocytic nevi and melanomas\n.\nMod Pathol . 2017 ; 30 :640 –9\n. 10.1038/modpathol.2016.237 .\n28186096 \n16. \n\nTetzlaff \nMT \n, \nReuben \nA \n, \nBillings \nSD \n, \nPrieto \nVG \n, \nCurry \nJL \n. Toward a Molecular-Genetic Classification of Spitzoid Neoplasms\n.\nClin Lab Med . 2017 ; 37 :431 –48\n. 10.1016/j.cll.2017.05.003 .\n28802494\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "12(2)",
"journal": "Oncotarget",
"keywords": "dermatopathology; diagnostic algorithm; melanocytic lesion; pediatric dermatology; spitzoid nevi",
"medline_ta": "Oncotarget",
"mesh_terms": null,
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "125-130",
"pmc": null,
"pmid": "33520116",
"pubdate": "2021-01-19",
"publication_types": "D002363:Case Reports",
"references": "31500314;28802494;24618612;21549244;31900433;26414472;27020384;17916202;24694641;26502337;15249862;21263245;30619857;28186096;31351802",
"title": "Standardized diagnostic algorithm for spitzoid lesions aids clinical decision-making and management: a case series from a Swiss reference center.",
"title_normalized": "standardized diagnostic algorithm for spitzoid lesions aids clinical decision making and management a case series from a swiss reference center"
} | [
{
"companynumb": "CH-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-029768",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "Creutzfeldt-Jakob disease is a degenerative disorder of the central nervous system that frequently presents with behavioral symptoms including depression. We report here a patient with Creutzfeldt-Jakob disease in whom electroconvulsive therapy (ECT) was highly effective in relieving depressive symptoms. Additionally, ECT had little or no effect on cognition in this patient, even transiently improving her cognitive function. Given its rapid onset of action, ECT may be considered safe and effective in depressive disorders associated with Creutzfeldt-Jakob disease.",
"affiliations": "Department of Psychiatry, Medical College of Pennsylvania, Allegheny Campus, Pittsburgh, Pennsylvania, USA.",
"authors": "Goetz|Kenneth L.|KL|;Price|Trevor R. P.|TR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-8055",
"issue": "9(1)",
"journal": "Convulsive therapy",
"keywords": null,
"medline_ta": "Convuls Ther",
"mesh_terms": null,
"nlm_unique_id": "8506311",
"other_id": null,
"pages": "58-62",
"pmc": null,
"pmid": "11941194",
"pubdate": "1993",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Electroconvulsive Therapy in Creutzfeldt-Jakob Disease.",
"title_normalized": "electroconvulsive therapy in creutzfeldt jakob disease"
} | [
{
"companynumb": "US-PFIZER INC-2019334714",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXEPIN HYDROCHLORIDE"
},
"drugadditional": nu... |
{
"abstract": "Radiation necrosis (RN) is a serious complication that can occur in up to 10% of brain radiotherapy cases, with the incidence dependent on both dose and brain location. Available medical treatment for RN includes steroids, vitamin E, pentoxifylline, and hyperbaric oxygen. In a significant number of patients, however, RN is medically refractory and the patients experience progressive neurological decline, disabling headaches, and decreased quality of life. Vascular endothelial growth factor (VEGF) is a known mediator of cerebral edema in RN. Recent reports have shown successful treatment of RN with intravenous bevacizumab, a monoclonal antibody for VEGF. Bevacizumab, however, is associated with significant systemic complications including sinus thrombosis, pulmonary embolus, gastrointestinal tract perforation, wound dehiscence, and severe hypertension. Using lower drug doses may decrease systemic exposure and reduce complication rates. By using an intraarterial route for drug administration following blood-brain barrier disruption (BBBD), the authors aim to lower the bevacizumab dose while increasing target delivery. In the present report, the authors present the cases of 2 pediatric patients with cerebral arteriovenous malformations, who presented with medically intractable RN following stereotactic radiosurgery. They received a single intraarterial infusion of 2.5 mg/kg bevacizumab after hyperosmotic BBBD. At mean follow-up duration of 8.5 months, the patients had significant and durable clinical and radiographic response. Both patients experienced resolution of their previously intractable headaches and reversal of cushingoid features as they were successfully weaned off steroids. One of the patients regained significant motor strength. There was an associated greater than 70% reduction in cerebral edema. Intraarterial administration of a single low dose of bevacizumab after BBBD was safe and resulted in durable clinical and radiographic improvements at concentrations well below those required for the typical systemic intravenous route. Advantages over the intravenous route may include higher concentration of drug delivery to the affected brain, decreased systemic toxicity, and a significantly lower cost.",
"affiliations": "Norton Neuroscience Institute and.",
"authors": "Dashti|Shervin R|SR|;Spalding|Aaron|A|;Kadner|Rob J|RJ|;Yao|Tom|T|;Kumar|Arooshi|A|;Sun|David A|DA|;LaRocca|Renato|R|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab",
"country": "United States",
"delete": false,
"doi": "10.3171/2014.9.PEDS14198",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1933-0707",
"issue": "15(1)",
"journal": "Journal of neurosurgery. Pediatrics",
"keywords": "AVM = arteriovenous malformation; BBB = blood-brain barrier; BBBD = BBB disruption; RN = radiation necrosis; SRS = stereotactic radiosurgery; VEGF = vascular endothelial growth factor; arteriovenous malformation; bevacizumab; blood-brain barrier disruption; intraarterial chemotherapy; oncology; radiation adverse effect; radiation necrosis; stereotactic radiosurgery",
"medline_ta": "J Neurosurg Pediatr",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D001921:Brain; D001929:Brain Edema; D002648:Child; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007261:Infusions, Intra-Arterial; D002538:Intracranial Arteriovenous Malformations; D008279:Magnetic Resonance Imaging; D009336:Necrosis; D011832:Radiation Injuries; D016634:Radiosurgery; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A",
"nlm_unique_id": "101463759",
"other_id": null,
"pages": "20-5",
"pmc": null,
"pmid": "25360851",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Targeted intraarterial anti-VEGF therapy for medically refractory radiation necrosis in the brain.",
"title_normalized": "targeted intraarterial anti vegf therapy for medically refractory radiation necrosis in the brain"
} | [
{
"companynumb": "US-VALIDUS PHARMACEUTICALS LLC-US-2016VAL002161",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PENTOXIFYLLINE"
},
"dru... |
{
"abstract": "X-linked agammaglobulinemia (XLA, OMIM#300300) is a rare monogenic primary immunodeficiency caused by mutations in the Bruton tyrosine kinase (BTK) gene. XLA is characterized by insufficient immunoglobulin levels and susceptibility to life-threatening bacterial infections. We report on a patient that presented with ecthyma gangrenosum and septicemia. Rapid trio whole-genome sequencing (rWGS) revealed an apparently de novo hemizygous pathogenic variant (c.726dupT; p.Ile243TyrfsTer15) in the BTK gene. Metagenomic analysis of rWGS sequences that did not align to the human genome revealed 770 aligned to the Pseudomonas aeruginosa PAO1 genome. The patient was diagnosed with XLA and pseudomonal sepsis.",
"affiliations": "Rady Children's Institute of Genomic Medicine, San Diego, California 92123, USA.;Rady Children's Institute of Genomic Medicine, San Diego, California 92123, USA.;Rady Children's Institute of Genomic Medicine, San Diego, California 92123, USA.;Rady Children's Institute of Genomic Medicine, San Diego, California 92123, USA.;Division of Allergy and Immunology, Department of Pediatrics, UCSD, San Diego, California 92093, USA.;Division of Pediatric Critical Care Medicine, Department of Pediatrics, UCSD, San Diego, California 92093, USA.;Rady Children's Institute of Genomic Medicine, San Diego, California 92123, USA.;Rady Children's Institute of Genomic Medicine, San Diego, California 92123, USA.;Division of Infectious Disease, Department of Pediatrics, UCSD, San Diego, California 92093, USA.",
"authors": "Sanford|Erica|E|;Farnaes|Lauge|L|0000-0002-8569-4771;Batalov|Serge|S|0000-0003-2036-2888;Bainbridge|Matthew|M|0000-0003-3193-3471;Laubach|Susan|S|0000-0002-7470-9616;Worthen|H Michael|HM|;Tokita|Mari|M|;Kingsmore|Stephen F|SF|0000-0002-3758-4631;Bradley|John|J|0000-0001-6963-9978",
"chemical_list": "D000077329:Agammaglobulinaemia Tyrosine Kinase",
"country": "United States",
"delete": false,
"doi": "10.1101/mcs.a003244",
"fulltext": "\n==== Front\nCold Spring Harb Mol Case StudCold Spring Harb Mol Case StudcshmcscshmcscshmcsCold Spring Harbor Molecular Case Studies2373-2873Cold Spring Harbor Laboratory Press 3055931110.1101/mcs.a003244MCS003244SanRapid CommunicationConcomitant diagnosis of immune deficiency and Pseudomonas sepsis in a 19 month old with ecthyma gangrenosum by host whole-genome sequencing WGS diagnosis of immunodeficiency and sepsisWGS diagnosis of immunodeficiency and sepsisSanford Erica 12http://orcid.org/0000-0002-8569-4771Farnaes Lauge 13http://orcid.org/0000-0003-2036-2888Batalov Serge 1http://orcid.org/0000-0003-3193-3471Bainbridge Matthew 1http://orcid.org/0000-0002-7470-9616Laubach Susan 4Worthen H. Michael 2Tokita Mari 1http://orcid.org/0000-0002-3758-4631Kingsmore Stephen F. 1http://orcid.org/0000-0001-6963-9978Bradley John 31 Rady Children's Institute of Genomic Medicine, San Diego, California 92123, USA;2 Division of Pediatric Critical Care Medicine, Department of Pediatrics, UCSD, San Diego, California 92093, USA;3 Division of Infectious Disease, Department of Pediatrics, UCSD, San Diego, California 92093, USA;4 Division of Allergy and Immunology, Department of Pediatrics, UCSD, San Diego, California 92093, USACorresponding author: esanford@ucsd.edu12 2018 4 6 a00324425 7 2018 24 9 2018 © 2018 Sanford et al.; Published by Cold Spring Harbor Laboratory Press2018This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.X-linked agammaglobulinemia (XLA, OMIM#300300) is a rare monogenic primary immunodeficiency caused by mutations in the Bruton tyrosine kinase (BTK) gene. XLA is characterized by insufficient immunoglobulin levels and susceptibility to life-threatening bacterial infections. We report on a patient that presented with ecthyma gangrenosum and septicemia. Rapid trio whole-genome sequencing (rWGS) revealed an apparently de novo hemizygous pathogenic variant (c.726dupT; p.Ile243TyrfsTer15) in the BTK gene. Metagenomic analysis of rWGS sequences that did not align to the human genome revealed 770 aligned to the Pseudomonas aeruginosa PAO1 genome. The patient was diagnosed with XLA and pseudomonal sepsis.\n\ncongenital neutropeniaimmune dysregulationsepsisRady Children's HospitalNational Institute of Child Health and Human Development 10.13039/100000071National Human Genome Research Institute 10.13039/100000051U19HD077693\n==== Body\nCASE PRESENTATION\nA 19-mo-old twin Hispanic male was admitted to the hospital with fever (38.5°C) and compensated septic shock. Physical examination revealed approximately one dozen deep, indurated purpuric plaques with necrotic changes on the extremities and buttocks (Fig. 1). The patient's twin brother had died of septic shock, purpura fulminans, and disseminated intravascular coagulation in an outside hospital 1 d prior, after a 2-d hospitalization for similar symptoms. The twin brothers were born at 36-wk gestation and had not previously been hospitalized, but the mother reported that for the past 8 mo they had been frequently ill with respiratory tract infections requiring multiple courses of antibiotics. At the time of admission, the patient's weight was 12 kg, which fell into the 70th percentile for age-matched male controls. There was no family history of immunodeficiency.\n\nFigure 1. Skin lesions in the affected patient showing (A) left hand, (B) left thigh, and (C) right lower leg pseudomonal ecthyma gangrenosum.\n\nLaboratory evaluation was significant for a white blood cell count of 2800 L−1 (reference 6000-14000) with 50% monocytes (2%–12%), 32% lymphocytes (30%–60%), 10% atypical lymphocytes (0%–10%), 2% segmented neutrophils (45%–70%), and 7% band neutrophils (0%–10%), C-reactive protein (CRP) level of 30.10 mg/dl (0.00–0.99), an erythrocyte sedimentation rate of 5 mm/h (0–10), procalcitonin level of 49.04 ng/ml (<2.0), prothrombin time (PT) of 34.7 sec (11.4–14), and an international normalized ratio (INR) of 3.4 (0.9–1.2). Immunoglobulin levels were IgG < 135 mg/dl (413–1112), IgA = 32 mg/dl (21–117), and IgM = 19 mg/dl (30–146).\n\nThe patient was started on vancomycin, ceftriaxone, doxycycline, and gentamicin, as the identity of the causative organism for this presumed community-acquired, life-threatening infection was not initially known. Cultures from the patient's blood were sterile. Filgrastim (G-CSF) was also administered subcutaneously at a dose of 5 mcg/kg daily for an absolute neutrophil count of 252 µl in the setting of overwhelming infection. Within the first 24 h of admission, the patient required intubation for respiratory failure as well as vasopressor therapy with multiple medications for fluid-refractory hypotension and poor perfusion. Because of concerns about hypercoagulability, intravenous immunoglobulin (IVIG) was initially held, but as the patient's condition worsened, a dose of 0.4 mg/kg of IVIG was given, which increased the patient's IgG level to 646 mg/dl.\n\nA tissue culture obtained from a 5-mm punch biopsy of a cutaneous lesion grew Pseudomonas aeruginosa on the third hospital day. At that point, meropenem was added to the regimen and other antibiotics were eventually stopped. The diagnosis of pseudomonal ecthyma gangrenosum in this patient and the presumptive identical diagnosis in his deceased twin brother were highly suspicious for a primary immune deficiency, but the combination of neutropenia and low IgG and IgM levels did not conclusively point to one diagnosis. A lymphocyte enumeration panel was sent and resulted a CD19 absolute count of <20 cells/µl (830–1880) the following day, consistent with absent B cells. Given the patient's critically ill state and the recent death of his twin, rapid trio whole-genome sequencing (rWGS) was undertaken simultaneously on the patient and his parents. In just more than 72 h, on the fourth hospital day, an apparently de novo hemizygous pathogenic variant (c.726dupT; p.Ile243TyrfsTer15; Table 1) in the BTK gene was detected and the patient was diagnosed with X-linked agammaglobulinemia (XLA, OMIM#300300). As a result, filgrastim injections were discontinued and IVIG was administered to maintain IgG levels of >800 mg/dl. On the same day (hospital day 4), verbal communication from the hospital where the patient's brother expired confirmed a positive blood culture for pseudomonas in the deceased twin. The patient's clinical status and level of cardiorespiratory support slowly improved on anti-pseudomonal antibiotics and IVIG therapy. He required regular debridement of the gangrenous lesions by plastic surgery and eventually underwent skin grafting. He was discharged from the hospital after a total of 5 mo.\n\nTable 1. Genomic findings\n\nGene\tGenomic location\tHGVS cDNA\tHGVS protein\tZygosity\tParent of origin\tVariant interpretation\t\nBTK\tNC_000023.10: Chr X:100615605 (GRCh37/hg19)\tNM_000061.2: c.726dupT\tNP_000052.1\np.Ile243TyrfsTer15\tHemizygous\tDe novo\tPathogenic\t\nTECHNICAL ANALYSIS AND METHODS\nThe patient was enrolled in an IRB-approved research study. Blood was drawn immediately following consent for trio rWGS. The WGS testing was performed in a CAP/CLIA environment. DNA was subsequently extracted and sequenced on a HiSeq 4000 (Illumina). Rapid alignment and nucleotide variant calling was performed using the Dragen (Edico Genome) hardware and software (Miller et al. 2015). Proband and parental samples were sequenced to a mean coverage of 40×. Variants were annotated and analyzed in Opal Clinical (Fabric Genomics) (Coonrod et al. 2013). Initially, variants were filtered to retain those with allele frequencies of <1% in the Exome Variant Server, 1000 Genomes Samples, and Exome Aggregation Consortium database (http://evs.gs.washington.edu/EVS/2016; Karczewski et al. 2017). A gene panel was built in Phenolyzer (Yang et al. 2015) using Human Phenotype Ontology (HPO) (Köhler et al. 2016). This panel included 1098 genes related to the following HPO terms: immunodeficiency (HP:0002721), neutropenia (HP:0001875), and sepsis (HP:0100806). Variants were further filtered to retain those mapping to these 1098 genes yielding 1068 proband calls (465 homozygous variants, 509 heterozygous inherited variants, and 15 heterozygous de novo variants). Manual curation revealed one variant as pathogenic by ACMG guidelines (Richards et al. 2015). Specifically, the criteria invoked to score this variant as pathogenic included PVS1 (null variant in a gene where loss of function is a known mechanism of disease), PS2 (de novo variant), and PM2 (variant is absent from controls). This variant was confirmed by Sanger sequencing. The diagnosis was made by rWGS in 4 d.\n\nVARIANT INTERPRETATION\nThis patient was found to be hemizygous for an apparently de novo known pathogenic frameshift variant (c.726dupT; p.Ile243TyrfsTer15) in the Bruton tyrosine kinase (BTK) gene. Pathogenic variants in BTK have been implicated in XLA (OMIM#300300).\n\nThe de novo p.Ile243TyrfsTer15 pathogenic variant has been previously reported in a single individual with XLA (Holinski-Feder et al. 1998). p.Ile243TyrfsTer15 is absent from the ExAC and gnomAD population databases. The deletion causes a frameshift starting with codon Isoleucine 243, changes this amino acid to a tyrosine residue, and creates a premature stop codon at position 15 of the new reading frame. This pathogenic variant is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated decay of the mRNA transcript.\n\nMETAGENOMICS\nPer institutional protocol, samples were processed via a standard clinically validated workflow, in addition to passing a battery of quality control (QC) scripts (Farnaes et al. 2018). Using the reference human genome hg37dh, the QC metric of percent aligned reads passed at 98.8% and did not have a statistically significant deviation from median of past samples (N = 100). Given the pseudomonas sepsis phenotype, a metagenomics exploration was performed: After isolating the unaligned portion of reads, the most frequent, randomly sampled 500 reads were checked against the NCBI NR database, and significant similarity to P. aeruginosa genome was noted, whereas similarity to other pathogenic or nonpathogenic genomes was not found. The random sampling was drawn from the 500 most abundant reads (including duplicates). Then, all unaligned reads were aligned to reference P. aeruginosa PAO1 genome and 770 paired reads (654 unique; duplication rate 14%) were aligned. The qualities of the PAO1-aligned reads were not significantly different from those that aligned to the reference human genome (mean Q in read 1 = 36.28 and in read 2 = 36.04, aligned to PAO1; mean Q in read 1 = 36.09 and in read 2 = 35.66, aligned to hg19). For negative controls, unaligned portions of the patient's parental genomic DNA as well as genomic DNA from five random, unrelated persons were aligned to the reference PAO1 genome and 0–3 paired reads aligned in each (establishing the level of random alignments). Furthermore, the pattern of spatial distribution of the 770 reads from the proband's DNA sample to PAO1 genome was nearly uniform over the full length of the PAO1 genome (6.2 Mb, 25 ± 10 reads in each 200 kb window, i.e., ∼1 read/8 kb), resulting in the conclusion of the bona fide low-titer presence of P. aeruginosa in the proband's DNA sample (Fig. 2).\n\nFigure 2. Uniformly random spatial distribution of 770 reads from the proband's DNA sample (in which the y-axis represents the number of reads) aligned to the PAO1 genome (in which the x-axis is position Mb of the PAO1 genome; total size = 6.2 Mb).\n\nDISCUSSION\nInherited defects of the immune system have an incidence of nearly 1 in 2000 children (Bonilla et al. 2015). More than 300 primary immunodeficiencies (PIDs) are currently known, with the list rapidly expanding (Bonilla et al. 2015; Picard et al. 2015). Between 2013 and 2015 alone, 34 new gene defects for PID were identified (Picard et al. 2015). The severity of infection in affected patients encompasses a spectrum ranging from recurrent respiratory illnesses to life-threatening systemic disease. Current consensus guidelines advocate for a stepwise approach to identifying a suspected PID (Bonilla et al. 2015). However, identifying specific immunodeficiencies in this manner can take weeks to months and delay in diagnosis is significantly associated with increased mortality in these patients (Joshi et al. 2009). More recently, whole-exome sequencing has started to be explored as a high-throughput approach to diagnosing patients with suspected PIDs, with a diagnostic rate of up to 40% (Stray-Pedersen et al. 2017). rWGS is emerging as a technology capable of making a specific genetic diagnosis in time to effect changes in acute clinical management. In our patient, the diagnosis of XLA was highly likely after the lymphocyte enumeration panel demonstrated absent B cells, and the next traditional step in the absence of rWGS would be to sequence the suspected gene (in this case, BTK), which takes several weeks to result. rWGS was able to make the diagnosis of XLA within 74.5 h.\n\nXLA is a primary humoral immunodeficiency typically characterized by severe hypogammaglobinemia and recurrent bacterial infections (Smith and Berglöf 2016). It is caused by mutations in BTK, which encodes Bruton tyrosine kinase (Btk) (Smith and Berglöf 2016). Btk is a signal transduction molecule essential to B-cell lineage development, and its loss impairs the progression of pre-B cells to mature lymphocytes (Ochs and Smith 1996). The lack of mature B lymphocytes results in insufficient immunoglobulin levels, and affected patients are unable to mount an appropriate antibody response to infection. Affected persons have normal levels of IgG at birth because of transplacental passage of maternal immunoglobulin, but become susceptible to bacterial and enteroviral infections as these levels gradually wane during the first year of life (Ochs and Smith 1996). The diagnosis of XLA is suspected when laboratory investigations demonstrate absent B cells and a reduction in all classes of immunoglobulins, and it is confirmed by identifying a pathogenic variant in BTK (Ochs and Smith 1996; Smith and Berglöf 2016).\n\nThe bacterial infections responsible for causing severe disease in patients with XLA are most frequently the pyogenic organisms Streptococcus pneumoniae and Hemophilus influenzae (Zenone and Souillet 1996; Winkelstein et al. 2006). Although uncommon, in addition to our patient there have been case reports of patients presenting with P. aeruginosa septicemia and ecthyma gangrenosum that were subsequently diagnosed with XLA (Nussinovitch et al. 1991; Zenone and Souillet 1996).\n\nThe diagnosis of XLA by rWGS explained the patient's susceptibility to pseudomonal sepsis, indicated the appropriate management to be regular IVIG infusions, and may have prevented additional life-threatening infections. Retrospectively, it also provided an explanation for the death of his twin brother. The patient will be closely followed by immunology for the duration of his lifetime. In addition to monthly IVIG infusions, the patient will have to avoid live vaccinations and his treating physicians should have a low threshold for initiating antibiotic therapy when he is ill.\n\nThe metagenomic analysis identification of 770 P. aeruginosa genome sequences confirmed the presence of the bacterial DNA in the patient's bloodstream (DNAemia) and the clinical diagnosis of severe sepsis. Blood cultures in our patient, while receiving broad spectrum antibiotics, never grew Pseudomonas, and the bacterium was identified by culture of a skin biopsy of one of the gangrenous lesions. Patients with bacterial sepsis infrequently have skin lesions available for biopsy—in the absence of that sample for this patient, nucleic acid analysis would potentially have been the only acute method for identifying the responsible bacterial agent. This raises the possibility that rWGS could potentially have utility in identification of disease-causing organisms, especially in cases of culture-negative sepsis, and warrants further exploration.\n\nSUMMARY\nWe report on a case of XLA presenting as pseudomonal ecthyma gangrenosum and severe sepsis that was diagnosed expeditiously by rWGS. rWGS identified a de novo frameshift variant (c.726dupT; p.Ile243TyrfsTer15) in BTK, the Bruton tyrosine kinase gene on Chromosome X. Thus, the proband was determined to be hemizygous for the monogenic disorder XLA. Additionally, metagenomic analysis of rWGS sequences that did not align to the human genome were found to align to the P. aeruginosa PAO1 genome.\n\nADDITIONAL INFORMATION\nData Deposition and Access\nThe variant was submitted to ClinVar (http://www.ncbi.b\\nih.nlm.gov/clinvar) and can be found under accession number SCV000809043.\n\nEthics Statement\nInformed and signed consent forms were obtained for all sequenced individuals in this study. The project is approved by the Institutional Review Board of the University of California at San Diego under protocol #160468 and has received nonsignificant risk status in a pre-Investigational Device Exemption submission to the Food and Drug Administration.\n\nAuthor Contributions\nE.S. prepared the manuscript and performed the phenotyping; L.F., S.F.K., and J.B. supervised and prepared the manuscript; S.B., M.B., and M.T. performed the variant interpretation and supervised the analysis; and S.L. and H.M.W. performed the clinical implementation. All authors contributed to the reviewing of the final version.\n\nFunding\nSupported by Rady Children's Hospital, National Institute of Child Health and Human Development, and National Human Genome Research Institute (grant U19HD077693).\n\nReferees\nDustin Baldridge\n\nJim Connelly\n\nEric W. Klee\n\nCompeting Interest Statement\nThe authors have declared no competing interest.\n==== Refs\nREFERENCES\nBonilla \nFA , Khan \nDA , Ballas \nZK , Chinen \nJ , Frank \nMM , Hsu \nJT , Keller \nM , Kobrynski \nLJ , Komarow \nHD , Mazer \nB . 2015 \nPractice parameter for the diagnosis and management of primary immunodeficiency . J Allergy Clin Immunol \n136 : 1186 –1205 .26371839 \nCoonrod \nEM , Margraf \nRL , Russell \nA , Voelkerding \nKV , Reese \nMG . 2013 \nClinical analysis of genome next-generation sequencing data using the Omicia platform . Expert Rev Mol Diagn \n13 : 529 –540 .23895124 \nFarnaes \nL , Hildreth \nA , Sweeney \nNM , Clark \nMM , Chowdhury \nS , Nahas \nS , Cakici \nJ , Bensen \nW , Kaplan \nR , Kronick \nR , \n2018 \nRapid whole-genome sequencing decreases infant morbidity and cost of hospitalization . NPJ Genom Med \n3 : 10 .29644095 \nHolinski-Feder \nE , Weiss \nM , Brandau \nO , Jedele \nKB , Nore \nB , Bäckesjö \nCM , Vihinen \nM , Hubbard \nSR , Belohradsky \nBH , Smith \nCI , \n1998 \nMutation screening of the BTK gene in 56 families with X-linked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course . Pediatrics \n101 : 276 –284 .9445504 \nJoshi \nAY , Iyer \nVN , Hagan \nJB , St. Sauver \nJL , Boyce \nTG . 2009 \nIncidence and temporal trends of primary immunodeficiency: a population-based cohort study . Mayo Clin Proc \n84 : 16 –22 .19121249 \nKarczewski \nKJ , Weisburd \nB , Thomas \nB , Solomonson \nM , Ruderfer \nDM , Kavanagh \nD , Hamamsy \nT , Lek \nM , Samocha \nKE , Cummings \nBB , \n2017 \nThe ExAC browser: displaying reference data information from over 60 000 exomes . Nucleic Acids Res \n45 : D840 –D845 .27899611 \nKöhler \nS , Vasilevsky \nNA , Engelstad \nM , Foster \nE , McMurry \nJ , Aymé \nS , Baynam \nG , Bello \nSM , Boerkoel \nCF , Boycott \nKM , \n2016 \nThe Human Phenotype Ontology in 2017 . Nucleic Acids Res \n45 : D865 –D876 .27899602 \nMiller \nNA , Farrow \nEG , Gibson \nM , Willig \nLK , Twist \nG , Yoo \nB , Marrs \nT , Corder \nS , Krivohlavek \nL , Walter \nA , \n2015 \nA 26-hour system of highly sensitive whole genome sequencing for emergency management of genetic diseases . Genome Med \n7 : 100 .26419432 \nNussinovitch \nM , Frydman \nM , Cohen \nHA , Varsano \nI . 1991 \nCongenital agammaglobulinemia presenting with ecthyma gangrenosum . Acta Paediatr Scand \n80 : 732 –734 .1867095 \nOchs \nHD , Smith \nCE . 1996 \nX-linked agammaglobulinemia a clinical and molecular analysis . Medicine \n75 : 287 –299 .8982147 \nPicard \nC , Al-Herz \nW , Bousfiha \nA , Casanova \nJL , Chatila \nT , Conley \nME , Cunningham-Rundles \nC , Etzioni \nA , Holland \nSM , Klein \nC , \n2015 \nPrimary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for primary immunodeficiency . J Clin Immunol \n35 : 696 –726 .26482257 \nRichards \nS , Aziz \nN , Bale \nS , Bick \nD , Das \nS , Gastier-Foster \nJ , Grody \nWW , Hegde \nM , Lyon \nE , Spector \nE , \n2015 \nStandards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology . Genet Med \n17 : 405 –424 .25741868 \nSmith \nCE , Berglöf \nA . 2016 \nX-linked agammaglobulinemia In GeneReviews® [Internet] (ed. Adam \nMP , Ardinger \nHH , Pagon \nRA , Wallace \nSE , Bean \nLJH , Stephens \nK , Amemiya \nA ). University of Washington , Seattle \nhttps://www.ncbi.nlm.nih.gov/books/NBK1453\nStray-Pedersen \nA , Sorte \nHS , Samarakoon \nP , Gambin \nT , Chinn \nIK , Coban Akdemir \nZH , Erichsen \nHC , Forbes \nLR , Gu \nS , Yuan \nB , \n2017 \nPrimary immunodeficiency diseases: genomic approaches delineate heterogeneous Mendelian disorders . J Allergy Clin Immunol \n139 : 232 –245 .27577878 \nWinkelstein \nJA , Marino \nMC , Lederman \nHM , Jones \nSM , Sullivan \nK , Burks \nAW , Conley \nME , Cunningham-Rundles \nC , Ochs \nHD . 2006 \nX-linked agammaglobulinemia: report on a United States registry of 201 patients . Medicine \n85 : 193 –202 .16862044 \nYang \nH , Robinson \nPN , Wang \nK . 2015 \nPhenolyzer: phenotype-based prioritization of candidate genes for human diseases . Nat Methods \n12 : 841 –843 .26192085 \nZenone \nT , Souillet \nG . 1996 \nX-linked agammaglobulinemia presenting as Pseudomonas aeruginosa septicemia . Scand J Infect Dis \n28 : 417 –418 .8893410\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2373-2873",
"issue": "4(6)",
"journal": "Cold Spring Harbor molecular case studies",
"keywords": "congenital neutropenia; immune dysregulation; sepsis",
"medline_ta": "Cold Spring Harb Mol Case Stud",
"mesh_terms": "D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia; D016470:Bacteremia; D004473:Ecthyma; D005734:Gangrene; D040181:Genetic Diseases, X-Linked; D006801:Humans; D007153:Immunologic Deficiency Syndromes; D007223:Infant; D008297:Male; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa; D018805:Sepsis; D012867:Skin; D000073336:Whole Genome Sequencing",
"nlm_unique_id": "101660017",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30559311",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "1867095;27899611;26192085;8982147;26371839;26482257;27899602;8893410;23895124;9445504;29644095;27577878;25741868;16862044;26419432;19121249",
"title": "Concomitant diagnosis of immune deficiency and Pseudomonas sepsis in a 19 month old with ecthyma gangrenosum by host whole-genome sequencing.",
"title_normalized": "concomitant diagnosis of immune deficiency and pseudomonas sepsis in a 19 month old with ecthyma gangrenosum by host whole genome sequencing"
} | [
{
"companynumb": "US-AMGEN-USASP2019017108",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nA substantial increase in amoxicillin-induced crystal nephropathy was recently reported in France. Our study aims to further characterize this safety issue from a worldwide perspective.\n\n\nMETHODS\nWe queried both the FDA Adverse Event Reporting System (FAERS) and the Eudravigilance databases, and performed disproportionality analysis, selecting only adverse events (AEs) related to crystal nephropathy where amoxicillin or amoxicillin/clavulanic acid were reported as suspect. In FAERS, the reporting odds ratios were calculated and deemed significant by the lower limit of the 95% confidence interval (LL95%CI) > 1, selecting all other drugs/events recorded in FAERS as comparator. Deduplication followed by case-by-case assessment and comparison between French and non-French cases were also performed in both databases.\n\n\nRESULTS\nOverall, 57,754 and 84,764 AE reports with amoxicillin or amoxicillin/clavulanic acid were recorded in FAERS and Eudravigilance, respectively, with France accounting for 18.7% and 22.0% of cases. Specific AEs of interest were retrieved in 144 and 239 cases, respectively. Increased reporting was found in FAERS for crystalluria (N = 99; LL95%CI 53.18), crystal nephropathy (24; 27.01), medication crystal in urine present (9; 92.00), crystal urine (8; 11.90), and crystal urine present (4; 1.57). In FAERS and Eudravigilance databases, reports were classified as serious in 98.8% and 91.2% of cases, respectively. Acute kidney injury (AKI) was found in 81.2% and 71.1% of patients. Amoxicillin was mainly given intravenously, and a dose ≥ 12 g/day was administered in 50.0% and 19.7% of cases in the FAERS and Eudravigilance databases, respectively.\n\n\nCONCLUSIONS\nAlthough causal association cannot be firmly inferred, a consistent signal of crystal nephropathy with amoxicillin emerged, especially in France. Clinicians should monitor patients for possible early AKI onset, especially when dealing with intravenous administration of daily doses > 12 g.",
"affiliations": "Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy. milo.gatti2@unibo.it.;Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.;Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.;Department of Experimental Diagnostic and Specialty Medicine, Alma Mater Studiorum - University of Bologna, Bologna, Italy.;Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.;Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.",
"authors": "Gatti|Milo|M|http://orcid.org/0000-0003-3018-3779;Fusaroli|Michele|M|http://orcid.org/0000-0002-0254-2212;Raschi|Emanuel|E|http://orcid.org/0000-0003-0487-7996;Capelli|Irene|I|http://orcid.org/0000-0003-4829-5664;Poluzzi|Elisabetta|E|http://orcid.org/0000-0002-7209-0426;De Ponti|Fabrizio|F|http://orcid.org/0000-0002-0367-9595",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.1007/s40620-021-01191-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1121-8428",
"issue": null,
"journal": "Journal of nephrology",
"keywords": "Acute kidney injury; Amoxicillin; Crystal nephropathy; Pharmacovigilance; Safety guidance",
"medline_ta": "J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "9012268",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34762277",
"pubdate": "2021-11-11",
"publication_types": "D016428:Journal Article",
"references": "32484940;22418755",
"title": "Crystal nephropathy and amoxicillin: insights from international spontaneous reporting systems.",
"title_normalized": "crystal nephropathy and amoxicillin insights from international spontaneous reporting systems"
} | [
{
"companynumb": "IT-GLAXOSMITHKLINE-IT2021GSK239106",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN"
},
"drugadditional": "3... |
{
"abstract": "The Rothman Index (RI) gives a visual picture of patient's condition and progress for the physician and family to view together. This case demonstrates how the RI graph facilitates physician-family communication. An 85-year-old man with normal pressure hydrocephalus and ventriculoperitoneal shunt presented with a subdural haematoma. He required a temporoparietal craniotomy and evacuation of left subdural haematoma, followed by care in an intensive inpatient rehabilitation unit. His course was complicated by aspiration pneumonia, dehydration, renal failure and phenytoin toxicity. During hospitalisation, the patient's RI graph was reviewed daily with his family. The RI provided an unambiguous visualisation of the trend of patient acuity, which depicted the patient's persistent decline in health, and made clear to the family the situation of the patient. This clarity was instrumental in prompting frank discussions of prognosis and consideration of comfort measures, resulting in timely transfer to hospice.",
"affiliations": "Intercoastal Medical Group, Sarasota, Florida, USA.",
"authors": "Bittleman|David B|DB|;Solinger|Alan B|AB|;Finlay|G Duncan|GD|",
"chemical_list": "D000927:Anticonvulsants; D010672:Phenytoin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000927:Anticonvulsants; D003142:Communication; D003196:Computer Graphics; D003657:Decision Making; D003681:Dehydration; D046648:Hematoma, Subdural, Intracranial; D017051:Hospice Care; D006801:Humans; D008297:Male; D062072:Patient Acuity; D010672:Phenytoin; D011015:Pneumonia, Aspiration; D011368:Professional-Family Relations; D051437:Renal Insufficiency",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24419639",
"pubdate": "2014-01-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17205000;23942218;22874626;23676795;23831554;21542415;22753911",
"title": "Shared decision-making at end-of-life is aided by graphical trending of illness severity.",
"title_normalized": "shared decision making at end of life is aided by graphical trending of illness severity"
} | [
{
"companynumb": "US-ACTAVIS-2015-07258",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a serious life-treating condition characterized by skin eruption, fever, haematologic abnormalities, and multi-organ involvement that can be fatal if unrecognized, especially in patients with liver failure. Diagnosis may be difficult because it is rarely described in children and can mimic many different conditions.\n\n\nMETHODS\nWe report two cases of DRESS syndrome due to prolonged antibiotic treatment in young children in whom recovery occurred following different therapeutic approaches. A previously healthy 5-year-old boy had been receiving intravenous vancomycin for right wrist and left elbow osteomyelitis and developed DRESS syndrome on day 30. The patient achieved a complete resolution of all symptoms with pulse methylprednisolone followed by oral prednisone. A 4-year-old girl with cystic fibrosis, pancreatic insufficiency, chronic pulmonary colonization by Gram-positive bacteria admitted for pulmonary exacerbation was treated with intravenous piperacillin-tazobactam and tobramycin. After 14 days of treatment, she developed DRESS syndrome: antibiotic treatment was therefore stopped, and without any further therapy, a progressive resolution of the patient's clinical features was observed within 7 days, while the normalization of laboratory abnormalities was achieved at 14 days.\n\n\nCONCLUSIONS\nOur cases highlight that paediatricians should be aware of the clinical presentations of and therapeutic approaches for DRESS syndrome, especially in children receiving long-term antibiotic treatment. The removal of the offending drug is crucial and may be the only life-saving measure. In more aggressive cases, corticosteroid or other immunosuppressive drugs should be considered to achieve the best outcome.",
"affiliations": "Cystic Fibrosis Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122, Milan, Italy.;Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, Piazza Menghini 1, 06132, Perugia, Italy.;Cystic Fibrosis Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122, Milan, Italy.;Cystic Fibrosis Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122, Milan, Italy.;Cystic Fibrosis Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122, Milan, Italy. carla.colombo@unimi.it.",
"authors": "Castellazzi|Massimo Luca|ML|;Esposito|Susanna|S|;Claut|Laura Elisabetta|LE|;Daccò|Valeria|V|;Colombo|Carla|C|",
"chemical_list": "D014640:Vancomycin; D014031:Tobramycin; D010878:Piperacillin",
"country": "England",
"delete": false,
"doi": "10.1186/s13052-018-0535-4",
"fulltext": "\n==== Front\nItal J PediatrItal J PediatrItalian Journal of Pediatrics1824-7288BioMed Central London 53510.1186/s13052-018-0535-4Case ReportDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in two young children: the importance of an early diagnosis Castellazzi Massimo Luca massimo.castellazzi@unimi.it 1Esposito Susanna susanna.esposito@unipg.it 2Claut Laura Elisabetta laura.claut@policlinico.mi.it 1Daccò Valeria valeria@italkid.org 1Colombo Carla +39 02 5503 2456carla.colombo@unimi.it 11 0000 0004 1757 2822grid.4708.bCystic Fibrosis Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy 2 0000 0004 1757 3630grid.9027.cPediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, Piazza Menghini 1, 06132 Perugia, Italy 15 8 2018 15 8 2018 2018 44 9314 6 2018 6 8 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a serious life-treating condition characterized by skin eruption, fever, haematologic abnormalities, and multi-organ involvement that can be fatal if unrecognized, especially in patients with liver failure. Diagnosis may be difficult because it is rarely described in children and can mimic many different conditions.\n\nCase presentation\nWe report two cases of DRESS syndrome due to prolonged antibiotic treatment in young children in whom recovery occurred following different therapeutic approaches. A previously healthy 5-year-old boy had been receiving intravenous vancomycin for right wrist and left elbow osteomyelitis and developed DRESS syndrome on day 30. The patient achieved a complete resolution of all symptoms with pulse methylprednisolone followed by oral prednisone. A 4-year-old girl with cystic fibrosis, pancreatic insufficiency, chronic pulmonary colonization by Gram-positive bacteria admitted for pulmonary exacerbation was treated with intravenous piperacillin-tazobactam and tobramycin. After 14 days of treatment, she developed DRESS syndrome: antibiotic treatment was therefore stopped, and without any further therapy, a progressive resolution of the patient’s clinical features was observed within 7 days, while the normalization of laboratory abnormalities was achieved at 14 days.\n\nConclusions\nOur cases highlight that paediatricians should be aware of the clinical presentations of and therapeutic approaches for DRESS syndrome, especially in children receiving long-term antibiotic treatment. The removal of the offending drug is crucial and may be the only life-saving measure. In more aggressive cases, corticosteroid or other immunosuppressive drugs should be considered to achieve the best outcome.\n\nKeywords\nAntibiotic reactionsAntibiotic therapyCutaneous adverse reactionsDRESS syndromeDrug exposureissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, life-threatening, drug-induced hypersensitivity reaction. Drug hypersensitivity reactions (DHR) are classified as immediate and non-immediate. Immediate DHRs include urticaria, angioedema and anaphylaxis and occur immediately or within the first 6 h after administration of the drug. Non-immediate DHRs tend to appear after many days of treatment, with a delayed T-cell-dependent type of allergic mechanism and DRESS syndrome is considered as one of this kind of reactions [1].\n\nDRESS is characterized by fever, rash, lymphadenopathy, elevated liver enzyme levels, and leukocytosis with eosinophilia [2]. DRESS syndrome is an uncommon condition with an estimated incidence that varies between 1:1000 and 1:10,000 drug exposures [3]. Furthermore, its prevalence is higher in adults than in children; therefore, paediatricians may not be sufficiently aware of this condition [4].\n\nPrompt recognition and adequate management of DRESS are crucial because its clinical manifestations can be severe, resulting in a mortality rate of 10% [2]. To increase the likelihood of this condition being recognized, the European Register of Severe Cutaneous Adverse Reactions (RegiSCAR) developed a scoring system based on clinical findings, the extent of affected skin, the type of organ involvement and the clinical course to classify DRESS syndrome as defined, probable or possible [5]. In this report, we describe two cases of DRESS syndrome secondary to prolonged antibiotic exposure in young children. Our aim is to highlight the possible clinical presentations of this condition, the diagnostic tools to recognize it and the therapeutic approaches used to treat it in paediatric patients.\n\nCase presentation\nTables 1 and 2 summarize the clinical and laboratory data for each of the two patients.Table 1 Clinical and laboratory data of the two children with drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome\n\n\tADMISSION\tDRESS SYNDROME ONSET\tDIAGNOSIS OF DRESS SYNDROME\tDISCHARGE\t\nCase 1\tCase 2\tCase 1\tCase 2\tCase 1\tCase 2\tCase 1\tCase 2\t\nLaboratory data (normal value)\tDay 1\tDay 1\tDay 26\tDay 14\tDay 30\tDay 18\tDay 40\tDay 28\t\nWBC (4800–12,100/μL)\t16,650\t5600\t14,980\t8320\t26,280\t12,140\t12,760\t7820\t\nLymphocytes (1500–16,500//μL)\t3120\t2040\t3800\t4500\t6710\t4200\t3200\t3320\t\nEosinophils (100–500//μL)\t200\t220\t2330\t30\t5010\t2940\t480\t440\t\nCRP (< 0.5 mg/dL)\t19.59\t0.59\t3.60\t10.31\t6.1\t3.19\t0.03\t0.14\t\nAST-ALT (5–36 U/L and 5–29 U/L)\t23–22\t31–28\t34–27\t402–62\t55–132\t1560–311\t25–45\t36–60\t\nLDH (120–300 U/L)\t198\t276\t779\t3637\t805\t10,880\t238\t300\t\nPT-aPTT (0.94–1.22 and 0.86–1.20)\tNot performed\tNot performed\t1.28–1.10\tNot performed\t1.31–1.06\t1.23–1.94\t0.98–0.95\t0.96–1.03\t\nD-dimer (< 230 ng/mL)\tNot performed\tNot performed\t1815\tNot performed\t2000\t68,384\t120\t230\t\nWBC white blood cells, CRP C-reactive protein, AST aspartate aminotransferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, PT prothrombin time, aPTT activated partial thromboplastin time\n\nTable 2 Results of the RegiSCAR scoring system used to diagnose drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in two children\n\nItems\tPatient 1\tScore: patient 1\tPatient 2\tScore: patient 2\t\nFever ≥ 38.5 °C\tYes\t0\tYes\t0\t\nEnlarged lymph nodes\tYes\t1\tYes\t1\t\nEosinophils a\tYes\t2\tYes\t2\t\nAtypical lymphocytes\tNo\t0\tNo\t0\t\nSkin rash > 50% of body surface area\tYes\t1\tYes\t1\t\nSkin rash suggesting DRESS\tYes\t1\tYes\t1\t\nSkin biopsy suggesting DRESS\tYes\t1\tNot applicable\t0\t\nLiver involvement\tYes\t1\tYes\t1\t\nResolution ≥ 15 days\tNo\t-1\tNo\t-1\t\nEvaluation other potential causes b\tNegative\t1\tNegative\t1\t\nTotal score\t\t7\t\t6\t\na: eosinophils 0.7–1.49 × 103/mmc = 1; ≥1.5 × 103/mmc = 2\n\nb: include ANA, blood culture, serology for HVA/ HVB/ HVC, Chlamydia/ Mycoplasma pneumonia, other serology/PCR. None positive and ≥ 3 of the above negative = 1\n\nLegend: Final score < 2: no case, final score 2–3: possible case, final score 4–5: probable case, and final score > 5: definite case\n\n\n\nCase 1\nA previously healthy 5-year-old boy had been receiving intravenous vancomycin (40 mg/kg/day four times per day) for 26 days due to right wrist and left elbow osteomyelitis. The patient had exhibited clinical and laboratory improvement. He then suddenly developed a generalized erythaematous maculopapular and pruritic rash involving the face, trunk, back and limbs followed by the appearance of a high-grade fever (up to 40 °C) and weakness. Bilateral cervical and inguinal enlarged lymph nodes were detected. Cardio-respiratory and abdominal examinations were normal. The child also developed facial, neck and scrotal oedema (Fig. 1).Fig. 1 Patient 1 with a diffuse maculopapular erythaematous rash involving the face, trunk, back, penis and scrotum (panel a), legs (panel b), and arms (panel c)\n\n\n\nLaboratory investigations revealed progressive leukocytosis (26,280/μL, normal value: 4800 − 12,100/ μL) and eosinophilia (5010/ μL; normal value: 100–500/ μL) on day 30. Liver function tests showed minimal alterations. In addition, lactate dehydrogenase (LDH) levels increased to 805 U/L (normal value: 120–300 U/lL. C-reactive protein (CRP) levels were slightly increased (6.10 mg/dL, normal value: < 0.5 mg/dL). Coagulation tests also showed alterations and a prolonged international normalized ratio (INR: 1.28, normal value: 0.94–1.22) and an increased d-dimer (1815 ng/mL, normal value: < 230 ng/ml). Renal function and electrolytes were normal. Virological examinations (including polymerase chain reaction for Epstein-Barr virus, cytomegalovirus, herpes-simplex virus, hepatitis and parvovirus) and autoimmune screening (anti-nuclear, anti-DNA, anti-neutrophil cytoplasmic, anti-smooth muscle, extractable nuclear antigen and anti-mitochondrial antibodies) were all negative.\n\nA bone marrow aspirate did not show abnormalities, while a skin biopsy confirmed the presence of eosinophilic infiltration. Based on the patient’s clinical history and laboratory findings, the RegiSCAR scoring system was applied, and the boy was diagnosed with DRESS syndrome (total score = 7) on day 30. Vancomycin administration was discontinued and switched to oral linezolid (10 mg/kg/dose three times per day), which was interrupted 3 days later as a result of a worsening of the skin rash and the patient’s general condition. Thus, pulse methylprednisolone (20 mg/kg/day for 3 days) was started, resulting in rapid defervescence and prompt remission of the rash and facial-neck and scrotal edema within a few days. Oral prednisone (1.5 mg/kg/day) was continued, and the patient achieved a complete resolution of all symptoms and normal laboratory tests within 10 days. Prednisone was gradually reduced and finally discontinued after 1 month.\n\nCase 2\nA 4-year-old girl with cystic fibrosis, pancreatic insufficiency and chronic pulmonary colonization by Gram-positive bacteria was admitted to our hospital for pulmonary exacerbation. Based on the last available sputum culture, intravenous piperacillin-tazobactam (150 mg/kg/day in three doses) and tobramycin (10 mg/kg in one dose) were started and resulted in progressive clinical improvement. Daily treatment with physiotherapy, an inhaled long-acting beta-agonist and oral pancreatic enzymes was continued throughout the patient’s hospitalization. After 14 days of treatment, she presented a high-grade fever (up to 40 °C) and a diffuse maculopapular erythaematous rash involving the trunk and eventually the whole body. She also developed generalized polyadenomegaly as well as hepatomegaly. Laboratory investigations showed a rise in CRP levels (10.31 mg/dL, normal value: < 0.5 mg/dL) and a progressive increase in serum transaminase levels, with aspartate aminotransferase and alanine aminotransferase levels > 40 U/L and > 10 times the upper limit of normal, respectively. Coagulation tests showed very high d-dimer concentrations (68,340 ng/mL, normal value: < 230 ng/mL), a prolonged activated partial thromboplastin time ratio (1.94, normal value: 0.86–1.20) and an INR of 1.23 (normal value: 0.94–1.22). LDH concentrations increased to 10,880 U/L at 4 days after the onset of symptoms. Also in this case, autoimmune, infective and haematologic tests were negative.\n\nA parallel progressive increase in the patient’s eosinophil count reached a maximum absolute value of 2940/mmc on the 18th day. A diagnosis of DRESS syndrome was established based on a RegiSCAR total score of 6. Antibiotic treatment was therefore stopped, and without any further therapy, a progressive resolution of the patient’s clinical features was observed within 7 days, while the normalization of laboratory abnormalities was achieved at 14 days following the onset of DRESS syndrome (the 28th hospitalization day overall).\n\nDiscussion and conclusions\nDRESS syndrome is a rare, severe, drug-induced reaction characterized by a spectrum of systemic manifestations and multiple organ involvement. Common pharmacologic triggers for DRESS include aromatic anticonvulsants (mainly phenobarbital, phenytoin, and carbamazepine), antibiotics (mainly trimethoprim-sulfamethoxazole, minocycline, vancomycin, and anti-tubercular drugs), dapsone, allopurinol and nevirapine [6]. However, the list of drugs that have been associated with the development of DRESS syndrome is becoming longer and now includes ibuprofen, acetylsalicylic acid, sulthiame, and griseofulvin as possible triggers in children [7–10]. The aetiology of DRESS syndrome is not yet clear, but it has been suggested that this condition is multifactorial and may include an immune-mediated hypersensitivity component that is a direct effect of an interaction between the drugs or their metabolites and a genetic susceptibility [4]. Furthermore, an interplay between drugs, viruses (mainly herpes virus 6 [HHV6], but also HHV7, Epstein-Barr virus and cytomegalovirus) and immune system may have a role as trigger of DRESS syndrome [11]. In particular, it was observed that in patients with DRESS and HHV6 reactivation there was a higher levels of serum thymus and activation-regulated chemokine (TARC) that would lead to a Th2-type immune reaction [12]. Moreover, serum TARC were identified as a marker of severity of inflammation in drug eruptions [13].\n\nDRESS syndrome typically manifests 2–6 weeks after the beginning of the administration of the offending drug [14]. However, early onset at 5 days has been described [15]. Interestingly, in a recent perspective study, children treated with antibiotics developed DRESS syndrome after an average latency of 5.8 days [16]. Fever usually precedes cutaneous eruption, which generally presents as a diffuse, pruritic, and macular rash [6, 14]. Furthermore, multiple organ systems may be involved. Lymphadenopathy is frequently described as similar to liver involvement and may progress to liver failure, which is the primary cause of death in DRESS syndrome [3]. Other systemic involvements include the kidneys, gastrointestinal tract, lungs, heart and central nervous system. Laboratory abnormalities associated with this condition include leukocytosis with peripheral eosinophilia, lymphocytosis and thrombocytopenia. Liver and renal function test results may also be altered [3, 14]. Because of its highly variable clinical presentation, other clinical conditions, such as acute viral infections, hepatitis, sepsis, autoimmune disease, and haematologic disorders, should be considered in the differential diagnosis of DRESS syndrome. In our patients, all the typical signs and symptoms of this condition (fever ≥38.5 °C, a skin rash extending over more than 50% of the body surface and lymphadenopathy) developed more than 14 days after the initiation of intravenous antibiotic therapy. Furthermore, both patients progressively presented typical biochemical abnormalities (eosinophilia and liver involvement). Atypical lymphocytes were not detected in our patients, and a skin biopsy was performed in only the first case. After other potential causes (autoimmune, infective and haematologic disorders) were excluded, the RegiSCAR scoring system was used to achieve a definite diagnosis of DRESS syndrome (total scores of 7 and 6 in cases 1 and 2, respectively; see Table 2).\n\nTo treat DRESS syndrome, the offending drug must be promptly removed. This may be sufficient to achieve the resolution of clinical and laboratory abnormalities, as we found in our second case. The pharmacological approach to treating this syndrome is not completely defined as such treatments have not yet been evaluated in clinical trials. Intravenous corticosteroids, administered alone or followed by oral steroid therapy, have been shown to be an effective treatment for DRESS syndrome [14, 17, 18]. However, there is no consensus regarding the dose and route of administration [19]. In our first case, considering the worsening of the skin rash and the general condition of the patient after the introduction of linezolid, pulse methylprednisolone was immediately administered, resulting in a rapid clinical improvement. In second patient, a progressive spontaneous resolution of the clinical features was observed within 7 days, while the normalization of laboratory abnormalities was achieved at 14 days following the onset of DRESS syndrome, highlighting the importance of an early diagnosis to avoid unfavourable outcome.\n\nOf note, different reports have demonstrated an association of DRESS syndrome with subsequent autoimmune diseases (i.e., Graves disease, Hashimoto’s disease, type 1 diabetes mellitus, and autoimmune hemolytic anemia) [20, 21]. A gradual tapering of corticosteroid after a starting dose of prednisone of 0.5–1.0 mg/kg/day may reduce the development of long-term autoimmune sequelae [22–26].\n\nThese case reports support the notion that paediatricians should be aware of the clinical presentations of and therapeutic approaches for DRESS syndrome, especially in children receiving long-term antibiotic treatment. A detailed medication history is essential to achieving a diagnosis. Furthermore, RegiSCAR is a simple and reliable instrument for confirming a clinical suspicion of DRESS. The removal of the offending drug is crucial and may be the only life-saving measure. In more aggressive cases, corticosteroid or other immunosuppressive drugs should be considered to achieve the best outcome.\n\nAbbreviations\nCRPC-reactive protein\n\nDHRDrug hypersensitivity reactions\n\nDRESSDrug reaction with eosinophilia and systemic symptoms\n\nINRInternational normalized ratio\n\nLDHLactate dehydrogenase\n\nRegiSCARRegister of Severe Cutaneous Adverse Reactions\n\nTARCSerum thymus and activation-regulated chemokine\n\nFunding\nNo sources of funding to declare.\n\nAvailability of data and materials\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n\nAuthors’ contributions\nMLC, LEC and VD wrote the first draft of the manuscript and contributed to the patients’ management. SE and CC critically revised the manuscript and supervised the patients’ management. All authors read and approved the final version of the manuscript.\n\nEthics approval and consent to participate\nThese case reports were approved by the Ethics Committee of Fondazione IRCCS Ca′ Granda Ospedale Maggiore Policlinico, Milan, Italy. For case reports, the Ethics Committee of Fondazione IRCCS Ca′ Granda Ospedale Maggiore Policlinico does not provide a reference number. Parents gave their written informed consent.\n\nConsent for publication\nWritten informed consent for the publication of this case report and any accompanying images was obtained from the patients’ parents. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, Khan DA, Lang DM, Park HS, Pichler W, Sanchez-Borges M, Shiohara T, Thong BY. International consensus on drug allergy. Allergy. 2014; 10.1111/all.12350.\n2. Spriet S, Banks TA. Drug reaction with eosinophilia and systemic symptoms syndrome. Allergy Asthma Proc. 2015; 10.2500/aap.2015.36.3903.\n3. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: Part I. Clinical perspectives. J Am Acad Dermatol. 2013; 10.1016/j.jaad.2013.01.033.\n4. Besli GE, Yldrm S, Ylmaz K, Yuksel E. Drug reaction with eosinophilia and systemic symptoms syndrome or hematologic malignancy? A case report of a 4-year-old boy. Pediatr Emerg Care. 2017; 10.1097/PEC.0000000000000489.\n5. Kardaun SH, Sidoroff A, Valeyrie-Allanore L, Halevy S, Davidovici BB, Mockenhaupt M, Roujeau JC. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol. 2007; 10.1111/j.1365-2133.2006.07704.x.\n6. Cacoub P, Musette P, Descamps V, Meyer O, Speirs C, Finzi L, Roujeau JC. The DRESS syndrome: a literature review. Am J Med. 2011; 10.1016/j.amjmed.2011.01.017.\n7. Koca T Akcam M Ibuprofen induced DRESS syndrome in a child Indian Pediatr 2016 53 745 10.1007/s13312-016-0924-y 27567654 \n8. Terlemez S, Demir F, Bulut Y, Cartı Ö, Gökdoğan D, Tokgöz Y, Yenigün A. DRESS syndrome developed related to acetylsalicylic acid use. Pediatr Allergy Immunol. 2016; 10.1111/pai.12484.\n9. Smith RJ, Boos MD, McMahon P. Probable griseofulvin-induced drug reaction with eosinophilia and systemic symptoms in a child. Pediatr Dermatol. 2016; 10.1111/pde.12935.\n10. Fong CY, Hashim N, Gan CS, Chow TK, Tay CG. Sulthiame-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Eur J Paediatr Neurol. 2016; 10.1016/j.ejpn.2016.07.023.\n11. Marcus N, Smuel K, Almog M, Prais D, Straussberg R, Landau D, Scheuerman O. Successful intravenous immunoglobulin treatment in pediatric aevere DRESS syndrome. J Allergy Clin Immunol Pract. 2017; 10.1016/j.jaip.2017.10.016.\n12. Cho YT, Yang CW, Chu CY. Drug reaction with eosinophilia and systemic symptoms (DRESS): an interplay among drugs, viruses, and immune system. Int J Mol Sci. 2017; 10.3390/ijms18061243.\n13. Komatsu-Fujii T, Chinuki Y, Niihara H, Hayashida K, Ohta M, Okazaki R, Kaneko S, Morita E. The thymus and activation-regulated chemokine (TARC) level in serum at an early stage of a drug eruption is a prognostic biomarker of severity of systemic inflammation. Allergol Int. 2018; 10.1016/j.alit.2017.06.001.\n14. Sultan SJ, Sameem F, Ashraf M. Drug reaction with eosinophilia and systemic symptoms: manifestations, treatment, and outcome in 17 patients. Int J Dermatol. 2015; 10.1111/ijd.12331.\n15. Cheng J, Rawal S, Roberts A, Guttman OR. Drug reaction with eosinophilia and systemic symptoms syndrome associated with antituberculosis medications. Pediatr Infect Dis J. 2013; 10.1097/INF.0b013e3182a09f20.\n16. Sasidharanpillai S, Sabitha S, Riyaz N, Binitha MP, Muhammed K, Riyaz A, Jayakrishnan MP, Reyila VP. Drug reaction with eosinophilia and systemic symptoms in children: a prospective study. Pediatr Dermatol. 2016; 10.1111/pde.12803.\n17. Kocaoglu C, Cilasun C, Solak ES, Kurtipek GS, Arslan S. Successful treatment of antiepileptic drug-iInduced DRESS syndrome with pulse methylprednisolone. Case Rep Pediatr. 2013; 10.1155/2013/928910.\n18. Teng P Tan B Carbamazepine-induced DRESS syndrome in a child: rapid response to pulsed corticosteroids Dermatol Online J 2013 19 18170 24011271 \n19. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: Part II. Management and therapeutics. J Am Acad Dermatol. 2013; 10.1016/j.jaad.2013.01.032.\n20. Kano Y, Tohyama M, Aihara M, Matsukura S, Watanabe H, Sueki H, Iijima M, Morita E, Niihara H, Asada H, Kabashima K, Azukizawa H, Hashizume H, Nagao K, Takahashi H, Abe R, Sotozono C, Kurosawa M, Aoyama Y, Chu CY, Chung WH, Shiohara T. Sequelae in 145 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: survey conducted by the Asian Research Committee on Severe Cutaneous Adverse Reactions (ASCAR). J Dermatol. 2015; 10.1111/1346-8138.12770.\n21. Chen YC Chang CY Cho YT Chiu HC Chu CY Long-term sequelae of drug reaction with eosinophilia and systemic symptoms: a retrospective cohort study from Taiwan J Am Acad Dermatol 2013 68 3 459 465 10.1016/j.jaad.2012.08.009 22959230 \n22. Cho YT, Chu CY. Treatments for severe cutaneous adverse reactions. J Immunol Res. 2017; 10.1155/2017/1503709.\n23. Seth D, Kamat D, Montejo J. DRESS syndrome: a practical approach for primary care practitioners. Clin Pediatr. 2008; 10.1177/0009922808320703.\n24. Newell BD, Moinfar M, Mancini AJ, Nopper AJ. Retrospective analysis of 32 pediatric patients with anticonvulsant hypersensitivity syndrome (ACHSS). Pediatr Dermatol. 2009; 10.1111/j.1525-1470.2009.00870.x.\n25. Kirchhof MG, Wong A, Dutz JP. Cyclosporine treatment of drug-induced hypersensitivity syndrome. JAMA Dermatol. 2016; 10.1001/jamadermatol.2016.2220.\n26. Takehara A Aoyama Y Kurosawa M Shirafuji Y Umemura H Kamiya K Ushigome Y Kano Y Shiohara T Iwatsuki K Longitudinal analysis of antibody profiles against plakins in severe drug eruptions: emphasis on correlation with tissue damage in drug-induced hypersensitivity syndrome and drug reaction with eosinophilia and systemic symptoms Br J Dermatol 2016 175 944 952 10.1111/bjd.14677 27087170\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1720-8424",
"issue": "44(1)",
"journal": "Italian journal of pediatrics",
"keywords": "Antibiotic reactions; Antibiotic therapy; Cutaneous adverse reactions; DRESS syndrome; Drug exposure",
"medline_ta": "Ital J Pediatr",
"mesh_terms": "D002675:Child, Preschool; D063926:Drug Hypersensitivity Syndrome; D004359:Drug Therapy, Combination; D042241:Early Diagnosis; D004802:Eosinophilia; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010019:Osteomyelitis; D010878:Piperacillin; D018410:Pneumonia, Bacterial; D018570:Risk Assessment; D012494:Sampling Studies; D014031:Tobramycin; D014640:Vancomycin; D028761:Withholding Treatment",
"nlm_unique_id": "101510759",
"other_id": null,
"pages": "93",
"pmc": null,
"pmid": "30111350",
"pubdate": "2018-08-15",
"publication_types": "D016428:Journal Article",
"references": "27001334;19840307;23691411;18648083;17300272;27397873;22959230;28665895;24738653;26534757;28598363;26928755;25623158;23602183;24697291;21592453;27567654;24569311;27524391;27087170;28648978;23602182;27438540;29445753;24011271",
"title": "Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in two young children: the importance of an early diagnosis.",
"title_normalized": "drug reaction with eosinophilia and systemic symptoms dress syndrome in two young children the importance of an early diagnosis"
} | [
{
"companynumb": "IT-PARI RESPIRATORY EQUIPMENT, INC.-2018PAR00050",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TOBRAMYCIN"
},
"drugad... |
{
"abstract": "A 69-year-old male presented with early stage non-small cell lung cancer in 2016. The tumor was resected; however, the patient experienced recurrence 2 years later and subsequently received paclitaxel/carboplatin concurrently with radiotherapy. Within weeks of completing this treatment, he developed a symptomatic pancoast tumor secondary to disease progression and commenced second line nivolumab. Following the second dose of nivolumab, he developed acute unilateral right hearing loss. He commenced intravenous methylprednisolone followed by a slow taper of oral prednisolone. With steroids, he noted a gradual improvement in hearing, confirmed by audiology. Restaging imaging post-nivolumab demonstrated a complete metabolic response. Two prior cases have reported bilateral sensorineural hearing loss post-immune checkpoint inhibitor (ICI). We postulate the hearing impairment relates to the development of autoimmune inner ear disease. To our knowledge, this is the only case of a patient experiencing unilateral loss of hearing following an ICI.",
"affiliations": "Queensland University of Technology, Faculty of Health, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Cancer and Ageing Research Program, Brisbane, Australia.;Queensland University of Technology, Faculty of Health, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Cancer and Ageing Research Program, Brisbane, Australia.;Greenslopes ENT, Greenslopes, Australia.;Queensland X-ray, Greenslopes Private Hospital, Greenslopes, Australia.;Queensland University of Technology, Faculty of Health, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Cancer and Ageing Research Program, Brisbane, Australia.",
"authors": "Rajapakse|Aleksandra|A|;O'Leary|Connor|C|;Gundelach|Raefe|R|;Deva|Rajeev|R|;O'Byrne|Ken|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/omcr/omaa077",
"fulltext": "\n==== Front\nOxf Med Case Reports\nOxf Med Case Reports\nomcr\nOxford Medical Case Reports\n2053-8855 Oxford University Press \n\n10.1093/omcr/omaa077\nomaa077\nAcademicSubjects/MED00010\nomcrep/1100\nomcrep/1500\nomcrep/2100\nCase Report\nUnilateral autoimmune inner ear disease in a patient with lung cancer treated with nivolumab\nRajapakse Aleksandra 12 O’Leary Connor 12 Gundelach Raefe 3 Deva Rajeev 4 O’Byrne Ken 125 1 \nQueensland University of Technology, Faculty of Health, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Cancer and Ageing Research Program, Brisbane, Australia\n2 \nTranslational Research Institute, Brisbane, Australia\n3 \nGreenslopes ENT, Greenslopes, Australia\n4 \nQueensland X-ray, Greenslopes Private Hospital, Greenslopes, Australia\n5 \nDepartment of Medical Oncology, Greenslopes Private Hospital, Greenslopes, Australia\nCorrespondence address. Queensland University of Technology, Faculty of Health, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Cancer and Ageing Research Program; Translational Research Institute, Brisbane, QLD, Australia. Tel: +61 7 3443 7320; E-mail: aleksandra.rajapakse@qut.edu.au\n9 2020 \n22 9 2020 \n22 9 2020 \n2020 9 omaa07727 5 2020 7 7 2020 21 7 2020 © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com2020This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comABSTRACT\nA 69-year-old male presented with early stage non-small cell lung cancer in 2016. The tumor was resected; however, the patient experienced recurrence 2 years later and subsequently received paclitaxel/carboplatin concurrently with radiotherapy. Within weeks of completing this treatment, he developed a symptomatic pancoast tumor secondary to disease progression and commenced second line nivolumab. Following the second dose of nivolumab, he developed acute unilateral right hearing loss. He commenced intravenous methylprednisolone followed by a slow taper of oral prednisolone. With steroids, he noted a gradual improvement in hearing, confirmed by audiology. Restaging imaging post-nivolumab demonstrated a complete metabolic response. Two prior cases have reported bilateral sensorineural hearing loss post-immune checkpoint inhibitor (ICI). We postulate the hearing impairment relates to the development of autoimmune inner ear disease. To our knowledge, this is the only case of a patient experiencing unilateral loss of hearing following an ICI.\n\nnon-small cell lung cancerimmune checkpoint inhibitorsautoimmune inner ear diseasenivolumabsensorineural hearing loss\n==== Body\nINTRODUCTION\nLung cancer is among the most frequently diagnosed cancers and the leading cause of cancer-related mortality [1]. The global burden will continue to rise as the world population increases, particularly due to tobacco smoking. Lung cancer can be treated through surgical intervention, radiation therapy, chemotherapy and targeted therapy. The type of treatment will vary depending on the stage, histology and molecular subtype. Immunotherapy targeting the programmed-death receptor 1 (PD1), programmed-death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) immune-checkpoint inhibitors (ICI) has transformed the treatment landscape for patients with non-small cell lung cancer (NSCLC) in the first- and second-line settings [2]. PD-L1 is an immune checkpoint protein expressed on the surface of cancer cells, which prevents anticancer immunity through interaction with the PD-1. As a result, cancer cells survive unhindered by the immune system. Nivolumab and pembrolizumab directly target PD-1, while atezolizumab and durvalumab inhibit PD-L1 from interacting with its receptor, with activity in NSCLC in various clinical settings [2–5]. These drugs pose a risk of immune overstimulation which forms the basis of the side effect profile of these drugs.\n\nFigure 1 (A) PET/CT at time of recurrence confirming FDG right upper lobe avid lesion. (B) PET/CT post two cycles of nivolumab showing no evidence of FDG avid disease. (C) Baseline audiometry showing complete loss of hearing affecting the right ear. (D) Evidence of initial recovery of low-frequency hearing after 10 days on steroids. (E) Continued improvement in hearing 3 months after discontinuation of nivolumab.\n\nFigure 2 (A) Axial high resolution T2 SPACE sequences demonstrating no structural retrocochlear lesion. (B) Axial T1 fat saturated post-Gadolinium demonstrating no abnormal enhancement of the vestibulocochlear apparatus.\n\nCASE REPORT\nA 69-year-old male was initially diagnosed in Germany with early stage NSCLC of the right upper lobe of the lung in 2016. This lesion was resected. No adjuvant chemotherapy or radiotherapy was offered at that point. In May 2018, the patient developed recurrent disease at the resection site (Fig. 1A). He received carboplatin and paclitaxel concurrently with radiotherapy over 6 weeks from June to July 2018. Within a few weeks of completing concurrent treatment, he developed a symptomatic pancoast tumor, with pain and swelling of the right upper limb. A computed tomography (CT) scan of his chest demonstrated an increase in tumor size. Due to disease progression, a decision was made to commence second line treatment with nivolumab. After the second dose of nivolumab, the patient presented to an ENT clinic with acute onset unilateral right-sided hearing loss. Unilateral sensorineural deafness was diagnosed on audiometry at both high- and low-frequency levels (Fig. 1C). That week he was subsequently reviewed at oncology follow-up. An MRI brain scan revealed no evidence of central nervous system involvement with disease (Fig. 2A and B). As no clear cause was evident on initial assessment to explain the hearing loss, the suspicion of immune related ototoxicity was raised. He commenced high-dose intravenous (IV) methylprednisolone for 3 days, followed by a slow wean of oral prednisolone post-IV treatment. The patient had a gradual improvement in hearing. Repeat audiology confirmed reversal of the sensorineural deafness over time (Fig. 1D).\n\nPositron emission tomography (PET)/CT imaging post-nivolumab demonstrated a marked reduction of fluorodeoxyglucose (FDG) avidity, consistent with a complete metabolic response to immunotherapy (Fig. 1B). Based on this and the neurotoxicity, the patient remained off systemic treatment. He remains in follow-up and is clinically well. Sequential scans demonstrate ongoing stability with metabolically inactive disease. Repeated audiology showed further evidence of improvement in the hearing of the right ear (Fig. 1E).\n\nDISCUSSION\nImmune checkpoint inhibitors have revolutionized the treatment of lung cancer, however, modulating the immune system can lead to immune-related adverse events [4]. A myriad of side effects have been observed in clinical trials, including dermatitis, colitis, hepatitis and myositis among others [4]. Grade 1–2 adverse events can usually be treated with oral steroids; however, grade 3–4 events require discontinuation of the ICI in most cases [6].\n\nThe first known case of autoimmune inner ear disease, reported an 82-year-old male who presented with metastatic mucosal melanoma and was initially treated with ipilimumab [5]. The patient was later commenced on pembrolizumab and developed acute hearing loss. He was diagnosed with bilateral sensorineural hearing loss. He received bilateral intratympanic dexamethasone injections. Otology confirmed an improvement in the patients’ hearing as well as a decrease in tumor size, 12 weeks later. The authors postulated that the cause was autoimmune in nature as a result of the pembrolizumab.\n\nThe second case, described a 67-year-old male who presented to the clinic with an invasive melanoma of the toe [3]. Following amputation of his toe, he was treated with pembrolizumab, however, developed severe bilateral sensorineural hearing loss after his first dose of therapy. The patient received intratympanic steroid injections and had a subjective return to baseline hearing. According to the authors, the FDA has already reported 22 cases of pembrolizumab-induced autoimmune inner ear disease with this case being 1 of 14 related to metastatic melanoma.\n\nA clear similarity among the cases is a sudden onset of loss in auditory function upon treatment with an ICI, with a notable, sometimes subjective improvement in hearing with treatment. In our case, the patient’s auditory function was measured after hearing loss occurred and twice thereafter during recovery. A limitation to this case report is the lack of audiometry measurements pre-nivolumab. Therefore, we are unable to confirm whether the patient had prior hearing difficulties at baseline that may have contributed to his acute hearing loss. Baseline audiometry tests and ENT review should be considered in patients presenting for treatment with evidence of hearing loss prior to commencing ICI. Furthermore, this finding re-iterates the importance of advising the patient to contact their oncologist to discuss any acute toxicity that emerges upon ICI therapy.\n\nHere, we described a case where a patient developed acute unilateral hearing loss of the right ear, after receiving a PD-1 inhibitor, nivolumab. Reversibility of the hearing impairment was apparent on treatment with steroids. Two prior case reports have described a similar phenomenon [3, 5]. Our case is the first to report unilateral sensorineural hearing loss in the lung cancer setting. We postulate the likely cause of the hearing impairment relates to autoimmune inner ear disease secondary to T-cell over activation affecting the vestibulocochlear nerve of the right ear. Given the clinical significance and potential reversibility, oncologists should be aware of this potential rare side effect. In the occurrence of ICI-induced hearing loss, we suggest early treatment with high dose steroids followed by a slow wean of oral steroids.\n\nACKNOWLEDGEMENTS\nNone.\n\nFUNDING\nThis research did not receive any funding.\n\n\nConflict of interest statement. No conflicts of interest.\n\nETHICAL APPROVAL\nNot applicable.\n\nCONSENT\nThe patient has reviewed the case content and has given written consent for his case to be published with this journal.\n\nGUARANTOR\nAleksandra Rajapakse, Queensland University of Technology, Faculty of Health, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Cancer and Ageing Research Program, Brisbane, QLD. Australia; Translational Research Institute, Brisbane, QLD, Australia.\n==== Refs\nREFERENCES\n1. \nFerlay J , Colombet M , Soerjomataram I , Mathers C , Parkin DM , Piñeros M et al. \nEstimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods\n. Int J Cancer 2019 ;144 :1941 –53\n. doi: 10.1002/ijc.31937 .30350310 \n2. \nReck M , Borghaei H , O'Byrne KJ \nNivolumab plus ipilimumab in non-small-cell lung cancer\n. Future Oncol 2019 ;15 :2287 –302\n. doi: 10.2217/fon-2019-0031 .31066582 \n3. \nHobelmann K , Fitzgerald D \nA case of pembrolizumab induced autoimmune sensorineural hearing loss\n. J Otol Rhinol 2019 ;8 :1 . doi: 10.4172/2324-8785.1000365 .\n4. \nRoberts K , Culleton V , Lwin Z , O'Byrne K , Hughes BG \nImmune checkpoint inhibitors: navigating a new paradigm of treatment toxicities\n. Asia Pac J Clin Oncol 2017 ;13 :277 –88\n. doi: 10.1111/ajco.12698 .28699304 \n5. \nZibelman M , Pollak N , Olszanski AJ \nAutoimmune inner ear disease in a melanoma patient treated with pembrolizumab\n. J Immunother Cancer 2016 ;4 :8 . doi: 10.1186/s40425-016-0114-4 .26885370 \n6. \nThompson JA \nNew NCCN guidelines: recognition and management of immunotherapy-related toxicity\n. J Natl Compr Canc Netw 2018 ;16 :594 –6\n. doi: 10.6004/jnccn.2018.0047 .29784734\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2053-8855",
"issue": "2020(9)",
"journal": "Oxford medical case reports",
"keywords": "autoimmune inner ear disease; immune checkpoint inhibitors; nivolumab; non-small cell lung cancer; sensorineural hearing loss",
"medline_ta": "Oxf Med Case Reports",
"mesh_terms": null,
"nlm_unique_id": "101642070",
"other_id": null,
"pages": "omaa077",
"pmc": null,
"pmid": "32995031",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": "28699304;30350310;26885370;29784734;31066582",
"title": "Unilateral autoimmune inner ear disease in a patient with lung cancer treated with nivolumab.",
"title_normalized": "unilateral autoimmune inner ear disease in a patient with lung cancer treated with nivolumab"
} | [
{
"companynumb": "AU-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-106926",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "Cancer-related thrombotic microangiopathy (CR-TMA) is a rare entity associated with a dismal prognosis. Usually, CR-TMA is associated with mucin-producing carcinomas among which stomach, breast, prostate, lung and pancreas tumours are the most frequent.\n\n\n\nWe describe for the first time three cases of CR-TMA due to adrenocortical carcinoma (ACC). All of them had mechanical hemolytic anemia and thrombocytopenia without any other identifiable cause. Bicytopenia was diagnosed either simultaneously with ACC or at the time of metastatic evolution. Two patients had acute kidney injury (AKI) with severe pathological findings on kidney biopsy. Despite total adrenalectomy, chemotherapy, and specific treatment of TMA with plasma-exchanges, renal failure and hemolytic anemia remained. The only manifestation of CR-TMA in the third patient was hemolytic anemia, which resolved after surgical removal of ACC. The evolutions in these patients suggests ACC-related TMA may be related to a circulating factor.\n\n\n\nCR-TMAs are rare. Here we describe the first case series of ACC-related TMA, among which two had renal involvement. This entity is associated with dismal renal prognosis despite specific treatment of TMA. According to patients' evolution, the persistence of TMA may reflect an uncontrolled malignancy.",
"affiliations": "Nephrology - Kidney Transplant Unit, Rouen University Hospital, 76031, Rouen, France. denattes.tristan@gmail.com.;Endocrine Unit, Rouen University Hospital, Rouen, France.;Endocrine Unit, Toulouse University Hospital, Toulouse, France.;Medical Oncology Department, Gustave Roussy Institute, Villejuif, France.;Department of Internal Medicine, Pitie-Salpetriere Hospital, AP-HP, Paris, France.;Nephrology - Kidney Transplant Unit, Rouen University Hospital, 76031, Rouen, France.;Department of Medical Critical Care, Rouen University Hospital, Rouen, France.",
"authors": "de Nattes|Tristan|T|0000-0002-3714-8768;Moreau-Grangé|Lucile|L|;Vezzosi|Delphine|D|;Hadoux|Julien|J|;Hie|Miguel|M|;Guerrot|Dominique|D|;Grangé|Steven|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12882-020-1703-5",
"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 170310.1186/s12882-020-1703-5Case ReportAdrenocortical carcinoma complicated by renal thrombotic microangiopathy, a case-series http://orcid.org/0000-0002-3714-8768de Nattes Tristan denattes.tristan@gmail.com 1Moreau-Grangé Lucile 2Vezzosi Delphine 3Haddoux Julien 4Hie Miguel 5Guerrot Dominique 1Grangé Steven 61 grid.41724.34Nephrology – Kidney Transplant Unit, Rouen University Hospital, 76031 Rouen, France 2 grid.41724.34Endocrine Unit, Rouen University Hospital, Rouen, France 3 0000 0001 1457 2980grid.411175.7Endocrine Unit, Toulouse University Hospital, Toulouse, France 4 0000 0001 2284 9388grid.14925.3bMedical Oncology Department, Gustave Roussy Institute, Villejuif, France 5 0000 0001 2150 9058grid.411439.aDepartment of Internal Medicine, Pitie-Salpetriere Hospital, AP-HP, Paris, France 6 grid.41724.34Department of Medical Critical Care, Rouen University Hospital, Rouen, France 30 1 2020 30 1 2020 2020 21 3528 11 2019 23 1 2020 © The Author(s). 2020Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nCancer-related thrombotic microangiopathy (CR-TMA) is a rare entity associated with a dismal prognosis. Usually, CR-TMA is associated with mucin-producing carcinomas among which stomach, breast, prostate, lung and pancreas tumours are the most frequent.\n\nCases presentation\nWe describe for the first time three cases of CR-TMA due to adrenocortical carcinoma (ACC). All of them had mechanical hemolytic anemia and thrombocytopenia without any other identifiable cause. Bicytopenia was diagnosed either simultaneously with ACC or at the time of metastatic evolution. Two patients had acute kidney injury (AKI) with severe pathological findings on kidney biopsy. Despite total adrenalectomy, chemotherapy, and specific treatment of TMA with plasma-exchanges, renal failure and hemolytic anemia remained. The only manifestation of CR-TMA in the third patient was hemolytic anemia, which resolved after surgical removal of ACC. The evolutions in these patients suggests ACC-related TMA may be related to a circulating factor.\n\nConclusions\nCR-TMAs are rare. Here we describe the first case series of ACC-related TMA, among which two had renal involvement. This entity is associated with dismal renal prognosis despite specific treatment of TMA. According to patients’ evolution, the persistence of TMA may reflect an uncontrolled malignancy.\n\nKeywords\nThrombotic microangiopathyHemolytic uremic syndromeAcute kidney injuryAdrenocortical carcinomaissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nThrombotic microangiopathy (TMA) is a rare entity due to a wide variety of diseases, all characterized by mechanical hemolytic anemia, thrombocytopenia and microvascular occlusions. Causes of TMA are separated between thrombotic thrombocytopenic purpura, typical Hemolytic uremic syndrome (HUS), primary atypical HUS in patients with an abnormality of the alternative complement pathway, and HUS secondary to a heterogeneous group of causes: infections, drugs, genetic disorders, systemic diseases and cancers [1]. Adrenocortical carcinoma (ACC) is a rare tumour, with an unfavourable prognosis. Hormonal complications often occur, but paraneoplastic syndromes are uncommon in the literature [2]. Here, we describe a case-series of ACC-associated TMA.\n\nCases presentation\nCase 1\nA 41-year-old woman was investigated in July 2016 for fatigue and loss of 10 kg over a few weeks. She was not taking any medication at this time and had no history of kidney disease. An abdominal computed tomography scan was performed in July, revealing a 13x13x10cm left adrenal mass of heterogeneous density with heterogeneous and prolonged enhancement after contrast agent administration. This mass was suggestive of ACC not associated with significant hormonal hypersecretion. Other lab results revealed plasma creatinine = 97 μmol/L, proteinuria = 0.7 g/g of urine creatinine, haemoglobin 9.9 g/dL, platelet 143 G/L.\n\nSurgical procedure was planned in early-August, and no treatment was introduced.\n\nAt admission, she had stage 3 KDIGO AKI with plasma creatinine at 439 μmol/L and 0.99 g/24 h proteinuria. Urine sediment was normal. Blood pressure was 119/70 mmHg, there was no clinical sign of other organ involvement. She presented thrombocytopenia (67G/L) and mechanical hemolytic anemia: haemoglobin = 7.9 g/dL, reticulocyte = 175G/L, presence of schistocytes, Lactate Dehydrogenase (LDH) = 1058 UI/L and haptoglobin < 0.1 g/L. Extensive laboratory investigations were performed for the differential diagnosis of cytopenias. Antinuclear factors were negative, as were antibodies for antiphospholipid syndrome and scleroderma. ADAMTS 13 activity was 93%, complement investigations were normal (C4, C4, CH50, Factor I and H, anti-Factor H antibody).\n\nThe specific treatment of TMA consisted in daily plasma-exchange therapy of 60 mL/kg with plasma as replacement fluid. Intermittent hemodialysis was started on the same day. Left adrenalectomy was performed with splenectomy because of peroperative splenic decapsulation. A kidney biopsy was also performed.\n\nACC was confirmed by pathology, with a Weiss score at 6/9, Ki67 = 45% and 25 mitotic figures per 50 high-power field. The resection was total, and mesenteric lymphadenopathy was not metastatic, leading to stage III according to ENSAT classification. Renal pathology confirmed TMA. Twenty-six glomeruli were observed, of which 11 were ischemic with fibrin thrombi within glomerular capillary loops. Thrombi were present in interlobular arteries, arterioles and glomerular capillaries with fibrinoid deposit. No duplication of the glomerular basement membranes was found. There was moderate acute tubular necrosis with mild interstitial fibrosis and tubular atrophy (Fig. 1).\nFig. 1 Histologic examination (H&E, × 40). Arrows: fibrin thrombi within glomerular capillary loops\n\n\n\nFourteen plasma-exchanges lead to correction of hemolysis, but the patient remained dialysis-dependent, and biological TMA reappeared a few days after plasma-exchange discontinuation. Owing to the isolated renal TMA, unfavourable renal prognosis according to pathology, kidney function evolution, and the lack of efficiency of terminal complement blockade in cancer-related TMA (CR-TMA), we decided not to escalate treatments and to undergo chronic hemodialysis.\n\nMitotane was started despite lack of pharmacokinetic knowledge on this treatment in hemodialysis patients, with a target plasma concentration between 14 and 20 mg/L. Eighteen months later, metastatic lesions occurred, leading to treatment by etoposide, doxorubicin and cisplatin. During all the follow-up, the patient remained anuric in hemodialysis and had persistent hemolysis with schistocytes, high LDH’s value and decreased haptoglobin. Twenty-four months after diagnosis, she died in a context of severe pneumonia.\n\nCase 2\nA 23-year-old woman was diagnosed with a right ACC in 2014. She first had nephrectomy and adrenalectomy. Despite Mitotane, cerebral, hepatic, pulmonary and bone metastasis occurred, leading to several chemotherapies: Cisplatin, Lenvatinib and Gemcitabine. In October 2018, she presented cardiac tamponade related to influenza-B virus. All investigations at this time did not find any argument for a paraneoplastic aetiology of the pericardial effusion. There was no evidence of TMA and renal function was normal with plasma creatinine 99 μmol/L. Two weeks later, biological data found a KDIGO 3 AKI with plasma creatinine = 200 μmol/L. Hemoglobin was 8.0 g/dL and platelet count 25 G/L. Two weeks later, she had a new cardiac tamponade which required a pericardium-to-pleural space window. Cytopenias were also investigated at this time and revealed TMA with haptoglobin < 0.1 g/L, schistocytes, LDH = 703 UI/L and plasma creatinine = 429 μmol/L. Investigations for this TMA with AKI did not find any other cause of TMA, and metastasis were stable. Due to cytopenias and high suspicious of renal TMA, it was decided not to perform a kidney biopsy.\n\nDaily plasma-exchanges were started for a suspicion of gemcitabine-related TMA. There were no hemodialysis criteria. After 14 plasma-exchanges, platelet count improved (145 G/L), and LDH decreased (422 UI/L) but schistocytes and undetectable haptoglobin persisted. There was no amelioration of kidney function (plasma creatinine 357 μmol/L). After discontinuation of plasma-exchanges, thrombocytopenia recurred. Due to the lack of efficiency of plasma-exchanges and the suspicion of gemcitabine-related TMA, eculizumab was started in December 2018. After second administration of eculizumab, systematic thoracic CT scan revealed new pulmonary metastasis. ACC related-TMA was diagnosed because (1) TMA and kidney function were not ameliorated by discontinuation of gemcitabine and treatment with plasma-exchanges and eculizumab, and (2) recurrent pericarditis with development of new metastatic lesions. Owing to the lack of efficiency of eculizumab in this particular issue, treatment was discontinued and chemotherapy was restarted.\n\nCase 3\nAn 81-year-old woman with a medical history of polymyalgia rheumatica and ischemic cardiomyopathy had been hospitalized for the investigation of a bicytopenia which had appeared and worsened over a month. Laboratory results revealed hemolytic anemia (Hb = 9.8 g/dL, haptoglobin < 0.1 g/L and schistocytes) and thrombocytopenia (platelet count 99 G/L). The patient had no organ involvement. Bone marrow morphology confirmed the peripheral origin of the bicytopenia and Coomb’s test was negative, leading to the diagnosis of TMA. Investigations were performed, and an abdominal CT scan revealed a 14 cm partially calcified left adrenal mass, which was not associated with significant hormonal hypersecretion. Left adrenalectomy was performed, with concomitant nephrectomy and splenectomy. Histopathology confirmed ACC with Weiss score at 5/9 and Ki 67 = 40%, ENSAT stage II. The next day, bicytopenia improved and haemolysis resolved, confirming CR-TMA. There was no recurrence of cytopenia during the 2 years follow-up.\n\nDiscussion and conclusion\nACC is a rare tumour, with an incidence of less than 2 cases per million per year and unfavourable prognosis with a 5-year survival rate of 13% in patients with stage-3 ACC [3]. When ACC is suspected, hormonal hypersecretion has to be investigated, especially cortisol, aldosterone and sex steroids. Complete surgical resection has to be performed for all tumours without metastasis [4]. An adjuvant treatment with mitotane is recommended. In patients with advanced disease, systemic chemotherapy with etoposide, doxorubicin and cisplatin is added [5].\n\nIn an extensive review, most CR-TMAs were attributed to metastatic adenocarcinomas of gastric, breast, prostate, and lung origin (decreasing frequency). Pathophysiological explanations of CR-TMA remain unclear. One hypothesis is that tumour cell emboli lead to microvascular obstruction, coagulation activation, and vessel wall proliferation. The direct invasion of bone marrow vasculature which results in release of Von Willebrand Factor multimer has also been described [6]. In other cases, activation of the coagulation cascade by mucin released from adenocarcinomas and immune mechanisms has been suggested.\n\nTMA secondary to endocrine malignancies are extremely rare and mainly reported with pheochromocytoma [7]. In those cases, severe hypertension was the most probable explanation of TMA reported by the authors [8–10].\n\nIn the first case of ACC-related TMA reported in the present case-series, TMA occurred before any medication, and extensive investigations were negative. In the second case, CR-TMA was treated as gemcitabine-associated TMA which did not improve either cytopenias or renal function. The paraneoplastic aetiology was affirmed by chronology and evolution of illness. In the third case, CR-TMA rapidly improved after total removal of tumor.\n\nThe latter case suggests that TMA in this particular situation could be explained by the secretion of a circulating factor by the ACC. This is substantiated by cases 1 and 2, in which plasma-exchange therapy lead to a transient improvement of hemolytic anemia, resuming at plasma-exchange discontinuation. The initial response to plasma-exchange therapy supports the role of a high molecular weight pathogenic factor with endothelial toxicity in the pathophysiology of ACC-related TMA. Considering the improvement of hemolytic anemia with plasma-exchange therapy, the recurrence of cytopenias at plasma-exchange discontinuation despite surgery and chemotherapy may suggest insufficient treatment of the tumor.\n\nTherefore, we suggest that patients with TMA in a context of ACC be treated by plasma-exchange therapy until specific treatment of tumor is performed, with total surgery if possible. Due to the lack of evidence for complement involvement in ACC-related TMA, and since eculizumab efficiency in CR-TMA is not established, we believe complement blockade should not be recommended as a suitable option in this setting.\n\nAccording to the first two cases, and as it is known for CR-TMA, renal prognosis in ACC-related TMA seems to be dismal. Indeed, despite plasma-exchange therapy, there was no improvement in renal function at the end of the follow-up.\n\nCR-TMAs are rare and associated with dismal prognosis. Here we describe the first case series of ACC-related TMA in 3 different patients. The evolutions in these patients suggests ACC-related TMA may be related to a circulating factor. We therefore suggest plasma-exchange therapy in this context until specific treatment of ACC is initiated.\n\nAbbreviations\nAACAdrenocortical carcinoma\n\nAKIAcute Kidney Injury\n\nCR-TMACancer-related Thrombotic Microangiopathy\n\nENSATEuropean Network for the Study of Adrenal Tumours\n\nHUSHemolytic uremic syndrome\n\nLDHLactate Dehydrogenase\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nTdN, LM-G, DV, JH and MH made substantial contributions to acquisition of data. TdN, DG and SG made substantial contribution to conception and design. TdN: data interpretation and analysis. TdN, JH, MH and LM-G: drafting manuscript. DV, DG, SG revised the manuscript. DG, SG: mentorship. All authors approved final manuscript. All the authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nFunding\nThis study was not funded.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent for case 2 and 3 were obtained from the patient for publication of this case report. Written informed consent for case 1 was obtained from the patient’s husband for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Goodship THJ Cook HT Fakhouri F Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “kidney disease: improving global outcomes” (KDIGO) controversies conference Kidney Int 2017 91 539 551 10.1016/j.kint.2016.10.005 27989322 \n2. Else T Kim AC Sabolch A Adrenocortical carcinoma Endocr Rev 2014 35 282 326 10.1210/er.2013-1029 24423978 \n3. Fassnacht M Johanssen S Quinkler M Limited prognostic value of the 2004 international union against cancer staging classification for adrenocortical carcinoma Cancer 2009 115 243 250 10.1002/cncr.24030 19025987 \n4. Puglisi S, Perotti P, Cosentini D, et al. Decision-making for adrenocortical carcinoma: surgical, systemic, and endocrine management options. Expert Rev Anticancer Ther. 2018:1–9. 10.1080/14737140.2018.1510325.\n5. Fassnacht M, Dekkers O, Else T, et al. European society of endocrinology clinical practice guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European network for the study of adrenal tumors. Eur J Endocrinol. 2018. 10.1530/EJE-18-0608.\n6. Govind Babu K Bhat GR Cancer-associated thrombotic microangiopathy Ecancermedicalscience 2016 10 649 10.3332/ecancer.2016.649 27433282 \n7. Lechner K Obermeier HL Cancer-related microangiopathic hemolytic anemia: clinical and laboratory features in 168 reported cases Medicine (Baltimore) 2012 91 195 205 10.1097/MD.0b013e3182603598 22732949 \n8. Sakai C Takagi T Oguro M Malignant pheochromocytoma accompanied by microangiopathic hemolytic anemia: a case report Jpn J Clin Oncol 1994 24 171 174 8007427 \n9. Gillett MJ Arenson RV Yew MK Diagnostic challenges associated with a complex case of cystic phaeochromocytoma presenting with malignant hypertension, microangiopathic haemolysis and acute renal failure Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc 2005 20 1014 10.1093/ndt/gfh742 \n10. Schweizer H Boehm J Winterer JT Phaeochromocytoma and thrombotic microangiopathy: favourable outcome despite advanced renal failure J Clin Pathol 2010 63 754 756 10.1136/jcp.2010.077511 20702482\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "21(1)",
"journal": "BMC nephrology",
"keywords": "Acute kidney injury; Adrenocortical carcinoma; Hemolytic uremic syndrome; Thrombotic microangiopathy",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D058186:Acute Kidney Injury; D000306:Adrenal Cortex Neoplasms; D018268:Adrenocortical Carcinoma; D000328:Adult; D000369:Aged, 80 and over; D000743:Anemia, Hemolytic; D005260:Female; D006801:Humans; D013921:Thrombocytopenia; D057049:Thrombotic Microangiopathies; D055815:Young Adult",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "35",
"pmc": null,
"pmid": "32000700",
"pubdate": "2020-01-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27433282;24423978;20702482;19025987;30299884;30117750;15769821;8007427;27989322;22732949",
"title": "Adrenocortical carcinoma complicated by renal thrombotic microangiopathy, a case-series.",
"title_normalized": "adrenocortical carcinoma complicated by renal thrombotic microangiopathy a case series"
} | [
{
"companynumb": "FR-ALEXION-A202002151",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ECULIZUMAB"
},
"drugadditional": "1",
"... |
{
"abstract": "BACKGROUND\nMajor depressive disorder (MDD) patients not responding to two or more different antidepressant treatments are currently considered to suffer from treatment resistant depression (TRD). Recently, intranasal esketamine has been approved by both the American Food and Drug Administration and European Medicines Agency for TRD and, more recently, in moderate to severe episode of MDD, as acute short-term treatment for the rapid reduction of depressive symptoms, which, according to clinical judgement, constitute a psychiatric emergency. There is currently no indication for obsessive-compulsive disorder (OCD) although recently published studies have already shown a rapid and significant reduction of OCD-like symptoms following ketamine administration. The etiology of OCD has not yet been fully elucidated but there is a growing evidence that glutamate signaling dysfunction in the cortico-striatal-thalamo-cortical circuitry plays an essential role. This case report exemplifies possible clinical effects of esketamine on both depressive and OCD symptoms.\n\n\nMETHODS\nWe present the case of a 39-year-old man suffering from TRD. During the first evaluation at our clinic, he also reported the presence of OCD spectrum symptoms, causing him to perform time-consuming mental rituals due to pathological doubts regarding the relationship with his wife as well as intrusive thoughts regarding his mental conditions. He underwent psychometric evaluations, therapeutic drug monitoring analysis, and pharmacogenomic tests. The overall results helped to explain patient's treatment-resistance. Moreover, we observed a significant reduction in both depressive and OCD symptoms after administration of esketamine.\n\n\nCONCLUSIONS\nThis case underlines the importance of pharmacogenomic tests in profiling TRD patients and confirms the possible use of esketamine in the treatment of comorbid OCD.",
"affiliations": "Psychiatric Department, San Gerardo Hospital, ASST Monza, Monza, Italy. m.marcatili@asst-monza.it.;Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.;Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.;Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.;Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.;Faculty of Medicine, University Vita-Salute San Raffaele, Milan, Italy.;Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia.;Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.;Psychiatric Department, San Gerardo Hospital, ASST Monza, Monza, Italy.;Psychiatric Department, San Gerardo Hospital, ASST Monza, Monza, Italy.;Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.;Psychiatric Department, San Gerardo Hospital, ASST Monza, Monza, Italy.;Psychiatric Department, San Gerardo Hospital, ASST Monza, Monza, Italy.;Psychiatry Unit, Department of Biomedical and Clinical Sciences \"Luigi Sacco\", University of Milan, Milan, Italy.;Cytogenetics and Medical Genetics Unit, Centre for Disorders of Iron Metabolism, San Gerardo Hospital, ASST Monza, Monza, Italy.;Cytogenetics and Medical Genetics Unit, Centre for Disorders of Iron Metabolism, San Gerardo Hospital, ASST Monza, Monza, Italy.;Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.;Clinical Chemistry Laboratory, San Gerardo Hospital, ASST Monza, Monza, Italy.;Psychiatric Department, San Gerardo Hospital, ASST Monza, Monza, Italy.",
"authors": "Matteo|Marcatili|M|http://orcid.org/0000-0002-1436-1961;Cristian|Pellicioli|P|;Laura|Maggioni|M|;Federico|Motta|M|;Chiara|Redaelli|R|;Lorenzo|Ghelfi|G|;Michaela|Krivosova|K|;Sibilla|Matteo|M|;Roberto|Nava|N|;Fabrizia|Colmegna|C|;Antonios|Dakanalis|D|;Alice|Caldiroli|C|;Enrico|Capuzzi|C|;Beatrice|Benatti|B|;Francesca|Bertola|B|;Nicoletta|Villa|V|;Alberto|Piperno|P|;Silvia|Ippolito|I|;Massimo|Clerici|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12991-021-00365-z",
"fulltext": "\n==== Front\nAnn Gen Psychiatry\nAnn Gen Psychiatry\nAnnals of General Psychiatry\n1744-859X\nBioMed Central London\n\n365\n10.1186/s12991-021-00365-z\nCase Report\nThe use of esketamine in comorbid treatment resistant depression and obsessive compulsive disorder following extensive pharmacogenomic testing: a case report\nhttp://orcid.org/0000-0002-1436-1961\nMatteo Marcatili m.marcatili@asst-monza.it\n\n12\nCristian Pellicioli 2\nLaura Maggioni 2\nFederico Motta 2\nChiara Redaelli 2\nLorenzo Ghelfi 3\nMichaela Krivosova 4\nSibilla Matteo 2\nRoberto Nava 1\nFabrizia Colmegna 1\nAntonios Dakanalis 2\nAlice Caldiroli 1\nEnrico Capuzzi 1\nBeatrice Benatti 56\nFrancesca Bertola 7\nNicoletta Villa 7\nAlberto Piperno 27\nSilvia Ippolito 8\nMassimo Clerici 12\n1 grid.415025.7 0000 0004 1756 8604 Psychiatric Department, San Gerardo Hospital, ASST Monza, Monza, Italy\n2 grid.7563.7 0000 0001 2174 1754 Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy\n3 grid.15496.3f Faculty of Medicine, University Vita-Salute San Raffaele, Milan, Italy\n4 grid.7634.6 0000000109409708 Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia\n5 grid.4708.b 0000 0004 1757 2822 Psychiatry Unit, Department of Biomedical and Clinical Sciences “Luigi Sacco”, University of Milan, Milan, Italy\n6 grid.4708.b 0000 0004 1757 2822 CRC “Aldo Ravelli” for Neurotechnology and Experimental Brain Therapeutics, University of Milan, Milan, Italy\n7 grid.415025.7 0000 0004 1756 8604 Cytogenetics and Medical Genetics Unit, Centre for Disorders of Iron Metabolism, San Gerardo Hospital, ASST Monza, Monza, Italy\n8 grid.415025.7 0000 0004 1756 8604 Clinical Chemistry Laboratory, San Gerardo Hospital, ASST Monza, Monza, Italy\n16 9 2021\n16 9 2021\n2021\n20 4331 5 2021\n25 8 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nMajor depressive disorder (MDD) patients not responding to two or more different antidepressant treatments are currently considered to suffer from treatment resistant depression (TRD). Recently, intranasal esketamine has been approved by both the American Food and Drug Administration and European Medicines Agency for TRD and, more recently, in moderate to severe episode of MDD, as acute short-term treatment for the rapid reduction of depressive symptoms, which, according to clinical judgement, constitute a psychiatric emergency. There is currently no indication for obsessive–compulsive disorder (OCD) although recently published studies have already shown a rapid and significant reduction of OCD-like symptoms following ketamine administration. The etiology of OCD has not yet been fully elucidated but there is a growing evidence that glutamate signaling dysfunction in the cortico-striatal–thalamo-cortical circuitry plays an essential role. This case report exemplifies possible clinical effects of esketamine on both depressive and OCD symptoms.\n\nCase presentation\n\nWe present the case of a 39-year-old man suffering from TRD. During the first evaluation at our clinic, he also reported the presence of OCD spectrum symptoms, causing him to perform time-consuming mental rituals due to pathological doubts regarding the relationship with his wife as well as intrusive thoughts regarding his mental conditions. He underwent psychometric evaluations, therapeutic drug monitoring analysis, and pharmacogenomic tests. The overall results helped to explain patient’s treatment-resistance. Moreover, we observed a significant reduction in both depressive and OCD symptoms after administration of esketamine.\n\nConclusion\n\nThis case underlines the importance of pharmacogenomic tests in profiling TRD patients and confirms the possible use of esketamine in the treatment of comorbid OCD.\n\nKeywords\n\nTreatment resistant depression\nTRD\nObsessive–compulsive disorder\nOCD\nEsketamine\nKetamine\nSLC6A4\nMTHFR\nGABRP\nGABRA6\nhttp://dx.doi.org/10.13039/501100002803 Fondazione Cariplo 2019-3396 Antonios Dakanalis issue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nMajor depressive disorder (MDD) is a common mental disorder and a leading cause of disability, affecting more than 264 million people worldwide [1, 2]. The STAR*D study demonstrated that only one third of patients achieved remission following the first antidepressant treatment and, even after 1 year of therapy with a sequence of four antidepressants administered for 12 weeks each, only two-third of patients achieved symptoms remission [3]. Although no single definition of treatment resistant depression (TRD) exists, it generally indicates patients who failed to respond to two or more trials of antidepressants, at adequate dosage and treatment duration [4]. As TRD patients seem not to respond sufficiently to traditional monoaminergic antidepressants, new treatment strategies acting on glutamatergic, cholinergic, and opioid systems are currently under investigation [5]. Pharmacogenomic testing (PGx) represents a decision-support tool that has been recently introduced into the clinical practice in psychiatry. Such personalized approach is especially useful in patients with conditions resistant to standard treatments due to genetic predisposition to poor psychopharmacological response or high susceptibility to severe side effects. PGx has several benefits: it could both lower the latency to clinical response or remission and increase patient’s compliance by reducing side effects impact and cost-effectiveness of the whole clinical management. The comorbidity of depression with other psychiatric disorders has been described in the past, and one of the most common comorbidities is represented by Obsessive–Compulsive Disorder (OCD) [6–8]. The coexistence of the two disorders seems to lead to a greater symptoms severity, less satisfactory response to treatment and an overall less favorable prognosis [8]. The disorders share common psychopathological characteristics and, in some cases, also treatment response [9–11]. Dysregulation of glutamate signaling in the cortico-striatal–thalamo-cortical circuitry appears to play a role in OCD as supported by preclinical, neuroimaging, and genetic studies [12–18].\n\nIntranasal esketamine has been approved by both the American Food and Drug Administration and the European Medicines Agency for TRD in adults and, more recently, in moderate to severe episode of MDD, as acute short-term treatment for the rapid reduction of depressive symptoms, which according to clinical judgement constitute a psychiatric emergency. Esketamine is the (S) enantiomer of ketamine, a non-competitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist that was introduced in clinics as an anesthetic and analgesic more than 50 years ago [19, 20]. The mechanism of antidepressant action of esketamine has not been fully clarified yet but modulation of different signaling pathways implicated in the pathophysiology of MDD, such as synaptogenesis and neuroplasticity pathways, may play a role [21, 22]. Although off-label, encouraging results have emerged from the use of intravenous ketamine in treatment resistant OCD as reported by previous clinical studies and case reports [23–26], hence the growing interest in the use of intranasal esketamine in treatment resistant OCD.\n\nThe aims of this case report were to support the role of pharmacogenomic testing in psychiatry, especially in TRD patients, and to evaluate the effects of intranasal esketamine in the treatment of TRD with comorbid OCD.\n\nCase presentation\n\nWe hereby present the case of M.G., a 39-year-old male married engineer, who presented at our clinic for a major depressive episode in the context of a TRD. He had a positive psychiatric family history, since his mother suffered from MDD, while his father had an alcohol use disorder.\n\nMDD onset in this patient had occurred at the age of 27, with a substantial recovery with the introduction of sertraline (50 mg/day) in combination with psychodynamic psychotherapy.\n\nDespite a long disease-free period, in 2019, after his first son’s birth, M.G. experienced a relapse of MDD, characterized by a significant mood deflection, emotional lability, and severe fatigue. Hence, multiple pharmacological trials were made (Table 1), with only partial benefit (Fig. 1).Table 1 Psychopharmacological history\n\nYear\tMedication\tDose\tDuration\tNotes\t\n2013\tSertraline\t50 mg\t5 years\tRecovery (primary treatment)\t\n2018\tSertraline\t200 mg\t6 months\tPartial response (primary treatment)\t\n03/2019\tRisperidone\t2 mg\t2 months\tStopped because of cognitive impairment (augmentation)\t\n05/2019\tAripiprazole\t5 mg\t5 months\tStopped because of cognitive impairment (augmentation)\t\n10/2019\tParoxetine\t40 mg\t6 months\tNo response (primary treatment, switched from Sertraline)\t\n10/2019\tBupropion\t300 mg\tOngoing\tPartial response (combination)\t\n01/2020\tOlanzapine\t5 mg\tOngoing\tPartial response (combination)\t\n01/2020\tLamotrigine\t150 mg\tOngoing\tPartial response (primary treatment)\t\n06/2020\tVenlafaxine\t225 mg\tOngoing\tPartial response (primary treatment)\t\n\nFig. 1 Mood variations from the first MDD episode to present\n\nIn November 2020, due to the persistence of depressive symptoms, M.G. was referred to our Treatment-Resistant Disorders Clinic at San Gerardo Hospital, Monza, Italy by his private psychiatrist. During our first assessment, M.G. reported the persistence of anhedonia, low energy, asthenia, remarkable levels of anxiety and cognitive impairment (e.g.: persistent poor concentration and attentional deficits), which led to poor performance at work. The patient also reported to be emotionally detached from his family, friends, and environment.\n\nTogether with typical MDD symptoms, M.G. showed disabling symptoms related to OCD spectrum that led to the additional diagnosis of OCD according to the DSM-5 criteria [27, 28].\n\nIndeed, over the last 2 years the patient had developed intrusive and egodystonic obsessions, consisting mainly in pathological doubts regarding his wife. Specifically, even if physically attracted to his partner, he felt forced to spend a considerable amount of time engaged in mental rituals, consisting of repetitively glancing at his partner to check her body features, such as her nose or chin and subsequently questioning himself about the meaning of these compulsions (e.g.: “Am I continuously checking her chin or nose because I don’t love her anymore?”, “I like her, so why do I have so many doubts about her?”). Such obsessive preoccupations, intrusive thoughts and rituals are what is commonly referred to as relationship obsessive–compulsive disorder [8, 29].\n\nIn addition, he also reported the presence of ritualistic intrusive and pervasive doubts regarding his mental health conditions. This implied the need to perform time-consuming mental rituals every morning (e.g.: independently from his psychopathological state, he used to repeat analytic checklists monitoring his conditions with precise order: “Am I feeling alright?”, “Am I depressed?”, “Am I happy?”, “Why did I cry?”, “Is it depression or something else?”, “If I feel I have little strength, does it mean that I am depressed?”).\n\nWhen M.G. first came to our clinic, his therapy consisted of venlafaxine 225 mg/die, bupropion 300 mg/die, lamotrigine 150 mg/die, and olanzapine 5 mg/die.\n\nIn line with our Treatment-Resistant Disorders clinic protocol, clinical consultation, psychometric assessment (Table 2), Therapeutic Drug Monitoring (TDM) (Table 3) and Pharmacogenomic analysis were performed (Table 4).Table 2 Psychometric assessment at first consultation\n\nRating scale\tScore\t\nBPRS\t27\t\nMADRS\t15\t\nYBOCS\t15\t\nCGI-S\t3\t\nBPRS Brief Psychiatric Rating Scale, MADRS Montgomery-Åsberg Depression Rating Scale, YBOCS Yale–Brown obsessive–compulsive scale, CGI-S clinical global impression-severity\n\nTable 3 Therapeutic drug monitoring of venlafaxine at first consultation\n\nMedication\tBlood level\tTherapeutic range*\t\nVenlafaxine\t484.5 ng/mL\t100–400 ng/mL\t\nSerum level of venlafaxine is measured as a level of venlafaxine active moiety (venlafaxine + 0-desmethylvenlafaxine). Method: LC–MS (Liquid chromatography–mass spectrometry). *According to Hiemke et al. [30]\n\nTable 4 Pharmacodynamic (A) and pharmacokinetic (B) gene variations\n\nGene\tGenotype\t\n(A)\t\t\nSLC6A4\n\n(rs63749047;\n\nrs25531)\n\n\tS/S\n\n[Low activity]\n\n\t\nMTHFR\n\n(rs1801133;\n\nrs1801131)\n\n\tC677T: C/T\n\nA1298C: A/C\n\n[Low to intermediate activity]\n\n\t\nADRA2A\n\n(rs1800544)\n\n\tC/G\n\n[Improved response]\n\n\t\nHTR2A\n\n(rs7997012)\n\n\tG/A\n\n[Normal response]\n\n\t\nBDNF\n\n(rs6265)\n\n\tVal/Val\n\n[Normal activity]\n\n\t\nCOMT\n\n(rs4680)\n\n\tVal/Met\n\n[Normal activity]\n\n\t\nHLA-A *31:01\tNegative\n\n[Normal]\n\n\t\nHLA-B *15:02\tNegative\n\n[Normal]\n\n\t\nDRD2\n\n(rs1799732)\n\n\tC/C\n\n[Normal activity]\n\n\t\nMC4R\n\n(rs489693)\n\n\tC/A\n\n[Normal activity]\n\n\t\n5HT2C\n\n(rs3813929)\n\n\tC/C\n\n[Standard weight gain risk]\n\n\t\nANK3\n\n(rs10994336)\n\n\tC/C\n\n[Normal activity]\n\n\t\nCACNA1C\n\n(rs1006737)\n\n\tG/G\n\n[Normal activity]\n\n\t\nOPRM1\n\n(rs1799971)\n\n\tA/A\n\n[Normal activity]\n\n\t\nGRIK1\n\n(rs2832407)\n\n\tA/A\n\n[Normal activity]\n\n\t\nGABRA6\n\n(rs3219151)\n\n\tT/T\n\n[Increased risk]\n\n\t\nGABRP\n\n(rs10036156)\n\n\tT/T\n\n[Increased risk]\n\n\t\n(B)\t\t\nCYP2B6\t*4/*5\n\nRM\n\n[High activity]\n\n\t\nCYP2C19\t*1/*17\n\nRM\n\n[High activity]\n\n\t\nCYP2D6\t*2/*4\n\nIM\n\n[Intermediate activity]\n\n\t\nUGT2B15\n\n(rs1902023)\n\n\t*2/*2\n\nIM\n\n[Decreased activity]\n\n\t\nCYP1A2\t*1A/H8\n\nEM\n\n[Normal activity]\n\n\t\nCYP2C9\t*1/*1\n\nEM\n\n[Normal activity]\n\n\t\nCYP3A4\t*1/*1\n\nEM\n\n[Normal activity]\n\n\t\nUGT1A4\n\n(rs2011425)\n\n\t*1a/*1a\n\nEM\n\n[Normal activity]\n\n\t\nABCB1\n\n(rs2032583)\n\n\tA/A\n\n[Normal activity]\n\n\t\nABCB1\n\n(rs1045642)\n\n\tG/G\n\n[Normal activity]\n\n\t\nIn the table pharmacodynamic as well as pharmacokinetic gene polymorphisms are listed along with a brief interpretation. RM rapid metabolizer, EM extensive (normal) metabolizer, IM intermediate metabolizer\n\nEven though the patient resulted to have moderate depressive and obsessive symptomatology at psychometric evaluations, the patient’s quality of life was deeply affected, as he suffered from frequent crying fits, inability to concentrate at work and to engage in leisurable activities. Following the clinical interview, the patient was diagnosed with TRD with OCD symptoms and enrolled for intranasal esketamine treatment. A standard administration scheme was followed (Table 5), maintaining current patient treatment.Table 5 Esketamine administration scheme\n\nPhase\tPeriod\tFrequency of administration\tDose\t\nInduction\tFirst month\t2 times/week\t56 mg\t\nMaintenance\tSecond month\t1 time/week\t56 mg\t\nMaintenance\tThird month and longer\t1 time/2 weeks\t56 mg\t\n\nAs a result of esketamine introduction, the patient showed a rapid resolution of depressive symptoms during the induction phase and a significant reduction of OCD symptoms during the maintenance phase (Fig. 2).Fig. 2 Variations of psychometric scales score. BPRS Brief Psychiatric Rating Scale, MADRS Montgomery-Åsberg Depression Rating Scale, YBOCS Yale–Brown obsessive–compulsive scale\n\nBy the time of the ninth esketamine administration, in consideration of the evident clinical improvement, olanzapine and lamotrigine were stopped after appropriate tapering. Some residual anxious symptoms were managed thanks to the introduction of pregabalin titrated up to 225 mg/die with further clinical benefit.\n\nConclusions and discussion\n\nThe present case report emphasizes the need for thorough diagnostic investigation to optimize the management of treatment-resistant cases. Indeed, TDM and genetic profiling are of relevant importance to determine optimal treatment.\n\nIn this case, serum levels of venlafaxine were 484.4 ng/mL, which is above the therapeutic range according to the TDM guidelines in neuropsychopharmacology [30]. Thus, the abnormal biotransformation of the drug was not considered as an explanation for the treatment resistance.\n\nConsidering the results of pharmacogenomic analysis, the presence of 2 common single nucleotide polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene in this patient, specifically C677T and A1298C, might have contributed to his vulnerability to psychiatric disorders. MTHFR is an enzyme catalyzing the conversion of folic acid into its active form, methylfolate, which plays an essential role in monoamine biosynthesis [31]. T allele in C677T and C allele in A1298C might lead to decreased enzymatic activity, thus, as previously reported, an increased risk of affective disorders, such as MDD or other psychiatric disorders [32–34].\n\nIn addition, the genetic profiling also showed the S/S 5-HTTLPR genotype in SLC6A4 gene. SLC6A4 is a serotonin transporter responsible for serotonin reuptake. Such variations (s allele), previously described in the literature, are linked to decreased serotonin transporter expression in neurons, leading to higher susceptibility to depression, as well as poorer response to Selective serotonin reuptake inhibitors (SSRIs) [35–38]. This might also explain the patient's non-response to previous treatments with first-line antidepressants.\n\nA prominent role in the brain control of stress plays GABA [39]. GABRA6 gene encodes the alpha6 subunit of GABA-A receptor and, according to previous studies, when exposed to recent negative stressful events, T allele carriers were at greater risk of depression- and anxiety-related symptoms which could also enhance suicidal risk [40]. Another study looked at the different types of recent life stressors and found that T/T genotype in patients, which was present in this case, interacts significantly with recent illness and personal problems stressors in influencing depression [41]. C allele carriers of another gene related to GABA, pi subunit of the GABA-A receptor (GABRP), were associated with good response to single antidepressant (either SSRI or venlafaxine) administered for at least 6 weeks [42]. In our patient the T/T genotype was found, representing a possible factor to his treatment refractoriness.\n\nIn addition, the patient was a CYP2B6 and CYP2C19 rapid metabolizer, potentially contributing to the inefficacy of bupropion and other SSRI. The predominant metabolic pathway of bupropion that leads to formation of its active metabolite hydroxybupropion is CYP2B6 enzyme-mediated. In case of rapid metabolizers, the therapeutic outcome of bupropion therapy is strongly affected [43].\n\nMoreover, this case not only validates the rapidity of esketamine in reverting depressive symptoms, but it also shows encouraging findings about the possible use of esketamine in treating OCD symptoms.\n\nIndeed, during the maintenance phase, the patient showed a significant reduction in his OCD symptomatology as showed by the Yale–Brown Obsessive–Compulsive Disorder (YBOCS) score reduction (Fig. 2, green line): after initial symptoms’ worsening due to a new-onset pathological doubt regarding treatment efficacy and side effects, the YBOCS score showed a 46.67% reduction (from 15 to 8). Since the pre-existing pharmacological treatment was not changed at our clinic, the reduction of the OCD symptoms might be directly referred to the use of esketamine.\n\nIt is worth noting that the time-ratio required to relieve OCD symptomatology maintained the 3:1 ratio usually seen with the use of serotonergic antidepressants [44, 45].\n\nLiterature regarding the possible use of ketamine in OCD remains sparse with some pre-clinical [46] and clinical studies [25, 26] showing a rapid reduction of OCD symptoms after the drug administration. Specifically, human studies indicated that ketamine could quickly and transiently decrease OCD behaviors. Nonetheless, these studies showed multiple limitations, mainly regarding small sample sizes and short-term observations. Thus, further investigation in the form of double-blind, randomized controlled trials is warranted.\n\nAbbreviations\n\nMDD Major depressive disorder\n\nNMDA N-Methyl-d-aspartate\n\nOCD Obsessive–compulsive disorder\n\nPGx Pharmacogenomic testing\n\nSSRI Selective serotonin reuptake inhibitors\n\nTDM Therapeutic drug monitoring\n\nTRD Treatment resistant depression\n\nYBOCS Yale–Brown obsessive–compulsive disorder\n\nAcknowledgements\n\nWe would like to pay our gratitude and our respects to our friend and colleague, Dr. Matteo Sibilla. After contributing to this paper, Dr. Matteo Sibilla passed away in August of 2021. He was a dedicated clinician, a passionate researcher and an outstanding colleague. He will be deeply missed.\n\nAuthors' contributions\n\nMM, NR, CF, PC, ML, MF, RC, SM, and GL were responsible for clinical consultations, psychometric analyses, and esketamine administrations. BF, VN, and PA were responsible for pharmacogenetic analyses along with MM and KM for their interpretation. IS performed TDM analysis. Major contributors for writing the report were MM, PC, ML, MF, RC, GL, and KM. The final revision was made by MM, BB, CA, CE, DA, and CM. All authors read and approved the final manuscript.\n\nFunding\n\nThis work has been supported by a grant (n° 2019–3396 to DA) from the Italian Cariplo Foundation, which had not any involvement in manuscript preparation, or decision to submit the article for publication.\n\nDeclarations\n\nAvailability of data and materials\n\nThe data sets generated and/or analysed during the current study are not publicly available due to privacy reasons.\n\nEthics approval and consent to participate\n\nWritten informed consent for the use of the anonymous clinical data was obtained.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Rehm J Shield KD Global burden of disease and the impact of mental and addictive disorders Curr Psychiatry Rep 2019 21 2 10 10.1007/s11920-019-0997-0 30729322\n2. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017 Lancet 2018 392 10159 1789 1858 10.1016/S0140-6736(18)32279-7 30496104\n3. Rush AJ Trivedi MH Wisniewski SR Nierenberg AA Stewart JW Warden D Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report Am J Psychiatry 2006 163 11 1905 1917 10.1176/ajp.2006.163.11.1905 17074942\n4. Gaynes BN Lux L Gartlehner G Asher G Forman-Hoffman V Green J Defining treatment-resistant depression Depress Anxiety 2020 37 2 134 145 10.1002/da.22968 31638723\n5. Papakostas GI Ionescu DF Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder Mol Psychiatry 2015 20 10 1142 1150 10.1038/mp.2015.92 26148812\n6. Bolhuis K Mcadams TA Monzani B Gregory AM Mataix-Cols D Stringaris A Aetiological overlap between obsessive-compulsive and depressive symptoms: a longitudinal twin study in adolescents and adults Psychol Med 2014 44 7 1439 1449 10.1017/S0033291713001591 23920118\n7. Denys D Tenney N van Megen HJGM de Geus F Westenberg HGM Axis I and II comorbidity in a large sample of patients with obsessive–compulsive disorder J Affect Disord 2004 80 2–3 155 162 10.1016/S0165-0327(03)00056-9 15207928\n8. Quarantini LC Torres AR Sampaio AS Fossaluza V de Mathis MA do Rosário MC Comorbid major depression in obsessive-compulsive disorder patients Compr Psychiatry 2011 52 4 386 393 10.1016/j.comppsych.2010.09.006 21087765\n9. de Almeida AG Quarantini LC Góis CR Santos-Jesus R Miranda-Scippa ÂMA de Oliveira IR Obsessive-compulsive disorder: an open-label pilot trial of escitalopram CNS Spectr 2007 12 7 519 524 10.1017/S1092852900021258 17603402\n10. McGrath PJ Khan AY Trivedi MH Stewart JW Morris DW Wisniewski SR Response to a selective serotonin reuptake inhibitor (citalopram) in major depressive disorder with melancholic features: a STAR*D report J Clin Psychiatry 2008 69 12 1847 1855 10.4088/JCP.v69n1201 19026268\n11. Moritz S Meier B Hand I Schick M Jahn H Dimensional structure of the Hamilton Depression Rating Scale in patients with obsessive-compulsive disorder Psychiatry Res 2004 125 2 171 180 10.1016/j.psychres.2003.11.003 15006440\n12. Rosenberg DR Macmaster FP Keshavan MS Fitzgerald KD Stewart CM Moore GJ Decrease in caudate glutamatergic concentrations in pediatric obsessive–compulsive disorder patients taking paroxetine J Am Acad Child Adolesc Psychiatry 2000 39 9 1096 1103 10.1097/00004583-200009000-00008 10986805\n13. Rosenberg DR Mirza Y Russell A Tang J Smith JM Banerjee SP Reduced anterior cingulate glutamatergic concentrations in childhood OCD and major depression versus healthy controls J Am Acad Child Adolesc Psychiatry 2004 43 9 1146 1153 10.1097/01.chi.0000132812.44664.2d 15322418\n14. Chakrabarty K Bhattacharyya S Christopher R Khanna S Glutamatergic dysfunction in OCD Neuropsychopharmacology 2005 30 9 1735 1740 10.1038/sj.npp.1300733 15841109\n15. Yücel M Wood SJ Wellard RM Harrison BJ Fornito A Pujol J Anterior cingulate glutamate-glutamine levels predict symptom severity in women with obsessive–compulsive disorder Aust N Z J Psychiatry 2008 42 6 467 477 10.1080/00048670802050546 18465373\n16. Starck G Ljungberg M Nilsson M Jönsson L Lundberg S Ivarsson T A 1H magnetic resonance spectroscopy study in adults with obsessive compulsive disorder: relationship between metabolite concentrations and symptom severity J Neural Transm 2008 115 7 1051 1062 10.1007/s00702-008-0045-4 18528631\n17. Bhattacharyya S Khanna S Chakrabarty K Mahadevan A Christopher R Shankar SK Anti-brain autoantibodies and altered excitatory neurotransmitters in obsessive–compulsive disorder Neuropsychopharmacology 2009 34 12 2489 2496 10.1038/npp.2009.77 19675532\n18. Pittenger C Bloch MH Williams K Glutamate abnormalities in obsessive compulsive disorder: neurobiology, pathophysiology, and treatment Pharmacol Ther 2011 132 3 314 332 10.1016/j.pharmthera.2011.09.006 21963369\n19. Hashimoto K Rapid-acting antidepressant ketamine, its metabolites and other candidates: a historical overview and future perspective Psychiatry Clin Neurosci 2019 73 10 613 627 10.1111/pcn.12902 31215725\n20. Jelen LA Young AH Stone JM Ketamine: a tale of two enantiomers J Psychopharmacol 2021 35 2 109 123 10.1177/0269881120959644 33155503\n21. Duman RS Aghajanian GK Sanacora G Krystal JH Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants Nat Med 2016 22 3 238 249 10.1038/nm.4050 26937618\n22. Lener MS Niciu MJ Ballard ED Park M Park LT Nugent AC Glutamate and gamma-aminobutyric acid systems in the pathophysiology of major depression and antidepressant response to ketamine Biol Psychiatry 2017 81 10 886 897 10.1016/j.biopsych.2016.05.005 27449797\n23. Rodriguez CI Kegeles LS Flood P Simpson HB Rapid resolution of obsessions after an infusion of intravenous ketamine in a patient with treatment-resistant obsessive-compulsive disorder J Clin Psychiatry 2011 72 4 567 569 10.4088/JCP.10l06653 21527129\n24. Bloch MH Wasylink S Landeros-Weisenberger A Panza KE Billingslea E Leckman JF Effects of ketamine in treatment-refractory obsessive–compulsive disorder Biol Psychiatry 2012 72 11 964 970 10.1016/j.biopsych.2012.05.028 22784486\n25. Rodriguez CI Kegeles LS Levinson A Feng T Marcus SM Vermes D Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept Neuropsychopharmacology 2013 38 12 2475 2483 10.1038/npp.2013.150 23783065\n26. Sharma LP Thamby A Balachander S Janardhanan CN Jaisoorya TS Arumugham SS Clinical utility of repeated intravenous ketamine treatment for resistant obsessive-compulsive disorder Asian J Psychiatr 2020 52 102183 10.1016/j.ajp.2020.102183 32554207\n27. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5). 2013. 10.1176/appi.books.9780890425596\n28. Franklin ME Budzyn S Freeman H Olatunji BO OCD Spectrum Disorders The Cambridge handbook of anxiety and related disorders 2019 Cambridge Cambridge University Press 603 623\n29. Doron G Derby D Szepsenwol O Nahaloni E Moulding R Relationship obsessive–compulsive disorder: interference, symptoms, and maladaptive beliefs Front Psychiatry 2016 7 58 10.3389/fpsyt.2016.00058 27148087\n30. Hiemke C Bergemann N Clement HW Conca A Deckert J Domschke K Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017 Pharmacopsychiatry 2018 51 1–02 9 62 28910830\n31. Stahl SM L-methylfolate: a vitamin for your monoamines J Clin Psychiatry 2008 69 9 1352 1353 10.4088/JCP.v69n0901 19193337\n32. López-León S Janssens ACJW González-Zuloeta Ladd AM Del-Favero J Claes SJ Oostra BA Meta-analyses of genetic studies on major depressive disorder Mol Psychiatry 2008 13 8 772 785 10.1038/sj.mp.4002088 17938638\n33. Peerbooms OLJ van Os J Drukker M Kenis G Hoogveld L de Hert M Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability? Brain Behav Immun 2011 25 8 1530 1543 10.1016/j.bbi.2010.12.006 21185933\n34. Evinova A Babusikova E Straka S Ondrejka I Lehotsky J Analysis of genetic polymorphisms of brain-derived neurotrophic factor and methylenetetrahydrofolate reductase in depressed patients in a Slovak (Caucasian) population Gen Physiol Biophys 2012 31 4 415 422 10.4149/gpb_2012_049 23255668\n35. Zanardi R Serretti A Rossini D Franchini L Cusin C Lattuada E Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-HTTLPR in delusional and nondelusional depression Biol Psychiatry 2001 50 5 323 330 10.1016/S0006-3223(01)01118-0 11543734\n36. Arias B Catalán R Gastó C Gutiérrez B Fañanás L 5-HTTLPR polymorphism of the serotonin transporter gene predicts non-remission in major depression patients treated with citalopram in a 12-weeks follow up study J Clin Psychopharmacology 2003 23 6 563 567 10.1097/01.jcp.0000095350.32154.73\n37. Serretti A Cusin C Rossini D Artioli P Dotoli D Zanardi R Further evidence of a combined effect of SERTPR and TPH on SSRIs response in mood disorders Am J Med Genet Neuropsychiatr Genet 2004 129B 1 36 40 10.1002/ajmg.b.30027\n38. Cervilla JA Rivera M Molina E Torres-González F Bellón JA Moreno B The 5-HTTLPR s/s genotype at the serotonin transporter gene (SLC6A4) increases the risk for depression in a large cohort of primary care attendees: the PREDICT-gene study Am J Med Genet B Neuropsychiatr Genet 2006 141B 8 912 917 10.1002/ajmg.b.30455 17063469\n39. Luscher B Shen Q Sahir N The GABAergic deficit hypothesis of major depressive disorder Mol Psychiatry 2011 16 4 383 406 10.1038/mp.2010.120 21079608\n40. Gonda X Sarginson J Eszlari N Petschner P Toth ZG Baksa D A new stress sensor and risk factor for suicide: the T allele of the functional genetic variant in the GABRA6 gene Sci Rep 2017 7 1 12887 10.1038/s41598-017-12776-8 29018204\n41. Gonda X Petschner P Eszlari N Sutori S Gal Z Koncz S Effects of different stressors are modulated by different neurobiological systems: the role of GABA-A versus CB1 receptor gene variants in anxiety and depression Front Cell Neurosci 2019 13 138 10.3389/fncel.2019.00138 31024264\n42. Pu M Zhang Z Xu Z Shi Y Geng L Yuan Y Influence of genetic polymorphisms in the glutamatergic and GABAergic systems and their interactions with environmental stressors on antidepressant response Pharmacogenomics 2013 14 3 277 288 10.2217/pgs.13.1 23394390\n43. Tran AX Ho TT Varghese GS Role of CYP2B6 pharmacogenomics in bupropion-mediated smoking cessation J Clin Pharm Ther 2019 44 2 174 179 10.1111/jcpt.12783 30578565\n44. Pittenger C Bloch MH Pharmacological treatment of obsessive-compulsive disorder Psychiatr Clin North Am 2014 37 3 375 391 10.1016/j.psc.2014.05.006 25150568\n45. Kayser RR Pharmacotherapy for treatment-resistant obsessive–compulsive disorder J Clin Psychiatry 2020 81 5 19ac13182 10.4088/JCP.19ac13182 32926602\n46. Tosta CL Silote GP Fracalossi MP Sartim AG Andreatini R Joca SRL S-ketamine reduces marble burying behaviour: involvement of ventromedial orbitofrontal cortex and AMPA receptors Neuropharmacology 2019 144 233 243 10.1016/j.neuropharm.2018.10.039 30385254\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1744-859X",
"issue": "20(1)",
"journal": "Annals of general psychiatry",
"keywords": "Esketamine; GABRA6; GABRP; Ketamine; MTHFR; OCD; Obsessive–compulsive disorder; SLC6A4; TRD; Treatment resistant depression",
"medline_ta": "Ann Gen Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101236515",
"other_id": null,
"pages": "43",
"pmc": null,
"pmid": "34530843",
"pubdate": "2021-09-16",
"publication_types": "D016428:Journal Article",
"references": "27449797;19193337;23920118;11543734;17074942;17603402;21963369;30729322;19675532;31638723;15207928;21087765;23255668;27148087;18528631;21185933;22784486;14624186;23394390;29018204;15006440;17063469;30385254;21527129;30496104;19026268;15841109;26937618;15274037;21079608;31024264;18465373;32926602;28910830;17938638;30578565;33155503;31215725;10986805;25150568;15322418;23783065;32554207;26148812",
"title": "The use of esketamine in comorbid treatment resistant depression and obsessive compulsive disorder following extensive pharmacogenomic testing: a case report.",
"title_normalized": "the use of esketamine in comorbid treatment resistant depression and obsessive compulsive disorder following extensive pharmacogenomic testing a case report"
} | [
{
"companynumb": "IT-MLMSERVICE-20220304-3415229-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": "1",... |
{
"abstract": "We encountered a 59-year-old man who first underwent left internal carotid endarterectomy for left internal carotid artery stenosis and then presented with postoperative swelling of the bilateral salivary glands. He then developed upper airway obstruction that required emergency tracheal intubation. The most likely cause was thought to be anesthesia mumps, which involves a complex interaction of multiple factors including pneumoparotitis, venous congestion, and excess saliva secretion. Many cases of salivary gland swelling recover after follow-up observation alone if there are no inflammatory findings; however, severe complications may sometimes occur. If upper airway obstruction develops as in the present case, then emergency airway management must also be considered and conscientious observation is necessary.",
"affiliations": "Department of Anesthesiology, Jikei University School of Medicine, Nishi-shinbashi 3-19-18, Minato-ku, Tokyo, Japan. yoiko0223@yahoo.co.jp.;Department of Anesthesiology, Jikei University School of Medicine, Nishi-shinbashi 3-19-18, Minato-ku, Tokyo, Japan.;Department of Anesthesiology, Jikei University School of Medicine, Nishi-shinbashi 3-19-18, Minato-ku, Tokyo, Japan.",
"authors": "Hamaguchi|Takayuki|T|http://orcid.org/0000-0003-4358-028X;Suzuki|Naho|N|;Kondo|Ichiro|I|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1186/s40981-018-0159-0",
"fulltext": "\n==== Front\nJA Clin RepJA Clin RepJA Clinical Reports2363-9024Springer Berlin Heidelberg Berlin/Heidelberg 15910.1186/s40981-018-0159-0Case ReportA case of anesthesia mumps that required postoperative re-intubation http://orcid.org/0000-0003-4358-028XHamaguchi Takayuki +81-03-3433-1111yoiko0223@yahoo.co.jp Suzuki Naho Kondo Ichiro 0000 0001 0661 2073grid.411898.dDepartment of Anesthesiology, Jikei University School of Medicine, Nishi-shinbashi 3-19-18, Minato-ku, Tokyo, Japan 26 2 2018 26 2 2018 12 2018 4 2219 12 2017 20 2 2018 © The Author(s) 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.We encountered a 59-year-old man who first underwent left internal carotid endarterectomy for left internal carotid artery stenosis and then presented with postoperative swelling of the bilateral salivary glands. He then developed upper airway obstruction that required emergency tracheal intubation. The most likely cause was thought to be anesthesia mumps, which involves a complex interaction of multiple factors including pneumoparotitis, venous congestion, and excess saliva secretion. Many cases of salivary gland swelling recover after follow-up observation alone if there are no inflammatory findings; however, severe complications may sometimes occur. If upper airway obstruction develops as in the present case, then emergency airway management must also be considered and conscientious observation is necessary.\n\nKeywords\nAnesthesia mumpsSalivary gland swellingParotid gland swellingUpper airway obstructionissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nAnesthesia mumps consists of acute and transient salivary gland swelling caused by general anesthesia. It is an extremely rare postoperative complication and occurs following various surgical procedures. It is usually a self-limiting disease and requires only follow-up observation [1, 2], and in few case reports, evaluation with imaging studies have been performed.\n\nWe encountered a patient who required emergency tracheal intubation due to upper airway obstruction after anesthesia mumps following an internal carotid artery (ICA) endarterectomy (CEA). We include discussion on imaging evaluation—since preoperative and postoperative neck computed tomography (CT) images were available for this patient partly because neck surgery was performed—and a brief literature review.\n\nCase presentation\nA 59-year-old man (170 cm, 78 kg) had cerebral infarction of the right precentral gyrus 2 years prior presentation and was diagnosed with bilateral ICA stenosis. He was treated conservatively (oral cilostazol and clopidogrel) and followed up; however, the stenosis of the left ICA progressed. Therefore, he was scheduled for CEA. There were no apparent complications related to his previous cerebral infarction. He was receiving an oral treatment for hypertension and dyslipidemia and had a long history of smoking (40 cigarettes per day for 40 years). There were no other notable findings in preoperative examinations. On the day of surgery, he was admitted to the operating room without premedication. Pre-oxygenation was performed using a mask without headband. Anesthesia was induced using 200 μg fentanyl and 5 mg midazolam, and 60 mg rocuronium was given to facilitate tracheal intubation. A Macintosh laryngoscope was used to expose the larynx. The view was classified as Cormack III. We attempted a tracheal intubation with a endotracheal tube (Shiley™ Endotracheal Tube with TaperGuard™ Cuff 7.5 mm), but the esophagus was inadvertently intubated, so it was removed. The second tracheal intubation by using a Macintosh laryngoscope was successful. Wheals appeared on the upper limbs, neck, and precordium without any vital sign changes after infusion of cefazolin sodium as a preoperative antibiotic, so administration was discontinued. The skin signs were believed to be an allergic reaction to cefazolin, which was changed to fosfomycin, and the patient also received an intravenous infusion containing 200 mg of hydrocortisone sodium phosphate. During surgery, he was placed in the supine position, but the neck was slightly rotated and lateroflexed to the right to secure the surgical field. Anesthesia was maintained with 1.4% sevoflurane and remifentanil at a dose of 0.2 μg/kg/min. Mild hypotension was observed intraoperatively. This was managed with fluid infusions and continuous administration of an appropriate dose of noradrenaline. Surgery was concluded without problems, and the preoperatively observed wheals resolved. Endotracheal aspiration was performed after waking up the patient, but it triggered a strong cough reflex. The patient was then extubated. The duration of surgery was 4 h and 57 min, the duration of anesthesia was 6 h and 29 min, the volume of blood loss was negligible, the in-out balance was + 3210 mL (crystalloid fluid 4175 mL, urine volume 965 mL), and mild swelling of the face and both upper limbs was noted. The patient was admitted to the intensive care unit (ICU) in a lucid state with a blood pressure of 120/70 mmHg, a heart rate of 110 beats/min, oxygen saturation of 100% on 3 L of nasal oxygen and respiratory rate of 12 breaths/min. His arterial blood gas analysis was normal, and mild hoarseness was noted without swelling of the neck or stridor. Six hours after admission to the ICU mild bilateral neck swelling appeared. The hoarseness rapidly worsened, and tachypnea and stridor appeared 1 h later without oxygen desaturation. Emergency intubation with a tube (Shiley™ Evac Endotracheal Tube with TaperGuard™ Cuff 7.5 mm) was immediately performed with mild sedation with propofol under spontaneous breathing on suspicion of upper airway obstruction. We used a video laryngoscope (HOYA Co. Ltd., airway scope) with a gum elastic bougie tube introducer. Laryngopharyngeal findings at this time included no epiglottic edema. However, the edema of the lateral and posterior pharyngeal walls was present, and it narrowed the oral and pharyngeal cavities. The neck swelling was pronounced, and the neck circumference was 63 cm (Fig. 1). A CT scan was performed to investigate the cause and to facilitate differential diagnosis of possible postoperative hemorrhage, but no bleeding was observed. The bilateral parotid and salivary glands were markedly swollen (Fig. 2), and the edema of the posterior pharyngeal wall was developed (Fig. 3) when compared to the preoperative state. Blood test results revealed a leukocyte count of 8000/μL (eosinophils 0%), amylase at 1790 U/L, mumps immunoglobulin G (IgG) at 16.6 (+), mumps IgM at 0.27 (−), and C-reactive protein at 0.18. Based on these findings, we concluded that the patient had previously suffered from a mumps infection, but had no active disease. Moreover, he only presented with the clinical features of sialadenitis. We commenced administration of steroids to reduce the edema. On postoperative day (POD) 2, the serum amylase decreased to 457 U/L, gradual improvement of the bilateral parotid gland swelling was observed, and the patient was extubated. The subsequent clinical course was favorable, and the neck swelling disappeared. The general condition, airways, and ability to swallow were all normal when the patient was discharged on POD 11.Fig. 1 Photograph showing the swelling of his neck 7 h after the operation\n\nFig. 2 Post-operative image of computed tomography scans at the parotid glands level shows the bilateral parotid glands were swollen compared to the pre-operative state\n\nFig. 3 Post-operative image of computed tomography scans shows the edema of the posterior pharyngeal wall was developed compared to the pre-operative state\n\n\n\nConclusions\nIn this case, emergency intubation was performed because upper airway obstruction strongly suspected due to expiratory stridor and rapidly worsen dyspnea. His neck was bilaterally swelling and CT showed the bilateral parotid glands swelling and the edema of the posterior pharyngeal wall without hematoma around surgical site. Blood test indicated serum amylase was abnormally elevated. Thus, we diagnosed upper airway obstruction due to the anesthesia mumps. Furthermore, he developed an allergic reaction, which might have caused or intensified the edematous changes in the pharyngeal wall. This might be one of the etiologies that caused upper airway obstruction.\n\nAnesthesia mumps is considered to be an extremely rare complication. According to reports in the literature, its occurrence is highly variable (0.2–17%) [3–5], and the exact incidence remains unknown. Although patients can develop postoperative salivary gland swelling, it is typically mild, with few subjective symptoms. Therefore, many cases resolve spontaneously without being noticed. Thus, we believe that the discrepancies in the incidence rate are largely due to variable amount of attention that is paid to this condition.\n\nThe cause and detailed pathophysiology of anesthesia mumps remains unknown, but salivary duct occlusion, sialorrhea, venous congestion and venostasis, involvement of the autonomic nerves, and side effects of medications have been suggested [5, 6].\n\nCauses of salivary gland obstruction include (1) physical compression by lateral position, positions that rotate and flex the neck, compression by endotracheal tubes, mucosal lesions and edema; (2) pneumoparotitis induced by the penetration of air as a result of retrograde flow into the salivary duct due to positive pressure in the oral cavity by mask ventilation, pharyngeal reflex, and cough reflex; and (3) dehydration, administration of atropine, and sympathetic nervous system activation due to invasiveness of surgery causing increased salivary viscosity, which may in turn itself cause an occlusion.\n\nSalivation is mediated by the autonomic nerves, and the main secretory innervation is parasympathetic. Intratracheal manipulation stimulates parasympathetic nerves that mediate the pharyngeal reflex, which promotes salivation and leads to vasodilation and hyperemia in the salivary gland [2]. Stimulation of the sympathetic nerves also evokes salivation, but it is relatively short-lasting, the saliva is usually thick and mucinous, and vasoconstriction occurs [7]. Actually, noradrenaline infusion increases salivary alpha-amylase, a digestive enzyme secreted from the salivary glands that has been proposed as a sensitive surrogate maker for activity stress [8].\n\nIn the present case, we observed bilateral swelling of the parotid and submandibular glands. Therefore, we considered it unlikely that there was only a mechanical regional occlusion related to patient positioning and pneumoparotitis. We believe that variety of causes led to development of anesthesia mumps. One of them is a venous congestion due to surgical procedure or stimuli of CEA, and the others are excess secretion of saliva due to reflex salivation, the pharyngeal reflex or continuous administration of noradrenaline. However, the exact causes remain unclear.\n\nSeveral reports state that most cases of anesthesia mumps resolve spontaneously with follow-up observation alone, it has been considered that rehydration therapy and anti-inflammatory drugs if needed are sufficient to treat it [1, 2]. However, there may be cases, such as the present case, in which patients suffer from severe complications, including upper airway obstruction [9, 10]. In our patient, the combined approach of a video laryngoscope and a gum elastic bougie tube introducer resulted in a successful re-intubation without the need for tracheostomy. Emergency tracheostomy might be often chosen because of difficult mask ventilation and the possibility of intubation difficulty for postoperative dyspnea and acute airway obstruction [10]. However, in cases involving massive edema and swelling of the neck, it is difficult to identify the location of the tracheostomy. Video laryngoscopes could well become the standard procedure for these types of patients who need emergency tracheal intubation. Hence, additional measures to treat these conditions are required, and conscientious follow-up observation is necessary.\n\nAbbreviations\nCEACarotid endarterectomy\n\nCTComputed tomography\n\nICAInternal carotid artery\n\nICUIntensive care unit\n\nPODPostoperative day\n\nFunding\nNo funding\n\nAuthors’ contributions\nTH wrote this manuscript. NS helped to revise this manuscript. IK supervised to shape this manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Ozdek A Bayir O Isik ME Tatar EC Saylam G Korkmaz H Anesthesia mumps resulting in temporary facial nerve paralysis after the auditory brainstem implantation in a 3-year-old child Int J Pediatr Otorhinolaryngol 2014 78 159 162 10.1016/j.ijporl.2013.09.030 24290005 \n2. Louis M Farisa S Bilateral parotid swelling: a review Oral Surg Oral Med Oral Pathol 2002 93 221 237 10.1067/moe.2002.119909 \n3. Reilly DJ Benign transient swelling of the parotid glands following general anesthesia: “anesthesia mumps” Anesth Analg 1970 49 560 563 10.1213/00000539-197007000-00009 5534667 \n4. Couper JL Benign transient enlargement of the parotid glands associated with anaesthesia S Afr Med J 1973 47 316 318 4692051 \n5. Matsuki A Wakayama S Oyama T Acute transient swelling of the salivary glands during and following endotracheal anaesthesia Anaesthesist 1975 24 125 128 1147203 \n6. Attas M Sabawala PB Keats AS Acute transient sialadenopathy during induction of anesthesia Anesthesiology 1968 29 1050 1052 10.1097/00000542-196809000-00036 5673133 \n7. Lawrence B Salivary gland enlargement during induction of anesthesia JAMA 1969 209 1716 1718 10.1001/jama.1969.03160240072025 5820172 \n8. Ulrike K Roland K Nadja H Claudia Z Guido S Ulrike E Petra H Norepinephrine infusion with and without alpha-adrenergic blockade by phentolamine increases salivary alpha amylase in healthy men Psychoneuroendocrinology 2014 49 290 298 10.1016/j.psyneuen.2014.07.023 25128931 \n9. Franco C Giorgio C Maria GA Angelo G Alessandro G Rodolfo P Massive facial edema and airway obstruction secondary to acute postoperative sialadenitis or “anesthesia mumps”: case report J Med Case Rep 2009 3 7073 10.1186/1752-1947-3-7073 19830135 \n10. Kiran S Lamba A Chhabra B Acute pansialadenopathy during induction of anesthesia causing airway obstruction Anesth Analg 1997 85 1052 1053 10.1213/00000539-199711000-00016 9356098\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2363-9024",
"issue": "4(1)",
"journal": "JA clinical reports",
"keywords": "Anesthesia mumps; Parotid gland swelling; Salivary gland swelling; Upper airway obstruction",
"medline_ta": "JA Clin Rep",
"mesh_terms": null,
"nlm_unique_id": "101682121",
"other_id": null,
"pages": "22",
"pmc": null,
"pmid": "32025931",
"pubdate": "2018-02-26",
"publication_types": "D016428:Journal Article",
"references": "24290005;4692051;11925529;25128931;5534667;5673133;5820172;19830135;1147203;9356098",
"title": "A case of anesthesia mumps that required postoperative re-intubation.",
"title_normalized": "a case of anesthesia mumps that required postoperative re intubation"
} | [
{
"companynumb": "JP-PFIZER INC-2018118437",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MIDAZOLAM HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Dabigatran is a new direct competitive inhibitor of thrombin and is equally effective and safe as warfarin in the prevention of thromboembolism in patients with nonvalvular atrial fibrillation. We present a case of a 60-year-old man with persistent nonvalvular atrial fibrillation who switched from acenocoumarol to dabigatran 110 mg twice daily. After five months the patient developed a large atrial thrombus, occlusion of the tibial arteries of the right foot, cerebellar infarction and multiple infarctions in kidneys and spleen. Blood test showed a dabigatran concentration of 35 ng/ml six hours after intake, correlating with a low trough concentration of 24-27 ng/mL and significantly increased thromboembolic risk. Other risk factors for thromboembolism were excluded. The present case indicates that in selected patients, there might be an indication for dose adjustments based on serum levels of dabigatran to ensure patient efficacy (thromboembolic events) and safety (bleeding).",
"affiliations": "Department of Internal Medicine, St.Elisabeth-TweeSteden Hospital, Tilburg, the Netherlands.",
"authors": "Janssen|A M|AM|;van de Kerkhof|D|D|;Szabó|B|B|;Durian|M F|MF|;van der Voort|P H|PH|",
"chemical_list": "D000069604:Dabigatran",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2977",
"issue": "74(7)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D001281:Atrial Fibrillation; D000069604:Dabigatran; D004452:Echocardiography; D006325:Heart Atria; D006331:Heart Diseases; D006801:Humans; D008297:Male; D008875:Middle Aged; D013927:Thrombosis; D017211:Treatment Failure",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "313-5",
"pmc": null,
"pmid": "27571947",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Left atrial thrombus under dabigatran in a patient with nonvalvular atrial fibrillation.",
"title_normalized": "left atrial thrombus under dabigatran in a patient with nonvalvular atrial fibrillation"
} | [
{
"companynumb": "NL-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-58023BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
... |
{
"abstract": "Published predictive equations are required when indirect calorimetry (IC) is unavailable in the clinical setting. Several medical conditions that are not accounted for by published predictive equations can impact a patient's resting energy expenditure, such as adrenal changes or alterations in thyroid-stimulating hormone (TSH). TSH levels significantly impact a patient's resting energy expenditure, with hypothyroidism decreasing and hyperthyroidism increasing energy requirements. Clinical hypothyroidism has been correlated with increased ventilator dependency in patients with critical illness and malnutrition. The following case study describes the utilization of IC to trigger a full evaluation for the diagnosis of hypothyroidism in an adult patient with multiple myeloma who was mechanically ventilated. IC results for this patient were 39% lower than estimated by predictive energy equations. TSH, thyroxine, and triiodothyronine serum assays were obtained to rule out hypothyroidism. Based on elevated TSH and low thyroxine, the patient was found to have undiagnosed hypothyroidism. Appropriate pharmaceutical and nutrition interventions were made based upon these results. This case demonstrates the impact hormonal changes can have on resting energy expenditure and how the utilization of IC can provide additional information other than energy requirements.",
"affiliations": "Department of Clinical and Preventive Nutrition Sciences, School of Health Professions, Rutgers University, Newark, New Jersey, USA.;Department of Clinical and Preventive Nutrition Sciences, School of Health Professions, Rutgers University, Newark, New Jersey, USA.",
"authors": "Hahn|Michaelann|M|https://orcid.org/0000-0002-1295-0199;Brody|Rebecca|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/ncp.10653",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0884-5336",
"issue": "36(4)",
"journal": "Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition",
"keywords": "energy expenditure; hypothyroidism; indirect calorimetry; multiple myeloma",
"medline_ta": "Nutr Clin Pract",
"mesh_terms": "D000328:Adult; D002153:Calorimetry, Indirect; D016638:Critical Illness; D004734:Energy Metabolism; D006801:Humans; D007037:Hypothyroidism; D009751:Nutritional Requirements; D012121:Respiration, Artificial",
"nlm_unique_id": "8606733",
"other_id": null,
"pages": "833-838",
"pmc": null,
"pmid": "33689191",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Utilization of indirect calorimetry to assist in determining undiagnosed hypothyroidism in a patient on mechanical ventilation.",
"title_normalized": "utilization of indirect calorimetry to assist in determining undiagnosed hypothyroidism in a patient on mechanical ventilation"
} | [
{
"companynumb": "US-AMGEN-USASP2021152922",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARFILZOMIB"
},
"drugadditional": "3",
... |
{
"abstract": "A previously healthy 49-year-old male patient presented with COVID-19 infection and required mechanical ventilation and extracorporeal membrane oxygenation due to severe hypoxemia. Echocardiography showed cardiac dysfunction with an apical sparing strain pattern, which rapidly normalized within a week. Apical sparing myocardial strain in patients with COVID-19 infection may suggest reverse-type stress cardiomyopathy.",
"affiliations": "Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ, USA.;Department of Cardiovascular Surgery, Mayo Clinic, Scottsdale, AZ, USA.;Department of Critical Care Medicine, Mayo Clinic, Scottsdale, AZ, USA.;Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ, USA.;Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ, USA.;Department of Critical Care Medicine, Mayo Clinic, Scottsdale, AZ, USA.;Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ, USA.;Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ, USA.",
"authors": "Chao|Chieh-Ju|CJ|0000-0001-6155-0266;DeValeria|Patrick A|PA|;Sen|Ayan|A|;Lee|Hong|H|;Pedrotty|Dawn M|DM|;Patel|Bhavesh|B|;Arsanjani|Reza|R|;Naqvi|Tasneem Z|TZ|0000-0002-3160-9025",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/echo.14807",
"fulltext": "\n==== Front\nEchocardiography\nEchocardiography\n10.1111/(ISSN)1540-8175\nECHO\nEchocardiography (Mount Kisco, N.y.)\n0742-2822\n1540-8175\nJohn Wiley and Sons Inc. Hoboken\n\n32856328\n10.1111/echo.14807\nECHO14807\nEcho Rounds\nECHO ROUNDS Section Editors ‐ Edmund Kenneth Kerut, M.D. and Michael R. McMullan, M.D.\nReversible cardiac dysfunction in severe COVID‐19 infection, mechanisms and case report\nCHAO et al.\nChao Chieh‐Ju MD https://orcid.org/0000-0001-6155-0266\n1\nDeValeria Patrick A. MD 2\nSen Ayan MD, M.Sc 3\nLee Hong MD 1\nPedrotty Dawn M MD, PhD 1\nPatel Bhavesh MD, RDMS 3\nArsanjani Reza MD 1\nNaqvi Tasneem Z. MD, FRCP, (Lon), MMM https://orcid.org/0000-0002-3160-9025\n1 naqvi.tasneem@mayo.edu\n\n1 Department of Cardiovascular Diseases Mayo Clinic Scottsdale AZ USA\n2 Department of Cardiovascular Surgery Mayo Clinic Scottsdale AZ USA\n3 Department of Critical Care Medicine Mayo Clinic Scottsdale AZ USA\n* Correspondence\nTasneem Z Naqvi, Department of Cardiovascular Diseases, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, Arizona 85259, USA.\nEmail: naqvi.tasneem@mayo.edu; #@tnaqvi2\n\n27 8 2020\n9 2020\n27 8 2020\n37 9 10.1111/echo.v37.9 14651469\n01 7 2020\n30 5 2020\n16 7 2020\n© 2020 Wiley Periodicals LLC\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nA previously healthy 49‐year‐old male patient presented with COVID‐19 infection and required mechanical ventilation and extracorporeal membrane oxygenation due to severe hypoxemia. Echocardiography showed cardiac dysfunction with an apical sparing strain pattern, which rapidly normalized within a week. Apical sparing myocardial strain in patients with COVID‐19 infection may suggest reverse‐type stress cardiomyopathy.\n\nCOVID‐19\nmyocarditis\nspeckle‐tracking strain\nstress‐induced cardiomyopathy\nsource-schema-version-number2.0\ncover-dateSeptember 2020\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:14.07.2022\nChao C‐J , DeValeria PA , Sen A , et al. Reversible cardiac dysfunction in severe COVID‐19 infection, mechanisms and case report. Echocardiography. 2020;37 :1465–1469. 10.1111/echo.14807 32856328\n==== Body\npmc1 INTRODUCTION\n\nThe novel COVID‐19 mainly attacks the respiratory system; however, the involvement of other end organs is common in critically ill patients. The most common symptoms of COVID‐19 infection are fever and cough, and 15% of patients may eventually require intensive care. 1 Myocardial injury or infarction, myocarditis, congestive heart failure, arrhythmias, and cardiogenic shock have been reported with COVID‐19 infection. 2 , 3 , 4 Among all patients with COVID‐19, myocardial injury was reported in more than 7% and 23% in critically ill patients. 5 Although the exact mechanism of cardiac involvement in COVID‐19 remains unclear, the possible pathogenesis is believed to be related to direct cardiac involvement through the ACE2 signaling pathway. 6 , 7 Increased secretion of ACE2 in patients with underlying cardiovascular diseases may also explain the significantly increased risk of death in this group of patients. 8 , 9\n\nMicrovascular dysfunction, demand ischemia, plaque rupture, or cytokine storm triggered by an imbalanced response to type 1 and type 2 T helper cells are other potential mechanisms of cardiac injury. Given that ACE2 is also found on vascular endothelial cells, infection‐medicated vasculitis is also possible. 10 Cytokine and inflammatory mediators can result in arterial inflammation, which could result in coronary plaque rupture. However, no reports yet associate SARS‐CoV‐2 with acute coronary syndrome (ACS). A case of presumably acute myocarditis due to COVID‐19 infection described LV apical hypokinesis, 11 and the other two cases reported decreased LVEF. 12 , 13 Apical‐type stress‐induced cardiomyopathy was recently reported as a possible presentation of COVID‐19–related cardiac involvement. 14 Herein, we discuss another potential presentation of cardiac injury in COVID 19 infection that occurred in a previously healthy patient who became critically ill with COVID‐19 infection.\n\n2 HISTORY OF PRESENTATION\n\nA previously healthy 49‐year‐old male patient presented to a local emergency department with fever, cough, and pneumonia, and tested positive for COVID‐19. He was transferred to the intensive care unit and placed on lung‐protective ventilation with a diagnosis of acute respiratory distress syndrome (ARDS) based on chest X‐ray and severe hypoxemia. Transthoracic echocardiogram (TTE) showed a left ventricular ejection fraction (LVEF) of 50%. He then developed refractory hypoxemia. Our emergency transport team performed an urgent offsite veno‐venous (V‐V) extracorporeal membrane oxygenation (ECMO) placement and transferred the patient to our intensive care unit. Initial ventilator settings were FiO2 100%, TV 450 mL, PEEP 18 cmH2O, and V‐V ECMO settings were 2850 rpm and 3.5 L/min flow. Initial ECG showed narrow QRS, precordial T‐wave inversion, QTc of 467 ms (Figure 1A), and 3 days later showed right bundle branch block, prolonged QTc of 539 ms, and mild diffuse ST elevation (Figure 1B). The initial chest X‐ray revealed severe diffuse bilateral pulmonary infiltrates consistent with ARDS (Figure 2A). Central venous O2 saturation was 79%. Laboratory data showed initial: troponin 526 ng/L, creatinine kinase 506 U/L, NT‐proBNP 4,573 pg/mL, ferritin 3601 mcg/L, C‐reactive protein 104.9 mg/L (<8 mg/L), IL‐6 > 400 pg/mL (<1.8 pg/mL), creatinine 0.83 mg/dL, total bilirubin 1.5 mg/dL, AST 124 U/L, ALT 55 U/L, procalcitonin 6.28 ng/mL, and lactate 3 mmol/L. The initial TTE at our hospital showed mild to moderately reduced LVEF of 40% with marked hypokinesis of basal and mid segments and preserved wall motion of apical segments (Figure 2B and Video S1). Global averaged LV global longitudinal peak systolic strain (GLS) was −13.2% (normal ≥ negative than −18%) with preserved apical strain (Figure 2C).\n\nFigure 1 Baseline and follow‐up ECGs. Panel A. The initial ECG showed sinus tachycardia, narrow QRS, QTc interval of 467 ms, and T‐wave inversion in the precordial leads V1‐V3, I and aVL. Panel B. Three days later, a repeat ECG showed right bundle branch block, QTc of 539 ms, and mild diffuse ST elevation\n\nFigure 2 Panel A. Baseline chest X‐ray AP view showing diffuse lung parenchymal opacities consistent with acute respiratory distress syndrome. Panel B. A baseline 2D transthoracic echocardiographic (TTE) apical 3‐chamber view in end‐diastole (upper left image), end‐systole (upper right image), and parasternal short‐axis view at midventricular level in end‐diastole (lower left image) and end‐systole (lower right image). Increased left ventricular (LV) end‐systolic cavity size from basal to mid segments is shown (Video S1). Panel C. 3‐, 2‐, and 4‐chamber strain maps and bull's eye plot showing regional and global averaged LV longitudinal peak systolic strain of ‐ 13.2% with an apical sparing pattern. Panel D. Follow‐up chest X‐ray AP view showing marked improvement in ARDS. E. Follow‐up 2D TTE shows an apical 3‐chamber view in end‐diastole (upper left image), end‐systole (upper right image), and parasternal short‐axis view at midventricular level in end‐diastole (lower left image) and end‐systole (lower right image). The change of LV chamber size over the cardiac cycle suggests normalization of wall motion and LV ejection fraction (Video S2). Panel F. Follow‐up regional strain maps and global averaged LV longitudinal peak systolic strain of −19.8% with near‐normal strain pattern\n\nMixed venous saturation was not consistent with a diagnosis of cardiogenic shock. Vasopressin and norepinephrine were infused to maintain adequate mean arterial pressure for refractory hypotension from vasodilatory shock. Broad‐spectrum antibiotics were started for possible pneumonia. The patient received two doses of Tocilizumab for signs and biomarkers suggestive of cytokine release syndrome. Hydroxychloroquine and azithromycin were administered initially, however, discontinued after 2 days due to QTc prolongation (Figure 1B).\n\nThe patient was continued on V‐V ECMO, mechanical ventilation, and antibiotics, and his oxygen requirements progressively decreased to FiO2 40%, TV 200‐300 mL, and PEEP 10 cmH2O. Troponin had decreased to 41 ng/L, ferritin to 788 mcg/L, C‐reactive protein to 6.5 mg/L (<8 mg/L), and IL‐6 to 181 pg/mL (normal < 1.8 pg/mL).\n\nSix days later, infiltrates started resolving on the chest X‐ray (Figure 2D), and a follow‐up TTE showed normalization of LVEF to 55% and marked improvement in regional wall motion abnormalities (Figure 2E and Video S2). LV GLS normalized to −19.8% (Figure 2F). The patient's pulmonary status continued to improve, tracheostomy was performed on day 10, and the patient was decannulated from V‐V ECMO on day 12. He remained culture negative.\n\n3 DISCUSSION\n\nIn this case, LV wall motion abnormalities in a noncoronary distribution followed by rapid normalization of wall motion do not suggest ACS and are most consistent with reverse type of stress cardiomyopathy involving basal and mid‐LV segments as opposed to apical LV segments in the classical type of stress or Takotsubo cardiomyopathy. A recent report also described a typical takotsubo presentation in a COVID‐19–infected patient who required V‐A ECMO support 14 ; a recent case series further reported a prevalence of stress cardiomyopathy of 4.2% in male COVID‐19 patients. 15 Perhaps, the most compelling mechanism of myocardial injury in our patient is secondary to cytokine storm and a hyperinflammatory state that occurred in the later stage of the disease after direct viral cytotoxicity of the pulmonary system (ARDS) and multi‐organ dysfunction. This case demonstrated a unique echocardiographic strain pattern associated with rapidly reversible COVID‐19 myocardial dysfunction in a critically ill COVID‐19–positive patient. Published case reports have described various mechanisms of COVID‐19–related myocardial injury and are listed in Table 1. Apical stress cardiomyopathy has been reported but reverse stress cardiomyopathy has not been reported thus far.\n\nTable 1 Echocardiographic features of COVID‐19–related myocardial injury in available case reports\n\n\tLV dimensions\tLV wall motion\tLVEF\tPericardial effusion\tDiagnosis\t\nCase 1 11\tNormal\tDiffuse hypokinesis\t40%\tCircumferential, 11 mm (max)\tAcute myopericarditis\t\nCase 2 12\t58 mm\t‐‐\t27%\tTrace, 2 mm (max)\tCoronavirus fulminant myocarditis\t\nCase 3 13\t61 mm\tDiffuse dyskinesia\t32%\tNo\tFulminant myocarditis\t\nCase 4 14\tNA\tRegional wall motion abnormality with apical ballooning\t20%\tNo\tApical‐type stress‐induced cardiomyopathy\t\nJohn Wiley & Sons, Ltd\n\nMyocardial inflammation and myocarditis can be detected by endomyocardial biopsy or by magnetic resonance imaging, which may show a variable pattern of Gadolinium enhancement. 16 Our patient did not undergo magnetic resonance imaging or endomyocardial biopsy, as these tests were not feasible in this critically ill patient. The markedly elevated troponin upon presentation, development of marked conduction abnormality, and diffuse appearing mild ST elevation on follow‐up ECG may be suggestive of myopericarditis with apical sparing possibly from reduced apical distribution of myocardial ACE 2 receptors. However, rapid cardiac recovery without steroids is highly unusual in myocardial inflammation or infection. The apical sparing LV strain distribution pattern in our patient is commonly seen in cardiac amyloidosis and nonischemic cardiomyopathy, 17 and has not been described in viral myocarditis. 18 While apical hypokinesis or ballooning is the most common echo finding in stress cardiomyopathy, 14 basal or mid segmental variant of stress cardiomyopathy 19 is not infrequent and is associated with basal to mid segmental hypokinesis with preserved apical wall motion and apical strain, 20 mild ST elevation, QT prolongation, T‐wave inversion, and rapid recovery of LV function—all present in our patient. It is interesting to note that recovery of LV systolic function, although associated with improvement in pulmonary status, occurred prior to the complete resolution of ARDS. Cytokine storm and sympathetic surge that occurred early in the course of our patient's illness were the likely triggers of stress cardiomyopathy and marked troponin elevation. 10 Improvement in cardiac function in our patient followed the administration of Tocilizumab, which is an IL‐6 inhibitor, improves cytokine release syndrome, and has also been reported to be effective in ARDS in a prior study. 21 The effectiveness of Tocilizumab in treating COVID‐19–related acute myocarditis is unclear. 21 Cases from China reported complete recovery of fulminant myocarditis treated with glucocorticoid and human immunoglobulin. 12 , 13 We did not need to use either of those therapies. Since Azithromycin and Hydroxychloroquine were given for a short period, and no steroids were administered, these likely did not contribute to the cardio‐pulmonary recovery.\n\n4 CONCLUSION\n\nWe describe a patient with COVID‐19 infection who developed severe ARDS requiring mechanical ventilation and V‐V ECMO, and acute myocardial dysfunction with rapid recovery of cardiac function. The cardiac dysfunction was associated with apical sparing of wall motion and strain. It was rapidly reversible, suggesting basal to mid variant of stress cardiomyopathy as the probable etiology of LV dysfunction. Our findings suggest that inflammatory and cardiac biomarkers, as well as ECG and echocardiographic assessment, should be performed in patients who develop a severe illness due to COVID 19 infection. Speckle‐tracking strain imaging can provide insight into the mechanism of cardiac dysfunction, particularly in the absence of cardiac magnetic resonance imaging (CMR) or endomyocardial biopsy. Follow‐up echo assessment, along with strain imaging, may determine a change in cardiac function as well as its potential mechanism. Wall motion abnormalities in a noncoronary distribution either in the distal LV segments or in the basal LV segments along with rapid normalization of cardiac function and wall motion in the absence of steroid administration should raise the suspicion for an apical or basal variant of Takotsubo cardiomyopathy. Assessment of myocardial strain in patients with COVID‐19 infection can aid in the detection of preserved basal or apical wall motion. It may provide a clue to the presence of stress cardiomyopathy and its potential reversibility. Both apical type and reverse type of stress‐induced cardiomyopathy can develop in the setting of COVID‐19 infection and should be considered in the differential diagnosis of mechanism of myocardial injury in COVID‐19 infection. The use of myocardial strain is invaluable in this setting.\n\nDISCLOSURES\n\nThere are no relevant disclosures or conflicts of interest for this work by any of the authors.\n\nSupporting information\n\nVideo S1\n\nClick here for additional data file.\n\nVideo S2\n\nClick here for additional data file.\n==== Refs\nREFERENCES\n\n1 Guan W , Ni Z , Hu Y , et al Clinical characteristics of coronavirus disease 2019 in China. New Engl J Medicine. 2020;382 (18 ):1708‐1720.\n2 Wang D , Hu B , Hu C , et al Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus‐Infected Pneumonia in Wuhan, China. JAMA. 2020;323 :1061‐1069.32031570\n3 Shi S , Qin M , Shen B , et al Association of cardiac injury with mortality in hospitalized patients with COVID‐19 in Wuhan, China. Jama Cardiol. 2020;5 :802.32211816\n4 Driggin E , Madhavan M , Bikdeli B , et al Cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID‐19) pandemic. J Am Coll Cardiol. 2020;75 :2352‐2371.32201335\n5 Clerkin KJ , Fried JA , Raikhelkar J , et al Coronavirus Disease 2019 (COVID‐19) and Cardiovascular Disease. Circulation. 2020;141 (20 ):1648‐1655.32200663\n6 Zheng Y‐Y , Ma Y‐T , Zhang J‐Y , Xie X . COVID‐19 and the cardiovascular system. Nat Rev Cardiol. 2020;17 (5 ):259‐260.32139904\n7 Oudit G , Kassiri Z , Jiang C , et al SARS‐coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur J Clin Invest. 2009;39 :618‐625.19453650\n8 Guo T , Fan Y , Chen M , Wu X , Zhang L , He T . Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID‐19). Jama Cardiol. 2019;2020 :5.\n9 Zhou F , Yu T , Du R , et al Clinical course and risk factors for mortality of adult inpatients with COVID‐19 in Wuhan, China: a retrospective cohort study. Lancet Lond Engl. 2020;395 :1054‐1062.\n10 Atri D , Siddiqi H , Lang J , Nauffal V , Morrow D , Bohula E . COVID‐19 for the Cardiologist: A Current Review of the Virology, Clinical Epidemiology, Cardiac and Other Clinical Manifestations and Potential Therapeutic Strategies. Jacc Basic Transl Sci; 2020;5 (5 ):518‐536.32292848\n11 Inciardi RM , Lupi L , Zaccone G , Italia L , Raffo M , Tomasoni D , Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID‐19). JAMA Cardiol. 2020;5 (7 ):819.32219357\n12 Hu H , Ma F , Wei X , Fang Y . Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin. Eur Heart J. 2020. 10.1093/eurheartj/ehaa190. [Epub ahead of print].\n13 Zeng J , Liu Y , Yuan J , et al First case of COVID‐19 complicated with fulminant myocarditis: a case report and insights. Infection. 2020;1–5 .\n14 Minhas A , Scheel P , Garibaldi B , et al Takotsubo Syndrome in the Setting of COVID‐19 Infection. Jacc Case Reports. 2020;2 (9 ):1321‐1325.32363351\n15 Giustino G , Croft L , Oates C , et al Takotsubo Cardiomyopathy in Males with Covid‐19. J Am Coll Cardiol. 2020:S0735‐1097(20)35551‐0. 10.1016/j.jacc.2020.05.068. [Epub ahead of print].\n16 Friedrich M , Marcotte F . Cardiac Magnetic Resonance Assessment of Myocarditis. Circulation Cardiovasc Imaging. 2018;6 :833‐839.\n17 Zuo H , Zhang Y , Ma F , et al Myocardial Deformation Pattern Differs between Ischemic and Non‐ischemic Dilated Cardiomyopathy: The Diagnostic Value of Longitudinal Strains. Ultrasound Med Biol. 2019;46 :233‐243.31718811\n18 Liu D , Hu K , Nordbeck P , Ertl G , Störk S , Weidemann F . Longitudinal strain bull’s eye plot patterns in patients with cardiomyopathy and concentric left ventricular hypertrophy. Eur J Med Res. 2016;21 :21.27165726\n19 Templin C , Ghadri JR , Diekmann J , et al Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy. New Engl J Med. 2015;373 :929‐938.26332547\n20 Manzanal A , Ruiz L , Madrazo J , Makan M , Perez J . Inverted Takotsubo cardiomyopathy and the fundamental diagnostic role of echocardiography. Tex Heart I J. 2013;40 :56‐59.\n21 Luo P , Liu Y , Qiu L , Liu X , Liu D , Li J . Tocilizumab treatment in COVID‐19: a single center experience. J Med Virol. 2020.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0742-2822",
"issue": "37(9)",
"journal": "Echocardiography (Mount Kisco, N.Y.)",
"keywords": "COVID-19; myocarditis; speckle-tracking strain; stress-induced cardiomyopathy",
"medline_ta": "Echocardiography",
"mesh_terms": "D000086382:COVID-19; D004452:Echocardiography; D006352:Heart Ventricles; D006801:Humans; D008297:Male; D008875:Middle Aged; D012075:Remission, Spontaneous; D018487:Ventricular Dysfunction, Left",
"nlm_unique_id": "8511187",
"other_id": null,
"pages": "1465-1469",
"pmc": null,
"pmid": "32856328",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32219357;32176300;32253759;27165726;23467068;19453650;32211816;32200663;32292848;32856328;32031570;32219356;32109013;31718811;24046380;32171076;26332547;32201335;32517962;32277408;32139904;32363351",
"title": "Reversible cardiac dysfunction in severe COVID-19 infection, mechanisms and case report.",
"title_normalized": "reversible cardiac dysfunction in severe covid 19 infection mechanisms and case report"
} | [
{
"companynumb": "US-TEVA-2020-US-1843887",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NOREPINEPHRINE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nKnowledge about the impact of coronavirus disease 2019 (COVID-19) on kidney transplant recipients (KTRs) concerning viral shedding and humoral immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is limited. The aim of this study is to analyze viral dynamics and the antibody response to SARS-CoV-2 in KTRs with COVID-19 and study their association with clinical data.\n\n\nMETHODS\nConsecutive KTRs diagnosed with COVID-19 at our center were evaluated for clinical presentation and outcome; duration of viral shedding and viral burden by reverse transcription-polymerase chain reaction assay cycle threshold; and magnitude of seroconversion to SARS-CoV-2.\n\n\nRESULTS\nSix KTRs identified with COVID-19 were hospitalized. Presenting symptoms were similar to those in the general population. Four patients had severe disease and, of these, 2 required mechanical ventilation, 4 had acute kidney injury, and 3 had secondary bacterial infections. Immunosuppression was reduced in all patients. Five patients were treated with hydroxychloroquine. No patient required dialysis or died. Patients with severe disease had a longer duration of viral shedding, which lasted more than 40 days, and had IgG antibodies against SARS-CoV-2, which were detected from 3 weeks to as long as 10 weeks after symptom onset. In patients with less severe disease no IgG antibodies where detected between 9 and 14 weeks after symptom onset.\n\n\nCONCLUSIONS\nIn our series, KTRs with severe COVID-19 had prolonged viral shedding and a stronger humoral immune response to SARS-CoV-2. These preliminary data need to be confirmed with further studies and over a longer period of time.",
"affiliations": "Nephrology Department, Centro Hospitalar Universitário de São João, Porto, Portugal. Electronic address: jlcsilvano@gmail.com.;Nephrology Department, Centro Hospitalar Universitário de São João, Porto, Portugal.;Nephrology Department, Centro Hospitalar Universitário de São João, Porto, Portugal.;Nephrology Department, Centro Hospitalar Universitário de São João, Porto, Portugal.;Nephrology Department, Centro Hospitalar Universitário de São João, Porto, Portugal; Faculdade de Medicina da Universidade do Porto, Porto, Portugal; Institute of Biomedical Engineering (INEB-I3S), Nephrology and Infectious Diseases Research and Development Group, University of Porto, Porto, Portugal.;Serviço de Patologia Clínica, Centro Hospitalar Universitário de São João, Porto, Portugal.;Serviço de Patologia Clínica, Centro Hospitalar Universitário de São João, Porto, Portugal; EPI-Unit, Instituto de Saúde Pública da Universidade do Porto, Porto, Portugal.;Serviço de Patologia Clínica, Centro Hospitalar Universitário de São João, Porto, Portugal.;Nephrology Department, Centro Hospitalar Universitário de São João, Porto, Portugal; Faculdade de Medicina da Universidade do Porto, Porto, Portugal; Institute of Biomedical Engineering (INEB-I3S), Nephrology and Infectious Diseases Research and Development Group, University of Porto, Porto, Portugal.;Nephrology Department, Centro Hospitalar Universitário de São João, Porto, Portugal; Faculdade de Medicina da Universidade do Porto, Porto, Portugal; Institute of Biomedical Engineering (INEB-I3S), Nephrology and Infectious Diseases Research and Development Group, University of Porto, Porto, Portugal.",
"authors": "Silvano|José|J|;Ferreira|Filipa|F|;Bustorff|Manuela|M|;Nunes|Ana Teresa|AT|;Tavares|Isabel|I|;Sobrinho Simões|Joana|J|;Ramos|Angélica|A|;Cardoso|Maria João|MJ|;Sampaio|Susana|S|;Pestana|Manuel|M|",
"chemical_list": "D000914:Antibodies, Viral; D007074:Immunoglobulin G; D012367:RNA, Viral",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.11.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "53(4)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000368:Aged; D000914:Antibodies, Viral; D000086382:COVID-19; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000086402:SARS-CoV-2; D013997:Time Factors; D017201:Virus Shedding",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1180-1186",
"pmc": null,
"pmid": "33419577",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Viral Clearance and Serological Response to SARS-CoV-2 in Kidney Transplant Recipients.",
"title_normalized": "viral clearance and serological response to sars cov 2 in kidney transplant recipients"
} | [
{
"companynumb": "PT-ACCORD-215157",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "A 22-year-old female with a history of developmental delay and seizures successfully treated with carbamazepine and levetiracetam developed fulminant hepatic failure and subsequently died. She had been admitted to the hospital following secondary generalized seizures of 35 min duration. A circulatory shock as well as intoxication was taken into consideration during the clinical course. Autopsy failed to reveal a macroscopically discernible cause of death. Significant findings on microscopic examination included acute tubular necrosis in the kidneys, pre-existing marked accumulation of neutral lipid within the hepatocytes as well as hyperacute liver damage with evidence of almost complete hepatocyte necrosis. Carbamazepine and levetiracetam were simultaneously determined from blood and tissues such as liver, lungs, muscle and kidneys by LC-MS/MS following addition of lamotrigine as an internal standard and liquid-liquid extraction. Validation data are given for levetiracetam. Both carbamazepine and levetiracetam were present in blood at concentrations within or below the therapeutic range, respectively. Moreover, tissue concentrations suggested long-term administration of anticonvulsant drugs, which is in accordance with the medical history. After excessive drug concentrations could be ruled out, the metabolic consequences of a prolonged carbamazepine therapy to cause severe hepatic injury in the present case are discussed. A mechanism of injury to the hepatocytes may be membrane damage by either an increased production of free radicals and/or a decreased free radical scavenging capacity. Following ischemia with reperfusion and during hyperthermia, large amounts of free radicals are formed. Induction of the mixed oxidase activity during longterm administration of carbamazepine may also increase production of free radicals, leaving the hepatic cell more vulnerable to oxidative injury.",
"affiliations": "Institut für Rechtsmedizin und Verkehrsmedizin.",
"authors": "Skopp|Gisela|G|;Schmitt|Horst Peter|HP|;Pedal|Ingo|I|",
"chemical_list": "D000927:Anticonvulsants; D005609:Free Radicals; D002220:Carbamazepine; D000077287:Levetiracetam; D010889:Piracetam",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-9225",
"issue": "217(5-6)",
"journal": "Archiv fur Kriminologie",
"keywords": null,
"medline_ta": "Arch Kriminol",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001344:Autopsy; D002220:Carbamazepine; D056486:Chemical and Drug Induced Liver Injury; D003616:Dandy-Walker Syndrome; D004359:Drug Therapy, Combination; D005260:Female; D005609:Free Radicals; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D000077287:Levetiracetam; D008099:Liver; D017114:Liver Failure, Acute; D009336:Necrosis; D010889:Piracetam; D013226:Status Epilepticus; D013375:Substance Withdrawal Syndrome; D014018:Tissue Distribution",
"nlm_unique_id": "0002256",
"other_id": null,
"pages": "161-75",
"pmc": null,
"pmid": "16910300",
"pubdate": "2006",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fulminant liver failure in a patient on carbamazepine and levetiracetam treatment associated with status epilepticus.",
"title_normalized": "fulminant liver failure in a patient on carbamazepine and levetiracetam treatment associated with status epilepticus"
} | [
{
"companynumb": "PHBS2006DE12201",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": "4",
"dru... |
{
"abstract": "We report on the screening and development of haploidentical hematopoietic stem cell transplantation (HSCT) for adult patients with clinically aggressive sickle cell disease (SCD) at our institution. Of 50 adult SCD patients referred for HSCT between January 2014 and March 2017, 20% were denied by insurance. Of 41 patients initially screened, 10% lacked an available haploidentical donor, 29% had elevated donor-specific antibodies (DSAs), and 34% declined to proceed to HSCT. All 10 patients who were transplanted received peripheral blood stem cells. The initial 2 were conditioned with alemtuzumab/total body irradiation (TBI) 3 Gy followed by post-transplant cyclophosphamide and failed to engraft. The next 8 patients received the regimen developed at Johns Hopkins University with TBI 3 Gy. Granulocyte colony-stimulating factor was administered from day +12 in those with HbS < 30%. All 8 patients engrafted with a median time to neutrophil >.5 × 109/L of 22 days (range, 18 to 23). One patient subsequently lost the graft, and 7 (87.5%) maintained >95% donor cell chimerism at 1-year post-HSCT. Two patients developed acute graft-versus-host disease (GVHD) of at least grade II. One had chronic GVHD and died >1 year after HSCT of unknown causes. With a median follow-up of 16 months (range, 11 to 29), 7 patients (87.5%) are alive. Our findings suggest that limited insurance coverage, high rate of DSAs, and patient declining HSCT may limit the availability of haploidentical HSCT in adult SCD patients. The modified Hopkins regimen used here demonstrates high engraftment and low morbidity rates and should be tested in larger, multicenter, prospective clinical trials.",
"affiliations": "Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, Illinois. Electronic address: ssaraf@uic.edu.;Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, Illinois.;Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, Illinois.;Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.;Department of Radiation Oncology, University of Illinois at Chicago, Chicago, Illinois.;Institute for Transfusion Medicine & Department of Pathology, University of Illinois at Chicago, Chicago, Illinois.;Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, Illinois.;Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, Illinois.;Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, Illinois.;Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, Illinois.;Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, Illinois.;Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, Illinois; Department of Medicine, Jesse Brown VA Medical Center, Chicago Illinois.;Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, Illinois.;Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, Illinois.;Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, Chicago, Illinois. Electronic address: drond@uic.edu.",
"authors": "Saraf|Santosh L|SL|;Oh|Annie L|AL|;Patel|Pritesh R|PR|;Sweiss|Karen|K|;Koshy|Matthew|M|;Campbell-Lee|Sally|S|;Gowhari|Michel|M|;Jain|Shivi|S|;Peace|David|D|;Quigley|John G|JG|;Khan|Irum|I|;Molokie|Robert E|RE|;Mahmud|Nadim|N|;Gordeuk|Victor R|VR|;Rondelli|Damiano|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2018.03.031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "24(8)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Donor specific antibody; G-CSF; Haploidentical; Sickle cell disease; Transplantation",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D000755:Anemia, Sickle Cell; D005260:Female; D006085:Graft Survival; D006801:Humans; D008297:Male; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D019172:Transplantation Conditioning; D000075442:Transplantation, Haploidentical",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1759-1765",
"pmc": null,
"pmid": "29656137",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "29472357;29296707;29170154;28939451;1922237;8311169;7581076;27965196;19513902;23416852;22659467;17334383;25058217;28644773;22435112;26348889;19855248;16338616;26348869;21239769;24790059;28249145;11607766;18489989;25054717;25809231;27625358;22955919",
"title": "Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease.",
"title_normalized": "haploidentical peripheral blood stem cell transplantation demonstrates stable engraftment in adults with sickle cell disease"
} | [
{
"companynumb": "US-MYLANLABS-2018M1067437",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "... |
{
"abstract": "A 99-year-old African-American male presented to the hospital with severe sepsis secondary to a urinary tract infection. Upon initial presentation he was tachycardic, hypotensive and had leukocytosis. While he had signs of acute kidney injury, no signs of acute liver injury were present with his alanine transferase (ALT) and amino transferase (AST) levels measuring at 22 and 44 U/L, respectively. During the treatment course the patient began to show signs of clinical improvement. Despite this, his ALT and AST began to increase on day 2 of treatment and reached their peak of 210 and 239 U/L on day 4. Cefepime-induced liver injury was suspected and cefepime was discontinued. Upon cefepime discontinuation, liver enzymes downtrended and gradually returned to normal. No other likely medication causes of liver injury could be identified and alternative medical causes were ruled out. The lack of an alternative cause and the temporal relationship of cefepime use to hepatic dysfunction support the diagnosis of cefepime-induced liver injury. The patient's Roussel Uclaf Causality Assessment Methods score was 7, indicating this was a possible case of cefepime-induced liver injury, and the Naranjo Nomogram score was 5 indicating this was a probable case of cefepime-induced liver injury. While cefepime-induced liver injury is rare, clinicians should be cognizant of the potential for this adverse effect if liver enzyme elevation is detected during cefepime therapy and other common causes have been ruled out.",
"affiliations": "Intermountain Medical Center, Murray, UT, USA.;Department of Pharmacy, Kingsbrook Jewish Medical Center, Brooklyn, NY, USA.;Department of Pharmacy, Kingsbrook Jewish Medical Center, Brooklyn, NY, USA.",
"authors": "Malhotra|Kyle|K|https://orcid.org/0000-0002-2931-1000;Fazylov|Roman|R|;Friedman-Jakubovics|Michelle|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/08971900211015046",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": null,
"journal": "Journal of pharmacy practice",
"keywords": "cefepime; drug-induced liver injury; mixed liver injury",
"medline_ta": "J Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "8971900211015046",
"pmc": null,
"pmid": "34098807",
"pubdate": "2021-06-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Case-Report of Drug-Induced Mixed Liver Injury Resulting From Cefepime Exposure.",
"title_normalized": "a case report of drug induced mixed liver injury resulting from cefepime exposure"
} | [
{
"companynumb": "TR-ALKEM LABORATORIES LIMITED-TR-ALKEM-2021-04012",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFIXIME"
},
"drugadd... |
{
"abstract": "BACKGROUND\nSince the COVID-19 pandemic, several therapeutic agents have been used in COVID-19 management. However, the results were controversial. Here, we aimed to evaluate the efficacy and safety of hydroxychloroquine (HCQ)/chloroquine (CQ) in COVID-19.\n\n\nMETHODS\nWe retrospectively reviewed the medical charts of patients with COVID-19 admitted to an inpatient ward in Wuhan from 2020/Feb/08 to 2020/Mar/05. Patients with HCQ/CQ and age, gender, disease severity matched ones without HCQ/CQ were selected at a 1:2 ratio. The clinical, laboratory and imaging findings were compared between these two groups. The multivariate linear regression analysis was performed to identify the factors that might influence patients' virus shedding periods (VSPs).\n\n\nRESULTS\nA total of 14 patients with HCQ/CQ and 21 matched ones were analyzed. The HCQ/CQ treatment lasted for an average of 10.36 ± 3.12 days. The mean VSPs were longer in the HCQ/CQ treatment group (26.57 ± 10.35 days vs. 19.10 ± 7.80 days, P = 0.020). There were 3 patients deceased during inpatient period, two patients were with HCQ/CQ treatment (P = 0.551). In the multivariate linear regression analysis, disease durations at admission (t = 3.643, P = 0.001) and HCQ/CQ treatment (t = 2.637, P = 0.013) were independent parameters for patients' VSPs. One patient with CQ had recurrent first-degree atrioventricular block (AVB) and obvious QTc elongation, another one complained about dizziness and blurred vision which disappeared after CQ discontinuation. One patient with HCQ had transient AVB.\n\n\nCONCLUSIONS\nIn summary, we identify that the HCQ/CQ administration is not related to less mortality cases at later phase of COVID-19. More studies are needed to explore whether HCQ/CQ treatment would lead to SARS-Cov-2 RNA clearance delay or not.",
"affiliations": "Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Beijing, China.;Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Beijing, China.;Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Beijing, China. chengyongjing3427@bjhmoh.cn.;Department of Emergency, Beijing Hospital, National Center of Gerontology, Beijing, China.;Department of Pulmonary and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Beijing, China.;Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Beijing, China.;Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Beijing, China.;Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Beijing, China.;Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Beijing, China.",
"authors": "Chen|Zhe|Z|;Liu|Aihua|A|;Cheng|Yongjing|Y|;Wang|Xutao|X|;Xu|Xiaomao|X|;Huang|Jia|J|;Ma|Yuqing|Y|;Gao|Ming|M|;Huang|Cibo|C|",
"chemical_list": "D012367:RNA, Viral; D006886:Hydroxychloroquine; D002738:Chloroquine",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-021-06477-x",
"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect Dis\nBMC Infectious Diseases\n1471-2334\nBioMed Central London\n\n6477\n10.1186/s12879-021-06477-x\nResearch Article\nHydroxychloroquine/chloroquine in patients with COVID-19 in Wuhan, China: a retrospective cohort study\nChen Zhe 1\nLiu Aihua 1\nCheng Yongjing chengyongjing3427@bjhmoh.cn\n\n1\nWang Xutao 2\nXu Xiaomao 3\nHuang Jia 1\nMa Yuqing 1\nGao Ming 1\nHuang Cibo 1\n1 grid.414350.7 0000 0004 0447 1045 Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Beijing, China\n2 grid.414350.7 0000 0004 0447 1045 Department of Emergency, Beijing Hospital, National Center of Gerontology, Beijing, China\n3 grid.414350.7 0000 0004 0447 1045 Department of Pulmonary and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Beijing, China\n12 8 2021\n12 8 2021\n2021\n21 80531 7 2020\n27 7 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nSince the COVID-19 pandemic, several therapeutic agents have been used in COVID-19 management. However, the results were controversial. Here, we aimed to evaluate the efficacy and safety of hydroxychloroquine (HCQ)/chloroquine (CQ) in COVID-19.\n\nMethods\n\nWe retrospectively reviewed the medical charts of patients with COVID-19 admitted to an inpatient ward in Wuhan from 2020/Feb/08 to 2020/Mar/05. Patients with HCQ/CQ and age, gender, disease severity matched ones without HCQ/CQ were selected at a 1:2 ratio. The clinical, laboratory and imaging findings were compared between these two groups. The multivariate linear regression analysis was performed to identify the factors that might influence patients’ virus shedding periods (VSPs).\n\nResults\n\nA total of 14 patients with HCQ/CQ and 21 matched ones were analyzed. The HCQ/CQ treatment lasted for an average of 10.36 ± 3.12 days. The mean VSPs were longer in the HCQ/CQ treatment group (26.57 ± 10.35 days vs. 19.10 ± 7.80 days, P = 0.020). There were 3 patients deceased during inpatient period, two patients were with HCQ/CQ treatment (P = 0.551). In the multivariate linear regression analysis, disease durations at admission (t = 3.643, P = 0.001) and HCQ/CQ treatment (t = 2.637, P = 0.013) were independent parameters for patients’ VSPs. One patient with CQ had recurrent first-degree atrioventricular block (AVB) and obvious QTc elongation, another one complained about dizziness and blurred vision which disappeared after CQ discontinuation. One patient with HCQ had transient AVB.\n\nConclusions\n\nIn summary, we identify that the HCQ/CQ administration is not related to less mortality cases at later phase of COVID-19. More studies are needed to explore whether HCQ/CQ treatment would lead to SARS-Cov-2 RNA clearance delay or not.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s12879-021-06477-x.\n\nKeywords\n\nHydroxychloroquine\nChloroquine\nVirus shedding periods\nCOVID-19\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nSince December 2019, the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection has swept over the whole world in a few months. By May 5, 2020, more than 3.5 million cases have been confirmed and the death toll raises to over 250 thousand all around the world. The SARS-Cov-2 infection results in the coronavirus disease-2019 (COVID-19), which is composed of a spectrum of clinical manifestations including pneumonia, heart/kidney/liver injury, and coagulopathy, etc. [1, 2].\n\nDue to lacking of specific anti-virus drugs, the management of COVID-19 is still challenging. The results of two randomized controlled clinical trials of the promising anti-virus agents, i.e. Lopinavir/Ritonavir and Remdesivir, showed that these drugs were not that effective as we had expected in Chinese patients with COVID-19 [3, 4]. Because of the dramatic elevation of several inflammatory factors, such as interferon-γ-induced protein 10, monocyte chemotactic protein-3, interleukin-13, et al., overreactive immunopathological mechanisms were surmised to be responsible for multiple organ damage in COVID-19 [5]. Some researchers hypothesized that patients with COVID-19 might benefit from some anti-rheumatic drugs, such as hydroxychloroquine (HCQ)/chloroquine (CQ) and tocilizumab (TCZ), for their dual effects on immune regulation and suppression [6].\n\nCQ is a traditional anti-malaria drug. As a derivate of CQ, HCQ is less toxic to retina and heart and is the background treatment in systemic lupus erythematosus (SLE) [7]. Yu and colleagues reported that HCQ treatment could reduce serum interleukin-6 (IL-6) levels in COVID-19 patients [8]. Except for the anti-inflammatory activity, HCQ/CQ has potential anti-virus effects [9, 10]. Liu et al. reported that both HCQ and CQ could inhibit SARS-Cov-2 replication and prevent the virus from entering into cells in vitro [11]. HCQ/CQ was recommended as an option in the COVID-19 management guideline in China [12, 13]. Furthermore, both the US Food and Drug Administration and the Indian Council for Medical Research had permitted the empiric use of HCQ in COVID-19 patients [14, 15]. With the surging demands for HCQ in COVID-19, some patients under long-term HCQ treatment for autoimmune disease, such as SLE, were threatened by HCQ shortage. Therefore, some rheumatologists campaigned for using HCQ rationally in COVID-19 in which the data and evidence were limited and inconclusive [16]. Unfortunately, the efficacy of HCQ/CQ in COVID-19 remained equivocal by far.\n\nAt the very beginning of the outbreak of COVID-19, a multidisciplinary medical team from Beijing Hospital took in charge of an independent inpatient ward to manage the COVID-19 patients in the Sino-French New City Branch of Tongji Hospital in Wuhan, China. Some patients took HCQ/CQ during their inpatient period. We performed the following retrospective analysis to evaluate the potential efficacy and safety of HCQ/CQ in COVID-19.\n\nMethods\n\nPatients\n\nMedical charts of patients admitted to one inpatient ward in Wuhan from February 08, 2020 to March 05, 2020 were reviewed. Due to the potential while uncertain efficacy of TCZ in COVID-19, patients receiving TCZ treatment were excluded from the study. Patients with HCQ/CQ treatment and age, gender, disease severity matched ones without HCQ/CQ treatment were analyzed. The matching process was performed with the SPSS software (version 26.0) and the propensity-score (PS) matching package at a 1:2 ratio. The Caliper value was 0.2.\n\nMethods\n\nThis was a retrospective cohort study. The demographic data, clinical manifestations, comorbidities, laboratory findings and image involvement patterns assessed by computed tomography (CT) were carefully and thoroughly collected from medical charts.\n\nThe disease severity was defined as mild, general, severe and critically severe according to the Chinese management guideline for COVID-19 (Additional file 1) [12]. The CURB-65 severity score was calculated according to the standard definition [17]. The estimated glomerular filtration rate (eGFR) was calculated via the CKD-EPI equation [18]. The concurrent respiratory pathogen infections, including type A influenza, type B influenza, mycoplasma pneumoniae, chlamydia pneumoniae, respiratory syncytial virus, adenovirus, parainfluenza virus and legionella pneumophilia infections, were confirmed by the presence of pathogen specific immunoglobulin M with the enzyme-linked immunosorbent assay.\n\nThe nasopharyngeal swabs were sampled based on physicians’ judgement on clinical purposes. And the ribonucleic acids (RNAs) of SARS-Cov-2 were examined with the polymerase chain reaction (PCR) method [19]. The virus shedding periods (VSPs) were defined from symptoms onset to the first day of the consecutive negative PCR results before discharge (Additional file 1). Drugs taken by the patients for COVID-19 management purposes before admission were recorded and analyzed as well. Receiving corticosteroids (GCs) treatment was defined as exposure to systemic GCs. The dosage of GCs was calculated by methylprednisolone (MP) (prednisone:methylprednisolone = 1.25:1). The complains and symptoms after HCQ/CQ initiation were carefully recorded.\n\nStatistical analysis\n\nStatistics analyses were conducted with the SPSS software (version 26.0). Numerical data was expressed as mean ± standard deviation (SD) or quartiles (Q1: first quartile; Q2: second quartile; Q3: third quartile), while categorical data was expressed as numbers and percentages. Numerical data was compared with the independent sample t-test. Categorical data was compared with the Chi-square or the Fisher’s exact test, as appropriate. The multivariate linear regression analysis was performed to identify the factors that might influence patients’ VSPs. Virus shedding periods were the dependent variable. Continuous or dichotomous parameters, such as disease duration at admission, with or without HCQ/CQ treatment, dosage of GCs et al. selected according to clinical judgment, were analyzed as probable predict variables with the stepwise method in the multivariate linear regression analysis (Additional file 1: Table S1). Laboratory results which were statistically different between patients with and without HCQ/CQ were selected as probable predict variables as well. MP dosage in patients without GCs was recorded as zero. All probabilities were 2-sided, and P values < 0.05 were considered to be statistically significant.\n\nResults\n\nFrom February 8, 2020 to March 5, 2020, a total of 63 COVID-19 patients were admitted to our ward. All the patients were confirmed with SARS-Cov-2 infection via PCR. Except for 5 patients who received TCZ treatment, 58 patients were treated by non-biological drugs. Among the 58 patients, 11 and 3 patients received HCQ and CQ treatment, respectively. After age, gender and disease severity matching, 21 patients without HCQ/CQ treatment were selected as controls and were further analyzed (Fig. 1).Fig. 1 The flow diagram of patient selection in the present study. COVID-19 corona virus disease-2019, TCZ tocilizumab, HCQ hydroxychloroquine, CQ chloroquine\n\nFor the 35 patients, the average age was 62.20 ± 11.88 years old with a male predominance. The span from symptoms onset to admission were 13.00 ± 7.24 days. Although common at disease onset (77.14%), fever was observed in only 20% of patients at admission. Twenty-six patients (74.28%) had at least a comorbidity, most of which was hypertension. Twenty-one out of the 35 patients suffered from multiple pathogen infections in addition to SARS-Cov-2. And influenza was the most common concomitant infectious disease (57.14%) (Table 1). Procalcitonin elevation was recorded in 9 patients. Serum ferritin and IL-6 levels were elevated in 34 and 17 patients, respectively. Serum IL-1β, IL-2R, IL-8, IL-10 and tumor necrosis factor-α (TNF-α) levels were tested in 14 patients. As a result, serum IL-1β, IL-2R, IL-8, IL-10 and TNF-α elevation were recorded in 1, 8, 2, 0 and 6 patients, respectively.Table 1 Clinical characteristics, laboratory and imaging findings of the 35 patients at admission\n\n\tTotal (n = 35)\tWith HCQ/CQ (n = 14)\tWithout HCQ/CQ (n = 21)\tP value\t\nAge\t62.20 ± 11.88\t61.00 ± 13.00\t63.00 ± 11.33\t0.633\t\nMale\t23\t10\t13\t0.721\t\nDisease duration (days)\t13.00 ± 7.24\t13.00 ± 7.14\t13.00 ± 7.49\t1.000\t\nClinical manifestation at beginning\t\n Fever\t27\t10\t17\t0.685\t\n Fatigue\t25\t11\t14\t0.704\t\n Cough\t26\t12\t14\t0.262\t\n Diarrhea\t8\t3\t5\t1.000\t\n Myalgia/arthralgia\t10\t7\t3\t0.053\t\n Fever at admission\t7\t2\t5\t0.676\t\nComorbidities\t\n Hypertension\t13\t7\t6\t0.199\t\n Diabetes mellites\t5\t2\t3\t1.000\t\n Carcinomaa\t5\t3\t2\t0.369\t\n Stroke\t1\t1\t0\t0.400\t\n Coronary artery disease\t2\t1\t1\t1.000\t\n Lung diseaseb\t6\t1\t5\t0.366\t\n HBV infection\t7\t3\t4\t1.000\t\nDisease severity status\t\n General\t19\t7\t12\t0.678\t\n Severe/critical\t16\t7\t9\t\t\nCURB-65 score\t\n 0\t15\t6\t9\t1.000\t\n 1–5\t20\t8\t12\t\t\nLaboratory results\t\n WBC (× 109/L)\t6.13 ± 2.45\t6.27 ± 2.96\t6.05 ± 2.12\t0.801\t\n Neu (× 109/L)\t4.33 ± 2.38\t4.68 ± 2.88\t4.10 ± 2.01\t0.490\t\n Lym (× 109/L)\t1.08 ± 0.52\t1.05 ± 0.56\t1.09 ± 0.50\t0.828\t\n Neu/Lym\t5.27 ± 4.31\t6.16 ± 5.13\t4.69 ± 3.67\t0.329\t\n Hb (g/L)\t123.17 ± 18.43\t126.14 ± 19.22\t121.19 ± 18.08\t0.444\t\n PLT (× 109/L)\t266.37 ± 111.96\t283.86 ± 110.58\t254.71 ± 114.04\t0.459\t\n ALT (U/L)\t33.14 ± 28.69\t27.00 ± 21.31\t37.24 ± 32.56\t0.308\t\n AST (U/L)\t32.11 ± 20.96\t27.00 ± 13.72\t35.52 ± 24.37\t0.244\t\n Alb (g/L)\t33.26 ± 5.60\t31.94 ± 6.51\t34.14 ± 4.87\t0.260\t\n LDH (U/L)\t282.69 ± 126.59\t310.00 ± 130.40\t264.48 ± 123.78\t0.304\t\neGFR (mL/min/1.73 m2)\t89.33 ± 15.88\t86.17 ± 12.15\t91.43 ± 17.92\t0.345\t\n > 90 mL/min/1.73 m2\t20\t7\t13\t0.486\t\n ≤ 90 mL/min/1.73 m2\t15\t7\t8\t\t\nFibrinogen (g/L)\t5.17 ± 1.59\t5.82 ± 1.19\t4.74 ± 1.66\t0.045\t\nd-Dimer (ug/mL FEU)\t3.63 ± 5.42\t4.30 ± 6.65\t3.18 ± 4.54\t0.556\t\n > 1.0 ug/mL FEU\t21\t8\t13\t0.778\t\n ≤ 1.0 ug/mL FEU\t14\t6\t8\t\t\nNT-pro-BNP (ug/mL)\t253.20 ± 346.51\t318.29 ± 520.19\t209.81 ± 152.60\t0.372\t\ncTnI (pg/mL)\t9.11 ± 9.51\t8.43 ± 9.38\t9.56 ± 9.79\t0.736\t\nESR (mm/h) (/n)\t47.75 ± 26.74 (32)\t58.62 ± 19.90 (13)\t40.32 ± 28.70 (19)\t0.056\t\nhsCRP (mg/L)\t33.89 ± 38.61\t31.47 ± 24.06\t35.50 ± 46.39\t0.767\t\nProcalcitonin (ng/mL)\t0.17 ± 0.46\t0.10 ± 0.08\t0.21 ± 0.60\t0.507\t\n ≥ 0.1 ng/mL\t9\t5\t4\t0.432\t\n < 0.1 ng/mL\t26\t9\t17\t\t\nFerritin (ug/L) (n)\t819.36 ± 628.02 (31)\t689.45 ± 494.53 (13)\t913.18 ± 707.92 (18)\t0.336\t\nIL-6 (ug/mL) (n)\t14.49 ± 15.62 (31)\t13.28 ± 9.27 (13)\t15.37 ± 19.19 (18)\t0.721\t\nOther respiratory pathogen infectionc\t21\t10\t11\t0.260\t\nImaging findings\t\t\t\t\t\n GGO\t30\t14\t16\t0.069\t\n Consolidation\t19\t7\t12\t0.678\t\n Bilateral pulmonary infiltration\t34\t14\t20\t1.000\t\n Interstitial changes\t17\t7\t10\t0.890\t\n Hydrothorax\t7\t1\t6\t0.203\t\nHBV hepatitis B virus, WBC white blood cell, Neu neutrophil, Lym lymphocyte, Hb hemoglobulin, PLT platelet, ALT alanine transaminase, AST oxaloacetic transaminase, LDH lactate dehydrogenase, eGFR estimated glomerular filter rate, NT-pro-BNP N-terminal pro-Brain Natriuretic Peptide, cTnI cardiac troponin I, ESR erythrocyte sedimentation rate, hsCRP high sensitivity C reactive protein, IL-6 interleukin-6, GGO ground glass opacity, HCQ hydroxychloroquine, CQ chloroquine\n\naIncluding carcinoma in the stomach (n = 2), urinary bladder (n = 1), bone (n = 1) and breast (n = 1)\n\nbLung disease refers to chronic obstructive lung disease (n = 3), emphysema (n = 2), bronchiectasis (n = 1), lung fibrosis (n = 1) and bullae (n = 1)\n\ncOther concurrent respiratory pathogen infection with a specific serum immunoglobulin M positive confirmed by the enzyme-linked immunosorbent assay includes type A influenza (n = 18), type B influenza (n = 2), mycoplasma pneumoniae (n = 2) and chlamydia pneumoniae (n = 1)\n\nTwenty-two patients took anti-influenza drugs, i.e., oseltamivir or arbidol or both. Most patients (94.28%) received traditional Chinese medicine (TCM) treatment. And the total types of anti-virus agents were similar between these two treatment groups (Table 2). Antibiotics were concomitantly administrated with HCQ/CQ in 17 patients. And moxifloxacin was the most commonly used antibiotic (13/17). HCQ/CQ was not administrated in combination with azithromycin in our patients. GCs were administrated in 12 (34.28%) patients. There were more patients taking GCs in the HCQ/CQ treatment group (57.14% vs. 19.05%, P = 0.031) (Table 2). The detailed information of GCs was available in 11 patients. Patients took GCs at a median of 14 days after symptoms onset (Q1: 12 days, Q3: 19 days). The GCs treatment lasted for a median of 6 days (Q1: 4 days, Q3: 7 days). And the median cumulated dosage of GCs was 280 mg (MP or equivalent, Q1: 160 mg, Q3: 480 mg).Table 2 Treatment and outcomes of the 35 patients\n\n\tTotal (n = 35)\tWith HCQ/CQ (n = 14)\tWithout HCQ/CQ (n = 21)\tP value\t\nTreatment\t\n Antivirus agents\t\t\t\t\t\n Ribavirin\t9\t4\t5\t1.000\t\n Lopinavir/Ritonavir\t4\t1\t3\t0.635\t\n Oseltamivir\t18\t8\t10\t0.581\t\n Arbidol\t10\t6\t4\t0.151\t\n TCM\t33\t14\t19\t0.506\t\n Types of antivirus agents\t2.11 ± 0.93\t2.36 ± 0.75\t1.95 ± 1.02\t0.213\t\n Corticosteroids\t12\t8\t4\t0.031\t\n IVIG\t9\t4\t5\t1.000\t\n Antibiotics\t22\t10\t12\t0.392\t\n Anticoagulant\t8\t3\t5\t1.000\t\nVirus shedding period (days)\t22.09 ± 9.51\t26.57 ± 10.35\t19.10 ± 7.80\t0.020\t\nSwab testing times\t3.81 ± 2.04\t5.15 ± 2.38\t2.89 ± 1.10\t0.001\t\nConsecutive swab testing negative times before discharging\t3.03 ± 1.23\t3.23 ± 1.42\t2.89 ± 1.10\t0.457\t\nSwab testing interval (days)\t6.10 ± 1.63\t5.77 ± 1.36\t6.34 ± 1.80\t0.346\t\nOutcomings\t\nDischarged\t 32\t12\t20\t0.551\t\nDeceased\t3\t2\t1\t\t\nTCM traditional Chinese medicine, IVIG intravenous immune globulin, HCQ hydroxychloroquine, CQ chloroquine\n\nThe dosage of HCQ was either 200 mg (n = 5) or 400 mg (n = 6) twice a day. And the dosage of CQ was 500 mg (n = 3) twice a day (Fig. 2). The average disease duration before HCQ/CQ initiation was 21.00 ± 5.98 days (Q1: 16.50 days; Q2: 22.00 days; Q3: 26.25 days). The HCQ/CQ treatment lasted for an average of 10.36 ± 3.12 days (Q1: 10.75 days; Q2: 11.00 days; Q3: 12.00 days). Only 1 of the 14 patients received HCQ/CQ treatment after virus shedding. The SARS-Cov-2 RNA tests turned negative after an average of 7.31 ± 6.05 days (Q1: 3.00 days; Q2: 5.00 days; Q3: 9.50 days) since HCQ/CQ initiation in the rest 13 patients. The average VSPs were 22.09 ± 9.51 days, which was a little longer in the HCQ/CQ treatment group (26.57 ± 10.35 days vs. 19.10 ± 7.80 days, P = 0.020). However, the average swab testing intervals didn’t differ between patients with and without HCQ/CQ treatment statistically (5.77 ± 1.36 days vs. 6.34 ± 1.80 days, P = 0.346) (Table 2). For the patients whose VSPs were longer than 22 days, the differences of average VSPs in patients with and without HCQ/CQ treatment were not statistically different (31.75 ± 9.72 days/n = 8 vs. 28.67 ± 3.56 days/n = 6, P = 0.477). In the multivariate linear regression analysis, disease durations at admission (t = 3.643, P = 0.001) and HCQ/CQ treatment (t = 2.637, P = 0.013) were independent predict parameters for patients’ VSPs prediction (Additional file 1: Table S1). The linear regression formulation was listed as following. Here is an example. One male patient with COVID-19 was admitted to the hospital at the 5th day after symptom onset. He received HCQ therapy in the hospital. Therefore his expected virus shedding period was 21 (10.039 + 0.697 × 5 + 7.140 × 1 = 20.664) days. Meanwhile, neither GCs treatment (t = − 0.313, P = 0.772) nor GCs dosage (t = − 0.706, P = 0.766) was related to VSPs statistically. And after treatment, acute exudation lesions were largely absorbed in pulmonary CT (Fig. 3). There were 3 patients deceased during inpatient period in our study, and two patients were with HCQ/CQ treatment (P = 0.551). Two patients died from multiple organ failure. And the other patient died suddenly. Their relatives refused of autopsy. Thus, the exact reasons for their death were unknown.Fig. 2 The detailed clinical, treatment and outcome information of patients with HCQ/CQ treatment. HCQ hydroxychloroquine, CQ chloroquine, ESR erythrocyte sedimentation rate, hsCRP high sensitivity C reactive protein, IL-6 interleukin-6, TCM traditional Chinese Medicine, GCs glucocorticoids. Comorbidities refers to the types of comorbidities in one single patient. Disease severity was classified according to the Chinese management guideline for COVID-19. Disease duration (days) was calculated from symptom onset to inpatient department admission. GCs were summed as methylprednisolone or equivalent and the total dosages of GCs were recorded in the corresponding square, respectively. Patient No.10 had transient first-degree atrioventricular block (AVB). Patient No.12 complained about dizziness and blurred vision which disappeared after CQ discontinuation. Patient No.14 had recurrent AVB and obvious QTc elongation even after CQ withdrawn. The virus shedding period was defined from symptoms onset to the first day of the consecutive negative PCR results before discharge. The X was put in the square in which the data was not available\n\nFig. 3 The computed tomography findings of one patient (No. 6) before (week 0) and 1, 2, 3 weeks after HCQ administration, respectively. After the comprehensive treatment together with HCQ, the ground-glass opacity lesions were largely absorbed, while some of the fibrosis stripe lesions were left\n\nVirus shedding period (days) = 10.039 + 0.697 × disease durations at admission + 7.140 × with or without HCQ/CQ treatment (0, if without HCQ/CQ treatment; 1, if with HCQ/CQ treatment).\n\nElectrocardiographs (ECGs) were conducted at least once in 12 out of the 14 patients (9 patients with HCQ treatment, and 3 patients with CQ treatment). First-degree atrioventricular block (AVB) was recorded in 2 patients. One patient received HCQ and the other received CQ. No second or third AVB was noticed. First-degree AVB disappeared after HCQ discontinuation. However, the first-degree AVB disappeared after CQ discontinuation and reoccurred 10 days later. The QTc interval longer than 500 ms was recorded in the identical patient with CQ treatment. Another patient with CQ treatment complained about dizziness and blurred vision. And the symptoms disappeared after CQ being withdrawn. No patient complained about new symptoms during HCQ treatment.\n\nDiscussion\n\nThe conventional anti-malaria drug HCQ/CQ was regarded as a promising agent for its dual effects on inflammation modulation and virus inhibition since the beginning of the pandemic [12, 14, 15].\n\nDuring the past decades, several researchers had confirmed the anti-virus effects of HCQ/CQ in vitro and in vivo [7, 9, 10]. HCQ/CQ could prevent the coronavirus from entering the host cells by interfering with endosomal acidification which is essential for membrane fusion. However, coronavirus could invade the host cells via alternative non-endosomal pathway which is not blocked by HCQ/CQ [20]. CQ could also interfere with virus post translation modification by pondus hydrogenii (PH) modulation [21]. At the meantime, HCQ/CQ could act on host cells directly. HCQ/CQ could inhibit glycosylation of the cell membrane protein angiotensin converting enzyme-2, to which the SARS-Cov-2 is attached [22]. HCQ/CQ could downregulate the toll like receptor (TLR) on activated immune cells and block TLR signal transduction, and prohibit inflammatory factors secretion, such as IL-6 [8, 23].\n\nBy far, a few clinical studies have analyzed the efficacy of HCQ/CQ in COVID-19. Gautret and colleagues reported that most patients with COVID-19 were virologicaly cured 6 days after HCQ initiation, especially those who received HCQ in combination with azithromycin [24]. However, Gautret et al.’s study had a relatively small sample size and two selection bias. First, patients in the treatment and control group were not from the same medical center. Second, the virus loads in the HCQ treatment group were lower compared to those in the control group at inclusion. Lower virus loads indicated that the patients in the HCQ treatment group were at a later disease phase of SARS-Cov-2 infection and were more likely to have autolimiting disease course [25]. In a randomized clinical trial (RCT), Chen and colleagues reported that after HCQ treatment with a dosage of 400 mg/day for 5 days, the clinical and radiological improve rates were higher compared to those in patients without HCQ treatment (80.6% vs. 54.8%) [26]. In another randomized study with mildly to moderately ill COVID-19 patients, Tang et al. noticed that the SARS-Cov-2 negative conversion rates were similar in patients with and without HCQ treatment (85.4% vs. 81.3%) [27]. In a retrospective study, Mallat and colleagues reported that HCQ treatment was an independent factor for longer VSPs. The median time span from nasopharyngeal swab positivity to negativity were 17 days in the HCQ treatment group and 10 days in the control group, respectively (P = 0.023). HCQ was administrated at an early stage of the disease course in Mallat’s study [28].\n\nIn our study, the number of mortality cases were not statistically different between patients with and without HCQ/CQ treatment. The result might be ascribed to several factors. Firstly, HCQ/CQ was administrated at a later phase of the disease course. In some patients, we used HCQ/CQ due to persistent SARS-Cov-2 RNA positivity for salvage treatment purposes. It is widely accepted that anti-virus should be taken as early as possible in influenza and corona virus infection [4, 29]. Secondly, the half-life of HCQ/CQ is as long as 40–60 days due to the large distribution volume in the blood. And it usually takes several weeks before HCQ/CQ reaching its maximal activity [30]. In COVID-19, HCQ/CQ treatment only lasted for an average of 10 days. Therefore, HCQ/CQ might be withdrawn before it worked. Thirdly, for ethic factors concern, several kinds of drugs, such as GCs, ribavirin, TCM et al., were administrated empirically and anecdotally at the same time. These concomitantly taken drugs might have covered up the potential therapeutic effects of HCQ/CQ on COVID-19. Fourthly, due to the small sample size, the death rates were not statistically different in patients with and without HCQ/CQ treatment. Taken together, the efficacy of HCQ/CQ in COVID-19 management should be verified in large randomized controlled trials.\n\nIn the present study, the average VSPs were similar to those reported in the previous study [31]. After the multivariate linear regression analysis, we identified that disease durations at admission and HCQ/CQ treatment were independent parameters related to patients’ VSPs, indicating patients might have better prognosis if being well treated earlier. Furthermore, VSPs were not statistically different between patients with longer VSPs (VSPs > 22 days) in these two treatment groups. It was interesting that there were more patients who took GCs in the HCQ/CQ treatment group. However, after being adjusted by other confounders, neither GCs treatment nor GCs dosage was an independent parameter for VSPs prediction. Actually, the effect of GCs on COVID-19 remains controversial and disputable. In SARS and Middle East Respiratory Syndrome (MERS), GCs administration was related to delayed virus RNA clearance [32, 33]. However, in the SARS or MERS studies, patients were either critically ill [33] or took rather high GCs dosage [32]. On the other hand, patients with SARS or influenza might benefit from low-to-moderate GCs [34, 35]. In the present study, our patients took a low-to-moderate dose of GCs during a relative short period of time. As a result, we didn’t find correlations between GCs treatment and prolonged VSPs. A team consist of front-line physicians from the Chinese Thoracic Society suggested that after careful benefits and harms evaluation, short term low-to-moderate dose of GCs could be prudently administrated in patients with COVID-19 [36].\n\nOne of the major concerns for HCQ/CQ treatment in COVID-19 is the side effect [37]. HCQ/CQ related retinopathy always occurs after months even years of HCQ/CQ administration [30]. Meanwhile, HCQ/CQ related arrythmia might be lethal. And the risk is rising together with other arrhythmogenic drugs, such as azithromycin [30]. Borba et al. reported that high dose of CQ (600 mg twice daily) was related to prolonged QTc interval and should not be recommended in critically ill patients [38]. Lane and colleagues reported that HCQ monotherapy was safe in COVID-19. However, HCQ in addition to azithromycin might result in heart failure and cardiovascular mortality [39]. Tang et al. found that HCQ was safe in patients with COVID-19, the most common adverse effects were diarrhea and vomiting [27]. Similarly, HCQ was safe and tolerable in our patients. On the contrast, among the three patients with CQ treatment, one patient complained about dizziness and blurred vision and another patient had recurrent first-degree AVB and obvious QTc elongation.\n\nThe major limitation of the study was the relatively small sample size. There were only 14 patients received HCQ/CQ treatment due to the unsettled debate on the safety profile of HCQ/CQ in COVID-19. The sample size of the patients without HCQ/CQ was expected to be 28. However, after age, gender and disease severity matching, only 21 patients without HCQ/CQ treatment met the matching criteria and were finally selected. Secondly, some patients were treated with HCQ/CQ for persistent SARS-Cov-2 RNA positivity. These patients, per se, were refractory to treatment. Therefore, selection bias exists in our patients. Thirdly, due to the retrospective nature of the study, although we found out that HCQ/CQ treatment was related to longer VSPs, we couldn’t tell whether HCQ/CQ prolonged SARS-Cov-2 RNA clearance or not.\n\nConclusions\n\nIn summary, we identify that the HCQ/CQ administration is not related to neither less mortality cases nor shorter VSPs at later phase of COVID-19. More studies are needed to explore whether HCQ/CQ treatment would lead to SARS-Cov-2 RNA clearance delay or not. And HCQ other than CQ is a safe and tolerable drug in COVID-19 patients.\n\nSupplementary Information\n\nAdditional file 1. The disease severity definition and discharging criteria according to the Chinese management guideline for COVID-19. Table S1. The details of model for VSPs prediction.\n\nAbbreviations\n\nHCQ Hydroxychloroquine\n\nCQ Chloroquine\n\nSARS-Cov-2 Severe acute respiratory syndrome coronavirus 2\n\nCOVID-19 Corona virus disease-2019\n\nSLE Systemic lupus erythematosus\n\nIL-6 Interleukin-6\n\nCT Computed tomography\n\neGFR Estimated glomerular filtration rate\n\nRNAs Ribonucleic acids\n\nPCR Polymerase chain reaction\n\nVSPs Virus shedding periods\n\nGCs Corticosteroids\n\nMP Methylprednisolone\n\nSD Standard deviation\n\nTNF-α Tumor necrosis factor-α\n\nTCM Traditional Chinese medicine\n\nECGs Electrocardiographs\n\nAVB Atrioventricular block\n\nTLR Toll like receptor\n\nRCT Randomized clinical trial\n\nMERS Middle East Respiratory Syndrome\n\nAcknowledgements\n\nWe thank all the medical workers from Beijing Hospital who treated patients in the Sino-French New City Branch of Tongji Hospital in Wuhan. We thank all the patients and their families involved in the study.\n\nAuthors’ contributions\n\nAll authors were involved in drafting the article or revising it critically for important intellectual content. YC and CH had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. AL, YC, XW, XX, MG and CH designed this study initially. ZC, JH and YM were responsible for data acquisition. ZC and AL analyzed and interpreted the data. ZC and AL drafted the main manuscript of the article. All authors read and approved the final manuscript.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAvailability of data and materials\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe study was approved by the institutional review board of Beijing Hospital (Approval letter number: 2020BJYYEC-084-01). Written informed consent has been obtained from all participants.\n\nConsent for publication\n\nNot applicable.\n\nCompeting interests\n\nThe authors declare that they have no competing interests to disclose.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nZhe Chen and Aihua Liu contributed equally to this article\n==== Refs\nReferences\n\n1. Guan WJ Ni ZY Hu Y Clinical characteristics of coronavirus disease 2019 in China N Engl J Med 2020 382 18 1708 1720 10.1056/NEJMoa2002032 32109013\n2. Zhang Y Xiao M Zhang S Coagulopathy and antiphospholipid antibodies in patients with Covid-19 N Engl J Med 2020 382 17 e38 10.1056/NEJMc2007575 32268022\n3. Cao B Wang Y Wen D A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19 N Engl J Med 2020 382 19 1787 1799 10.1056/NEJMoa2001282 32187464\n4. Wang YM Zhang DY Du GH Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial Lancet 2020 395 10236 1569 1578 10.1016/S0140-6736(20)31022-9 32423584\n5. Yang Y Shen C Li J Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19 J Allergy Clin Immunol 2020 10.1016/j.jaci.2020.04.027 33358893\n6. Sanders JM Monogue ML Jodlowski TZ Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review JAMA 2020 10.1001/jama.2020.6019 33165621\n7. Hughes G Hydroxychloroquine: an update Lupus 2018 27 9 1402 1403 10.1177/0961203318787040 30016931\n8. Yu B Li C Chen P Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19 Sci China Life Sci 2020 10.1007/s11427-020-1732-2 33398594\n9. Aguirre-Cruz L Torres KJ Jung-Cook H Short communication: preferential concentration of hydroxychloroquine in adenoid tissue of HIV-infected subjects AIDS Res Hum Retrovir 2010 26 3 339 342 10.1089/aid.2009.0129 20334568\n10. Ferner RE Aronson JK Chloroquine and hydroxychloroquine in covid-19 BMJ 2020 369 m1432 10.1136/bmj.m1432 32269046\n11. Liu J Cao R Xu M Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro Cell Discov 2020 6 16 10.1038/s41421-020-0156-0 33731711\n12. National Health Commission of the People’s Republic of China. Chinese management guideline for COVID-19 (version 6.0). http://www.nhc.gov.cn/yzygj/s7653p/202002/8334a8326dd94d329df351d7da8aefc2/files/b218cfeb1bc54639af227f922bf6b817.pdf. Accessed 19 Feb 2020. (in Chineses).\n13. Group TSC-cte: Experts Consensus on comprehensive treatment of COVID-19 in Shanghai. Zhonghua Chuan Ran Bing Za Zhi. 2020;38(3):134–8. 10.3760/cma.j.issn.1000-6680.2020.03.002. (in Chinese).\n14. Lenzer J Covid-19: US gives emergency approval to hydroxychloroquine despite lack of evidence BMJ 2020 369 m1335 10.1136/bmj.m1335 32238355\n15. Indian Council for Medical Research. Recommendation for empiric use of hydroxychloroquine for prophylaxis of SARS-CoV-2 infection. https://icmr.nic.in/sites/default/files/upload_documents/HCQ_Recommendation_22March_final_MM_V2.pdf.\n16. Yazdany J Kim AHJ Use of hydroxychloroquine and chloroquine during the COVID-19 pandemic: what every clinician should know Ann Intern Med 2020 10.7326/M20-1334 32976026\n17. Lim WS van der Eerden MM Laing R Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study Thorax 2003 58 5 377 382 10.1136/thorax.58.5.377 12728155\n18. Guo X Qin Y Zheng K Improved glomerular filtration rate estimation using new equations combined with standardized cystatin C and creatinine in Chinese adult chronic kidney disease patients Clin Biochem 2014 47 13–14 1220 1226 10.1016/j.clinbiochem.2014.05.060 24886770\n19. Ye C Cai S Shen G Clinical features of rheumatic patients infected with COVID-19 in Wuhan, China Ann Rheum Dis 2020 79 8 1007 1013 10.1136/annrheumdis-2020-217627 32444415\n20. Zumla A Chan JF Azhar EI Coronaviruses—drug discovery and therapeutic options Nat Rev Drug Discov 2016 15 5 327 347 10.1038/nrd.2015.37 26868298\n21. Randolph VB Winkler G Stollar V Acidotropic amines inhibit proteolytic processing of flavivirus prM protein Virology 1990 174 2 450 458 10.1016/0042-6822(90)90099-d 2154882\n22. Vincent MJ Bergeron E Benjannet S Chloroquine is a potent inhibitor of SARS coronavirus infection and spread Virol J 2005 2 69 10.1186/1743-422X-2-69 16115318\n23. Alia E Grant-Kels JM Does hydroxychloroquine combat COVID-19? A timeline of evidence J Am Acad Dermatol 2020 83 1 e33 e34 10.1016/j.jaad.2020.04.031 32283236\n24. Gautret P Lagier JC Parola P Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Int J Antimicrob Agents 2020 2020 105949 10.1016/j.ijantimicag.2020.105949\n25. Kim AHJ Sparks JA Liew JW A rush to judgment? Rapid reporting and dissemination of results and its consequences regarding the use of hydroxychloroquine for COVID-19 Ann Intern Med 2020 172 12 819 821 10.7326/M20-1223 32227189\n26. Chen Z Hu J Zhang Z Jiang S Han S Yan D Zhuang R Hu B Zhang Z Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial medRxiv 2020 10.1101/2020.03.22.20040758 33354688\n27. Tang W Cao Z Han M Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial BMJ 2020 369 m1849 10.1136/bmj.m1849 32409561\n28. Mallat J Fadi H Balkis M Mohamed MA Mooty M Malik A Nusair A Bonilla F Hydroxychloroquine is associated with slower viral clearance in clinical COVID-19 patients with mild to moderate disease: a retrospective study medRxiv 2020 10.1101/2020.04.27.20082180\n29. Chen C Yi Z Huang J Yin P Cheng Z Wu J Chen S Zhang Y Chen B Lu M Luo Y Ju L Zhang J Wang X Favipiravir versus arbidol for COVID-19: a randomized clinical trial medRxiv 2020 10.1101/2020.03.17.20037432 33354688\n30. Schrezenmeier E Dorner T Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology Nat Rev Rheumatol 2020 16 3 155 166 10.1038/s41584-020-0372-x 32034323\n31. Xiao AT Tong YX Zhang S Profile of RT-PCR for SARS-CoV-2: a preliminary study from 56 COVID-19 patients Clin Infect Dis 2020 10.1093/cid/ciaa460 33367581\n32. Lee N Allen Chan KC Hui DS Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients J Clin Virol 2004 31 4 304 309 10.1016/j.jcv.2004.07.006 15494274\n33. Arabi YM Mandourah Y Al-Hameed F Corticosteroid therapy for critically ill patients with middle east respiratory syndrome Am J Respir Crit Care Med 2018 197 6 757 767 10.1164/rccm.201706-1172OC 29161116\n34. Chen RC Tang XP Tan SY Treatment of severe acute respiratory syndrome with glucosteroids: the Guangzhou experience Chest 2006 129 6 1441 1452 10.1378/chest.129.6.1441 16778260\n35. Li H Yang SG Gu L Effect of low-to-moderate-dose corticosteroids on mortality of hospitalized adolescents and adults with influenza A(H1N1)pdm09 viral pneumonia Influenza Other Respir Viruses 2017 11 4 345 354 10.1111/irv.12456 28464462\n36. Shang L Zhao J Hu Y On the use of corticosteroids for 2019-nCoV pneumonia Lancet 2020 395 10225 683 684 10.1016/S0140-6736(20)30361-5 32122468\n37. Eljaaly K Alireza KH Alshehri S Hydroxychloroquine safety: a meta-analysis of randomized controlled trials Travel Med Infect Dis 2020 36 101812 10.1016/j.tmaid.2020.101812 32645478\n38. Borba MGS Val FFA Sampaio VS Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial JAMA Netw Open 2020 3 4 e208857 10.1001/jamanetworkopen.2020.8857 32330277\n39. Lane JCE Weaver J Kostka K Duarte-Salles T Abrahao MTF Alghoul H Alser O Alshammari TM Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid widespread use for COVID-19: a multinational, network cohort and self-controlled case series study medRxiv 2020 10.1101/2020.04.08.20054551 33269355\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "21(1)",
"journal": "BMC infectious diseases",
"keywords": "COVID-19; Chloroquine; Hydroxychloroquine; Virus shedding periods",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000086382:COVID-19; D002738:Chloroquine; D006801:Humans; D006886:Hydroxychloroquine; D058873:Pandemics; D012367:RNA, Viral; D012189:Retrospective Studies; D000086402:SARS-CoV-2",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "805",
"pmc": null,
"pmid": "34384388",
"pubdate": "2021-08-12",
"publication_types": "D016428:Journal Article",
"references": "15494274;33350752;32360286;26868298;32034323;32645478;32330277;32238355;16115318;28464462;32282022;32268022;30016931;32409561;32187464;32306036;20334568;24886770;2154882;32122468;32109013;12728155;32423584;32227189;32444415;32232419;32418114;32269046;29161116;32283236;32205204;16778260",
"title": "Hydroxychloroquine/chloroquine in patients with COVID-19 in Wuhan, China: a retrospective cohort study.",
"title_normalized": "hydroxychloroquine chloroquine in patients with covid 19 in wuhan china a retrospective cohort study"
} | [
{
"companynumb": "CN-LUPIN PHARMACEUTICALS INC.-2021-20257",
"fulfillexpeditecriteria": "2",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugad... |
{
"abstract": "BACKGROUND\nPlatinum-based therapy combined with cetuximab is standard first-line therapy for recurrent or metastatic squamous cell carcinoma of the head and neck (RMSCCHN). Preclinical studies have suggested that mammalian target of rapamycin inhibitors may overcome resistance to epidermal growth factor receptor blockers and may augment cetuximab antitumor activity. We conducted a phase 1b trial of carboplatin, cetuximab, and everolimus for untreated RMSCCHN.\n\n\nMETHODS\nPatients received carboplatin (area under the curve = 2 mg/ml/min; 3 weeks on, 1 week off), cetuximab (with a loading dose of 400 mg/m(2) and then 250 mg/m(2) weekly), and dose-escalating everolimus (2.5, 5.0, 7.5, and 10 mg/day) with a 3+3 design. After 4 cycles, patients without progression continued cetuximab/everolimus until progression or intolerable toxicity. Patients (age ≥ 18 years) had previously untreated, unresectable RMSCCHN not amenable to radiotherapy and an Eastern Cooperative Oncology Group performance status of 0 to 2.\n\n\nRESULTS\nThe study enrolled 20 patients (male/female = 18/2) with RMSCCHN; the median age was 65 years (44-75 years). Thirteen patients received everolimus (male/female = 92%). Two of 6 patients receiving 2.5 mg/day experienced dose-limiting toxicity (DLT) with grade 3 hyponatremia and nausea. In 7 patients receiving de-escalated everolimus (2.5 mg every other day), grade 3 hyperglycemia produced DLT in 1 of 6 patients. The objective response rate (RR) was 61.5% (all partial responses). Progression-free survival (PFS) was 8.15 months. The pharmacokinetics of everolimus was described with a 2-compartment mixed-effects model. There was a significant correlation between tumor p-p44/42 staining and response (P = .044) and a marginally significant correlation between phosphorylated mammalian target of rapamycin and overall survival.\n\n\nCONCLUSIONS\nThe maximum tolerated dose of everolimus with cetuximab and carboplatin was 2.5 mg every other day. The regimen was associated with an encouraging RR and PFS, and this suggested possible clinical efficacy in a select group of patients with squamous cell carcinoma of the head and neck.",
"affiliations": "Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia.",
"authors": "Saba|Nabil F|NF|;Hurwitz|Selwyn J|SJ|;Magliocca|Kelly|K|;Kim|Sungjin|S|;Owonikoko|Taofeek K|TK|;Harvey|Donald|D|;Ramalingam|Suresh S|SS|;Chen|Zhengjia|Z|;Rogerio|Jackie|J|;Mendel|Jennifer|J|;Kono|Scott A|SA|;Lewis|Colleen|C|;Chen|Amy Y|AY|;Higgins|Kristin|K|;El-Deiry|Mark|M|;Wadsworth|Trad|T|;Beitler|Jonathan J|JJ|;Shin|Dong M|DM|;Sun|Shi-Yong|SY|;Khuri|Fadlo R|FR|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000068338:Everolimus; D016190:Carboplatin; D000068818:Cetuximab; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.28965",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "120(24)",
"journal": "Cancer",
"keywords": "everolimus in head and neck cancer; everolimus in squamous cell carcinoma; everolimus, cetuximab, and carboplatin; mTOR inhibition in head and neck cancer; mTOR inhibition in squamous cell carcinoma; pharmacokinetics, and NONMEM",
"medline_ta": "Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002294:Carcinoma, Squamous Cell; D000068818:Cetuximab; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D000068338:Everolimus; D005260:Female; D006258:Head and Neck Neoplasms; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D012008:Recurrence; D020123:Sirolimus; D000077195:Squamous Cell Carcinoma of Head and Neck",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "3940-51",
"pmc": null,
"pmid": "25103371",
"pubdate": "2014-12-15",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase 1 and pharmacokinetic study of everolimus in combination with cetuximab and carboplatin for recurrent/metastatic squamous cell carcinoma of the head and neck.",
"title_normalized": "phase 1 and pharmacokinetic study of everolimus in combination with cetuximab and carboplatin for recurrent metastatic squamous cell carcinoma of the head and neck"
} | [
{
"companynumb": "US-CIPLA LTD.-2014US03007",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CETUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "End-stage renal disease in the human immunodeficiency virus-positive population is increasing. Kidney transplant is the optimal therapy for this population rather than dialysis modalities if some criteria are met. These include undetectable plasma human immunodeficiency virus RNA, CD4 cell count over 200 cells/μL, and the absence of any AIDS-defining illness. Here, we describe the first living-donor kidney transplant in a human immunodeficiency virus-positive recipient in Turkey. The patient, a 52-year-old male diagnosed as human immunodeficiency virus positive, was on antiretroviral therapy, which consisted of 400 mg twice daily darunavir, 100 mg/day ritonavir, and 50 mg/day dolutegravir. He had been negative for human immunodeficiency virus RNA for the past 3 years. The patient developed renal insufficiency without any known cause and started hemodialysis. A living donor transplant from his son was performed, and the patient received ATG Fresenius-S (Neovii Biotech, Rapperswil, Switzerland) induction and a maintenance immunosuppression therapy consisting of methyl-prednisolone, mycophenolate mofetil, and tacrolimus. There were no incidences of delayed graft function or acute rejection. Because of tacrolimus and ritonavir interaction, tacrolimus trough levels were too high. With tacrolimus withdrawn, tacrolimus trough level decreased to detectable levels 2 weeks later. Antiretroviral therapy was continued on the same dosage. At month 4 posttransplant, the patient's creatinine level was 1.01 mg/dL. At present, the patient has had no complications and no episodes of rejection. Kidney transplant is the most favorable replacement therapy for HIV-positive patients who are under controlled AIDS care with highly active antiretroviral therapy. However, drug interactions should be carefully evaluated.",
"affiliations": "From the Nephrology Department, Ege University School of Medicine, Izmir, Turkey.",
"authors": "Yılmaz|Mümtaz|M|;Gökengin|Deniz|D|;Bozbıyık|Osman|O|;Hoşcoşkun|Cüneyt|C|;Uyan|Ayşe|A|;Töz|Hüseyin|H|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2017.0013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": null,
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": null,
"nlm_unique_id": "101207333",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28969531",
"pubdate": "2017-09-30",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Kidney Transplant in a Human Immunodeficiency Virus-Positive Patient: Case Report of Drug Interactions.",
"title_normalized": "kidney transplant in a human immunodeficiency virus positive patient case report of drug interactions"
} | [
{
"companynumb": "TR-ACCORD-059884",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
"druga... |
{
"abstract": "Numerous drugs cause hepatotoxicity clinically or biologically. Neuropsychiatric drugs constitute 16% of these drugs. The occurrence of hepatotoxicity induced by the use of olanzapine is expressed by the researchers. In such cases, generally the dose of olanzapine is reduced or the drug is completely discontinued and the treatment of the patient fails. The aim of this study is to report the case for whom elevated liver enzymes were observed but the process was managed without changing treatment dose and drug and to discuss this case with literature information. The present study has characteristics of being the first in the literature concerning management of the process.",
"affiliations": "1 Department of Child and Adolescent Psychiatry, Inonu University , Malatya, Turkey .;1 Department of Child and Adolescent Psychiatry, Inonu University , Malatya, Turkey .;1 Department of Child and Adolescent Psychiatry, Inonu University , Malatya, Turkey .;2 Department of Psychiatry, Inonu University , Malatya, Turkey .;3 Department of Pediatric Gastroenterology, Inonu University , Malatya, Turkey .",
"authors": "Dönmez|Yunus Emre|YE|;Özcan|Özlem|Ö|;Soylu|Nusret|N|;Sarıoğlu|Fatma Kartal|FK|;Selimoğlu|Ayşe|A|",
"chemical_list": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000077152:Olanzapine",
"country": "United States",
"delete": false,
"doi": "10.1089/cap.2016.0178",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1044-5463",
"issue": "27(3)",
"journal": "Journal of child and adolescent psychopharmacology",
"keywords": "atypical antipsychotics; hepatotoxicity; liver enzymes; olanzapine; side effects",
"medline_ta": "J Child Adolesc Psychopharmacol",
"mesh_terms": "D000818:Animals; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D056486:Chemical and Drug Induced Liver Injury; D006801:Humans; D008111:Liver Function Tests; D000077152:Olanzapine; D051381:Rats",
"nlm_unique_id": "9105358",
"other_id": null,
"pages": "293-294",
"pmc": null,
"pmid": "28398814",
"pubdate": "2017-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Management of Hepatotoxicity Induced by the Use of Olanzapine.",
"title_normalized": "management of hepatotoxicity induced by the use of olanzapine"
} | [
{
"companynumb": "TR-MYLANLABS-2017M1032458",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": "1",
... |
{
"abstract": "We report here the case of a young adult affected by pre B-cell acute lymphoblastic leukemia (ALL), who developed, during a pediatric-like chemotherapy consolidation schedule with high dosage of Methotrexate, a severe neurological toxicity. Clinical presentation and neuroimaging data were diagnostic for posterior reversible encephalopathy syndrome (PRES). A complete resolution was quickly obtained with medical blood pressure control and anticonvulsants administration. To the best of our knowledge, this is the first case of PRES described in the adult ALL setting. Currently, the clinical management of this aggressive disease is moving towards a pediatric-like approach also in adult patients, due to the better outcome reached with intensive chemotherapeutic regimens in children population. However, therapy-related toxicities have to be taken into account, since their onset may adversely affect patients' clinical outcome.",
"affiliations": "Department of Experimental, Diagnostic and Specialty Medicine, Bologna University , Italy.;Department of Experimental, Diagnostic and Specialty Medicine, Bologna University , Italy.;Department of Experimental, Diagnostic and Specialty Medicine, Bologna University , Italy.;Department of Experimental, Diagnostic and Specialty Medicine, Bologna University , Italy.;Department of Experimental, Diagnostic and Specialty Medicine, Bologna University , Italy.;Department of Experimental, Diagnostic and Specialty Medicine, Bologna University , Italy.",
"authors": "Papayannidis|Cristina|C|;Volpato|Francesca|F|;Iacobucci|Ilaria|I|;Abbenante|Maria Chiara|MC|;Sartor|Chiara|C|;Martinelli|Giovanni|G|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/hr.2014.5565",
"fulltext": "\n==== Front\nHematol RepHematol RepHRHematology Reports2038-83222038-8330PAGEPress Publications, Pavia, Italy 10.4081/hr.2014.5565Case ReportPosterior Reversible Encephalopathy Syndrome in a B-Cell Acute Lymphoblastic Leukemia Young Adult Patient Treated with a Pediatric-Like Chemotherapeutic Schedule Papayannidis Cristina Volpato Francesca Iacobucci Ilaria Abbenante Maria Chiara Sartor Chiara Martinelli Giovanni Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine, Bologna University, via Massarenti 9, 40138 Bologna, Italy. +39.051.636.3973 - +39.051.636.4037. cristina.papayannidis@unibo.itContributions: the authors contributed equally.\n\nConflict of interests: the authors declare no potential conflict of interest.\n\n30 9 2014 26 8 2014 6 3 556521 7 2014 21 7 2014 © Copyright C. Papayannidis et al.2014Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.We report here the case of a young adult affected by pre B-cell acute lymphoblastic leukemia (ALL), who developed, during a pediatric-like chemotherapy consolidation schedule with high dosage of Methotrexate, a severe neurological toxicity. Clinical presentation and neuroimaging data were diagnostic for posterior reversible encephalopathy syndrome (PRES). A complete resolution was quickly obtained with medical blood pressure control and anticonvulsants administration. To the best of our knowledge, this is the first case of PRES described in the adult ALL setting. Currently, the clinical management of this aggressive disease is moving towards a pediatric-like approach also in adult patients, due to the better outcome reached with intensive chemotherapeutic regimens in children population. However, therapy-related toxicities have to be taken into account, since their onset may adversely affect patients’ clinical outcome.\n\nKey words\nposterior reversible encephalopathy syndromeacute lymphoblastic leukemiamethotrexateseizurebrain magnetic resonance imaging\n==== Body\nCase Report\nAn 18-year-old boy was admitted to our hospital (Bologna, Italy) due to onset of fatigue and persistent fever, unresponsive to antibacterial therapy. Blood analyses showed a white blood cell count of 93,850/µL, with 99% of lymphoid blast cells, hemoglobin of 11 g/dL, and a platelet count of 70,000/µL. The bone marrow evaluation was diagnostic for a pre-B cell acute lymphoblastic leukemia (ALL), CD34, CD19 and CD22 positive at the immunophenotype analysis, with normal karyotype and without central nervous system (CNS) involvement.\n\nAccording to institutional guidelines and after informed consent was signed, the patient received a chemotherapeutic program, based on the AIEOP LAL2000 clinical protocol backbone, including a steroid pre-treatment, an induction phase 1A (Vincristine, Daunorubicin, L-Asparaginase, Prednisone and intrathecal CNS prophylaxis) and a phase 1B (Cyclophosphamide, oral 6-Mercaptopurine and Cytarabine). After this treatment, the patient obtained a complete morphologic remission, with the persistence of positive minimal residual disease, evaluated by polymerase chain reaction rearrangement of immunoglobulin H gene on day 33, which became negative on day 78.\n\nThus, the patient underwent a third cycle of chemotherapy, which included high dose of Methotrexate (MTX) (3 g/m2) followed by Cyclophosphamide (400 mg), Cytarabine (3900 mg), Vincristine (2 mg) and intrathecal MTX (10 mg). This therapy was well tolerated, and no adverse events occurred. Therefore, after hematologic recovery was reached, the second dosage of HD-MTX was administered, followed by Vindesine (5 mg), Ifosfamide (3200 mg) and Daunorubicin (50 mg).\n\nNine days after MTX infusion, during the iatrogenic aplasia phase, the patient suddenly developed generalized tonic clonic seizures, with loss of consciousness. His blood pressure was 160/100 mmHg; he was confused, and a detailed neurologic examination showed a strong-force defect involving the left arm. Coagulation investigation was normal. Promptly, Diazepam and Dexametasone were administered, with a momentaneus improvement of his clinical condition.\n\nDespite the resolution of this event, the patient showed two further episodes of epilepsy during the same day. Therefore, a brain computed tomography (CT) was immediately performed, revealing the presence of hypodense areas in the bilateral frontal lobes and right parietal parasagittal region, with no intracranial bleeding or venous thrombosis. Consistently, MRI fluid-attenuated inversion recovery and diffusion-weighted imaging revealed subcortical and cortical hyperintensities in the bilateral frontal lobes and parietal parasagittal region (Figure 1A,B). In addiction, the apparent diffusion coefficient (ADC) map showed elevated signal intensities in the bilateral frontal lobes (Figure 1C). These MRI observations were suggestive of vasogenic edema rather than cytotoxic edema. In order to exclude CNS infective involvement, a lumbar puncture was performed, which resulted negative for microbiological agents and leukemic cells. Therefore, based on neuroimaging results and clinical presentation, a diagnosis of posterior reversible encephalopathy syndrome (PRES) was made.\n\nThe patient was admitted to the Intensive Care Unit for monitoring and seizure treatment. A prophylactic therapy with phenytoin and anti-hypertensive drugs was introduced, and a progressive improvement of clinical conditions, neurological symptoms and cognitive status was observed. The patient reached a complete hematological recovery, but due to the severe neurological complication, his chemotherapeutic program was prematurely stopped. Seven months later, a brain MRI demonstrated a complete resolution of previous detected lesions (Figure 1D,E). Unfortunately, the patient relapsed eight months later and died as a consequence of progression disease.\n\nDiscussion and Conclusions\nPosterior reversible encephalopathy syndrome is a clinical-neuroradiological entity, firstly identified by Hinchey et al. in 1996. This condition is often associated with different diseases such as cancer, hypertension, autoimmune abnormalities, eclampsia, sepsis, renal disorders, drugs and bone marrow and solid organ transplant. The clinical presentation is characterized by seizure, which is the most common symptom, headache, confusion, decreased level of consciousness and coma. Visual disturbances include hemianopia, visual neglect and cortical blindness. At neuroimaging, PRES is characterized by transient bilateral lesions, that predominantly affect white matter of the occipital-parietal lobes and can be identified by MRI scan, that allows a more accurate etiological diagnosis compared to CT. PRES management includes withdrawal of damaging agents, blood pressure control and anticonvulsants in patients with seizures. Previously, neurotoxicity has been observed after the administration of high-dose and/or intrathecal MTX in the pediatric population; conversely, little is known in adult patients. To the best of our knowledge, this is the first report of a pre-B ALL young adult patient treated with high dose of MTX, who developed a PRES.\n\nCurrently, in ALL, there is a trend towards more intensive treatment of adult patients with pediatric-inspired regimens, based on the high remission rates obtained by this kind of approach. However, an accurate knowledge of potential therapy related toxicities, including neurologic adverse events, is required for the safe and correct management of these patients.\n\nFigure 1. A,B) Brain magnetic resonance imaging (MRI) imaging (Flair T2 sequence), showing hyperintense lesions in the subcortical white matter of frontal lobes and right parietal parasagittal region consistent with vasogenic edema. C) Apparent diffusion coefficient map showing elevated signal intensities in these lesions. D,E) MRI imaging nine months later, showing almost complete resolution of the lesions.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2038-8322",
"issue": "6(3)",
"journal": "Hematology reports",
"keywords": "acute lymphoblastic leukemia; brain magnetic resonance imaging; methotrexate; posterior reversible encephalopathy syndrome; seizure",
"medline_ta": "Hematol Rep",
"mesh_terms": null,
"nlm_unique_id": "101556723",
"other_id": null,
"pages": "5565",
"pmc": null,
"pmid": "25317320",
"pubdate": "2014-08-26",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Posterior reversible encephalopathy syndrome in a B-cell acute lymphoblastic leukemia young adult patient treated with a pediatric-like chemotherapeutic schedule.",
"title_normalized": "posterior reversible encephalopathy syndrome in a b cell acute lymphoblastic leukemia young adult patient treated with a pediatric like chemotherapeutic schedule"
} | [
{
"companynumb": "IT-PFIZER INC-2014290511",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nSarcoidosis is a multisystem granulomatous disease. This condition has a documented association with the diagnosis of melanoma and can be induced in melanoma patients receiving anti-neoplastic therapy. We evaluated a case series of melanoma patients who developed immunotherapy-induced sarcoidosis.\n\n\nMETHODS\nThree patients with melanoma (n = 1 resected Stage III, n = 2 metastatic) treated with anti-programmed cell death (PD)-1 antibody therapy at two institutions developed biopsy-proven sarcoidosis. We used mass cytometry to determine expression of the relevant chemokine receptors (CR) by peripheral blood mononuclear cells for two of the three patients who developed sarcoidosis and 13 melanoma patients who did not. Blood samples were collected before receiving PD-1 checkpoint inhibitor therapy.\n\n\nRESULTS\nImmunophenotypic analysis demonstrated abnormally high numbers of circulating Th17.1 (CCR6+ CCR4- CXCR3+ CCR10- ) cells prior to commencing PD-1 checkpoint inhibitor therapy in five of 15 melanoma patients, including both the patients who developed sarcoidosis during the course of therapy.\n\n\nCONCLUSIONS\nOur findings support prior literature implicating Th17.1 cells in the pathogenesis of sarcoidosis. However, we demonstrate these findings in patients with melanoma prior to administration of checkpoint therapy and before the onset of clinically symptomatic sarcoidosis. The identification of elevated Th17.1 cells in melanoma patients who have not developed sarcoidosis may reflect the established association between melanoma and sarcoidosis. With some patients receiving these agents over a prolonged period, the clinical course of immunotherapy-induced sarcoidosis is uncertain.",
"affiliations": "Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.;University of Sydney, Sydney, New South Wales, Australia.;Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.;University of Sydney, Sydney, New South Wales, Australia.;Centenary Institute, Sydney, New South Wales, Australia.;Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.;Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.;University of Sydney, Sydney, New South Wales, Australia.;Kossard Dermatopathologists, Sydney, New South Wales, Australia.;Pathology North - Hunter, Newcastle, New South Wales, Australia.;John Hunter and Calvary Mater Hospitals, Newcastle, New South Wales, Australia.;University of Sydney, Sydney, New South Wales, Australia.;University of Sydney, Sydney, New South Wales, Australia.;University of Sydney, Sydney, New South Wales, Australia.;University of Sydney, Sydney, New South Wales, Australia.",
"authors": "Lomax|Anna J|AJ|http://orcid.org/0000-0002-6087-2826;McGuire|Helen M|HM|;McNeil|Catriona|C|;Choi|Clara J|CJ|;Hersey|Peter|P|;Karikios|Deme|D|;Shannon|Kerwin|K|;van Hal|Sebastian|S|;Carr|Urszula|U|;Crotty|Anne|A|;Gupta|Sandeep K|SK|;Hollingsworth|Jane|J|;Kim|Haewon|H|;Fazekas de St Groth|Barbara|B|;McGill|Neil|N|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000074322:Antineoplastic Agents, Immunological; D015415:Biomarkers; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor",
"country": "England",
"delete": false,
"doi": "10.1111/1756-185X.13076",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1756-1841",
"issue": "20(9)",
"journal": "International journal of rheumatic diseases",
"keywords": "melanoma; nivolumab; pembrolizumab; programmed cell death 1; sarcoidosis",
"medline_ta": "Int J Rheum Dis",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D015415:Biomarkers; D001706:Biopsy; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D009367:Neoplasm Staging; D010641:Phenotype; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests; D061026:Programmed Cell Death 1 Receptor; D017565:Sarcoidosis, Pulmonary; D012878:Skin Neoplasms; D058504:Th17 Cells; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101474930",
"other_id": null,
"pages": "1277-1285",
"pmc": null,
"pmid": "28480561",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Immunotherapy-induced sarcoidosis in patients with melanoma treated with PD-1 checkpoint inhibitors: Case series and immunophenotypic analysis.",
"title_normalized": "immunotherapy induced sarcoidosis in patients with melanoma treated with pd 1 checkpoint inhibitors case series and immunophenotypic analysis"
} | [
{
"companynumb": "AU-009507513-1706AUS000169",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Parry Romberg Syndrome (PRS) is a rare condition of unknown cause and pathophysiology. It is characterized by progressive facial hemiatrophy, and neurological abnormalities are found in 20% of cases. We describe a 50-year-old woman with PRS and severe neurological involvement (lateralised epileptic seizure activity and facial pain refractory to medication). Pain intensity and frequency was reduced and control of epileptic crises was improved using levetiracetam as an additional therapy. In previous published cases associated with facial pain, the most frequent diagnoses were migraine and trigeminal neuralgia. Our findings suggest that in this patient PRS-related persistent pain has peculiar features possibly attributed to the underlying musculoskeletal abnormalities.",
"affiliations": "Department of Neurology, San Raffaele Scientific Institute, via Olgettina 48, 20132 Milan, Italy. gloria.dallacosta@gmail.com",
"authors": "Dalla Costa|Gloria|G|;Colombo|Bruno|B|;Dalla Libera|Dacia|D|;Martinelli|Vittorio|V|;Comi|Giancarlo|G|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "20(9)",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Chronic facial pain; PRS; Parry Romberg Syndrome; Progressive facial hemiatrophy",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D059350:Chronic Pain; D005150:Facial Hemiatrophy; D005157:Facial Pain; D005260:Female; D006801:Humans; D008875:Middle Aged",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "1320-2",
"pmc": null,
"pmid": "23528409",
"pubdate": "2013-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Parry Romberg syndrome associated with chronic facial pain.",
"title_normalized": "parry romberg syndrome associated with chronic facial pain"
} | [
{
"companynumb": "IT-RANBAXY-2013R1-73852",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": null,
... |
{
"abstract": "Peritoneal catheter exit-site infections (ESI's) continue to impact significantly on morbidity and catheter longevity. The controversy concerning protocols for daily exit-site care continues for frequency, methodology, cleansing agent, and dressing. Routine daily exit-site care prior to January 1991 consisted of daily showers using liquid soap, povidone scrub, rinsing the shower, and drying with a 4 x 4-in. gauze pad. Catheters have always been immobilized, either with tape or an immobilizing device. Hydrogen peroxide was used only when needed to soften crust formation prior to showering. A light dressing, usually 2 x 2 in., was optional. A recent survey revealed that povidone iodine was the antiseptic of choice for catheter care in 75% of the respondents. However, povidone iodine irritates and dries the skin predisposing it to infection. ESI's are prospectively monitored as part of our quality improvement (QI) program. An incidence of 0.76 episodes/patient-year was noted between January 1989 and May 1991. Given the relative high frequency of ESI's, the protocol was modified and introduced during the January-May 1991 time frame. Routine care now consists of daily showers using only CC-500, a gentle antibacterial cleaner (Care-Tech Laboratories, Inc.), rinsing in the shower, and drying with a 4 x 4-in. gauze. Use of hydrogen peroxide and dressings has remained the same. Additionally, a protocol addressing the prophylaxis for traumatized exist sites was initiated. The incidence of ESI's has dropped significantly to 0.12 episodes/patient-year. Although our population size is small (n = 18), this study does point out the utility of prospectively monitoring trends for appropriate indicators within a QI program.(ABSTRACT TRUNCATED AT 250 WORDS)",
"affiliations": "Department of Medicine, Fitzsimons Army Medical Center, Aurora, Colorado 80045-5001.",
"authors": "Hasbargen|B J|BJ|;Rodgers|D J|DJ|;Hasbargen|J A|JA|;Quinn|M J|MJ|;James|M K|MK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0896-8608",
"issue": "13 Suppl 2()",
"journal": "Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis",
"keywords": null,
"medline_ta": "Perit Dial Int",
"mesh_terms": "D002408:Catheters, Indwelling; D006801:Humans; D017053:Infection Control; D010530:Peritoneal Dialysis; D011182:Postoperative Care; D011785:Quality Assurance, Health Care",
"nlm_unique_id": "8904033",
"other_id": null,
"pages": "S313-5",
"pmc": null,
"pmid": "8399597",
"pubdate": "1993",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Exit-site care--is it time for a change?",
"title_normalized": "exit site care is it time for a change"
} | [
{
"companynumb": "US-BECTON DICKINSON-2018BDN00372",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SOAP"
},
"drugadditional": null,
... |
{
"abstract": "The PELICAN trial evaluates for the first time efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line treatment of metastatic breast cancer (MBC).\n\n\n\nThis randomized, phase III, open-label, multicenter trial enrolled first-line MBC patients who were ineligible for endocrine or trastuzumab therapy. Cumulative adjuvant anthracyclines of 360 mg/m2 doxorubicin or equivalent were allowed. Left ventricular ejection fraction of >50 % was required. Patients received PLD 50 mg/m2 every 28 days or capecitabine 1250 mg/m2 twice daily for 14 days every 21 days. The primary endpoint was time-to-disease progression (TTP).\n\n\n\n210 patients were randomized (n = 105, PLD and n = 105, capecitabine). Adjuvant anthracyclines were given to 37 % (PLD) and 36 % (capecitabine) of patients. No significant difference was observed in TTP [HR = 1.21 (95 % confidence interval, 0.838-1.750)]. Median TTP was 6.0 months for both PLD and capecitabine. Comparing patients with or without prior anthracyclines, no significant difference in TTP was observed in the PLD arm (log-rank P = 0.64). For PLD versus capecitabine, respectively, overall survival (median, 23.3 months vs. 26.8 months) and time-to-treatment failure (median, 4.6 months vs. 3.7 months) were not statistically significantly different. Compared to PLD, patients on capecitabine experienced more serious adverse events (P = 0.015) and more cardiac events among patients who had prior anthracycline exposure (18 vs. 8 %; P = 0.31).\n\n\n\nBoth PLD and capecitabine are effective first-line agents for MBC.",
"affiliations": "Breast Center, Department of Obstetrics and Gynecology and CCC of LMU, University of Munich, Munich, Germany. nadia.harbeck@med.uni-muenchen.de.;Department of Obstetrics and Gynecology, Technical University of Munich, Munich, Germany.;Oncology and Hematology, Krankenhaus Nordwest, Frankfurt, Germany.;Department of Obstetrics and Gynecology, Johannes Gutenberg University, Mainz, Germany.;Universitätsfrauenklinik, Ulm, Germany.;Onkologische Schwerpunktpraxis, Leer, Germany.;Onkologische Praxis Oldenburg, Oldenburg, Germany.;MSD Sharp & Dohme, Haar, Germany.;Department of Obstetrics and Gynecology, Technical University of Munich, Munich, Germany.;Brustzentrum, Krankenhaus Köln-Holweide, Cologne, Germany.;Trium Analysis Online GmbH, Munich, Germany.;Helios Klinikum Berlin-Buch, Berlin, Germany.;Vivantes Klinikum Neukoelln, Berlin, Germany.;Dr.-Horst-Schmidt-Kliniken Wiesbaden, Wiesbaden, Germany.;Dr.-Horst-Schmidt-Kliniken Wiesbaden, Wiesbaden, Germany.;Kliniken Essen-Mitte, Essen, Germany.;Klinikum des Landkreises Deggendorf, Deggendorf, Germany.;Crown Princess Mary Cancer Centre Westmead, Sydney, Australia.;Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Erlangen, Germany.;Oncology and Hematology, Krankenhaus Nordwest, Frankfurt, Germany.",
"authors": "Harbeck|Nadia|N|;Saupe|Steffen|S|;Jäger|Elke|E|;Schmidt|Marcus|M|;Kreienberg|Rolf|R|;Müller|Lothar|L|;Otremba|Burkhard Joerg|BJ|;Waldenmaier|Dirk|D|;Dorn|Julia|J|;Warm|Mathias|M|;Scholz|Michael|M|;Untch|Michael|M|;de Wit|Maike|M|;Barinoff|Jana|J|;Lück|Hans-Joachim|HJ|;Harter|Philipp|P|;Augustin|Doris|D|;Harnett|Paul|P|;Beckmann|Matthias W|MW|;Al-Batran|Salah-Eddin|SE|;|||",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D000069287:Capecitabine; D004317:Doxorubicin",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10549-016-4033-3",
"fulltext": "\n==== Front\nBreast Cancer Res TreatBreast Cancer Res. TreatBreast Cancer Research and Treatment0167-68061573-7217Springer US New York 403310.1007/s10549-016-4033-3Clinical TrialA randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study Harbeck Nadia nadia.harbeck@med.uni-muenchen.de 1Saupe Steffen 2Jäger Elke 3Schmidt Marcus 4Kreienberg Rolf 5Müller Lothar 6Otremba Burkhard Joerg 7Waldenmaier Dirk 8Dorn Julia 2Warm Mathias 9Scholz Michael 10Untch Michael 11de Wit Maike 12Barinoff Jana 13Lück Hans-Joachim 13Harter Philipp 14Augustin Doris 15Harnett Paul 16Beckmann Matthias W. 17Al-Batran Salah-Eddin 3On behalf of the PELICAN Investigators 1 Breast Center, Department of Obstetrics and Gynecology and CCC of LMU, University of Munich, Munich, Germany 2 Department of Obstetrics and Gynecology, Technical University of Munich, Munich, Germany 3 Oncology and Hematology, Krankenhaus Nordwest, Frankfurt, Germany 4 Department of Obstetrics and Gynecology, Johannes Gutenberg University, Mainz, Germany 5 Universitätsfrauenklinik, Ulm, Germany 6 Onkologische Schwerpunktpraxis, Leer, Germany 7 Onkologische Praxis Oldenburg, Oldenburg, Germany 8 MSD Sharp & Dohme, Haar, Germany 9 Brustzentrum, Krankenhaus Köln-Holweide, Cologne, Germany 10 Trium Analysis Online GmbH, Munich, Germany 11 Helios Klinikum Berlin-Buch, Berlin, Germany 12 Vivantes Klinikum Neukoelln, Berlin, Germany 13 Dr.-Horst-Schmidt-Kliniken Wiesbaden, Wiesbaden, Germany 14 Kliniken Essen-Mitte, Essen, Germany 15 Klinikum des Landkreises Deggendorf, Deggendorf, Germany 16 Crown Princess Mary Cancer Centre Westmead, Sydney, Australia 17 Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Erlangen, Germany 31 10 2016 31 10 2016 2017 161 1 63 72 18 10 2016 19 10 2016 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Purpose\nThe PELICAN trial evaluates for the first time efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line treatment of metastatic breast cancer (MBC).\n\nMethods\nThis randomized, phase III, open-label, multicenter trial enrolled first-line MBC patients who were ineligible for endocrine or trastuzumab therapy. Cumulative adjuvant anthracyclines of 360 mg/m2 doxorubicin or equivalent were allowed. Left ventricular ejection fraction of >50 % was required. Patients received PLD 50 mg/m2 every 28 days or capecitabine 1250 mg/m2 twice daily for 14 days every 21 days. The primary endpoint was time-to-disease progression (TTP).\n\nResults\n210 patients were randomized (n = 105, PLD and n = 105, capecitabine). Adjuvant anthracyclines were given to 37 % (PLD) and 36 % (capecitabine) of patients. No significant difference was observed in TTP [HR = 1.21 (95 % confidence interval, 0.838–1.750)]. Median TTP was 6.0 months for both PLD and capecitabine. Comparing patients with or without prior anthracyclines, no significant difference in TTP was observed in the PLD arm (log-rank P = 0.64). For PLD versus capecitabine, respectively, overall survival (median, 23.3 months vs. 26.8 months) and time-to-treatment failure (median, 4.6 months vs. 3.7 months) were not statistically significantly different. Compared to PLD, patients on capecitabine experienced more serious adverse events (P = 0.015) and more cardiac events among patients who had prior anthracycline exposure (18 vs. 8 %; P = 0.31).\n\nConclusion\nBoth PLD and capecitabine are effective first-line agents for MBC.\n\nKeywords\nPegylated liposomal doxorubicinCapecitabineMetastatic breast cancerPELICANhttp://dx.doi.org/10.13039/100008897Janssen Pharmaceuticalshttp://dx.doi.org/10.13039/100004334Merckhttp://dx.doi.org/10.13039/100007110Schering-PloughEssex Pharma GmbHissue-copyright-statement© Springer Science+Business Media New York 2017\n==== Body\nIntroduction\nMetastatic breast cancer (MBC), though not considered curable by today’s therapies, deserves effective treatment. With appropriate chemotherapy, many patients derive its potential benefits, including symptom relief, maintenance of quality of life (QoL), and prolongation of survival. Much research effort has been devoted to identifying the most effective yet tolerable chemotherapy regimens for MBC. The use of sequential single-agent chemotherapy is generally less toxic than combination therapy and yields survival rates similar to those observed with multi-agent regimens [1–3]. In studies that have demonstrated a statistically significant survival benefit for combination therapy, tolerability must be considered and toxicity is often prohibitive in this palliative setting [4].\n\nThe choice among active chemotherapy agents for MBC hinges on efficacy and patient preference, particularly regarding potential side effects. Among the active agents, in particular in the current clinical setting of anthracycline and taxane pre-treatment in the adjuvant setting, are pegylated liposomal doxorubicin (PLD) and capecitabine. Both have demonstrated single-agent efficacy in MBC, are supported by established guidelines, and are relatively well tolerated [5–11].\n\nAdequate evaluation of anthracyclines as first-line treatment for metastatic disease is required due to their routine use in the adjuvant setting. However, use of conventional anthracyclines in the palliative setting is hindered by both acute toxicities and the long-term risk of cardiotoxicity. The pegylated liposomal formulation of doxorubicin prolongs the plasma half-life and may enhance tumor localization of the drug while lowering toxicity to normal tissues. A phase III trial comparing PLD to conventional doxorubicin as first-line therapy for MBC showed comparable efficacy between the two agents with reduced cardiotoxicity in PLD-treated patients [6]. Median progression-free survival (PFS) times were 6.9 months for PLD versus 7.8 months for doxorubicin (hazard ratio [HR] 1.00; 95 %; confidence interval [CI] 0.82–1.22) and median overall survival (OS) times were 21 months for PLD versus 22 months for doxorubicin (HR = 0.94; 95 % CI 0.74–1.19). Clinical congestive heart failure (CHF) occurred in 2 patients treated with PLD and 12 patients treated with doxorubicin. The most frequent PLD-associated toxicity was palmar-plantar erythema (PPE; 48 % all grades, 17 % grade 3 or 4). With PLD having similar efficacy and a more favorable cardiotoxicity profile than conventional doxorubicin, comparing PLD to an effective non-anthracycline regimen in the first-line setting is warranted.\n\nCapecitabine is an oral fluoropyrimidine that mimics infusional 5-fluorouracil (5-FU) and, in the presence of elevated intratumoral thymidine phosphorylase concentrations, generates 5-FU preferentially at the tumor site [12]. Capecitabine produced a response rate of 36 % and median time-to-progression of 3.0 months in anthracycline-pretreated patients [7]. As first-line therapy in women aged 55 years and older, capecitabine produced a response rate of 30 %, median time to progression (TTP) of 4.1 months, and median OS time of 19.6 months, parameters similar to the combination comparator arm of cyclophosphamide, methotrexate and 5-FU (CMF) [8]. Capecitabine was associated with grade 3–4 PPE in 15 % of patients and grade 3–4 diarrhea and stomatitis in 8 % of patients each.\n\nThe current phase III trial, PELICAN, is the first trial to evaluate the efficacy and safety of PLD versus capecitabine as first-line treatment of MBC.\n\nPatients and methods\nStudy design\nPELICAN is a randomized, phase III, open-label, multicenter trial. Patients were centrally randomized in a 1:1 ratio using a computer-generated randomization scheme that was balanced by permutated blocks and stratified according to age and prior anthracycline and/or taxane treatment.\n\nThe primary objective of the study is to compare between the two arms TTP, defined as the duration from first study drug administration to the first documented evidence of progression as assessed by the investigator or death from any cause. Secondary endpoints are to compare overall response rate, overall survival, time to treatment failure, QoL, and safety between the two treatment arms. An additional secondary endpoint, to assess the impacts of PLD and capecitabine on age- and comorbidity-related treatment burdens in all patients via geriatric assessment, will be reported in a separate publication.\n\nPatients\nEligible patients were women aged ≥18 years with metastatic disease of cytologically or histologically confirmed breast cancer whose clinical condition allowed monotherapy treatment or who expressed a desire to be treated with monotherapy. Other inclusion criteria included Eastern Cooperative Oncology Group (ECOG) performance status 0–2; sufficient life expectancy to receive chemotherapy, adequate renal, liver, and bone marrow function; and normal sodium and potassium serum levels.\n\nExclusion criteria included prior chemotherapy for metastatic disease (prior endocrine therapy was permitted); eligibility for hormone therapy (those having progressed on endocrine therapy were permitted); eligibility for trastuzumab; concomitant treatment for metastatic disease except bisphosphonates and including hormonal therapy, radiation, trastuzumab, or other biological; prior treatment with capecitabine; prior adjuvant anthracycline exceeding a cumulative dose of 360 mg/m2 doxorubicin or equivalent; anthracycline-resistant disease (defined as developing locally-recurrent or metastatic disease during, or relapse <12 months after completion of anthracycline therapy); central nervous system metastasis unless asymptomatic for ≥3 months; dyspnea on exertion; and cardiac disease of New York Heart Association (NYHA) Class II or greater, or clinical evidence of congestive heart failure or myocardial infarct within 6 months or a left ventricular ejection fraction (LVEF) <50 %.\n\nTreatment\nRandomized patients received either PLD 50 mg/m2 every 28 days or capecitabine 1250 mg/m2 twice daily for 14 days every 21 days, i.e., the registered doses. Treatment continued until disease progression or unacceptable toxicity. Adjustments for grade 2 or 3 neutropenia or thrombocytopenia consisted of a treatment delay until absolute neutrophil count ≥1500 cells/mm3 and/or platelets ≥75,000 cells/mm3. Grade 4 neutropenia or thrombocytopenia necessitated delay until recovery and dose reduction to 75 % for capecitabine and 80 % for PLD. Adjustments for non-hematologic toxicities were toxicity- and drug-specific, consisting of capecitabine dose reductions to 75 or 50 % and PLD dose reductions to 80 or 60 %. Patients received supportive care per institutional guidelines. Use of erythropoietic factors and granulocyte colony stimulating factors was allowed; the protocol did not specify guidelines supporting or prohibiting prophylactic use. If LVEF decreased by ≥20 % absolute percentage points or if LVEF decreased by ≥10 % absolute percentage points and to <50 %, PLD was to be discontinued.\n\nAssessments\nBaseline and end of study assessments included physical exam, routine laboratory tests (complete blood count and complete metabolic panel), appropriate imaging studies to assess measurable disease, multiple gated acquisition scan (MUGA) or echocardiogram (ECHO), adverse events, QoL, and ECOG performance status. On Day 1 of each cycle, assessments included physical exam, ECOG PS, routine laboratory tests, QoL, and adverse events. On Days 7–14 of each cycle, patients were monitored for adverse events, particularly skin toxicity, at the study center or by their family physician. Response assessment was based on Response Evaluation Criteria in Solid Tumors (RECIST) [13] and occurred every 3 months using the same imaging technique as at baseline. Response or stable disease was confirmed >4 and <12 weeks later. Cardiac assessment was conducted by MUGA or ECHO prior to each PLD course when the total cumulative anthracycline dose reached ≥450 mg/m2 doxorubicin or equivalent, upon clinical evidence of cardiac dysfunction (cardiomegaly on chest X-ray; basilar rales; S3 gallop; or either paroxysmal nocturnal dyspnea orthopnea, or significant dyspnea on exertion), or at any time per the treating physician. Quality of life was assessed using the European Organization for Research and Treatment of Cancer (EORTC) QoL Questionnaire (QLQ)-C30 [14], with an addendum of 4 questions addressing hand-foot syndrome and stomatitis, and the Subjective Significance Questionnaire (SSQ), which is designed to determine the significance to patients of changes in health-related QoL scores addressed by the EORTC QLQ-C30 [15]. After the end of treatment, patients were assessed at least every 6 months for progression, survival, and subsequent treatment.\n\nStatistics\nThe initial planned sample size of 346 was reduced to 210 patients. The reduction was based on a larger-than-initially expected difference in estimated average times to progression between the two regimens of 4 months for capecitabine and 6.9 months for PLD in the first-line setting, which were derived from data published during protocol development. [6, 8, 16–23] From these times, an estimated hazard ratio of 0.58 was calculated; however, a more conservative estimate of 0.65 was applied, requiring approximately 95 patients per arm and 210 patients total, assuming 10 % loss. Type I and type II errors were set at 0.05 and 0.2, respectively. Three planned interim safety analyses occurred during the study; the final analysis, which occurred November 30, 2010, is reported here.\n\nData for baseline characteristics and safety were summarized. Time to disease progression and overall survival were analyzed using the Kaplan–Meier method. The log-rank test was used to compare TTP between the two treatments. If the trial failed to detect a significant difference between the two treatments, the results of the superiority trial were to be summarized by means of a one-sided 97.5 % CI for the HR (PLD vs. capecitabine). The upper end of that CI provides a quantitative estimate of the minimum estimated effect of PLD relative to capecitabine. If this estimate fell below the margin for non-inferiority, PLD would be considered as being non-inferior to capecitabine. The prospectively defined margin for non-inferiority was a HR of 1.143 reflecting a clinically acceptable difference in TTP of 0.75 months under an expected median TTP of up to 6 months in the comparator. The overall survival curves were compared using a two-tailed log-rank statistic to test for homogeneity of survival functions. Chi square was used to compare overall response rates between groups. Efficacy analyses were performed on the intent-to-treat population, defined as all randomized patients. The safety analysis included all randomized patients who received at least a partial dose of study medication. Quality of life endpoints were analyzed with a one-way analysis of covariance (ANCOVA), with the baseline values included as a covariate.\n\nEthics\nThe study was performed in accordance with the International Conference on Harmonisation guidelines for Good Clinical Practice. All patients provided written informed consent and Institutional Review Board approval was secured at each site. The study was sponsored by Merck, formerly Schering-Plough Corporation and Essex Pharma GmbH and is registered with European Union Drug Regulating Authorities Clinical Trials (EudraCT; Number 2005-003164-35) and clinicaltrials.gov (NCT00266799).\n\nResults\nBetween January 2006 and October 2010, 210 patients were randomized (Fig. 1). The intent-to-treat analysis comprised 210 patients (n = 105 in the PLD arm and n = 105 in the capecitabine arm). Baseline characteristics were well balanced between groups (Table 1). Anthracyclines had been previously administered to 37 % of patients in the PLD arm and 36 % of patients in the capecitabine arm. Patients in both arms received a median of 5 cycles with a range of 0–24 cycles in the PLD arm and 0–41 cycles in the capecitabine arm (P = 0.078).Fig. 1 CONSORT diagram. *Completed patients were those who stopped study treatment due to progressive disease\n\n\nTable 1 Baseline characteristics\n\n\tPLD N = 105\tCapecitabine N = 105\t\n\nN (%)\t\nN (%)\t\nMedian age of patient, years (range)\t62 (36–82)\t63 (22–85)\t\nECOG performance status\t\n Missing\t5 (4)\t1 (1)\t\n 0\t51 (49)\t53 (50)\t\n 1\t43 (41)\t45 (43)\t\n 2\t6 (6)\t5 (5)\t\n 3\t0\t1 (1)\t\nPrior anthracyclines\t\n Yes\t39 (37)\t38 (36)\t\n No\t66 (63)\t67 (64)\t\nMenopausal status\t\n Premenopausal\t5 (5)\t5 (5)\t\n Postmenopausal\t85 (83)\t87 (85)\t\n Not known/examined\t15 (14)\t13 (12)\t\n\n\n\nEfficacy\nThe primary endpoint, TTP, was not statistically significantly different between arms (Fig. 2a). The HR for PLD versus capecitabine was 1.08 (95 % confidence interval 0.76—1.54; P = 0.67). The upper bound of the one-sided 97.5 % CI for the HR of PLD is 1.54. Since this bound is greater than the bound for non-inferiority (1.143), PLD cannot be considered non-inferior to capecitabine. When analyzed by prior adjuvant anthracycline administration (Table 2), TTP in the PLD arm remained similar. In the capecitabine arm, patients who had received prior anthracyclines had a statistically significantly shorter TTP compared to those without prior anthracyclines (median TTP 4.8 months vs. 8.3 months; log-rank P = 0.04).Fig. 2 Time to disease progression (a), overall survival (b), and time to treatment failure (c)\n\n\nTable 2 Time to progression by prior adjuvant anthracycline administration\n\n\tPLD N = 98\tCapecitabine N = 102\t\nPrior anthracycline\t\nNo\tYes\tNo\tYes\t\nNumber of patients\t61\t37\t64\t38\t\nNumber of events\t34\t27\t38\t30\t\nMedian TTP (months)\t7.1\t5.8\t8.3\t4.8\t\nLog-rank P value\t0.64\t0.04\t\nProportion without progression (%)\t\n At 6 months\t54\t47\t56\t42\t\n At 12 months\t21\t18\t36\t13\t\n\n\n\nBoth confirmed and unconfirmed overall response rates were similar between arms. The confirmed overall response rate according to investigator assessment was 7.3 % in the PLD arm (n = 82) and 13.8 % in the capecitabine arm (n = 87; P = 0.17). One complete response was observed in the PLD arm. The corresponding overall response rates according to RECIST were 10.7 % among 84 assessable patients on the PLD arm and 12.9 % among 85 assessable patients on the capecitabine arm (P = 0.65).\n\nAt the time of the analysis, 70 patients were still alive: 34 patients on the PLD arm (34.7 %) and 36 patients on the capecitabine arm (35.3 %). Overall survival was not statistically significantly different between treatments (Fig. 2b). Time-to-treatment failure was also similar between arms (Fig. 2c).\n\nSafety\nThe most common adverse events of any grade included PPE, stomatitis, and fatigue in the PLD arm and PPE, fatigue, and diarrhea in the capecitabine arm (Table 3). Patients receiving PLD experienced a greater incidence of all-grade leukopenia (38 vs. 17 %; P = 0.002), stomatitis (40 vs. 17 %; P = 0.0007), ear, nose and throat abnormalities (43 vs. 17 %; P < 0.0001), alopecia (28 vs. 10 %; P = 0.002), and constipation (26 vs. 10 %; P = 0.005); patients receiving capecitabine had higher rates of diarrhea (43 vs. 16 %; P < 0.0001), and pulmonary embolism (6 vs. 0 %; P = 0.04). More patients in the capecitabine arm experienced thromboembolism of any type (17 vs. 2 %). Serious adverse events (SAE) of any type were more common in the capecitabine arm. A total of 59 SAEs occurred in the PLD arm compared to 112 in the capecitabine arm. Because the treatment duration of capecitabine was longer than PLD, the adverse event incidence density was calculated and revealed a statistically significant difference in favor of PLD for SAEs (0.023, PLD vs. 0.037, capecitabine; P = 0.003). The incidence of cardiac events was not statistically significantly different between arms, irrespective of prior anthracycline exposure (Table 3); however, among patients with prior anthracycline exposure, the proportion of cardiac events was somewhat elevated in the capecitabine arm (18 vs. 8 %; P = 0.31). One patient in the PLD arm experienced a grade 5 cardiac event consisting of cardiac decompensation. Among patients with both a baseline and at least one post-baseline LVEF measurement (n = 86, PLD and n = 90, capecitabine), an absolute decrease in LVEF of ≥10 % occurred in 6 patients (7 %) in the PLD arm and 8 patients (9 %) in the capecitabine arm (P = 0.64); a decrease of ≥20 to <50 % occurred in no patients in the PLD arm and in 2 patients (2 %) in the capecitabine arm (P = 0.16).Table 3 Adverse events\n\nAdverse Event\tPLD N = 98\tCapecitabine N = 102\t\nP\na\n\t\nAll grades No. (%)\tGrade 3–4 No. (%)\tAll grades No. (%)\tGrade 3–4 No. (%)\t\nHematologic Toxicity\t\n Leukopenia\t37 (38)\t4 (4)\t17 (17)\t1 (1)\t.002\t\n Anemia\t25 (26)\t1 (1)\t21 (20)\t5 (5)\t.10\t\n Neutropenia\t18 (18)\t3 (3)\t10 (10)\t2 (2)\t.19\t\n Thrombocytopenia\t6 (6)\t1 (1)\t6 (6)\t1 (1)\t1.0\t\nNon-hematologic toxicity occurring in ≥20 % of patients in either arm\t\n Hand-foot syndrome\t65 (66)\t38 (39)\t69 (67)\t27 (26)\t.08\t\n Stomatitis\t39 (40)\t6 (6)\t18 (17)\t0\t.0007\t\n Fatigue\t53 (54)\t4 (4)\t55 (54)\t7 (7)\t.71\t\n Ear, nose, throat abnormality\t42 (43)\t6 (6)\t17 (17)\t0\t<.0001\t\n Nausea\t41 (42)\t0\t42 (41)\t2 (2)\t.59\t\n Alopecia\t27 (28)\t–\t10 (10)\t–\t.002\t\n Constipation\t25 (26)\t0\t10 (10)\t0\t.005\t\n Vomiting\t18 (18)\t0\t30 (30)\t2 (2)\t.09\t\n Peripheral sensory neuropathy\t17 (17)\t1 (1)\t25 (24)\t0\t.19\t\n Diarrhea\t16 (16)\t0\t44 (43)\t13 (13)\t<.0001\t\n Dyspnea\t14 (14)\t3 (3)\t24 (24)\t7 (7)\t.23\t\nCardiac events\t\n Total events\t9 (9)\t1 (1)\t13 (13)\t0\t.50\t\nWithout anthracycline pretreatment\t\t\n Total no. of patients\t61\t64\t\t\n Patients with cardiac events, no. (%)\t6 (10)\t1 (2)\t6 (9)\t0 (0)\t1.0b\n\t\nWith anthracycline pretreatment\t\t\n Total no. of patients\t37\t38\t\t\n Patients with cardiac events, no. (%)\t3 (8)\t0\t7 (18)\t0\t0.31b\n\t\n\na Fisher’s exact test for grade 0 versus 1–2 versus 3–5\n\n\nb Fisher’s exact test\n\n\n\n\nQuality of life\nThe two therapies generally had a similar effect on QoL. Mean changes from baseline in EORTC QLQ C-30 scores were significantly different between PLD and capecitabine at selected timepoints in certain domains (Table 4). For all SSQ domains, the majority of responses across all cycles were categorized as same or better since the last visit in both arms (Table 5).Table 4 Mean Change from baseline in EORTC QLQ-C30\n\nDomain\tParameter\tCycle 1\tCycle 2\tCycle 3\tCycle 4\tEOT/EOS\t\nPLD\tCAPE\tPLD\tCAPE\tPLD\tCAPE\tPLD\tCAPE\tPLD\tCAPE\t\nPhysical functioning\tNo. patients\t\nn = 19\t\nn = 10\t\nn = 52\t\nn = 36\t\nn = 48\t\nn = 28\t\nn = 30\t\nn = 23\t\nn = 5\t\nn = 5\t\nScore changea\n\t0\t0\t−1.0\t−13.0\t−2.8\t−10.7\t−0.7\t−15.9\t−10.7\t−24.0\t\n\nP\nc\n\t.86\t.01\t.06\t.006\t.31\t\nRole functioning\tNo. patients\t\nn = 19\t\nn = 10\t\nn = 51\t\nn = 36\t\nn = 48\t\nn = 28\t\nn = 30\t\nn = 24\t\nn = 5\t\nn = 5\t\nScore changea\n\t2.6\t−3.3\t−5.2\t−15.3\t−6.6\t−14.3\t−4.4\t−22.2\t−16.7\t−23.3\t\n\nP\nc\n\t.33\t.24\t.25\t.02\t.67\t\nCognitive functioning\tNo. patients\t\nn = 19\t\nn = 10\t\nn = 52\t\nn = 36\t\nn = 47\t\nn = 28\t\nn = 30\t\nn = 26\t\nn = 5\t\nn = 5\t\nScore changea\n\t4.4\t−13.3\t−1.0\t−0.9\t2.8\t1.8\t−0.6\t2.6\t0\t−23.3\t\n\nP\nc\n\t.04\t.73\t.98\t.26\t.18\t\nGlobal health status\tNo. patients\t\nn = 16\t\nn = 9\t\nn = 45\t\nn = 31\t\nn = 43\t\nn = 21\t\nn = 27\t\nn = 20\t\nn = 5\t\nn = 4\t\nScore changea\n\t8.3\t−6.5\t6.5\t−4.0\t4.4\t−2.0\t0\t−16.2\t−13.3\t2.1\t\n\nP\nc\n\t.25\t.29\t.63\t.04\t.99\t\nFatigue\tNo. patients\t\nn = 19\t\nn = 10\t\nn = 52\t\nn = 36\t\nn = 48\t\nn = 29\t\nn = 30\t\nn = 25\t\nn = 5\t\nn = 5\t\nScore changeb\n\t−3.2\t2.2\t4.6\t11.4\t3.7\t8.4\t1.8\t19.1\t11.1\t24.4\t\n\nP\nc\n\t.41\t.49\t.29\t.02\t.54\t\nConstipation\tNo. patients\t\nn = 19\t\nn = 8\t\nn = 52\t\nn = 35\t\nn = 47\t\nn = 27\t\nn = 30\t\nn = 23\t\nn = 5\t\nn = 5\t\nScore changeb\n\t−3.5\t0\t10.9\t−2.8\t10.6\t−4.9\t17.8\t−13.0\t0\t−6.7\t\n\nP\nc\n\t.44\t.07\t.22\t.004\t.48\t\nDermatology/skin\tNo. patients\t\nn = 15\t\nn = 9\t\nn = 42\t\nn = 28\t\nn = 40\t\nn = 20\t\nn = 22\t\nn = 19\t\nn = 5\t\nn = 3\t\nScore changb\n\t6.1\t−5.6\t9.1\t1.2\t33.3\t12.1\t37.1\t22.8\t18.3\t44.4\t\n\nP\nc\n\t.08\t.20\t.04\t.26\t.70\t\nIncludes only domains for which a statistically significant difference between arms was observed at any timepoint. Domains excluded are EORTC QLQ C30 Emotional Functioning, Social Functioning, Nausea/Vomiting, Pain, Dyspnea, Insomnia, Appetite Loss, Diarrhea and Financial Problems\n\n\nCAPE capecitabine, EORTC QLQ-C30 European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C-30, EOS end of study, EOT end of treatment, PLD pegylated liposomal doxorubicin\n\n\naMean change in score from screening; negative value indicates deterioration in QoL, positive value indicates improvement\n\n\nbMean change in score from screening; greater value indicates worse symptoms\n\n\ncANCOVA; for comparison between treatment arms in change from screening\n\n\nTable 5 Proportion of responses to the subjective significance questionnaire (SSQ) across all cycles categorized as same or better since last visit\n\nDomain\tPLD\tCapecitabine\t\nNo. responses across all cycles\t522\t708\t\nPhysical condition (%)\t\t\t\n Same\t56.8\t56.2\t\n Better\t14.8\t19.8\t\nEmotional condition (%)\t\t\t\n Same\t58.8\t57.3\t\n Better\t13.8\t19.5\t\nSocial life enjoyment (%)\t\t\t\n Same\t63.6\t62.4\t\n Better\t13.2\t16.5\t\nOverall quality of life (%)\t\t\t\n Same\t55.5\t55.7\t\n Better\t14.3\t18.2\t\nBetter category combines the following responses: “a little better”, “moderately better”, and “very much better”\n\n\nPLD pegylated liposomal doxorubicin\n\n\n\n\nDiscussion\nThe PELICAN trial evaluated for the first time the first-line efficacy of PLD and capecitabine in a randomized setting for all patients. A recent Dutch phase III trial compared first-line PLD versus capecitabine in elderly patients with MBC but had to be closed prematurely due to slow accrual and lack of supply of PLD. In the Dutch phase III trial, PLD and capecitabine demonstrated comparable efficacy, the number of geriatric conditions correlated with grade 3–4 toxicities, and frailty correlated with shorter survival [24, 25]. In our phase III PELICAN trial, efficacy of first-line PLD was neither superior nor non-inferior to capecitabine in patients with MBC, as reflected by TTP (HR = 1.08; P = 0.67) and OS (HR = 1.12; P = 0.53). Notably, alopecia was absent in a majority of patients in both arms, making both therapies very attractive for first-line use. Other acute toxicities differed between the two agents with more leucopenia and mucositis of any grade occurring with PLD and diarrhea and thromboembolic events of any grade and of high grades occurring more frequently with capecitabine. Patients in the capecitabine arm experienced a higher rate of serious adverse events and a non-statistically significant elevation in cardiac events among those with previous anthracycline exposure. One high-grade cardiac event was observed, occurring in the PLD arm.\n\nThe efficacy observed with PLD in this study was consistent with prior first-line experience. Median TTP of 6.0 months and median OS of 23.3 months were similar to those observed in the trial of PLD versus doxorubicin in which patients on PLD experienced a median PFS of 6.9 months and median OS of 21 months [6]. Conversely, the efficacy of capecitabine (median TTP, 6.1 months; median OS, 26.8 months) was somewhat more favorable compared to median TTP between 3.9 and 7.4 months in prior first-line studies [8, 22–26]. These differences may account for the lack of superiority of PLD over capecitabine in the current trial.\n\nWith the widespread use of adjuvant anthracyclines, repeat use of these agents in the metastatic setting has warranted caution due to potential reduction in efficacy and increased cardiotoxicity. The PELICAN trial addressed these key issues. Results clearly demonstrated that the benefit from PLD was present regardless of prior anthracycline use (median TTP 7.1 months with prior exposure versus 5.8 months without; P = 0.64). Surprisingly, prior anthracycline use affected the efficacy of capecitabine; those without prior anthracycline exposure had a statistically significantly higher TTP than those with previous exposure (P = 0.04; median 8.3 vs. 4.8 months). The difference between groups is driven by an unexpectedly long TTP in unexposed patients; in phase II trials that included fewer than 30 % of anthracycline-pretreated patients, median TTP with first-line capecitabine ranged from 3.9 to 6 months [8, 16, 22].\n\nCardiac safety data from the current trial corroborates the favorable profile of PLD, and allays fears of increased cardiotoxicity with use following prior anthracycline exposure. The trial demonstrated no increase in overall cardiac events in the PLD arm compared to the capecitabine arm. In fact, among patients with prior anthracycline exposure, a numerically higher rate of cardiac events occurred in the capecitabine arm (18 vs. 8 %; P = 0.31). The high-grade cardiac event in the PLD arm occurred in a patient without prior anthracycline treatment. The current trial required patients to enter without evidence of clinical CHF and a LVEF of ≥50 %. Thus, patients who had persistent cardiac decompensation following prior anthracycline use were excluded while anthracycline-naïve patients were not subject to a therapeutic trial that might select individuals particularly sensitive to cardiotoxicity. These results highlight the need for biomarkers to predict which patients are most susceptible to anthracycline-induced cardiac damage.\n\nThe primary endpoint (TTP) was similar between PLD and capecitabine (median TTP, 6.0 months versus 6.1 months, respectively). PLD failed to demonstrate superiority as first-line therapy in unselected patients with MBC. Use of a prior anthracycline did not affect the TTP of patients treated with PLD, a particularly relevant outcome as most patients today have received an anthracycline-taxane regimen in the adjuvant setting. The lack of alopecia and similar QoL observed with both agents make each agent a favorable first-line treatment option. It can be concluded from the PELICAN trial that both PLD and capecitabine are active and represent effective and relatively well-tolerated treatment options for first-line MBC. For the individual patient, chemotherapy choice may depend on the physician’s and patient’s preferences, with consideration given to prior adjuvant therapy as well as each drug’s safety profile.\n\nResearch support was provided by Merck, formerly Schering-Plough Corporation and Essex Pharma GmbH. Schering-Plough Corporation provided an unrestricted grant for editorial assistance with the manuscript, provided by Phillips Gilmore. Approval of the final manuscript rested solely with the authors.\n\nCompliance with ethical standards\nConflict of interest\nMShmidt is named inventor on patent applications regarding prediction of chemotherapeutic response in breast cancer and molecular markers for breast cancer prognosis. Consultant for Pfizer, Roche, Eisai, Celgene, Novartis, TEVA, and Sividon. He has received honoraria from AstraZeneca, Novartis, Pfizer, Celgene, Pierre-Fabre, GlaxoSmithKline, Eisai, Roche, Sividon, TEVA, and Amgen. He has also received previous funding from Bayer Healthcare AG, Sanofi-Aventis, and Bundesministerium für Bildung und Forschung (BMBF). DW was an employee of Shering-Plough Corp. and MDS Sharp & Dohme at the time the study was conducted. NH, SS, EJ, LM, RK, BO, JD, MW, MScholz, MU, MdW, JB, HJL, PHarnet, DA, PHarter, MB and SEAB declare no conflicts of interest.\n==== Refs\nReferences\n1. Fountzilas G Dafni U Dimopoulos MA A randomized phase III study comparing three anthracycline-free taxane-based regimens, as first line chemotherapy, in metastatic breast cancer: a Hellenic Cooperative Oncology Group study Breast Cancer Res Treat 2009 115 87 99 10.1007/s10549-008-0047-9 18483853 \n2. Martín M Ruiz A Muñoz M Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial Lancet Oncol 2007 8 219 225 10.1016/S1470-2045(07)70041-4 17329192 \n3. Joensuu H Holli K Heikkinen M Combination chemotherapy versus single-agent therapy as first- and second-line treatment in metastatic breast cancer: a prospective randomized trial J Clin Oncol 1998 16 3720 3730 9850014 \n4. Carrick S Parker S Thornton CE Single agent versus combination chemotherapy for metastatic breast cancer Cochrane Database Syst Rev 2009 19370586 \n5. Keller AM Mennel RG Georgoulias VA Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer J Clin Oncol 2004 22 3893 3901 10.1200/JCO.2004.08.157 15459210 \n6. O’Brien MER Wigler N Inbar M Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX™/Doxil® ) versus conventional doxorubicin for first-line treatment of metastatic breast cancer Ann Oncol 2004 15 440 449 10.1093/annonc/mdh097 14998846 \n7. Talbot DC Moiseyenko V Van Belle S Randomised, phase II trial comparing oral capecitabine (Xeloda® ) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines Br J Cancer 2002 86 1367 1372 10.1038/sj.bjc.6600261 11986765 \n8. O’Shaughnessy JA Blum J Moiseyenko V Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer Ann Oncol 2001 12 1247 1254 10.1023/A:1012281104865 11697835 \n9. Blum JL Jones SE Buzdar AU Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer J Clin Oncol 1999 17 485 493 10080589 \n10. National Comprehensive Cancer Network (2015) Clinical practice guidelines in oncology: breast cancer. Version 2.2015. http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf. Accessed 11 Mar 2015\n11. Hanf V Schütz F Liedtke C Thill M AGO recommendations for the diagnosis and treatment of patients with advanced and metastatic breast cancer Breast Care 2014 9 3 202 209 10.1159/000363551 25177262 \n12. Miwa M Ura M Nishida M Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue Eur J Cancer 1998 34 1274 1281 10.1016/S0959-8049(98)00058-6 9849491 \n13. Therasse P Arbuck SG Eisenhauer EA New guidelines to evaluate the response to treatment in solid tumors J Nat Cancer Inst 2000 92 205 216 10.1093/jnci/92.3.205 10655437 \n14. Aaronson N Ahmedzai S Bergman B The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology J Natl Cancer Inst 1993 85 360 376 10.1093/jnci/85.5.365 \n15. Osoba D Rodrigues G Myles J Interpreting the significance of changes in health-related quality-of-life scores J Clin Oncol 1998 16 139 144 9440735 \n16. Bajetta E Procopio G Celio L Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women J Clin Oncol 2005 23 2155 2161 10.1200/JCO.2005.02.167 15710946 \n17. Ranson MR Carmichael J O’Byrne K Stewart S Smith D Howell A Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial J Clin Oncol 1997 15 3185 3191 9336354 \n18. Lyass O Uziely B Ben-Yosef R Tzemach D Heshing NI Lotem M Brufman G Gabizon A Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma Cancer 2000 89 1037 1049 10.1002/1097-0142(20000901)89:5<1037::AID-CNCR13>3.0.CO;2-Z 10964334 \n19. Yardley DA Shipley DM Greco FA Phase II randomized trial of pegylated liposomal doxorubicin vs. weekly docetaxel with subsequent crossover as first-line chemotherapy for metastatic breast cancer Breast Cancer Res Treat 2004 88 S203 \n20. Huober J Fett W Nusch A A multicentric observational trial of pegylated liposomal doxorubicin for metastatic breast cancer BMC Cancer 2010 10 2 10.1186/1471-2407-10-2 20047698 \n21. Minea LN Stanculeanu DL Cringeanu A Anghel RM Capecitabine monotherapy for elderly patients with metastatic breast cancer J Clin Oncol 2004 22 14 S797 \n22. Stockler MR Harvey VJ Francis PA Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer J Clin Oncol 2011 29 34 4498 4504 10.1200/JCO.2010.33.9101 22025143 \n23. El-Helw L Coleman RE Reduced dose capecitabine is an effective and well-tolerated treatment in patients with metastatic breast cancer Breast 2005 14 368 374 10.1016/j.breast.2004.12.005 16216738 \n24. Smorenburg CH de Groot SM van Leeuwen-Stok AE A randomized phase III study comparing pegylated liposomal doxorubicin with capecitabine as first-line chemotherapy in elderly patients with metastatic breast cancer: results of the OMEGA study of the Dutch Breast Cancer Research Group BOOG Ann Oncol 2014 25 3 599 605 10.1093/annonc/mdt588 24504445 \n25. Hamaker ME Seynaeve C Wymenga AN Baseline comprehensive geriatric assessment is associated with toxicity and survival in elderly metastatic breast cancer patients receiving single-agent chemotherapy: results from the OMEGA study of the Dutch breast cancer trialists’ group Breast 2014 23 81 87 10.1016/j.breast.2013.11.004 24314824 \n26. Kaufmann M Maass N Costa SD First-line therapy with moderate dose capecitabine in metastatic breast cancer is safe and active: results of the MONICA trial Eur J Cancer 2010 46 3184 3191 10.1016/j.ejca.2010.07.009 20797843\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0167-6806",
"issue": "161(1)",
"journal": "Breast cancer research and treatment",
"keywords": "Capecitabine; Metastatic breast cancer; PELICAN; Pegylated liposomal doxorubicin",
"medline_ta": "Breast Cancer Res Treat",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D001943:Breast Neoplasms; D000069287:Capecitabine; D018450:Disease Progression; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011092:Polyethylene Glycols; D011788:Quality of Life; D012307:Risk Factors; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8111104",
"other_id": null,
"pages": "63-72",
"pmc": null,
"pmid": "27798749",
"pubdate": "2017-01",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "19370586;22025143;15710946;14998846;10655437;15459210;11697835;9850014;16216738;9336354;18483853;24504445;10964334;8433390;9849491;20047698;24314824;17329192;25177262;9440735;20797843;10080589;11986765",
"title": "A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study.",
"title_normalized": "a randomized phase iii study evaluating pegylated liposomal doxorubicin versus capecitabine as first line therapy for metastatic breast cancer results of the pelican study"
} | [
{
"companynumb": "DE-JNJFOC-20161114140",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "Objectives: The aim of this study was to describe the tolerability, safety, and effectiveness of ocrelizumab for primary progressive multiple sclerosis (PPMS) and relapsing multiple sclerosis (RMS) in a clinical practice setting. Methods: In this retrospective observational study, we analyzed clinical and MRI data in all patients with PPMS and RMS who had received at least one infusion of ocrelizumab in two health areas in south-eastern Spain. Patients involved in any ocrelizumab trial and those patients with a follow-up shorter than 6 months were excluded. Results: The cohort included 70 patients (42 women) who had received ocrelizumab; 30% had PPMS and 70%, RMS. At baseline, patients' mean age was 47.1 years in the PPMS group and 39.2 years in the RMS group, while the median EDSS was 3.0 and 2.5, respectively. Median follow-up was 13.6 months. The median number of treatment cycles was three. Most patients remained free from clinical and MRI activity after ocrelizumab initiation. Baseline MRI showed T1 Gd-enhancing lesions in 57% of the patients; by the first MRI control at 4-6 months, all patients except one were free of T1 Gd-enhancing lesions (69/70, 98.6% P < 0.001). The proportion of patients with NEDA was 94% in the group of RMS patients who were followed for at least 1 year. Ocrelizumab was generally well-tolerated; the most common adverse events were infusion-related reactions and infections, none of which were serious. Conclusions: Our real-world study supports the tolerability, safety, and effectiveness of ocrelizumab in clinical practice.",
"affiliations": "Neurology Service, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain.;Neurology Service, Hospital Marina Baixa, Villajoyosa, Spain.;Department of Clinical Medicine, Miguel Hernández University, San Juan de Alicante, Spain.;Pharmacy Department, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain.;Department of Radiology, Hospital General Universitario de Alicante, Alicante, Spain.;Department of Radiology, Hospital General Universitario de Alicante, Alicante, Spain.;Neurology Service, Hospital Marina Baixa, Villajoyosa, Spain.;Department of Clinical Medicine, Miguel Hernández University, San Juan de Alicante, Spain.",
"authors": "Sempere|Angel P|AP|;Berenguer-Ruiz|Leticia|L|;Borrego-Soriano|Ines|I|;Burgos-San Jose|Amparo|A|;Concepcion-Aramendia|Luis|L|;Volar|Lucian|L|;Aragones|Miguel|M|;Palazón-Bru|Antonio|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fneur.2020.592304",
"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295 Frontiers Media S.A. \n\n10.3389/fneur.2020.592304\nNeurology\nOriginal Research\nOcrelizumab in Multiple Sclerosis: A Real-World Study From Spain\nSempere Angel P. 12* Berenguer-Ruiz Leticia 3 Borrego-Soriano Ines 2 Burgos-San Jose Amparo 4 Concepcion-Aramendia Luis 5 Volar Lucian 5 Aragones Miguel 3 Palazón-Bru Antonio 2 1Neurology Service, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain\n2Department of Clinical Medicine, Miguel Hernández University, San Juan de Alicante, Spain\n3Neurology Service, Hospital Marina Baixa, Villajoyosa, Spain\n4Pharmacy Department, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain\n5Department of Radiology, Hospital General Universitario de Alicante, Alicante, Spain\nEdited by: Francesca Gilli, Dartmouth College, United States\n\nReviewed by: Antonio Carotenuto, University of Naples Federico II, Italy; Cavit Boz, Karadeniz Technical University, Turkey\n\n*Correspondence: Angel P. Sempere angel.perezs@umh.esorcid.org/0000-0002-0195-2834This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology\n\n\n15 1 2021 \n2020 \n11 59230406 8 2020 07 12 2020 Copyright © 2021 Sempere, Berenguer-Ruiz, Borrego-Soriano, Burgos-San Jose, Concepcion-Aramendia, Volar, Aragones and Palazón-Bru.2021Sempere, Berenguer-Ruiz, Borrego-Soriano, Burgos-San Jose, Concepcion-Aramendia, Volar, Aragones and Palazón-BruThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Objectives: The aim of this study was to describe the tolerability, safety, and effectiveness of ocrelizumab for primary progressive multiple sclerosis (PPMS) and relapsing multiple sclerosis (RMS) in a clinical practice setting.\n\nMethods: In this retrospective observational study, we analyzed clinical and MRI data in all patients with PPMS and RMS who had received at least one infusion of ocrelizumab in two health areas in south-eastern Spain. Patients involved in any ocrelizumab trial and those patients with a follow-up shorter than 6 months were excluded.\n\nResults: The cohort included 70 patients (42 women) who had received ocrelizumab; 30% had PPMS and 70%, RMS. At baseline, patients' mean age was 47.1 years in the PPMS group and 39.2 years in the RMS group, while the median EDSS was 3.0 and 2.5, respectively. Median follow-up was 13.6 months. The median number of treatment cycles was three. Most patients remained free from clinical and MRI activity after ocrelizumab initiation. Baseline MRI showed T1 Gd-enhancing lesions in 57% of the patients; by the first MRI control at 4–6 months, all patients except one were free of T1 Gd-enhancing lesions (69/70, 98.6% P < 0.001). The proportion of patients with NEDA was 94% in the group of RMS patients who were followed for at least 1 year. Ocrelizumab was generally well-tolerated; the most common adverse events were infusion-related reactions and infections, none of which were serious.\n\nConclusions: Our real-world study supports the tolerability, safety, and effectiveness of ocrelizumab in clinical practice.\n\nmultiple sclerosisdrug therapyocrelizumabsafetytolerabilityreal-worldeffectivenessMRI\n==== Body\nIntroduction\nThe humanized anti-CD20 B cell-depleting antibody ocrelizumab is approved in Europe for treating adults who have relapsing forms of multiple sclerosis (RMS) with active disease or early primary progressive multiple sclerosis (PPMS) with imaging features characteristic of inflammatory activity (1). The pool of PPMS patients who are candidates for this drug differs from the population studied in the pivotal phase 3 randomized clinical trials (RCT) with respect to the requirement of evidence of inflammatory activity from magnetic resonance imaging (MRI) (T1 Gd-enhancing lesions and/or new or enlarging T2 lesions), which was not present in the RCT inclusion criteria (2).\n\nIn the 96-weeks OPERA I and II trials in patients with RMS, ocrelizumab significantly reduced annualized relapse rates vs. interferon β-1a by 46% and the number of gadolinium-enhancing lesions by 94% (3). Likewise, in the ORATORIO trial in patients with PPMS, ocrelizumab significantly reduced the risk of confirmed disability progression relative to placebo (2). Ocrelizumab was generally well-tolerated in these studies, with mild to moderate infusion-related reactions and infections being the most common adverse events (4).\n\nAlthough RCTs are essential to establish the efficacy of a new drug, they have limited validity because their results may not be widely generalizable, since the enrollment of patients with different comorbidities or previous treatments may be limited by the inclusion criteria. Real-world studies can thus provide useful information on the treatment tolerability, effectiveness and safety (5). Real-world data on ocrelizumab is limited as only a few studies have been published in Europe (6–8). The aim of this study was to describe the tolerability, safety and effectiveness of ocrelizumab for PPMS and RMS in clinical practice in a different geographical setting.\n\nMethods\nPatients and Study Design\nThis retrospective, observational study was performed in two health areas in the province of Alicante: Marina Baixa and Alicante, both situated in south-eastern Spain with a combined population of about 500,000. Patients with multiple sclerosis were attended at Marina Baixa General Hospital and Alicante General Hospital. The patients of both centers were evaluated jointly, under the same protocol. The healthcare system in Spain is universal and free at the point of service.\n\nThe main inclusion criteria was a history of initiation of ocrelizumab. Patients involved in any ocrelizumab trial and those patients with a follow-up shorter than 6 months were excluded. We retrospectively analyzed data in all patients with PPMS and RMS who had received at least one infusion of ocrelizumab. Multiple sclerosis was diagnosed according to the McDonald criteria (9). Clinical relapse, disease progression, and adverse events during ocrelizumab treatment were assessed by reviewing medical reports until September 18, 2020.\n\nThe standard patient follow-up included visits at 3, 6, and 12 months and every 6 months thereafter. During follow-up visits, clinicians considered new relapses and assessed patients using the Expanded Disability Status Scale (EDSS). Trained examiners with Neurostatus certification (APS, LBR) performed all EDSS assessments.\n\nPatients underwent brain MRI scans before ocrelizumab initiation (baseline); at 4–6 months (before the second cycle of ocrelizumab), at 12 months, and at 24 months. Spinal cord and brain MRI scans, using 1.5 T and 3 T scanners, were done on an individual basis. At least contiguous, 3-mm axial sections, T2-weighted, FLAIR and gadolinium-enhanced T1-weighted scans through the whole brain were acquired in all patients according to published guidelines (10). MRI scans were read by experienced radiologists.\n\nBaseline data collected from medical records were as follows: (a) demographic variables, (b) type of multiple sclerosis, (c) disease-modifying therapy before starting on ocrelizumab, (d) EDSS score, (e) number of relapses in the previous year, (f) time since diagnosis, (g) number of gadolinium-enhancing lesions on MRI, and (g) reason for starting ocrelizumab. Variables and outcomes assessed during follow-up were: (a) duration of follow-up, (b) number of relapses, (c) EDSS at the last visit, (d) number of ocrelizumab cycles, (e) adverse events, (f) number of gadolinium-enhancing lesions on the first MRI after ocrelizumab initiation (4–6 months), (g) number of new T2-lesions and T1 gadolinium-enhancing lesions in the annual MRI, and (h) discontinuation of ocrelizumab.\n\nClinical and MRI Outcomes\nA relapse was defined as new or recurrent symptoms and objective typical findings of multiple sclerosis with a duration of at least 24 h, in the absence of fever or infection (9). Disability progression was defined as a sustained (≥3 months) increase in the EDSS score, of: 1.5 points if the baseline EDSS score was 0; 1 point if the baseline score was 1–5.5; and 0.5 points if the baseline EDSS score was 6.0 or more. Disability improvement was defined as a sustained (≥3 months) decrease in the EDSS score, of: 0.5 points if the baseline EDSS score was 6.5 or more, or one point if the baseline score was 6.0 or less (11).\n\nClinical activity was defined as relapse and/or disability progression, and MRI activity was defined as the presence of T1 gadolinium-enhancing lesions at any time point or new T2 lesions on the annual MRI (compared to the MRI performed at 4–6 months). Highly active disease was defined as one or more relapse in the previous year and one or more T1 gadolinium-enhancing lesion on the baseline MRI.\n\nNo evidence of disease activity (NEDA) outcome was assessed in RMS patients who were followed for at least 1 year. NEDA status was defined as the combined absence of clinical (relapses and disability progression) and MRI activity (12).\n\nTreatment Protocol\nOcrelizumab was administered according to the schedule recommended in its summary of product characteristics (1). Before ocrelizumab administration, all patients were evaluated by their attending neurologist about symptoms suggestive of COVID-19 after Covid pandemic. The initial 600 mg cycle was administered as two separate intravenous infusions of 300 mg, at a 2-weeks interval. Subsequent cycles were administered as a single 600 mg intravenous infusion every 6 months. The premedication for all cases consisted of 100 mg intravenous methylprednisolone, 10 mg of cetirizine or 5 mg of dexchlorpheniramine, and 1,000 mg of paracetamol. Patients were monitored at hospital during the infusion and for 1 h after its completion. Infusion-related reactions included all symptoms and events occurring during or within 24 h of the infusion (in hospital or at home) and were graded as mild, moderate, severe, or life-threatening according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (13).\n\nStatistical Analysis\nQuantitative variables are described using the mean ± standard deviation (SD) or median and range and they were compared with Student test or Mann–Whitney U depending on the normality of the distribution. Qualitative variables are presented as absolute and relative frequencies and were compared with chi-squared test. We compared the number of patients with T1 gadolinium-enhancing lesions on MRI at baseline and follow-up using McNemar's test. All calculations were performed with a statistical significance of 5% and for every relevant parameter, we calculated the confidence interval (CI) of 95%. The statistical package used was the IBM SPSS Statistics version 25.\n\nResults\nCohort Characteristics\nA total of 70 patients (42 female and 28 male), who had received at least the first cycle of ocrelizumab and with a follow-up longer than 6 months were included. There were no significant differences in baseline demographics and clinical characteristics (age, sex, EDSS, disease duration) for the two centers. Their clinical characteristics are summarized in Table 1. Twenty-one patients (30%) with a mean age 47.1 years had PPMS, and 49 patients (70%) with a mean age of 39.2 years, RMS. Relevant comorbidities according to the treating neurologist were present in 24% of patients (Table 2).\n\nTable 1 Baseline characteristics in our cohort of 70 patients with multiple sclerosis treated with ocrelizumab.\n\nPatients\tRMS (n = 49)\tPPMS (n = 21)\t\nAge at ocrelizumab start\t39.2 ± 10.9\t47.1 ± 10.5\t\nSex (Female)\t69%\t38%\t\nTime since diagnosis (years)\t7.7 ± 6.7\t2.8 ± 4.1\t\nBaseline EDSS; median (IQR)\t2.5 (2–3)\t3.0 (3–4.8)\t\nARR previous year\t1.3 ± 0.65\t–\t\nTreatment naive n/N (%)\t10/49 (20%)\t19/21 (90%)\t\nPatients with at least one Gd-enhancing lesions, n/N (%)\t31/49 (63%)\t9/21 (43%)\t\nARR, anualized relapse rate; EDSS, Expanded Disability Status Scale; IQR, interquartile range.\n\nTable 2 Comorbidities in patients treated with ocrelizumab (n = 70).\n\nComorbidity\tN patients\t\nBipolar disease\t1\t\nCerebral palsy\t1\t\nChronic migraine\t1\t\nDiabetes mellitus\t2\t\nHeart disease\t2\t\nHepatitis B inactive carrier\t1\t\nHodgkin's lymphoma in remission\t1\t\nHypertension\t2\t\nMorbid obesity\t2\t\nPituitary adenoma\t1\t\nPsoriasis\t1\t\nThrombocythemia\t1\t\nUveitis\t1\t\nThe main reason for switching to ocrelizumab for RMS was treatment failure due to clinical relapse, MRI activity or both (36/39, 92%). One patient on fingolimod was switched due to hepatic toxicity, and another one (also on fingolimod) because of persistent vomiting after bariatric surgery. The patient on rituximab was switched due to serum sickness.\n\nIn the RMS group at baseline, median EDSS at was 2.5, the annualized relapse rate in the previous year was 1.3 ± 0.65, 63% (31/49) of patients had gadolinium-enhancing lesions on MRI, and 61% (30/49) had highly active disease. In the PPMS group at baseline, median EDSS was 3.0 and 43% (9/21) of the patients had gadolinium-enhancing lesions on MRI.\n\nNinety percent of PPMS patients were treatment-naive, compared to 20% of RMS patients. Before starting ocrelizumab, patients' most recent treatments included beta-interferon (n = 12), dimethyl fumarate (n = 11), fingolimod (n = 10), teriflunomide (n = 2), cladribine (n = 2), glatiramer acetate (n = 2), rituximab (n = 1), and alemtuzumab (n = 1). No patient switched from natalizumab to ocrelizumab. There was no washout period after beta-interferon and glatiramer acetate, but for patients on fingolimod, it was 1 month; on teriflunomide, 2 weeks, after undergoing the accelerated elimination procedure with cholestyramine; and on dimethyl fumarate, 1 week, except for one patient with lymphopenia that required a longer washout interval. The washout period for the patient on rituximab was 6 months, and the patient on alemtuzumab began ocrelizumab 16 months after the second cycle of alemtuzumab. No patient experienced a relapse during the washout period.\n\nClinical Course After Treatment Initiation With Ocrelizumab\nThe clinical course was assessed in all the patients who began treatment with ocrelizumab, with a mean follow-up of 13.6 months (range 6–32). Follow-up was longer in the patients with PPMS compared to those with RMS (17 vs. 12 months, p < 0.05). No patient was lost to follow-up. The median number of treatment cycles was 3 (range 2–6).\n\nThe clinical and MRI outcomes after ocrelizumab initiation are outlined in Table 3. Among the 21 patients with PPMS, one patient (5%) experienced disability progression and discontinued treatment. In the 49 patients with RMS, only one had a relapse, none experienced disability progression, and nine showed disability improvement (18%, 95% CI 10–31%). The annualized relapse rate fell from 1.3 ± 0.65 before ocrelizumab initiation to 0.02 ± 014 after (P < 0.001). There was no evidence of clinical activity (relapses and/or disability progression) in 98% of RMS patients.\n\nTable 3 Clinical and MRI outcomes (n = 70).\n\nOutcome\t\t\nRelapses in RMS patients\t\nARR 12 months prior to study inclusion\t1.3\t\nARR after ocrelizumab initiation\t0.02\t\nDisability progression (EDSS)\t1/70 (1.4%)\t\nMRI\t\nPatients with Gadolinium-enhancing lesions at:\t\n Baseline\t40/70 (57%)\t\n 4–6 months\t1/70 (1.4%)\t\n 12 months\t0/46 (0%)\t\nNew or enlarging T2-hyperintense lesions at 12 months\t1/46 (2.2%)\t\nARR, annualized relapse rate; RMS, relapsing multiple sclerosis.\n\nBaseline MRI showed T1 Gd-enhancing lesions in 57% of the patients (RMS: 63%, PPMS: 43%). All patients except one were free of T1 Gd-enhancing lesions at the first control MRI performed at 4–6 months (69/70, 98.6% P < 0.001). At the MRI at 12 months, all patients were free of T1 Gd-enhancing lesions (0/46, P < 0.001), and only one patient showed new T2 lesions compared to the previous MRI (2.2%).\n\nThe proportion of patients with NEDA was 94% (31/33) in the group of RMS patients who were followed for at least 1 year.\n\nTolerance and Safety\nJust over half (37/70, 53%) of the patients reported adverse events, none of which were serious (Table 4). The risk of adverse events was higher in the group of patients with previous DMT (59%) than in the group of patients who were treatment-naïve (45%) but the difference was not statistically significant (P = 0.257). The most frequent adverse events were infusion-related reactions: 43% (95% CI 32–55%) reported at least one; all of these were mild to moderate and were treated by reducing the infusion rate and administering symptomatic therapy if needed. The rate of this complication decreased from 40% (28/70) in the first cycle to 16% (11/70) thereafter. Aspirin 300 mg was included in the premedication protocol in some patients to prevent flushing.\n\nTable 4 Adverse events in 70 patients treated with ocrelizumab.\n\nAdverse event\tn (%)\t\nAny adverse event\t37 (53%)\t\nInfusion-related reactions*\t30 (43%)\t\n Mild\t14 (20%)\t\n Moderate\t16 (23%)\t\n Severe\t0\t\nInfections\t9 (13%)\t\n Urinary tract infections\t5\t\n Pneumonia\t1\t\n Cellulitis\t1\t\n Gastroenteritis\t1\t\n Dental phlegmon\t1\t\nOthers\t2 (3%)\t\n Alopecia areata\t1\t\n Biliary colic\t1\t\n* Infusion-related reactions included pruritus, sore throat, rash, flushing, urticaria, erythema, headache, irritability and myalgias.\n\nNine patients had infections: five had urinary tract infections and one each pneumonia, gastroenteritis, cellulitis, and dental phlegmon. No patient developed symptoms suggestive of COVID-19. No patient required hospitalization, and no malignancies were detected. The switch from rituximab to ocrelizumab due to rituximab-induced serum sickness was well-tolerated and the patient did not develop serum sickness after the first cycle (two infusions) of ocrelizumab.\n\nTwo patients (2.9%) discontinued ocrelizumab; one due to pregnancy and the other one because of lack of efficacy, but none did so because of an adverse event or tolerability.\n\nDiscussion\nOcrelizumab has recently been approved in Europe for the treatment of patients with multiple sclerosis, but European data on its real-world use are limited (6–8). Our results support the safety and effectiveness of ocrelizumab in a clinical practice setting.\n\nThe results of clinical trials of ocrelizumab may not be generalizable to clinical practice if patients' baseline characteristics are significantly different from those of trial participants. With regard to age, disease duration and the percentage of treatment-naïve patients, our cohort of PPMS patients was similar to that in the ORATORIO phase 3 trial of ocrelizumab. The number of patients with gadolinium-enhancing lesions on the baseline MRI was slightly higher (43.5 vs. 27.5%). Only one of the 21 patients with PPMS in our cohort experienced confirmed disability progression (mean follow-up of 17 months). A recent real-world data study confirmed that ocrelizumab can stabilize disability progression in patients with PPMS and three out of 17 patients even showed clinically relevant improvement in disability status (8). In the ORATORIO trial, pre-specified non-powered subgroup analyses indicated that patients who were younger or had T1 Gd-enhancing lesions at baseline had a greater treatment benefit than older patients or those without T1 Gd-enhancing lesions, which may explain the low rate of disability progression in our cohort (14).\n\nOur results confirm the rapid suppression of new focal brain MRI lesion activity with ocrelizumab. In our cohort, 98.6% of patients were free of T1 Gd-enhancing lesions at the first control MRI performed at 4–6 months. The analysis of phase 2 MRI data of the ocrelizumab 600 mg dose revealed near-complete suppression of T1 Gd-enhancing lesions by week 12 (15). MRI data were lacking in the already published ocrelizumab real-world studies (6–8).\n\nThe overall annualized relapse rate of patients with RMS in the study by Ellwardt et al. was 0.17 (95% CI 0.10–0.24), which was very similar to that of the OPERA 1 phase 3 clinical trial (0.16, 95% CI 0.12–0.20). In our cohort, the proportion of patients with NEDA was 94% in the group of RMS patients who were followed for at least 1 year. The greater treatment benefit observed in our study may be due to the higher number of patients with highly active disease (61%). Subgroup analyses comparing ocrelizumab and other disease-modifying therapies (natalizumab, alemtuzumab, fingolimod, cladribine, teriflunomide, and dimethyl fumarate) have found higher efficacy in patients with more active disease (16–22).\n\nAbout three quarters of the RMS patients included in the OPERA trial were treatment-naive, and the most common previous therapies were interferon and glatiramer acetate (3). In contrast, in our cohort and in other observational studies most RMS patients had been previously treated with other disease-modifying therapies (6, 7). Nonetheless, prior treatment per se did not impact the magnitude of the beneficial effect of ocrelizumab although previous therapies in the pivotal trial and in the observational cohorts were rather different (16). Ocrelizumab in the observational cohorts showed efficacy not only after switching from first-line injectable treatments but also after switching from highly effective therapies such as alemtuzumab, natalizumab, fingolimod, and cladribine, although the participant numbers were small.\n\nAs observed in the phase 3 trials and in the real-world studies, mild to moderate infusion-related reactions and mild infections were the most common adverse events. The percentage of infusion-related reactions in our study (43%) was similar to that of the pivotal clinical trials (ORATORIO: 39.9%, OPERA 1: 30.7%, OPERA 2: 37.6%) and higher than in other observational studies (6, 7). The premedication protocol in the three observational cohorts included intravenous methylprednisolone, antipyretics, and antihistamines, but the dose of methylprednisolone was different: we used 100 mg as indicated in the summary of product characteristics while 250 mg was used in the other two studies. Whether the reason for the observed difference in the rate of infusion-related reactions resides in the different doses of methylprednisolone or underreporting from patients warrants further study.\n\nThe most common infections observed in the clinical trials of ocrelizumab were upper respiratory tract and urinary tract infections. Minor infections were reported in 8 and 5% of patients in other observational cohorts (6, 7). In our cohort, this proportion was higher (13%) which may be explained by the longer follow-up with ocrelizumab in our series. Besides, it is likely that in our case there was underreporting of upper respiratory tract infections since most patients do not consult their physicians for symptoms of nasopharyngitis. While most reported infections to date have been minor, there have been a few isolated case reports of severe viral infections, such as a fulminant hepatitis associated with echovirus 25 and HSV-2 encephalitis, in patients on ocrelizumab (23, 24). We did not observe any serious infections, while the rate was 1.3% in the OPERA trial and 6.2% in the ORATORIO trial (2, 3).\n\nWe observed a very low treatment discontinuation rate with ocrelizumab, consistent with findings from the phase 3 trials and other observational studies. Only two patients (2.9%) discontinued ocrelizumab; one due to pregnancy and the other one because of lack of efficacy, but none did so due to safety issues. The rate of treatment discontinuation due to adverse events was 3.2% in the 96-weeks OPERA 1 trial and 4.1% in the ≥120-weeks ORATORIO trial (2, 3). The annual discontinuation rate (3%) was lower for rituximab, another anti-CD20 B cell–depleting antibody, compared to other DMTs in patients with newly diagnosed RMS in a real-world study from Sweden (25).\n\nThe effectiveness of ocrelizumab in this study is similar to that of rituximab in a similar general hospital setting although there are some differences concerning secondary infectious adverse events and discontinuation rate (26). The discontinuation rate in this study was 2.8% and no patient required hospitalization due to infectious adverse events while the discontinuation rate was 14.4% in the rituximab observational study from Sweden and four patients (4.8%) required hospitalization due to infectious adverse events. However, the follow-up was longer and the patients slightly older in the Swedish cohort which may explain the observed differences.\n\nThe main limitations of this study are the small sample, its retrospective design, a short time of follow-up and the absence of a control group. On the other hand, the study provides MRI and NEDA data that are not available from other real-world studies and a longer time of follow-up. Besides, the study was conducted in a general hospital setting with universal healthcare access, eliminating the bias of a tertiary referral center or unequal access to healthcare or DMTs.\n\nIn conclusion, our data confirm the short-term effectiveness, tolerability, and safety of ocrelizumab in real-world clinical practice. Further studies are needed to assess patient outcomes with longer follow-up periods.\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by the Institutional Ethics Committee of the Hospital General Universitario de Alicante (reference number: PI-2019-116). The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\nAS and LB-R: study design, analysis, drafting and revision of manuscript. IB-S: study design and drafting. AB-SJ: revision of manuscript. LC-A and LV: MRI analyses and revision of manuscript. MA: contributed patients and revised the manuscript. AP-B: performed the statistics and revised the manuscript. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\nLB-R has received personal compensation for consulting, serving on a scientific advisory board or speaking with Almirall, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi-Aventis, and Teva. AS has received personal compensation for consulting, serving on a scientific advisory board or speaking with Almirall, Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis, Roche, Sanofi-Aventis, and Teva. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nWe would like to thank Meggan Harris for English language editing.\n\nFunding. The Article Processing Charge was funded by ISABIAL.\n==== Refs\nReferences\n1. Ocrevus: EPAR-Product information Available online at: https://www.ema.europa.eu/en/documents/product-information/ocrevus-epar-product-information_en.pdf (accessed March 8, 2020).\n2. Montalban X Hauser SL Kappos L Arnold DL Bar-Or A Comi G . Ocrelizumab versus placebo in primary progressive multiple sclerosis\n. N Engl J Med. (2017 ) 376 :209 –20\n. 10.1056/NEJMoa1606468 28002688 \n3. Hauser SL Bar-Or A Comi G Giovannoni G Hartung HP Hemmer B . Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis\n. N Engl J Med. (2017 ) 376 :221 –34\n. 10.1056/NEJMoa1601277 28002679 \n4. Syed YY . Ocrelizumab: a review in multiple sclerosis\n. CNS Drugs. (2018 ) 32 :883 –90\n. 10.1007/s40263-018-0568-7 30171504 \n5. Kalincik T Kuhle J Pucci E Rojas JI Tsolaki M Sirbu CA . Data quality evaluation for observational multiple sclerosis registries\n. Mult Scler. (2017 ) 23 :647 –55\n. 10.1177/1352458516662728 27481209 \n6. Ellwardt E Rolfes L Klein J Pape K Ruck T Wiendl H . Ocrelizumab initiation in patients with MS: A multicenter observational study\n. Neurol Neuroimmunol Neuroinflamm. (2020 ) 7 :e719 . 10.1212/NXI.0000000000000719 32273482 \n7. Prockl V Nickel FT Utz KS Fröhlich K Engelhorn T Hilz MJ . Real world application of ocrelizumab in multiple sclerosis: single-center experience of 128 patients [published online ahead of print 2020\n. J Neurol Sci. (2020 ) 415 :116973 . 10.1016/j.jns.2020.116973 32563101 \n8. Daniels K van der Nat PB Frequin STFM van der Wees PJ Biesma DH Hoogervorst ELJ . Real-world results of ocrelizumab treatment for primary progressive multiple sclerosis\n. Mult Scler Int. (2020 ) 2020 :5463451 . 10.1155/2020/5463451 32607256 \n9. Thompson AJ Banwell BL Barkhof F Carroll WM Coetzee T Comi G . Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria\n. Lancet Neurol. (2017 ) 17 :162 –73\n. 10.1016/S1474-4422(17)30470-2 29275977 \n10. Traboulsee A Simon JH Stone L Fisher E Jones DE Malhotra A . Revised recommendations of the consortium of MS centers task force for a standardized MRI protocol and clinical guidelines for the diagnosis and follow-up of multiple sclerosis\n. Am J Neuroradiol. (2016 ) 37 :394 –401\n. 10.3174/ajnr.A4539 26564433 \n11. Kalincik T Cutter G Spelman T Jokubaitis V Havrdova E Horakova D . Defining reliable disability outcomes in multiple sclerosis\n. Brain. (2015 ) 138 :3287 –98\n. 10.1093/brain/awv258 26359291 \n12. Giovannoni G Turner B Gnanapavan S Offiah C Schmierer K Marta M . Is it time to target no evident disease activity (NEDA) in multiple sclerosis?\n\nMult Scler Relat Disord. (2015 ) 4 :329 –33\n. 10.1016/j.msard.2015.04.006 26195051 \n13. National Cancer Institute \nCommon Terminology Criteria for Adverse Events v4.0 . Available online at: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf (accessed March 8, 2020).\n14. Ocrevus: EPAR-Public assessment report Available online at: https://www.ema.europa.eu/documents/assessment-report/ocrevus-epar-public-assessment-report_en.pdf (accessed April 30, 2020).\n15. Barkhof F Kappos L Wolinsky JS Li DKB Bar-Or A Hartung HP . Onset of clinical and MRI efficacy of ocrelizumab in relapsing multiple sclerosis\n. Neurology. (2019 ) 93 :e1778 –86\n. 10.1212/WNL.0000000000008189 31484710 \n16. Turner B Cree BAC Kappos L Montalban X Papeix C Wolinsky JS . Ocrelizumab efficacy in subgroups of patients with relapsing multiple sclerosis\n. J Neurol. (2019 ) 266 :1182 –93\n. 10.1007/s00415-019-09248-6 30820738 \n17. Hutchinson M Kappos L Calabresi PA Confavreux C Giovannoni G Galetta SL . The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL [published correction appears\n. J Neurol . (2009 ) 256 :405 –15\n. 10.1007/s00415-009-0093-1 19308305 \n18. Coles AJ Twyman CL Arnold DL Cohen JA Confavreux C Fox EJ . Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial\n. Lancet. (2012 ) 380 :1829 –839\n. 10.1016/S0140-6736(12)61768-1 23122650 \n19. Derfuss T Ontaneda D Nicholas J Meng X Hawker K . Relapse rates in patients with multiple sclerosis treated with fingolimod: subgroup analyses of pooled data from three phase 3 trials\n. Mult Scler Relat Disord. (2016 ) 8 :124 –30\n. 10.1016/j.msard.2016.05.015 27456887 \n20. Giovannoni G Cook S Rammohan K Rieckmann P Sørensen PS Vermersch P . Sustained disease-activity-free status in patients with relapsing–remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis\n. Lancet Neurol. (2011 ) 10 :329 –37\n. 10.1177/1352458510391344 21397565 \n21. Miller AE O'Connor P Wolinsky JS Confavreux C Kappos L Olsson TP . Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis\n. Mult Scler. (2012 ) 18 :1625 –32\n. 10.1177/1352458512450354 22723573 \n22. Hutchinson M Fox RJ Miller DH Phillips JT Kita M Havrdova E . Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing–remitting multiple sclerosis: subgroup analyses of the CONFIRM study\n. J Neurol. (2013 ) 260 :2286 –96\n. 10.1007/s00415-013-6968-1 23749293 \n23. Nicolini LA Canepa P Caligiuri P Mikulska M Novi G Viscoli C . Fulminant hepatitis associated with echovirus 25 during treatment with ocrelizumab for multiple sclerosis\n. JAMA Neurol. (2019 ) 76 :866 –7\n. 10.1001/jamaneurol.2019.0522 30958517 \n24. Dudek MIR Thies K Kammenhuber S Bösel J Rösche J . HSV-2-encephalitis in a patient with multiple sclerosis treated with ocrelizumab\n. J Neurol. (2019 ) 266 :2322 –3\n. 10.1007/s00415-019-09391-0 31115675 \n25. Granqvist M Boremalm M Poorghobad A Svenningsson A Salzer J Frisell T . Comparative effectiveness of rituximab and other initial treatment choices for multiple sclerosis\n. JAMA Neurol. (2018 ) 75 :320 –7\n. 10.1001/jamaneurol.2017.4011 29309484 \n26. Hellgren J Risedal A Källén K . Rituximab in multiple sclerosis at general hospital level\n. Acta Neurol Scand. (2020 ) 141 :1 –9\n. 10.1111/ane.13225 31990978\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "11()",
"journal": "Frontiers in neurology",
"keywords": "MRI; drug therapy; effectiveness; multiple sclerosis; ocrelizumab; real-world; safety; tolerability",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "592304",
"pmc": null,
"pmid": "33519676",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "27456887;31484710;27481209;23749293;30820738;32563101;30171504;22723573;32273482;32607256;26195051;28002688;21397565;29275977;19308305;29309484;26564433;31990978;26359291;23122650;31115675;28002679;30958517",
"title": "Ocrelizumab in Multiple Sclerosis: A Real-World Study From Spain.",
"title_normalized": "ocrelizumab in multiple sclerosis a real world study from spain"
} | [
{
"companynumb": "ES-002147023-NVSC2021ES169558",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FINGOLIMOD"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nIn this report, we describe an unusual case of post-operative Acremonium falciforme endophthalmitis with orbital and extra-orbital involvement following combined cataract and glaucoma surgery.\n\n\nMETHODS\nA 68-year-old Caucasian man with glaucoma presented with endophthalmitis characterized by pain, redness and impaired vision in the left eye fifteen days after combined cataract and filtering surgery. He subsequently underwent a pars plana vitrectomy, with vitreous sampling, silicone oil placement and intra-vitreal injection of antibiotics, but only after a second vitrectomy we identified Acremonium falciforme as the causative agent for the endophthalmitis. An antifungal systemic and topical therapy was started, but meanwhile the infection extended to orbital and peri-orbital tissues. Following these procedures, even if the eye went slowly in phthisis, we were able to limit the further extension and circumscribe the orbital and extra-orbital involvement.\n\n\nCONCLUSIONS\nTo our knowledge, this report is the first describe Acremonium falciforme endophthalmitis with orbital and extra-orbital involvement, following anterior segment combined surgery. Ophthalmologists and physicians should be aware of the extension risk of a fungal panophthalmitis, but also to potentially serious side effects related to systemic therapy.",
"affiliations": "Department of Surgical and Biomedical Sciences, University of Perugia, Ospedale S Maria della Misericordia, Sant'Andrea delle Fratte, Piazza Menghini 1, 06156 Perugia, Italy. carlo.cagini@unipg.it.",
"authors": "Cagini|Carlo|C|;Iannone|Alessia|A|;Fiore|Tito|T|;Lupidi|Marco|M|;Spadea|Leopoldo|L|",
"chemical_list": "D000935:Antifungal Agents",
"country": "England",
"delete": false,
"doi": "10.1186/1752-1947-8-373",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-8-3732540637410.1186/1752-1947-8-373Case ReportPost-operative endophthalmitis caused by Acremonium falciforme with orbital and extra-orbital involvement following combined cataract and glaucoma surgery: a case report Cagini Carlo 1carlo.cagini@unipg.itIannone Alessia 1alessia-iannone@hotmail.itFiore Tito 1titofiore@hotmail.comLupidi Marco 1dr.marco.lupidi@gmail.comSpadea Leopoldo 2leopoldo.spadea@uniroma1.it1 Department of Surgical and Biomedical Sciences, University of Perugia, Ospedale S Maria della Misericordia, Sant’Andrea delle Fratte, Piazza Menghini 1, 06156 Perugia, Italy2 Department of Biotechnology and Medical-Surgical Sciences, University of Rome “La Sapienza”, Via Benozzo Gozzoli 34, 00142 Roma, Italy2014 19 11 2014 8 373 373 8 4 2014 28 8 2014 Copyright © 2014 Cagini et al.; licensee BioMed Central Ltd.2014Cagini et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nIn this report, we describe an unusual case of post-operative Acremonium falciforme endophthalmitis with orbital and extra-orbital involvement following combined cataract and glaucoma surgery.\n\nCase presentation\nA 68-year-old Caucasian man with glaucoma presented with endophthalmitis characterized by pain, redness and impaired vision in the left eye fifteen days after combined cataract and filtering surgery. He subsequently underwent a pars plana vitrectomy, with vitreous sampling, silicone oil placement and intra-vitreal injection of antibiotics, but only after a second vitrectomy we identified Acremonium falciforme as the causative agent for the endophthalmitis. An antifungal systemic and topical therapy was started, but meanwhile the infection extended to orbital and peri-orbital tissues. Following these procedures, even if the eye went slowly in phthisis, we were able to limit the further extension and circumscribe the orbital and extra-orbital involvement.\n\nConclusion\nTo our knowledge, this report is the first describe Acremonium falciforme endophthalmitis with orbital and extra-orbital involvement, following anterior segment combined surgery. Ophthalmologists and physicians should be aware of the extension risk of a fungal panophthalmitis, but also to potentially serious side effects related to systemic therapy.\n\nCataract surgeryFungal endophthalmitisOrbital involvement\n==== Body\nIntroduction\nPost-operative fungal endophthalmitis is a rare complication that frequently carries a worse prognosis than bacterial endophthalmitis. Approximately 90% of post-operative endophthalmitis cases develop after cataract surgery [1-5], and bacteria, such as coagulase-negative staphylococci and Propionibacterium acnes, are the most common causes. Various fungi are known to be major causes of delayed-onset endophthalmitis [6], and the prognosis appears to be related to many factors, including the extent of intra-ocular involvement, the timing and mode of intervention and the virulence of the organism involved. Although the outcome may be positive with vision recovery in some patients, in other cases the prognosis is not favorable [6]. Orbital and extra-orbital involvement is a rare complication of fungal endophthalmitis.\n\nWe describe a case of a patient with Acremonium falciforme endophthalmitis which developed two weeks after combined cataract and glaucoma surgery with important involvement of orbital and extra-orbital structures. To the best of our knowledge, there have been no other similar cases described in the literature to date.\n\nCase presentation\nA 68-year-old Caucasian man with glaucoma who was receiving chronic therapy was referred to our institution with a diagnosis of post-operative endophthalmitis in the left eye. The patient had inflammation in the left eye that had started a few days earlier and was associated with impaired vision. Two weeks before presentation he had undergone cataract surgery combined with a glaucoma shunt implant at another eye clinic.\n\nUpon presentation, he had a corrected distance visual acuity (CDVA) of 20/80 in the right eye, a cortical and nuclear cataract and filtering bleb that had developed after previous glaucoma surgery. Upon presentation, he had a corrected distance visual acuity (CDVA) of 20/80 in the right eye, a filtering bleb and a cortical and nuclear cataract developed after the previous glaucoma surgery performed two years earlier.\n\nA glaucomatous optic disc excavation was present and the visual field was significantly narrowed in the inferior nasal area. He was receiving therapy with bimatoprost eyedrops in this eye.\n\nHis CDVA in the left eye was 1/200, and he showed marked conjunctival injection, corneal edema, inflammatory aqueous cells (Tyndall 3+) and fibrin on the front face of the intra-ocular lens (IOL). The glaucoma shunt implant (EX-PRESS® Glaucoma Filtration Device; Alcon Laboratories, Fort Worth, TX, USA) was in site with a non-inflamed filtering bleb. There was dense vitritis, and it was impossible to visualize the retina and the optic disc. A 25-gauge pars plana vitrectomy (PPV) was performed using a CONSTELLATION® vitrectomy system (Alcon Surgical, Tokyo, Japan), and infusion fluid (BSS PLUS®; Alcon Surgical) was devoid of any antibiotics. At a site 4.0mm from and parallel to the limbus, three trocars were inserted at a 30° angle (one in the inferonasal area for the infusion), creating tunnel sclerotomies. Initially, a vitreous sample (with the infusion channel closed) was collected using the vitrectome, then the remaining vitrectomy with hyaloid removal was completed. The vitreous cavity was filled with silicone oil, and ceftazidime and vancomycin were injected intravitreally. All the sclerotomies were sutured because of the risk of leakage.\n\nDuring surgery, the retina appeared to be covered by an abundant fibrinous exudation. After surgery, the patient’s CDVA was 1/30, and therapy with topical vancomycin (50mg/ml) and ceftazidime (50mg/ml) eyedrops six times per day was started. The IOL and the glaucoma valve were left in place because the patient strongly expressed this desire, given the low visual acuity of the other eye. Cultures taken from the aqueous and vitreous were negative, and his early post-operative course was uneventful and without signs of significant inflammation, except for a thin layer of fibrin on the front face of the IOL. He was discharged some five days after surgery, and he continued the therapy at home and returned for scheduled checks. During these checks, his CDVA was 1/20 and there were no signs of inflammation in the anterior chamber; however, the retina could not be easily evaluated, owing to fibrin plaque on the surface of the IOL.Forty-five days after this surgery, he experienced acute, increasing pain in the left eye with severe inflammation, corneal edema, anterior chamber inflammation (Tyndall 4+) and hypopyon occupying three-fourths of the anterior chamber (Figure 1). He underwent a new anterior chamber washout with aqueous sample and a vitrectomy with silicone oil tamponade.\n\nFigure 1 Left eye of the patient before vitrectomy. Pre-operative photograph shows diffuse subconjunctival hemorrhage and complete filling of the anterior chamber with hypopyon.\n\nTwo days after his second surgery, an increase of intra-ocular pressure was observed (treated with topical and systemic therapy) associated with the formation of a thick white plaque on the anterior surface of the IOL that prevented observation of the retina and the optic disc. His CDVA at this time was 1/200. Systemic therapy with fluconazole (400mg/day) and amphotericin B 0.15% eyedrops (six times per day) was started, which led to progressive reduction of the exudation in the anterior chamber. One week later, Acremonium falciforme species were identified in cultures obtained from samples, and the systemic therapy was switched to intravenous voriconazole 6mg/kg every 12 hours for the first day, then 4mg/kg intravenously every 12 hours for 10 days, followed by 200mg orally every 12 hours. This therapy led to a further reduction of the exudation in the anterior chamber. After seven days, it was possible to evaluate the red reflex of the retina, which revealed a slight improvement of CDVA to 1/60.Ten days later, the patient presented with liver function test impairment and sharp pain in the left orbital region that radiated to the same side of the head due to extension of the inflammatory process to the orbit and peri-orbital tissue. A magnetic resonance imaging (MRI) scan showed that there was evidence of left orbital inflammation with inhomogeneous appearance of the eyeball and peri-bulbar inflammation, which was more evident at the lacrimal gland (Figure 2). A faint hyperintensity of the optic nerve in T2 and slight signs of inflammation at the apex of the left orbital cavity were reported (Figure 3). At this time, therapy with systemic diclofenac and oral prednisone (25mg twice daily for two weeks) was started, which led to significant pain reduction. The condition of the left eye showed a gradual further improvement, but it was necessary to stop the systemic antifungal therapy after 22 days because of liver toxicity. The topical drugs were continued unchanged. One month later, unremitting pain in the orbital region reappeared; therefore, systemic antifungal therapy (voriconazole 6mg/kg intravenously every 12 hours for the first day, then 4mg/kg intravenously every 12 hours for 10 days, followed by 200mg orally every 12 hours) combined with pain therapy (acetaminophen 500mg/, codeine 30mg/day and gabapentin 300mg/day) was restarted, which led to progressive reduction of the patient’s ocular and peri-orbital pain.Immediately after this therapy, the patient showed significant ingravescent neurologic symptoms with visual hallucinations, postural instability, slight ideomotor slowdown, retropulsion and dynamic ataxia. Brain MRI excluded vascular lesions, but this examination highlighted enhancement of the left temporal muscle associated with ectasia of contiguous vessels, it was an evident index of inflammation (Figure 4). His electroencephalography results were normal, and lumbar puncture was performed to exclude infectious processes of the brain. Cerebrospinal fluid was clear, but showed albumin cytological dissociation. Once infectious or inflammatory processes were excluded, the cause of neurological symptoms was attributed to a toxic effect induced by the recently introduced analgesic therapy. After one week, we observed an improvement in neurologic symptomatology, but it was indispensable to maintain therapy with paracetamol, codeine and gabapentin. During this period, while the patient’s left eye began to show signs of phthisis, CDVA in his right eye decreased to 20/100 due to worsening of the cataract that was associated with progressive impairment of the optic nerve.After three months, voriconazole was suspended because of an increase in the cholestasis and hepatic cytolysis indices, but topical therapy was maintained for nine months. During this period, the patient was observed with close follow-up. He had no more signs of ocular inflammation; however, the white plaque on the anterior surface of the IOL did not disappear (Figure 5), and his pain was controlled with decreasing doses of analgesic oral therapy. The left eye’s condition deteriorated slowly into phthisis.\n\nFigure 2 Coronal T1-weighted magnetic resonance imaging scan. Contrast agent was injected with fat suppression mode on. Peri-bulbar inflammation is more evident at the left lacrimal gland (red arrow).\n\nFigure 3 Coronal short tau inversion recovery magnetic resonance imaging scan. Faint hyperintensity of the left optic nerve can be seen in T2 (red arrow).\n\nFigure 4 Coronal contrast-enhanced, T1-weighted magnetic resonance imaging scan. Contrast agent was injected with fat suppression mode on,, and enhancement of the left temporal muscle (red arrow) associated with ectasia of contiguous vessels (green arrow) is evident as an index of inflammation.\n\nFigure 5 Final appearance of the eyeball. Photograph shows a wide corneal leukoma with limbal neovascularization involving the superotemporal area and pupillary region.\n\nConclusions\nIn this report, we describe an unusual manifestation of post-operative Acremonium falciforme endophthalmitis with serious orbital and extra-orbital involvement in a fully immunocompetent patient. To our knowledge, Acremonium falciforme endophthalmitis after cataract surgery has been described only once previously [7] and no cases of Acremonium panophthalmitis have previously been reported in the literature.\n\nFungal intra-ocular infections sometimes show a specific pattern that can guide the specialist toward a prompt diagnosis. In other cases, they present an absolutely nonspecific manifestation and can be identified only by using one or more microbiological tests with aqueous or vitreous samples. This could be due to an uncertain medical history or, as in our case, to the advanced stage of inflammation at the time of the first visit. There are several reported cases of post-surgical, delayed-onset endophthalmitis. The wide majority of these cases are caused by bacteria. Only 0% to 4% of post-surgical endophthalmitis cases are caused by fungal infection. Therefore, after the negative outcome of the first cultures and in consideration of the severity of the clinical appearance in our patient, we established that a first therapeutic approach with broad-spectrum antibiotics associated with pars plana vitrectomy (PPV), is widely deemed the gold standard in fungal endophthalmitis management.\n\nAcremonium species, formerly termed Cephalosporium species, are soil fungi that are ubiquitous environmental contaminants. They are saprophytic molds and have septate, colorless hyphae like those of other hyaline molds [8-10]. Although invasive disease may occur in an immunocompromised person, most cases of human disease, unlike other filamentous fungi, occur in immunocompetent hosts [11]. Ocular involvement of Acremonium falciforme is very uncommon.\n\nExogenous fungal endophthalmitis is known to occur in a variety of clinical settings, including contiguous spread of fungal keratitis, penetrating keratoplasty, cataract surgery, glaucoma filtering surgery, retinal detachment surgery and many others [9]. Moreover, Acremonium species may post-operatively invade through wounds, contaminated air solutions (such as humidifier fluid) or objects [10].\n\nThe initial symptoms of Acremonium endophthalmitis are similar to those of most delayed-onset endophthalmitis, including mild pain, redness, floaters and slightly decreased visual acuity [7-10]. The interval between surgery and endophthalmitis onset ranges from two to six weeks [12].\n\nAt present, no treatment modality for these fungal infections has been well established. Weissgold et al. [9] suggested that higher or repeated drug doses of amphotericin B (possibly in combination with vitrectomy) may be necessary to adequately treat these kinds of infections. Cameron et al. [7] reported that Acremonium remains viable in the anterior chamber despite surgical removal of the bulk of the fungal mass and treatment with several antifungal medications, including topical natamycin, topical amphotericin B, subconjunctival miconazole injection and oral ketoconazole. Joe et al. [13] treated the remaining white plaque in the anterior chamber after vitrectomy with voriconazole medication for six months. Mattei et al.[14] reported that voriconazole treatment appeared to be very effective in their case report of fungemia caused by Acremonium. Voriconazole is a triazole derivative that achieves a therapeutic level in aqueous and vitreous liquids by oral administration [14,15].\n\nThe possibility that the fungus remains in the glaucoma shunt implant or on the IOL despite topical and systemic therapy is well-known, and all the implants must be removed to eradicate the infection. We did not perform such a surgical procedure in our patient, first because he refused and later because of his poor general condition. We were aware of the risk of using systemic steroids to treat fungal infections, but the infectologist arranged this therapy while the patient was already taking a systemic antifungal drug. Moreover, we were faced with a post-operative infection with a subsequent inflammatory process that at first was apparently limited to the eye and the intra-orbital structures. We were unable to deliver the systemic antifungal therapy as we wished because of the risk of liver toxicity. Despite this rare infection that spread to the orbital, peri-orbital and temporal tissues, as well as the adverse events induced by the drugs (that is, liver toxicity and neurological impairment caused by antifungal therapy and analgesic drugs, respectively), we were able to manage the inflammatory damage and its complications.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nCDVA: Corrected distance visual acuity; IOL: Intra-ocular lens; MRI: Magnetic resonance imaging; PPV: Pars plana vitrectomy.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nCC and AI analyzed and interpreted the patient data regarding the ophthalmic disease. TF performed the eye surgery. ML analyzed and interpreted the patient data regarding the orbital and extra-orbital involvement and was a major contributor to the writing of the manuscript. LS participated in coordination of the report and helped to draft the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgments\nThe authors thank G Guercini, MD, for his work in the analysis and interpretation of MRI images and Prof B Bell for the final language review of the manuscript.\n==== Refs\nBainbridge JW Teimory M Tabandeh H Kirwan JF Dalton R Reid F Rostron CK Intraocular lens implants and risk of endophthalmitis Br J Ophthalmol 1998 82 1312 1315 10.1136/bjo.82.11.1312 9924340 \nEndophthalmitis Vitrectomy Study Group Results of the Endophthalmitis Vitrectomy Study: a randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis Arch Ophthalmol 1995 113 1479 1496 7487614 \nKattan HM Flynn HW JrPflugfelder SC Robertson C Forster RK Nosocomial endophthalmitis survey: current incidence of infection after intraocular surgery Ophthalmology 1991 98 227 238 10.1016/S0161-6420(91)32312-1 2008282 \nAaberg TM JrFlynn HW JrSchiffman J Newton J Nosocomial acute-onset postoperative endophthalmitis survey: a 10-year review of incidence and outcomes Ophthalmology 1998 105 1004 1010 10.1016/S0161-6420(98)96000-6 9627649 \nMeredith TA Ryan SJ, Hinton DR, Schachat AP, Wilkinson CP Vitrectomy for infectious endophthalmitis Retina, Volume 3 2006 4 Philadelphia: Mosby 2260 2261 \nMcGuire TW Bullock JD Bullock JD JrElder BL Funkhouser JW Fungal endophthalmitis: an experimental study with a review of 17 human ocular cases Arch Ophthalmol 1991 109 1289 1296 10.1001/archopht.1991.01080090115034 1929959 \nCameron JA Badawi EM Hoffman PA Tabara KF Chronic endophthalmitis caused by Acremonium falciforme Can J Ophthalmol 1996 31 367 368 8971458 \nScott IU Flynn HW JrMiller D Delayed-onset endophthalmitis following cataract surgery caused by Acremonium strictum Ophthalmic Surg Lasers Imaging 2005 36 506 507 16355956 \nWeissgold DJ Maguire AM Brucker AJ Management of postoperative Acremonium endophthalmitis Ophthalmology 1996 103 749 756 10.1016/S0161-6420(96)30620-9 8637683 \nFridkin SK Kremer FB Bland LA Padhye A McNeil MM Jarvis WR Acremonium kiliense endophthalmitis that occurred after cataract extraction in an ambulatory surgical center and was traced to an environmental reservoir Clin Infect Dis 1996 22 222 227 10.1093/clinids/22.2.222 8838176 \nFleming RV Walsh TJ Anaissie EJ Emerging and less common fungal pathogens Infect Dis Clin North Am 2002 16 915 933 10.1016/S0891-5520(02)00041-7 12512187 \nVescia N Cavarischia R Valente A Fabiani M Melchionda C Mastroeni I Case report: multiple etiology post-surgery endophthalmitis Mycoses 2002 45 41 44 11856436 \nJoe SG Lim J Lee JY Yoon YH Case report of Acremonium intraocular infection after cataract extraction Korean J Ophthalmol 2010 24 119 122 10.3341/kjo.2010.24.2.119 20379462 \nMattei D Mordini N Lo Nigro C Gallamini A Osenda M Pugno F Viscoli C Successful treatment of Acremonium fungemia with voriconazole Mycoses 2003 46 511 514 10.1046/j.0933-7407.2003.00924.x 14641626 \nCagini C Piccinelli F Lupidi M Messina M Cergualglia A Manes S Fiore T Pellegrino RM Ocular penetration of topical antibiotics: study on the penetration of chloramphenicol, tobramycin and netilmicin into the anterior chamber after topical administration Clin Exp Ophthalmol 2013 41 644 647\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "8()",
"journal": "Journal of medical case reports",
"keywords": null,
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000164:Acremonium; D000368:Aged; D000935:Antifungal Agents; D002387:Cataract Extraction; D009877:Endophthalmitis; D015821:Eye Infections, Fungal; D018463:Filtering Surgery; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D009915:Orbit",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "373",
"pmc": null,
"pmid": "25406374",
"pubdate": "2014-11-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11856436;12512187;14641626;2008282;1929959;7487614;23433257;8838176;8971458;9627649;9924340;16355956;20379462;8637683",
"title": "Post-operative endophthalmitis caused by Acremonium falciforme with orbital and extra-orbital involvement following combined cataract and glaucoma surgery: a case report.",
"title_normalized": "post operative endophthalmitis caused by acremonium falciforme with orbital and extra orbital involvement following combined cataract and glaucoma surgery a case report"
} | [
{
"companynumb": "IT-TEVA-703746ACC",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
"d... |
{
"abstract": "The purpose of this study was to report toxicity and long-term survival outcomes of 2 prospective trials evaluating mitomycin C (MMC) with 5-fluorouracil-based adjuvant chemoradiation in resected periampullary adenocarcinoma.\nFrom 1996 to 2002, 119 patients received an adjuvant 4-drug chemotherapy regimen of 5-fluorouracil, leucovorin, MMC, and dipyridamole with chemoradiation on 2 consecutive trials (trials A and B). Trial A patients received upfront chemoradiation (50 Gy split-course, 2.5 Gy/fraction) followed by 4 cycles of the 4-drug chemotherapy with bolus 5-fluorouracil. Trial B patients received 1 cycle of the 4-drug chemotherapy with continuous infusion 5-fluorouracil followed by continuous chemoradiation (45-54 Gy, 1.8 Gy/fraction) and 2 additional cycles of chemotherapy. Cox proportional hazards models were performed to identify prognostic factors for overall survival (OS).\nOf the 62 trial A patients, 61% had pancreatic and 39% nonpancreatic periampullary carcinomas. Trial B (n = 57) consisted of 68% pancreatic and 32% nonpancreatic periampullary carcinomas. Resection margin and lymph node status were similar for both trials. Median follow-up was longer for trial A than trial B (197.5 vs 107.0 months), with median OS of 32.2 and 24.2 months, respectively. Rates of 3-, 5-, and 10-year OS were 48%, 31%, and 26% in trial A and 32%, 23%, and 9% in trial B. On multivariate analysis, lymph node-positive resection was the strongest prognostic factor for OS. A pancreatic primary and positive margin status were also associated with inferior survival (P < .05). Rates of grade ≥3 treatment-related toxicity in trials A and B were 2% and 7%, respectively.\nThis is the first study to report long-term outcomes of MMC with 5-fluorouracil-based adjuvant chemoradiation in periampullary cancers. Because MMC may be considered in DNA repair-deficient carcinomas, randomized trials are needed to determine the true benefit of adjuvant MMC.",
"affiliations": "Department of Radiation Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Radiation Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Radiation Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Radiation Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.;Department of Radiation Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Radiation Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.",
"authors": "Schunke|Kathryn J|KJ|;Rosati|Lauren M|LM|;Zahurak|Marianna|M|;Herman|Joseph M|JM|;Narang|Amol K|AK|;Usach|Irina|I|;Klein|Alison P|AP|;Yeo|Charles J|CJ|;Korman|Larry T|LT|;Hruban|Ralph H|RH|;Cameron|John L|JL|;Laheru|Daniel A|DA|;Abrams|Ross A|RA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.adro.2017.07.008",
"fulltext": "\n==== Front\nAdv Radiat OncolAdv Radiat OncolAdvances in Radiation Oncology2452-1094Elsevier S2452-1094(17)30113-610.1016/j.adro.2017.07.008Gastrointestinal CancerLong-term analysis of 2 prospective studies that incorporate mitomycin C into an adjuvant chemoradiation regimen for pancreatic and periampullary cancers Schunke Kathryn J. PhDab1Rosati Lauren M. BSa1Zahurak Marianna MScHerman Joseph M. MD, MScaNarang Amol K. MDaUsach Irina dKlein Alison P. MHS, PhDdYeo Charles J. MDeKorman Larry T. BSNaHruban Ralph H. MDfCameron John L. MDgLaheru Daniel A. MDdAbrams Ross A. MDross_a_abrams@rush.eduah*a Department of Radiation Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Marylandb Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Marylandc Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Marylandd Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Marylande Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvaniaf Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Marylandg Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Marylandh Department of Radiation Oncology, Rush University Medical Center, Chicago, Illinois* Corresponding author. Department of Radiation Oncology, Rush University Medical Center, 500 S Paulina, Atrium Building, Ground Floor, Chicago, IL 60612Department of Radiation OncologyRush University Medical Center500 S PaulinaAtrium BuildingGround FloorChicagoIL60612 ross_a_abrams@rush.edu1 K.J.S. and L.M.R. contributed equally to this work.\n\n03 8 2017 Jan-Mar 2018 03 8 2017 3 1 42 51 13 6 2017 20 7 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nThe purpose of this study was to report toxicity and long-term survival outcomes of 2 prospective trials evaluating mitomycin C (MMC) with 5-fluorouracil–based adjuvant chemoradiation in resected periampullary adenocarcinoma.\n\nMethods and materials\nFrom 1996 to 2002, 119 patients received an adjuvant 4-drug chemotherapy regimen of 5-fluorouracil, leucovorin, MMC, and dipyridamole with chemoradiation on 2 consecutive trials (trials A and B). Trial A patients received upfront chemoradiation (50 Gy split-course, 2.5 Gy/fraction) followed by 4 cycles of the 4-drug chemotherapy with bolus 5-fluorouracil. Trial B patients received 1 cycle of the 4-drug chemotherapy with continuous infusion 5-fluorouracil followed by continuous chemoradiation (45-54 Gy, 1.8 Gy/fraction) and 2 additional cycles of chemotherapy. Cox proportional hazards models were performed to identify prognostic factors for overall survival (OS).\n\nResults\nOf the 62 trial A patients, 61% had pancreatic and 39% nonpancreatic periampullary carcinomas. Trial B (n = 57) consisted of 68% pancreatic and 32% nonpancreatic periampullary carcinomas. Resection margin and lymph node status were similar for both trials. Median follow-up was longer for trial A than trial B (197.5 vs 107.0 months), with median OS of 32.2 and 24.2 months, respectively. Rates of 3-, 5-, and 10-year OS were 48%, 31%, and 26% in trial A and 32%, 23%, and 9% in trial B. On multivariate analysis, lymph node–positive resection was the strongest prognostic factor for OS. A pancreatic primary and positive margin status were also associated with inferior survival (P < .05). Rates of grade ≥3 treatment-related toxicity in trials A and B were 2% and 7%, respectively.\n\nConclusions\nThis is the first study to report long-term outcomes of MMC with 5-fluorouracil–based adjuvant chemoradiation in periampullary cancers. Because MMC may be considered in DNA repair-deficient carcinomas, randomized trials are needed to determine the true benefit of adjuvant MMC.\n==== Body\nSummary\nThis is the first prospective study with long-term follow-up that evaluates mitomycin C with standard split-course or continuous 5-fluorouracil–based adjuvant chemoradiation in resected pancreatic or periampullary cancer. Incorporation of mitomycin C appears safe and effective in the adjuvant setting. In an era in which the resected periampullary tumor can be sequenced and analyzed for mutations in DNA repair pathways, it may be worthwhile to integrate mitomycin C into a standard regimen for the patients.\n\nAlt-text: Unlabelled box\n\n\n\nIntroduction\nPeriampullary adenocarcinomas originate in one of 4 anatomical locations: the pancreatic head or uncinate process (pancreatic ductal adenocarcinoma [PDAC]), distal common bile duct, ampulla of Vater, or duodenum. Their incidence has been increasing and the associated prognosis is generally poor. Projected 5-year postresection survival rates range from 7% to 29% for patients with PDAC and 23% to 69% for patients with non-PDAC periampullary adenocarcinoma.1, 2, 3, 4, 5, 6, 7, 8\n\nNo standard adjuvant therapy regimen has been established for these patients, and management is typically extrapolated from PDAC paradigms as treatment strategies continue to evolve.4, 9 Historic studies used split-course radiation therapy,10, 11, 12 whereas modern studies incorporate continuous radiation therapy.13, 14, 15 Previously, Isacoff et al reported improved outcomes with 5-fluorouracil (5-FU), leucovorin (LV), mitomycin C (MMC), and dipyridamole (DPM) in patients with locally advanced PDAC.16, 17 Studies have suggested that MMC may be most effective in PDAC patients with certain mutations, in particular those who have a family history of PDAC and/or harbor mutations in a gene coding for DNA repair proteins (such as BRCA2 or PALB2).18, 19, 20, 21, 22, 23 With the current rise in next-generation sequencing and precision medicine, the impact of DNA-intercalating agents such as MMC on outcomes in patients with such dismal prognoses as periampullary cancer is brought into question.\n\nIn an effort to further investigate the efficacy of MMC integration with 5-FU–based chemoradiation therapy (CRT) for these malignancies, we enrolled patients with resected periampullary adenocarcinoma on a pair of prospective trials. In 1996 and 1999, respectively, we initiated 2 consecutive clinical trials incorporating adjuvant 5-FU, leucovorin, MMC, and DPM with CRT for patients with resected periampullary adenocarcinoma. Patients in trial A received upfront CRT with bolus 5-FU and split-course CRT as outlined previously,1 with timing similar to the Gastrointestinal Tumor Study Group trial, followed by 4 cycles of the same chemotherapy.11 The second trial (trial B) incorporated 1 cycle of the 4-drug chemotherapy with continuous infusion 5-FU followed by a continuous course of CRT and 2 additional cycles of the same chemotherapy. Herein, we present the long-term clinical and therapeutic outcomes of the first 2 prospective clinical trials with long-term follow-up to evaluate the integration of MMC with standard 5-FU–based adjuvant CRT in resected PDAC or non-PDAC periampullary cancer.\n\nMethods and materials\nPatient eligibility\nBoth trials A and B were approved by our institutional review board. The study populations consisted of patients with PDAC or non-PDAC periampullary adenocarcinoma who underwent curative resection. Patients with negative (R0), microscopic (R1), or macroscopic residual disease (R2) at the time of resection were eligible. Restaging after surgery included complete history and physical examination, computed tomography scan of the chest/abdomen/pelvis, and laboratory studies. The final cohort included 62 patients in trial A and 57 patients in trial B.\n\nEligibility criteria included (1) age ≥18 years; (2) Karnofsky performance status ≥70%; (3) adequate bone marrow function; (4) adequate hepatic function; and (5) adequate renal function. Patients were excluded for: (1) prior malignancy within 5 years; (2) prior abdominal irradiation; (3) distant metastatic disease; and (4) poorly controlled medical condition(s) that could be exacerbated by the treatment.\n\nSurgery\nAll patients underwent pancreaticoduodenectomy. Resection margins were positive (R1) if the carcinoma was close (within 1 mm) or present at the final soft-tissue margin. Gross residual disease (R2) was based on the surgical report and/or residual disease seen on first postoperative imaging. Postoperatively, patients were evaluated by radiation and medical oncologists to discuss treatment options and determine eligibility.24\n\nAdjuvant therapy\nTherapy schemas are outlined in Table S1 (available as supplementary material online only at www.advancesradonc.org). Radiation for trials A and B consisted of 15-MV photons. All patients were simulated on the Picker AcQ Sim-CT simulator (Picker, Inc., Cleveland, OH), and treatment planning was completed using computerized dosimetry. Isodose curves were generated on axial slices at the isocenter and at least 2 additional levels. Critical normal organs at risk and tumor target volumes were electronically contoured by 1 radiation oncologist. The treatment volume was designed to include the preoperative tumor volume, primary lymph node drainage stations, and the para-aortic lymph nodes with a 1.5- to 2-cm margin. The encompassed vertebral body levels were T11-L4 inclusive. For both trials, the dose range was 50.4 to 54 Gy.\n\nTrial A (9625): Adjuvant chemoradiation followed by maintenance chemotherapy\nPatients were treated on trial A from April 1996 to July 1999.1 Chemotherapy details can be found in Table S1. Radiation was delivered as a split course of 50 Gy with a 2-week break after the initial delivery of 25 Gy. Irradiation was delivered using 3- or 4-field technique, custom alloy blocking, 2.5 Gy per fraction, 1 fraction per day, and 5 fractions per week. The daily spinal cord dose did not exceed 1.9 Gy per fraction. Portions of the kidney, specifically the right kidney, received a full dose, although the treatment plan ensured that 50% of the functioning renal parenchyma received no more than 35% of the daily dose or a total of 17.5 Gy. Radiation and chemotherapy began concurrently on day 1, 41 to 86 days after surgery. Two cycles of chemotherapy were administered during radiation, followed by 4 additional cycles of identical chemotherapy.\n\nTrial B (9940): Chemotherapy prior to and following adjuvant chemoradiation\nPatients were treated on trial B from August 1999 to April 2002. Chemotherapy was administered similarly to trial A, with the exception that patients received continuous infusion 5-FU and an 8 mg/m2/day dose of MMC (2 mg lower). Radiation was delivered to patients in trial B according to the technical aspects outlined for trial A; however, daily fractions of 1.8 Gy were delivered continuously (with no planned break) for 25 to 30 fractions. Furthermore, 1 cycle of chemotherapy was administered before CRT and 2 additional cycles were delivered after CRT.\n\nToxicity analysis and dose modifications\nAll patients were evaluated for toxicity weekly during therapy. Toxicity was graded using the National Cancer Institute Common Toxicity Criteria version 1.0 (1994). Treatment was held for absolute neutrophil count <1000/mm3 and platelet count <75,000/mm3. For any nonhematologic toxicity of grade ≥3 attributable to radiation, further treatments were held until toxicity resolved to grade ≤1 toxicity. Radiation dose escalation was not allowed. If treatment delayed radiation for >12 weeks, the patient was removed from the study.\n\nModifications of 5-FU, LV, DPM, and MMC were based on nadir absolute neutrophil count and platelet counts or worst-grade nonhematologic toxicity attributable to these chemotherapies in the immediately preceding cycle. The 5-FU/LV/DPM was delayed until toxicity had resolved to grade 0 or 1. The dose of DPM was decreased by 25% for DPM-related toxicities such as headache, whereas 5-FU and LV doses were not modified.\n\nHematologic toxicities were measured at different time points on the 2 protocols. For the split-course treatment in trial A, toxicity was assessed twice, once during CRT and once after CRT. Toxicities were assessed once after CRT in trial B.\n\nFamily history\nPaper and electronic charts as well as the National Familial Pancreatic Tumor Registry25 were reviewed to examine possible correlations of family history of cancer with overall survival (OS). A family history of PDAC was defined as having at least 1 first-degree relative with a diagnosis of PDAC. A family history of breast or ovarian cancer was defined as having at least 1 first- or second-degree relative with either of these carcinomas.\n\nStatistical analysis\nThe primary statistical endpoints are toxicity and OS of patients treated on trials A and B. Toxicity is reported descriptively. Follow-up information was obtained from medical records, with restaging occurring every 3 months for year 1, every 4 months for year 2, and every 6 months thereafter. Outcomes between the 2 trials were not directly compared because the study designs were single-arm and treatment was not randomized. Event time distributions were estimated using the Kaplan-Meier method26 and comparisons within each trial were made using the log-rank statistic27 or the proportional hazards regression model.28 All factors in Table 1, in addition to family history of PDAC, gastrointestinal cancers, and breast or ovarian cancer, were tested for an association with OS. Median follow-up was calculated with the reverse Kaplan-Meier method. Binomial probabilities were compared with χ2 tests and reported with exact binomial 95% confidence intervals (CIs). The Cochran-Mantel-Haenszel test was used to evaluate the association of PDAC with positive margins stratifying for protocol. The Breslow-Day test for homogeneity of odds ratios was used to confirm assumptions of stratified analyses. 2-sided significance testing was used throughout the analysis, and a P value of .05 was considered statistically significant.Table 1 Patient characteristics: demographics and surgical outcomes\n\nTable 1\tTrial A (9625)\n(n = 62)\tTrial B (9940)\n(n = 57)\t\nStudy dates (y)\tApril 29, 1996-July 16, 1999\tAugust 6, 1999-April 10, 2002\t\nMedian age (IQR), y\t60 (39-79)\t50 (29-77)\t\nSex, n (%)\t\t\t\n Male\t35 (56)\t29 (51)\t\n Female\t27 (44)\t28 (49)\t\nRace, n (%)\t\t\t\n Caucasian\t60 (97)\t53 (93)\t\n African American\t1 (2)\t2 (4)\t\n Other\t1 (2)\t2 (4)\t\nPrimary tumor site, n (%)\t\t\t\n Pancreas\t38 (61)\t39 (68)\t\n Ampullary\t7 (11)\t8 (14)\t\n DCBD\t24 (39)\t18 (32)\t\n Duodenum\t2 (3)\t3 (5)\t\nT stage\t\t\t\n T1\t2 (3)\t0 (0)\t\n T2\t6 (10)\t6 (11)\t\n T3\t41 (66)\t49 (86)\t\n T4\t13 (21)\t2 (4)\t\nTumor size, n (%)\t\t\t\n ≥ 3 cm\t36 (58)\t30 (53)\t\n < 3 cm\t26 (42)\t27 (47)\t\nHistologic grade, n (%)\t\t\t\n Well-differentiated\t0 (0)\t2 (4)\t\n Well to moderately\t1 (2)\t3 (5)\t\n Moderately differentiated\t31 (50)\t24 (42)\t\n Moderately to poorly\t11 (18)\t14 (25)\t\n Poorly differentiated\t19 (31)\t14 (25)\t\nNegative margins, n (%)\t45 (73)\t46 (81)\t\nPositive margins, n (%)\t17 (27)\t11 (19)\t\n Microscopic\t14 (23)\t9 (16)\t\n Macroscopic\t3 (5)\t2 (4)\t\nRadical lymph node dissection, n (%)\t19 (31)\t7 (12)\t\nPositive lymph nodes, n (%)\t53 (85)\t49 (86)\t\nMedian number of positive lymph nodes (IQR), n\t3 (0-24)\t2 (0-16)\t\nLymphovascular invasion, n (%)\t26 (42)\t22 (39)\t\nPerineural invasion, n (%)\t48 (77)\t45 (80)\t\nMedian time to start RT (IQR), days\t67 (35-96)\t64 (41-87)\t\nDCBD, distal common bile duct; IQR, interquartile range; RT, radiation therapy.\n\n\n\nResults\nDemographic, tumor, and treatment characteristics for both trials are given in Table 1. The patients on these protocols had very similar demographics and disease characteristics. The median (interquartile range [IQR]) age of patients on trials A and B was 60 (IQR, 56, 67) and 59 (IQR, 54, 67), respectively. Both trials had approximately 60% of patients with PDAC, included more than 92% Caucasian patients, and were approximately evenly split on gender. Tumor characteristics were mostly similar (Table 1). One notable difference was radical lymph node dissection, which was more common on trial A (31%; 95% CI, 19.56-43.65) compared with 12% (95% CI, 5.08-23.68) on trial B, likely because of a separate overlapping surgical clinical trial.29, 30, 31\n\nUnivariate analysis\nMedian follow-up was 197.5 months for trial A and 107.7 months for trial B. Median OS in trial A was 32.2 months and 24.2 months in trial B (Fig 1). Rates of 3-, 5-, and 10-year OS were 48%, 31%, and 26% in trial A and 32%, 23%, and 9% in trial B. Univariate OS analyses for both trials are shown in Table 2.Figure 1 Kaplan-Meier overall survival curve of all patients separated by trial A versus trial B.\n\nFigure 1Table 2 Significant univariate associations with OS for trials A and B\n\nTable 2\tN\tMedian\t3-y OS\t5-y OS\t10-y OS\tHR\t95% CI\tP value\t\nTrial A (9625)\t\nDiagnosis\t\t\t\t\t\t\t\t\t\n Non-PDAC\t24\t49.9\t71 (55-92)\t46 (30-71)\t32 (18-58)\t1.00\t-\t.016\t\n PDAC\t38\t16.9\t34 (22-53)\t21 (11-39)\t21 (11-39)\t2.02\t1.14-3.58\t\nMargins\t\t\t\t\t\t\t\t\t\n Negative\t45\t39.5\t60 (47-76)\t36 (24-53)\t33 (22-50)\t1.00\t-\t.026\t\n Positive\t17\t15.7\t18 (6-49)\t18 (6-49)\t6 (1-39)\t1.98\t1.09-3.6\t\nNode status\t\t\t\t\t\t\t\t\t\n Negative\t9\t164.4\t89 (71-00)\t78 (55-100)\t65 (39-100)\t1.00\t-\t.017\t\n Positive\t53\t18.2\t42 (30-57)\t23 (14-37)\t19 (11-33)\t2.84\t1.21-6.69\t\nFamily of breast or ovarian cancer\t\t\t\t\t\t\t\t\t\n No\t52\t34.4\t50 (38-66)\t37 (26-52)\t30 (20-46)\t1.00\t-\t.039\t\n Yes\t10\t22.6\t40 (19-85)\t0 (NA-NA)\t0 (NA-NA)\t2.13\t1.04-4.36\t\nT stage\t\t\t\t\t\t\t\t\t\n 1-2\t8\t164.4\t75 (50-100)\t75 (50-100)\t75 (50-100)\t1.00\t-\t.05\t\n 3-4\t54\t27.3\t44 (33-60)\t24 (15-39)\t18 (10-32)\t2.37\t1-5.61\t\n\t\t\t\t\t\t\t\t\t\nTrial B (9940)\t\nDiagnosis\t18\t38.5\t56 (37-84)\t39 (22-69)\t28 (13-59)\t1.00\t-\t.026\t\n Non-PDAC\n PDAC\t39\t21.7\t21 (11-38)\t15 (7-32)\t0 (NA-NA)\t2.07\t1.09-3.94\t\t\nSize, cm\t\t\t\t\t\t\t\t\t\n < 3\t20\t25.3\t45 (28-73)\t35 (19-64)\t25 (12-53)\t1.00\t-\t.054\t\n ≥ 3\t37\t21.7\t24 (14-43)\t16 (8-34)\t0 (NA-NA)\t1.84\t0.99-3.4\t\nPerineural invasion\t\t\t\t\t\t\t\t\t\n No\t11\t61.3\t73 (51-100)\t55 (32-94)\t23 (5-87)\t1.00\t-\t.011\t\n Yes\t45\t21.6\t22 (13-38)\t16 (8-31)\t6 (2-20)\t2.92\t1.28-6.64\t\nLymph node dissection\t\t\t\t\t\t\t\t\t\n Standard\t50\t22.54\t26 (16-42)\t18 (10-33)\t4 (1-20)\t1.00\t-\t.015\t\n Radical\t7\tNR\t71 (45-100)\t57 (30-100)\t57 (30-100)\t0.23\t0.07-0.75\t\nTumor differentiation\t\t\t\t\t\t\t\t\t\n Well to moderately poorly\t43\t26.1\t37 (25-55)\t28 (17-45)\t10 (4-30)\t1.00\t-\t.045\t\n Poorly\t14\t15.6\t14 (4-52)\t7 (1-47)\t7 (1-47)\t1.93\t1.01-3.66\t\nCI, confidence interval; HR, hazard ratio; OS, overall survival; NA, not available; NR, not reported; PDAC, pancreatic ductal adenocarcinoma.\n\n\n\nOn trial A, a PDAC diagnosis, margin-positive resection, lymph node–positive resection, and T stage 3-4 were associated with decreased OS (Table 2). Although PDAC patients in trial A had a significantly inferior OS than non-PDAC patients (median, 16.9 vs 49.9 months; P = .016), long-term OS rates in PDAC were impressive (34% 3-year, 21% 5-year, and 21% 10-year; Fig 2A). Patients on trial A with a family history of PDAC had a trend toward improved OS (median, 164.4 vs 28.7 months, P = .058), whereas those with a family history of breast or ovarian cancer had decreased OS (P = .039; Fig S1).Figure 2 Kaplan-Meier overall survival curve of (A) trial A and (B) trial B patients separated by a PDAC versus non-PDAC diagnosis. Med, median; PDAC, pancreatic ductal adenocarcinoma.\n\nFigure 2\n\nA PDAC diagnosis was also associated with decreased OS in trial B (Table 2). Additional risk factors for worse OS included female sex, tumor size ≥3 cm, perineural invasion, and poor differentiation (Table 2). Of note, the 3-, 5-, and 10-year OS rates for patients with PDAC on trial B were 21%, 15%, and 0%, and 56%, 39%, and 28% for non-PDAC patients (Fig 2B). A family history of cancer, PDAC or breast/ovarian, was not associated with OS in this trial. The few patients with radical lymph node dissections (n = 7) had significantly improved OS (P = .015).\n\nMultivariate analysis\nIn multivariate analysis, lymph node-positive resection was the strongest factor associated with OS (Table 3). Positive margins were more likely in patients with PDAC (31.2% vs 9.5%, Cochran-Mantel-Haenszel P = .01). This correlation makes it difficult to determine whether the PDAC diagnosis or margin status is a greater contributing factor to inferior OS; however, each factor alone is also significantly associated with decreased OS after adjusting for lymph node status (all P < .05).Table 3 Significant multivariate associations with OS for trials A and B\n\nTable 3\tHR (95% CI)\tP value\t\nTrial A (9625)\t\n PDAC vs non-PDAC diagnosis\t1.65 (0.91-2.98)\t.10\t\n Positive vs negative margins\t1.69 (0.91-3.12)\t.10\t\n Positive vs negative node status\t2.48 (1.04-5.90)\t.04\t\nTrial B (9940)\t\n PDAC vs non-PDAC diagnosis\t1.90 (0.97-3.71)\t.06\t\n Female vs male sex\t1.89 (1.04-3.44)\t.04\t\n PNI vs no PNI\t2.80 (1.18-6.63)\t.02\t\n Poorly vs well to moderately-poorly differentiated tumors\t2.41 (1.22-4.78)\t.01\t\nPNI, perineural invasion. All other abbreviations as in Table 2.\n\n\n\nAdjusting for other significant factors on multivariate analysis, a diagnosis of PDAC was also marginally associated with decreased OS in trial B (Table 3). Margin status was not a significant factor for patients on trial B on univariate or multivariate analyses. Factors significantly associated with worse OS included female sex, perineural invasion, and poor differentiation. A radical lymph node dissection was not significantly associated with OS on multivariate analysis when adjusted for other factors.\n\nLong-term survivors\nFor strictly descriptive purposes, we also report characteristics of long-term survivors defined as ≥5 years of OS from surgery. Trial A had 19 patients who survived longer than 5 years, in comparison with 11 patients in trial B, for a total of 30 of 119 (25%) long-term survivors. Long-term survivors were more likely to be male (63%) and had a median age of 60 years (IQR, 56, 65). The majority of long-term survivors had PDAC (43%), followed by distal common bile duct (30%), ampullary (17%), and duodenal (10%) carcinomas. The majority had a margin-negative resection (87%) and moderately differentiated tumors (47%), with a median tumor size of 3.0 cm (IQR, 2.0, 4.0).\n\nToxicity\nNonhematologic and hematologic grade ≥3 toxicities on both trials are itemized in Table 4. Overall, rates of grade ≥3 nonhematologic toxicity in trials A and B were 14.4% and 23.4%, respectively. For all types of nonhematologic toxicity, the proportion on either protocol was ≤5%. The acute and late grade ≥3 toxicity rates in trial A were 6.4% and 8.0%, respectively. In trial B, there were more late versus acute grade ≥3 toxicities (19.8% vs 3.6%, respectively). All 9 adverse events on trial A were standalone events, whereas on trial B, 1 patient had 3 adverse events, another patient had 2 adverse events, and the remaining 8 patients had 1 adverse event. Two patients on trial A had a grade 5 toxicity, with 1 patient dying of gangrenous bowel 6 months after local disease recurrence and another experiencing a gut infarct 3 years after CRT. No grade 5 toxicities were observed in trial B. Upon further evaluation, only 1 (1.6%) adverse event was deemed attributed to CRT in trial A, whereas 4 (7.2%) adverse events were considered attributable to CRT in trial B.Table 4 Hematologic and nonhematologic grade ≥3 toxicity\n\nTable 4\tTrial A (9625, n = 62)\tTrial B (9940, n = 57)\t\nTotal grade ≥3, %\tGrade 3, %\tGrade 4, %\tGrade 5, %\tTotal grade ≥3, %\tGrade 3, %\tGrade 4, %\tGrade 5, %\t\nNonhematologic\t\nGastrointestinal bleed\t4.8\t4.8\t0\t0\t3.6\t1.8\t1.8\t0\t\nIschemia\t3.2\t0\t0\t3.2\t0\t0\t0\t0\t\nUlcer\t0\t0\t0\t0\t0\t0\t0\t0\t\nBowel obstruction\t1.6\t1.6\t0\t0\t1.8\t1.8\t0\t0\t\nGastric obstruction\t0\t0\t0\t0\t3.6\t3.6\t0\t0\t\nPancreatitis\t1.6\t1.6\t0\t0\t0\t0\t0\t0\t\nCholangitis\t1.6\t1.6\t0\t0\t1.8\t1.8\t0\t0\t\nEnteritis\t0\t0\t0\t0\t0\t0\t0\t0\t\nColitis\t0\t0\t0\t0\t3.6\t1.8\t1.8\t0\t\nEsophagitis\t0\t0\t0\t0\t1.8\t1.8\t0\t0\t\nPain\t0\t0\t0\t0\t5.4\t5.4\t0\t0\t\nSepsis\t1.6\t1.6\t0\t0\t1.8\t1.8\t0\t0\t\nTotal\t14.4\t11.2\t0\t3.2\t23.4\t19.8\t3.6\t0\t\nHematologica\t\nNeutropenia\t39\t23\t16\t0\t39\t23\t16\t0\t\n38\t23\t15\t0\t\nThrombocytopenia\t6\t19%\t3\t0\t22\t19\t3\t0\t\n32\t16%\t16\t0\t\nAnemia\t2\t2\t0\t0\t10\t10\t0\t0\t\n10\t10\t0\t0\t\na Hematologic toxicity was measured at 2 separate time points in trial A.\n\n\n\nDiscussion\nThrough next-generation sequencing, it is now possible to determine whether a patient's cancer has mutations in DNA repair pathways.32 Studies suggest integration of MMC into the treatment paradigm of patients with these mutations may result in improved outcomes.20, 33 This is the first prospective study with long-term follow-up to evaluate this approach. In summary, these 2 clinical trials suggest that MMC may be safely incorporated into either split-course or continuous 5-FU–based (continuous infusion or bolus) adjuvant CRT regimens in patients with resected PDAC or non-PDAC periampullary adenocarcinoma. Furthermore, these regimens (trials A and B) resulted in as high as an 18-month OS benefit in comparison with other studies.2, 6, 7, 34, 35, 36 Also consistent with the literature, patients with non-PDAC periampullary tumors were found to have a more favorable prognosis and extended OS after surgical resection than patients with PDAC.1, 2, 35\n\nThe rationale behind the novel adjuvant regimens used in this study was based on innovative agents, including MMC and DPM, under investigation during the development of the study.16 Although the proportion of long-term survivors (>5 years) was larger in trial A, it is unclear if this difference is attributable to patient selection, the duration or type of chemotherapy, or the split-course radiation treatment (2.5 vs 1.8 Gy/fraction), which had about 5% to 8% more biological equivalent dose for α/β ratios of 10 or 6, respectively, and about 15% more potent for an α/β ratio of 3 (not counting repopulation). In addition, the split-course regimen in trial A was associated with similar rates of toxicity when compared with the continuous CRT regimen used in trial B, suggesting that MMC can be safely integrated into adjuvant CRT for patients with periampullary cancers, even when combined with bolus 5-FU (in trial A), which has been shown to be associated with unfavorable toxicity.37\n\nConsistent with previous studies, positive resection margins and lymph nodes appear to be independently associated with worse OS.3, 7, 38, 39 Because neoadjuvant therapy has been associated with a higher likelihood of margin- and node-negative resection in patients with borderline resectable and resectable PDAC,40, 41 delivery of chemotherapy and/or CRT before surgery may confer improved local control and long-term survival in patients with resectable PDAC and/or non-PDAC periampullary adenocarcinoma.42, 43 Earlier detection of these tumors and a better understanding of the genomic profile before surgery may be coupled with neoadjuvant therapy to select patients who may benefit from surgery. Positron emission tomography imaging, in particular, may allow for detection of nodal disease before resection. In fact, 1 study suggests that lymph nodes with maximum standard uptake value ≥2.8 were an independent factor for prognosis after resection.44, 45\n\nTo our knowledge, this is the largest report prospectively evaluating the role of MMC in the adjuvant management of periampullary cancers.1, 46 MMC has been suggested to convert unresectable patients to surgical candidates,42 enhance the therapeutic effects of adjuvant CRT,47 and improve local control48 in periampullary adenocarcinoma. Although it has not been extensively studied in PDAC, MMC has been used in other cancers such as anal cancer,49, 50, 51 and recent studies suggest its promising role in PDAC patients with a family history of PDAC and/or carcinomas with an inactivating mutation in a Fanconi anemia pathway gene (such as BRCA1, BRCA2, or PALB2).18, 19, 20, 21, 22, 23 Study results from trial A demonstrated that having a family history of PDAC specifically resulted in a borderline significant improvement in OS (164.4 vs 28.7 months, P = .058). In contrast, however, having a family history of breast or ovarian cancer was associated with inferior OS (22.6 vs 34.4 months, P = .039). These conclusions are limited by the fact that only a small proportion of patients fit these criteria; therefore, larger trials are needed to further determine whether MMC is beneficial in 1 subgroup or another.\n\nIn addition to the relatively small sample size, there are numerous limitations to this study. To achieve an analyzable sample size for these rare cancers, all periampullary cancers were included; however, this increases the difficulty of interpreting the results because of the differences in prognoses. To acknowledge this, we separated survival outcomes into PDAC and non-PDAC periampullary cancers. Of note, the American Joint Committee on Cancer staging system at the time in which patients were enrolled on these clinical trials differs from that in current use today; although it appears that patients with advanced disease were enrolled on the clinical trials, this is not the case and, as such, T stage was not included in the multivariate model. Furthermore, the study design of these historic prospective trials is outdated with the use of bolus 5-FU and split-course CRT. Nonetheless, the purpose of this study is to share the long-term results of these studies and to suggest that MMC can indeed be combined with standard adjuvant CRT in periampullary cancers and may be beneficial in patients with mutations in the DNA repair pathway.\n\nThese prospective studies indicate that an MMC may be safely incorporated into a 5-FU–based CRT regimen in patients with PDAC and non-PDAC periampullary cancers, with promising results of long-term survival. A family history of PDAC correlated with a trend toward improved OS in trial A. It is unclear if these improvements in OS are due to MMC and will therefore need to be prospectively evaluated in a larger, randomized series with integrated cancer sequencing for DNA repair defects.32\n\nSupplementary data\nThe following is the supplementary data to this article:Figure S1\nKaplan-Meier OS curve of patients enrolled onto Trial A with (A) a family history of pancreatic ductal adenocarcinoma (PDAC) or (B) breast or ovarian cancer.\n\nFigure S1 \n\nTable S1\nTreatment schema for Trials A and B.\n\nTable S1 \n\nSources of support: National Institutes of Health SPORE grant CA62924.\n\nConflict of interest: Dr. Hruban receives royalty payments from Myriad Genetics for the PALB2 invention.\n\nSupplementary material for this article (http://dx.doi.org/10.1016/j.adro.2017.07.008) can be found at www.advancesradonc.org.\n==== Refs\nReferences\n1 Chakravarthy A. Abrams R.A. Yeo C.J. Intensified adjuvant combined modality therapy for resected periampullary adenocarcinoma: Acceptable toxicity and suggestion of improved 1-year disease-free survival Int J Radiat Oncol Biol Phys 48 2000 1089 1096 11072167 \n2 Morak M.J. van der Gaast A. Incrocci L. Adjuvant intra-arterial chemotherapy and radiotherapy versus surgery alone in resectable pancreatic and periampullary cancer: A prospective randomized controlled trial Ann Surg 248 2008 1031 1041 19092348 \n3 Gutierrez J.C. Franceschi D. Koniaris L.G. How many lymph nodes properly stage a periampullary malignancy? J Gastrointest Surg 12 2008 77 85 17701264 \n4 Neoptolemos J.P. Moore M.J. Cox T.F. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: The ESPAC-3 periampullary cancer randomized trial JAMA 308 2012 147 156 22782416 \n5 Aiura K. Takahashi S. Matsui J. Ueda M. Kitagawa Y. Beneficial effects of 5-fluorouracil and heparin-based portal infusion chemotherapy combined with mitomycin C and cisplatin after curative resection of pancreatic cancer Pancreatology 10 2010 250 258 20484963 \n6 Jiang Z.Q. Varadhachary G. Wang X. A retrospective study of ampullary adenocarcinomas: Overall survival and responsiveness to fluoropyrimidine-based chemotherapy Ann Oncol 24 2013 2349 2353 23704197 \n7 He J. Ahuja N. Makary M.A. 2564 resected periampullary adenocarcinomas at a single institution: Trends over three decades HPB (Oxford) 16 2014 83 90 23472829 \n8 American Cancer Society Cancer facts & figures 2017 Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf \n9 Wolfgang C.L. Herman J.M. Laheru D.A. Recent progress in pancreatic cancer CA Cancer J Clin 63 2013 318 348 23856911 \n10 Moertel C.G. Frytak S. Hahn R.G. Therapy of locally unresectable pancreatic carcinoma: A randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The gastrointestinal tumor study group Cancer 48 1981 1705 1710 7284971 \n11 Kalser M.H. Ellenberg S.S. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection Arch Surg 120 1985 899 903 4015380 \n12 Neoptolemos J.P. Dunn J.A. Stocken D.D. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: A randomised controlled trial Lancet 358 2001 1576 1585 11716884 \n13 Regine W.F. Winter K.A. Abrams R.A. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: A randomized controlled trial JAMA 299 2008 1019 1026 18319412 \n14 Tempero M.A. Malafa M.P. Behrman S.W. Pancreatic adenocarcinoma, version 2.2014: Featured updates to the NCCN guidelines J Natl Compr Canc Netw 12 2014 1083 1093 25099441 \n15 Ling T.C. Slater J.M. Mifflin R. Evaluation of normal tissue exposure in patients receiving radiotherapy for pancreatic cancer based on RTOG 0848 J Gastrointest Oncol 6 2015 108 114 25830030 \n16 Todd K.E. Gloor B. Lane J.S. Isacoff W.H. Reber H.A. Resection of locally advanced pancreatic cancer after downstaging with continuous-infusion 5-fluorouracil, mitomycin-C, leucovorin, and dipyridamole J Gastrointest Surg 2 1998 159 166 9834413 \n17 Isacoff W.H. Bendetti J.K. Barstis J.J. Jazieh A.R. Macdonald J.S. Philip P.A. Phase II trial of infusional fluorouracil, leucovorin, mitomycin, and dipyridamole in locally advanced unresectable pancreatic adenocarcinoma: SWOG S9700 J Clin Oncol 25 2007 1665 1669 17470859 \n18 van der Heijden M.S. Brody J.R. Dezentje D.A. In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor Clin Cancer Res 11 2005 7508 7515 16243825 \n19 Wang L. Brune K.A. Visvanathan K. Elevated cancer mortality in the relatives of patients with pancreatic cancer Cancer Epidemiol Biomarkers Prev 18 2009 2829 2834 19843679 \n20 Villarroel M.C. Rajeshkumar N.V. Garrido-Laguna I. Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer Mol Cancer Ther 10 2011 3 8 21135251 \n21 Cui Y. Brosnan J.A. Blackford A.L. Genetically defined subsets of human pancreatic cancer show unique in vitro chemosensitivity Clin Cancer Res 18 2012 6519 6530 22753594 \n22 Navarrete A. Armitage E.G. Musteanu M. Metabolomic evaluation of mitomycin C and rapamycin in a personalized treatment of pancreatic cancer Pharmacol Res Perspect 2 2014 e00067 25505613 \n23 Vyas O. Leung K. Ledbetter L. Clinical outcomes in pancreatic adenocarcinoma associated with BRCA-2 mutation Anticancer Drugs 26 2015 224 226 25304989 \n24 Herman J.M. Swartz M.J. Hsu C.C. Analysis of fluorouracil-based adjuvant chemotherapy and radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: Results of a large, prospectively collected database at the johns hopkins hospital J Clin Oncol 26 2008 3503 3510 18640931 \n25 Johns Hopkins National Familial Pancreatic Tumor Registry Available at: http://pathology.jhu.edu/pancreas/nfptr/index.php \n26 Kaplan E.L. Meier P. Nonparametric estimation from incomplete observations J Am Stat Assoc 53 1958 457 481 \n27 Mantel N. Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease J Natl Cancer Inst 22 1959 719 748 13655060 \n28 Cox D. Regression models and life tables JR Stat Soc B34 1972 187 220 \n29 Riall T.S. Cameron J.L. Lillemoe K.D. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma—part 3: Update on 5-year survival J Gastrointest Surg 9 2005 1191 1206 16332474 \n30 Yeo C.J. Cameron J.L. Sohn T.A. Pancreaticoduodenectomy with or without extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma: Comparison of morbidity and mortality and short-term outcome Ann Surg 229 1999 613 624 10235519 \n31 Yeo C.J. Cameron J.L. Lillemoe K.D. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: Randomized controlled trial evaluating survival, morbidity, and mortality Ann Surg 236 2002 355 368 12192322 \n32 Humphris J.L. Patch A.M. Nones K. Hypermutation in pancreatic cancer Gastroenterology 152 2017 68 74 e2 27856273 \n33 Chalasani P. Kurtin S. Dragovich T. Response to a third-line mitomycin C (MMC)-based chemotherapy in a patient with metastatic pancreatic adenocarcinoma carrying germline BRCA2 mutation JOP 9 2008 305 308 18469443 \n34 Abrams R.A. Grochow L.B. Chakravarthy A. Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma: Survival results and observations regarding patterns of failure, radiotherapy dose and CA19-9 levels Int J Radiat Oncol Biol Phys 44 1999 1039 1046 10421536 \n35 Lee J.H. Whittington R. Williams N.N. Outcome of pancreaticoduodenectomy and impact of adjuvant therapy for ampullary carcinomas Int J Radiat Oncol Biol Phys 47 2000 945 953 10863064 \n36 Turan N. Benekli M. Unal O.U. Impact of adjuvant treatment modalities on survival outcomes in curatively resected pancreatic and periampullary adenocarcinoma Chin J Cancer Res 27 2015 408 416 26361410 \n37 Mahaseth H. Brutcher E. Kauh J. Modified FOLFIRINOX regimen with improved safety and maintained efficacy in pancreatic adenocarcinoma Pancreas 42 2013 1311 1315 24152956 \n38 Schnelldorfer T. Ware A.L. Sarr M.G. Long-term survival after pancreatoduodenectomy for pancreatic adenocarcinoma: Is cure possible? Ann Surg 247 2008 456 462 18376190 \n39 Smith R.A. Bosonnet L. Ghaneh P. Preoperative CA19-9 levels and lymph node ratio are independent predictors of survival in patients with resected pancreatic ductal adenocarcinoma Dig Surg 25 2008 226 232 18577869 \n40 Katz M.H. Marsh R. Herman J.M. Borderline resectable pancreatic cancer: Need for standardization and methods for optimal clinical trial design Ann Surg Oncol 20 2013 2787 2795 23435609 \n41 Sen N. Falk S. Abrams R.A. Role of chemoradiotherapy in the adjuvant and neoadjuvant settings for resectable pancreatic cancer Clin Oncol (R Coll Radiol) 26 2014 551 559 25024090 \n42 Weese J.L. Nussbaum M.L. Paul A.R. Increased resectability of locally advanced pancreatic and periampullary carcinoma with neoadjuvant chemoradiotherapy Int J Pancreatol 7 1990 177 185 2081923 \n43 Reilley M.J. Shroff R. Varadhachary G.R. Adjuvant/perioperative therapy in pancreatic and periampullary cancer Indian J Surg 77 2015 403 408 \n44 Kalady M.F. Clary B.M. Clark L.A. Clinical utility of positron emission tomography in the diagnosis and management of periampullary neoplasms Ann Surg Oncol 9 2002 799 806 12374664 \n45 Kobayashi S. Nagano H. Hoshino H. Diagnostic value of FDG-PET for lymph node metastasis and outcome of surgery for biliary cancer J Surg Oncol 103 2011 223 229 21140426 \n46 Splinter T.A. Obertop H. Kok T.C. Jeekel J. Adjuvant chemotherapy after resection of adenocarcinoma of the periampullary region and the head of the pancreas. A non-randomized pilot study J Cancer Res Clin Oncol 115 1989 200 202 2715169 \n47 Coia L. Hoffman J. Scher R. Preoperative chemoradiation for adenocarcinoma of the pancreas and duodenum Int J Radiat Oncol Biol Phys 30 1994 161 167 8083109 \n48 Tomikawa M. Kubota T. Matsuzaki S.W. Mitomycin C and cisplatin increase survival in a human pancreatic cancer metastatic model Anticancer Res 17 1997 3623 3625 9413214 \n49 Kachnic L.A. Winter K. Myerson R.J. RTOG 0529: A phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal Int J Radiat Oncol Biol Phys 86 2013 27 33 23154075 \n50 Vinayan A. Glynne-Jones R. Anal cancer—what is the optimum chemoradiotherapy? Best Pract Res Clin Gastroenterol 30 2016 641 653 27644911 \n51 Peixoto R.D. Wan D.D. Schellenberg D. Lim H.J. A comparison between 5-fluorouracil/mitomycin and capecitabine/mitomycin in combination with radiation for anal cancer J Gastrointest Oncol 7 2016 665 672 27563458\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2452-1094",
"issue": "3(1)",
"journal": "Advances in radiation oncology",
"keywords": null,
"medline_ta": "Adv Radiat Oncol",
"mesh_terms": null,
"nlm_unique_id": "101677247",
"other_id": null,
"pages": "42-51",
"pmc": null,
"pmid": "29556579",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "18469443;23435609;17470859;21135251;16332474;12192322;11716884;17701264;9413214;27856273;23856911;25304989;18640931;2081923;10421536;22753594;27563458;10235519;18577869;25505613;25024090;10863064;25099441;26361410;24152956;19092348;13655060;18376190;27644911;22782416;2715169;16243825;23704197;20484963;12374664;9834413;18319412;23154075;7284971;11072167;21140426;26722204;25830030;4015380;23472829;8083109;19843679",
"title": "Long-term analysis of 2 prospective studies that incorporate mitomycin C into an adjuvant chemoradiation regimen for pancreatic and periampullary cancers.",
"title_normalized": "long term analysis of 2 prospective studies that incorporate mitomycin c into an adjuvant chemoradiation regimen for pancreatic and periampullary cancers"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-004656",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIPYRIDAMOLE"
},
... |
{
"abstract": "A confused and agitated 18-year-old woman presented to the emergency unit with orolingual movements, eye deviation, and a temperature of 38°C. The symptoms had begun 2 weeks prior to the admission when she developed a severe headache associated with pathologic laughing and intermittent episodes of upgaze deviation. A urine pregnancy test was positive and a transvaginal ultrasonography showed a 9-week-old fetus. An MRI of the brain was unremarkable and results of the CSF analysis were also unremarkable apart from a CSF pleocytosis (62 lymphocytes) and slightly elevated protein (55 mg/dL; normal range 0-45 mg/dL). Extensive microbiologic and serologic studies with CSF were all negative. She gradually lost consciousness, experienced respiratory failure, and was intubated. There were semirhythmic movements consisting of complex patterns of mouth opening, chewing, facial grimacing, synchronous flexion-extension, and supination-pronation limb movements, which persisted during the period of unresponsiveness. She also had generalized hyperreflexia, persistent hyperthermia, and a full bladder. Three EEGs showed diffuse slow waves with no epileptic discharges. A diagnosis of anti-NMDA receptor (NMDAR) encephalitis was made on clinical grounds and strongly positive serum NMDAR antibodies.",
"affiliations": "From the Chulalongkorn Center of Excellence on Parkinson's Disease and Related Disorders (P.J., R.B.), Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; University of Oxford (A.V.), UK; and the Geffen School of Medicine at UCLA (R.B.), Los Angeles, CA.",
"authors": "Jagota|Priya|P|;Vincent|Angela|A|;Bhidayasiri|Roongroj|R|",
"chemical_list": "D000906:Antibodies; D016194:Receptors, N-Methyl-D-Aspartate",
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0000000000000384",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "82(18)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000161:Acoustic Stimulation; D000293:Adolescent; D000906:Antibodies; D001921:Brain; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D054220:Malformations of Cortical Development; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D011248:Pregnancy Complications; D016194:Receptors, N-Methyl-D-Aspartate; D016216:Ultrasonography, Prenatal",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "1662-3",
"pmc": null,
"pmid": "24706012",
"pubdate": "2014-05-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20196492;17703228;22752087;22606296;20427647;20625099;22825272",
"title": "Transplacental transfer of NMDA receptor antibodies in an infant with cortical dysplasia.",
"title_normalized": "transplacental transfer of nmda receptor antibodies in an infant with cortical dysplasia"
} | [
{
"companynumb": "TH-PFIZER INC-2018470978",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"druga... |
{
"abstract": "Parkinson's disease (PD) can present with lateral trunk flexion (LTF). Abnormal posture associated with PD has been treated, but the effectiveness of these treatments is limited, resulting in unsatisfactory outcomes. Unilateral hypertrophy and unilateral hyperactivity may be useful for deciding targets for injection of botulinum toxin or physical rehabilitation. However, such findings may be limited such as the obliquus abdominis muscle or thoracic paraspinal muscles, and several other muscles may have a causative role in LTF. We investigated 8 patients whether other muscles show unilateral hypertrophy by analyzing computed tomographic scans. Cobb's angle was 11° to 34°. The area of the paravertebral muscles was large contralateral to the bending side and this trend intensified from L4 to Th10. The lumbar quadrate muscle and psoas major muscle showed unilateral enlargement. These larger muscles were prominent contralateral to the bending side in five patients and ipsilateral to the bending side in two patients. This unilateral muscle change was mildly seen in the internal and external abdominal oblique muscles. The lumbar quadrate muscle or psoas major muscle showed two hypertrophic patterns, and these muscles might be new therapeutic targets for treatments such as botulinum toxin.",
"affiliations": "Department of Neurology, Nara Medical University, Kashihara, Nara, Japan. Electronic address: hk55@naramed-u.ac.jp.;Department of Neurology, Nara Medical University, Kashihara, Nara, Japan.;Department of Neurology, Nara Medical University, Kashihara, Nara, Japan.",
"authors": "Kataoka|Hiroshi|H|;Sawa|Nobuhiro|N|;Ueno|Satoshi|S|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-510X",
"issue": "358(1-2)",
"journal": "Journal of the neurological sciences",
"keywords": "Lateral trunk flexion; Lumbar quadrate muscle; Muscle hypertrophy; Paravertebral muscles; Parkinson; Pisa",
"medline_ta": "J Neurol Sci",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D006984:Hypertrophy; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal; D010300:Parkinson Disease; D060726:Torso",
"nlm_unique_id": "0375403",
"other_id": null,
"pages": "435-9",
"pmc": null,
"pmid": "26375624",
"pubdate": "2015-11-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Identification of a new target muscle for treatment in patients with Parkinson's disease who have lateral trunk flexion?",
"title_normalized": "identification of a new target muscle for treatment in patients with parkinson s disease who have lateral trunk flexion"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-11997BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PRAMIPEXOLE"
},
... |
{
"abstract": "OBJECTIVE\nThe purpose of this study was to determine the potential of tissue fluorescence imaging by using Visually Enhanced Lesion Scope (VELscope) for the detection of osteonecrosis of the jaw induced by bisphosphonates (BRONJ).\n\n\nMETHODS\nWe investigated 20 patients (11 females and 9 males; mean age 74 years, standard deviation ± 6.4 years), over a period of 18 month with the diagnosis of BRONJ in this prospective cohort study. All patients received doxycycline as a fluorescending marker for osseous structures. VELscope has been used intraoperatively using the loss of fluorescence to detect presence of osteonecrosis. Osseous biopsies were taken to confirm definite histopathological diagnosis of BRONJ in each case.\n\n\nRESULTS\nDiagnosis of BRONJ was confirmed for every patient. In all patients except one, VELscope was sufficient to differentiate between healthy and necrotic bone by visual fluorescence retention (VFR) and visual fluorescence loss (VFL). 19 cases out of a total of 20 showed no signs of recurrence of BRONJ during follow-up (mean 12 months, range 4-18 months).\n\n\nCONCLUSIONS\nVELscope examination is a suitable tool to visualize necrotic areas of the bone in patients with bisphosphonate related osteonecrosis of the jaw. Loss of fluorescence in necrotic bone areas is useful intraoperatively as a tool for fluorescence-guided bone resection with relevant clinical interpretation.",
"affiliations": "Department of Oral and Maxillofacial Surgery (Head: Professor Max Heiland MD, DMD, PhD), University Medical Center Hamburg Eppendorf, University of Hamburg, 20246 Hamburg, Germany. Electronic address: a.assaf@uke.uni-hamburg.de.;Department of Oral and Maxillofacial Surgery (Head: Professor Max Heiland MD, DMD, PhD), University Medical Center Hamburg Eppendorf, University of Hamburg, 20246 Hamburg, Germany.;Department of Oral and Maxillofacial Surgery (Head: Professor Max Heiland MD, DMD, PhD), University Medical Center Hamburg Eppendorf, University of Hamburg, 20246 Hamburg, Germany.;Department of Oral and Maxillofacial Surgery (Head: Professor Max Heiland MD, DMD, PhD), University Medical Center Hamburg Eppendorf, University of Hamburg, 20246 Hamburg, Germany.;Department for Pathology, University Medical Center Hamburg Eppendorf, University of Hamburg, Martinistr. 52, 20246 Hamburg, Germany.;Department of Oral and Maxillofacial Surgery (Head: Professor Max Heiland MD, DMD, PhD), University Medical Center Hamburg Eppendorf, University of Hamburg, 20246 Hamburg, Germany.;Department of Oral and Maxillofacial Surgery (Head: Professor Max Heiland MD, DMD, PhD), University Medical Center Hamburg Eppendorf, University of Hamburg, 20246 Hamburg, Germany.;Department of Oral and Maxillofacial Surgery (Head: Professor Max Heiland MD, DMD, PhD), University Medical Center Hamburg Eppendorf, University of Hamburg, 20246 Hamburg, Germany.;Department of Oral and Maxillofacial Surgery (Head: Professor Max Heiland MD, DMD, PhD), University Medical Center Hamburg Eppendorf, University of Hamburg, 20246 Hamburg, Germany.",
"authors": "Assaf|Alexandre T|AT|;Zrnc|Tomislav A|TA|;Riecke|Björn|B|;Wikner|Johannes|J|;Zustin|Jozef|J|;Friedrich|Reinhard E|RE|;Heiland|Max|M|;Smeets|Ralf|R|;Gröbe|Alexander|A|",
"chemical_list": "D005456:Fluorescent Dyes; D004318:Doxycycline",
"country": "Scotland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1010-5182",
"issue": "42(5)",
"journal": "Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery",
"keywords": "Bisphosphonates; Fluorescence imaging; Intraoperative visualization; Osteonecrosis; VELscope(®)",
"medline_ta": "J Craniomaxillofac Surg",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D015331:Cohort Studies; D004318:Doxycycline; D005260:Female; D005453:Fluorescence; D005456:Fluorescent Dyes; D005500:Follow-Up Studies; D006801:Humans; D007430:Intraoperative Care; D008297:Male; D008336:Mandibular Diseases; D008439:Maxillary Diseases; D061848:Optical Imaging; D011446:Prospective Studies; D014081:Tooth Extraction",
"nlm_unique_id": "8704309",
"other_id": null,
"pages": "e157-64",
"pmc": null,
"pmid": "24011463",
"pubdate": "2014-07",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Intraoperative efficiency of fluorescence imaging by Visually Enhanced Lesion Scope (VELscope) in patients with bisphosphonate related osteonecrosis of the jaw (BRONJ).",
"title_normalized": "intraoperative efficiency of fluorescence imaging by visually enhanced lesion scope velscope in patients with bisphosphonate related osteonecrosis of the jaw bronj"
} | [
{
"companynumb": "PHHY2015DE039499",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "High anion gap metabolic acidosis might be caused by 5-oxoproline (pyroglutamic acid). As it is very easy to treat, it might be worth drawing attention to this uncommon and probably often overlooked diagnosis. We present three cases of high anion gap metabolic acidosis due to 5-oxoproline seen within a period of six months.",
"affiliations": "Department of Internal Medicine, VU University Medical Center, Amsterdam, the Netherlands.",
"authors": "Kortmann|W|W|;van Agtmael|M A|MA|;van Diessen|J|J|;Kanen|B L J|BL|;Jakobs|C|C|;Nanayakkara|P W B|PW|",
"chemical_list": "D011761:Pyrrolidonecarboxylic Acid",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2977",
"issue": "66(8)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D000136:Acid-Base Equilibrium; D000141:Acidosis, Renal Tubular; D000368:Aged; D005260:Female; D006801:Humans; D044342:Malnutrition; D008875:Middle Aged; D011761:Pyrrolidonecarboxylic Acid; D051437:Renal Insufficiency; D012307:Risk Factors",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "354-7",
"pmc": null,
"pmid": "18809985",
"pubdate": "2008-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "5-Oxoproline as a cause of high anion gap metabolic acidosis: an uncommon cause with common risk factors.",
"title_normalized": "5 oxoproline as a cause of high anion gap metabolic acidosis an uncommon cause with common risk factors"
} | [
{
"companynumb": "NL-PERRIGO-08NL017603",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional": nu... |
{
"abstract": "We report the case of a 13-year-old boy with cystic fibrosis with a pulmonary exacerbation concomitant to the first isolation of Pandoraea sputorum. The imipenem and trimethoprim-sulfamethoxazole treatments failed, with persistence of the bacteria, bronchial congestion and a decline in lung function. Pandoraea sp. is rarely isolated, with only 10 cases reported in France in 2011.",
"affiliations": "From the *CHU de Bordeaux, Service des Maladies Infectieuses et Tropicales, Bordeaux, France; †CHU de Bordeaux, Service de pneumologie pédiatrique, CRCM Pédiatrique, Bordeaux, France; ‡CIC 0005, Inserm, Centre d'investigation clinique pédiatrique, Hôpital Pellegrin-enfants, Bordeaux, France; and §CHU de Bordeaux, Laboratoire de Bactériologie, Bordeaux, France.",
"authors": "Pugès|Mathilde|M|;Debelleix|Stéphane|S|;Fayon|Michael|M|;Mégraud|Francis|F|;Lehours|Philippe|P|",
"chemical_list": "D000890:Anti-Infective Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0000000000000843",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0891-3668",
"issue": "34(10)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D000293:Adolescent; D000890:Anti-Infective Agents; D042521:Burkholderiaceae; D003550:Cystic Fibrosis; D024881:Drug Resistance, Bacterial; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D008297:Male",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "1135-7",
"pmc": null,
"pmid": "26176630",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Persistent Infection Because of Pandoraea sputorum in a Young Cystic Fibrosis Patient Resistant to Antimicrobial Treatment.",
"title_normalized": "persistent infection because of pandoraea sputorum in a young cystic fibrosis patient resistant to antimicrobial treatment"
} | [
{
"companynumb": "FR-WATSON-2016-01262",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditiona... |
{
"abstract": "OBJECTIVE\nTo assess the safety of cetirizine during pregnancy.\n\n\nMETHODS\nA prospective observational cohort study with data of the Berlin teratology information center from 1992 until 2006. Pregnancy outcome was compared between a cohort of pregnant women exposed to cetirizine during the first trimester (n=196) and a control group not exposed to potential teratogens (n=1686).\n\n\nRESULTS\nMajor birth defects were not more common in the study group than in the control group (OR 1.07; CI 0.21-3.59). We also compared the crude rate of spontaneous abortions (OR 0.97; CI 0.54-1.65), of preterm deliveries (OR 0.76; CI 0.35-1.5), and the birth weight of term newborns (p=0.13).\n\n\nCONCLUSIONS\nThis prospective observational study on cetirizine in pregnancy suggests that the use of cetirizine is relatively safe during the first trimester.",
"affiliations": "Pharmakovigilanz- und Beratungszentrum Embryonaltoxikologie Berlin, Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Spandauer Damm 130, Haus 10, 14050 Berlin, Germany. weber@embryotox.de",
"authors": "Weber-Schoendorfer|Corinna|C|;Schaefer|Christof|C|",
"chemical_list": "D039563:Histamine H1 Antagonists, Non-Sedating; D017332:Cetirizine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.reprotox.2008.05.053",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-6238",
"issue": "26(1)",
"journal": "Reproductive toxicology (Elmsford, N.Y.)",
"keywords": null,
"medline_ta": "Reprod Toxicol",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000022:Abortion, Spontaneous; D000293:Adolescent; D000328:Adult; D001724:Birth Weight; D017332:Cetirizine; D005260:Female; D005858:Germany; D039563:Histamine H1 Antagonists, Non-Sedating; D006801:Humans; D007231:Infant, Newborn; D018811:Maternal Exposure; D008875:Middle Aged; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D047928:Premature Birth; D011446:Prospective Studies",
"nlm_unique_id": "8803591",
"other_id": null,
"pages": "19-23",
"pmc": null,
"pmid": "18571373",
"pubdate": "2008-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The safety of cetirizine during pregnancy. A prospective observational cohort study.",
"title_normalized": "the safety of cetirizine during pregnancy a prospective observational cohort study"
} | [
{
"companynumb": "DE-CIPLA LTD.-2015DE02948",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CETIRIZINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nThis case of giant cell arteritis is noteworthy because it evaded standard diagnostic criteria and only emerged as fever of unknown origin. In this regard, we present 18F-fluorodeoxyglucose positron emission tomography as a valid diagnostic method.\n\n\nMETHODS\nThis case report describes a 58-year-old Caucasian woman who is a cigarette smoker with a 10-week history of fever of unknown origin, night sweats and weight loss of 12 kg. Initially, clinical presentation was suspicious of malignant disease. Laboratory findings detected significantly elevated inflammatory blood parameters including C-reactive protein and elevated erythrocyte sedimentation rate (110 mm/hour). Extensive diagnostic workup including microbiological and rheumatological assessment, ultrasonography, endoscopy and computed tomography of abdomen and thorax did not indicate any septic or malignant focus. Eventually, 18F-fluorodeoxyglucose positron emission tomography was able to reveal arteritis of her aortic arch and supraaortic branches. Subsequently, she commenced steroid and methotrexate therapy that led to sustained remission.\n\n\nCONCLUSIONS\nThis case of giant cell arteritis may promote discussion regarding a more specific classification for this disease entity. Furthermore, it confirms that 18F-fluorodeoxyglucose positron emission tomography might serve as a valuable tool for diagnosis of giant cell arteritis, because it could facilitate an accurate and non-invasive detection of lesions of large vessels.",
"affiliations": "Department of Medicine B, University of Münster, Albert-Schweitzer-Campus 1, D-48129 Münster, Germany. markus.brueckner@ukmuenster.de.",
"authors": "Brückner|Markus|M|;Bettenworth|Dominik|D|;Hengst|Karin|K|;Weckesser|Matthias|M|;Willeke|Peter|P|;Heidemann|Jan|J|",
"chemical_list": "D019788:Fluorodeoxyglucose F18",
"country": "England",
"delete": false,
"doi": "10.1186/1752-1947-8-356",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-8-3562534857610.1186/1752-1947-8-356Case ReportGiant cell arteritis exclusively detected by 18F-fluorodeoxyglucose positron emission tomography: a case report Brückner Markus 1markus.brueckner@ukmuenster.deBettenworth Dominik 1Dominik.Bettenworth@ukmuenster.deHengst Karin 1Karin.Hengst@ukmuenster.deWeckesser Matthias 2Matthias.Weckesser@ukmuenster.deWilleke Peter 3willeke.peter@ukmuenster.deHeidemann Jan 4jan.heidemann@klinikumbielefeld.de1 Department of Medicine B, University of Münster, Albert-Schweitzer-Campus 1, D-48129 Münster, Germany2 Department of Nuclear Medicine, University of Münster, Albert-Schweitzer-Campus 1, D-48129 Münster, Germany3 Department of Medicine D, University of Münster, Albert-Schweitzer-Campus 1, D-48129 Münster, Germany4 Klinikum Bielefeld, Department of Gastroenterology, Teutoburger Str. 50, D-33604 Bielefeld, Germany2014 28 10 2014 8 356 356 28 4 2014 27 8 2014 Copyright © 2014 Brückner et al.; licensee BioMed Central Ltd.2014Brückner et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nThis case of giant cell arteritis is noteworthy because it evaded standard diagnostic criteria and only emerged as fever of unknown origin. In this regard, we present 18F-fluorodeoxyglucose positron emission tomography as a valid diagnostic method.\n\nCase presentation\nThis case report describes a 58-year-old Caucasian woman who is a cigarette smoker with a 10-week history of fever of unknown origin, night sweats and weight loss of 12kg. Initially, clinical presentation was suspicious of malignant disease. Laboratory findings detected significantly elevated inflammatory blood parameters including C-reactive protein and elevated erythrocyte sedimentation rate (110mm/hour). Extensive diagnostic workup including microbiological and rheumatological assessment, ultrasonography, endoscopy and computed tomography of abdomen and thorax did not indicate any septic or malignant focus. Eventually, 18F-fluorodeoxyglucose positron emission tomography was able to reveal arteritis of her aortic arch and supraaortic branches. Subsequently, she commenced steroid and methotrexate therapy that led to sustained remission.\n\nConclusions\nThis case of giant cell arteritis may promote discussion regarding a more specific classification for this disease entity. Furthermore, it confirms that 18F-fluorodeoxyglucose positron emission tomography might serve as a valuable tool for diagnosis of giant cell arteritis, because it could facilitate an accurate and non-invasive detection of lesions of large vessels.\n\nFever of unknown origin18F-FDG PET18F-fluorodeoxyglucose positron emission tomographyGiant cell arteritisLarge vessel vasculitis\n==== Body\nIntroduction\nGiant cell arteritis (GCA) is the most common rheumatological vasculopathy in Caucasians in Europe [1]. Clinical findings comprise new onset of temporal headache, jaw claudication, visual loss, temporal artery induration, thoracic aortic aneurysm or intense pain in pectoral and pelvic girdle with morning stiffness [2]. In addition, systemic symptoms including fatigue, weight loss or fever occur in up to 50%. Furthermore, GCA may be the cause of fever of unknown origin (FUO) in up to 17% of patients with FUO above 50 years of age [3,4]. A retrospective study of 100 patients with GCA found fever to exceed 39°C in 15% [5]; fever can be the single presenting symptom.\n\nIn contrast to common presentations of GCA, we describe an exceptional clinical course presenting with FUO as the only clinical feature in the absence of other usual clinical characteristics.\n\nCase presentation\nA 58-year-old Caucasian obese woman (body mass index 31.5kg/m2) was admitted to our hospital with a history of continuous FUO varying from 38°C to 39.5°C for 10 weeks despite several courses of antibiotic therapy. Her history included 30 pack years of cigarette smoking. Currently, she suffered from night sweats, continuous weight loss of 12kg and dyspnea on exertion. No signs of rheumatic or neurological diseases were present, especially no temporal pain, headache or visual impairment. There were no skin lesions, no myalgia of pectoral or pelvic girdle or morning stiffness, and no arthralgia. Her blood pressure was 140/90mmHg on both arms. Initial suspected diagnosis involved malignant or infectious diseases. Laboratory findings showed elevated systemic parameters of inflammation including C-reactive protein (CRP; 22mg/dL) and accelerated erythrocyte sedimentation rate (ESR; 110mm/hour). Complete blood count showed total white blood cell 13.8/μL, total red blood cell 5 million/μL, hemoglobin 13.4g/dL, hematocrit 42.8%, mean corpuscular volume 84.4fL, mean corpuscular hemoglobin 26.4pg, mean corpuscular hemoglobin concentration 31.3g/dL, and platelet 278,000/μL. Differential blood count showed neutrophil granulocytes 88.1%, lymphocytes 8.1%, monocytes 3.6%, eosinophil granulocytes 0.1%, and basophil granulocytes 0.5%. Mean platelet volume was 10.4fL. Serum albumin showed 32.8g/L and β2 microglobulin 1.9mg/L. Detailed blood tests for rheumatic disorders were negative. Repeated microbiological blood tests, stool cultures as well as serological testing for specific pathogens, including Orthomyxoviridae, Herpesviridae, Mycobacteriaceae, Legionellaceae, Spirochaetaceae, Chlamydiaceae and Mycoplasmataceae were negative.\n\nEndoscopic evaluations, including bronchoscopy, esophagogastroduodenoscopy and colonoscopy as well as transesophageal echocardiography were without pathological findings. In addition, computed tomography (CT) of her thorax and abdomen showed atherosclerotic lesions only; however, no evidence of any inflammatory or malignant focus was detected. In particular, there were no alterations of the vessel wall indicative of inflammation. We decided to perform 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET; Figure 1). 18F-FDG PET demonstrated increased metabolic activity in her supraaortic arteries with the most intense involvement of the subclavian arteries and also slightly elevated glucose metabolism in the aortic arch. A borderline asymmetry of the femoral artery was regarded as within physiological limits. There were no additional foci of increased glucose metabolism in her body. Thus, GCA of the supraaortic arteries was proposed as the inflammatory focus. Other causes for aortitis or arteritis (Gsell-Erdheim disease, syphilitic aortitis) and FUO had been excluded initially. After commencement of steroid therapy with 90mg prednisolone daily intravenously, her inflammatory markers dropped rapidly within 10 days (CRP 6mg/dL) and she was discharged in good health. Over a period of 6 weeks steroids were reduced to the lowest effective dose of 40mg daily orally with parameters of disease being clinical symptoms, CRP, and ESR. Methotrexate was added at a dose of 20mg weekly subcutaneous injection to support steroid tapering. Today, she consults our rheumatologic out-patient clinic at intervals of 6 months, the medication has been reduced to 2mg oral prednisolone daily and methotrexate 20mg weekly subcutaneous injection.\n\nFigure 1 18F-fluorodeoxyglucose positron emission tomography whole-body image. In particular, subclavian arteries (arrows) show increased metabolic activity (maximal standardized uptake value 3.0, mean liver standardized uptake value 1.8). The oblique projection shows increased glucose metabolism in the aortic arch (arrow heads) too. No other foci of increased metabolism like solid tumors were detectable in this imaging.\n\nDiscussion\nOur case clearly shows the limitations of 1990 American College of Rheumatology criteria for GCA [6]: age over 50 years, new onset of localized headache, temporal artery tenderness, elevated ESR for more than 50mm/hour and biopsy sample showing necrotizing arteritis with giant cells. Weyand and Goronzy [7] report blindness, headache and jaw claudication as the classical clinical symptoms in cranial arteritis. However, rather systemic characteristics of GCA such as night sweats, loss of weight, and in particular FUO can be the only presenting symptoms, highlighting the necessity of a more specific classification. Weyand et al. [8,9] suggested clinical subtypes of GCA affecting distinct vascular territories with different patterns of cytokine production, leading to occlusive or non-occlusive disease and different features in temporal artery biopsy. These subtypes are cranial arteritis, large vessel arteritis or aortitis, isolated polymyalgia rheumatica and, as depicted in the present case, systemic inflammatory syndrome with arteritis.\n\nIf GCA presents as systemic inflammatory syndrome only, then FUO diagnostics provoke high costs for diagnostic management and duration of hospitalization [10,11]. As the causes for FUO are numerous and heterogeneous, there is no gold standard in the diagnostic process. Since FUO is well known to be a possible symptom in patients with GCA, temporal artery biopsy is crucial in the diagnostic workup after initial negative findings [12]. Biopsy is still recommended as the gold standard as a sophisticated procedure in local anesthesia with low complication rates; however, only 50% of biopsy samples show multinucleated giant cells with even 10 to 25% false negative results [13]. Moreover, even the combination of FUO and asymptomatic thoracic manifestations such as pleural effusions may be presenting symptoms of GCA [14]. Because of its clinical heterogeneity, initial diagnosis of GCA and evaluation of its extent remain challenging, leading to specific advantages and disadvantages of conventional imaging procedures such as CT and magnetic resonance imaging [15]. In obscure cases like ours, nuclear imaging as a second line of diagnostic provides high standards concerning sensitivity and specificity [16,17] helping to identify the cause of fever. In our patient, inflammation of the aortic arch and subclavian arteries could only be visualized by 18F-FDG PET.\n\nRecently, it could be shown that 18F-FDG PET provides a high level of effectiveness in assessing initial diagnosis, extent and activity of GCA [18,19]. Other nuclear methods such as gadolinium scanning are also available for detection of vascular wall inflammation, although they possess less sensitivity and specificity. However, there are several limitations of 18F-FDG PET, which cannot reliably be used to diagnose or monitor inflammation of the temporal artery due to the limited spatial resolution of PET alone; the combination of PET and CT (PET-CT) generally has superior spatial resolution. For this reason, PET cannot replace temporal artery biopsy if the disease is limited to the temporal arteries [20]. Finally, atherosclerosis as the most frequent inflammatory disease of the arteries is the most important differential diagnostic feature of increased tracer uptake in the blood vessels.\n\nConclusions\nIn the case presented here, classical clinical characteristics of GCA were missing, while FUO was the leading symptom. Finally, our case proves that 18F-FDG PET is able to serve as a valuable tool for diagnosis of GCA. 18F-FDG PET can be a valid diagnostic method when manifestations such as vascular insufficiency are lacking. In addition, new criteria for the classification of GCA are needed to detect this disease at early stage.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nCRP: C-reactive protein; CT: Computed tomography; ESR: Erythrocyte sedimentation rate; 18F-FDG PET: 18F-fluorodeoxyglucose positron emission tomography; FUO: Fever of unknown origin; GCA: Giant cell arteritis.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nMB and DB designed and wrote the paper and took care of the patient. MW analyzed and provided images of 18F-FDG PET and revised the paper as a senior physician for nuclear medicine. PW wrote the paper, revised it as a senior physician for rheumatology and took care of the patient. JH and KH wrote the paper, revised it as senior physicians for internal medicine and took care of the patient. All authors read and approved the final manuscript.\n==== Refs\nPenn H Dasgupta B Giant cell arteritis Autoimmun Rev 2003 2 199 203 10.1016/S1568-9972(03)00012-0 12848946 \nSalvarani C Cantini F Hunder GG Polymyalgia rheumatica and giant-cell arteritis Lancet 2008 372 234 245 10.1016/S0140-6736(08)61077-6 18640460 \nVanderschueren S Knockaert D Adriaenssens T Demey W Durnez A Blockmans D Bobbaers H From prolonged febrile illness to fever of unknown origin: the challenge continues Arch Intern Med 2003 163 1033 1041 10.1001/archinte.163.9.1033 12742800 \nKnockaert DC Vanderschueren S Blockmans D Fever of unknown origin in adults: 40 years on J Intern Med 2003 253 263 275 10.1046/j.1365-2796.2003.01120.x 12603493 \nCalamia KT Hunder GG Giant cell arteritis (temporal arteritis) presenting as fever of undetermined origin Arthritis Rheum 1981 24 1414 1418 10.1002/art.1780241113 7317119 \nHunder GG Bloch DA Michel BA Stevens MB Arend WP Calabrese LH Edworthy SM Fauci AS Leavitt RY Lie JT Lightfoot RW Masi AT McShane DJ Mills JA Wallace SL Zvaifler NJ The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis Arthritis Rheum 1990 33 1122 1128 2202311 \nWeyand CM Goronzy JJ Medium- and large-vessel vasculitis N Engl J Med 2003 349 160 169 10.1056/NEJMra022694 12853590 \nWeyand CM Goronzy JJ Giant-cell arteritis and polymyalgia rheumatica Ann Intern Med 2003 139 505 515 10.7326/0003-4819-139-6-200309160-00015 13679329 \nWeyand CM Tetzlaff N Bjornsson J Brack A Younge B Goronzy JJ Disease patterns and tissue cytokine profiles in giant cell arteritis Arthritis Rheum 1997 40 19 26 10.1002/art.1780400105 9008596 \nde Kleijn EM Vandenbroucke JP van der Meer JW Fever of unknown origin (FUO). I A. prospective multicenter study of 167 patients with FUO, using fixed epidemiologic entry criteria. The Netherlands FUO Study Group Medicine (Baltimore) 1997 76 392 400 10.1097/00005792-199711000-00002 9413425 \nMourad O Palda V Detsky AS A comprehensive evidence-based approach to fever of unknown origin Arch Intern Med 2003 163 545 551 10.1001/archinte.163.5.545 12622601 \nBleeker-Rovers CP Vos FJ de Kleijn EM Mudde AH Dofferhoff TS Richter C Smilde TJ Krabbe PF Oyen WJ van der Meer JW A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol Medicine (Baltimore) 2007 86 26 38 10.1097/MD.0b013e31802fe858 17220753 \nNess T Bley TA Schmidt WA Lamprecht P The diagnosis and treatment of giant cell arteritis Dtsch Arztebl Int 2013 110 376 385 quiz 386 23795218 \nSchattner A Klepfish A Left pleural effusion and fever of unknown origin – a clue to thoracic arterial pathology J Gen Intern Med 2012 27 1084 1087 10.1007/s11606-012-2008-6 22362125 \nTso E Flamm SD White RD Schvartzman PR Mascha E Hoffman GS Takayasu arteritis: utility and limitations of magnetic resonance imaging in diagnosis and treatment Arthritis Rheum 2002 46 1634 1642 10.1002/art.10251 12115196 \nMeller J Altenvoerde G Munzel U Jauho A Behe M Gratz S Luig H Becker W Fever of unknown origin: prospective comparison of [18F]FDG imaging with a double-head coincidence camera and gallium-67 citrate SPET Eur J Nucl Med 2000 27 1617 1625 10.1007/s002590000341 11105817 \nBalink H Collins J Bruyn GA Gemmel F F-18 FDG PET/CT in the diagnosis of fever of unknown origin Clin Nucl Med 2009 34 862 868 10.1097/RLU.0b013e3181becfb1 20139818 \nWalter MA Melzer RA Schindler C Muller-Brand J Tyndall A Nitzsche EU The value of [18F]FDG-PET in the diagnosis of large-vessel vasculitis and the assessment of activity and extent of disease Eur J Nucl Med Mol Imaging 2005 32 674 681 10.1007/s00259-004-1757-9 15747154 \nLee SG Ryu JS Kim HO Oh JS Kim YG Lee CK Yoo B Evaluation of disease activity using F-18 FDG PET-CT in patients with Takayasu arteritis Clin Nucl Med 2009 34 749 752 10.1097/RLU.0b013e3181b7db09 19851167 \nBrodmann M Lipp RW Passath A Seinost G Pabst E Pilger E The role of 2-18F-fluoro-2-deoxy-D-glucose positron emission tomography in the diagnosis of giant cell arteritis of the temporal arteries Rheumatology (Oxford) 2004 43 241 242 13130153\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "8()",
"journal": "Journal of medical case reports",
"keywords": null,
"medline_ta": "J Med Case Rep",
"mesh_terms": "D005260:Female; D019788:Fluorodeoxyglucose F18; D013700:Giant Cell Arteritis; D006801:Humans; D008875:Middle Aged; D049268:Positron-Emission Tomography; D014057:Tomography, X-Ray Computed; D051598:Whole Body Imaging",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "356",
"pmc": null,
"pmid": "25348576",
"pubdate": "2014-10-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12622601;12115196;12848946;7317119;12603493;22362125;9413425;19851167;13679329;9008596;2202311;12742800;20139818;23795218;13130153;15747154;18640460;11105817;12853590;17220753",
"title": "Giant cell arteritis exclusively detected by 18F-fluorodeoxyglucose positron emission tomography: a case report.",
"title_normalized": "giant cell arteritis exclusively detected by 18f fluorodeoxyglucose positron emission tomography a case report"
} | [
{
"companynumb": "DE-ANTARES PHARMA, INC.-2015-LIT-ME-0085",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditio... |
{
"abstract": "Aim: Infectious uveitis is one of the most visually devastating causes of uveitis worldwide and accounts for 19.6% of all cases of uveitis in New Zealand. With the burgeoning use of intravitreal injections, there has been a commensurate increase in the number of injection-related complications and reports of infectious uveitis following their administration in recent years. We present a case series of four patients with infectious uveitis after local injections.Method: We retrospectively reviewed the data of four patients (mean age, 67.25 ± 7.58 years) who presented to the department of ophthalmology at Auckland District Health Board with infectious uveitis which occurred or worsened after local triamcinolone acetonide (TA) and/or methotrexate (MTX) injections.Results: Three patients received local TA and one patient received intravitreal MTX. All patients were immunosuppressed prior to treatment. Two patients had toxoplasma chorioretinitis which worsened with local TA and one patient developed cytomegalovirus (CMV) retinitis after intravitreal TA. The last patient had syphilis retinopathy which worsened with intravitreal MTX. There were atypical presentations, as demonstrated by a case of presumed birdshot chorioretinopathy flare which tested positive for toxoplasma chorioretinitis with polymerase chain reaction (PCR).Conclusion: Uveitis due to infectious etiologies needs to be carefully excluded prior to the use of local steroid and/or methotrexate injections. Disease presentations may be atypical in the presence of marked immunosuppression following local therapy. Polymerase chain reaction (PCR) can play an important role in the diagnosis in this setting.",
"affiliations": "Department of Ophthalmology, Southern District Health Board, Dunedin, New Zealand.;Department of Ophthalmology, Auckland District Health Board, Auckland, New Zealand.;Department of Ophthalmology, Auckland District Health Board, Auckland, New Zealand.",
"authors": "Ong|Aaron Pc|AP|https://orcid.org/0000-0003-3979-6141;Sims|Joanne L|JL|;Niederer|Rachael L|RL|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2020.1860230",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": null,
"journal": "Ocular immunology and inflammation",
"keywords": "Infectious uveitis; intravitreal; methotrexate; triamcinolone",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": null,
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "1-5",
"pmc": null,
"pmid": "33792480",
"pubdate": "2021-04-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Infectious Uveitis after Local Steroid and/or Methotrexate Injections at A Tertiary Referral Center in New Zealand: A Case Series.",
"title_normalized": "infectious uveitis after local steroid and or methotrexate injections at a tertiary referral center in new zealand a case series"
} | [
{
"companynumb": "AR-MACLEODS PHARMACEUTICALS US LTD-MAC2021030841",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EFAVIRENZ"
},
"drugadd... |
{
"abstract": "Delayed post-hypoxic leukoencephalopathy is a rare clinical phenomenon usually observed in a small number of carbon monoxide poisoning survivors. A similar phenomenon is reported here in a patient who successfully recovered from a large overdose of diazepam and methadone, but then abruptly declined 3 weeks after the initial event. Magnetic resnance revealed confluent white matter hyperintensity on fluid-attenuated inversion recovery and T2 weighted sequences, and spectroscopy revealed elevated peaks in choline, creatinine, and lactate. Analysis and review of the literature suggests this phenomenon occurs on average about 19 days after the initial event. Although the pathophysiology remains obscure, it is noted here that the mean lucid interval coincides approximately with the replacement half-life for myelin related lipids and proteins.",
"affiliations": "Department of Neurology, Tennova Health Care , Knoxville, TN, USA.",
"authors": "Meyer|Michael Andrew|MA|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/ni.2013.e13",
"fulltext": "\n==== Front\nNeurol IntNeurol IntNINeurology International2035-83852035-8377PAGEPress Publications, Pavia, Italy 2414721010.4081/ni.2013.e13Case ReportDelayed Post-Hypoxic Leukoencephalopathy: Case Report with a Review of Disease Pathophysiology Meyer Michael Andrew Department of Neurology, Tennova Health Care, Knoxville, TN, USADepartment of Neurology, Tennova Health Care, Knoxville, 930 Emerald Avenue, Suite 511, Knoxville, TN 37917, USA.\nTel. +1.865.647.3330.\nE-mail: michaelandrewmeyer@gmail.comConflict of interests: the author declares no potential conflict of interests.\n\n22 7 2013 22 8 2013 5 3 e1306 5 2013 10 7 2013 ©Copyright M.A. Meyer2013Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Delayed post-hypoxic leukoencephalopathy is a rare clinical phenomenon usually observed in a small number of carbon monoxide poisoning survivors. A similar phenomenon is reported here in a patient who successfully recovered from a large overdose of diazepam and methadone, but then abruptly declined 3 weeks after the initial event. Magnetic resnance revealed confluent white matter hyperintensity on fluid-attenuated inversion recovery and T2 weighted sequences, and spectroscopy revealed elevated peaks in choline, creatinine, and lactate. Analysis and review of the literature suggests this phenomenon occurs on average about 19 days after the initial event. Although the pathophysiology remains obscure, it is noted here that the mean lucid interval coincides approximately with the replacement half-life for myelin related lipids and proteins.\n\nKey words\nwhite matterleukoencephalopathymyelinMRI\n==== Body\nIntroduction\nPlum et al.1 recognized as early as 1962 that rarely there may be a delayed deterioration after anoxic injury. Although subsequent autopsy reports by Ginsberg et al.,2 on post-hypoxic leukoencephalopathy noted extensive symmetrical necrotic lesions of the central white matter, with minimal damage to gray matter structures, it was not until later reports using magnetic resonance imaging (MRI) that revealed this could occur as a delayed effect of hypoxic injury, with an intervening lucid interval of many days where the patient is completely normal. Since the initial reports of Plum and colleagues, this phenomenon of delayed neurological deterioration after anoxia has been found in almost 3% of carbon monoxide poisoning cases.3 According to this study of 65 patients by Choi, the lucid interval between the event and delayed deterioration averaged 22.4 days with a mean age of 56.1 years; 75% of patients appeared to have recovered within one year of the event.\n\nSince the publication these early reports, a number of MRI studies have been published which document extensive confluent changes within the white matter as delayed complication to carbon monoxide poisoning,4-8 with the largest series of 15 cases reported by Chang et al.9\n\nSimilar changes are reported here for hypoxia in association with a benzodiazepine overdose in a 43 year old who attempted suicide, but was successfully revived and discharged in a fully alert and ambulatory state with a full return to her previously normal mental status, but then suffered a delayed abrupt neurological deterioration with confluent white matter changes seen on both computed tomography (CT) and MRI. The MR spectroscopy changes are also reported here, with a description of the clinical findings to promote greater awareness of this unusual clinical phenomenon.\n\nCase Report\nA 43 year old female with chronic back pain developed depression and attempted suicide with an overdose of diazepam and methadone after an argument with her husband in the evening. She intentionally consumed approximately 40 to 50 tablets of diazepam at 5 mg strength as well as an unknown quantity of methadone tablets was found the following day in an unresponsive state with a respiratory state of only 4 breaths per minute but was revived at a local hospital with the use of naloxone. Although she could awaken and answer questions appropriately, this was only transient and required a naloxone drip infusion over 24 hours; no flumazenil had been used. Her potassium was also elevated initially at 7.6 that later normalized and had a leukocytosis secondary to mild aspiration pneumonia that was successfully treated with antibiotics. She was discharged within one week in a much improved state to a psychiatric facility. After two days as in-patient for psychiatric care, she was discharged to home in a markedly improved state with a mental status that was back to her baseline and fully able to be self-sufficient without any cognitive deficits. Interview with family and friends confirmed that she was cognitively normal and fine up until 3 weeks after the event when she abruptly changed midday and seemed confused and forgetful with a rapid worsening the following day. She was first noted not be able to play cards with her family, had developed social withdrawal with a lack of personal hygiene, and became incontinent as well. She appeared very lethargic and not very interactive. After this continued for approximately 5 days without any improvement, she was evaluated at the Emergency Dept. and admitted after a CT head exam disclosed marked and diffuse hypointensity throughout the subcortical white matter (Figure 1A). This was later evaluated by MRI as being a confluent change throughout the entire white matter, and appeared diffusely hyperintense on both FLAIR and T2 weighted sequences (Figure 1B), with hyper-intensity also noted on diffusion weighted imaging. The unusual feature though was that the cerebellar white mater had been spared, and that the change was a strictly supratentorial effect (Figure 2A) without altering signal intensity for the white matter tracts in the internal capsule and brain stem area. Using large voxels placed over the semi-centrum ovale, MR spectroscopic analysis at 1.5 Tesla showed elevated abnormal elevations in the choline and creatinine peaks with a small peak seen for lactic acid as well (Figure 2B). Neurological exam revealed a blunted flat affect with abnormally slow gait and left side neglect, with disorientation and very poor short term recall. As the patient had a detectable benzodiazepine level at approximately 83 ng/mL, 1.0 mg flumazenil was given in 0.2 mg increments every 30 seconds during EEG monitoring. Although background slowing improved slightly, there was a clear and definite transient neurological improvement. Serum benzodiazepine levels continued to decline from 67.9 to 32.8 ng/mL over 4 days, with modest clinical improvement in her mental status also observed. Follow-up evaluation revealed substantial improvement both clinically and radiographically, with a normal mental status and normal MR imaging of the brain within one year of the event, with normal metabolism of both the gray and white matter of the brain, as assessed by 18F-FDG PET imaging (Figure 3).\n\nDiscussion and Conclusions\nThis case displays some similarities to that described by Gottfired et al.10 who observed delayed post-hypoxic leukoencephalopathy in a 36 year old who overdosed on benzodiazepines, opiates, and amphetamines, and was revived at a local hospital where he was discharged 8 days later in a completely normal state. However, at day 24, he began to act strangely and was became confused and declined thereafter with confluent diffuse white matter changes on MRI and MR Spectroscopy showing elevated choline and lactate. Although the investigators postulated that partial loss of activity for Arylsulfatase A enzyme may have predisposed to the condition, other case reports exist of patients with normal enzyme activities. A case reported by Lee and Lyketsos involved an accidental benzodiazepine overdose in a 71 year old who was discharged in a fully normal condition after a 3 day hospitalization,11 and did fine for 2 weeks until a rapid decline occurred with confluent white matter changes then noted on MRI; arylsufatase levels were normal.\n\nThe cause for the delayed post-hypoxic white matter deterioration remains obscure. However, a possible explanation may relate to the half life for myelin related proteins, which in animals has been determined to be in the same approximate time frame as the clinic deterioration seen in these cases of DPHLE (Figure 4; mean time for lucid interval: 19 days). A study by Ando et al.12 found that the half-replacement times as judged by newly synthesized molecule incorporation rate in young adult mice was 20 days for phosphatidylcholine, 25 days for phosphatidylethanolamine. If this process of replacement was to abruptly halt after ischemia, conduction within central myelin could still occur until a critical threshold of loss was achieved where conduction block and failure would occur. Sabri and colleagues noted that half-life of the fast component of myelin basic protein pool was 19-22 days.13 Hayes et al.14 has also found that half-life of the fast turning-over pool of cerebrosides of myelin was 22 days for the adult rat brain, which also is within the same time frame for the lucid interval of 19 days in DPHLE.\n\nOf potential theoretical concern is the lack of any use of flumazenil in the acute stage of this patient’s illness; it was not until the patient was symptomatic with DPHLE that flumazenil was first used to successfully improve cognition and improve EEG slowing on a transient basis. Pharmacokinetic studies have shown that the diazepam metabolite, n-desmethyldiazepam, has a elimination half life of about 139 hours, versus 58 hours for the antipyrene related hepatic microsomal enzyme induction rate;15 animal studies show that it accumulates to a high degree within central white matter regions,16 and does not efflux very readily relative to diazepam. It is therefore hypothesized that prolonged retention of diazepam metabolites may play an additional role in the pathogenesis of diazepam related DPHLE, with accumulation of this metabolite likely occurring within central white matter.\n\nIn summary, patients with delayed deterioration after benzodiazepine overdose may reflect the above described changes seen in DPHLE, and that further investigation with MRI may be helpful to evaluate for this rare syndrome associated with recent hypoxia. The exact mechanism still remains obscure but further research is clearly warranted. Since flumazenil had a transient beneficial effect here, PET imaging studies using 11C-flumazenil may be of additional value to understand disease pathophysiology.17 DPHLE is relatively rare but fortunately reversible over time with a complete and full recovery documented here for this case and other, and requires extensive support care in the initial phases of the illness;18 however, a comprehensive pathophysiologic explanation for the lucid interval and delayed deterioration phase is not known and largely remains obscure – further research is clearly needed on this unusual and fascinating yet unfortunate neurological problem.\n\nFigure 1. A) Computed tomography appearance at the time of initial development of encephalopathic changes; B) three dimensional reconstruction of coronal T2 sequences obtained with magnetic resonance imaging revealing the extensively confluent subcortical white matter signal hyper-intense change.\n\nFigure 2. A) Axial T2 weighted image reveals extensive confluent hyper-intense signal abnormality throughout the subcortical white matter with no obvious signal change within the cortex. The white box within the left semi-centrum ovale subcortical white matter represents the voxel used for generating magnetic resonance spectroscopy, shown in figure two; B) magnetic resonance spectroscopy of the subcortical white matter revealing an abnormally high peak for creatinine and choline downstream and to the left of the main central NAA peak with a small yet abnormal presence of a lactic acid peak upstream from the NAA peak.\n\nFigure 3. Resolution of symptoms over the next few months with follow-up brain 18FFDG PET scan showing normal uptake patterns for the cerebral cortex and sub-cortical white matter.\n\nFigure 4. Retrospective review of lucid interval in days (y-axis) in relation age in years (x-axis) for delayed post hypoxic leukoencephalopathy cases from references four through nine, along with the current case.\n==== Refs\nReferences\n1. Plum F Posner JB Hain RF \nDelayed neurological deterioration after anoxia . Arch Intern Med 1962 ;110 :18 -25 14487254 \n2. Ginsberg MD Hedley-Whyte ET Richardson EP Jr \nHypoxic-ischemic leukoencephalopathy in man . Arch Neurol 1976 ;33 :5 -14 1247396 \n3. Choi IS \nDelayed neurologic sequelae in carbon monoxide intoxication . Arch Neurol 1983 ;40 :433 -5 6860181 \n4. Kim JH Chang KH Song IC \nDelayed encephalopathy of acute carbon monoxide intoxication: diffusivity of cerebral white matter lesions . AJNR Am J Neuroradiol 2003 ;24 :1592 -7 13679276 \n5. Murata T Kimura H Kado H \nNeuronal damage in the interval form of CO poisoning determined by serial diffusion weighted magnetic resonance imaging plus 1H-magnetic resonance spectroscopy . J Neurol Neurosurg Psychiatry 2001 ;71 :250 -3 11459905 \n6. Kamada K Houkin K Aoki T \nCerebral metabolic changes in delayed carbon monoxide sequelae studied by proton MR spectroscopy . Neuroradiology 1994 ;36 :104 -6 8183444 \n7. Hayashi R Hayashi K Inoue K Yanagisawa N \nA serial computerized tomographic study of the interval form of CO poisoning . Eur Neurol 1993 ;33 :27 -9 8440282 \n8. Kinoshita T Sugihara S Matsusue E \nPallidoreticular damage in acute carbon monoxide poisoning: diffusion-weighted MR imaging findings . AJNR Am J Neuroradiol 2005 ;26 :1845 -8 16091540 \n9. Chang KH Han MH Kim HS \nDelayed encephalopathy after acute carbon monoxide intoxication: MR imaging features and distribution of cerebral white matter lesions . Radiology 1992 ;184 :117 -22 1609067 \n10. Gottfried JA Mayer SA Shungu DC \nDelayed posthypoxic demyelination. Association with arylsulfatase A deficiency and lactic acidosis on proton MR spectroscopy . Neurology 1997 ;49 :1400 -4 9371929 \n11. Lee HB Lyketsos CG Delayed post-hypoxic leukoencephalopathy . Psychosomatics 2001 ;42 :530 -3 11815692 \n12. Ando S Tanaka Y Toyoda Y Kon K \nTurnover of myelin lipids in aging brain . Neurochem Res 2003 ;28 :5 -13 12587659 \n13. Sabri MI Bone AH Davison AN \nTurnover of myelin and other structural proteins in the developing rat brain . Biochem J 1974 ;142 :499 -507 4142927 \n14. Hayes LW Jungalwala FB \nSynthesis and turnover of cerebrosides and phosphatidylserine of myelin and microsomal fractions of adult and developing rat brain . Biochem J 1976 ;160 :195 -204 1008849 \n15. Ohnhaus EE Park BK Colombo JP Heizmann P \nThe effect of enzyme induction on diazepam metabolism in man . Br J Clin Pharmacol 1979 ;8 :557 -63 42427 \n16. Placidi GF Tognoni G Pacifici GM \nRegional distribution of diazepam and its metabolites in the brain of cat after chronic treatment . Psychopharmacology (Berl) 1976 ;48 :133 -7 826924 \n17. Meyer M Koeppe RA Frey KA \nPositron emission tomography measures of benzodiazepine binding in Alzheimer’s disease . Arch Neurol 1995 ;52 :314 -7 7872887 \n18. Shprecher D Mehta L \nThe syndrome of delayed post-hypoxic leukoencephalopathy . Neuro Rehabilitation 2010 ;26 :65 -72 20166270\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2035-8385",
"issue": "5(3)",
"journal": "Neurology international",
"keywords": "MRI; leukoencephalopathy; myelin; white matter",
"medline_ta": "Neurol Int",
"mesh_terms": null,
"nlm_unique_id": "101551564",
"other_id": null,
"pages": "e13",
"pmc": null,
"pmid": "24147210",
"pubdate": "2013",
"publication_types": "D002363:Case Reports",
"references": "7872887;12587659;826924;4142927;13679276;1008849;6860181;14487254;1247396;11815692;8440282;11459905;1609067;9371929;8183444;42427;16091540;20166270",
"title": "Delayed post-hypoxic leukoencephalopathy: case report with a review of disease pathophysiology.",
"title_normalized": "delayed post hypoxic leukoencephalopathy case report with a review of disease pathophysiology"
} | [
{
"companynumb": "US-TEVA-538489USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": null,
"drug... |
{
"abstract": "Antiepileptic drugs (AEDs) can cause hypersensitivity reactions in children. These reactions are mainly cutaneous, self-limiting, and benign, but life-threatening severe cutaneous adverse reactions can occur. Infections can lead to skin eruptions and mimic drug hypersensitivity reactions, if a drug is taken at the same time. The aims of our study were to confirm or rule out the diagnosis of hypersensitivity reactions to AEDs in children and to detect an infection which mimics these reactions.\n\n\n\nA prospective survey was conducted in a group of 100 children with histories of hypersensitivity reactions to AEDs by performing patch tests, delayed-reading intradermal test, and, in case of negative results, challenge test. In all children, a study was performed to detect infections by viruses or Mycoplasma pneumoniae.\n\n\n\nMaculopapular exanthema and delayed-appearing urticaria were the most reported hypersensitivity reactions to AEDs. Sixty-six (66%) of 100 children had confirmed hypersensitivity reactions to AEDs. Fifty-nine children had positive patch test. No children had positive challenge tests. The most common AEDs causing hypersensitivity reactions were carbamazepine (45.4%) and lamotrigine (43.6%). Thirty-two children had positive tests for viruses or M pneumoniae, and nine of them had also a positive allergy work-up.\n\n\n\nConsidering that there are no specific tests to distinguish between a viral infection and hypersensitivity reactions to AEDs in the acute phase, a diagnostic work-up should be performed in all children with suspected hypersensitivity reactions to AEDs, as well as infectious agent study, to remove a false label of hypersensitivity.",
"affiliations": "Faculty of Medicine, University of Belgrade, Belgrade, Serbia.;University Children's Hospital, Belgrade, Serbia.;University Children's Hospital, Belgrade, Serbia.;Faculty of Chemistry, University of Belgrade, Belgrade, Serbia.;Faculty of Chemistry, University of Belgrade, Belgrade, Serbia.;Faculty of Medicine, University of Belgrade, Belgrade, Serbia.;Faculty of Medicine, University of Belgrade, Belgrade, Serbia.",
"authors": "Atanasković-Marković|Marina|M|0000-0003-1354-6072;Janković|Jelena|J|;Tmušić|Vladimir|V|;Gavrović-Jankulović|Marija|M|;Ćirković Veličković|Tanja|T|;Nikolić|Dimitrije|D|;Škorić|Dejan|D|",
"chemical_list": "D000485:Allergens; D000927:Anticonvulsants; D002220:Carbamazepine; D000077213:Lamotrigine",
"country": "England",
"delete": false,
"doi": "10.1111/pai.13055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0905-6157",
"issue": "30(5)",
"journal": "Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology",
"keywords": "antiepileptic drugs; children; hypersensitivity reactions; non-immediate reactions",
"medline_ta": "Pediatr Allergy Immunol",
"mesh_terms": "D000293:Adolescent; D000485:Allergens; D000927:Anticonvulsants; D002220:Carbamazepine; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D004342:Drug Hypersensitivity; D005076:Exanthema; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed; D007223:Infant; D000077213:Lamotrigine; D008297:Male; D009177:Mycoplasma pneumoniae; D011019:Pneumonia, Mycoplasma; D011446:Prospective Studies; D055771:Serbia; D012882:Skin Tests; D014777:Virus Diseases",
"nlm_unique_id": "9106718",
"other_id": null,
"pages": "547-552",
"pmc": null,
"pmid": "30951222",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Hypersensitivity reactions to antiepileptic drugs in children.",
"title_normalized": "hypersensitivity reactions to antiepileptic drugs in children"
} | [
{
"companynumb": "RS-GLAXOSMITHKLINE-RS2019GSK064688",
"fulfillexpeditecriteria": "1",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": "3... |
{
"abstract": "The treatment options for metastatic malignant melanoma have drastically changed recently,including the increased use of immunotherapeutic agents that offer significant responses. Accordingly, it hasbecome common for sequential administration of such agents. Despite this, no guidelines exist on propersequencing or potential unique toxicities associated with such sequencing.\n\n\n\nWe describe here the first incidence, to our knowledge, of clinically significant rhabdomyolysis associated with high-dose interleukin-2 after prior treatment with ipilimumab, genetically engineered T-cell therapy and subsequent single agent pembrolizumab in a patient with BRAF wild type metastatic malignant melanoma.\n\n\n\nFurther studies into the biology of sequential immunotherapy in the treatment of cancer are warranted.",
"affiliations": "Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S 1st Avenue, Maywood, IL, 60153, USA. jclark@lumc.edu.;Advocate Lutheran General Hospital, Park Ridge, IL, USA.;Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S 1st Avenue, Maywood, IL, 60153, USA.;Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S 1st Avenue, Maywood, IL, 60153, USA.",
"authors": "Clark|Joseph I|JI|;Bufalino|Shams|S|;Singh|Shruti|S|0000-0002-2879-1364;Borys|Ewa|E|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D007376:Interleukin-2; D000074324:Ipilimumab; C582435:pembrolizumab",
"country": "England",
"delete": false,
"doi": "10.1186/s40425-018-0370-6",
"fulltext": "\n==== Front\nJ Immunother CancerJ Immunother CancerJournal for Immunotherapy of Cancer2051-1426BioMed Central London 37010.1186/s40425-018-0370-6Case ReportRhabdomyolysis during high dose interleukin-2 treatment of metastatic melanoma after sequential immunotherapies: a case report Clark Joseph I. 708-327-3236jclark@lumc.edu 1Bufalino Shams shams.bufalino@advocatehealth.com 2http://orcid.org/0000-0002-2879-1364Singh Shruti ssingh4@lumc.edu 1Borys Ewa eborys@lumc.edu 11 0000 0001 2215 0876grid.411451.4Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S 1st Avenue, Maywood, IL 60153 USA 2 0000 0004 0435 6004grid.413334.2Advocate Lutheran General Hospital, Park Ridge, IL USA 14 6 2018 14 6 2018 2018 6 5327 12 2017 30 5 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe treatment options for metastatic malignant melanoma have drastically changed recently,including the increased use of immunotherapeutic agents that offer significant responses. Accordingly, it hasbecome common for sequential administration of such agents. Despite this, no guidelines exist on propersequencing or potential unique toxicities associated with such sequencing.\n\nCase presentation\nWe describe here the first incidence, to our knowledge, of clinically significant rhabdomyolysis associated with high-dose interleukin-2 after prior treatment with ipilimumab, genetically engineered T-cell therapy and subsequent single agent pembrolizumab in a patient with BRAF wild type metastatic malignant melanoma.\n\nConclusion\nFurther studies into the biology of sequential immunotherapy in the treatment of cancer are warranted.\n\nKeywords\nRhabdomyolysisIL-2Metastatic melanomaCase reportissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nTreatment options for metastatic malignant melanoma have drastically changed over the last decade. Targeted agents, including BRAF and MEK inhibitors, improve progression free survival and overall survival in patients with BRAF-mutated metastatic melanoma but to date durable remissions have not been consistently observed [1–5]. Immunotherapeutic agents including high-dose interleukin-2 (HD IL-2), and checkpoint inhibitors, such as the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab and the anti-programmed cell death protein 1 (PD-1) antibodies nivolumab and pembrolizumab, have the ability of inducing significant responses [6–15]. Among these treatments however, HD IL-2 has traditionally been the only agent associated with long term, durable remission, lasting > 5 years [7, 16]. Although it is anticipated that such results are likely to be observed with single agent and/or combination checkpoint inhibitors.\n\nAn alternative immunotherapeutic option includes talimogene laherparepvec, (T-VEC), an oncolytic virus that mediates local and systemic antitumor activity by direct cancer cell lysis and an “in situ vaccine” effect [17]. Investigational approaches aimed at immune-mediated mechanisms of antitumor activity that remain viable options include dendritic cell vaccines, tumor cell vaccines and engineered T-cells that target tumor cells directly [18–20].\n\nSequential therapy involving any number of immunotherapeutic agents is not an uncommon approach in the treatment of patients with metastatic malignant melanoma, regardless of BRAF status, once their disease progresses. Formal evaluation of safety and efficacy of such sequential treatments has not been reported. As such, unexpected toxicities are certain to arise. We report here, to our knowledge, the first incidence of clinically significant rhabdomyolysis associated with HD IL-2 after prior treatment with ipilimumab, genetically engineered T-cell therapy and subsequent single agent pembrolizumab in a patient with BRAF wild type metastatic malignant melanoma.\n\nCase presentation\nA 42 year old male presented to his primary care physician with a 20 pound unintentional weight loss over a 3 month period and new left axillary lymphadenopathy. A core biopsy of his axillary mass revealed metastatic malignant melanoma. He had no prior history of a primary melanoma. A staging PET/CT revealed abnormal FDG uptake in his left axilla and small bowel. A left axillary lymph node dissection was performed and revealed 2 of 19 lymph nodes involved with metastatic melanoma, BRAF wild type, the largest of which measured 10.1 cm. His medical history was significant for oligodendroglioma, which was surgically resected eight years prior to presentation, followed by radiation therapy for recurrence five years prior to presentation. He received four doses of systemic ipilimumab for his metastatic melanoma without incident. Post-treatment imaging revealed disease progression with new diffuse subcutaneous, lung, liver and bilateral axillary lymph node metastases.\n\nHe subsequently enrolled on a genetically engineered T-cell trial, targeting tyrosinase. He received fludarabine and cyclophosphamide as a conditioning regimen, then his engineered T-cells were infused, followed by one week of low dose IL-2, (72,000 U/kg IV q8 hours). Per the treatment protocol, unfractionated creatinine kinase (CK) levels were obtained just prior to and for two weeks after infusion of the genetically engineered T-cells. The CK levels were within normal limits during the course of this treatment. He initially experienced disease response, however, four months after his T-cell therapy, he again developed diffuse progression with new hilar lymphadenopathy and progression of his lung and axillary lymph node metastases.\n\nHe was next treated with three doses of pembrolizumab but post-treatment imaging again revealed disease progression in his lungs. CK levels were not checked during treatment with either ipilumumab or pembrolizumab. Despite multiple lines of therapy, the patient continued to have an excellent performance status, so he thus proceeded to treatment with HD IL-2 (600,000 IU/kg IV over 15 min every 8 h day 1–5 and day 15–19), which began nine months after receiving his engineered T-cell infusion.\n\nDuring cycle one of course 1 (day 1–5) of HD IL2, he received 10 out of 14 possible doses and experienced the expected adverse effects of hypotension, sinus tachycardia, oliguria, metabolic acidosis, and acute kidney injury. Serum CK was monitored per protocol and was initially normal but peaked at 641 (50–320 IU/L) during the fourth day of treatment without associated symptoms or cardiac findings on EKG.\n\nHe had an uncomplicated recovery and was re-admitted to the hospital for cycle 2 of course 1 (day 15–19) of HD IL-2, without complaints and a normal serum CK level of 133 (50–320 IU/L). After 6 doses of HD-IL2, he began to experience diffuse myalgias and rigors. He was noted to have a rapid rise in CK to 2700 and increase in his serum creatinine from 2.5 to 4.4 (0.6–1.4 mg/dL). An EKG revealed sinus tachycardia and his serum troponin level was normal at 0.02 (0.00–0.04 ng/mL). The rise in CK was attributed to rigors and he was continued on therapy. He went on to receive 2 additional doses of HD IL-2. When his CK rose further to 3900 and the myalgias became more severe despite resolution of his rigors, subsequent doses were held.\n\nFurther investigation revealed an elevated serum aldolase of 32.7 (1.2–7.6 U/L), and elevated urine myoglobin of 132 (< 28 mcg/L). MB fractionation of CK was not performed. Urinalysis demonstrated large blood without red blood cells. Serial EKGs demonstrated sinus tachycardia but not sequelae of hyperkalemia, such as peaked T waves. Other labs for serologic autoimmunity, e.g. anti-nuclear antibody, anti-double stranded DNA anti-striated muscle antibody and anti-smooth muscle antibody, were not checked. Muscle function was not assessed with electromyography (EMG). He received supportive care and aggressive intravenous hydration with normal saline. He recovered fully from this episode of rhabdomyolysis.\n\nSubsequent staging with a PET/CT revealed a mixed response in his pulmonary nodules with mild improvement in his hilar and axillary lymphadenopathy. Given his full recovery from previous toxicity and the mixed response on imaging, the decision was made to proceed with a second course of HD-IL2 therapy with close monitoring of CK levels and a low threshold for discontinuation of therapy.\n\nHe received only two doses of HD IL-2 and again developed diffuse myalgias with a rapid rise in his serum CK level from 184 to 1680. Serum aldolase and urine myoglobin were again significantly elevated, at 16.2 and 3430, respectively. All further doses of HD IL-2 were held and he was again supported with aggressive intravenous hydration. His clinical symptoms resolved and his CK level trended down to the normal range.\n\nDue to this unusual toxicity, a muscle biopsy was performed to further evaluate for rhabdomyolysis and to ascertain if his engineered T-cells were present in his muscle tissue. The biopsy revealed rare myofiber necrosis and myophagocytosis and scant endomysial infiltrate. The infiltrate consisted of a mixture of CD3 and CD4 positive T-lymphocytes, CD68 positive macrophages and lesser numbers of CD8 positive T-lymphocytes, suggestive of an immune-mediated toxicity causing necrotizing myopathy (Fig. 1). It was difficult to ascertain if the T-lymphocyte present represented his engineered T-cells. Of note, the engineered T-cells remained detectable in the circulation at this time. He was discharged home and follow up PET/CT imaging revealed a near complete response. At the time of this follow up, he was found to have new onset vitiligo involving his neck, upper back, chest, and upper arms (Fig. 2). A skin biopsy at the edge of his neck vitiligo again revealed CD3+ T-cell infiltration (Fig. 3).Fig. 1 Right thigh muscle biopsy demonstrated scattered necrotic myofibers some of which were infiltrated by macrophages (myophagocytosis). There was scant endomysial inflammatory infiltrate composed of a mixture of CD3 and CD4 positive T-lymphocytes, CD68 positive macrophages and lesser numbers of CD8 positive T-lymphocytes. Type II fiber atrophy was also noted. Findings were those of necrotizing myopathy with accompanying type II fiber atrophy\n\nFig. 2 Vitiligo involving neck and upper back\n\nFig. 3 Skin biopsy revealing diffuse CD3+ T-cell infiltration\n\n\n\nNo further HD-IL2 therapy has been administered and he continues to experience a durable response on imaging nearly two and a half years since completion of his HD IL-2 therapy. Of note, CK levels had not been checked when the patient had received prior therapy with ipilumumab or pembrolizumab. CK levels were, however, monitored at the time of treatment with engineered T-cells and were noted to be within the reference range.\n\nDiscussion\nTo our knowledge, the development of rhabdomyolysis has not been reported as a toxicity associated with HD-IL2 treatment in metastatic melanoma. Prior case reports have cited the development of rhabdomyolysis in the treatment of various disease entities that involved interferon alpha (IFN-α) administration. As early as 1994, Greenfield et al., noted the development of rhabdomyolysis in the treatment of hepatitis C with IFN-α [21]. In 1997, Reinhold et al. described the association of a fatal case of rhabdomyolysis with the use of adjuvant high dose IFN-α for high risk malignant melanoma [22]. An additional case of rhabdomyolysis secondary to adjuvant high dose IFN-α for the treatment of high risk melanoma was detailed by van Londen et al. [23]. In this case it was noted that serum CPK levels remained elevated despite the patient being asymptomatic and IFN-α being held for up to 6 weeks. Anderlini et al. described the case of a female patient who developed rhabdomyolysis after receiving biochemotherapy with IFN-α, IL-2 and chemotherapy (cisplatin, vinblastine and dacarbazine) [24]. This patient’s rhabdomyolysis was believed to be secondary to IFN-α since there were no previously reported toxicities of clinically significant rhabdomyolysis with the other agents.\n\nInterestingly, Esteva-Lorenzo et al. published a case report in 1995 reporting the first case of necrotizing myositis in a patient with metastatic renal cell carcinoma undergoing treatment with HD-IL2 after autologous tumor vaccine [25]. The severe autoimmune mediated muscle injury resolved with discontinuation of therapy. The patient had a disease response to therapy despite this unexpected toxicity.\n\nImmune-related adverse events are known to be associated with immune checkpoint therapy. Bilen et al. described an interesting case of an elderly patient with metastatic papillary urothelial cancer who was treated on a clinical trial with combination ipilumumab and nivolumab and subsequently developed rhabdomyolysis and severe polymyositis. The patient did not have any known prior autoimmune conditions but after his second cycle of treatment presented to the emergency department for lower back pain, muscle weakness and difficulty opening his mouth, eating and speaking. Subsequent laboratory workup was consistent with rhabdomyolyis with polymyositis and the patient received supportive care as well as immunosuppressive treatment with glucocorticoids and infliximab. A paraneoplastic antibody panel was ordered and revealed an elevated anti-smooth muscle antibody titer to 1:61440 (normal 1:≤120). Anti-smooth muscle antibody level on a pre-treatment blood sample was then run and also noted to be elevated to 1:15360 [26]. Similarly, Sakai et al. reported a case of a patient with metastatic melanoma treated with nivolumab who developed severe mononeuropathy multiplex and rhabdomyolysis. This patient did not have a pre-existing history of an underlying autoimmune condition and autoimmune serologies assessed after the onset of the patient’s symptoms were unremarkable [27].\n\nAs the literature shows, rhabdomyolysis has not been reported as a toxicity related to HD IL-2 therapy alone. The patient presented here and the patient presented by Esteva-Lorenzo both received genetically modified immune modulating therapy followed by HD IL-2. Notable similarities exist between the two cases including the development of severe autoimmune mediated muscle injury that resolved after discontinuation of HD IL-2 treatment and disease response to therapy. One explanation for this unique toxicity could be that the immune response initiated by either genetically engineered T-cells or tumor vaccine, respectively, was somehow reactivated or enhanced by HD IL-2. In both instances, this manifested as both on-target and off-target responses. An alternative pathophysiologic explanation for the development of rhabdomyolysis is that there was subclinical rhabdomyolysis (or at minimum serum elevation in CK) during treatment with ipilumumab and/or pembrolizumab but that formal diagnosis of rhabdomyolysis went undetected since CK levels are not routinely checked in asymptomatic patients with either of these treatments. Exposure to HD-IL2 therapy subsequently led to an autoimmune reactivation or exacerbation that led to clinically symptomatic rhabdomyolysis.\n\nConclusion\nThe majority of patients with metastatic melanoma will receive multiple lines of various immune mediated therapies during their disease course. It appears that manipulating the immune system at different time points and by various mechanisms may predispose to unexpected immune mediated toxicities and possibly a disease response. The use of tumor vaccine or modified T-cell therapy in combination or sequentially with HD IL-2 may be valuable in the treatment of malignancies such as metastatic melanoma and renal cell carcinoma. Further studies into the biology of sequential immunotherapy in the treatment of cancer are warranted.\n\nAbbreviations\nCTLA4cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)\n\nHD-IL2high-dose interleukin-2\n\nPD-1programmed cell death protein-1\n\nTVECtalimogene laherparepvec\n\nPresented in part at the 2015 SITC National Harbor, MD\n\nAuthors’ contributions\nJC and SB were major contributors in developing the manuscript. SS performed a literature review and assisted with developing the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nOur case report included human data and was performed in accordance with Declaration of Helsinki. As noted in the consent, consent was obtained from the patient for publication of images. Ethics committee approval was waived.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this information and any accompanying images. A copy of the written consent is available for review.\n\nCompeting interests\nDr. Clark is a member of speakers’ bureaus for BMS and Merck. He is an unpaid consultant for Prometheus.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Chapman PB Hauschild A Robert C Haanen JB Ascierto P Larkin J Improved survival with vemurafenib in melanoma with BRAF V600E mutation N Engl J Med 2011 364 2507 2516 10.1056/NEJMoa1103782 21639808 \n2. Sosman JA Kim KB Schuchter L Gonzalez R Pavlick AC Weber JS Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib N Engl J Med 2012 366 707 714 10.1056/NEJMoa1112302 22356324 \n3. Hauschild A Grob JJ Demidov LV Jouary T Gutzmer R Millward M Dabrafenib in BRAF-mutated metastatic melanoma: a multi-Centre, open-label, phase 3 randomised controlled trial Lancet 2012 380 358 365 10.1016/S0140-6736(12)60868-X 22735384 \n4. Robert C Karaszewska B Schachter J Rutkowski P Mackiewicz A Stroiakovski D Improved overall survival in melanoma with combined dabrafenib and tramentinib N Engl J Med 2015 372 30 39 10.1056/NEJMoa1412690 25399551 \n5. Larkin J Ascierto PA Dréno B Atkinson V Liszkay G Maio M Combined vemurafenib and cobimetinib in BRAF-mutated melanoma N Engl J Med 2014 371 1867 1876 10.1056/NEJMoa1408868 25265494 \n6. Atkins MB Lotze MT Dutcher JP High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993 J Clin Oncol 1999 17 2105 2116 10.1200/JCO.1999.17.7.2105 10561265 \n7. Atkins MB Kunkel L Sznol M High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update Cancer J Sci Am 2000 6 suppl 1 S11 S14 10685652 \n8. Hodi FS O’Day SJ McDermott DF Weber RW Sosman JA Haanen JB Improved survival with ipilimumab in patients with metastatic melanoma N Engl J Med 2010 363 711 723 10.1056/NEJMoa1003466 20525992 \n9. Schadendorf D Hodi FS Robert C Weber JS Margolin K Hamid O Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma J Clin Oncol 2015 33 1889 1894 10.1200/JCO.2014.56.2736 25667295 \n10. Topalian SL Hodi FS Brahmer JR Gettinger SN Smith DC McDermott DF Safety, activity, and immune correlates of anti-PD-1 antibody in cancer N Engl J Med 2012 366 2443 2454 10.1056/NEJMoa1200690 22658127 \n11. Hamid O Robert C Daud A Hodi FS Hwu WJ Kefford R Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma N Engl J Med 2013 369 134 144 10.1056/NEJMoa1305133 23724846 \n12. Robert C Schachter J Long GV Arance A Grob JJ Mortier L Pembrolizumab versus ipilimumab in advanced melanoma N Engl J Med 2015 372 2521 2532 10.1056/NEJMoa1503093 25891173 \n13. Wolchok JD Kluger H Callahan MK Postow MA Rizvi NA Lesokhin AM Nivolumab plus ipilimumab in advanced melanoma N Engl J Med 2013 369 122 133 10.1056/NEJMoa1302369 23724867 \n14. Postow MA Chesney J Pavlick AC Robert C Grossman K McDermott D Nivolumab and ipilimumab versus ipilimumab in untreated melanoma N Engl J Med 2015 372 2006 2017 10.1056/NEJMoa1414428 25891304 \n15. Larkin J Chiarion-Sileni V Gonzalez R Grob JJ Cowey CL Lao CD Schadendorf D Combined nivolumab and ipilimumab or monotherapy in untreated melanoma N Engl J Med 2015 373 23 34 10.1056/NEJMoa1504030 26027431 \n16. Alva A Daniels GA Wong MKK Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma Cancer Immuno Immunother 2016 65 1533 1544 10.1007/s00262-016-1910-x \n17. Andtbacka RH Talimogene taherparepvec improves durable response rate in patients with advanced melanoma J Clin Oncol 2015 33 2780 2788 10.1200/JCO.2014.58.3377 26014293 \n18. de Rosa F Ridolfi L Dendritic cell vaccination for metastatic melanoma: a 14-year monoinstitutional experience Melanoma Res 2017 27 4 351 357 10.1097/CMR.0000000000000356 28654547 \n19. Bethune MT Joglekar AV Personalized T cell-mediated cancer immunotherapy: progress and challenges Curr Opin Biotechnol 2017 48 142 152 10.1016/j.copbio.2017.03.024 28494274 \n20. Chhabra A Mukherji B Batra D Activation induced cell death (AICD) of human melanoma antigen-specific TCR engineered CD8 T cells involves JNK, Bim and p53 Expert Opin Ther Targets 2017 21 2 117 129 10.1080/14728222.2017.1270941 27935327 \n21. Greenfield SM Harvey RS Thompson RPH Rhabdomyolosis after treatment with interferon alpha BMJ 1994 309 20 27 10.1136/bmj.309.6953.512a \n22. Reinhold U Hartl C Hering R Fatal rhabdomyolosis and multiple organ failure associated with adjuvant high-dose interferon-alpha in malignant melanoma Lancet 1997 349 540 541.20 10.1016/S0140-6736(97)80091-8 9048796 \n23. Van Londen GJ Mascarenhas B Kirkwood JM Rhabdomyolosis, when observed with high dose interferon-alpha, does not always exclude resumption of HDI J Clin Oncol 2001 19 3794 10.1200/JCO.2001.19.17.3794 11533109 \n24. Alderlini P Buzaid AC Legha SS Acute rhabdomyolysis after concurrent administration of interleukin-2, interferon-alfa, and chemotherapy for metastatic melanoma Cancer 1995 76 678 679 10.1002/1097-0142(19950815)76:4<678::AID-CNCR2820760422>3.0.CO;2-Q 8625165 \n25. Esteva-Lorenzo FJ Janik JE Fenton RG Myositis associated with interleukin-2 therapy in a patient with metastatic renal cell carcinoma Cancer 1995 76 1219 1223 10.1002/1097-0142(19951001)76:7<1219::AID-CNCR2820760719>3.0.CO;2-O 8630901 \n26. Bilen MA Subudhi SK Acute rhabdomyolysis with severe polymyositis following ipilumumab-nivolumab treatment in a cancer patient with elevated anti-striated muscle antibody J Immunother Cancer 2016 4 36 10.1186/s40425-016-0139-8 27330809 \n27. Sakai K Mochizuki H A case of nivolumab-induced severe mononeuropathy multiplex and rhabdomyolysis Case Rep Med 2017 1093858 4\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2051-1426",
"issue": "6(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "Case report; IL-2; Metastatic melanoma; Rhabdomyolysis",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D003131:Combined Modality Therapy; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma; D012206:Rhabdomyolysis; D013601:T-Lymphocytes",
"nlm_unique_id": "101620585",
"other_id": null,
"pages": "53",
"pmc": null,
"pmid": "29898784",
"pubdate": "2018-06-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25399551;23724867;22356324;27714434;22658127;8630901;28494274;25891304;29312452;25667295;10561265;20525992;23724846;26014293;25891173;9048796;21639808;22735384;10685652;25265494;8625165;11533109;26027431;27330809;28654547;27935327",
"title": "Rhabdomyolysis during high dose interleukin-2 treatment of metastatic melanoma after sequential immunotherapies: a case report.",
"title_normalized": "rhabdomyolysis during high dose interleukin 2 treatment of metastatic melanoma after sequential immunotherapies a case report"
} | [
{
"companynumb": "US-009507513-1806USA012061",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Patients lacking humoral response have been suggested to develop a less severe COVID-19, but there are some reports with a prolonged, relapsing or deadly course. From April 2020, there is growing evidence on the benefits of COVID-19 convalescent plasma (CCP) for patients with humoral immunodeficiency. Most of them had a congenital primary immunodeficiency or were on treatment with anti CD20 antibodies. We report on three patients treated in our hospital and review thirty-one more cases described in the literature. All patients but three resolved clinical picture with CCP. A dose from 200 to 800ml was enough in most cases. Antibody levels after transfusion were negative or low, suggesting consumption of them in SARS-CoV-2 neutralization. These patients have a protracted clinical course shortened after CCP. CCP could be helpful for patients with humoral immunodeficiency. It avoid relapses and chronification. CCP should be transfused as early as possible in patients with COVID-19 and humoral immunodeficiency.",
"affiliations": "Infectious Diseases Department, Hospital Regional Universitario de Málaga, Spain. Electronic address: med006803@gmail.com.;Centro de Transfusión, Tejidos y Células (CTTC), Málaga, Spain.;Microbiology Department, Hospital Universitario Clínico San Cecilio, Granada, Spain.;Hematology Department, Hospital Regional Universitario de Málaga, Spain.;Director of \"Red andaluza de Medicina transfusional, tejidos y células\" del Sistema Sanitario Público de Andalucía, Spain.;Endocrinology Department, Hospital Regional Universitario de Málaga, Spain.;Internal Medicine Department, Hospital Regional Universitario de Málaga, Spain.;Internal Medicine Department, Hospital Regional Universitario de Málaga, Spain.;Infectious Diseases Department, Hospital Regional Universitario de Málaga, Spain.;Infectious Diseases Department, Hospital Regional Universitario de Málaga, Spain.;Infectious Diseases Department, Hospital Regional Universitario de Málaga, Spain.",
"authors": "Delgado-Fernández|Marcial|M|;García-Gemar|Gracia Mar|GM|;Fuentes-López|Ana|A|;Muñoz-Pérez|Manuel Isidro|MI|;Oyonarte-Gómez|Salvador|S|;Ruíz-García|Ignacio|I|;Martín-Carmona|Jessica|J|;Sanz-Cánovas|Jaime|J|;Castaño-Carracedo|Manuel Ángel|MÁ|;Reguera-Iglesias|José María|JM|;Ruíz-Mesa|Juan Diego|JD|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": "10.1016/j.eimc.2021.01.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2529-993X",
"issue": null,
"journal": "Enfermedades infecciosas y microbiologia clinica (English ed.)",
"keywords": "Convalescent plasma; Covid-19; Humoral immunodeficiency; Inmunodeficiencia humoral; Obinutuzumab; Plasma de convalecientes; Rituximab",
"medline_ta": "Enferm Infecc Microbiol Clin (Engl Ed)",
"mesh_terms": null,
"nlm_unique_id": "101777541",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33741148",
"pubdate": "2021-02-11",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "33098200;33009361;32591357;32777130;33115920;33216852;32994125;32861333;32387167;30646343;32420691;32636116;33103195;32541689;32710500;32398875;32319118;32557623;32947026;32376969;33424856;32409782;32606046;32682684;33395474;32356910;32859609;32933879;33043962;33523609;32374890;32959052;33246166;32945944;33338534;32420609;32413374;33416095;33039649;32593180;33048424;25556904;32694044;17965121;33307029;32703664;2689968;32554285;32652938;16611321;32654064;33406391;32986807;33382764;32898996;33008453;32359789;33391280;33324223;33406353;32421281;32652231;33165238;32557918;33406279;32818593;33403488",
"title": "Treatment of COVID-19 with convalescent plasma in patients with humoral immunodeficiency - Three consecutive cases and review of the literature.",
"title_normalized": "treatment of covid 19 with convalescent plasma in patients with humoral immunodeficiency three consecutive cases and review of the literature"
} | [
{
"companynumb": "ES-ROCHE-2803827",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nNasopharyngeal carcinoma (NPC) is a commonly encountered type of tumor. Fluorouracil (FU) is an effective treatment providing satisfactory oncologic outcomes in nasopharyngeal carcinoma patients. We describe a unique case of colonic perforation in an NPC patient treated with FU. Thus far, only two cases of intestinal perforation associated with FU treatment have been reported. We hope that the analysis of the relationship between the adverse effects of FU and physiological factors will help to reduce the incidence of colonic perforation in patients with nasopharyngeal carcinoma treated with FU.\n\n\nMETHODS\nA 67-year-old female patient suffered from NPC stage pT3N2M0. She had a history of three surgical procedures: Partial enterectomy, partial sigmoidectomy, and sigmoidostomy. After the administration of 2.75 g FU, a bloody stool appeared and the patient developed abdominal pain. Subsequent examination indicated colitis and intestinal perforation.\n\n\nCONCLUSIONS\nFU is a commonly used drug in NPC chemotherapy. The most common adverse effect of FU is gastrointestinal reaction, and the colonic perforation found here is thought to be caused by gastrointestinal mucosal injury consequential to the FU treatment. When selecting chemotherapy drugs, their side effects and the physical condition of patients should be considered, particularly in patients with a history of gastrointestinal surgery.",
"affiliations": "Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong Province, China.;Department of Radiotherapy, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong Province, China.;Department of Radiotherapy, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong Province, China. dxcflk@gzucm.edu.cn.",
"authors": "Lu|Wei-Jia|WJ|;Li|Gong|G|;Gao|Lei|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v8.i9.1693",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2307-8960",
"issue": "8(9)",
"journal": "World journal of clinical cases",
"keywords": "Case report; Chemotherapy; Colonic perforation; Fluorouracil; Nasopharyngeal carcinoma; Reaction",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "1693-1697",
"pmc": null,
"pmid": "32420303",
"pubdate": "2020-05-06",
"publication_types": "D002363:Case Reports",
"references": "22020693;10506695;19081732;18680241;31165410;9083147;18024857;8339228;19552944",
"title": "Colonic perforation in a nasopharyngeal carcinoma patient treated with fluorouracil: A case report.",
"title_normalized": "colonic perforation in a nasopharyngeal carcinoma patient treated with fluorouracil a case report"
} | [
{
"companynumb": "CN-ACCORD-183774",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "1",
"dru... |
{
"abstract": "No data on inotuzumab ozogamicin (InO) in infant acute lymphoblastic leukaemia (ALL) have been published to date. We collected data internationally on infants/young children (<3 years) with ALL treated with InO. Fifteen patients (median 4.4 months at diagnosis) received InO due to relapsed or refractory (R/R) disease. Median percentage of CD22+ blasts was 72% (range 40-100%, n = 9). The median dose in the first course was 1.74 mg/m2 (fractionated). Seven patients (47%) achieved complete remission; one additional minimal residual disease (MRD)-positive patient became MRD-negative. Six-month overall survival was 47% (95% confidence interval [CI] 27-80%). Two patients developed veno-occlusive disease after transplant. Further evaluation of InO in this subgroup of ALL is justified.",
"affiliations": "Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.;Division of Pediatric Hematology Oncology, CHC-Clinique du MontLégia - Liège, Liège, Belgium.;Department of Pediatrics, Stanford School of Medicine, Stanford, CA, USA.;Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.;Department of Oncology and Hematology, CHU de Nantes, Nantes, France.;Department of Oncology and Hematology, Children's Hospital, CHRU Nancy, Vandoeuvre Lès Nancy, France.;Pediatric Hematology -Oncology, Schneider Children's Medical Center of Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Cancer Centre for Children, The Children's Hospital at Westmead, Westmead, Australia.;Pediatric Hematology and Stem Cell Transplantation Department, Central Hospital of Southern Pest - National Institute of Hematology and Infectious Diseases, Budapest, Hungary.;Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong SAR, China.;Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.;R.M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Pavlov University, Saint-Petersburg, Russia.;Department of Pediatrics and Adolescent Medicine, Rigshospitalet Copenhagen University Hospital; Institute of Clinical Medicine, Faculty of Health, University of Copenhagen, Copenhagen, Denmark.;Department Oncology, University Children's Hospital Zürich, Zürich, Switzerland.;Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.;Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.;Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.",
"authors": "Brivio|Erica|E|0000-0001-5285-1702;Chantrain|Christophe F|CF|;Gruber|Tanja A|TA|;Thano|Adriana|A|;Rialland|Fanny|F|;Contet|Audrey|A|;Elitzur|Sarah|S|;Dalla-Pozza|Luciano|L|;Kállay|Krisztián Miklós|KM|;Li|Chi-Kong|CK|;Kato|Motohiro|M|;Markova|Inna|I|;Schmiegelow|Kjeld|K|;Bodmer|Nicole|N|;Breese|Erin H|EH|;Hoogendijk|Raoull|R|;Pieters|Rob|R|;Zwaan|Christian Michel|CM|",
"chemical_list": "D000080045:Inotuzumab Ozogamicin",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.17333",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "193(6)",
"journal": "British journal of haematology",
"keywords": "ALL; infants; inotuzumab ozogamicin",
"medline_ta": "Br J Haematol",
"mesh_terms": "D064591:Allografts; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D000080045:Inotuzumab Ozogamicin; D008297:Male; D018365:Neoplasm, Residual; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D015996:Survival Rate",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "1172-1177",
"pmc": null,
"pmid": "33529389",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia: a case series.",
"title_normalized": "inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia a case series"
} | [
{
"companynumb": "NL-PFIZER INC-2020010023",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "INOTUZUMAB OZOGAMICIN"
},
"drugadditional": nu... |
{
"abstract": "Influenza (flu) is a prominent infectious disease that worsens the general prognosis of older adults. We herein report a case of a clinically odd and rare reaction on an instant diagnostic kit for influenza. An 81-year-old man with a fever and rhinorrhea consulted our hospital. He had a history of dementia of Alzheimer's type and rheumatoid arthritis and had been treated with oral prednisolone (10 mg/day). Instant diagnostic test kit A using exudation from the upper pharynx showed positivity for antigen of flu A virus, and computed tomography indicated acute pneumonia. Immediately after the diagnosis, 150 mg/day of oseltamivir was started for 5 days. However, a high fever over 38.0°C persisted, and flu A antigen from the upper pharynx was repeatedly detected using test kit A. Despite subsequent oral treatment with 100 mg/day of amantadine and single venous infusion of 300 mg/day of peramivir, the high fever continued, and the detection of C-reactive protein in the serum as well as flu A antigen in the upper pharynx persisted. We suspected test failure, and the results of another test kit (kit B) were indeed negative. Furthermore, polymerase chain reaction performed by two independent laboratories failed to detect flu gene fragments. We concluded that the patient did not have the flu, and results of test kit A had been a false positive. The patient was successfully treated with ABPC/SBT infusions. We should consider the implications of diagnosing flu using instant test kits.",
"affiliations": "Department of General Medicine, Nagoya City West Medical Center.;Department of General Medicine, Nagoya City West Medical Center.;Department of Gastroenterology, Nagoya City West Medical Center.",
"authors": "Kikuchi|Motoo|M|;Fujita|Shouko|S|;Senoo|Kyouji|K|",
"chemical_list": "D011933:Reagent Kits, Diagnostic",
"country": "Japan",
"delete": false,
"doi": "10.3143/geriatrics.57.195",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-9173",
"issue": "57(2)",
"journal": "Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics",
"keywords": "Influenza; Instant diagnostic kit; Polymerase chain reaction",
"medline_ta": "Nihon Ronen Igakkai Zasshi",
"mesh_terms": "D000369:Aged, 80 and over; D005189:False Positive Reactions; D006801:Humans; D007251:Influenza, Human; D008297:Male; D011014:Pneumonia; D011379:Prognosis; D011933:Reagent Kits, Diagnostic",
"nlm_unique_id": "7507332",
"other_id": null,
"pages": "195-199",
"pmc": null,
"pmid": "32475947",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of acute pneumonia with prolonged false-positive results using an influenza test kit.",
"title_normalized": "a case of acute pneumonia with prolonged false positive results using an influenza test kit"
} | [
{
"companynumb": "JP-BAUSCH-BL-2020-017888",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Hyponatraemia is the most common electrolyte disorder encountered in clinical practice. Symptomatic hyponatraemia reflects brain damage because of cerebral swelling. Some coexisting factors such as extreme ages, hypoxia and female sex are associated with poor prognosis. In this report, we describe the case of a 75-year-old patient who suffered from hyponatraemic encephalopathy after elective vaginal hysterectomy under spinal anaesthesia. After being transferred to the ward, she developed nausea, vomiting, hypertensive crisis and intense anxiety. These symptoms were followed by grand mal seizure. Serum sodium level was 108 mmol/l. She also presented hypoxia, considered an aggravating factor, which was probably caused by the combination of benzodiazepine intake and cerebral oedema. However, fast raise of serum sodium level was achieved by immediate treatment with hypertonic saline, and she was discharged home without any sequelae.",
"affiliations": null,
"authors": "Suan|C|C|;Pozo|G Yerga|GY|",
"chemical_list": "D012462:Saline Solution, Hypertonic; D012964:Sodium",
"country": "England",
"delete": false,
"doi": "10.1111/aas.12248",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5172",
"issue": "58(2)",
"journal": "Acta anaesthesiologica Scandinavica",
"keywords": null,
"medline_ta": "Acta Anaesthesiol Scand",
"mesh_terms": "D000368:Aged; D001007:Anxiety; D001927:Brain Diseases; D005260:Female; D006801:Humans; D006973:Hypertension; D007010:Hyponatremia; D000860:Hypoxia; D007045:Hysterectomy, Vaginal; D007177:Inappropriate ADH Syndrome; D011183:Postoperative Complications; D020250:Postoperative Nausea and Vomiting; D012462:Saline Solution, Hypertonic; D012964:Sodium; D016896:Treatment Outcome",
"nlm_unique_id": "0370270",
"other_id": null,
"pages": "254-7",
"pmc": null,
"pmid": "24563921",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Post-operative hyponatraemic encephalopathy: a successful outcome despite hypoxia.",
"title_normalized": "post operative hyponatraemic encephalopathy a successful outcome despite hypoxia"
} | [
{
"companynumb": "ES-MYLANLABS-2015M1032153",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ENALAPRIL"
},
"drugadditional": null,
... |
{
"abstract": "Invasive candidiasis remains an important cause of mortality and morbidity in patients with underlying diseases. Here, we report a case of gastric perforation due to Candia glabrata infection in a 74-year-old-male with Paroxysmal nocturnal hemoglobinuria (PNH) who received long-term corticosteroid treatment of hemophagocytic syndrome associated with acute cholecystitis. Total gastrectomy was performed, and he was treated liposomal amphotericin B. The patient was extubated successfully on the 2nd postoperative day, but the patient died of Pneumocystis jirovecii pneumonia (PJP). An autopsy revealed that there was a small amount of the cystic form of Pneumocystic jirovecii, but there was not the presence of Candida spp. Concerning the prophylaxis of invasive candidiasis, there is no strong evidence-based data in clinical practice in immunocompromised patients, such as those receiving long-term immunomodulatory therapy or corticosteroids. Our present case suggests the importance of fungal management and may indicate the need for a new approach to the fungal prophylaxis in such patients.",
"affiliations": "Department of Hematology, Rinku General Medical Center, Japan.;Department of Hematology, Rinku General Medical Center, Japan.;Department of Pathology, Kaizuka City Hospital, Japan.;Department of Pathology, Rinku General Medical Center, Japan.;Department of Hematology, Rinku General Medical Center, Japan.",
"authors": "Karasuno|Takahiro|T|;Sata|Hiroshi|H|;Noda|Yuri|Y|;Imakita|Masami|M|;Yasumi|Masato|M|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2019.e00627",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(19)30192-110.1016/j.idcr.2019.e00627e00627ArticleInvasive candidiasis leading to gastric perforation in an immunocompromised patient Karasuno Takahiro gd2tkrsn@sensyu.ne.jpa⁎Sata Hiroshi aNoda Yuri bImakita Masami cYasumi Masato aa Department of Hematology, Rinku General Medical Center, Japanb Department of Pathology, Kaizuka City Hospital, Japanc Department of Pathology, Rinku General Medical Center, Japan⁎ Corresponding author at: 2-3 Ourai-Kita, Rinku, Izumisano, Osaka, 598-8577, Japan. gd2tkrsn@sensyu.ne.jp20 8 2019 2019 20 8 2019 18 e006273 7 2019 18 8 2019 18 8 2019 © 2019 The Author2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Invasive candidiasis remains an important cause of mortality and morbidity in patients with underlying diseases. Here, we report a case of gastric perforation due to Candia glabrata infection in a 74-year-old-male with Paroxysmal nocturnal hemoglobinuria (PNH) who received long-term corticosteroid treatment of hemophagocytic syndrome associated with acute cholecystitis. Total gastrectomy was performed, and he was treated liposomal amphotericin B. The patient was extubated successfully on the 2nd postoperative day, but the patient died of Pneumocystis jirovecii pneumonia (PJP). An autopsy revealed that there was a small amount of the cystic form of Pneumocystic jirovecii, but there was not the presence of Candida spp. Concerning the prophylaxis of invasive candidiasis, there is no strong evidence-based data in clinical practice in immunocompromised patients, such as those receiving long-term immunomodulatory therapy or corticosteroids. Our present case suggests the importance of fungal management and may indicate the need for a new approach to the fungal prophylaxis in such patients.\n\nKeywords\nInvasive candidiasisGastric perforationImmunocompromised patient\n==== Body\nIntroduction\nCandida spp. are a major constituent of the normal commensal flora of the gastrointestinal tract, but Candida infections of the gastrointestinal tract are rare and gastric perforation caused by Candida infections is extremely rare. Invasive candidiasis can occur as a result of a compromised immune status and is associated with high morbidity and mortality [1]. Treatment of invasive candidiasis is frequently very difficult and the fungal prophylaxis is increasingly being used in patients at high risk of fungal infection, such as neutropenic patients with hematological malignancies and recipients of hematopoietic stem cell transplantation. Goodman et al. demonstrated that fluconazole prophylaxis reduced the incidence of fungal infections in severely immunocompromised patients undergoing bone marrow transplantation [2]. On the other hand, in less severely immunocompromised patients, such as those receiving long-term corticosteroids, studies on the clinical efficacy and cost-effectiveness of the fungal prophylaxis have not been conducted.\n\nHerein, we present a rare case of invasive gastric candidiasis combined with gastric perforation in a patients with paroxysmal nocturnal hemoglobinuria who received long-term corticosteroid treatment for the complications and discuss the management of fungal infections.\n\nCase report\nA 74-year-old man was diagnosed with Paroxysmal nocturnal hemoglobinuria (PNH) in 2002. He was treated with cyclosporine A (CyA) (200 mg/day) and methenolone acetate (15 mg/day), and the pancytopenia gradually improved. In August 2017, he developed a fever, chills, and palpitation for five days prior to admission to our hospital. The physical examination findings revealed a body temperature of 40.0℃ and anemic conjunctiva, and he had slightly right upper quadrant abdominal tenderness. The laboratory findings showed severe anemia and thrombocytopenia, and a marked elevation of hepatobiliary enzymes. Abdominal Computed tomography (CT) revealed swelling and wall thickening of the gallbladder and large gallstones (15 mm). On other laboratory findings, the level of ferritin and soluble IL-2R were elevated to 1505.0 ng/ml and 4490 U/mL, respectively. A bone marrow study showed hypocellular marrow and hemophagocytic histiocytes with few blast features. Based on these findings, he was diagnosed with PNH-associated hemolysis and hemophagocytic syndrome associated with acute cholecystitis. He received cefoperazone/sulbactam (CPZ/SBT) antibiotic therapy and steroid therapy with 80 mg/day (1 mg/Kg/day) prednisolone (PSL). Fever disappeared and his Hb level and hepatobiliary enzymes level improved. However, the platelet count recovery was incomplete and repeated bone marrow aspiration showed residual hemophagocytosis. PSL was gradually reduced and was administered over 1 month. His hemoglobin A1c was elevated to 8.5%, indicating the onset of steroid-induced diabetes mellitus (DM)\n\nThe patient had a fever again about 1 month after PSL treatment and chest CT showed ground-glass attenuation with halo sign. Serum β-D-glucan level was not elevated, but the galactomannan antigen was positive. The diagnosis of invasive pulmonary aspergillosis (IPA) was made based on these observations, and voriconazole (VRCZ) administration resulted in the elimination of fever. However, he began to experience progressive dyspnea with a dry cough one week after VRCZ treatment. Chest X-ray showed an interstitial pattern on both sides and chest CT showed ground-glass opacification (GGO) on both sides of the lung. Serum β-D-glucan level was not elevated and serum Krebs von den Lungen-6 (KL-6) was 768U/ml (normal range:<500 U/ml). The diagnosis was drug-induced lung injury by VRCZ. Methylprednisolone pulse therapy (500 mg/day x 3days) was started and liposomal amphotericin B (L-AmB) was administered to IPA instead of VRCZ. His respiratory condition was improved.\n\nAfter 6 days of methylprednisolone treatment, he suddenly developed sever epigastric pain to all abdominal quadrants. Chest X‐ray and abdominal CT revealed gastric perforation. His clinical course up to gastric perforation is shown in Fig. 1. Methylprednisolone was discontinued and an emergency laparotomy was performed that revealed turbid bilious fluid and perforation of the lesser curvature of the stomach with black large ulcer (8.5 cm x 5.5 cm) (Fig. 2). The peritoneal fluid culture was positive for Candida glabrata. Pathological examination revealed necrotic tissues associated with inflammation, a large number of budding yeasts, and some of them inside blood vessels (Fig. 3). Fungal organisms were identified on Periodic acid-Schiff (PAS) and Grocott staining. These were immunohistochemically positive for Candida (Fig. 4) (negative for Aspergillus: data not shown, for mucormycosis: not tested). The patient was extubated successfully on the 2nd postoperative (PT) day and we continued to use L-AmB for the treatment of IPA and Candida glabrata peritonitis. However, his respiratory condition worsened on the 7th PT day. In chest CT, GGO was observed on both sides of the lung, and β-D-glucan increased to 78.1 pg/ml. Pneumocystis jirovecii pneumonia (PJP) was diagnosed and the anti-PJP agent was started. However, his respiratory condition did not improve, and he died on the 12th PT day. An autopsy revealed many lesions of bronchopneumonitis caused by gram-positive cocci, and a small amount of the cystic form of Pneumocystic jirovecii. On the other hand, Candida spp. and Aspergillus were not present in the lung.Fig. 1 The clinical course course up to the gastric perforation. CPZ/SBT: cefoperazone/sulbactam, VRCZ: voriconazole, L-AmB: Liposomal Amphotericin B, PSL: prednisolone.\n\nFig. 1Fig. 2 The macroscopic appearance of transmural gastric necrosis and perforation of the lesser curvature of the stomach.\n\nFig. 2Fig. 3 The histological appearance in the ulcer part showing (a) necrosis with acute inflammation (H-E stain, x10), (b) a large number of budding yeasts (H-E stain, x40) and (c) some of yeasts inside blood vessels (H-E stain, x100). H-E: hematoxylin and eosin.\n\nFig. 3Fig. 4 The histochemical stain. (a) Periodic acid-Schiff stain, (b) Grocott stain and (c) immunohistochemical stain for Candida (x100).\n\nFig. 4\n\nDiscussion\nAlthough generally rare, the prevalence of Candida infection of the gastrointestinal tract has significantly increased over the past 20 years due to advances in supportive care and intensive chemotherapy. The term “immunocompromised” is mainly related to underlying diseases such as acquired immune deficiency syndrome, solid organ transplantation, and hematopoietic stem cell transplantation. However, many other forms of immunocompromised patients are also susceptible to fungal infections, including patients on long-term immunomodulatory therapy or corticosteroids, and patients with malnutrition or chronic debilitating disease [[3], [4], [5]]. This report seems to be highly suggestive in that it shows the importance of management of fungal infections in less severely immunocompromised patients\n\nInvasive candidiasis remains an important problem of mortality and morbidity in patients with underlying diseases. Despite the availability of some antifungal agents, the outcome of invasive candidiasis is poor and the mortality rate of 42% has recently been reported [6]. The identification of patients at risk is extremely important for the management of candidiasis. Previous reports indicated that risk factors for candidiasis included the use of broad-spectrum antibiotics, diabetes mellitus, neutropenia, impairing of T cell immunity by corticosteroid or CyA [[7], [8], [9], [10], [11], [12]]. Recently candida infections in elderly people (over the age of 65 years) are important and expanding clinical problems [13]. Our patient was 74-years-old and received an antibiotic, CyA and corticosteroid. In addition, he had risk factors to promote invasive candidiasis because he suffered from diabetes mellitus in the course of corticosteroid treatment to hemophagocytic syndrome and drug-induced lung injury. These risk factors were likely to explain the ease of invasion of candida and the progress of invasive candidiasis. Concerning the prophylaxis of invasive candidiasis, that with new antifungal drugs has been improved and carried out, especially in patients undergoing intensive chemotherapy for acute leukemia or hematopoietic stem cell transplantation [14,15]. On the other hand, in less severely immunocompromised patients, such as those receiving high-dose and long-term corticosteroids, there are some problems for determining fungal prophylaxis in clinical practice because there are not strong evidence-based data for prophylaxis and the benefit. However, since severe fungal infection as a complication is related to poor prognosis, identification of patients at risk is crucial. Therefore, it may be important to propose a scoring system combining the above risk factors and determine the clinical benefits, including cost-effectiveness in such patients.\n\nA comprehensive review suggested that the gut is the primary source of invasive candidiasis [16]. Oral and intestinal Candida colonization has been reported to be associated with a significantly higher incidence of invasive candidiasis [17,18]. Marr at al. demonstrated that oral Candida colonization contributes to a 3-fold increase in the risk of candidemia in allogeneic stem cell transplantation patients [19]. Thus, identification of oral colonization is of great interest in the selection of patients at risk for subsequent invasive candidiasis, as well as for the implementation of prophylaxis strategies. In immunocompromised patients, oral monitoring culture from mouth-wash samples may be useful for reducing the incidence of invasive candidiasis.\n\nThe patients with PNH are frequently characterized by intravascular hemolysis and thrombosis leading to high mortality. In our patient, the autopsy revealed that there was not an appearance of thrombosis, therefore, the perforation was thought to be not caused by PNH-induced thrombosis, but the influence of invasive candidiasis. The finding of no appearance of thrombosis is consistent with the previous report by Nishimura et al. showed a lower incidence of thrombosis in Japanese patients than white patients [20]. The gastric perforation by Candida glabrata in our case occurred during the treatment of antifungal agents. Unfortunately, we could not conduct the antifungal susceptibility test of the isolated Candida glabrata, but it was not considered to be multidrug-resistant because no antifungal agents were administered to our patient until IPA occurred. It remains unclear why the perforation by Candida infection occurred. The short-term treatment was likely to explain its occurrence.\n\nIn conclusion, our present case suggests the importance of fungal management and may demonstrate the need for new approaches to the fungal prophylaxis in immunocompromised patients.\n\nAuthor statement\nThe Authors state that the views expressed in the submitted article are their own and not official position of the institution or funder.\n\nDeclaration of Competing Interest\nThe authors declare that they have no conflict of interest.\n==== Refs\nReferences\n1 Pappas P.G. Kauffman C.A. Andes D.R. Clancy C.J. Marr K.A. Ostrosky-Zeichner L. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America Clin Infect Dis 62 2016 409 417 26810419 \n2 Goodman J.L. Winston D.J. Greenfield R.A. Chandrasekar P.H. Fox B. Kaizer H. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation N Engl J Med 326 1992 845 851 1542320 \n3 Parize P. Rammaert B. Lortholary O. Emerging invasive fungal diseases in transplantation Curr Infect Dis Rep 14 2012 668 675 23065419 \n4 Schwesinger G. Junghans D. Schröder G. Bernhardt H. Knoke M. Candidosis and aspergillosis as autopsy findings from 1994 to 2003 Mycoses 48 2005 176 180 15842333 \n5 Bitar D. Van Cauteren D. Lanternier F. Dannaoui E. Che D. Dromer F. Increasing incidence of zygomycosis (mucormycosis), France, 1997-2006 Emerg Infect Dis 15 2009 1395 1401 19788806 \n6 Bassetti Matteo Giacobbe Daniele R. Vena Antonio Trucchi Cecilia Ansaldi Filippo Antonelli Massimo Incidence and outcome of invasive candidiasis in intensive care units (ICUs) in Europe: results of the EUCANDICU project Crit Care 23 2019 219 225 31200780 \n7 Soysa N.S. Samaranayake L.P. Ellepola A.N. Diabetes mellitus as a contributory factor in oral candidosis Diabet Med 23 2006 455 459 16681553 \n8 Sano T. Ozaki K. Terayama Y. Kodama Y. Matsuura T. A novel diabetic murine model of Candida albicans-induced mucosal inflammation and proliferation J Diabetes Res 2014 509325 \n9 Taieb F. Méchaï F. Lefort A. Lanternier F. Bougnoux M.E. Lortholary O. Management of candidemia and invasive candidiasi Rev Med Interne 32 2011 173 180 20951474 \n10 Conti H.R. Shen F. Nayyar N. Stocum E. Sun J.N. Lindemann M.J. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis J Exp Med 206 2009 299 311 19204111 \n11 Mansueto P. Pisciotta G. Tomasello G. Cabibi D. Seidita A. D’Alcamo A. Malignant tumor-like gastric lesion due to Candida albicans in a diabetic patient treated with cyclosporin: a case report and review of the literature Clin Exp Med 12 2012 201 205 21904834 \n12 Leenders N.H. Oosterheert J.J. Ekkelenkamp M.B. De Lange D.W. Hoepelman A.I. Peters E.J. Candidemic complications in patients with intravascular catheters colonized with Candida species: an indication for preemptive antifungal therapy? Int J Infect Dis 15 2011 e453 8 21530350 \n13 Barchiesi F. Orsetti E. Mazzanti S. Trave F. Salvi A. Nitti C. Candidemia in the elderly: What does it change? PLoS One 12 2017 e0176576 \n14 Marr K.A. Crippa F. Leisenring W. Hoyle M. Boeckh M. Balajee S.A. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants Blood 103 2004 1527 1533 14525770 \n15 Ananda-Rajah M.R. Grigg A. Downey M.T. Bajel A. Spelman T. Cheng A. Comparative clinical effectiveness of prophylactic voriconazole/posaconazole to fluconazole/itraconazole in patients with acute myeloid leukemia/myelodysplastic syndrome undergoing cytotoxic chemotherapy over a 12-year period Haematologica 97 2012 459 463 22058198 \n16 Nucci M. Anaissie E. Revisiting the source of candidemia: skin or gut? Clin Infect Dis 33 2001 1959 1967 11702290 \n17 Martino P. Girmenia C. Micozzi A. De Bernardis F. Boccanera M. Cassone A. Prospective study of Candida colonization, use of empiric amphotericin B and development of invasive mycosis in neutropenic patients Eur J Clin Microbiol Infect Dis 13 1994 797 804 7889948 \n18 Zollner-Schwetz I. Auner H.W. Paulitsch A. Buzina W. Staber P.B. Ofner-Kopeinig P. Oral and intestinal Candida colonization in patients undergoing hematopoietic stem-cell transplantation J Infect Dis 198 2008 150 153 18491972 \n19 Marr K.A. Seidel K. White T.C. Bowden R.A. Candidemia in allogeneic blood and marrow transplant recipients: evolution of risk factors after the adoption of prophylactic fluconazole J Infect Dis 181 2000 309 316 10608780 \n20 Nishimura J. Kanakura Y. Ware R.E. Shichishima T. Nakakuma H. Ninomiya H. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan Medicine (Baltimore) 83 2004 193 207 15118546\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "18()",
"journal": "IDCases",
"keywords": "Gastric perforation; Immunocompromised patient; Invasive candidiasis",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e00627",
"pmc": null,
"pmid": "31516828",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "1542320;19204111;14525770;20951474;16681553;26810419;21904834;24693542;19788806;15118546;22058198;18491972;10608780;7889948;21530350;28493896;23065419;31200780;15842333;11702290",
"title": "Invasive candidiasis leading to gastric perforation in an immunocompromised patient.",
"title_normalized": "invasive candidiasis leading to gastric perforation in an immunocompromised patient"
} | [
{
"companynumb": "JP-FRESENIUS KABI-FK201910933",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Cryptococcus neoformans CNS infection frequently affects HIV-infected patients and is often lethal, despite antifungal therapy. The most recent treatment guidelines for Cryptococcal meningitis recommend therapy with lyposomal amphotericin B and possible association with flucitosine. However, clinical response rates in HIV-infected patients are not satisfactory, with a persistent high mortality rate and long term therapy is affected by a high risk of major side effects. Posaconazole, the latest broad-spectrum azole, with both in vitro- and in vivo-documented potent activity against C. neoformans, clearly showed no antagonism with amphotericin B, echinocandins or flucytosine and it has both in vitro and in vivo agonistic activity with flucytosine against C. neoformans. We report two cases of successful salvage therapy based on the addition of posaconazole to a standard treatment based on liposomal amphotericin B and Flucytosine. In addition we used posaconazole also in a maintenance therapeutic regimen with no evidence of recurrences in the follow up of these patients. Our report confirms that posaconazole has clinical activity in the CNS against C. neoformans infection. In addition posaconazole showed no antagonism with any other currently available antifungal agent, and was in fact synergistic to some of them (flucytosine); consequently, it seems to be an ideal candidate for antimicrobial combination salvage therapies. Finally posaconazole represents a good alternative to parenteral therapy and an ideal candidate for long-term maintenance therapy due to its competent toxicity profile and oral bioavailability.",
"affiliations": "III U.O. di Malattie Infettive A.O. Cotugno, Via T. Tasso, Napoli, Italy. esposvin@libero.it",
"authors": "Esposito|V|V|;Viglietti|R|R|;Gargiulo|M|M|;Parrella|R|R|;Onofrio|M|M|;Sangiovanni|V|V|;Ambrosino|D|D|;Chirianni|A|A|",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; C068538:liposomal amphotericin B; C101425:posaconazole; D000666:Amphotericin B; D005437:Flucytosine",
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0258-851X",
"issue": "23(3)",
"journal": "In vivo (Athens, Greece)",
"keywords": null,
"medline_ta": "In Vivo",
"mesh_terms": "D000328:Adult; D000666:Amphotericin B; D000935:Antifungal Agents; D004359:Drug Therapy, Combination; D005437:Flucytosine; D006801:Humans; D008297:Male; D016919:Meningitis, Cryptococcal; D008875:Middle Aged; D014230:Triazoles",
"nlm_unique_id": "8806809",
"other_id": null,
"pages": "465-8",
"pmc": null,
"pmid": "19454515",
"pubdate": "2009",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of Cryptococcal meningitis with a combination of liposomal amphotericin B, flucytosine and posaconazole: two case reports.",
"title_normalized": "successful treatment of cryptococcal meningitis with a combination of liposomal amphotericin b flucytosine and posaconazole two case reports"
} | [
{
"companynumb": "IT-MYLANLABS-2021M1023960",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "POTASSIUM"
},
"drugadditional": "2",
... |
{
"abstract": "Three patients using a postoperative combination of topical ketorolac (Acular) and neomycin/polymyxin B sulfate/dexamethasone (Maxitrol) were diagnosed with atypical keratopathy soon after routine cataract surgery. An immediate retrospective analysis of hospital patients who had used this topical drug combination in the previous year identified 10 other patients who also had significant corneal pathology after uneventful cataract surgery. Five of the 13 affected patients had corneal melting and 1 patient had corneal perforation and endophthalmitis. At the last recorded follow-up appointment, 8 of the 13 patients had a visual acuity of 6/36 or worse. Corneal melting is a rare complication of topical nonsteroidal anti-inflammatory drugs (NSAIDs). We propose that the combined use of topical NSAIDs and other agents, such as neomycin and benzalkonium, that further compromise the corneal epithelium, should be used with vigilance and increased awareness of potential keratopathy and permanent visual morbidity.",
"affiliations": "From the Moorfields Eye Hospital, London, United Kingdom.",
"authors": "Cabourne|Emily|E|;Lau|Nicola|N|;Flanagan|Declan|D|;Nott|Julie|J|;Bloom|Jill|J|;Angunawela|Romesh|R|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D004338:Drug Combinations; D009883:Ophthalmic Solutions; D055553:Prescription Drugs; C049064:Maxitrol; D005477:Fluprednisolone; D009355:Neomycin; D011112:Polymyxin B; D020910:Ketorolac",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jcrs.2019.08.033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0886-3350",
"issue": "46(1)",
"journal": "Journal of cataract and refractive surgery",
"keywords": null,
"medline_ta": "J Cataract Refract Surg",
"mesh_terms": "D060433:Administration, Ophthalmic; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002387:Cataract Extraction; D003316:Corneal Diseases; D004338:Drug Combinations; D005260:Female; D005477:Fluprednisolone; D006801:Humans; D020910:Ketorolac; D008297:Male; D009355:Neomycin; D009883:Ophthalmic Solutions; D011112:Polymyxin B; D055553:Prescription Drugs; D012189:Retrospective Studies; D014792:Visual Acuity",
"nlm_unique_id": "8604171",
"other_id": null,
"pages": "138-142",
"pmc": null,
"pmid": "32050243",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe corneal melting after cataract surgery in patients prescribed topical postoperative NSAIDs and dexamethasone/neomycin combination therapy.",
"title_normalized": "severe corneal melting after cataract surgery in patients prescribed topical postoperative nsaids and dexamethasone neomycin combination therapy"
} | [
{
"companynumb": "GB-ALLERGAN-2008948US",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE\\NEOMYCIN SULFATE\\POLYMYXIN B SULFATE"
},
... |
{
"abstract": "Invasive pulmonary aspergillosis (IPA) is difficult to diagnose because it requires histopathology and tissue culture, as well as due to its rapid progression. Invasive pulmonary aspergillosis is the primary cause of pulmonary mycosis in China, which can occur in patients with neutrophil deficiency, leukaemia or lymphoma, malignant tumours, or chronic obstructive pulmonary disease with long-term corticosteroid use or bacterial exacerbations. Such fungal infections can lead to disseminated disease and death within weeks, and the mortality rate for untreated invasive aspergillosis is high. Therefore, increased awareness of invasive aspergillosis in non-traditional hosts is warranted due to the high mortality rate experienced by patients with this disease. Invasive pulmonary aspergillosis has become a principal cause of life-threatening infections in immunocompromised patients. Invasive aspergillosis frequently involves the lung parenchyma and is infrequently accompanied by soft tissue lesions. We present an unusual case of a patient with agranulocytosis that was caused by methimazole that was given to control his hyperthyroidism, and IPA that was accompanied by unusual maxillofacial soft tissue swelling that required treatment with voriconazole. Upon follow-up 11 months later, a chest computed tomography scan (CT) revealed that most lesions had been completely absorbed. Moreover, his maxillofacial ulcers had become encrusted, and the soft tissue swelling had subsided.",
"affiliations": "Department of Pulmonology Medicine, Anhui Geriatric Institute, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, PR China.;Department of Pulmonology Medicine, Anhui Geriatric Institute, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, PR China.;Department of Pulmonology Medicine, Anhui Geriatric Institute, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, PR China.;Department of Pulmonology Medicine, Anhui Geriatric Institute, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, PR China.;Department of Pulmonology Medicine, Anhui Geriatric Institute, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, PR China.",
"authors": "Fan|Xiao-Yun|XY|;Wang|Wei-Min|WM|;Yan|Xue-Bo|XB|;Wang|Cong-Hui|CH|;Liu|Rong-Yu|RY|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5114/ceji.2015.50844",
"fulltext": "\n==== Front\nCent Eur J ImmunolCent Eur J ImmunolCEJICentral-European Journal of Immunology1426-39121644-4124Polish Society of Experimental and Clinical Immunology 5084410.5114/ceji.2015.50844Case ReportInvasive pulmonary aspergillosis accompanied by soft tissue lesions during treatment of a patient with hyperthyroidism: a case report Fan Xiao-Yun Wang Wei-Min Yan Xue-Bo Wang Cong-Hui Liu Rong-Yu Department of Pulmonology Medicine, Anhui Geriatric Institute, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, PR ChinaCorrespondence: Prof. Rong-Yu Liu, MD, PhD, Department of Pulmonology Medicine, Anhui Geriatric Institute, the First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022, Anhui, PR China. tel. +86-551-62922807. e-mail: rongyuliu@gmail.com22 4 2015 2015 40 1 117 121 02 9 2014 12 12 2014 Copyright © Central European Journal of Immunology 20152015This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License, permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Invasive pulmonary aspergillosis (IPA) is difficult to diagnose because it requires histopathology and tissue culture, as well as due to its rapid progression. Invasive pulmonary aspergillosis is the primary cause of pulmonary mycosis in China, which can occur in patients with neutrophil deficiency, leukaemia or lymphoma, malignant tumours, or chronic obstructive pulmonary disease with long-term corticosteroid use or bacterial exacerbations. Such fungal infections can lead to disseminated disease and death within weeks, and the mortality rate for untreated invasive aspergillosis is high. Therefore, increased awareness of invasive aspergillosis in non-traditional hosts is warranted due to the high mortality rate experienced by patients with this disease. Invasive pulmonary aspergillosis has become a principal cause of life-threatening infections in immunocompromised patients. Invasive aspergillosis frequently involves the lung parenchyma and is infrequently accompanied by soft tissue lesions. We present an unusual case of a patient with agranulocytosis that was caused by methimazole that was given to control his hyperthyroidism, and IPA that was accompanied by unusual maxillofacial soft tissue swelling that required treatment with voriconazole. Upon follow-up 11 months later, a chest computed tomography scan (CT) revealed that most lesions had been completely absorbed. Moreover, his maxillofacial ulcers had become encrusted, and the soft tissue swelling had subsided.\n\ninvasive pulmonary aspergillosisAspergillusvoriconazolehyperthyroidismagranulocytosismethimazole\n==== Body\nInvasive fungal infections are serious, often lethal diseases in severely immunocompromised patients [1, 2]. An autopsy study concerning fungal infection has demonstrated that Candida most commonly affects the gastrointestinal tract, while Aspergillus is more likely to affect the lung [3]. Invasive pulmonary aspergillosis (IPA) is the primary cause of pulmonary mycosis in China [4]. Invasive pulmonary aspergillosis can occur in patients with neutrophil deficiency, leukaemia or lymphoma, malignant tumours, or chronic obstructive pulmonary disease (COPD) with long-term corticosteroid use or bacterial exacerbations [2, 5, 6]. Such fungal infections can lead to disseminated disease and death within weeks, and the mortality rate for untreated invasive aspergillosis is high [7, 8]. Therefore, increased awareness of invasive aspergillosis in non-traditional hosts is warranted due to the high mortality rate experienced by patients with this disease. Herein, we present a case of agranulocytosis that had invasive pulmonary aspergillosis accompanied by unusual maxillofacial soft tissue swelling.\n\nCase report\nA 43-year-old, previously healthy male was referred with complaints of recurrent fever for over 20 days and a cough with expectoration of white purulent sputum for two days before admission. He had no known history of pulmonary diseases such as COPD, asthma, underlying diseases such as diabetes, hypertension, any other diseases or risk factors of immunological deficits such as chronic diseases or recurrent infections. He had no addictions such as taking drugs, smoking, or alcoholism. Fifty days prior to referral, the patient was diagnosed with hyperthyroidism and prescribed 30 mg/day of methimazole by an endocrinologist. The initial laboratory evaluation before treatment with methimazole revealed white blood cells were 7.03 × 109/l (neutrophils 56.2%, lymphocytes 37.9%, and eosinophils 2.3%), haemoglobin 127 g/l, and platelets 206 × 109/l. However, he did not review the blood test after taking methimazole until he exhibited a fever with a maximum temperature of 40°C accompanied by chills after taking methimazole for twelve days, and finished more than seven days of ineffective antibiotic treatment. With a white blood cell count of 0.7 × 109/l and absolute number of neutrophilic granulocytes 0.01 × 109/l, he was on admission in the Department of Haematology, and then he ended up taking methimazole. He was then administered granulocyte colony-stimulating factor (subcutaneous injection of 450 µg/day for 4 days), imipenem and cilastatin sodium, vancomycin, and caspofungin acetate for anti-infective therapy.\n\nHowever, the patient's fever remained at 38°C and was accompanied by paroxysmal irritating cough and expectoration with white purulent sputum, and oral ulcers scattered, the skin of his left external nose and eyelid swelling, and the left nasal had acute congestion with white and yellow purulent secretions. A computed tomography (CT) of the chest revealing an air crescent sign (Fig. 1 A) is highly suggestive of infection by an angioinvasive fungus, most commonly Aspergillus. The patient was transferred from the Department of Haematology to Respiratory Medicine. The patient was conscious with no enlargement of superficial lymph nodes, maxillary sinus tenderness, or maxillofacial soft tissue swelling due to inflammation (Fig. 2). On the sixth day of hospitalisation, a laboratory test showed white blood cell count of 6.27 × 109/l. Aspergillus fumigatus was detected in both fungal and bacterial culture of the patient's sputum. The fungal isolate demonstrated typical characteristics of A. fumigatus, including colony formation, abundant sporulation, and profuse growth. The conidia were nearly spherical and appeared similar to a chrysanthemum (Fig. 3). In addition, the concentration of the PLATELIA™ ASPERGILLUS Ag (BIORAD, California, USA) was 0.5 pg/ml, and the fungi (1, 3)-β-D-glucan detection system (Chinese Horseshoe Crab Reagent Manufactory Co., Ltd., Xiamen, China) detected 78.80 pg/ml of analyte. We diagnosed the patient with invasive A. fumigatus infection induced by agranulocytosis. He was administered voriconazole (0.4 g/day) intravenously in addition to symptomatic treatment. The patient's cough and expectoration were improving, and his temperature dropped to 37.4-38.8oC. Upon admission, review of the patient's blood showed that the white blood cell count was 4.44 × 109/l (56.24% neutrophils, 30% lymphocytes, and 13.37% monocytes). On the 25th day of hospitalisation, a repeat CT scan revealed that the oval nodules were smaller and the cavity had essentially disappeared (Fig. 1 B); moreover, his maxillofacial ulcers had become encrusted and the soft tissue swelling had subsided. On the 35th day of hospitalisation, the patient refused further hospitalisation and continued taking voriconazole orally (0.4 g/day) at home for two months. Two months later, a follow-up CT scan showed that the oval nodules were much smaller than in previous images (Fig. 1 C). At the time of writing, the patient's temperature was almost normal, and a CT scan showed that the oval nodules had almost completely disappeared (Fig. 1 D). The patient's nose remained deformed with no secretions, however.\n\nFig. 1 \nA) In the initial chest CT, a ‘halo sign’ and ‘air crescent sign’ are visible. B) CT during hospitalization. C) CT after 2 months of treatment. D) CT after 11 months of treatment\n\nFig. 2 \nA) Inflammation of the bilateral ethmoid sinus and B) maxillary sinus. C) Thickening of soft tissue on the left side of the ala nasi in the paranasal sinus CT. D) Maxillofacial soft tissue swelling\n\nFig. 3 Microscopic examination of Aspergillus fumigatus (A, 10× magnification), and microscopic examination revealing conidial heads (B, 40× magnification)\n\nDiscussion\nIn the present case study, invasive pulmonary aspergillosis occurred in an agranulocytosis patient as a result of methimazole administration. Granulocytopaenia and agranulocytosis are common side effects of methimazole treatment. The incidence of granulocytopaenia is 3-12%, while that of agranulocytosis is 0.1-0.6% [9], which is the one of the primary causes of death due to hyperthyroidism. Although hyperthyroidism is a cause of neutropaenia, agranulocytosis induced by hyperthyroidism is not common. Moreover, the patient's leukocytes were within normal limits before taking methimazole. After he started taking methimazole and accepted the treatment, his white blood cell count returned to normal. There was no leukopaenia during followed-up of at least two years. Consequently, we considered that his agranulocytosis was caused by the treatment with methimazole.\n\n\nAspergillus is an opportunistic pathogen, and immunocompromised patients who have experienced the administration of immunosuppressive therapy or glucocorticoids for more than three weeks, have had allogeneic hematopoietic stem cell or solid organ transplantation, or have a congenital immune deficiency are at risk of infection with invasive aspergillosis [10]. Recent evidence indicates that IPA can occur in patients without these factors; other relevant conditions include COPD, alcoholism, and severe sepsis [11–13].\n\nInvasive pulmonary aspergillosis infections occur almost exclusively in immunocompromised patients [10]. Aspergillus fumigatus is the most common agent for Aspergillus infection in humans, accounting for 70-80% of these infections [14]. Aspergillus fumigatus spores are widely distributed in the environment. Most IPA is caused by inhaled Aspergillus spores, and the lower respiratory tract is the primary site of infection. Invasive pulmonary aspergillosis is seldom found on the skin, paranasal sinuses, gastrointestinal tract or other parts of the human body. This case also affected the paranasal sinus skin and lung tissue, which was likely caused when the skin infection spread to the lungs with the blood.\n\nThe definition of IPA in immunocompromised patients has recently been revised [10]. However, accurate diagnosis of IPA is difficult because the typical signs and symptoms are nonspecific. Culture and microscopic analysis of respiratory tract samples, such as sputum and bronchoalveolar lavage fluid (BALF), exhibit a sensitivity and specificity of approximately 50% [15]. A definitive diagnosis is obtained from tissue biopsies that demonstrate Aspergillus upon microscopic examination or in culture, and the endoscopic appearance of Aspergillus observed in this study is identical to observations from previous reports [16].\n\nFever, dyspnoea exacerbation, cough, chest pain, and haemoptysis are the most common complaints of patients presenting with IPA. In this case, the patient had a fever lasting for more than 20 days, accompanied by paroxysmal irritating cough and expectoration with white purulent sputum for two days, with a weight loss of 13 kg, no chest pain, no haemoptysis, and no dyspnoea for the duration of disease. Computed tomography scanning and (1, 3)-β-D-glucan have predictive value for early diagnosis [17], and the presence of (1, 3)-β-D-glucan in the BALF is particularly useful [18]. In this case study, our patient's fungal infection was diagnosed through a combination of granulocytopaenia, serological tests (galactomannan antigen assay, 78.80 pg/ml) and radiography tests, with a ‘halo sign’ and ‘air crescent sign’ in a CT being highly suggestive of IPA. Finally, microbiological histological data (A. fumigatus was detected in both fungal and bacterial cultures of sputum) confirmed the diagnosis of invasive aspergillosis infection. Vascular invasion by this fungus resulted in a thrombosis of small-to-medium-sized vessels that caused ischaemic necrosis.\n\nAs the clinical signs and symptoms of IPA patients are not typical, the diagnosis depends on tissue culture and histopathological examination; however, those patients who nurtured the same fungus by lower respiratory tract secretions repeatedly, with high risk factors for fungal infections as well as the typical imaging features, could have a clinical diagnosis made. Thereby, the patients with high risk factors of fungal infections should accept antifungal therapy as soon as possible if the anti-bacterial infection therapy is ineffective. Antifungal pharmacotherapy with voriconazole or amphotericin B can improve the chance of survival for patients with IPA [19]. Amphotericin B damages the kidney, however, so it is of limited use in the clinic. The antifungal medication triazole voriconazole is recommended as first-line treatment of IPA.\n==== Refs\nReferences\n1 Varkey JB Perfect JR Rare and emerging fungal pulmonary infections Semin Respir Crit Care Med 2008 29 121 131 18365994 \n2 Perkhofer S Lass-Flörl C Anidulafungin and voriconazole in invasive fungal disease: pharmacological data and their use in combination Expert Opin Investig Drugs 2009 18 1393 1404 \n3 Lehrnbecher T Frank C Engels K Trends in the postmortem epidemiology of invasive fungal infections at a university hospital J Infect 2010 61 259 265 20624423 \n4 Liu YN She DY Sun TY A multicentre retrospective study of pulmonary mycosis clinically proven from 1998 to 2007 Zhonghua Jie He He Hu Xi Za Zhi 2011 34 86 90 21426723 \n5 Chakrabarti A Chatterjee SS Das A Invasive aspergillosis in developing countries Med Mycol 2011 49 S35 47 20718613 \n6 Niu YM Tong ZH Invasive pulmonary aspergillosis in chronic obstructive pulmonary disease Rev Med Chil 2010 138 612 620 20668818 \n7 Bassetti M Righi E De Pascale G How to manage aspergillosis in non-neutropenic intensive care unit patients Crit Care 2014 18 458 25167934 \n8 Beck J Broniszewska M Schwienbacher M Characterization of the Aspergillus fumigatus chitosanase CsnB and evaluation of its potential use in serological diagnostics Int J Med Microbiol 2014 304 696 702 24880790 \n9 Ibáńez L Vidal X Ballarín E Population-based drug-induced agranulocytosis Arch Intern Med 2005 165 869 874 15851637 \n10 De Pauw B Walsh TJ Donnelly JP Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group Clin Infect Dis 2008 46 1813 1821 18462102 \n11 Meersseman W Lagrou K Maertens J Invasive aspergillosis in the intensive care unit Clin Infect Dis 2007 45 205 216 17578780 \n12 Trof RJ Beishuizen A Debets-Ossenkopp YJ Management of invasive pulmonary aspergillosis in non-neutropenic critically ill patients Intensive Care Med 2007 33 1694 1703 17646966 \n13 Stevens DA Melikian GL Aspergillosis in the ‘nonimmunocompromised’ host Immunol Invest 2011 40 751 766 21985304 \n14 Barchiesi F Mazzocato S Mazzanti S Invasive aspergillosis in liver transplant recipients: Epidemiology, clinical characteristics, treatment and outcome in 116 cases Liver Transpl 2014 21 204 212 25348192 \n15 Ader F Bienvenu AL Rammaert B Nseir S Management of invasive aspergillosis in patients with COPD: Rational use of voriconazole Int J Chron Obstruct Pulmon Dis 2009 4 279 287 19684861 \n16 Alhambra A Catalán M Moragues MD Isolation of Aspergillus lentulus in Spain from a critically ill patient with chronic obstructive pulmonary disease Rev Iberoam Micol 2008 25 246 249 19071895 \n17 Pfeiffer CD Fine JP Safdar N Diagnosis of invasive aspergillosis using a galactomannan assay: A meta-analysis Clin Infect Dis 2006 42 1417 1427 16619154 \n18 Meersseman W Lagrou K Maertens J Galactomannan in bronchoalveolar lavage fluid: a tool for diagnosing aspergillosis in intensive care unit patients Am J Respir Crit Care Med 2008 177 27 34 17885264 \n19 Takemoto K Yamamoto Y Ueda Y Comparative study on the efficacy of liposomal amphotericin B and voriconazole in a murine pulmonary aspergillosis model Chemotherapy 2009 55 105 113 19151551\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1426-3912",
"issue": "40(1)",
"journal": "Central-European journal of immunology",
"keywords": "Aspergillus; agranulocytosis; hyperthyroidism; invasive pulmonary aspergillosis; methimazole; voriconazole",
"medline_ta": "Cent Eur J Immunol",
"mesh_terms": null,
"nlm_unique_id": "9702239",
"other_id": null,
"pages": "117-21",
"pmc": null,
"pmid": "26155194",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "18462102;20624423;20718613;19071895;19656074;21985304;19684861;21426723;17646966;25348192;24880790;16619154;17885264;20668818;19151551;18365994;17578780;25167934;15851637",
"title": "Invasive pulmonary aspergillosis accompanied by soft tissue lesions during treatment of a patient with hyperthyroidism: a case report.",
"title_normalized": "invasive pulmonary aspergillosis accompanied by soft tissue lesions during treatment of a patient with hyperthyroidism a case report"
} | [
{
"companynumb": "CN-MYLANLABS-2015M1018494",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHIMAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND Sigmoid volvulus (SV) is a life-threatening condition occasionally seen in adults. Adult Hirschsprung's disease (HD)-related SV is rarely complicated by difficult-to-control hypertension. In this report we present the case of an elderly man with a rare constellation of HD, SV, and refractory hypertension. CASE REPORT An 82-year-old man had long-term constipation, moderate abdominal pain, and progressive abdominal distension. A CT scan revealed the typical \"coffee bean sign\". Blood pressure was abnormal high. Subsequently, the patient's condition deteriorated. Therefore, he underwent a Hartmann's procedure. A giant and redundant sigmoid colon (length more than 60 cm, maximal diameter about 15 cm) was demonstrated to be the cause of SV during the process of surgery. Moreover, abdominal compartment syndrome caused by SV resulted in his high and refractory blood pressure (BP). Postoperative pathological results revealed HD in his sigmoid colon. CONCLUSIONS SV is rarely combined with conditions like refractory hypertension or HD among the elderly. Clinical features of SV typically present with long-term constipation, severe abdominal pain, and progressive abdominal distension. The \"coffee bean sign\" could be observed in imaging examinations. It is important to note that the management of SV is to relieve the obstruction and prevent recurrence, no matter which therapy is used in elderly patients with Hirschsprung's disease.",
"affiliations": "Department of General Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China (mainland).;Department of Dermatology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China (mainland).;Department of Clinical Pathology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China (mainland).;Department of General Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China (mainland).",
"authors": "Wu|Shaohan|S|;Sun|Xiaofang|X|;Yu|Yawei|Y|;Shen|Yiyu|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.908389",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2967460610.12659/AJCR.908389908389ArticlesHirschsprung’s Disease-Related Giant Sigmoid Volvulus Complicated by Refractory Hypertension in an Elderly Man Wu Shaohan BCEG1*Sun Xiaofang BEF2*Yu Yawei BCD3Shen Yiyu AG1\n1 Department of General Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, P.R. China\n2 Department of Dermatology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, P.R. China\n3 Department of Clinical Pathology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, P.R. ChinaAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\n* These authors contributed equally to this work\n\nConflict of interest: None declared\n\nSource of support: This study was sponsored by the Science and Technology Program of Jiaxing (Grant numbers 2017AY33037 and 2015AY23019)\n\nCorresponding Author: Yiyu Shen, e-mail: doctorSYY01@163.com2018 20 4 2018 19 467 471 05 12 2017 19 2 2018 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 82\n\nFinal Diagnosis: Hirschsprung’s disease-related sigmoid volvulus complicated with refractory hypertension\n\nSymptoms: Constipation • moderate abdominal pain and progressive abdominal distension • hypertension\n\nMedication: Antihypertension medication\n\nClinical Procedure: CT scan • Hartmann’s procedure\n\nSpecialty: General Surgery\n\nObjective:\nRare disease\n\nBackground:\nSigmoid volvulus (SV) is a life-threatening condition occasionally seen in adults. Adult Hirschsprung’s disease (HD)-related SV is rarely complicated by difficult-to-control hypertension. In this report we present the case of an elderly man with a rare constellation of HD, SV, and refractory hypertension.\n\nCase Report:\nAn 82-year-old man had long-term constipation, moderate abdominal pain, and progressive abdominal distension. A CT scan revealed the typical “coffee bean sign”. Blood pressure was abnormal high. Subsequently, the patient’s condition deteriorated. Therefore, he underwent a Hartmann’s procedure. A giant and redundant sigmoid colon (length more than 60 cm, maximal diameter about 15 cm) was demonstrated to be the cause of SV during the process of surgery. Moreover, abdominal compartment syndrome caused by SV resulted in his high and refractory blood pressure (BP). Postoperative pathological results revealed HD in his sigmoid colon.\n\nConclusions:\nSV is rarely combined with conditions like refractory hypertension or HD among the elderly. Clinical features of SV typically present with long-term constipation, severe abdominal pain, and progressive abdominal distension. The “coffee bean sign” could be observed in imaging examinations. It is important to note that the management of SV is to relieve the obstruction and prevent recurrence, no matter which therapy is used in elderly patients with Hirschsprung’s disease.\n\nMeSH Keywords:\nAntihypertensive AgentsHirschsprung DiseaseSigmoid Diseases\n==== Body\nBackground\nSigmoid volvulus (SV) is a life-threatening condition that results from the twisting of the sigmoid colon on its mesenteric axis. It is the third leading causes of large bowel obstruction, after cancer and diverticulitis, in adults [1,2]. SV accounts for 4% of total cases of large bowel obstruction in the United States [3], and is much higher in Africa, Asia, and India [1,2]. The main cause of SV is a long and redundant sigmoid colon with an elongated mesentery, which is prone to rotating on itself [4,5]. Hirschsprung’s disease (HD or HSCR) [6,7] is an uncommon cause of those redundant SVs in elderly patients. The incidence of HD in the elderly is less than 1/1 million [8], and very few cases have been reported in the English literature.\n\nSV is an abdominal emergency issue which is seen more commonly in the elderly, but it can occur in young adults, pregnant women, and children [9–11]. Clinical symptoms vary with disease progression. However, it has 3 typical presentations: constipation, severe abdominal pain, and progressive abdominal distension. SV is not difficult to diagnose among these elderly patients according to their symptoms and auxiliary examinations, but it may be difficult to deal with because older adults usually have other difficult complications or diseases. Herein, we described a case of an 82-year-old man with the triad of symptoms. A computed tomography (CT) scan revealed the typical “coffee bean sign”, and the patient had very high blood pressure (BP). This elderly patient was postoperatively diagnosed with HD.\n\nCase Report\nAn 82-year-old man was admitted to our department with a 3-day history of abdominal distention, pain, obstipation, and constipation. He had a 25-year history of hypertension and an old myocardial infarction. He regularly took antihypertension medication and his systolic BP was always reasonably controlled at 130–145 mm Hg. Physical examination of his abdomen disclosed obvious abdominal distention, tympanitic percussion, decreased bowel sounds, and a prominent loop in his abdomen. However, there were no signs suggesting perforation or necrosis of his bowel. His BP was 181/109 mmHg, HR was 86 bpm, BT was 36.5°C, and SpO2 was 83.7%. Blood tests revealed that WBC was 8.0×109/ml and Hs-CRP was 3.96 mg/ml. A CT scan of the abdomen depicted a dilated sigmoid colon with the classic “coffee bean sign” (Figure 1A, 1B) pre-operatively. Thus, these findings helped us to quickly make the diagnosis of SV in this patient.\n\nHe was afebrile and hemodynamically stable, and there was no evidence of peritonitis. In consideration of his medical history, at that moment, his BP was relatively high (181/109 mmHg). Therefore, he was first given flexible nasal intestinal decompression tube implantation to keep gastrointestinal decompression, somatostatin to inhibit the secretion of digestive juices, fasting treatment, and antihypertension medication. Unfortunately, the situation of the patient was not improved significantly. By 24 h later, the abdominal distention, and pain were more severe than before, and he had peritonitis symptoms of tenderness, rigidity, and rebound tenderness. Meanwhile, the BP was up to 210/116 mmHg despite using antihypertension medications. The BT was 38.5°C. In consideration of all the facts mentioned above, this patient was immediately taken to the operating room.\n\nA midline laparotomy was used to explore, exteriorize, and resect the redundant sigmoid colon and mesosigmoid. Surprisingly, during the emergency laparotomy procedure, the high BP quickly declined to 143/79 mmHg. Additionally, we found a markedly dilated sigmoid colon (length more than 60 cm, maximal diameter about 15 cm), and a redundant mesentery of the sigmoid colon (Figure 2A, 2C). The bowel seemed nonviable. His sigmoid colon had obvious ischemia and necrosis 14 cm above the anus. Next, the patient underwent a Hartmann’s procedure (HP). Sigmoidectomy, proximal colostomy, and closure of the distal colon were performed to treat this severe SV (Figure 2B). The resected sigmoid was sent for histopathology analysis.\n\nPostoperatively, the patient recovered well. His BP returned to 136/75mmHg. A CT scan of the abdomen illustrated no evidence of leakage and intestinal obstruction. The histopathology results of the resected sigmoid colon revealed inflammatory reaction with necrosis and hemorrhage (Figure 3A). Especially, immunohistochemical staining, with S-100 (Soluble protein 100) [12] which used to confirm the HD, indicated occasional ganglion cells and neuronal hypogenesis (small ganglia, Figure 3B). Hyperplasia of nerve bundles was huge and wave-shaped in the distal spastic intestine (Figure 3C). The immunohistochemical results revealed HD of his sigmoid colon. The patient was discharged uneventfully on postoperative day 11. This patient was followed-up for more than 6 months and reported a dramatic improvement in his bowel function and quality of life.\n\nDiscussion\nSV typically occurred in the elderly, especially in frail patients or individuals with dementia or a psychiatric illness [13]. By 2020, over 23% of China’s population is expected to be over 65 years [14]; therefore, doctors and nurses in China need to know more about SV. SV can cause adult large bowel obstruction, with a 33%–80% mortality rate in patients with intestinal perforation and necrosis. However, the mortality rate is relatively lower in cases without ischemia (0–7%), so early diagnosis and treatment are essential [2,15,16]. Anatomically, the mobile and redundant sigmoid colon, and bowel adhesions associated to abdominal surgery, have been reported as major factors of SV [17]. Although the complaints vary, abdominal distention, pain, and constipation are more common in SV. However, some patients with SV have difficult-to-control BP. In fact, our patient’s BP was always controlled and relatively stable because he took antihypertension medication and consulted the doctor on a regular basis, in spite of his 25-year history of hypertension. When he was admitted in our department, his BP was already 181/109 mmHg, so a cardiology consultation was immediately done to guide the use of antihypertensive drugs. Unfortunately, there was no drop in his difficult-to-control hypertension despite using nitroglycerin injection, irbesartan, hydrochlorothiazide tablets, and isosorbide dinitrate tablets. In contrast, along with the progression of abdominal intension, his BP was up to 210/116 mmHg. But it gradually went to 143/79 mmHg after his abdomen was opened. Thus, we thought the abdominal compartment syndrome (ACS) caused by SV was mainly induced by intra-abdominal hypertension and the difficult-to-control high BP. Additionally, his anxieties and fears may also have result in high BP. However, the relationship between SV and severe hypertension is unclear and worth further exploration.\n\nWith acute onset of SV, the major symptoms are usually constipation, severe abdominal pain, and progressive abdominal distension, but these situations might be reduced in chronic SV [16]. Diagnosis can be achieved according to clinical features, as well as radiologic and endoscopic findings. Most cases can be diagnosed only with X-ray imaging showing a dilated sigmoid loop known as “coffee bean sign”. Actually, it has much higher sensitivity on CT scan [18,19]. In this report, the patient had the “coffee bean sign” (Figure 1A, 1B), consistent with SV (Figure 2). Notably, hematoxylin and eosin (HE) staining showed edema and inflammatory cell infiltration in the sigmoid (Figure 3A). Immunohistochemical staining of sigmoid specimens showed intestinal neuronal dysplasia and hypertrophied nerve bundles in the myenteric and submucosal of distal narrow zone of colon (Figure 3B, 3C). These observations demonstrated that this patient had Hirschsprung’s disease (HD or HSCR). HD is a congenital disorder caused by sparse ganglion cells or intestinal neuronal dysplasia or nerve fibers dysplasia in both submucosal and myenteric plexuses and the transitional segment of colon during development [6,7]. Those disorders lead to the functional obstruction manifesting as severe chronic constipation and colorectal distension, which can result in SV [20,21]. HD mostly causes SV in infants and children and is rare in elderly patients. A few of these patients live to old age, even if they were diagnosed with a giant colon. HD might be misdiagnosed or missed due to the chronic constipation, which can cause acquired giant colon. Moreover, after surgical operation, the diseased colon may not conduct immunohistochemical staining-related HD in adult patients. In fact, further considering the patient’s medical history in this case, he also had decades of constipation and had received multiple conservative treatments. Surgery is the definitive treatment method for adult HD [22,23].\n\nThere is no unified therapeutic guideline for the treatment of SV. Dealing with the intestinal volvulus relies on relieving the obstruction and preventing recurrence [24]. Generally speaking, SV treatment is classified into nonsurgical and surgical treatment. Non-operative therapy, such as decompression through a nasogastric tube or colonoscopy, can convert an emergency procedure in an elective procedure. In our case, decompression through colonoscopy was not used due to the 3-day pain history, which was considered an absolute contraindication for decompression through colonoscopy. If there was ischemic colon necrosis, decompression through colonoscopy might lead to bowel perforation during the process. Urgent surgery is recommended if there was evidence of bowel ischemia or necrosis. The findings during the operation, as well as the preference of the surgeon, dictate the surgical alternatives. A prospective, randomized study indicated that sigmoid resection, done either as a HP when a necrotic colon is discovered at laparotomy or as one-stage resection with primary anastomosis in the setting of a viable colon, had the lowest rate of recurrence [25]. In the present report, this huge dilated sigmoid colon with a redundant mesentery was nonviable because of chronic SV. His sigmoid colon had obvious ischemia and necrosis 14 cm from the anus. Considering this and the patient’s complex situation, in our case, we chosen the HP through laparotomy. A previous report discussed use of a minimal-access HP to deal SV. A single skin incision of ≤4 cm at the proposed colostomy site was used to remove the redundant mesosigmoid and sigmoid colon. The same incision was used to mature the end colostomy [26]. In this way, the operation was incisionless, and there was no laparoscopy performed. This might be a preferred approach for surgery to decompress SV in elderly patients.\n\nConclusions\nSV is a potentially life-threatening situation predominantly affecting the elderly. Clinical features typically present with the triad of constipation, severe abdominal pain, and progressive abdominal distension. The “coffee bean sign” can be observed in imaging examinations. Although HD is most often diagnosed in the perinatal period and infancy, it can present during childhood, adulthood, and even in old age. SV may lead to difficult-to-control BP, which can increase short-term risk. Then, the management of SV is to relieve the obstruction and prevent recurrence no matter which therapy was used, especially in the elderly.\n\nConflict of interest\n\nNone.\n\nFigure 1. (A, B) Computerized tomography scan demonstrated the giant sigmoid volvulus and coffee bean sign, as well as the distended sigmoid compartments with central double walls.\n\nFigure 2. (A) The patient underwent a Hartmann’s procedure (HP) with midline laparotomy. (B) The proximal colostomy and closure of distal colon was performed to treat this severe SV. (C) A giant and redundant sigmoid colon was found during the process of surgery, length more than 60 cm, maximal diameter about 15 cm.\n\nFigure 3. Immunohistochemical staining of resected sigmoid showed inflammatory reaction and Hirschsprung’s disease. (A) Hematoxylin and eosin (HE) staining. (B) One occasional ganglion cell with S-100 (soluble protein 100) staining. (C) Hypertrophied and wave-shaped nerve bundles with S-100.\n==== Refs\nReferences:\n1. Raveenthiran V Madiba TE Atamanalp SS De U Volvulus of the sigmoid colon Colorectal Dis 2010 12 e1 17 20236153 \n2. Osiro SB Cunningham D Shoja MM The twisted colon: A review of sigmoid volvulus Am Surg 2012 78 271 79 22524761 \n3. Halabi WJ Jafari MD Kang CY Colonic volvulus in the United States: Trends, outcomes, and predictors of mortality Ann Surg 2014 259 293 301 23511842 \n4. Akinkuotu A Samuel JC Msiska N The role of the anatomy of the sigmoid colon in developing sigmoid volvulus: A case-control study Clin Anat 2011 24 634 37 21322064 \n5. Lieske B Antunes C Sigmoid Volvulus StatPearls, StatPearls Publishing LLC. Treasure Island FL 2017 \n6. Moore SW Total colonic aganglionosis and Hirschsprung’s disease: A review Pediatr Surg Int 2015 31 1 9 25367097 \n7. Das K Mohanty S Hirschsprung disease – current diagnosis and management Indian J Pediatr 2017 84 618 23 28600660 \n8. Ranjan A Jain V Sharma S Gupta DK Sigmoid volvulus: An uncommon complication of Hirschsprung’s disease BMJ Case Rep 2016 2016 pii: bcr2016214693 \n9. Al Maksoud AM Barsoum AK Moneer MM Sigmoid volvulus during pregnancy: A rare non-obstetric complication. Report of a case and review of the literature Int J Surg Case Rep 2015 17 61 64 26551555 \n10. Parolini F Orizio P Bulotta AL Endoscopic management of sigmoid volvulus in children World J Gastrointest Endosc 2016 8 439 43 27358669 \n11. Tannouri S Hendi A Gilje E Pediatric colonic volvulus: A single-institution experience and review J Pediatr Surg 2017 52 6 1062 66 28202185 \n12. Matsuda H Hirato J Kuroiwa M Nakazato Y Histopathological and immunohistochemical study of the enteric innervations among various types of aganglionoses including isolated and syndromic Hirschsprung disease Neuropathology 2006 26 8 23 16521475 \n13. Ueda M Onishi T Hata T Usability of elective laparoscopic sigmoidectomy and feasibility of single-incision laparoscopic surgery for sigmoid volvulus: Report of three cases Int Surg 2015 100 408 13 25785318 \n14. Jiang Y Huang S Fu X Epidemiology of chronic cutaneous wounds in China Wound Repair Regen 2011 19 181 88 21362085 \n15. Katsikogiannis N Machairiotis N Zarogoulidis P Management of sigmoid volvulus avoiding sigmoid resection Case Rep Gastroenterol 2012 6 293 99 22754489 \n16. Atamanalp SS Ozturk G Sigmoid volvulus in the elderly: Outcomes of a 43-year, 453-patient experience Surg Today 2011 41 514 19 21431484 \n17. Alatise OI Ojo O Nwoha P The role of the anatomy of the sigmoid colon in developing sigmoid volvulus: A cross-sectional study Surg Radiol Anat 2013 35 249 57 23143017 \n18. Ladizinski B Amjad H Rukhman E Sankey C The coffee bean sign and sigmoid volvulus in an elderly adult J Am Geriatr Soc 2013 61 1843 44 24117312 \n19. Yigit M Turkdogan KA Coffee bean sign, whirl sign and bird’s beak sign in the diagnosis of sigmoid volvulus Pan Afr Med J 2014 19 56 25667718 \n20. Jiao CL Chen XY Feng JX Novel insights into the pathogenesis of Hirschsprung’s-associated enterocolitis Chin Med J (Engl) 2016 129 1491 97 27270548 \n21. Zeng M Amodio J Schwarz S Hirschsprung disease presenting as sigmoid volvulus: A case report and review of the literature J Pediatr Surg 2013 48 243 46 23331823 \n22. Dingemann J Puri P Isolated hypoganglionosis: Aystematic review of a rare intestinal innervation defect Pediatr Surg Int 2010 26 1111 15 20721562 \n23. Martinez JP Adult Hirschsprung’s disease CJEM 2015 17 704 5 26014478 \n24. Atamanalp SS Treatment of sigmoid volvulus: A single-center experience of 952 patients over 46.5 years Tech Coloproctol 2013 17 561 69 23636444 \n25. Akcan A Akyildiz H Artis T Feasibility of single-stage resection and primary anastomosis in patients with acute noncomplicated sigmoid volvulus Am J Surg 2007 193 421 26 17368281 \n26. Alhindawi R Kelly N Holubar S Incisionless Hartmann’s procedure: An innovative minimal access technique for surgical treatment of sigmoid volvulus in debilitated patients with faecal incontinence Tech Coloproctol 2008 12 337 39 19018465\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "19()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D004351:Drug Resistance; D006627:Hirschsprung Disease; D006801:Humans; D006973:Hypertension; D045822:Intestinal Volvulus; D008297:Male",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "467-471",
"pmc": null,
"pmid": "29674606",
"pubdate": "2018-04-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28202185;23331823;27270548;25785318;25367097;27229747;21431484;17368281;25667718;21322064;26014478;27358669;28600660;19018465;23511842;24117312;22524761;16521475;23143017;20236153;23636444;26551555;22754489;21362085;20721562",
"title": "Hirschsprung's Disease-Related Giant Sigmoid Volvulus Complicated by Refractory Hypertension in an Elderly Man.",
"title_normalized": "hirschsprung s disease related giant sigmoid volvulus complicated by refractory hypertension in an elderly man"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2018R1-191338",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISOSORBIDE"
},
"drug... |
{
"abstract": "Clozapine-induced cardiomyopathy is a rare but fatal complication with a reported incidence of 0.4% in Japan. Clozapine-induced cardiomyopathy develops at an average of 14.4 months after initiating clozapine, and to our knowledge, has a duration no longer than seven years. We present a patient who developed dilated cardiomyopathy after 17 years of clozapine treatment and made a full recovery of cardiac function at 40 weeks after clozapine treatment cessation. A 43-year-old male with a 24-year history of schizophrenia was treated with clozapine (600 mg/day) for 17 years. No abnormal findings were revealed at follow up until he pre- sented with dyspnea with no accompanying symptoms while walking. He was suspected of worsening asthma due to his past history and lack of abnormalities of ECG and CXR. However, as he experienced gradually worsening dyspnea accompanied by listlessness and lightheaded- ness, he was referred to a cardiologist. The echocardiogram revealed left ventricular dilatation and systolic dysfunction (left ventricular ejection fraction, LVEF=40%), which made a diagno- sis of dilated cardiomyopathy. We excluded cardiac ischemia and other possible causes of dilated cardiomyopathy with cardiac catheterization and endomyocardial biopsy. Clozapine treatment was stopped and switched to olanzapine along with standard heart failure medica- tions. The symptoms and left ventricular function improved following clozapine discontinua- tion. The symptoms resolved and echocardiogram showed a LVEF of 50% within 11 weeks after treatment with clozapine was ended. LVEF was reported at 59% 40weeks after cessation of clozapine. At the present time, 32 months since ceasing clozapine treatment, no worsening of symptoms has been presented. After ceasing clozapine and inducing standard heart failure medications, the patient presented the excellent recovery and the normalization of his echocar- diogram. Despite this outcome, there is currently insufficient evidence to conclusively establish a causal relationship between clozapine and cardiomyopathy in this case. In addition, this case demonstrates that we cannot exclude cardiomyopathy due to lack of abnormal findings of ECG and CXR. Therefore, we recommend that echocardiograms should be performed annually. The mortality associated with clozapine-induced cardiomyopathy is high, so if patients undergoing therapy with clozapine develop new symptoms or signs suggestive of cardiac dysfunction such as dyspnea, a focused cardiovascular examination should be considered.",
"affiliations": null,
"authors": "Okubo|Ryo|R|;Hashimoto|Naoki|N|;Kusachi|Mami|M|;Narita|Hisashi|H|;Kusumi|Ichiro|I|",
"chemical_list": "D003024:Clozapine",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-2658",
"issue": "118(10)",
"journal": "Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica",
"keywords": null,
"medline_ta": "Seishin Shinkeigaku Zasshi",
"mesh_terms": "D000328:Adult; D002311:Cardiomyopathy, Dilated; D003024:Clozapine; D006801:Humans; D008297:Male",
"nlm_unique_id": "9801787",
"other_id": null,
"pages": "735-743",
"pmc": null,
"pmid": "30620827",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Dilated Cardiomyopathy after 17 Years of Clozapine Treatment.",
"title_normalized": "a case of dilated cardiomyopathy after 17 years of clozapine treatment"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-205355",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"druga... |
{
"abstract": "Common variable immunodeficiency is characterized by low levels of serum immunoglobulins and antibodies, recurrent infections, and a predisposition to malignancy. Here, we present the 18F-FDG PET/CT findings of a 7-y-old boy with common variable immunodeficiency and Hodgkin lymphoma.",
"affiliations": "Department of Nuclear Medicine, Ataturk Chest Diseases and Thoracic Surgery Training and Research Hospital, Ankara, Turkey ebrualkandr@yahoo.com.;Department of Nuclear Medicine, Ataturk Chest Diseases and Thoracic Surgery Training and Research Hospital, Ankara, Turkey.;Department of Pediatric Oncology and Haematology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey; and.;Department of Nuclear Medicine, Ataturk Chest Diseases and Thoracic Surgery Training and Research Hospital, Ankara, Turkey.;Department of Radiology, Ataturk Chest Diseases and Thoracic Surgery Training and Research Hospital, Ankara, Turkey.;Department of Pediatric Oncology and Haematology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey; and.;Department of Nuclear Medicine, Ataturk Chest Diseases and Thoracic Surgery Training and Research Hospital, Ankara, Turkey.",
"authors": "Tatci|Ebru|E|;Biner|Inci Uslu|IU|;Tanyildiz|Hikmet Gulsah|HG|;Ozmen|Ozlem|O|;Gokcek|Atila|A|;Sahin|Gurses|G|;Tazeler|Zuhal|Z|",
"chemical_list": "D019788:Fluorodeoxyglucose F18",
"country": "United States",
"delete": false,
"doi": "10.2967/jnmt.116.175745",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-4916",
"issue": "44(4)",
"journal": "Journal of nuclear medicine technology",
"keywords": "PET/CT; immunodeficiency; lymphoma",
"medline_ta": "J Nucl Med Technol",
"mesh_terms": "D002648:Child; D017074:Common Variable Immunodeficiency; D019788:Fluorodeoxyglucose F18; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D000072078:Positron Emission Tomography Computed Tomography",
"nlm_unique_id": "0430303",
"other_id": null,
"pages": "259-260",
"pmc": null,
"pmid": "27363447",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "18F-FDG PET/CT Imaging of Hodgkin Lymphoma in a Child with Common Variable Immunodeficiency.",
"title_normalized": "18f fdg pet ct imaging of hodgkin lymphoma in a child with common variable immunodeficiency"
} | [
{
"companynumb": "TR-JNJFOC-20170121411",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
},
"drugadditional": null,
... |
{
"abstract": "New-onset refractory status epilepticus (NORSE) describes prolonged or recurring new onset seizures which fail to respond to antiseizure medications. NORSE poses a challenge in diagnosis and treatment, and limited high-quality evidence exists to guide management. The efficacy of Electroconvulsive therapy (ECT) in aborting refractory status epilepticus has been described in case reports, but its application remains uncommon, particularly in young children. We describe a case of NORSE in a 3-year old child in which ECT played an important role in aborting status epilepticus, facilitating the diagnosis and surgical excision of an underlying focal cortical dysplasia. Although further research is needed, our case suggests that ECT can be a valuable tool in the treatment of refractory status epilepticus in children.",
"affiliations": "Cohen Children's Medical Center, New York; Zucker School of Medicine at Hofstra/Northwell, USA.;Cohen Children's Medical Center, New York; Zucker School of Medicine at Hofstra/Northwell, USA.;Cohen Children's Medical Center, New York; Zucker School of Medicine at Hofstra/Northwell, USA.;Zucker Hillside Hospital, Northwell Health; Zucker School of Medicine at Hofstra/Northwell, USA.;Cohen Children's Medical Center, New York; Zucker School of Medicine at Hofstra/Northwell, USA.;Zucker Hillside Hospital, Northwell Health; Zucker School of Medicine at Hofstra/Northwell, USA.;Cohen Children's Medical Center, New York; Zucker School of Medicine at Hofstra/Northwell, USA.",
"authors": "Nath|Manan|M|;Shah|Yash D|YD|;Theroux|Liana M|LM|;Petrides|Georgios|G|;Karkare|Shefali|S|;Sanghani|Sohag N|SN|;Kothare|Sanjeev V|SV|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0028-3886.329559",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3886",
"issue": "69(5)",
"journal": "Neurology India",
"keywords": "Electroconvulsive therapy (ECT); pediatric; refractory status epilepticus",
"medline_ta": "Neurol India",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D004565:Electroconvulsive Therapy; D006801:Humans; D012008:Recurrence; D013226:Status Epilepticus",
"nlm_unique_id": "0042005",
"other_id": null,
"pages": "1374-1379",
"pmc": null,
"pmid": "34747817",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Role for Electroconvulsive Therapy in the Management of New Onset Refractory Status Epilepticus (NORSE) in a Young Child.",
"title_normalized": "a role for electroconvulsive therapy in the management of new onset refractory status epilepticus norse in a young child"
} | [
{
"companynumb": "US-drreddys-LIT/USA/22/0146003",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",... |
{
"abstract": "Pancreatitis is inflammation of pancreas associated most commonly with chronic alcoholism and gallstones. Other less common causes of pancreatitis are hyperlipidemia, infections, surgery, trauma, post endoscopic retrograde cholangiopancreatography, and drugs. Drugs are now increasingly recognized as a cause of pancreatitis, and high suspicion and exclusion of other most common causes is required before considering drug-induced pancreatitis. There are few case reports of acute pancreatitis in the literature after statin use, but out of these, only 3 are after starting pravastatin. We are reporting a case of 49-year-old male who presented with nausea, vomiting, and abdominal pain. His laboratory findings were significant for lipase more than 10 000 on admission, and computed tomography scan of abdomen was showing peripancreatic fat stranding and inflammation. After exclusion of most common causes of pancreatitis, pravastatin was found probable culprit for his symptoms, which he started taking 2 weeks ago. We also reviewed the literature on statins-induced acute pancreatitis. With increased uses of statins, physician need to be vigilant to suspect statins as a culprit in cases of pancreatitis with unknown etiology. Prompt discontinuation of statins is required in these cases.",
"affiliations": "University of Missouri, Columbia, MO, USA.;Lehigh Valley Health Network, Allentown, PA, USA.;University of Missouri, Columbia, MO, USA.;Loyola Medicine, MacNeal Hospital, Berwyn, IL, USA.;Premier Health Miami Valley Hospital, Dayton, OH, USA.",
"authors": "Tarar|Zahid Ijaz|ZI|;Zafar|Muhammad Usman|MU|;Ghous|Ghulam|G|;Farooq|Umer|U|;Shoukat|Hafiz Muhammad Hassan|HMH|",
"chemical_list": "D017035:Pravastatin",
"country": "United States",
"delete": false,
"doi": "10.1177/23247096211028386",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096\nSAGE Publications Sage CA: Los Angeles, CA\n\n34180257\n10.1177/23247096211028386\n10.1177_23247096211028386\nCase Report\nPravastatin-Induced Acute Pancreatitis: A Case Report and Literature Review\nTarar Zahid Ijaz MD 1\nZafar Muhammad Usman MD 2\nGhous Ghulam MD 1\nFarooq Umer MD 3\nShoukat Hafiz Muhammad Hassan MD 4\n1 University of Missouri, Columbia, MO, USA\n2 Lehigh Valley Health Network, Allentown, PA, USA\n3 Loyola Medicine, MacNeal Hospital, Berwyn, IL, USA\n4 Premier Health Miami Valley Hospital, Dayton, OH, USA\nZahid Ijaz Tarar, MD, Department of Internal Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO 65211, USA. Email: Ztmbc@health.missouri.edu\n28 6 2021\nJan-Dec 2021\n9 2324709621102838615 5 2021\n3 6 2021\n9 6 2021\n© 2021 American Federation for Medical Research\n2021\nAmerican Federation for Medical Research\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nPancreatitis is inflammation of pancreas associated most commonly with chronic alcoholism and gallstones. Other less common causes of pancreatitis are hyperlipidemia, infections, surgery, trauma, post endoscopic retrograde cholangiopancreatography, and drugs. Drugs are now increasingly recognized as a cause of pancreatitis, and high suspicion and exclusion of other most common causes is required before considering drug-induced pancreatitis. There are few case reports of acute pancreatitis in the literature after statin use, but out of these, only 3 are after starting pravastatin. We are reporting a case of 49-year-old male who presented with nausea, vomiting, and abdominal pain. His laboratory findings were significant for lipase more than 10 000 on admission, and computed tomography scan of abdomen was showing peripancreatic fat stranding and inflammation. After exclusion of most common causes of pancreatitis, pravastatin was found probable culprit for his symptoms, which he started taking 2 weeks ago. We also reviewed the literature on statins-induced acute pancreatitis. With increased uses of statins, physician need to be vigilant to suspect statins as a culprit in cases of pancreatitis with unknown etiology. Prompt discontinuation of statins is required in these cases.\n\ngastroenterology\nacute pancreatitis\ndrug-induced pancreatitis\npravastatin\nstatins side effects\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nAcute pancreatitis is a life-threatening condition. It is one of the leading gastrointestinal causes of hospitalization in the United States. 1 Among the numerous documented etiologies of acute pancreatitis, gallstones and alcoholism are the most common. Among other less common causes, drug-induced causes account for less than 2%.2,3 Drug-induced pancreatitis has been reported since 1950s, and with time, new medications are added in the list. 4 Even with advances in diagnostic medicine, etiologies in 30% cases of pancreatitis remains unknown. 5 Previously, drug-induced pancreatitis was classified as definite, probable, or possible, but now used classification was introduced by Badalov and colleagues in which drugs are divided into 5 classes: 1a, 1b, II, III, and IV. This classification is based on number of case reports, ability to exclude other causes, latency period, and available rechallenge data. Pravastatin is defined as class 1a drug based on the presence of at least 1 case report and positive rechallenge data. 6 Few other drugs frequently used in clinical practice associated with pancreatitis are angiotensin-converting enzyme inhibitors, diuretics, oral contraceptives, highly active antiretroviral therapy, valproic acid, atypical antipsychotics, antibiotics, and antivirals.4,6\n\nThere are a few reported cases of statin-induced pancreatitis, and in our research, we found only 3 cases of pravastatin-induced pancreatitis. We are reporting the fourth case of pravastatin-induced pancreatitis. Drug-induced pancreatitis is a diagnosis of exclusion, and one needs a high index of suspicion to recognize it.\n\nCase Presentation\n\nA 49-year-old male with past medical history of dyslipidemia, hypertension, coronary artery disease status post coronary artery bypass grafting, diabetes mellitus, liver cirrhosis secondary to hepatitis C presented with a 3-day history of epigastric pain radiating to the back, nausea, and vomiting. He reported that the pain was started initially in the right lower quadrant but later migrated to epigastric area, 9/10 in intensity, and sharp in character. He also endorsed associated fever, shortness of breath, decreased appetite, and abdominal distention. On presentation, he was normotensive with blood pressure of 130/80 mm Hg, heart rate 78 beats/minute, temperature 97.8 °F, and respiratory rate of 18 breaths/minute. Physical examination was significant for severe epigastric tenderness. There was no rebound tenderness or rigidity. The patient denied any history of similar complaints in the past. He denied cigarette smoking, and there was no known alcohol or illicit drug abuse. He also denied any recent abdominal trauma. He denied family history of chronic pancreatitis and personal history of cystic fibrosis or any other autoimmune diseases.\n\nInvestigations\n\nAt the time of admission, laboratory findings were significant for a lipase greater than 10 000 units/L. Other significant laboratory values were white blood cell 11.5, alanine aminotransferases 115 units/L, aspartate aminotransferases 102 units/L, creatinine 1.37 mg/dL, and alkaline phosphatase 78. Electrocardiogram and chest X-ray were unremarkable. Based on history, physical examination findings, and elevated lipase, a diagnosis of acute pancreatitis was made. This was confirmed with computed tomography scan of abdomen showing peripancreatic fat stranding consistent with acute pancreatitis, and it was negative for intra- or extrahepatic biliary ductal dilatation (Figures 1 and 2).\n\nFigure 1. Computed tomography (axial view) scan of abdomen showing diffuse peripancreatic inflammatory changes and fat stranding.\n\nFigure 2. Computed tomography (coronal view) scan of abdomen showing diffuse peripancreatic inflammatory changes and fat stranding.\n\nFurther workup was done to find the etiology of his pancreatitis. Ultrasound of abdomen was negative for gallstones. Triglyceride level was 78 mg/dL and calcium were 8.8 mg/dL. A urine drug screen was negative. The patient denied alcohol intake and had no prior history of alcohol abuse. No other causes were identified. A review of his home medication revealed that he was recently started on 80 mg of pravastatin 2 weeks ago. We believe that pravastatin was the probable cause of his acute pancreatitis. The Naranjo Nomogram for adverse drug reaction assessment Naranjo score was 6 (Table 1).\n\nTable 1. Naranjo assessment scale depicting a score of 6 in the present case; a score of <1 is doubtful, 1–4 possible, 5–8 probable, >9 definitive for adverse drug reaction.\n\nQuestions\tYes\tNo\tDo not know\tPatients score\t\n1. Are there previous conclusive reports on this reaction?\t+1\t0\t0\t+1\t\n2. Did the adverse event appear after the suspected drug was administered?\t+2\t−1\t0\t+2\t\n3. Did the adverse reaction improve when the drug was discontinued, or a specific antagonist was administered?\t+1\t0\t0\t+1\t\n4. Did the adverse event reappear when the drug was readministered?\t+2\t−1\t0\t\t\n5. Are there alternative causes (other than the drug) that could on their own have caused the reaction?\t−1\t+2\t0\t+2\t\n6. Did the reaction reappear when a placebo was given?\t−1\t+1\t0\t\t\n7. Was the drug detected in blood (or other fluids) in concentration known to be toxic?\t+1\t0\t0\t\t\n8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?\t+1\t0\t0\t\t\n9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?\t+1\t0\t0\t\t\n10. Was the adverse event confirmed by any objective evidence?\t+1\t0\t0\t\t\nTotal score\t\t\t\t6\t\n\nTreatment and Outcome\n\nThe patient was placed on bowel rest, started on intravenous fluids and pain medications. All his medications were continued except pravastatin. His hospital course was complicated by small bowel obstruction, managed with nasogastric tube insertion connected to suction. After discontinuing pravastatin, his abdominal pain, nausea, and vomiting resolved. Repeat lipase at 48 hours was 378 U/L, and at 96 hours, it had dropped down to 90 U/L. His small bowel obstruction also resolved, and his diet was advanced as tolerated. At discharge, he was hemodynamically stable and asymptomatic. All his medications were continued except pravastatin. After stopping pravastatin, patient recovered well, and at 2-week follow-up in clinic, he was asymptomatic and pain free.\n\nDiscussion\n\nStatins are generally well tolerated, but there are reported cases of acute pancreatitis with different statins that point toward a class effect.7,8 Exact mechanism of statin-induced pancreatitis is not well recognized, but different mechanisms are described, which include immune-mediated inflammatory response, direct cellular toxicity, and metabolic effect. 4\n\nOur patient was not an alcoholic and had no family history of pancreatitis. In addition, other causes of pancreatitis were ruled out, which further strengthen the possibility that pravastatin was the probable etiology of acute pancreatitis. In literature, there are reports of pancreatitis due to atorvastatin,9-14 lovastatin,15-17 rosuvastatin,11,18 fluvastatin,19,20 pravastatin,21-23 and simvastatin.8,24-29 There are, so far, 3 reports of pravastatin-induced pancreatitis, and we are reporting the fourth case.\n\nIn previously reported cases, pancreatitis developed when statins were introduced in presence of another drug that led to pancreatitis.10,13,16,17 This could indicate a possible drug interaction as a mechanism of statin-induced pancreatitis. Our patient was on lisinopril for the past 3 years, which has been reported as a cause of drug-induced pancreatitis, 30 but lisinopril was not stopped and his symptoms were resolved. We, therefore, suggest that our patient developed pancreatitis due to pravastatin.\n\nIn majority of statin-induced pancreatitis, patient outcome was favorable except in 1 case where patient had a fatal outcome. 24 The exact time of developing pancreatitis is not well defined as in 1 case, it developed right after starting statins,9,27 and in other cases, it developed within months to years.13,17,26 In few cases, statins were reintroduced, which lead to recurrence of pancreatitis,15,19,21,25 except in one case where readministration of statin was not associated with recurrence. 17 We did not challenge our patient with statin.\n\nWe reviewed the literature in detail and found 22 case reports of acute pancreatitis secondary to statins between inception and April 10, 2021. The previously reported cases of statin-induced pancreatitis and our case are reported in Table 2.\n\nTable 2. Cases of Statins induced pancreatitis previously reported in the literature.\n\nAuthors\tAge, gender\tDrugs\tOnset of symptoms after statin use\tRechallenge\tOutcome\t\nBelaïche et al 9\t63, male\tAtorvastatin 10 mg daily\t8 hours\tNo\tComplete recovery\t\nKanbay et al 10\t86, male\tAtorvastatin 20 mg daily, lisinopril 10 mg daily\t9 months\tNo\tComplete recovery\t\nSing et al 11\t77, female\tAtorvastatin and rosuvastatin\tNot known\tYes: recurrence with rosuvastatin\tComplete recovery\t\nPrajapati et al 12\t58, male\tAtorvastatin 10 mg\t6 months\tNo\tComplete recovery\t\nMiltiadous et al 13\t60, male\tAtorvastatin 40 mg daily, salicylates 100 mg daily\t5 years\tNo\tComplete recovery\t\nDeshpande et al 14\t53, male\tAtorvastatin 10 mg daily\t1.5 months\tNo\tComplete recovery\t\nPluhar 15\t46, male\tLovastatin 20 mg BID\t1 week\tYes: recurrence\tComplete recovery\t\nAbdul-Ghaffar and el-Sonbaty 16\t55, female\tLovastatin 20 mg BID, gemfibrozil 300 mg BID\t2 months\tNo\tComplete recovery\t\nWong et al 17\t73, male\tLovastatin 20 mg daily, erythromycin\t7 years\tYes: no recurrence\tComplete recovery\t\nChintanaboina and Gopavaram 18\t50, female\tRosuvastatin\tFew days, recurrence after 8 weeks\tYes: recurrence\tComplete recovery\t\nTysk et al 19\t36, male\tFluvastatin 40 mg daily\t3 months\tYes: recurrence\tComplete recovery\t\nHunninghake et al 20\tUnknown\tFluvastatin\tUnknown\tUnknown\tComplete recovery\t\nAnagnostopoulos et al 21\t56, male\tPravastatin 40 mg daily\t6 months\tYes: recurrence\tComplete recovery\t\nBecker et al 22\t60, male\tPravastatin 40 mg daily\tUnknown\tNo\tComplete recovery\t\nTsigrelis and Pitchumoni 23\t50, male\tPravastatin 10 mg daily\t4 days\tNo\tComplete recovery\t\nEtienne and Reda 8\t58, male\tSimvastatin 10 mg daily, venlafaxine\t10 years\tNo\tComplete recovery\t\nMcDonald et al 24\t70, male\tSimvastatin 10 mg daily plus fenofibrate\t6 months\tNo\tFatal\t\nRamdani et al 25\t40, male\tSimvastatin 10 mg daily\t8 months\tYes: recurrence\tComplete recovery\t\nCouderc et al 26\t55, female\tSimvastatin 10 mg daily\t3 months\tNo\tComplete recovery\t\nLons and Chousterman 27\t50, male\tSimvastatin 20 mg daily\t12 hours\tNo\tComplete recovery\t\nAntonopoulos et al 28\t58, male\tSimvastatin and salicylates\t2 months\tNo\tComplete recovery\t\nPezzilli et al 29\t64, male\tSimvastatin 20 mg daily\t6 months\tYes: recurrence\tComplete recovery\t\nCurrent case\t49, male\tPravastatin 80 mg daily\t2 weeks\tNo\tComplete recovery\t\nAbbreviation: BID, twice daily.\n\nBased on these findings, statins should be considered a possible cause of pancreatitis in patients who are on statin and need immediate attention and discontinuation. More prospective studies are needed on a large population to look into this association of statin-induced pancreatitis.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.\n==== Refs\nReferences\n\n1 Peery AF Crockett SD Murphy CC , et al . Burden and cost of gastrointestinal, liver, and pancreatic diseases in the United States: update 2018. Gastroenterology. 2019;156 :254-272.e11.\n2 Tenner S Baillie J DeWitt J Vege SS ; American College of Gastroenterology. American College of Gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol. 2013;108 :1400-1416.23896955\n3 Lankisch PG Dröge M Gottesleben F. Drug induced acute pancreatitis: incidence and severity. Gut. 1995;37 :565-567.7489946\n4 Kaurich T. Drug-induced acute pancreatitis. Proc (Bayl Univ Med Cent). 2008;21 :77-81.18209761\n5 Testoni PA. Acute recurrent pancreatitis: etiopathogenesis, diagnosis and treatment. World J Gastroenterol. 2014;20 : 16891-16901.25493002\n6 Badalov N Baradarian R Iswara K Li J Steinberg W Tenner S. Drug-induced acute pancreatitis: an evidence-based review. Clin Gastroenterol Hepatol. 2007;5 :648-661.17395548\n7 Jones MR Hall OM Kaye AM Kaye AD. Drug-induced acute pancreatitis: a review. Ochsner J. 2015;15 :45-51.25829880\n8 Etienne D Reda Y. Statins and their role in acute pancreatitis: case report and literature review. World J Gastrointest Pharmacol Ther. 2014;5 :191-195.25133048\n9 Belaïche G Ley G Slama JL. Acute pancreatitis associated with atorvastatine therapy [in French]. Gastroenterol Clin Biol. 2000;24 :471-472.10844297\n10 Kanbay M Sekuk H Yilmaz U Gur G Boyacioglu S. Acute pancreatitis associated with combined lisinopril and atorvastatin therapy. Dig Dis. 2005;23 :92-94.15920330\n11 Singh S Nautiyal A Dolan JG. Recurrent acute pancreatitis possibly induced by atorvastatin and rosuvastatin. Is statin induced pancreatitis a class effect? JOP. 2004;5 :502-504.15536291\n12 Prajapati S Shah S Desai C Desai M Dikshit RK. Atorvastatin-induced pancreatitis. Indian J Pharmacol. 2010;42 :324-325.21206629\n13 Miltiadous G Anthopoulou A Elisaf M. Acute pancreatitis possibly associated with combined salicylate and atorvastatin therapy. JOP. 2003;4 :20-21.12555012\n14 Deshpande PR Khera K Thunga G Hande M Gouda STG . Atorvastatin-induced acute pancreatitis. J Pharmacol Pharmacother. 2011;2 :40-42.21701646\n15 Pluhar W. A case of possible lovastatin-induced pancreatitis in concomitant Gilbert syndrome [in German]. Wien Klin Wochenschr. 1989;101 :551-554.2800552\n16 Abdul-Ghaffar NU el-Sonbaty MR. Pancreatitis and rhabdomyolysis associated with lovastatin-gemfibrozil therapy. J Clin Gastroenterol. 1995;21 :340-341.8583121\n17 Wong PW Dillard TA Kroenke K. Multiple organ toxicity from addition of erythromycin to long-term lovastatin therapy. South Med J. 1998;91 :202-205.9496876\n18 Chintanaboina J Gopavaram D. Recurrent acute pancreatitis probably induced by rosuvastatin therapy: a case report. Case Rep Med. 2012;2012 :973279.22536267\n19 Tysk C Al-Eryani AY Shawabkeh AA. Acute pancreatitis induced by fluvastatin therapy. J Clin Gastroenterol. 2002;35 : 406-408.12394230\n20 Hunninghake D Bakker-Arkema RG Wigand JP , et al . Treating to meet NCEP-recommended LDL cholesterol concentrations with atorvastatin, fluvastatin, lovastatin, or simvastatin in patients with risk factors for coronary heart disease. J Fam Pract. 1998;47 :349-356.9834769\n21 Anagnostopoulos GK Tsiakos S Margantinis G Kostopoulos P Arvanitidis D. Acute pancreatitis due to pravastatin therapy. JOP. 2003;4 :129-132.12743419\n22 Becker C Hvalic C Delmore G Krähenbühl S Schlienger R. Recurrent acute pancreatitis during pravastatin-therapy [in German]. Praxis (Bern 1994). 2006;95 :111-116.16485606\n23 Tsigrelis C Pitchumoni CS. Pravastatin: a potential cause for acute pancreatitis. World J Gastroenterol. 2006;12 :7055-7057.17109506\n24 McDonald KB Garber BG Perreault MM. Pancreatitis associated with simvastatin plus fenofibrate. Ann Pharmacother. 2002;36 :275-279.11847949\n25 Ramdani M Schmitt AM Liautard J , et al . Simvastatin-induced acute pancreatitis: two cases [in French]. Gastroenterol Clin Biol. 1991;15 :986.\n26 Couderc M Blanc P Rouillon JM Bauret P Larrey D Michel H. A new case of simvastatin-induced acute pancreatitis [in French]. Gastroenterol Clin Biol. 1991;15 :986-987.\n27 Lons T Chousterman M. Simvastatin: a new drug responsible for acute pancreatitis? [in French]. Gastroenterol Clin Biol. 1991;15 :93-94.2010079\n28 Antonopoulos S Mikros S Kokkoris S , et al . A case of acute pancreatitis possibly associated with combined salicylate and simvastatin treatment. JOP. 2005;6 :264-268.15883478\n29 Pezzilli R Ceciliato R Corinaldesi R Barakat B. Acute pancreatitis due to simvastatin therapy: increased severity after rechallenge. Dig Liver Dis. 2004;36 :639-640.15460851\n30 Brown KV Khan AZ Paterson IM. Lisinopril-induced acute pancreatitis. J R Army Med Corps. 2007;153 :191-192.18200917\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2324-7096",
"issue": "9()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "acute pancreatitis; drug-induced pancreatitis; gastroenterology; pravastatin; statins side effects",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D015746:Abdominal Pain; D000208:Acute Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010195:Pancreatitis; D017035:Pravastatin; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "23247096211028386",
"pmc": null,
"pmid": "34180257",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "15920330;12555012;2800552;17395548;18209761;8583121;12743419;1783260;9496876;22536267;12394230;2010079;25133048;15460851;1783261;18200917;25829880;17109506;21701646;21206629;9834769;11847949;16485606;15536291;23896955;30315778;25493002;10844297;15883478;7489946",
"title": "Pravastatin-Induced Acute Pancreatitis: A Case Report and Literature Review.",
"title_normalized": "pravastatin induced acute pancreatitis a case report and literature review"
} | [
{
"companynumb": "US-APOTEX-2021AP020629",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PRAVASTATIN"
},
"drugadditional": "1",
... |
{
"abstract": "The objective of this study was to investigate the efficacy and tolerability of 5-fluorouracil-oxaliplatin (FOLFOX) in advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs).\n\n\n\nRetrospective analysis of consecutive 72 advanced GEP-NENs treated with FOLFOX between 2005 and 2016 at a single German referral center for NENs was performed. We assessed treatment response by response evaluation criteria in solid tumors 1.0 criteria, progression-free survival by Kaplan-Meyer method, and risk factor analysis by Cox-regression model.\n\n\n\nPatients were 44.5% G1/G2, 55.5% G3, receiving a median of 7 treatment cycles (range, 2-21), and had a median of 18 months of follow-up (range, 3-111 months). Disease control was achieved in 75.0% of cases but 91.3% in the 23 patients receiving FOLFOX as first line (P = 0.04). Median progression-free survival of the overall population was 8 months. A better outcome was significantly related to treatment duration (P = 0.02) and grade of histological differentiation for G3 patients (well differentiated vs poorly differentiated, P = 0.03). Adverse events occurred in 88.8% of patients, mostly grade 1 and 2 hematotoxicity and chemotherapy-induced peripheral sensory neuropathy (84.1% and 50.0% of patients, respectively).\n\n\n\nOur results support FOLFOX as therapeutic option in advanced GEP-NENs with poor prognosis, either at first or further therapy line. Longer duration of therapy was associated with a more durable benefit.",
"affiliations": "Digestive Endoscopy Unit, Division of Gastroenterology, Humanitas Clinical and Research Center, Rozzano Milan, Italy.;Department of Pathology, Charité Mitte.;Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Charité Mitte, Charité Universitätsmedizin, Berlin.;Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Charité Mitte, Charité Universitätsmedizin, Berlin.",
"authors": "Merola|Elettra|E|;Dal Buono|Arianna|A|;Denecke|Timm|T|;Arsenic|Ruza|R|;Pape|Ulrich-Frank|UF|;Jann|Henning|H|;Wiedenmann|Bertram|B|;Pavel|Marianne E|ME|",
"chemical_list": "D000077150:Oxaliplatin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1097/MPA.0000000000001593",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0885-3177",
"issue": "49(7)",
"journal": "Pancreas",
"keywords": null,
"medline_ta": "Pancreas",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D005472:Fluorouracil; D005770:Gastrointestinal Neoplasms; D006801:Humans; D007239:Infections; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases; D018358:Neuroendocrine Tumors; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8608542",
"other_id": null,
"pages": "912-917",
"pmc": null,
"pmid": "32658073",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and Toxicity of 5-Fluorouracil-Oxaliplatin in Gastroenteropancreatic Neuroendocrine Neoplasms.",
"title_normalized": "efficacy and toxicity of 5 fluorouracil oxaliplatin in gastroenteropancreatic neuroendocrine neoplasms"
} | [
{
"companynumb": "NVSC2021IT004320",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUCOVORIN CALCIUM"
},
"drugadditional": "3",
... |
{
"abstract": "To test if acute kidney injury (AKI) is preventable in patients in the neonatal intensive care unit and if infants at high-risk of nephrotoxic medication-induced AKI can be identified using a systematic surveillance program previously used in the pediatric non-intensive care unit setting.\n\n\n\nQuality improvement project that occurred between March 2015 and September 2017 in a single center, level IV neonatal intensive care unit. Infants were screened for high-risk nephrotoxic medication exposure (≥3 nephrotoxic medication within 24 hours or ≥4 calendar days of an intravenous [IV] aminoglycoside). If infants met criteria, a daily serum creatinine (SCr) was obtained until 2 days after end of exposure or end of AKI, whichever occurred last. The study was divided into 3 eras: pre-Nephrotoxic Injury Negated by Just-in-time Action (NINJA), initiation, and sustainability. Differences for 5 metrics across 3 eras were compared: SCr surveillance, high nephrotoxic medication exposure rate (per 1000 patient-days), AKI rate (per 1000 patient-days), nephrotoxin-AKI percentage, and AKI intensity (number of AKI days per 100 susceptible patient-days).\n\n\n\nComparing the initiation with sustainability era, there was a reduction in high nephrotoxic medication exposures from 16.4 to 9.6 per 1000 patient-days (P = .03), reduction in percentage of nephrotoxic medication-AKI from 30.9% to 11.0% (P < .001), and reduction in AKI intensity from 9.1 to 2.9 per 100 susceptible patient-days (P < .001) while maintaining a high SCr surveillance rate. This prevented 100 AKI episodes during the 18-month sustainability era.\n\n\n\nA systematic surveillance program to identify high-risk infants can prevent nephrotoxic-induced AKI and has the potential to prevent short and long-term consequences of AKI in critically ill infants.",
"affiliations": "Department of Pediatrics, University of Alabama at Birmingham; Department of Pediatrics, Children's of Alabama. Electronic address: christinestoops@uabmc.edu.;Department of Pediatrics, Children's of Alabama.;Department of Pediatrics, Children's of Alabama.;Department of Pediatrics, Children's of Alabama; The Pediatric and Infant Center for Acute Nephrology (PICAN).;Department of Pediatrics, Children's of Alabama.;Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL.;Department of Pediatrics, Cincinnati Children's Hospital Medical Center; Center for Acute Care Nephrology (CACN), Cincinnati, OH.;Department of Pediatrics, University of Alabama at Birmingham; Department of Pediatrics, Children's of Alabama.;Department of Pediatrics, University of Alabama at Birmingham; Department of Pediatrics, Children's of Alabama; The Pediatric and Infant Center for Acute Nephrology (PICAN).",
"authors": "Stoops|Christine|C|;Stone|Sadie|S|;Evans|Emily|E|;Dill|Lynn|L|;Henderson|Traci|T|;Griffin|Russell|R|;Goldstein|Stuart L|SL|;Coghill|Carl|C|;Askenazi|David J|DJ|",
"chemical_list": "D003404:Creatinine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpeds.2019.08.046",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3476",
"issue": "215()",
"journal": "The Journal of pediatrics",
"keywords": "acute renal failure; neonate",
"medline_ta": "J Pediatr",
"mesh_terms": "D058186:Acute Kidney Injury; D000407:Alabama; D016303:Clinical Pharmacy Information Systems; D002985:Clinical Protocols; D003404:Creatinine; D006760:Hospitalization; D006801:Humans; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D010348:Patient Care Team; D010595:Pharmacists; D015397:Program Evaluation; D011446:Prospective Studies; D058996:Quality Improvement",
"nlm_unique_id": "0375410",
"other_id": null,
"pages": "223-228.e6",
"pmc": null,
"pmid": "31761141",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "28255805;29732396;22113526;28754457;19238451;14058156;23940245;24168068;24928698;25726515;29599299;21212419;27217196",
"title": "Baby NINJA (Nephrotoxic Injury Negated by Just-in-Time Action): Reduction of Nephrotoxic Medication-Associated Acute Kidney Injury in the Neonatal Intensive Care Unit.",
"title_normalized": "baby ninja nephrotoxic injury negated by just in time action reduction of nephrotoxic medication associated acute kidney injury in the neonatal intensive care unit"
} | [
{
"companynumb": "US-ROCHE-2502848",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
"drugadditi... |
{
"abstract": "This present case pertains to a 48-year-old woman with a history of antiphospholipid syndrome, who presented with progressive fatigue, generalized weakness, and orthopnea acutely. She had a prior diagnosis of antiphospholipid syndrome with recurrent deep vein thromboses (DVTs) and repeated demonstration of lupus anticoagulants. She presented in cardiogenic shock with markedly elevated troponin and global myocardial dysfunction on echocardiography, and cardiac catheterization revealed minimal disease. Cardiac magnetic resonance imaging was performed, which revealed findings of perfusion defects and microvascular obstruction, consistent with the pathophysiology of catastrophic antiphospholipid syndrome (CAPS). Diagnosis was made based on supportive imaging, including head magnetic resonance imaging (MRI) revealing multifocal, acute strokes; microvascular thrombosis in the dermis; and subacute renal infarctions. The patient was anticoagulated with intravenous unfractionated heparin and received high-dose methylprednisolone, plasmapheresis, intravenous immunoglobulin, and one dose each of rituximab and cyclophosphamide. She convalesced with eventual myocardial recovery after a complicated course. The diagnosis of CAPS relies on the presence of (1) antiphospholipid antibodies and (2) involvement of multiple organs in a microangiopathic thrombotic process with a close temporal association. The myocardium is frequently affected, and heart failure, either as the presenting symptom or cause of death, is common. Despite echocardiographic evidence of myocardial dysfunction in such patients, MRIs of CAPS have not previously been reported. This case highlights the utility in assessing the involvement of the myocardium by the microangiopathic process with MRI. Because the diagnosis of CAPS requires involvement in multiple organ systems, cardiac MRI is likely an underused tool that not only reaffirms the pathophysiology of CAPS, but could also clue clinicians in to the possibility of a diffuse thrombotic process.",
"affiliations": "Department of Medicine, Mayo Clinic, Rochester, MN, USA Rosenbaum.Andrew@mayo.edu.;Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Division of Rheumatology, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.",
"authors": "Rosenbaum|A N|AN|;Anavekar|N S|NS|;Ernste|F C|FC|;Mankad|S V|SV|;Le|R J|RJ|;Manocha|K K|KK|;Barsness|G W|GW|",
"chemical_list": "D017152:Antibodies, Antiphospholipid; D016756:Immunoglobulins, Intravenous; D016682:Lupus Coagulation Inhibitor; D006493:Heparin; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1177/0961203315587960",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "24(12)",
"journal": "Lupus",
"keywords": "Antiphospholipid syndrome; cardiovascular disease; lupus anticoagulant",
"medline_ta": "Lupus",
"mesh_terms": "D017152:Antibodies, Antiphospholipid; D016736:Antiphospholipid Syndrome; D002388:Catastrophic Illness; D005260:Female; D006493:Heparin; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007674:Kidney Diseases; D016682:Lupus Coagulation Inhibitor; D008279:Magnetic Resonance Imaging; D008775:Methylprednisolone; D008875:Middle Aged; D010956:Plasmapheresis; D012770:Shock, Cardiogenic; D020246:Venous Thrombosis",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "1338-41",
"pmc": null,
"pmid": "26014099",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of catastrophic antiphospholipid syndrome: first report with advanced cardiac imaging using MRI.",
"title_normalized": "a case of catastrophic antiphospholipid syndrome first report with advanced cardiac imaging using mri"
} | [
{
"companynumb": "US-PFIZER INC-2016480949",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nImmunocompromised children are susceptible to infectious diarrhea. Oral administration of human serum immunoglobulins to treat immunocompromised patients with viral gastroenteritis caused by viruses like rotavirus and norovirus has been reported.\n\n\nOBJECTIVE\nThe aim of this study was to assess the efficacy of oral immunoglobulin (OIG) in treating hospitalized immunocompromised children with diarrheal illness.\n\n\nMETHODS\nWe conducted a retrospective cohort review of the Mayo Clinic electronic medical records from January 1, 2005, through April 30, 2019. We included children who were immunocompromised and received OIG as a treatment for a diarrheal illness that was classified as acute (< 4 weeks) or chronic (> 4 weeks) at the time of their treatment. Response to therapy was defined by 50% reduction in stool output.\n\n\nRESULTS\nNineteen children were identified (11 males); average age at the time of treatment was 11 (0.25-18) years. In the acute diarrhea cohort, the mean duration of symptoms was 9.5 days (4-21). In the chronic diarrhea cohort, the mean duration of symptoms was 41 days (28-90). All 19 children were treated with OIG with doses in the range of 100-300 mg/kg/day for 1-5 days. Eighteen patients (95%) had improvement. Overall average time to response was 3.1 (1-9) days after receiving the OIG.\n\n\nCONCLUSIONS\nOral administration of human serum immunoglobulin in immunocompromised children presenting with acute and chronic diarrheal illness appeared helpful in reducing stool output by 50% in the majority of patients.",
"affiliations": "Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics and Adolescent Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA. alexander.erin@mayo.edu.;Division of Pediatric Gastroenterology and Hepatology, Blank Children's Hospital, Des Moines, IA, USA.;Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics and Adolescent Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.;Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics and Adolescent Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.;Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics and Adolescent Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.",
"authors": "Alexander|Erin|E|http://orcid.org/0000-0001-7373-4329;Hommeida|Salim|S|;Stephens|Michael C|MC|;Manini|Mhd Louai|ML|;Absah|Imad|I|",
"chemical_list": "D007136:Immunoglobulins",
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40272-020-00389-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1174-5878",
"issue": "22(3)",
"journal": "Paediatric drugs",
"keywords": null,
"medline_ta": "Paediatr Drugs",
"mesh_terms": "D000284:Administration, Oral; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003967:Diarrhea; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007136:Immunoglobulins; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D012189:Retrospective Studies; D012400:Rotavirus Infections",
"nlm_unique_id": "100883685",
"other_id": null,
"pages": "331-334",
"pmc": null,
"pmid": "32180169",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Role of Oral Administration of Immunoglobulin in Managing Diarrheal Illness in Immunocompromised Children.",
"title_normalized": "the role of oral administration of immunoglobulin in managing diarrheal illness in immunocompromised children"
} | [
{
"companynumb": "NVSC2020US179289",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "A 73-year-old woman was admitted to the intensive care unit following vomiting and diarrhoea onset after completing oral bowel preparation prior to colonoscopy to investigate haematochezia. She had a history of severe chronic obstructive pulmonary disease, Crohn's disease, diverticular disease, hypertension and dyslipidaemia. She was resuscitated with intravenous fluids, antibiotics and required epinephrine, norepinephrine and vasopressin infusions. She improved over her 4-day intensive care admission and was discharged to the general medical ward, but ultimately died 19 days after presentation.",
"affiliations": "Intensive Care Unit, Queensland Health, Gold Coast, Queensland, Australia angus.loraine@health.qld.gov.au.",
"authors": "Loraine|Angus|A|http://orcid.org/0000-0002-1338-4491",
"chemical_list": "D002400:Cathartics; D002951:Citrates; D009942:Organometallic Compounds; D010847:Picolines; C005701:picosulfate sodium",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-233406",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(3)",
"journal": "BMJ case reports",
"keywords": "adult intensive care; endoscopy; gastroenterology; inflammatory bowel disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D002400:Cathartics; D002951:Citrates; D003113:Colonoscopy; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D009942:Organometallic Compounds; D010847:Picolines; D011300:Preoperative Care; D012307:Risk Factors; D012772:Shock, Septic",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32161080",
"pubdate": "2020-03-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bowel preparation agent inducing profound shock precolonoscopy.",
"title_normalized": "bowel preparation agent inducing profound shock precolonoscopy"
} | [
{
"companynumb": "AU-FERRINGPH-2020FE02575",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ANHYDROUS CITRIC ACID\\MAGNESIUM OXIDE\\SODIUM PICOSULFATE"
... |
{
"abstract": "OBJECTIVE\nThe reports submitted to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from 1997 to 2011 were reviewed to assess serious adverse events induced by the administration of antipsychotics to children.\n\n\nMETHODS\nFollowing pre-processing of FAERS data by elimination of duplicated records as well as adjustments to standardize drug names, reports involving haloperidol, olanzapine, quetiapine, clozapine, ziprasidone, risperidone, and aripiprazole were analyzed in children (age 0-12). Signals in the data that signified a drug-associated adverse event were detected via quantitative data mining algorithms. The algorithms applied to this study include the empirical Bayes geometric mean, the reporting odds ratio, the proportional reporting ratio, and the information component of a Bayesian confidence propagation neural network. Neuroleptic malignant syndrome (NMS), QT prolongation, leukopenia, and suicide attempt were focused on as serious adverse events.\n\n\nRESULTS\nIn regard to NMS, the signal scores for haloperidol and aripiprazole were greater than for other antipsychotics. Significant signals of the QT prolongation adverse event were detected only for ziprasidone and risperidone. With respect to leukopenia, the association with clozapine was noteworthy. In the case of suicide attempt, signals for haloperidol, olanzapine, quetiapine, risperidone, and aripiprazole were detected.\n\n\nCONCLUSIONS\nIt was suggested that there is a level of diversity in the strength of the association between various first- and second-generation antipsychotics with associated serious adverse events, which possibly lead to fatal outcomes. We recommend that research be continued in order to gather a large variety and quantity of related information, and that both available and newly reported data be placed in the context of multiple medical viewpoints in order to lead to improved levels of care.",
"affiliations": "1. Center for Integrative Education in Pharmacy and Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.;1. Center for Integrative Education in Pharmacy and Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.;2. Department of Clinical System Onco-Informatics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.;3. Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.;3. Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.;3. Kobe University Graduate School of Medicine, Kobe 650-0017, Japan ; 4. Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.;1. Center for Integrative Education in Pharmacy and Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan ; 4. Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.;2. Department of Clinical System Onco-Informatics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.",
"authors": "Kimura|Goji|G|;Kadoyama|Kaori|K|;Brown|J B|JB|;Nakamura|Tsutomu|T|;Miki|Ikuya|I|;Nisiguchi|Kohshi|K|;Sakaeda|Toshiyuki|T|;Okuno|Yasushi|Y|",
"chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D010879:Piperazines; D015363:Quinolones; D013844:Thiazoles; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; C092292:ziprasidone; D000068180:Aripiprazole; D006220:Haloperidol; D000077152:Olanzapine",
"country": "Australia",
"delete": false,
"doi": "10.7150/ijms.10453",
"fulltext": "\n==== Front\nInt J Med SciInt J Med SciijmsInternational Journal of Medical Sciences1449-1907Ivyspring International Publisher Sydney 10.7150/ijms.10453ijmsv12p0135Research PaperAntipsychotics-Associated Serious Adverse Events in Children: An Analysis of the FAERS Database Kimura Goji 1Kadoyama Kaori 1✉Brown J.B. 2Nakamura Tsutomu 3Miki Ikuya 3Nisiguchi Kohshi 34Sakaeda Toshiyuki 14Okuno Yasushi 2✉1. Center for Integrative Education in Pharmacy and Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan2. Department of Clinical System Onco-Informatics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan3. Kobe University Graduate School of Medicine, Kobe 650-0017, Japan4. Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan✉ Corresponding author: Kaori Kadoyama, Ph.D., Center for Integrative Education in Pharmacy and Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan, Tel.: +81-75-753-4522, Fax: +81-75-753-9253, e-mail: kao-kado@pharm.kyoto-u.ac.jp; Yasushi Okuno, Ph.D., Department of Clinical System Onco-Informatics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan, Tel.&Fax: +81-75-753-4559, e-mail: okuno@pharm.kyoto-u.ac.jpCompeting Interests: The authors have declared that no competing interest exists.\n\n2015 5 1 2015 12 2 135 140 1 9 2014 10 12 2014 © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.2015Objective: The reports submitted to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from 1997 to 2011 were reviewed to assess serious adverse events induced by the administration of antipsychotics to children.\n\nMethods: Following pre-processing of FAERS data by elimination of duplicated records as well as adjustments to standardize drug names, reports involving haloperidol, olanzapine, quetiapine, clozapine, ziprasidone, risperidone, and aripiprazole were analyzed in children (age 0-12). Signals in the data that signified a drug-associated adverse event were detected via quantitative data mining algorithms. The algorithms applied to this study include the empirical Bayes geometric mean, the reporting odds ratio, the proportional reporting ratio, and the information component of a Bayesian confidence propagation neural network. Neuroleptic malignant syndrome (NMS), QT prolongation, leukopenia, and suicide attempt were focused on as serious adverse events.\n\nResults: In regard to NMS, the signal scores for haloperidol and aripiprazole were greater than for other antipsychotics. Significant signals of the QT prolongation adverse event were detected only for ziprasidone and risperidone. With respect to leukopenia, the association with clozapine was noteworthy. In the case of suicide attempt, signals for haloperidol, olanzapine, quetiapine, risperidone, and aripiprazole were detected.\n\nConclusions: It was suggested that there is a level of diversity in the strength of the association between various first- and second-generation antipsychotics with associated serious adverse events, which possibly lead to fatal outcomes. We recommend that research be continued in order to gather a large variety and quantity of related information, and that both available and newly reported data be placed in the context of multiple medical viewpoints in order to lead to improved levels of care.\n\nantipsychoticschildrenserious adverse eventsFAERSdata miningpharmacovigilance\n==== Body\nIntroduction\nSecond-generation antipsychotic drugs (SGAs) are thought to provide different therapeutic outcomes from first-generation antipsychotic drugs (FGAs), due to their relatively low affinity for dopamine D2 receptors and affinities for other receptors. SGAs are believed to improve negative symptoms, depression and quality of life more than FGAs 1. Medical doctors understand that improved efficacy for these problems is a great advantage of SGAs; however, little information is available concerning their superiority 1. Weight gain, hyperprolactinemia, and extrapyramidal symptoms (EPS) are commonly found in patients treated with FGAs or SGAs 2-5. Additionally, neuroleptic malignant syndrome (NMS), QT prolongation, leukopenia, and suicidal behavior are reported for both 2-5; however again, we do not have a consensus on which is better. Additionally, in 2009, a meta-analysis was published to compare the safety and efficacy of FGAs and SGAs, in which 150 double-blind studies were included with 21,533 participants 1. The analysis concluded that SGAs differed in many properties and were not a homogenous class, strongly suggesting the importance of detailed investigation of each drug 1.\n\nRecently, the use of antipsychotics, especially SGAs, has been increasing in children. This is, in part, explained by their off-label uses, including those for Attention Deficit / Hyperactivity Disorder (ADHD) 6-8. In the USA, the use of SGAs for children has been approved since 2006, and this has also contributed to the increase. The surveillance of adverse event reports submitted to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) suggested that antipsychotics are included in the top 5 reported suspect therapeutic drug classes in children 9. In this study, the FAERS database was used to assess the associations between 5 representative SGAs and adverse events in children. A FGA, haloperidol, and the recently developed aripiprazole were also subjected to the investigation, and we focused on 4 rare adverse events, including NMS, QT prolongation, leukopenia, and suicidal behavior. Data mining algorithms were used for the quantitative detection of signals 10-18, where a signal means a statistical association between a drug and an adverse event or a drug-associated adverse event.\n\nMethods\nData sources\nInput data for this study were taken from the public release of the FAERS database, covering the period from the fourth quarter of 1997 through the third quarter of 2011. The total number of reports used was 4,671,217. Besides those from manufactures, reports can be submitted from health care professionals and the public. The database's data structure adheres to the international safety reporting guidance issued by the International Conference on Harmonisation ICH E2B. A data set consists of 7 data tables: report sources (RPSR), patient demographic and administrative information (DEMO), drug therapy start and end dates (THER), indications for use/diagnosis (INDI), drug/biologic information (DRUG), adverse events (REAC), and patient outcomes (OUTC). Preferred terms (PTs) in the Medical Dictionary for Regulatory Activities (MedDRA) serve as the terminology for registration of adverse events in REAC table. Here, version 16.1 of MedDRA was used.\n\nBefore data mining was executed, several pre-processing steps of FAERS were undertaken. First, duplicated reports, which appear with multiple CASE field values in the database, were filtered by applying the FDA's recommendation of adopting the most recent CASE number. This processing step reduced the number of reports from 4,671,217 to 3,472,494, a 25.7% reduction. Next, in order to account for registration of arbitrary drug names including trade names and abbreviations, which is permissible within the FAERS system, drug names were mapped into unified generic names via text mining. As a part of the standardization process, GNU Aspell was applied to detect spelling errors. Additionally, records of side effects that are not registered as associated with the use of a pharmaceutical, such as foods, beverages, or other medical treatments including radiation therapy were eliminated. Similarly, adverse event records with ambiguous drug names such as generic “beta blockers” were filtered out. As a final filter, only records were retained in which demographic information indicated that children less than 12 years old were the recipients of treatment. After applying this pre-mining filter pipeline, the total number of reports used was 94,635. Consequently, a total of 1,098,811 co-occurrences were found in 94,635 reports, where a co-occurrence was a pair constituting a drug and a drug-associated adverse event.\n\nDefinition of adverse events\nAccording to MedDRA version 16.1, NMS, QT prolongation, leukopenia, and suicide attempt are coded with preferred terms PT10029282, PT10014387, PT10024384, and PT10042464 with 7, 10, 5, and 5 lower level of terms (LLTs) assigned, respectively.\n\nSignal Detection Data Mining\nOnce a collection of filtered adverse event records are assembled, a key question is how to weight and extract meaningful events as adverse event signals. To this end, a number of algorithms have been developed, where the common element of the algorithms is that signals are defined as those events reported with a greater frequency than can be expected, given an estimated expectation for reporting frequency derived from the drugs and ADRs (adverse drug reaction events) in the record collection to be analyzed 14-18. The algorithms used in this study include: (1) the proportional reporting ratio (PRR) 10 which is used by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK; (2) the reporting odds ratio (ROR) 11 in use at the Netherlands Pharmacovigilance Centre; (3) the information component (IC) criteria 12 employed by the World Health Organization (WHO); (4) and the empirical Bayes geometric mean (EBGM) 13 which is a part of FDA analytical methods.\n\nThe PRR, ROR, IC, and EBGM methods all employ the use of 2x2 confusion matrices of drug-event counts; that is, a drug and an event are placed on the rows and columns of a matrix, and the frequency of the four possible outcomes is tabulated. Where the algorithms then differ is that IC and EBGM use Bayesian reasoning, while the PRR and ROR methods take the frequentist approach to statistical inference. Readers are encouraged to consult the references of each method to obtain extended details.\n\nHere, we summarize the ways in which each test uses its reasoning and formulation to “detect” a signal. First we consider the classical, frequentist statistical approaches. In the PRR method, a signal is detected if the number of co-occurrences is 3 or more, and additionally, if the PRR is 2 or more with an associated χ2 value of 4 or more 10. Using ROR, when the lower bound of the 95% two-sided confidence interval exceeds 1, it is an indication of an ADR signal 11.\n\nNext, we consider the Bayesian methods for signal detection. The IC algorithm performs signal detection via the IC025 metric, which is a lower bound of the 95% two-sided confidence interval of IC, with an ADR signal indicated by the IC025 value exceeding 0 12. For the EGBM method, a lower one-sided 95% confidence bound of the EBGM, termed the EB05 metric, is used; EB05 is greater than or equal to 2.0 results in an ADR signal 13.\n\nFinally, we need a criterion to unite our use of the various signal detection methods. In this study, we elect for the most direct, simple strategy: an adverse event is drug-associated when at least 1 of the 4 algorithms meets its above criteria for signal detection.\n\nResults\nThe total number of drug and reported adverse event co-occurrences with haloperidol was 1,600, with 2,802 for olanzapine, 2,440 for quetiapine, 519 for clozapine, 623 for ziprasidone, 5,219 for risperidone, and 2,553 for aripiprazole, representing 0.146%, 0.255%, 0.222%, 0.047%, 0.056%, 0.475%, and 0.232% of all co-occurrences in children in the filtered database, respectively. In total, 181, 345, 313, 119, 139, 380, and 269 adverse events were extracted as antipsychotics-associated adverse events with 999, 1,644, 1,386, 310, 361, 3,104, and 1,530 co-occurrences with a signal detected, respectively.\n\nThe signals for NMS were detected with the 5 antipsychotics other than clozapine and ziprasidone, and signal scores for haloperidol and aripiprazole were greater than for other antipsychotics in Table 1. As for QT prolongation, signals were detected for only ziprasidone and risperidone, and signal scores suggested a stronger association for ziprasidone (Table 2). The signal scores for leukopenia are listed in Table 3. Although signals were detected for quetiapine, clozapine, and risperidone, the association with clozapine was noteworthy. Table 4 shows the signal scores for suicide attempt, and signals for 5 antipsychotics; haloperidol, olanzapine, quetiapine, risperidone, and aripiprazole, were detected.\n\nDiscussion\nAccording to some recent reports, number of prescriptions for antipsychotics among younger patients has been increasing 6-8. Furthermore, the Guideline “Clinical Investigation of Medicinal Products in the Pediatric Population” 19, which was developed by the ICH expert working group, categorized “children” as 2 to 11 years. Therefore, in this study, we focused on children less than 12 years old.\n\nNMS is a rare, but potentially fatal complication of treatment with antipsychotic medication and is characterized by the development of severe muscle rigidity and hyperthermia, first described by Delay et al. in 1968 20. In spite of the long period of time since the first description, to the best of our knowledge, there have been few reports concerning the association between SGAs and NMS in children. In our study, signals were detected for 5 antipsychotics, i.e., haloperidol, quetiapine, ziprasidone, risperidone, and aripiprazole (Table 1). Signal scores were higher for haloperidol and aripiprazole than for the other antipsychotics, suggesting that SGAs show lower susceptibility to NMS. The precise pathophysiology of NMS remains unknown. It has been suggested that NMS is the result of dopamine D2 receptor blockade 20-22, whereas, dopamine D2 receptor antagonism does not fully explain all of the signs and symptoms of NMS 22. According to antipsychotic receptor-binding profiles, relative affinities for the dopamine D2 receptor of haloperidol and aripiprazole are higher, and those of quetiapine and risperidone are lower 4, 21. Moreover, aripiprazole controls the dopaminergic function by acting as a partial agonist of dopamine D2 receptor subtypes, while high concentrations of aripiprazole induce dopaminergic blockade 4. Therefore, our observation may be partially attributed to these drug action mechanisms.\n\nQT prolongation is also a serious adverse event accompanying the administration of SGAs, and results from blockade of the delayed rectifier potassium current (IKr). It is associated with presyncope, syncope, polymorphic ventricular tachycardia, the subtype torsade de pointes, and sudden cardiac death 23. Poluzzi et al. reported the torsadogenic risk of antipsychotics including QT prolongation using FAERS 24, and Wenzel-Seifert et al. suggested that QT prolongation occurs most significantly with ziprasidone in SGAs 25. However, neither of them provided data after stratifying by age. Here, the signals for QT prolongation were detected for ziprasidone and risperidone, with the signal score being higher for the former than the latter (Table 2). In this study, it was confirmed that ziprasidone is most strongly associated with QT prolongation in children.\n\nHematologic abnormalities induced by antipsychotics may be life-threatening in some patients. Several studies revealed the association between clozapine and leukopenia in children, and clozapine is generally recommended for drug-resistant cases 26-28. In addition, Etain et al. reported that leukopenia was induced by risperidone 29. Our results reproduced these observations, but the signal was also detected for quetiapine (Table 3).\n\nThe incidence of suicide attempt is more frequent in individuals with schizophrenia than in general 30, 31. Previous studies suggested that the suicide risk differs among antipsychotics 30-33; however, the impact of antipsychotics on suicide attempt has been a matter of controversy. Moreover, adherence to antipsychotics is likely to reduce the suicide risk 30, so suicide attempt in individuals who take antipsychotics may be due to weakness of efficacy. On the other hand, an adverse event is generally defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment 34. Therefore, in this study, we regarded suicide attempt accompanied with the administration of antipsychotics as adverse events even if it derives from weakness of efficacy, and FAERS database was reviewed in order to confirm if the suicide risk differs among antipsychotics and is associated with them. As a result, signals were detected for antipsychotics other than clozapine and ziprasidone, and the scores were higher for olanzapine and risperidone (Table 4). Tiihonen et al. revealed that use of clozapine might be more effective than that of other antipsychotics for reducing suicidal attempt 30. This might have contributed to the lack of a signal detection for clozapine.\n\nIn conclusion, reports in the FAERS database were reviewed to assess the antipsychotics-associated serious adverse events in children. Based on 94,635 reports from 1997 to 2011, it was suggested that there is a level of diversity in the strength of the association between various first- and second-generation antipsychotics with associated serious adverse events, which possibly lead to fatal outcomes. We recommend that research be continued in order to gather a large variety and quantity of related information, and that both available and newly reported data be placed in the context of multiple medical viewpoints in order to lead to improved levels of care.\n\nThis study was partially supported by the Funding Program for Next Generation World-Leading Researchers and JSPS KAKENHI Grant Number 25460209.\n\nAbbreviations\nEBGMempirical Bayes geometric mean\n\nFDAFood and Drug Administration\n\nFAERSFDA Adverse Event Reporting System\n\nFGAsfirst-generation antipsychotic drugs\n\nICinformation component\n\nMedDRAMedical Dictionary for Regulatory Activities\n\nNMSneuroleptic malignant syndrome\n\nPRRproportional reporting ratio\n\nPTpreferred term\n\nRORreporting odds ratio\n\nSGAssecond-generation antipsychotic drugs\n\nTable 1 Signal scores for antipsychotics-associated neuroleptic malignant syndrome.\n\nAntipsychotics\tN\tPRR\n(χ2)\tROR\n(95% CI)\tIC\n(95% CI)\tEBGM\n(95% CI)\t\nHaloperidol\t8\t26.92 (174.0)*\t27.98 (13.77, 42.18)*\t2.71 (1.72, 3.71)*\t22.97 (12.11)*\t\nOlanzapine\t3\t5.74 (7.5)*\t5.81 (1.86, 9.77)*\t1.21 (-0.31, 2.73)\t2.27 (0.83)\t\nQuetiapine\t8\t17.62 (109.2)*\t18.30 (9.02, 27.59)*\t2.55 (1.56, 3.54)*\t15.03 (6.97)*\t\nClozapine\tN.A.\t\t\t\t\t\nZiprasidone\tN.A.\t\t\t\t\t\nRisperidone\t10\t10.28 (75.0)*\t10.76 (5.70, 15.83)*\t2.41 (1.52, 3.31)*\t8.15 (3.79)*\t\nAripiprazole\t14\t29.54 (357.0)*\t31.64 (18.36, 44.92)*\t3.30 (2.53, 4.07)*\t26.82 (16.85)*\t\nN: the number of co-occurrences. N.A.: Not Available\n\nPRR: the proportional reporting ratio, ROR: the reporting odds ratio, IC: the information component, EBGM: the empirical Bayes geometric mean. CI: the confidence interval (two-sided for ROR and IC, and one-sided for EBGM).\n\nAn asterisk (*) indicates a statistically significant association, i.e., the adverse events are detected as signals.\n\nTable 2 Signal scores for antipsychotics-associated QT prolongation.\n\nAntipsychotics\tN\tPRR\n(χ2)\tROR\n(95% CI)\tIC\n(95% CI)\tEBGM\n(95% CI)\t\nHaloperidol\t2\t1.41 (0.0)\t1.41 (0.35, 2.47)\t0.06 (-1.72, 1.84)\t0.97 (0.31)\t\nOlanzapine\t1\t0.40 (0.4)\t0.40 (0.06, 0.75)\t-1.19 (-3.46, 1.08)\t0.40 (0.09)\t\nQuetiapine\t3\t1.39 (0.1)\t1.39 (0.45, 2.33)\t0.15 (-1.36, 1.66)\t1.05 (0.41)\t\nClozapine\tN.A.\t\t\t\t\t\nZiprasidone\t15\t27.83 (353.1)*\t28.25 (16.86, 39.64)*\t3.32 (2.59, 4.05)*\t25.07 (16.02)*\t\nRisperidone\t9\t1.95 (3.3)\t1.96 (1.02, 2.90)*\t0.76 (-0.16, 1.68)\t1.65 (0.94)\t\nAripiprazole\t3\t1.33 (0.1)\t1.33 (0.43, 2.20)\t0.11 (-1.40, 1.62)\t1.02 (0.39)\t\nN: the number of co-occurrences. N.A.: Not Available\n\nPRR: the proportional reporting ratio, ROR: the reporting odds ratio, IC: the information component, EBGM: the empirical Bayes geometric mean. CI: the confidence interval (two-sided for ROR and IC, and one-sided for EBGM).\n\nAn asterisk (*) indicates a statistically significant association, i.e., the adverse events are detected as signals.\n\nTable 3 Signal scores for antipsychotics-associated leukopenia\n\nAntipsychotics\tN\tPRR\n(χ2)\tROR\n(95% CI)\tIC\n(95% CI)\tEBGM\n(95% CI)\t\nHaloperidol\tN.A.\t\t\t\t\t\nOlanzapine\t2\t0.82 (0.0)\t0.83 (0.21, 1.45)\t-0.44 (-2.22, 1.34)\t0.69 (0.22)\t\nQuetiapine\t11\t5.25 (33.6)*\t5.30 (2.92, 7.68)*\t1.89 (1.05, 2.73)*\t3.77 (2.19)*\t\nClozapine\t8\t18.15 (111.3)*\t18.30 (9.07, 27.52)*\t2.56 (1.57, 3.54)*\t15.33 (27.65)*\t\nZiprasidone\tN.A.\t\t\t\t\t\nRisperidone\t9\t2.00 (3.6)\t2.01 (1.04, 2.98)*\t0.79 (-0.13, 1.71)\t1.68 (0.96)\t\nAripiprazole\t2\t0.91 (0.0)\t0.91 (0.23, 1.59)\t-0.35 (-2.13, 1.43)\t0.74 (0.24)\t\nN: the number of co-occurrences. N.A.: Not Available\n\nPRR: the proportional reporting ratio, ROR: the reporting odds ratio, IC: the information component, EBGM: the empirical Bayes geometric mean. CI: the confidence interval (two-sided for ROR and IC, and one-sided for EBGM).\n\nAn asterisk (*) indicates a statistically significant association, i.e., the adverse events are detected as signals.\n\nTable 4 Signal scores for antipsychotic-associated suicide attempt.\n\nAntipsychotics\tN\tPRR\n(χ2)\tROR\n(95% CI)\tIC\n(95% CI)\tEBGM\n(95% CI)\t\nHaloperidol\t5\t9.36 (29.4)*\t9.47 (3.91, 15.03)*\t1.84 (0.63, 3.06)*\t4.65 (1.75)\t\nOlanzapine\t10\t10.69 (78.3)*\t10.96 (5.84, 16.08)*\t2.44 (1.55, 3.32)*\t8.56 (3.97)*\t\nQuetiapine\t6\t7.36 (26.9)*\t7.46 (3.33, 11.60)*\t1.84 (0.72, 2.96)*\t4.03 (1.79)\t\nClozapine\tN.A.\t\t\t\t\t\nZiprasidone\t1\t4.80 (0.4)\t4.81 (0.67, 8.94)\t0.34 (-1.94, 2.62)\t1.15 (0.25)\t\nRisperidone\t13\t7.45 (66.5)*\t7.69 (4.41, 10.96)*\t2.30 (1.51, 3.08)*\t5.75 (3.24)*\t\nAripiprazole\t4\t4.68 (8.2)*\t4.72 (1.76, 7.69)*\t1.28 (-0.06, 2.62)\t2.36 (1.00)\t\nN: the number of co-occurrences. N.A.: Not Available\n\nPRR: the proportional reporting ratio, ROR: the reporting odds ratio, IC: the information component, EBGM: the empirical Bayes geometric mean. CI: the confidence interval (two-sided for ROR and IC, and one-sided for EBGM).\n\nAn asterisk (*) indicates a statistically significant association, i.e., the adverse events are detected as signals.\n==== Refs\n1 Leucht S Corves C Arbter D Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis Lancet 2009 373 31 41 19058842 \n2 Zhang JP Gallego JA Robinson DG Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis Int J Neuropsychopharmacol 2013 16 1205 1218 23199972 \n3 Kane JM McGlashan TH Treatment of schizophrenia Lancet 1995 346 820 825 7545770 \n4 Gareri P Fazio PD Fazio SD Adverse effects of atypical antipsychotics in the elderly. A review Drugs Aging 2006 23 937 956 17154659 \n5 Gentile S Adverse effects associated with second-generation antipsychotic long-acting injection treatment: A Comprehensive Systematic Review Pharmacotherapy 2013 33 1087 1106 23776129 \n6 Alexander GC Gallagher SA Mascola A Increasing off-label use of antipsychotics medications in the United States. 1995-2008 Pharmacoepidemiol Drug Saf 2011 20 177 184 21254289 \n7 Harrison JN Cluxton-Keller F Gross D Antipsychotic Medication Prescribing Trends in Children and Adolescents J Pediatr Health Care 2012 2 139 145 22360933 \n8 Rani F Murray ML Byrn PJ Epidemiologic features of antipsychotic prescribing to children and adolescents in primary care in the United Kingdom Pediatrics 2008 121 1002 1009 18450906 \n9 Johann-Liang R Wyeth J Chen M Pediatric drug surveillance and the Food and Drug Administration's adverse event reporting system: an overview of reports. 2003-2007 Pharmacoepidemiol Drug Saf 2009 18 1 24 27 19009550 \n10 Evans SJ Waller PC Davis S Use of Proportional Reporting Ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports Pharmacoepidemiol Drug Saf 2001 10 483 486 11828828 \n11 Van Puijenbroek EP Bate A Leufkens HG A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions Pharmacoepidemiol Drug Saf 2002 11 3 10 11998548 \n12 Bate A Lindquist M Edwards IR A Bayesian neural network method for adverse drug reaction signal generation Eur J Clin Pharmacol 1998 54 315 321 9696956 \n13 Szarfman A Machao SG O'Neill RT Use of screening algorithms and computer systems to efficiently signal higher-than-expected combinations of drugs and events in the US FDA's spontaneous reports database Drug Saf 2002 25 381 392 12071774 \n14 Bate A Evans SJ Quantitative signal detection using spontaneous ADR reporting Pharmacoepidemiol Drug Saf 2009 18 427 436 19358225 \n15 Hauben M Reich L Drug-induced pancreatitis: lessons in data mining Br J Clin Pharmacol 2004 58 560 562 15521907 \n16 Almenoff J Tonning JM Gould AL Perspectives on the use of data mining in pharmacovigilance Drug Saf 2005 28 981 1007 16231953 \n17 Almenoff JS Pattishall EN Gibbs TG Novel statistical tools for monitoring the safety of marketed drugs Clin Pharmacol Ther 2007 82 157 166 17538548 \n18 Hauben M Bate A Decision support methods for the detection of adverse events in post-marketing data Drug Discov Today 2009 14 343 357 19187799 \n19 GUIDELINE for Efficacy, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Clinical Investigation of Medicinal Products in the Pediatric Population Tokyo, Japan Pharmaceuticals and Medicinal Devices Agency http://www.pmda.go.jp/ich/e/e11_00_12_15e.pdf \n20 Neuhut R Lindenmayer JP Silva R Neuroleptic malignant syndrome in children and adolescents on atypical antipsychotic medication: A review J Child Adolesc Psychopharmacol 2009 19 415 422 19702493 \n21 Cerovecki A Musil R Klimke A Withdrawal symptoms and rebound syndromes associated with switching and discontinuing atypical antipsychotics: theoretical background and practical recommendations CNS Drugs 2013 27 545 572 23821039 \n22 Minns AB Clark RF Toxicology and overdose of atypical antipsychotics J Emerg Med 2012 43 906 913 22555052 \n23 Ozeki Y Fujii K Kurimoto N QTc prolongation and antipsychotic medications in a sample of 1017 patients with schizophrenia Prog Neuropsychopharmacol Biol Psychiatry 2010 34 401 405 20079791 \n24 Poluzzi E Raschi E Koci A Antipsychotics and torsadogenic risk: signals emerging from the US FDA Adverse Event Reporting System database Drug Saf 2013 36 467 479 23553446 \n25 Wenzel-Seifert K Wittmann M Haen E QTc prolongation by psychotropic drugs and the risk of torsade de pointes Dtsch Arztebl Int 2011 108 687 693 22114630 \n26 Maher KN Tan M Tossell JW Risk factors for neutropenia in clozapine-treated children and adolescents with childhood-onset schizophrenia J child adolesc psychopharmacol 2013 23 110 116 23510445 \n27 Schneider C Corrigall R Hayes D Systematic review of the efficacy and tolerability of Clozapine in the treatment of youth with early onset schizophrenia Eur Psychiatry 2014 29 1 10 24119631 \n28 Manfredi G Solfanelli A Dimitri G Risperidone-induced leucopenia: a case report and brief review of literature Gen Hosp Psychiatry 2013 35 102.e3 102.e6 22520716 \n29 Etain B Roubaud L Le Heuzey MF A case of leukopenia in treatment with risperidone in an adolescent Encepahle 2000 26 81 84 \n30 Meltzer HY Alphs L Green AI Clozapine treatment for suicidality in schizopherenia: Internal Suicide Prevention Trial Arch Gen Psychiatry 2003 60 82 91 12511175 \n31 Tiihonen J Loonqvist J Wahlbeck K 11-year Follow-Up of Mortality in Patients with Schizophrenia: A Population-Based Cohort Study (FIN11 Study) Lancet 2009 374 620 627 19595447 \n32 Crocq MA Naber D Lader MH Suicide attempts in a prospective cohort of patients with schizophrenia treated with Sertindole or Riperidone Eur Neuropsychopharmaco 2010 20 829 838 \n33 Haukka J Tiihonen J Harkanen T Association between medication and Risk of suicide, attempted suicide and death in nationwide cohort of suicidal patients with schizophrenia Pharmacoepidemiol Drug Saf 2008 17 686 696 18327869 \n34 GUIDELINE for Efficacy, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting Tokyo, Japan Pharmaceuticals and Medicinal Devices Agency http://www.pmda.go.jp/ich/e/e11_00_12_15e.pdf\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1449-1907",
"issue": "12(2)",
"journal": "International journal of medical sciences",
"keywords": "FAERS; antipsychotics; children; data mining; pharmacovigilance; serious adverse events",
"medline_ta": "Int J Med Sci",
"mesh_terms": "D000465:Algorithms; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D001569:Benzodiazepines; D057225:Data Mining; D016208:Databases, Factual; D003987:Dibenzothiazepines; D006220:Haloperidol; D006801:Humans; D000077152:Olanzapine; D010879:Piperazines; D000069348:Quetiapine Fumarate; D015363:Quinolones; D013844:Thiazoles",
"nlm_unique_id": "101213954",
"other_id": null,
"pages": "135-40",
"pmc": null,
"pmid": "25589889",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "11192809;24119631;11998548;12071774;12511175;7545770;9696956;15521907;16231953;17154659;17538548;18450906;18327869;19058842;19009550;19187799;19358225;19595447;19702493;20079791;20926264;21254289;22114630;22360933;22555052;22520716;23510445;23553446;23199972;23821039;23776129;11828828",
"title": "Antipsychotics-associated serious adverse events in children: an analysis of the FAERS database.",
"title_normalized": "antipsychotics associated serious adverse events in children an analysis of the faers database"
} | [
{
"companynumb": "JP-JNJFOC-20150114724",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "Comorbid obsessive-compulsive disorder (OCD) and bipolar disorder (BD) have long been an intractable problem in clinical practice. The increased risk of manic/hypomanic switch hinders the use of antidepressants for managing coexisting OCD symptoms in BD patients. We herein present a case of a patient with BD-OCD comorbidity, who was successfully treated with mood stabilizers and aripiprazole augmentation. The young female patient reported recurrent depressive episodes and aggravating compulsive behaviors before hospitalization. Of note, the patient repetitively attempted suicide and reported dangerous driving because of intolerable mental sufferings. The preexisting depressive episode and OCD symptoms prompted the use of paroxetine, which consequently triggered the manic switching. Her diagnosis was revised into bipolar I disorder. Minimal response with mood stabilizers prompted the addition of aripiprazole (a daily dose of 10 mg), which helped to achieve significant remission in emotional and obsessive-compulsive symptoms. This case highlights the appealing efficacy of a small dose of aripiprazole augmentation for treating BD-OCD comorbidity. Well-designed clinical trials are warranted to verify the current findings.",
"affiliations": "Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine; The Key Laboratory of Mental Disorder's Management in Zhejiang Province.;Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine.;The Key Laboratory of Mental Disorder's Management in Zhejiang Province; Department of Psychiatry, Mental Health Centre, Xiaoshan Hospital of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.;The Key Laboratory of Mental Disorder's Management in Zhejiang Province; Department of Psychiatry, Mental Health Centre, Xiaoshan Hospital of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.;Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine; The Key Laboratory of Mental Disorder's Management in Zhejiang Province.;Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine; The Key Laboratory of Mental Disorder's Management in Zhejiang Province.",
"authors": "Lai|Jianbo|J|;Lu|Qiaoqiao|Q|;Zhang|Peng|P|;Xu|Tingting|T|;Xu|Yi|Y|;Hu|Shaohua|S|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/NDT.S122316",
"fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNeuropsychiatric Disease and TreatmentNeuropsychiatric Disease and Treatment1176-63281178-2021Dove Medical Press 10.2147/NDT.S122316ndt-13-087Case ReportAripiprazole augmentation in managing comorbid obsessive–compulsive disorder and bipolar disorder: a case with suicidal attempts Lai Jianbo 12Lu Qiaoqiao 1Zhang Peng 23Xu Tingting 23Xu Yi 12Hu Shaohua 121 Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine2 The Key Laboratory of Mental Disorder’s Management in Zhejiang Province3 Department of Psychiatry, Mental Health Centre, Xiaoshan Hospital of Zhejiang Province, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Shaohua Hu; Yi Xu, Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, People’s Republic of China, Tel +86 571 5672 3002; +86 138 0574 6579, Fax +86 571 5672 3001, Email dorhushaohua@zju.edu.cn; xuyizju61@163.com2017 28 12 2016 13 87 90 © 2017 Lai et al. This work is published and licensed by Dove Medical Press Limited2017The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Comorbid obsessive–compulsive disorder (OCD) and bipolar disorder (BD) have long been an intractable problem in clinical practice. The increased risk of manic/hypomanic switch hinders the use of antidepressants for managing coexisting OCD symptoms in BD patients. We herein present a case of a patient with BD–OCD comorbidity, who was successfully treated with mood stabilizers and aripiprazole augmentation. The young female patient reported recurrent depressive episodes and aggravating compulsive behaviors before hospitalization. Of note, the patient repetitively attempted suicide and reported dangerous driving because of intolerable mental sufferings. The preexisting depressive episode and OCD symptoms prompted the use of paroxetine, which consequently triggered the manic switching. Her diagnosis was revised into bipolar I disorder. Minimal response with mood stabilizers prompted the addition of aripiprazole (a daily dose of 10 mg), which helped to achieve significant remission in emotional and obsessive–compulsive symptoms. This case highlights the appealing efficacy of a small dose of aripiprazole augmentation for treating BD–OCD comorbidity. Well-designed clinical trials are warranted to verify the current findings.\n\nKeywords\naripiprazolebipolar disorderobsessive–compulsive disordersuicide\n==== Body\nIntroduction\nAlthough the phenomenology of coexisting obsessive–compulsive disorder (OCD) and bipolar disorder (BD) has been identified for more than 100 years,1 the etiological and nosological aspects of this medical issue remain largely unknown. Symptoms of OCD may occur before, during, or after the first mood episode and, in most cases, fluctuate with mood swings.2 In this regard, the majority of BD–OCD comorbidities are considered to be a subtype of BD, rather than two separate diseases.3\n\nTo date, no standard pharmacotherapy for cooccurring BD–OCD has been established. Antidepressants, especially for selective serotonin reuptake inhibitors (SSRIs), which are first-line options for OCD treatment, are strictly restricted for BD–OCD individuals because of the potential to elicit manic/hypomanic switching.4 In majority of the cases, a combination of multiple mood stabilizers or augmentative antipsychotics to mood stabilizers constitute the routine medication regimens.5 However, due to the lack of well-designed clinical trials, case reports of successful treatment in patients with comorbid BD–OCD are of important reference value for clinical practice.\n\nWe herein present a case of a young female patient who suffered from recurrent mood episodes and symptoms of OCD. This patient reported repetitive suicidal ideations and behaviors. A combination of quetiapine and valproate stabilized her mood; however, it did not lead to apparent improvement of her OCD symptoms. Therefore, a small dose of aripiprazole was added to the mood stabilizers, which consequently achieved significant remission in her obsessive–compulsive symptoms. This case report favors the use of augmentative aripiprazole in patients with comorbid BD–OCD who respond poorly to mood stabilizers.\n\nCase presentation\nVery briefly, we would like to introduce our case report as follows. Mrs A, a 28-year-old woman, was admitted to the Department of Psychiatry in our hospital because of recurrent depressive episodes and aggravating compulsive behaviors. Two years prior to admission, this patient developed her first depressive episode after breaking up with her ex-boyfriend. Thereafter, this patient became depressed and had insomnia, loss of appetite, and loss of interest. Meanwhile, she began to repetitively tidy up her belongings and check whether the windows and doors were closed. There was no suicidal ideation reported at that moment and she could still adhere to the work as a bank staff. However, pressure at work made her situation worse. Her obsessive behaviors gradually aggravated, with repetition rate remarkably increasing from several times per day to dozens of times per day. The obsessive behaviors always worsen when her mood became labile. This patient became easily upset and agitated when being persuaded by her family members. About half a year prior to admission, this patient reported the first suicidal attempt after fighting with her parents. She went into emotional outburst, stood at the window, and claimed to end her own life. Her parents even kneeled on the floor to take her out of committing suicide. Since then, she had reported repetitive suicidal attempts. She would rush to the balcony or windows and would attempt to commit suicide by jumping down from the building, while she was also reported with dangerous driving behaviors. Consequently, her daily life and job were seriously disrupted.\n\nThe patient was then sent to our hospital by her parents. A primary diagnosis of OCD was made, and paroxetine was prescribed at a daily dose of 40 mg. About a week later, the patient became extremely excited, talkative, and vigorous. Although paroxetine was discontinued soon afterward and quetiapine was initiated, her manic state lasted for nearly 3 weeks. Therefore, hospitalization was suggested by her doctor.\n\nAfter admission, a comprehensive physical and laboratory examinations were performed to exclude unknown underlying physical diseases. Besides, cranial magnetic resonance imaging scan was also normal. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, this patient was dually diagnosed with bipolar I disorder and OCD. Quetiapine was gradually titrated up to 700 mg per day with concomitant valproate at 1,000 mg per day. Although her emotion became stable with these mood stabilizers, the patient reported an inadequate response in symptoms of OCD. A small dose of atypical antipsychotics was considered to enhance the treatment efficacy. Fascinatingly, an add-on therapy of aripiprazole 10 mg per day promoted accelerating alleviation of her obsessive behaviors. Meanwhile, no severe adverse events were observed. Her remission in emotional and OCD symptoms was well maintained in the follow-up visits. No suicidal attempt was reported after hospital discharge. A detailed rating of clinical scales is recorded in Figure 1.\n\nThis work was approved by the Institute Ethical Committee of the First Affiliated Hospital, Zhejiang University School of Medicine, and written informed consent was obtained from the patient and her guardians.\n\nDiscussion\nThe condition of BD–OCD comorbidity has always been common in clinical practice. However, “spurious” OCD comorbidity in BD should be carefully differentiated from the “true” comorbidity. In most cases of comorbid subjects, the OCD symptoms appear to be closely linked to affective symptoms, manifesting dominantly an episodic and mood-dependent course.6 In other words, the OCD symptoms in these individuals were part of BD rather than a separate disease. To date, the optimal treatment protocols for BD–OCD comorbidity were not sufficiently elucidated. Our study indicates that low-dose augmentation with aripiprazole may help to relieve the accompanying symptoms of OCD in BD patients. Although a combination of mood stabilizers effectively alleviated the emotional symptoms, additional aripiprazole may be necessary to address the remaining symptoms of OCD. To our knowledge, the dose of aripiprazole (10 mg per day) in our patient was lower than other documented cases (15–25 mg per day).7,8 Moreover, no published literature has ever discussed the impact of augmentative medications on suicidal risk in BD–OCD patients.\n\nAripiprazole, an atypical antipsychotic, acts as a partial agonist at the D2 and 5-HT1A receptors, as well as an antagonist at 5-HT2A receptor.9 Aripiprazole monotherapy, or as an adjuvant to mood stabilizers, is efficacious in managing acute mania and stabilization phases of BD, but not bipolar depression.10 Besides, recent evidence favors the use of augmentative aripiprazole for SSRIs-refractory OCD.11,12 However, long-term use of aripiprazole is associated with increased risk of extrapyramidal syndromes (EPSs).10 Therefore, defining the minimum effective dose of aripiprazole is essential for preventing EPSs. In our patient, a low-dose of aripiprazole augmentation exhibited remarkable anti-OCD effect. Of note, the add-on therapy to mood stabilizers was initiated after partial remission in emotional symptoms. The aforementioned information implies a promising two-step strategy for BD–OCD treatment. That is, first to attenuate the mood problem with mood stabilizers and then, if necessary, deal with the obsessive behaviors with an adjuvant, such as the employment of aripiprazole indicated in our study. This two-step strategy not only helps avoid the unnecessary add-on medications if adequate response was observed with mood stabilizers but also facilitates the determination of minimum effective dose of the adjuvant.\n\nThe suicidal risk in BD–OCD patients has not been fully elucidated, as well as drug-induced suicidal ideations. Patients with BD–OCD comorbidity reported more suicidal attempts than those without morbidity.13 Several antipsychotics, including risperidone,14 olanzapine,15 quetiapine,16 and aripiprazole,7,8 were suggested due to the benefits in relieving the OCD symptoms in BD patients. However, in these studies, little attention has been paid to the emergent suicidal ideations following the antipsychotic augmentation. A few case reports documented the possible link of using aripiprazole with suicidal ideation.17 However, epidemiological data in large sample revealed that consuming aripiprazole was not associated with more suicide events compared to other atypical antipsychotics.18 Moreover, aripiprazole users had reported significantly lower risk of all-cause mortality among various antipsychotics.19 Given the recurrent onset of suicidal attempts in our patient, special attention should be paid to the suicidal profiles of antipsychotic augmentation in BD–OCD patients.\n\nTo conclude, the present case study provides supporting evidence that aripiprazole augmentation to mood stabilizers was efficacious in patients with BD–OCD comorbidity. A brief two-step strategy for managing BD–OCD comorbidity was raised. Besides, paying special attention to suicidal risk surround antipsychotic augmentation was also suggested. In the future, well-designed studies are warranted to verify our findings.\n\nAcknowledgments\nThis work was supported by a grant of National Clinical Research Center for Mental Health Disorders (2015BAI1-3B02). The authors appreciate the patient and her guardians for their understanding.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Detailed record of the scores of clinical scales during in-patient treatment.\n\nNotes: As quetiapine was already initiated before hospitalization, it was continued at a dose of 400 mg/day after admission and gradually titrated up to 700 mg/d in 2 weeks. Valproate was initiated in the second week and titrated up to 1,000 mg/d in 1 week. Aripiprazole was added 3 weeks after admission at an initial dose of 5 mg/d and increased to 10 mg/d 3 days later.\n\nAbbreviations: HAMD-24, Hamilton depression rating scale (24 items); BRMS, Beth–Rafaelsen mania scale; Y-BOCS, Yale–Brown obsessive–compulsive scale.\n==== Refs\nReferences\n1 Morel BA Traité des maladies mentales 2nd ed Paris, France Masson 1860 French \n2 Tonna M Amerio A Odone A Comorbid bipolar disorder and obsessive-compulsive disorder: which came first? Aust N Z J Psychiatry 2016 50 7 695 698 \n3 Amerio A Tonna M Odone A Ghaemi SN Comorbid Bipolar Disorder and Obsessive-Compulsive Disorder: An Old Debate Renewed Psychiatry Investig 2016 13 3 370 371 \n4 Perugi G Toni C Frare F Travierso MC Hantouche E Akiskal HS Obsessive-compulsive-bipolar comorbidity: a systematic exploration of clinical features and treatment outcome J Clin Psychiatry 2002 63 12 1129 1134 12523872 \n5 Amerio A Odone A Marchesi C Ghaemi SN Treatment of comorbid bipolar disorder and obsessive-compulsive disorder: a systematic review J Affect Disord 2014 166 258 263 25012439 \n6 Amerio A Odone A Liapis CC Ghaemi SN Diagnostic validity of comorbid bipolar disorder and obsessive-compulsive disorder: a systematic review Acta Psychiatr Scand 2014 129 5 343 358 24506190 \n7 Uguz F Successful treatment of comorbid obsessive-compulsive disorder with aripiprazole in three patients with bipolar disorder Gen Hosp Psychiatry 2010 32 5 556 558 20851277 \n8 Patra S Treat the disease not the symptoms: successful management of obsessive compulsive disorder in bipolar disorder with aripiprazole augmentation Aust N Z J Psychiatry 2016 50 8 809 810 \n9 Davies MA Sheffler DJ Roth BL Aripiprazole: a novel atypical antipsychotic drug with a uniquely robust pharmacology CNS Drug Rev 2004 10 4 317 336 15592581 \n10 Meduri M Gregoraci G Baglivo V Balestrieri M Isola M Brambilla P A meta-analysis of efficacy and safety of aripiprazole in adult and pediatric bipolar disorder in randomized controlled trials and observational studies J Affect Disord 2016 191 187 208 26674213 \n11 Sayyah M Sayyah M Boostani H Ghaffari SM Hoseini A Effects of aripiprazole augmentation in treatment-resistant obsessive-compulsive disorder (a double blind clinical trial) Depress Anxiety 2012 29 10 850 854 22933237 \n12 Dold M Aigner M Lanzenberger R Kasper S Antipsychotic augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: an update meta-analysis of double-blind, randomized, placebo-controlled trials Int J Neuropsychopharmacol 2015 18 9 pii: pyv047 \n13 Ozdemiroglu F Sevincok L Sen G Comorbid obsessive-compulsive disorder with bipolar disorder: a distinct form? Psychiatry Res 2015 230 3 800 805 26561371 \n14 Raja M Azzoni A Clinical management of obsessive-compulsive-bipolar comorbidity: a case series Bipolar Disord 2004 6 3 264 270 15117406 \n15 Petrikis P Andreou C Bozikas VP Karavatos A Effective use of olanzapine for obsessive-compulsive symptoms in a patient with bipolar disorder Can J Psychiatry 2004 49 8 572 573 \n16 Stratta P de Cataldo S Mancini G Gianfelice D Rinaldi O Rossi A Quetiapine as adjunctive treatment of a case of rapid-cycling bipolar disorder with comorbidity Hum Psychopharmacol 2003 18 7 559 560 14533138 \n17 Selvaraj V Ramaswamy S Sharma A Wilson D New-onset psychosis and emergence of suicidal ideation with aripiprazole Am J Psychiatry 2010 167 12 1535 1536 21131415 \n18 Ulcickas Yood M Delorenze G Quesenberry CP Jr Epidemiologic study of aripiprazole use and the incidence of suicide events Pharmacoepidemiol Drug Saf 2010 19 11 1124 1130 20925132 \n19 Ringbäck Weitoft G Berglund M Lindström EA Nilsson M Salmi P Rosén M Mortality, attempted suicide, re-hospitalisation and prescription refill for clozapine and other antipsychotics in Sweden-a register-based study Pharmacoepidemiol Drug Saf 2014 23 3 290 298 24435842\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6328",
"issue": "13()",
"journal": "Neuropsychiatric disease and treatment",
"keywords": "aripiprazole; bipolar disorder; obsessive–compulsive disorder; suicide",
"medline_ta": "Neuropsychiatr Dis Treat",
"mesh_terms": null,
"nlm_unique_id": "101240304",
"other_id": null,
"pages": "87-90",
"pmc": null,
"pmid": "28096676",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "24506190;26674213;12523872;24435842;21131415;14533138;26685183;20851277;15117406;26561371;15453108;20925132;25012439;25939614;27247606;22933237;15592581;27357710",
"title": "Aripiprazole augmentation in managing comorbid obsessive-compulsive disorder and bipolar disorder: a case with suicidal attempts.",
"title_normalized": "aripiprazole augmentation in managing comorbid obsessive compulsive disorder and bipolar disorder a case with suicidal attempts"
} | [
{
"companynumb": "CN-ABBVIE-17P-035-1841516-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
"drugadditional": ... |
{
"abstract": "Pituitary apoplexy is a rare condition involving pituitary necrosis following either pituitary haemorrhage or infarction. Similarly, reversible cerebral vasoconstrictive syndrome is a cerebrovascular disorder characterised by diffuse, multifocal narrowing of cerebral arteries. Both may present with an acute, intense headache and associated neurological deficits. In postpartum women, these conditions should be considered in the differential diagnosis of post-dural puncture headache following regional anaesthesia, as serious morbidity may ensue if they are left untreated. We report the case of a patient who developed pituitary apoplexy during an emergency caesarean section under spinal anaesthesia. It was further complicated by the development of reversible cerebral vasoconstriction syndrome and stroke.",
"affiliations": "Department of Women's Anaesthesia, KK Women's and Children's Hospital, Singapore.",
"authors": "Mathur|D|D|;Lim|L F M|LF|;Mathur|M|M|;Sng|B L|BL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0310057X1404200118",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0310-057X",
"issue": "42(1)",
"journal": "Anaesthesia and intensive care",
"keywords": "caesarean section; pituitary apoplexy; postpartum headache; pregnancy; reversible cerebral vasoconstrictive syndrome; spinal anaesthesia; stroke; subarachnoid haemorrhage",
"medline_ta": "Anaesth Intensive Care",
"mesh_terms": "D000328:Adult; D000773:Anesthesia, Obstetrical; D000775:Anesthesia, Spinal; D002561:Cerebrovascular Disorders; D002585:Cesarean Section; D004630:Emergencies; D005260:Female; D006261:Headache; D006801:Humans; D010899:Pituitary Apoplexy; D011247:Pregnancy; D011644:Puerperal Disorders",
"nlm_unique_id": "0342017",
"other_id": null,
"pages": "99-105",
"pmc": null,
"pmid": "24471671",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pituitary apoplexy with reversible cerebral vasoconstrictive syndrome after spinal anaesthesia for emergency caesarean section: an uncommon cause for postpartum headache.",
"title_normalized": "pituitary apoplexy with reversible cerebral vasoconstrictive syndrome after spinal anaesthesia for emergency caesarean section an uncommon cause for postpartum headache"
} | [
{
"companynumb": "SG-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-300889",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENYLEPHRINE HYDROCHLORIDE"
}... |
{
"abstract": "A 72-year-old Japanese man was admitted to our hospital for treatment of severe COVID-19 pneumonia and was started on favipiravir, heparin calcium, and methylprednisolone pulse therapy. He recovered from respiratory failure about one month later. However, he soon developed purpura in his lower limbs and thrombocytopenia, and immune thrombocytopenia was subsequently diagnosed. Although immune thrombocytopenia is one of the early complications of COVID-19, the use of corticosteroids for COVID-19 is thought to be a factor in the late onset of immune thrombocytopenia. In cases of severe COVID-19 for which corticosteroids were used for treatment, autoimmune diseases such as immune thrombocytopenia may manifest themselves late in the disease course.",
"affiliations": "Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Hematology, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.",
"authors": "Sato|Shintaro|S|;Kurachi|Moegi|M|;Ohta|Hiroki|H|;Nakamura|Tomohiko|T|;Oba|Tomohiro|T|;Kawabe|Rie|R|;Yamakawa|Hideaki|H|;Amano|Masako|M|;Matsushima|Hidekazu|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2021.101563",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071\nElsevier\n\nS2213-0071(21)00225-2\n10.1016/j.rmcr.2021.101563\n101563\nCase Report\nDelayed onset of severe immune thrombocytopenia associated with COVID-19 pneumonia\nSato Shintaro smallerss@hotmail.com\na∗\nKurachi Moegi b\nOhta Hiroki a\nNakamura Tomohiko a\nOba Tomohiro a\nKawabe Rie a\nYamakawa Hideaki a\nAmano Masako a\nMatsushima Hidekazu a\na Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan\nb Department of Hematology, Saitama Red Cross Hospital, Saitama, Japan\n∗ Corresponding author. Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5 Shintoshin, Chuo-ku, Saitama, 330-8553, Japan. smallerss@hotmail.com\n02 12 2021\n2021\n02 12 2021\n34 10156325 7 2021\n17 11 2021\n28 11 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nA 72-year-old Japanese man was admitted to our hospital for treatment of severe COVID-19 pneumonia and was started on favipiravir, heparin calcium, and methylprednisolone pulse therapy. He recovered from respiratory failure about one month later. However, he soon developed purpura in his lower limbs and thrombocytopenia, and immune thrombocytopenia was subsequently diagnosed. Although immune thrombocytopenia is one of the early complications of COVID-19, the use of corticosteroids for COVID-19 is thought to be a factor in the late onset of immune thrombocytopenia. In cases of severe COVID-19 for which corticosteroids were used for treatment, autoimmune diseases such as immune thrombocytopenia may manifest themselves late in the disease course.\n\nKeywords\n\nCOVID-19\nDiffuse alveolar hemorrhage\nImmune thrombocytopenia\nPurpura\nAbbreviations\n\nCOVID, coronavirus disease 2019\nDAH, diffuse alveolar hemorrhage\nHD, hospital day\nHFNC, high-flow nasal cannula\nIVIG, intravenous immunoglobulin\nRT-PCR, reverse transcription polymerase chain reaction\nSARS-CoV-2, severe acute respiratory syndrome coronavirus-2\n==== Body\npmc1 Introduction\n\nCoronavirus disease 2019 (COVID-19) is a global pandemic caused by infection from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). As of May 2021, more than 160 million confirmed cases and 3.3 million deaths have been reported [1]. COVID-19 is known to cause a variety of extrapulmonary manifestations, although the primary target of SARS-CoV-2 is the respiratory tract [2]. Among these extrapulmonary manifestations, hematologic abnormalities such as deep vein thrombosis, pulmonary embolism, and arterial thrombosis account for most of the hematologic manifestations, and there are limited reports of autoimmune hematologic abnormalities [3]. We present a case of delayed onset of severe immune thrombocytopenia associated with severe COVID-19 pneumonia.\n\n2 Case presentation\n\nA 72-year-old Japanese man with well-controlled hypertension presented to his local physician 7 days prior to admission for cough and shortness of breath, and a reverse transcription polymerase chain reaction (RT-PCR) test for SARS-CoV-2 via nasopharyngeal swab was positive. He was admitted to a nearby hospital and received oxygen therapy but was referred to our hospital due to deterioration of his general condition and respiratory status.\n\nOn admission, he complained primarily of progressive dyspnea, cough, and fever at its highest of 38.5 °C. Vital signs included a pulse rate of 62 beats per minute, blood pressure of 148/86 mmHg, body temperature of 36.6 °C, respiratory rate of 16 breaths per minute, and O2 saturation of 90% on O2 at 5 L/min via mask. Chest auscultation revealed fine crackles across the bilateral lung fields. Chest X-ray revealed diffuse bilateral consolidations, and high-resolution computed tomography (HRCT) revealed extensive ground-glass opacities, consolidation with traction bronchiectasis, and volume reduction predominantly in the left lung (Fig. 1A). Laboratory tests showed a hemoglobin concentration of 118 g/L (normal range 130–170), white blood cell count of 12.6 × 109/L (4.0–9.0), lymphopenia of 0.5 × 109/L (1.0–4.0), platelet count of 34.1 × 109/μL (15.0–40.0), C-reactive protein of 17.0 mg/dL (<0.3), ferritin of 972 ng/mL (39.4–340), and D-dimer of 3.5 μL/mL (<1.0). We diagnosed the patient as having a severe case of COVID-19 pneumonia. Treatment was begun with high-flow nasal cannula (HFNC) for his respiratory failure and favipiravir 3600 mg/day on the 1st day, followed by 1600 mg/day, piperacillin/tazobactam 13.5 g/day, azithromycin 500 mg/day, heparin calcium 10,000 U/day, and methylprednisolone pulse therapy (Fig. 2). Severe respiratory failure requiring the use of HFNC continued for approximately two weeks after admission, during which two courses of high-dose intravenous pulse therapy were administered. HRCT on the 26th hospital day (HD) showed significant improvement in the ground-glass opacities and consolidation although reticular shadows indicative of fibrotic changes remained, and he was weaned from oxygen therapy on the 32nd HD (Fig. 1, Fig. 2).Fig. 1 Chest high-resolution computed tomography (HRCT) images of the upper and lower lobes. (A) On the day of admission, extensive ground-glass opacities and consolidation were seen predominantly in the left lung, and traction bronchiectasis and volume reduction were also present. (B) On the 26th hospital day, antiviral therapy and corticosteroid treatment including two rounds of steroid pulse therapy resulted in a marked reduction of ground-glass opacities and consolidation although reticular shadows indicative of fibrotic changes were still present. (C) On the 39th hospital day, ground-glass opacities and consolidation reappeared in the bilateral lungs superimposed on reticular shadows indicating residual fibrotic change after COVID-19 pneumonia along with hemoptysis, purpura, and thrombocytopenia. A diagnosis of diffuse alveolar hemorrhage was made by bronchoalveolar lavage after the patient was intubated. (D) On the 51st hospital day, HRCT findings improved markedly with the increase in corticosteroid dosage.\n\nFig. 1\n\nFig. 2 Timeline of platelet counts in the 72-year-old male patient with immune thrombocytopenia during treatment of COVID-19 pneumonia. BMA, bone marrow aspiration; HFNC, high-flow nasal cannula; mPDN, methylprednisolone; MV, mechanical ventilation; PDN, prednisolone.\n\nFig. 2\n\nOn the 35th HD, epistaxis and purpura on his lower limbs suddenly appeared (Fig. 3A), and a complete blood count revealed isolated thrombocytopenia with a platelet count of 1.0 × 109/μL that further declined to 0.2 × 109/μL on the 38th HD (Fig. 2). The patient's coagulation times and fibrinogen level were normal, and there were no signs of hemolysis or microangiopathy on laboratory tests. Heparin-induced thrombocytopenia antibodies and testing for HBV, HCV, HIV, and CMV were negative. Antineutrophil cytoplasmic antibodies and connective tissue disease-related autoantibodies were also negative. Bone marrow aspiration revealed hypocellular marrow with megakaryocyte hyperplasia. On the 39th HD, his respiratory condition rapidly deteriorated with the occurrence of hemoptysis, and HRCT showed the new appearance of extensive ground-glass opacities superimposed on reticular shadows indicative of residual fibrotic changes such as those seen after COVID-19 pneumonia (Fig. 1C). HRCT findings were similar to those at the onset of his COVID pneumonia, but RT-PCR testing for SARS-CoV-2 was negative. We transferred the patient to the intensive care unit for mechanical ventilatory treatment, and bronchoscopy was performed after endotracheal intubation. Bronchoalveolar lavage in the left B3c showed increasingly hemorrhagic returns with a 74% recovery rate (Fig. 3B). The fluid contained 2.8 × 105 cells/mL consisting of 56.2% macrophages, 3.0% lymphocytes, 40.4% neutrophils, and 0.2% eosinophils and was negative for microorganisms including that by Pneumocystis jirovecii PCR. Cytological examination of the bronchoalveolar lavage fluid revealed a significant hemorrhagic component and hemosiderin-containing alveolar macrophages stained with iron (Fig. 3C and D). Based on these findings, a diagnosis of immune thrombocytopenia complicated with diffuse alveolar hemorrhage (DAH) associated with COVID-19 was made, and we started methylprednisolone pulse therapy. On the 43rd HD, the patient's platelet count recovered to 3.4 × 109/μL without the administration of intravenous immunoglobulin (IVIG), and the patient was extubated after 5 days of mechanical ventilation. Corticosteroids were tapered from 70 mg/day (1 mg/kg) of prednisolone to 10 mg/day every other week (Fig. 2). The patient's HRCT findings had generally improved by the 52nd HD (Fig. 1D), and he was discharged on the 73rd HD after undergoing rehabilitation.Fig. 3 (A) Purpuric lesions on the patient's lower extremity. (B) Bronchoalveolar lavage fluid from the left B3 bronchus had a sanguineous appearance. (C) Cytological examination of the bronchoalveolar lavage fluid revealed histiocytes and neutrophils against a background of bleeding components (Papanicolaou stain) and (D) hemosiderin contained in alveolar macrophages (iron stain).\n\nFig. 3\n\n3 Discussion\n\nWe gained two important clinical insights from this case. The first is that treatment including that with corticosteroids for COVID-19 pneumonia may lead to the delayed onset of immune thrombocytopenia. The second is that lung fibrosis caused by COVID-19 may predispose patients to DAH.\n\nThe use of corticosteroids may delay the onset of immune thrombocytopenia associated with COVID-19. Immune thrombocytopenia is secondarily manifested by autoimmune and lymphoproliferative disorders and infectious diseases (e.g., Helicobacter pylori, human immunodeficiency virus, hepatitis C virus, Epstein-Barr virus, cytomegalovirus, and varicella zoster virus) [4]. In addition to these viral infections, the recent pandemic of SARS-CoV-2 has also been found to be one of the causes of immune thrombocytopenia [3]. The pathophysiology of thrombocytopenia includes activation of T cells due to viral infection, modification of host immune function by cytokine release, and cross-reactions of antiviral antibodies with glycoproteins such as GP IIb/IIIA and GP Ib/IX expressed on platelets and megakaryocytes [5]. Furthermore, heparin, azithromycin, chloroquine, hemodialysis, and extra-corporeal membrane oxygenation used in the treatment of COVID-19 may also be triggers for the onset of the disease [6,7]. In the latest systematic review, the mean number of days from the onset of COVID-19 to the diagnosis of immune thrombocytopenia was reported to be 13.3 ± 7.3 days [3]. In our patient, 47 days had elapsed between the onset of COVID-19 and the diagnosis of immune thrombocytopenia, and, to our knowledge, such a late onset of immune thrombocytopenia has not been previously reported. The platelet count of our patient increased after methylprednisolone pulse therapy, but it clearly decreased with the subsequent tapering of corticosteroids (Fig. 2). Therefore, we speculate that the immune thrombocytopenia may have become apparent as the corticosteroids were tapered off following improvement of COVID-19 pneumonia and that it had initially been suppressed by corticosteroids for some time after hospitalization. Corticosteroids are effective in reducing mortality and the rate of mechanical ventilation in severe COVID-19 [8], and recent guidelines recommend corticosteroids treatment for 10 days or until discharge for patients with severe or critical COVID-19 [9]. In patients with COVID-19 treated with corticosteroids or those who used corticosteroids for an autoimmune disease, it may be necessary to monitor coagulation functions for some time after COVID-19 treatment ends (Table 1).Table 1 Reported cases of COVID-19 pneumonia with severe immune thrombocytopenia.\n\nTable 1Author\tAge\n/Sex\tSeverity of COVID-19 pneumoniaa\tCS\tHeparin\tTime from COVID-19 onset to immune thrombocytopenia diagnosis\tSeverity of immune\nthrombocytopeniab\tTreatment of immune\nthrombocytopenia\tOutcome\t\nMartincic [10]\t48/M\tcritical\tunused\tused\t12days\tsevere (gastrointestinal bleeding)\tCS, IVIG\tAlive\t\nDeruelle [11]\t41/M\tcritical\tunused\tused\t27days\tsevere (tracheal hemorrhage)\tCS, IVIG\tAlive\t\nLevesque [12]\t53/M\tcritical\tunused\tused\t27days\tsevere (intracranial bleeding)\tCS, IVIG, PT romiplostim、vincristine\tAlive\t\nZulfigar [13]\t65/F\tsevere\tunused\tused\t4days\tsevere (intracranial bleeding)\tCS, IVIG, PT\tN.D.\t\nBomhof [14]\t67/M\tcritical\tunused\tused\t21days\tsevere (intracranial bleeding)\tPT\tDead\t\nMahevas [15]\t74/M\tsevere\tN.D.\tN.D.\t12days\tsevere (gastrointestinal bleeding)\tCS\tAlive\t\nMahevas [15]\t66/F\tsevere\tN.D.\tN.D.\t8days\tsevere (intracranial bleeding)\tCS, IVIG, eltrombopag\tAlive\t\nOur case\t72/M\tsevere\tused\tused\t47days\tsevere (diffuse alveolar hemorrhage)\tCS\tAlive\t\nCS, corticosteroid; PT, platelet transfusion; IVIG, intravenous immunoglobulin.\n\na Severity of COVID-19 is based on NIH COVID-19 treatment guidelines.\n\nb Severity of immune thrombocytopenia is based onan international working group report of immune thrombocytopenic purpura of adults.\n\nTo understand the characteristics of severe immune thrombocytopenia associated with COVID-19 that requires therapeutic intervention, we summarized the previously reported cases in the Table 1 [[10], [11], [12], [13], [14], [15], [16]]. Clinicians need to be cautious when discussing immune thrombocytopenia based on its severity because methods to assess immune thrombocytopenia-specific bleeding have not yet been validated in large prospective studies, and a system for classifying the severity of adult immune thrombocytopenia is not yet established [16]. An international working group has proposed that severe immune thrombocytopenia should be defined as bleeding that is clinically relevant and requires therapeutic intervention [16], and we used this definition in this report. As shown in the table, 8 patients with a mean age of 60.7 years have been reported, and the severity of COVID-19 pneumonia as classified by the World Health Organization was critical in 4 patients and severe in the other 4 [17]. Corticosteroids were used as a therapeutic agent for COVID-19 in only one patient, whereas heparin was used in 6 patients. Low-molecular-weight heparin is the only anticoagulant recommended for the treatment of coagulation abnormalities associated with COVID-19 [18]. We think that the effect of heparin on internal bleeding in immune thrombocytopenia is assumed to be small because most of the bleeding during heparin use in COVID-19 patients occurs intramuscularly [19]. The mean number of days from the onset of COVID-19 to the diagnosis of immune thrombocytopenia was 19.7 ± 13.9 days, and this tended to be longer than the number of days reported in the systematic review cited earlier (13.3 ± 7.3 days) [3]. Therefore, in patients with severe or critical COVID-19, clinicians should be alert to the development of immune thrombocytopenia for up to 4 or 5 weeks after the onset of COVID-19.\n\nThe incidence of DAH associated with immune thrombocytopenia is rare, and only a few cases have been reported [20]. To our knowledge, the present patient is the first to show DAH in immune thrombocytopenia associated with COVID-19. Several factors may have led to the development of DAH in this patient. First, the lung damage caused by COVID-19 may have resulted in tissue fragility leading to easy bleeding. The pulmonary pathology of COVID-19 shows diffuse damage to alveolar and vascular epithelium, which is often permanent [21]. In our patient, the extent of the lesions shown on chest CT at the onset of COVID-19 and with DAH were similar (Fig. 1A, C), suggesting that the site of lung injury caused by COVID-19 may have been predisposed to alveolar hemorrhage at the occurrence of immune thrombocytopenia. Nagaharu et al. pointed out that DAH can occur in COVID-19-negative immune thrombocytopenia due to underlying respiratory disease [20]. The second factor is the effect of corticosteroids used in COVID-19 treatment. Unlike the other reported patients, our patient was the only one in whom corticosteroids were used to treat COVID-19 (Table), and we cannot rule out the possibility that corticosteroids may have prolonged the healing process of lung injury.\n\nIn the treatment of severe immune thrombocytopenia in these patients, most responded to corticosteroids and IVIG, but 2 patients had a refractory course requiring drugs such as romiplostim, vincristine, and eltrombopag in addition to corticosteroids and IVIG. Practical guidance from the British Society of Haematology recommends corticosteroids as first-line treatment and IVIG as second line treatment for COVID-19-positive immune thrombocytopenia. However, thrombopoietin receptor agonists and platelet transfusions should be avoided because of the risk of increased thrombosis, as should immunosuppressive drugs including rituximab because their impact on COVID-19 is still unclear [22]. Of these reported patients, one patient who received only platelet transfusion died, but all of the patients treated with corticosteroids or IVIG survived, indicating that even severe immune thrombocytopenia is likely to respond to standard therapy.\n\nIn conclusion, we experienced a case of delayed-onset immune thrombocytopenia associated with COVID-19 pneumonia. Because of the possibility of the delayed development of thrombocytopenia in patients after treatment of COVID-19 with corticosteroid-containing drugs, they should be followed up for a certain period of time. In addition, residual fibrotic changes in the lung due to COVID-19 pneumonia may be associated with complications of DAH in patients with immune thrombocytopenia.\n\nDeclaration of competing interest\n\nThe authors declare no Conflicts of Interest (COI) in association with this article.\n==== Refs\nReferences\n\n1 (Retrieved on June 25, 2021) https://covid19.who.int/\n2 Gupta A. Madhavan M.V. Sehgal K. Extrapulmonary manifestations of COVID-19 Nat. Med. 7 2020 1017 1032\n3 Taherifard E. Taherifard E. Movahed H. Hematologic autoimmune disorders in the course of COVID-19: a systematic review of reported cases Hematology 26 2021 225 239 33594951\n4 Cines D.B. Liebman H. Stasi R. Pathobiology of secondary immune thrombocytopenia Semin. Hematol. 46 2009 S2 S14 19245930\n5 Audia S. Mahévas M. Samson M. Pathogenesis of immune thrombocytopenia Autoimmun. Rev. 16 2017 620 632 28428120\n6 Liu Y. Sun W. Guo Y. Association between platelet parameters and mortality in coronavirus disease 2019: retrospective cohort study Platelets 31 2020 490 496 32297540\n7 Pavord S. Thachil J. Hunt B.J. Practical guidance for the management of adults with immune thrombocytopenia during the COVID-19 pandemic Br. J. Haematol. 189 2020 1038 1043 32374026\n8 Pulakurthi Y.S. Pederson J.M. Saravu K. Corticosteroid therapy for COVID-19: a systematic review and meta-analysis of randomized controlled trials Medicine (Baltim.) 100 2021 e25719\n9 Retrieved on July 25, 2021) https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/\n10 Martincic Z. Skopec B. Rener K. Severe immune thrombocytopenia in a critically ill COVID-19 patient Int. J. Infect. Dis. 99 2020 269 271 32771636\n11 Deruelle E. Ben Hadj Salem O. Sep Hieng S. Immune thrombocytopenia in a patient with COVID-19 Int. J. Hematol. 112 2020 883 888 32677007\n12 Lévesque V. É Millaire Corsilli D. Severe immune thrombocytopenic purpura in critical COVID-19 Int. J. Hematol. 112 2020 746 750 32613314\n13 Zulfiqar A.A. Lorenzo-Villalba N. Hassler P. Immune thrombocytopenic purpura in a patient with covid-19 N. Engl. J. Med. 30 2020 e43\n14 Bomhof G. Mutsaers P.G.N.J. Leebeek F.W.G. COVID-19-associated immune thrombocytopenia Br. J. Haematol. 190 2020 e61 e64 32420612\n15 Mahévas M. Moulis G. Andres E. Clinical characteristics, management and outcome of COVID-19-associated immune thrombocytopenia: a French multicentre series Br. J. Haematol. 190 2020 e224 e229 32678953\n16 Rodeghiero F. Stasi R. Gernsheimer T. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group Blood 113 2009 2386 2393 19005182\n17 WHO Clinical management of covid-19—interim guidance Retrieved on July 25, 2021 https://www.who.int/publications/i/item/clinical-management-of-covid-19\n18 Thachil J. Tang N. Gando S. ISTH interim guidance on recognition and management of coagulopathy in COVID-19 J. Thromb. Haemostasis 18 2020 1023 1026 32338827\n19 Lucatelli P. De Rubeis G. Citone M. Heparin-related major bleeding in covid-19-positive patient: perspective from the outbreak Cardiovasc. Intervent. Radiol. 43 2020 1216 1217 32468143\n20 Nagaharu K. Masuya M. Kawakami K. Successful management of immune thrombocytopenia presenting with lethal alveolar hemorrhage Case Rep Hematol 2019 5170282 31281686\n21 Batah S.S. Fabro A.T. Pulmonary pathology of ARDS in COVID-19: a pathological review for clinicians Respir. Med. 2021 106239 33246294\n22 Pavord S. Thachil J. Hunt B.J. Practical guidance for the management of adults with immune thrombocytopenia during the COVID-19 pandemic Br. J. Haematol. 189 2020 1038 1043 32374026\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "34()",
"journal": "Respiratory medicine case reports",
"keywords": "COVID, coronavirus disease 2019; COVID-19; DAH, diffuse alveolar hemorrhage; Diffuse alveolar hemorrhage; HD, hospital day; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; Immune thrombocytopenia; Purpura; RT-PCR, reverse transcription polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101563",
"pmc": null,
"pmid": "34873569",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32677007;32468143;28428120;19005182;19245930;32771636;31281686;33246294;32338827;32297540;32613314;32678953;33594951;32420612;32374026",
"title": "Delayed onset of severe immune thrombocytopenia associated with COVID-19 pneumonia.",
"title_normalized": "delayed onset of severe immune thrombocytopenia associated with covid 19 pneumonia"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-323361",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN"
},
"dr... |
{
"abstract": "BACKGROUND\nHepatitis E virus (HEV) is one of the common causes of acute and chronic viral hepatitis with a global distribution. Genotypes 1 and 2 only affect humans and produce acute hepatitis epidemics in endemic regions (Asia, Africa). In nonendemic areas (America, Europe), genotypes 3 and 4 are considered a zoonosis and cause sporadic acute hepatitis. HEV has been described in solid organ transplant recipients; however, data on lung transplant patients are limited.\n\n\nOBJECTIVE\nTo present the first 3 cases of HEV infection in lung transplant recipients in our unit.\n\n\nMETHODS\nWe report 3 cases of HEV infection in post-transplant patients presenting with symptoms and alterations in liver enzymes. All patients have no history of travel outside Spain prior to observing abnormalities in the liver function. Diagnoses were made with in-home polymerase chain reaction and enzyme-linked immunosorbent assay (IgG/IgM). The first patient was not treated and died of progressive hepatic disease, with postmortem diagnosis of HEV infection complications. The other 2 patients were treated with ribavirin after the diagnosis of HEV infection. Ribavirin was discontinued in 1 patient because of anemia necessitating red blood cell transfusions.\n\n\nCONCLUSIONS\nHEV should be considered in the differential diagnosis of patients with abnormal liver enzymes after transplant. Early detection and treatment have implications in the prevention of liver failure and mortality. Large prospective seroprevalence studies of HEV in lung transplant patients are warranted to recognize the epidemiology of this infection in lung transplant recipients.",
"affiliations": "Section of Pulmonary Medicine, University of the Philippines-Philippine General Hospital, Manila, Philippines.;Section of Pulmonary Medicine, Hospital Universitario Puerta de Hierro, Majadahonda, Spain. Electronic address: s.aguado.ibanez@gmail.com.;Section of Pulmonary Medicine, Hospital Universitario Puerta de Hierro, Majadahonda, Spain.;Section of Pulmonary Medicine, Hospital Universitario Puerta de Hierro, Majadahonda, Spain.;Section of Pulmonary Medicine, Hospital Universitario Puerta de Hierro, Majadahonda, Spain.;Section of Microbiology, Instituto de Salud Carlos III, Madrid, Spain.;Section of Microbiology, Hospital Universitario Puerta de Hierro, Majadahonda, Spain.;Section of Pulmonary Medicine, Hospital Universitario Puerta de Hierro, Majadahonda, Spain.;Section of Pulmonary Medicine, Hospital Universitario Puerta de Hierro, Majadahonda, Spain.",
"authors": "Ambrocio|G P L|GPL|;Aguado|S|S|;Carrillo|J|J|;Laporta|R|R|;Lazaro-Carrasco|M|M|;Avellon|A|A|;Aran-Toha|G|G|;Ussetti|M|M|;Aguilar|M|M|",
"chemical_list": "D000998:Antiviral Agents; D012254:Ribavirin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2018.10.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "51(2)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016751:Hepatitis E; D016752:Hepatitis E virus; D006801:Humans; D016867:Immunocompromised Host; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012254:Ribavirin; D066027:Transplant Recipients",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "376-379",
"pmc": null,
"pmid": "30879545",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatitis E Virus Infection in Lung Transplant Recipients: A Case Series.",
"title_normalized": "hepatitis e virus infection in lung transplant recipients a case series"
} | [
{
"companynumb": "PH-FRESENIUS KABI-FK201903853",
"fulfillexpeditecriteria": "1",
"occurcountry": "PH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": ... |
{
"abstract": "OBJECTIVE\nNeoadjuvant chemotherapy may represent an alternative to irradiation in locally advanced squamous cell cervical cancer. Aims of this study were to compare a three-drug (paclitaxel, ifosfamide, and cisplatin [TIP]) with a two-drug (ifosfamide and cisplatin [IP]) regimen and to assess the prognostic value of pathologic response on survival.\n\n\nMETHODS\nPatients (n = 219) were randomly assigned to ifosfamide 5 g/m(2) during 24 hours plus cisplatin 75 mg/m(2), or paclitaxel 175 mg/m(2) plus ifosfamide 5 g/m(2) during 24 hours and cisplatin 75 mg/m(2) every 3 weeks for three courses.\n\n\nRESULTS\nGrades 3 to 4 neutropenia, anemia, and thrombocytopenia were more frequent with TIP. We recorded four deaths related to toxicity. The optimal pathologic response (OPT) rate (residual disease < 3 mm stromal invasion) was higher with TIP than with IP (48% v 23%; odds ratio, 3.22; 95% CI, 1.69 to 5.88; P = .0003). At a median follow-up of 43.4 months, 79 women experienced disease progression or died (46 in the IP arm, 33 in the TIP arm). Patients receiving TIP experienced a treatment failure rate 25% less than those receiving IP, but this difference was not statistically significant (hazard ratio [HR], 0.75; 95% CI, 0.48 to 1.17; P = .20). Sixty-one patients died (37 in the IP arm, 24 in the TIP arm), and the HR of death was in favor of TIP, although not significantly (HR, 0.66; 95% CI, 0.39 to 1.10; P = .11). In patients assessable for response (n = 189), the average death rates were higher in the group that did not achieve OPT (HR, 5.88; 95% CI, 2.50 to 13.84; P < .0001).\n\n\nCONCLUSIONS\nThe TIP regimen is associated with a higher response rate than the IP regimen, without a statistically significant effect on overall survival. OPT was a prognostic factor for survival.",
"affiliations": "Department of Obstetrics and Gynecology, University of Milano-Bicicca, San Gerardo Hospital, Monza, Italy.",
"authors": "Buda|Alessandro|A|;Fossati|Roldano|R|;Colombo|Nicoletta|N|;Fei|Francesca|F|;Floriani|Irene|I|;Gueli Alletti|Desiderio|D|;Katsaros|Dionyssios|D|;Landoni|Fabio|F|;Lissoni|Andrea|A|;Malzoni|Carmine|C|;Sartori|Enrico|E|;Scollo|Paolo|P|;Torri|Valter|V|;Zola|Paolo|P|;Mangioni|Costantino|C|",
"chemical_list": "D043823:Taxoids; D002945:Cisplatin; D007069:Ifosfamide",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2005.04.172",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "23(18)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D016009:Chi-Square Distribution; D002945:Cisplatin; D005260:Female; D006801:Humans; D007069:Ifosfamide; D007558:Italy; D016015:Logistic Models; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D016016:Proportional Hazards Models; D016019:Survival Analysis; D043823:Taxoids; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "4137-45",
"pmc": null,
"pmid": "15961761",
"pubdate": "2005-06-20",
"publication_types": "D016430:Clinical Trial; D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Randomized trial of neoadjuvant chemotherapy comparing paclitaxel, ifosfamide, and cisplatin with ifosfamide and cisplatin followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study.",
"title_normalized": "randomized trial of neoadjuvant chemotherapy comparing paclitaxel ifosfamide and cisplatin with ifosfamide and cisplatin followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma the snap01 studio neo adjuvante portio italian collaborative study"
} | [
{
"companynumb": "IT-PFIZER INC-2021089586",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MESNA"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nRetinal and choroidal vascular occlusion is a vision-threatening complication of therapeutic injections in the facial region. The early identification and early treatment are necessary to reduce the risk of harm to the patient.\nWe report an extremely rare case of embolic retinal and choroidal vascular occlusion after peribulbar triamcinolone injection in a patient with thyroid-associated ophthalmopathy.\nCentral retinal artery occlusion.\n\n\nMETHODS\nFirst, we performed a fundus examination in the patient. Triamcinolone embolus was observed in both retinal and choroidal vessels. Anterior chamber paracentesis and ocular massage combined with venous injections of alprostadil and Ginaton as well as an acupoint injection of compound anisodine were performed immediately. Sublingual glyceryl trinitrate and intraocular pressure-lowering drugs were also administered. Fundus autofluorescence, optical coherence tomography-angiography, fundus fluorescein angiography (FFA), and indocyanine green angiography (ICGA) were also conducted to evaluate the patient's condition.\n\n\nRESULTS\nOne month after the onset of the situation, the triamcinolone embolus had disappeared. The retinal edema and retinal blood perfusion were also improved. The patient's visual acuity had recovered from inexact light perception to 0.02.\n\n\nCONCLUSIONS\nEmbolic retinal and choroidal vascular occlusion is vision-threatening disease. Measures such as careful aspiration before injecting in the facial region must be taken to avoid such complications.",
"affiliations": "Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing.;Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing.;Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.;Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing.",
"authors": "Li|Gang|G|;Xu|Dongdong|D|;Hu|Zhirou|Z|;Li|Hui|H|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D014221:Triamcinolone",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000010467",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29703002MD-D-17-0778910.1097/MD.0000000000010467004675800Research ArticleClinical Case ReportEmbolic retinal and choroidal vascular occlusion after peribulbar triamcinolone injection A case reportLi Gang MDaXu Dongdong MD, PhDaHu Zhirou MDbLi Hui MDa∗NA. a Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijingb Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.∗ Correspondence: Hui Li, Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China (e-mail: lihuipumch@126.com).4 2018 27 4 2018 97 17 e046718 12 2017 24 3 2018 26 3 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nRetinal and choroidal vascular occlusion is a vision-threatening complication of therapeutic injections in the facial region. The early identification and early treatment are necessary to reduce the risk of harm to the patient.\n\nPatient concerns:\nWe report an extremely rare case of embolic retinal and choroidal vascular occlusion after peribulbar triamcinolone injection in a patient with thyroid-associated ophthalmopathy.\n\nDiagnoses:\nCentral retinal artery occlusion.\n\nInterventions:\nFirst, we performed a fundus examination in the patient. Triamcinolone embolus was observed in both retinal and choroidal vessels. Anterior chamber paracentesis and ocular massage combined with venous injections of alprostadil and Ginaton as well as an acupoint injection of compound anisodine were performed immediately. Sublingual glyceryl trinitrate and intraocular pressure-lowering drugs were also administered. Fundus autofluorescence, optical coherence tomography-angiography, fundus fluorescein angiography (FFA), and indocyanine green angiography (ICGA) were also conducted to evaluate the patient's condition.\n\nOutcomes:\nOne month after the onset of the situation, the triamcinolone embolus had disappeared. The retinal edema and retinal blood perfusion were also improved. The patient's visual acuity had recovered from inexact light perception to 0.02.\n\nLessons:\nEmbolic retinal and choroidal vascular occlusion is vision-threatening disease. Measures such as careful aspiration before injecting in the facial region must be taken to avoid such complications.\n\nKeywords\ncentral retinal artery occlusionperibulbar injectionthyroid-associated ophthalmopathytriamcinolone acetonideOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nThyroid-associated ophthalmopathy (TAO), which is the most common extrathyroidal manifestation of Graves’ disease, is an orbital disease that usually manifests in thyroid dysfunction. Repeated peribulbar injections of triamcinolone acetonide are an effective treatment for moderate-to-severe TAO, of which the most frequent side-effect is increased intraocular pressure.[1] Vision-threatening complications such as embolization of the retinal and choroidal circulation may follow therapeutic injections around the eyes, nose, and ears.[2–4] This article reports a rare case of acute vision loss with combined retinal arteriolar occlusion and choriocapillaris following a periocular injection of triamcinolone acetonide.\n\n2 Case presentation\nA 48-year-old female patient with moderate-to-severe TAO was given the fourth superior-nasal periocular injections of 20 mg triamcinolone acetonide around her eyes. Approximately 20 minutes after the injection, the patient described acute loss of vision and feelings of swelling and pain in her left eye. Ocular examinations showed inexact perception of light in the left eye with obvious subconjunctival hemorrhage and chemosis. The left pupil was dilated, and both direct and consensual pupillary light reflexes were insensitive. A fundus examination was conducted immediately, which showed deposits of whitish material in the temporal retinal vessels and subretinal yellowish white strips in the left eye (Fig. 1A and B). A day later, fundus photography revealed ischemic retinal whitening with a cherry red spot (Fig. 1C). Fundus autofluorescence showed hypoautofluorescence of the nonperfused retina (Fig. 1D). Optical coherence tomography-angiography (OCT-A) was performed at the area of the posterior pole. The OCT-A scan showed that the vascular density in the left eye was significantly decreased compared with the right eye. The retinal capillary network was discontinuous, and capillary dropout was noticeable. The thickness of the retinal neurosensory layer was increased (Fig. 2A and B). Fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) were also performed. Areas of hypofluoresence in the choroid were suggestive of choroidal nonperfusion areas. Retinal arteriolar filling defects were present in the paramacular area, and fluorescein leakage was obvious (Fig. 3A and B). All observations were thought to be associated with the blockage of multiple choroidal vessels and the retinal arteries by triamcinolone acetonide particles.\n\nFigure 1 Fundus photograph of the left eye showing the deposition of triamcinolone particles in the retinal terminal arteries (white arrow in [B]) and choriocapillaris (white arrow in [A]) when the patient suffered vision loss. The fundus photograph also shows ischemic retinal whitening with a cherry red spot (white arrow in [C]). Fundus autofluorescence shows hypoautofluorescence of the nonperfused retina (white arrow in [D]).\n\nFigure 2 Vascular density in the left eye is significantly decreased compared with the right eye. The retinal capillary network is discontinuous, and a capillary drop out is noticeable (A). The thickness of the retinal neurosensory layer is increased (B).\n\nFigure 3 Fundus fluorescein angiography (FFA) showing retinal arteriolar filling defects in the paramacular area (yellow arrow in [A]). The obvious fluorescein leakage is caused by ischemia of the retina (red arrow in [A]). Indocyanine green angiography (ICGA) shows hypofluoresence area in the choroid, suggesting areas of choroidal hypoperfusion due to triamcinolone emboli blocking the choroidal capillaries (yellow arrow in [B]). FFA = fundus fluorescein angiography, ICGA = indocyanine green angiography.\n\nAnterior chamber paracentesis and ocular massage were performed in the patient immediately in addition to venous injections of alprostadil and Ginaton and acupoint injection of compound anisodine. Antiglaucoma drugs such as carteolol, brinzolamide, and Alphagan eye drops were administered to the patient's left eye. Sublingual glyceryl trinitrate was administered immediately after the diagnosis.\n\nThe patient was followed-up for more than 1 month. OCT-A was repeated 12 days after the first visit. The vascular density in the left eye was increased, and the retinal neurosensory layer edema was improved (Fig. 4). At 40 days, fundus photography showed the absorption of triamcinolone particles (Fig. 5) and her visual acuity improved from inexact light perception to 0.02. At the last visit 26 months later, the patient‘s visual acuity recovered to 0.05.\n\nFigure 4 OCT-A showing that vascular density (A) in the left eye is increased and the retinal neurosensory layer edema is improved (B).\n\nFigure 5 Follow-up showing that the crystals of triamcinolone acetonide in the retinal vessels and choroidal capillaries had disappeared.\n\n3 Discussion\nCentral retinal artery occlusion (CRAO)is an ophthalmic emergency because it is a severe threat to vision. The incidence of CRAO is approximately 1 in 100,000 people, which accounts for 1 in 10,000 ophthalmological outpatient visits. Most cases of RAO were reported to be caused by thromboembolic disease due to atherosclerosis.[5] In 1978, Ellis[6] reported a case of CRAO after retrobulbar corticosteroid injection. After intralesional steroid injection in the craniofacial region RAO was also reported in recent years.[3,7–10] The mechanisms were explained as follows. First, because there are diffuse anastomoses in the facial arterial system, facial injections might cause retrograde embolization of the ophthalmic or central retinal arteries.[3,8] Second, the inattentive intra-arterial injection of the glucocorticoids and the consequent retrograde flow of glucocorticoid suspension could cause vascular occlusion.[10] Third, the particle size in glucocorticoid suspension ranges from 1 to 1000 μm.[11] The mean caliber of the retinal arteriole is 144.1 ± 14.4 μm (SD), and the mean caliber of the venular is 214.0 ± 22.2 μm.[12] The reason for the embolism might be that the diameter of some particles is larger than the caliber of the blood vessels in the retina. Fourth, the forceful injection might have promoted the embolism in the ophthalmic artery.[9]\n\nIn this study, the patient was a 48-year-old female who developed an acute onset of CRAO after a supposed peribulbar triamcinolone injection for TAO. To the best of our knowledge, this is the first documented case of CRAO after a peribulbar triamcinolone injection for TAO. The inattentive intra-arterial injection of triamcinolone could have caused CRAO in this patient. A fundus examination was performed as soon as the patient presented with severe vision loss. Yellowish white embolic material was observed to be deposited in both small retinal vessels and choridal vessels. Glucocorticoid embolus in retinal vessels was reported previously, but not in choridal vessels.[3,6] Thus, the present case might be the first reported in which triamcinolone embolus was seen in choridal vessels. Retinal edema and cherry red spot in macula appeared 24 hours after the triamcinolone injection. It reminds us that fundus examination should be performed if a patient suffer from acute vision loss after triamcinolone injection in facial region and central retinal artery occlusion should be seriously considered if embolic material in retinal and choroidal vessel were observed, because typical cherry red spot appeared 24 hours after CRAO onsets in our case. In the patient, fundus autofluorescence showed hypoautofluorescence in the nonperfused region in the retina. The etiology of the hypoautofluorescence might be that the inner retinal swelling blocked the retinal pigment epithelium autofluorescence[13] or the oxygenated and deoxygenated nicotinamide adenine dinucleotide (NADH), and the flavin adenine dinucleotide (FAD) emission spectra produced the phenomenon of low fluorescence.[14] OCT and OCT-A are noninvasive examinations that are conducted to evaluate retina and retinal vessel density. In this patient, OCT and OCT-A showed retinal neurosensory layer edema and significantly decreased vascular density. Discontinuous retinal capillary network and capillary dropout were also observed in the OCT-A, which were caused by retina ischemia. FFA and ICGA were also performed in this patient. Areas of hypofluoresence were detected in the choroid, indicating nonperfusion areas. Retinal arteriolar filling defects in the paramacular area and obvious fluorescein leakage were observed. Anterior chamber paracentesis, ocular massage, venous injections of alprostadil, and Ginaton as well as acupoint injections of compound anisodine, sublingual glyceryl trinitrate, and antiglaucoma drugs were administered as soon as the diagnosis was made. During the follow-up, the OCT and OCT-A scan showed that retinal edema and retinal vessel density were improved at one month in, which indicated that these examinations were useful in patients with CRAO. The patient's visual acuity improved from the inexact perception of light to 0.02 after treatment was administered without delay.\n\nTo the best of our knowledge, this study is the first to describe the medical record of a patient with CRAO caused by after retrobulbar corticosteroid injection. The images of fundus photo, FFA, ICGA, OCT, and OCT-A were well recorded, and the treatment and the prognosis were well documented. These findings could provide significant information for ophthalmologists in evaluating similar patients.\n\n4 Conclusion\nEmbolic retinal and choroidal vascular occlusion is a vision-threatening complication of therapeutic injections in the facial region. In patients with significant visual loss after facial triamcinolone injection, CRAO is strongly indicated if embolic material in the retinal and choridal vessels is observed. If treatment is delayed, typical manifestations of CRAO, such as cherry red spots, might occur, and the optimal intervention window might be missed. To avoid this complication, utmost care should be taken and careful aspiration must be performed before injecting a steroid suspension in the facial region.\n\nAcknowledgment\nThe authors thank the patient who participated in the present study for providing written permission to publish this case report.\n\nAuthor contributions\nConceptualization: Gang Li, Dongdong Xu, Hui Li.\n\nData curation: Gang Li, Dongdong Xu, Zhirou Hu, Hui Li.\n\nFormal analysis: Hui Li.\n\nFunding acquisition: Hui Li.\n\nGang Li & Dongdong Xu carried out the entire procedure including performed examination, literature search, drafted the manuscript, revised submitted the manuscript, these two authors contributed equally to this article. Hui Li conceived of the diagnosis and treatment of this patient, coordinated and participated in the entire process of drafting and revised the manuscript. Zhirou Hu contributed to data collection and revision the manuscript. All authors have contributed significantly. All authors read and approved the final manuscript\n\nInvestigation: Gang Li, Dongdong Xu, Zhirou Hu, Hui Li.\n\nMethodology: Gang Li, Dongdong Xu, Zhirou Hu, Hui Li.\n\nProject administration: Gang Li, Dongdong Xu, Hui Li.\n\nResources: Gang Li, Dongdong Xu, Hui Li.\n\nSoftware: Gang Li, Dongdong Xu, Zhirou Hu, Hui Li.\n\nSupervision: Gang Li, Dongdong Xu, Hui Li.\n\nValidation: Gang Li, Dongdong Xu, Hui Li.\n\nVisualization: Gang Li, Dongdong Xu, Zhirou Hu, Hui Li.\n\nWriting – original draft: Gang Li, Dongdong Xu, Hui Li.\n\nWriting – review & editing: Gang Li, Dongdong Xu, Hui Li.\n\nAbbreviations: CRAO = central retinal artery occlusion, FFA = fundus fluorescein angiography, ICGA = indocyanine green angiography, OCT-A = optical coherence tomography-angiography, TAO = thyroid-associated ophthalmopathy.\n\nEthical approval: Since this is a case report, ethical approval is not required.\n\nFigure Ownership: All figures submitted are owned solely by the corresponding author.\n\nGL and DX both were co-first authors and contributed equally to this article.\n\nConsent for publishing the clinical details and the images was obtained from the patient.\n\nConflicts of Interest and Source of Funding: All authors have contributed significantly and are in agreement with the content of the manuscript. All authors have no relevant financial relationships to disclose.\n==== Refs\nReferences\n[1] Bordaberry M Marques DL Pereira-Lima JC \nRepeated peribulbar injections of triamcinolone acetonide: a successful and safe treatment for moderate to severe Graves’ ophthalmopathy . Acta Ophthalmol \n2009 ;87 :58 –64 .18937809 \n[2] Cohen E Yatziv Y Leibovitch I \nA case report of ophthalmic artery emboli secondary to calcium hydroxylapatite filler injection for nose augmentation-long-term outcome . BMC Ophthalmol \n2016 ;16 :98 .27391691 \n[3] Chavala SH Williamson JF Postel EA \nEmbolic central retinal artery occlusion after subcutaneous auricular steroid injection . Lancet \n2016 ;387 :2235 .26631356 \n[4] Moshfeghi DM Lowder CY Roth DB \nRetinal and choroidal vascular occlusion after posterior sub-tenon triamcinolone injection . Am J Ophthalmol \n2002 ;134 :132 –4 .12095826 \n[5] Varma DD Cugati S Lee AW \nA review of central retinal artery occlusion: clinical presentation and management . Eye (Lond) \n2013 ;27 :688 –97 .23470793 \n[6] Ellis PP \nOcclusion of the central retinal artery after retrobulbar corticosteroid injection . Am J Ophthalmol \n1978 ;85 :352 –6 .655214 \n[7] Gupta V Sharma SC Gupta A \nRetinal and choroidal microvascular embolization with methylprednisolone . Retina \n2002 ;22 :382 –6 .12055481 \n[8] Edwards AO \nCentral retinal artery occlusion following forehead injection with a corticosteroid suspension . Pediatr Dermatol \n2008 ;25 :460 –1 .18789088 \n[9] Liu OG Chunming L Juanjuan W \nCentral retinal artery occlusion and cerebral infraction following forehead injection with a corticosteroid suspension for vitiligo . Indian J Dermatol Venereol Leprol \n2014 ;80 :177 –9 .24685869 \n[10] Gaur N Singh P Chawla R \nTriamcinolone emboli leading to central retinal artery occlusion: a multimodal imaging study . BMJ Case Rep \n2017 ;2017 :bcr2016218908 .\n[11] Benzon HT Chew TL McCarthy RJ \nComparison of the particle sizes of different steroids and the effect of dilution: a review of the relative neurotoxicities of the steroids . Anesthesiology \n2007 ;106 :331 –8 .17264728 \n[12] Wong TY Islam FM Klein R \nRetinal vascular caliber, cardiovascular risk factors, and inflammation: the multi-ethnic study of atherosclerosis (MESA) . Invest Ophthalmol Vis Sci \n2006 ;47 :2341 –50 .16723443 \n[13] Sekiryu T Iida T Maruko I \nClinical application of autofluorescence densitometry with a scanning laser ophthalmoscope . Invest Ophthalmol Vis Sci \n2009 ;50 :2994 –3002 .19182249 \n[14] Schweitzer D Quick S Klemm M \nTime-resolved autofluorescence in retinal vascular occlusions . Ophthalmologe \n2010 ;107 :1145 –52 .20552361\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "97(17)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D002829:Choroid; D015862:Choroid Diseases; D005260:Female; D006801:Humans; D056965:Injections, Intraocular; D008875:Middle Aged; D015356:Retinal Artery Occlusion; D014221:Triamcinolone",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e0467",
"pmc": null,
"pmid": "29703002",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24685869;27391691;23470793;20552361;26631356;655214;12055481;16723443;17264728;12095826;19182249;18937809;18789088;28228436",
"title": "Embolic retinal and choroidal vascular occlusion after peribulbar triamcinolone injection: A case report.",
"title_normalized": "embolic retinal and choroidal vascular occlusion after peribulbar triamcinolone injection a case report"
} | [
{
"companynumb": "CN-CMP PHARMA-2018CMP00015",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
"drugadditional"... |
{
"abstract": "Metastatic prognosis in uveal melanoma is assessed by gene expression profiling (GEP) testing of the tumor cells, usually obtained by fine needle aspiration (FNA). GEP has demonstrated high accuracy in distinguishing class I and II tumors, both having different metastatic potential. Transcriptomic studies identified distinct mutations including somatic mutations in GNAQ and GNA11, detected in more than 80%, and contribute to the upregulation of the mitogen-activated protein kinase (MAPK) pathway and the development of uveal melanoma (UM). The role of these mutations in treatment selection and possible benefit from targeted therapy are somewhat unclear. However, until the discovery of novel agents, local versus systemic therapies remain options for treatment that can still be considered for disease control in certain cases. We report a series of patients with metastatic UM with distinct mutational profiles. One had significant liver metastases with proven GNQ-209P mutation on tissue biopsy while peripheral blood molecular profiling did not show these mutations. The other three cases had no GNQ-209P mutation. All cases received nab-paclitaxel (Abraxane) as a treatment drug, and we record their responses to treatment and their molecular-profiling results.",
"affiliations": "Department of Hematology-Oncology, University of Cincinnati, Cincinnati, OH, USA.;Department of Hematology-Oncology, University of Cincinnati, Cincinnati, OH, USA.;Department of Hematology-Oncology, University of Cincinnati, Cincinnati, OH, USA.;Department of Hematology-Oncology, University of Cincinnati, Cincinnati, OH, USA.;Department of Hematology-Oncology, University of Cincinnati, Cincinnati, OH, USA.;Department of Interventional Radiology, University of Cincinnati, Cincinnati, OH, USA.;Department of Ophthalmology, University of Cincinnati, Cincinnati, OH, USA.",
"authors": "Abdel Karim|Nagla|N|;Eldessouki|Ihab|I|0000-0002-1325-2579;Taftaf|Ahmad|A|0000-0003-2754-051X;Ayham|Deeb|D|;Gaber|Ola|O|0000-0003-3113-8902;Makramalla|Abouelmagd|A|;Correa|Zelia M|ZM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2018/4256365",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2018/4256365Case Report\nGNQ-209P Mutation in Metastatic Uveal Melanoma and Treatment Outcome Abdel Karim Nagla \n1\nhttp://orcid.org/0000-0002-1325-2579Eldessouki Ihab ihab_del@yahoo.com\n1\nhttp://orcid.org/0000-0003-2754-051XTaftaf Ahmad \n1\nAyham Deeb \n1\nhttp://orcid.org/0000-0003-3113-8902Gaber Ola \n1\nMakramalla Abouelmagd \n2\nCorrea Zelia M. \n3\n\n1Department of Hematology-Oncology, University of Cincinnati, Cincinnati, OH, USA\n2Department of Interventional Radiology, University of Cincinnati, Cincinnati, OH, USA\n3Department of Ophthalmology, University of Cincinnati, Cincinnati, OH, USAAcademic Editor: Raffaele Palmirotta\n\n2018 4 4 2018 2018 425636528 11 2017 11 3 2018 Copyright © 2018 Nagla Abdel Karim et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Metastatic prognosis in uveal melanoma is assessed by gene expression profiling (GEP) testing of the tumor cells, usually obtained by fine needle aspiration (FNA). GEP has demonstrated high accuracy in distinguishing class I and II tumors, both having different metastatic potential. Transcriptomic studies identified distinct mutations including somatic mutations in GNAQ and GNA11, detected in more than 80%, and contribute to the upregulation of the mitogen-activated protein kinase (MAPK) pathway and the development of uveal melanoma (UM). The role of these mutations in treatment selection and possible benefit from targeted therapy are somewhat unclear. However, until the discovery of novel agents, local versus systemic therapies remain options for treatment that can still be considered for disease control in certain cases. We report a series of patients with metastatic UM with distinct mutational profiles. One had significant liver metastases with proven GNQ-209P mutation on tissue biopsy while peripheral blood molecular profiling did not show these mutations. The other three cases had no GNQ-209P mutation. All cases received nab-paclitaxel (Abraxane) as a treatment drug, and we record their responses to treatment and their molecular-profiling results.\n==== Body\n1. Introduction\nUveal melanoma (UM) is significantly less common than cutaneous melanoma and has a distinct molecular pathogenesis. Meanwhile, it is the most common primary intraocular tumor in adults [1]. Despite the high success rate of disease control with local therapy, the potential for developing metastases remains high even after a prolonged period of remission [2–4]. The predominant target organ for metastasis is the liver although disease involvement of the skin, bone, brain, and lungs has also been reported [5, 6]. Key mutations in the disease are GNAQ and GNA11 mutations. It was reported that 83% of the cases have somatic mutations in GNAQ or GNA11 [7]. GNAQ gene is the gene coding for the alpha subunit of heterotrimeric G proteins. The latter proteins couple seven-transmembrane domain receptors to intracellular signaling machinery [8], and they are composed of three subunits, namely, alpha, beta, and gamma. The alpha subunit is the G-protein molecular switch, activated when it is bound to guanosine triphosphate (GTP), and when GTP is hydrolyzed to guanosine diphosphate (GDP), it is deactivated [9]. The alpha subunit has a key glutamine that contacts the GTP molecule, located at position 209 (Q209) in Gαq and is substituted when mutated to either leucine or proline [10–13]. At this point, the alpha subunit is locked in a constitutively active state, and its GTPase activity is blocked [14–16]. Taxanes work by preventing microtubule disassembly, so the mitotic functions are inhibited, leading to cell death [17]. They have shown reasonable activity in several phase II studies [18]. Nab-paclitaxel is a solvent-free formula that renders the drug more competent in the treatment of UM. Multiple therapeutic approaches for metastatic UM have been studied although none has shown any impact on the overall survival, and thus standard of care has not yet been established for these patients. In our report, we present the case of a patient with metastatic uveal carcinoma to the liver who was successfully treated with nab-paclitaxel, allowing for recovery from life-threatening spontaneous tumor lysis.\n\n2. Methods\n\nGNAQ and GNA11 mutations were assessed by genomic hybridization on paraffin-embedded blocks obtained from the primary tumor tissue. Mutations were followed up by circulating tumor DNA in plasma using next-generation sequencing using serial blood samples.\n\n3. Case Presentation\nThis is a 75-year-old man with a history of choroidal melanoma of the right eye diagnosed in 1984 and treated by radioactive Co-60 plaque. Thirty years later, he presented with progressive abdominal distention, early satiety, and weight loss of 20 pounds over a period of 6 months. He was seen by his primary care physician who requested a CT scan of the abdomen that showed a large hepatic mass measuring 34 cm by 26 cm, replacing the majority of the liver without retroperitoneal or mesenteric lymphadenopathy (Figure 1). Hepatic tumor biopsy revealed metastatic melanoma consistent with his primary choroidal melanoma. While completing his diagnostic workup, the patient developed generalized weakness prompting his hospital admission due to acute renal failure, hyperkalemia, and spontaneous tumor lysis. He started hemodialysis promptly followed by the administration of weekly nab-paclitaxel 150 mg/m2 and then reduced to 75 mg/m2 thereafter due to severe neutropenia. The patient recovered his renal function as serum creatinine improved from 4.93 mg/dl to 0.69 mg/dl (normal values 0.60–1.20 mg/dl) and demonstrated clinical improvement of his generalized weakness, abdominal distention, and edema of the legs after three doses of nab-paclitaxel. A repeat abdominal CT scan one month after the therapy revealed a good response to treatment with significant decrease in tumor burden. This is donated by full clinical recovery and total resolution of tumor lysis manifestations. However, according to RECIST criteria, the response can be minimal followed by maintained stable disease. CT scan of the abdomen after 4 cycles of nab-paclitaxel revealed shrinkage of the hepatic lesion to 24 × 15 cm in maximum diameter (approximately 7% decrease in the largest lesion per RECIST criteria) (Figure 2). This patient is still alive and continues to have excellent functional status, ECOG performance status of I, and no signs or symptoms of disease progression for 32 months now.\n\nOur patient with this metastatic uveal melanoma with extensive liver metastases with GNQ-209P mutation on the tissue biopsy (Figures 3 and 4) and undetectable mutations on the peripheral blood molecular profiling in serial follow-up samples suggests marked response to nab-paclitaxel. This can be understood by the dramatic tumor response on CT scans which was accompanied clinically by spontaneous tumor lysis syndrome followed by very prolonged disease control up to 30 months indicating nab-paclitaxel efficacy. All other patients with metastatic ocular melanoma, who did not have the GNQ-209P mutation, did not respond and did not have prolonged survival when treated with nab-paclitaxel.\n\nOur patient has received 8 cycles of Abraxane with initial minimal response followed by no increase and stable tumor size in the following imaging scans. In an attempt to achieve further response, the patient received an anti-PD-L1 in a clinical trial for 9 cycles. No further reduction in tumor size was achieved, and the patient was disqualified from the study after he developed sarcoidosis/interstitial pneumonitis. He was then restarted on Abraxane, achieving clinical and radiological stabilization of his disease with no major toxicities, and remains fully functional. He has received to date 12 cycles of Abraxane (in addition to the prior cycles of Abraxane received initially).\n\n4. Discussion\nUM has a high potential for developing a rapidly progressive course despite local or systemic therapies [1]. Even with several FDA-approved agents for advanced cutaneous melanoma, there is a lack of agents that show survival benefit in patients with advanced UM. This issue is likely twofold from the rare occurrence of the disease itself as well as a lack of complete understanding regarding the pathogenesis and immunobiology that underlies this disease process. Current studies are ongoing to uncover these uncertainties in hopes of ultimately identifying potentially treatable targets and more effective treatments [19, 20]. Until a standard of care is established, however, existing treatment options must be applied on a case-by-case basis [21, 22].\n\nIn metastatic disease, different approaches have been studied including surgical resection in suitable candidates in addition to local versus systemic infusion of cytotoxic agents. A comprehensive review of the role of metastectomy in selected surgical candidates showed improved survival in patients who had a complete liver metastases resection compared to patients for whom a complete resection was not feasible [23]. Local therapies including the hepatic arterial infusion of melphalan or fotemustine revealed in randomized trial, a significant improvement in progression-free survival (PFS) but not overall survival when compared to the systemic infusion of the same agents [24]. In contrast, a retrospective study from Mayo Clinic showed only improvement in overall survival among patients treated with different local therapies in comparison to different systemic agents including bevacizumab, ipilimumab, and kinase inhibitors [25]. Systemic chemotherapy options have shown minimal benefit in treatment. Single agents such as cisplatin or paclitaxel versus combined agents such as the BOLD regimen (bleomycin + vincristine + lomustine + dacarbazine) plus recombinant interferon alpha 2-b have been studied with no more than 20% response rate (RR) and absence of survival advantages [7, 26]. A similar study to ours that was presented at the ASCO annual meeting shows clinically useful responses in two of four patients with metastatic ocular melanoma treated with nab-paclitaxel [27]. In terms of targeted therapy, the ability to understand the genetic characteristic of UM has helped in identifying different mutations and key signaling pathways that can permit therapeutic intervention at a site specific to the pathway abnormality. UM is genetically characterized by frequent, mutually exclusive mutations in guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) and guanine nucleotide-binding protein subunit alpha-11 (GNA11) which can be detected in 83% of patients with UM [12]. GNAQ stimulates the mitogen-activated protein kinase (MAPK), which is parallel to the consequence of mutations in the BRAF or NRAS oncogenes in cutaneous melanomas. Furthermore, GNAQ stimulates the transcriptional coactivator YAP that is essential for UM cell proliferation. The aforementioned MAPK pathway is highly interconnected with the PI3K/ACT pathway, and both of them converge on the same downstream targets. MEK inhibitor, PI3K inhibitor, mTOR inhibitor, and YAP inhibitor each represent novel therapeutic target for UM, and studies are ongoing to uncover the role of these agents either as a single or dual inhibition approach in patients with advanced disease or early disease associated with high-risk features [10, 20, 28].\n\nOur patient presented with acute renal failure secondary to spontaneous tumor lysis, and there was an urgent need for disease control, which was achieved by using systemic chemotherapy with nab-paclitaxel. The absence of standard of care in these patients and the extrapolated data from the phase III trial of nab-paclitaxel when compared to dacarbazine [29] in patients with cutaneous melanoma led to the use of this agent in our patient who was not a candidate for cisplatin. In his case, the tissue from the liver biopsy was insufficient to run molecular testing, so we used a liquid biopsy (circulating tumor DNA) obtained from the patient, to search for genomic alterations that came back negative for mutations; however, subsequent liver biopsy revealed GNAQ exon 5 Q209 mutation where the GNA11 mutation or amplification was not detected.\n\nIn comparison to this case (Case 1), we had other patients (Case 2, 3, and 4) in our institution, in whom a diagnosis of metastatic UM was made. All patients started on treatment with nab-paclitaxel, but they had metastatic disease that continued to progress. In patients (Cases 2 and 3), a molecular testing of DNA circulating in the blood revealed GNAQ/Q209L mutation while our patient (Case 1) had GNAQ-Q209P (Tables 1 and 2). This might draw our attention that GNQ-209P might be a predictive marker of sensitivity to nab-paclitaxel in metastatic uveal melanoma.\n\n5. Conclusion\nAlthough our understanding of the molecular underpinnings of UM continues to improve and certain targeted agents are showing promise, genomic alteration studies might play a role in treatment selection. As we see from the cases we present, GNAQ-Q209P and not Q209L mutation could be associated with a considerable disease control when treated with nab-paclitaxel chemotherapy. We suggest the implication of molecular profiling with specific attention to the status of not only GNAQ but also the exon 209P or Q209L for personalized use of therapies in future clinical trials designed to treat patients with metastatic UM. Such clinical trials are needed to prove the efficacy and survival advantages of nab-paclitaxel in patients with metastatic UM and to study its role in comparison to the evolving targeted or immunotherapeutic agents. In general, reports of rare and less commonly encountered cases can have a pivotal effect on the collective clinical experience and drug research.\n\nAcknowledgments\nThe authors thank their colleagues in the pathology department who helped with this work.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Abdominal CT scan at diagnosis.\n\nFigure 2 CT scan 24 months after the treatment.\n\nFigure 3 Liver biopsy (H&E).\n\nFigure 4 Liver biopsy (MART).\n\nTable 1 Different types of genomic mutations in patients with metastatic melanoma of the liver.\n\nCase number\tAge (years)\tGender\tGenomic mutation\t\n1\t75\tMale\t\nGNAQ-Q209P by tissue testing\t\n2\t77\tFemale\t\nGNAQ-Q209L by peripheral circulating DNA\t\n3\t70\tFemale\t\nGNAQ-Q209L\t\n4\t78\tFemale\tKit H580y\t\nTable 2 Comparison between GNAQ-Q209P and GNAQ-Q209L.\n\nMutations\tLocation of mutation\tFrequency of mutations among GNAQ-mutated primary uveal melanoma\t\n\nGNAQ-Q209P\tExon 5\t∼64%\t\n\nGNAQ-Q209L\tExon 5\t∼33%\n==== Refs\n1 Singh A. D. Bergman L. Seregard S. Uveal melanoma: epidemiologic aspects Ophthalmology Clinics of North America 2005 18 1 75 84 10.1016/j.ohc.2004.07.002 2-s2.0-14844307061 15763193 \n2 Scotto J. Fraumeni J. F. Lee J. A. Melanomas of the eye and other noncutaneous sites: epidemiologic aspects Journal of the National Cancer Institute 1976 56 3 489 491 10.1093/jnci/56.3.489 2-s2.0-0017258327 1255781 \n3 Kujala E. Ma¨kitie T. Kivela¨ T. Very long-term prognosis of patients with malignant uveal melanoma Investigative Opthalmology and Visual Science 2003 44 11 p. 4651 10.1167/iovs.03-0538 2-s2.0-0142200859 \n4 Diener-West M. Reynolds S. M. Agugliaro D. J. Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: collaborative ocular melanoma study group report no. 26 Archives of Ophthalmology 2005 123 12 1639 1643 10.1001/archopht.123.12.1639 2-s2.0-28944437419 16344433 \n5 The Collaborative Ocular Melanoma Study Group Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the Collaborative Ocular Melanoma Study (COMS): COMS report no. 15 Archives of Ophthalmology 2001 119 5 670 676 10.1001/archopht.119.5.670 11346394 \n6 Bakalian S. Marshall J. C. Logan P. Molecular pathways mediating liver metastasis in patients with uveal melanoma Clinical Cancer Research 2008 14 4 951 956 10.1158/1078-0432.ccr-06-2630 2-s2.0-39749174411 18281525 \n7 Van Raamsdonk C. D. Griewank K. G. Crosby M. B. Mutations in GNA11 in uveal melanoma New England Journal of Medicine 2010 363 23 2191 2199 10.1056/nejmoa1000584 2-s2.0-78651446131 21083380 \n8 Neves S. R. Ram P. T. Iyengar R. G protein pathways Science 2002 296 5573 1636 1639 10.1126/science.1071550 2-s2.0-0037205055 12040175 \n9 Markby D. Onrust R. Bourne H. Separate GTP binding and GTPase activating domains of a G alpha subunit Science 1993 262 5141 1895 1901 10.1126/science.8266082 8266082 \n10 Van Raamsdonk C. D. Bezrookove V. Green G. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi Nature 2009 457 7229 599 602 10.1038/nature07586 2-s2.0-59049107421 19078957 \n11 Lamba S. Felicioni L. Buttitta F. Mutational profile of GNAQQ209 in human tumors PLoS One 2009 4 8 article e6833 10.1371/journal.pone.0006833 2-s2.0-69949119638 \n12 Onken M. D. Worley L. A. Long M. D. Oncogenic mutations in GNAQ occur early in uveal melanoma Investigative Opthalmology and Visual Science 2008 49 12 5230 5234 10.1167/iovs.08-2145 2-s2.0-58149216961 \n13 Bauer J. Kilic E. Vaarwater J. Bastian B. C. Garbe C. De Klein A. Oncogenic GNAQ mutations are not correlated with disease-free survival in uveal melanoma British Journal of Cancer 2009 101 5 813 815 10.1038/sj.bjc.6605226 2-s2.0-70249134535 19654573 \n14 Landis C. A. Masters S. B. Spada A. Pace A. M. Bourne H. R. Vallar L. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours Nature 1989 340 6236 692 696 10.1038/340692a0 2549426 \n15 Kalinec G. Nazarali A. J. Hermouet S. Xu N. Gutkind J. S. Mutated alpha subunit of the Gq protein induces malignant transformation in NIH 3T3 cells Molecular and Cellular Biology 1992 12 10 4687 4693 10.1128/mcb.12.10.4687 1328859 \n16 Sondek J. Lambright D. G. Noel J. P. Hamm H. E. Sigler P. B. GTPase mechanism of Gproteins from the 1.7-Å crystal structure of transducin α - GDP AIF−4 Nature 1994 372 6503 276 279 10.1038/372276a0 7969474 \n17 Schiff P. B. Horwitz S. B. Taxol stabilizes microtubules in mouse fibroblast cells Proceedings of the National Academy of Sciences 1980 77 3 1561 1565 10.1073/pnas.77.3.1561 \n18 Leon-Ferre R. A. Markovic S. N. Nab-paclitaxel in patients with metastatic melanoma Expert Review of Anticancer Therapy 2015 15 12 1371 1377 10.1586/14737140.2015.1110024 2-s2.0-84949320076 26536477 \n19 Luke J. J. Triozzi P. L. McKenna K. C. Biology of advanced uveal melanoma and next steps for clinical therapeutics Pigment Cell and Melanoma Research 2015 28 2 135 147 10.1111/pcmr.12304 2-s2.0-85028257855 25113308 \n20 Agarwala S. S. Eggermont A. M. M. O’Day S. Zager J. S. Metastatic melanoma to the liver: a contemporary and comprehensive review of surgical, systemic, and regional therapeutic options Cancer 2014 120 6 781 789 10.1002/cncr.28480 2-s2.0-84896710920 24301420 \n21 Karim N. A. Schuster J. Eldessouki I. Pulmonary sarcomatoid carcinoma: University of Cincinnati experience Oncotarget 2018 9 3 10.18632/oncotarget.23468 \n22 Karim N. Eldessouki I. Yellu M. Namad T. Wang J. Gaber O. A case study in advanced lung cancer patients with vimentin over expression Clinical Laboratory 2017 63 10 10.7754/clin.lab.2017.170201 \n23 Pingpank J. F. Hughes M. S. Alexander H. R. A phase III random assignment trial comparing percutaneous hepatic perfusion with melphalan (PHP-mel) to standard of care for patients with hepatic metastases from metastatic ocular or cutaneous melanoma Journal of Clinical Oncology 2010 28 18 p. LBA8512 10.1200/jco.2010.28.18_suppl.lba8512 \n24 Moser J. C. Pulido J. S. Dronca R. S. McWilliams R. R. Markovic S. N. Mansfield A. S. The Mayo Clinic experience with the use of kinase inhibitors, ipilimumab, bevacizumab, and local therapies in the treatment of metastatic uveal melanoma Melanoma Research 2015 25 1 59 63 10.1097/cmr.0000000000000125 2-s2.0-84920265061 25396683 \n25 Flaherty L. E. Unger J. M. Liu P. Y. Mertens W. C. Sondak V. K. Metastatic melanoma from intraocular primary tumors American Journal of Clinical Oncology 1998 21 6 568 572 10.1097/00000421-199812000-00008 2-s2.0-0031765674 9856657 \n26 Kivelä T. Suciu S. Hansson J. Bleomycin, vincristine, lomustine and dacarbazine (BOLD) in combination with recombinant interferon alpha-2b for metastatic uveal melanoma European Journal of Cancer 2003 39 8 1115 1120 10.1016/s0959-8049(03)00132-1 2-s2.0-0038402749 12736111 \n27 Smith T. J. Temin S. Alesi E. R. American Society of Clinical Oncology provisional clinical opinion: the integration of palliative care into standard oncology care Journal of Clinical Oncology 2012 30 8 880 887 10.1200/jco.2011.38.5161 2-s2.0-84858847594 22312101 \n28 Hersh E. M. Del Vecchio M. Brown M. P. Kefford R. F. Phase 3, randomized, open-label, multicenter trial of nab-paclitaxel (nab-P) vs dacarbazine (DTIC) in previously untreated patients with metastatic malignant melanoma (MMM) Pigment Cell & Melanoma Research 2012 25 p. 863 \n29 Hesketh P. J. Kris M. G. Basch E. Antiemetics: American Society of Clinical Oncology clinical practice guideline update Journal of Clinical Oncology 2017 35 28 3240 3261 10.1200/jco.2017.74.4789 2-s2.0-85030166801 28759346\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2018()",
"journal": "Case reports in oncological medicine",
"keywords": null,
"medline_ta": "Case Rep Oncol Med",
"mesh_terms": null,
"nlm_unique_id": "101581035",
"other_id": null,
"pages": "4256365",
"pmc": null,
"pmid": "29850322",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "6103535;14578381;28759346;18719078;22312101;29035448;12736111;21083380;19654573;24301420;2549426;12040175;19718445;8266082;25113308;11346394;19078957;1328859;25396683;16344433;1255781;26536477;18281525;9856657;29423107;7969474;15763193",
"title": "GNQ-209P Mutation in Metastatic Uveal Melanoma and Treatment Outcome.",
"title_normalized": "gnq 209p mutation in metastatic uveal melanoma and treatment outcome"
} | [
{
"companynumb": "US-CELGENEUS-USA-20180503645",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "A 29-year-old man with diarrhoea, fever, abdominal pain and multiple purple papular lesions, neither pruriginous nor painful, was diagnosed with HIV-1 infection and disseminated Kaposi sarcoma (KS) with gastrointestinal involvement. He was started on highly active antiretroviral therapy immediately, as well as doxorubicin. Three weeks later, the patient developed bilateral moderate pleural effusion and large-volume ascites compatible with chylothorax and chylous ascites. An immune reconstitution inflammatory syndrome (IRIS) reaction was assumed. KS flare was associated with lymphatic obstruction and infiltration of thoracic duct by the tumour itself with leakage of chylous into pleural and peritoneal cavities. KS is the most common tumour in HIV patients and the existence of related effusions is not uncommon. KS-related chylothorax is an unusual manifestation of KS; there are only four cases described in the literature of chylous ascites related to KS-HIV. Overall survival is improving in KS but explosive and debilitating IRIS reactions can explain cases with poor prognosis.",
"affiliations": "Department of Internal Medicine, Hospital de Cascais, Cascais, Portugal.;Department of Internal Medicine, Hospital de Cascais, Cascais, Portugal.;Department of Internal Medicine, Hospital de Cascais, Cascais, Portugal.;Department of Internal Medicine, Hospital de Cascais, Cascais, Portugal.",
"authors": "Cipriano|Patrícia|P|http://orcid.org/0000-0002-0222-2171;Nabais|Inês|I|;Melo|Nuno|N|;Alves|Ana Rafaela|AR|",
"chemical_list": "C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-228406",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(3)",
"journal": "BMJ case reports",
"keywords": "HIV/aids; haematology (incl blood transfusion)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D002915:Chylous Ascites; D003937:Diagnosis, Differential; D004317:Doxorubicin; D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D008297:Male; D011092:Polyethylene Glycols; D011379:Prognosis; D012514:Sarcoma, Kaposi; D000072339:Sexual and Gender Minorities; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30904896",
"pubdate": "2019-03-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10749966;12647476;2671281;18605999;27335837;11189982;16232048;1571260;7977258;19591823;23368874;16844940;16051964;18582204;9412716;18808357;22395672;7997879;11964546;28388419",
"title": "Chylous ascites in disseminated Kaposi sarcoma: an unusual manifestation as immune reconstitution inflammatory syndrome.",
"title_normalized": "chylous ascites in disseminated kaposi sarcoma an unusual manifestation as immune reconstitution inflammatory syndrome"
} | [
{
"companynumb": "PT-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-220241",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOLUTEGRAVIR"
},
"dr... |
{
"abstract": "Glucocorticoid treatment is frequently associated with transiently impaired attention, concentration, and memory. In rare cases, cognitive changes may be prominent and may persist for substantial periods of time after steroid discontinuation. This largely unrecognized complication has been termed the \"steroid dementia syndrome\" and may reflect steroid neuroendangerment or neurotoxicity. Several clinical cases of this syndrome, with shared phenomenological and neuropsychological features, are presented here.",
"affiliations": "University of California, San Francisco, School of Medicine, 401 Parnassus Ave., Box F-0984, San Francisco, CA 94143-0984, USA. owenw@itsa.ucsf.edu",
"authors": "Wolkowitz|Owen M|OM|;Lupien|Sonia J|SJ|;Bigler|Erin|E|;Levin|R Bronson|RB|;Canick|Jonathan|J|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D001067:Appetite Depressants; D005938:Glucocorticoids; D005277:Fenfluramine; D010645:Phentermine; D011241:Prednisone; D006854:Hydrocortisone",
"country": "United States",
"delete": false,
"doi": "10.1196/annals.1314.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0077-8923",
"issue": "1032()",
"journal": "Annals of the New York Academy of Sciences",
"keywords": null,
"medline_ta": "Ann N Y Acad Sci",
"mesh_terms": "D000328:Adult; D000506:Alopecia Areata; D000893:Anti-Inflammatory Agents; D001067:Appetite Depressants; D001921:Brain; D002648:Child; D003704:Dementia; D005260:Female; D005277:Fenfluramine; D005938:Glucocorticoids; D006801:Humans; D006854:Hydrocortisone; D008279:Magnetic Resonance Imaging; D019300:Medical Errors; D009483:Neuropsychological Tests; D020258:Neurotoxicity Syndromes; D010645:Phentermine; D011241:Prednisone; D011605:Psychoses, Substance-Induced",
"nlm_unique_id": "7506858",
"other_id": null,
"pages": "191-4",
"pmc": null,
"pmid": "15677408",
"pubdate": "2004-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The \"steroid dementia syndrome\": an unrecognized complication of glucocorticoid treatment.",
"title_normalized": "the steroid dementia syndrome an unrecognized complication of glucocorticoid treatment"
} | [
{
"companynumb": "US-PFIZER INC-2018139719",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"druga... |
{
"abstract": "Drug induced QT prolongation occurs in patients with substance use disorders from prescription medications that prolong the QT, such as methadone. Knowing the prevalence of QT prolongation in this population is important for prescribers. This study aimed to investigate the prevalence of QT prolongation in patients with current substance use disorders.\n\n\n\nWe undertook a retrospective review of electrocardiograms (ECG) from patients with substance use disorders from an urban general hospital with a large drug and alcohol service and toxicology unit. ECGs were taken from patients seen by the alcohol and drug unit over three years. The QT interval was measured manually on each ECG and defined as abnormal if above the line on the QT nomogram. The QT was also heart rate corrected using Fridericia's formula (QTcF) to investigate associated factors.\n\n\n\nNine of 446 (2.0%; 95% confidence interval 1.0-3.9%) patients had an ECG with a prolonged QT interval. Three were prescribed methadone for opiate dependence (80, 90 and 125 mg daily), one also with hypokalemia; one prescribed escitalopram with hypokalaemia/hypomagnesaemia; three more with hypokalaemia alone. Only two patients had a prolonged QT with no identifiable cause. There was no association between QTcF and sex (P = 0.34), but there was a statistically significant association with age (Pearson R = 0.19, 95% confidence interval 0.10-0.28, P < 0.0001).\n\n\n\nQT prolongation is rare in patients with substance use disorders and is most likely similar to the general population once cases related to methadone use and electrolyte abnormalities are excluded. [Scott AJ, Dunlop AJ, Brown A, Craig S. The prevalence of QT prolongation in a population of patients with substance use disorders. Drug Alcohol Rev 2017;36:239-244].",
"affiliations": "School of Medicine and Public Health, University of Newcastle, Newcastle, Australia.;School of Medicine and Public Health, University of Newcastle, Newcastle, Australia.;Drug and Alcohol Clinical Services, Hunter New England Local Health District, Newcastle, Australia.;School of Medicine and Public Health, University of Newcastle, Newcastle, Australia.;School of Medicine and Public Health, University of Newcastle, Newcastle, Australia.",
"authors": "Scott|Alexander J|AJ|;Dunlop|Adrian J|AJ|;Brown|Amanda|A|;Sadler|Craig|C|;Isbister|Geoffrey K|GK|",
"chemical_list": "D008691:Methadone",
"country": "Australia",
"delete": false,
"doi": "10.1111/dar.12415",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-5236",
"issue": "36(2)",
"journal": "Drug and alcohol review",
"keywords": "QT interval; drug and alcohol; electrocardiogram; methadone; population",
"medline_ta": "Drug Alcohol Rev",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D004562:Electrocardiography; D005260:Female; D006769:Hospitals, General; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D008691:Methadone; D008875:Middle Aged; D009293:Opioid-Related Disorders; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D019966:Substance-Related Disorders",
"nlm_unique_id": "9015440",
"other_id": null,
"pages": "239-244",
"pmc": null,
"pmid": "27241860",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The prevalence of QT prolongation in a population of patients with substance use disorders.",
"title_normalized": "the prevalence of qt prolongation in a population of patients with substance use disorders"
} | [
{
"companynumb": "AU-MYLANLABS-2016M1030517",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ESCITALOPRAM OXALATE"
},
"drugadditional": "3... |
{
"abstract": "Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by JC virus reactivation. Its occurrence is very rare after solid organ transplantation, especially liver transplantation. We report a patient who received liver transplantation due to liver failure resulting from autoimmune hepatitis and advanced PML presenting with aphasia. A 41-year-old female with a history of liver transplantation who received a usual immunosuppression regimen was admitted with a stroke attack resulting in right hemiplegia 2 months after liver transplantation. Surprisingly, she gradually developed dysarthria and left central facial paresis. A brain MRI showed an abnormal multifocal area with a high T2/flair signal in the deep subcortical white matter of the left hemisphere as well as the splenium of the corpus callosum. PCR evaluation of CSF for JCV was positive while other PCR results were negative. A liver transplant recipient receiving immunosuppressive treatment for a long time could develop PML due to JCV reactivation. Only eight cases of JCV infection were reported after liver transplantation by the time of reporting this case. Unfortunately, there is no definite treatment for PML.",
"affiliations": "Liver transplantation Research Center, Department of Infectious Diseases, Imam Khomeini Hospital complex, Tehran University of Medical Sciences, Tehran, Iran.;Department of Infectious Diseases, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran. talebi.fatemeh5018@yahoo.com.;Department of Radiology, Advanced Diagnostic and Interventional Radiology (ADIR) Research Center, Tehran University of Medical Science, Tehran, Iran.;Liver transplantation Research Center, Department of Infectious Diseases, Imam Khomeini Hospital complex, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Ahmadinejad|Zahra|Z|;Talebi|Fatemeh|F|;Yazdi|Niloofar Ayoobi|NA|;Ghiasvand|Fereshteh|F|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1007/s13365-019-00742-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-0284",
"issue": "25(4)",
"journal": "Journal of neurovirology",
"keywords": "JC virus; Liver transplant; Progressive multifocal leukoencephalopathy",
"medline_ta": "J Neurovirol",
"mesh_terms": "D000328:Adult; D001037:Aphasia; D002540:Cerebral Cortex; D003337:Corpus Callosum; D004401:Dysarthria; D005260:Female; D006429:Hemiplegia; D019693:Hepatitis, Autoimmune; D006801:Humans; D007166:Immunosuppressive Agents; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal; D008099:Liver; D016031:Liver Transplantation; D008279:Magnetic Resonance Imaging; D020521:Stroke; D014775:Virus Activation",
"nlm_unique_id": "9508123",
"other_id": null,
"pages": "605-607",
"pmc": null,
"pmid": "31140129",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10360779;10680816;10693627;11726086;11738115;12424695;15816900;16633317;19034021;20298966;21134241;28991708;6302172;7482750;8178356;9346614",
"title": "A 41-year-old female with progressive multifocal leukoencephalopathy after liver transplant.",
"title_normalized": "a 41 year old female with progressive multifocal leukoencephalopathy after liver transplant"
} | [
{
"companynumb": "IR-ACCORD-161424",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
"druga... |
{
"abstract": "We report the case of an eight-year-old partially immunized boy who presented with presumed bacterial tonsillitis. He was initially prescribed amoxicillin-clavulanic acid which resulted in the development of an erythematous maculopapular over the face which spread to the trunk and extremities including palms and soles and resolved over the next three days. He was diagnosed to have diphtheria and infectious mononucleosis (IMN) co-infection. He made an uneventful recovery and an extensive review of the literature showed that the incidence of diphtheria and IMN co-infection is a relatively rare clinical entity. We wish to highlight the possibility of such co-infections which often mimic one another.",
"affiliations": "Pediatrics, Aster Medcity, Kochi, IND.;Infectious Diseases, Aster Medcity, Kochi, IND.;Infectious Diseases, Aster Medcity, Kochi, IND.;Infectious Diseases, Aster Medcity, Kochi, IND.;Otolaryngology - Head and Neck Surgery, Aster Medcity, Kochi, IND.",
"authors": "Cyril|Gladys|G|;Rathish|Balram|B|;Wilson|Arun|A|;Warrier|Anup|A|;Viswam|Vineeth|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.11227",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.11227\nPediatrics\nInfectious Disease\nPublic Health\nA Case of Diphtheria and Infectious Mononucleosis Co-Infection in a Partially Vaccinated Boy\nMuacevic Alexander Adler John R Cyril Gladys 1 Rathish Balram 2 Wilson Arun 2 Warrier Anup 2 Viswam Vineeth 3 \n1 \nPediatrics, Aster Medcity, Kochi, IND \n\n2 \nInfectious Diseases, Aster Medcity, Kochi, IND \n\n3 \nOtolaryngology - Head and Neck Surgery, Aster Medcity, Kochi, IND \n\nBalram Rathish balramrnair@gmail.com\n28 10 2020 \n10 2020 \n12 10 e1122728 10 2020 Copyright © 2020, Cyril et al.2020Cyril et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/42693-a-case-of-diphtheria-and-infectious-mononucleosis-co-infection-in-a-partially-vaccinated-boyWe report the case of an eight-year-old partially immunized boy who presented with presumed bacterial tonsillitis. He was initially prescribed amoxicillin-clavulanic acid which resulted in the development of an erythematous maculopapular over the face which spread to the trunk and extremities including palms and soles and resolved over the next three days. He was diagnosed to have diphtheria and infectious mononucleosis (IMN) co-infection. He made an uneventful recovery and an extensive review of the literature showed that the incidence of diphtheria and IMN co-infection is a relatively rare clinical entity. We wish to highlight the possibility of such co-infections which often mimic one another.\n\ndiphtheriainfectious mononucleosisco-infectionvaccinationThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nDiphtheria is caused by Corynebacterium diphtheria which is an aerobic, gram-positive, non-motile, non-capsulated, non-spore-forming, toxin-producing bacillus. It is a vaccine-preventable disease and the hallmark of the disease involves a pseudomembrane on the site of colonization, usually involving the tonsils [1]. Most cases of infectious mononucleosis (IMN) are caused by the Epstein-Barr virus (EBV). After exposure, the EBV infects the epithelial cells of the salivary glands and the oropharynx. Lymphoid hyperplasia occurs and may present as predominantly cervical lymphadenopathy and tonsillitis, making it a close differential diagnosis for diphtheria [2]. These infections can mimic one another due to the similarity between their clinical presentations. An extensive review of the literature showed that the incidence of diphtheria and IMN co-infection is very rare with only three reported cases [3-5]. We wish to highlight the possibility of such co-infections that can mimic one another and may often be missed.\n\nCase presentation\nAn eight-year-old boy with no co-morbid illnesses presented with a history of sore throat and swelling of the neck for the past three days. He had been under treatment elsewhere with amoxicillin-clavulanate for presumed bacterial tonsillitis and had been on the antibiotic since the onset of symptoms. His medical history was remarkable for his partially immunized status with missed booster doses of the diphtheria-pertussis-tetanus (DPT) vaccine. On clinical examination, he was febrile with a temperature of 100 F. Examination of the throat showed enlarged tonsils with evidence of a greyish membrane, and neck examination showed cervical lymphadenopathy (Figure 1). Abdominal examination revealed hepatosplenomegaly. Workup showed a total leukocyte count of 27,690 (4000-11,000/uL) with 66% lymphocytes and atypical lymphocytes on the peripheral blood smear. His C-reactive protein (CRP) was 12 (<10 mg/dl), erythrocyte sedimentation rate (ESR) was 16 (0-15 mm/h), aspartate aminotransferase (AST) was 415 (0-35 u/L) and alanine aminotransferase (ALT) was 293 (0-35 u/L).\n\nFigure 1 Greyish-white membrane seen over enlarged tonsils.\nA throat swab was obtained for culture & sensitivity, and testing for diphtheria. Given his partial immunization status and the clinical picture, he was started on anti-diphtheritic serum (80,000 units) along with parenteral crystalline penicillin and oral Clindamycin. Two days later, he developed blood-stained nasal discharge along with hoarseness of voice and stridor. A lateral radiograph of the neck was normal. A mono spot was positive. An EBV panel consisting of IgM EBV-viral capsid antigen (VCA), IgG-VCA, IgG-early antigen, and nuclear antigen was sent on day five of illness, and IgG early antigen and IgM-VCA came positive. EBV quantitative polymerize chain reaction (PCR) was sent on the same day, which showed significant copies (36,275 copies/ml) confirming primary EBV infection.\n\nHis throat swab inoculated on sheep blood, MacConkey, and Tellurite blood agar cultures, but all were sterile. A repeat sample for inoculation on Loeffler's agar could only be collected 36 hours after starting crystalline penicillin and this too was sterile, and an Elek test could not be performed. However, PCR was positive for a toxigenic strain of Corynebacterium diphtheriae, confirming the diagnosis of diphtheria.\n\nBy day seven of illness, he improved clinically with a decrease in soft tissue swelling, reduction in hoarseness, and disappearance of stridor. However, he continued to spike a fever. In view of the persisting fever spikes despite appropriate antibiotics, the possibility of an abscess or suppurative cervical lymphadenitis was considered. CT scan of the neck was done and it showed considerable enlargement of the tonsils, adenoids, edema of the posterior glottis, and cervical lymphadenopathy (Figures 2, 3). The antibiotics were continued and the fever spikes resolved on day 10 of the illness. \n\nFigure 2 Axial cut of CT showing considerable enlargement of the tonsils (Red arrow).\nFigure 3 Coronal cut of CT showing multiple enlarged cervical nodes on the left side of the neck (Red arrow). \nHe developed a rash suggestive of IMN on day 10 of the illness (eight days after receiving amoxicillin-clavulanic acid) which started as an erythematous maculopapular over the face, spreading to the trunk and extremities including palms and soles. This rash resolved in the next three days. He made an uneventful recovery and was closely monitored for features of myocarditis in the second week of illness and neuropathy in the later weeks. Contact tracing for diptheria was carried out, but no probable or possible sources were found. All immediate contacts were initiated on chemoprophylaxis and given a dose of the tetanus-diphtheria (Td) vaccine. On follow up, the boy was vaccinated with a booster dose of the Tdap vaccine.\n\nDiscussion\nDiphtheria presents as a pseudomembrane on the site of colonization, usually the tonsils of the patient. There can also be the presence of a sore throat and cervical lymphadenopathy. Rapid administration of diphtheria antitoxin and antibiotic therapy is the mainstay of treatment. Commonly used antibiotics include penicillin and erythromycin, usually for a minimum of two weeks [1]. In India, the National Immunization Schedule (NIS) recommends administration of a pentavalent vaccine (diphtheria, pertussis, tetanus, and hepatitis B and Haemophilus influenzae type b) at six, 10 & 14 weeks of age followed by booster doses of DPT vaccine at 16-24 weeks, and five to six years of age [6].\n\nIn our case, the membrane over the tonsils and his partially immunized status led to the suspicion of diphtheria even though Kerala is not a known endemic area. The relatively indolent nature and confinement of the infection to a local area were attributed to the three doses of pentavalent vaccine that the boy had received as part of the NIS. However, the incidence of a co-infection with EBV could have been easily missed. The classical clinical triad of IMN consists of fever, pharyngitis, and lymphadenopathy. Treatment is generally supportive unless complications such as airway obstruction or splenic rupture occurs [2]. The persistence of symptoms despite the administration of antitoxin as well as antibiotics coupled with the deranged liver functions led to the workup and further identification of the EBV co-infection in our case.\n\nThe development of a skin rash following the administration of amoxicillin in patients with IMN is quite frequently reported [7]. Since penicillin is recommended in the treatment of diphtheria, in the event of a co-infection with EBV, the use of penicillin can result in the development of such a rash, which can cause further distress to the patient. This makes the identification of such co-infections even more important. \n\nAn extensive review of the literature showed that the incidence of diphtheria and IMN co-infection is a relatively rare clinical entity. Mattos-Guaraldi et al described a similar case in Brazil [3]. Two other cases reported were from the United Kingdom by Perkins et al and Canada by Haight et al [4,5]. The reported cases highlighted the partially immunized status of the patients. All cases had a good clinical outcome following standard treatment of diphtheria similar to ours. \n\nConclusions\nWe report here a case of diphtheria and IMN co-infection in a partially immunized child from Kerala, India. This case serves to highlight the difficulty in the diagnosis of diphtheria, especially in a non-endemic region. Even if the area is not an endemic one, an inadequate immunization status should prompt the clinician to actively search for evidence of diphtheria. \n\nWe also wish to highlight the possibility of such co-infections which often mimic one another. A high degree of clinical suspicion is warranted in similar cases to avoid missing the second infection. Diphtheria may be mistaken for IMN and vice versa, which can lead to a delay in the correct diagnosis. This may also result in the inadequate treatment of either infection. In the case of such a co-infection, antibiotics such as ampicillin or amoxicillin may be avoided to prevent the IMN rash which can further cause unnecessary anxiety for the patient.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Corynebacterium Diphtheriae Chaudhary A Pandey S Treasure Island (FL) StatPearls Publishing 2020 https://www.ncbi.nlm.nih.gov/books/NBK559015/ \n2 Mononucleosis Mohseni M Boniface MP Graham C Treasure Island (FL) StatPearls Publishing 2020 https://www.ncbi.nlm.nih.gov/books/NBK470387/ \n3 Concurrent diphtheria and infectious mononucleosis: difficulties for management, investigation and control of diphtheria in developing countries J Med Microbiol Mattos-Guaraldi AL Damasco PV Gomes DLR 1685 1688 60 2011 21680765 \n4 When infections co-exist: infectious mono and diphtheria Can Fam Physician Haight K Holden FA 785 788 28 1982 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2306543/ 21286207 \n5 Investigations and control measures following a non-travel-associated case of toxigenic Corynebacterium diphtheriae, London, United Kingdom, December 2009-January 2010 Euro Surveill Perkins S Cordery R Nixon G 19544 15 2010 20430002 \n6 National immunization schedule (NIS) for infants, children and pregnant Women 8 2020 2020 https://main.mohfw.gov.in/sites/default/files/245453521061489663873.pdf \n7 Amoxicillin rash in patients with infectious mononucleosis: evidence of true drug sensitization All Asth Clin Immun Ónodi-Nagy K Kinyó Á Meszes A 1 11 2015\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(10)",
"journal": "Cureus",
"keywords": "co-infection; diphtheria; infectious mononucleosis; vaccination",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e11227",
"pmc": null,
"pmid": "33269155",
"pubdate": "2020-10-28",
"publication_types": "D002363:Case Reports",
"references": "20430002;21286207;21680765;25784943",
"title": "A Case of Diphtheria and Infectious Mononucleosis Co-Infection in a Partially Vaccinated Boy.",
"title_normalized": "a case of diphtheria and infectious mononucleosis co infection in a partially vaccinated boy"
} | [
{
"companynumb": "IN-PFIZER INC-2020507644",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLINDAMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "This is the first case report of the safety of therapeutic repetitive transcranial magnetic stimulation (rTMS) in a patient with an intracranial space-occupying lesion who had recurrent major depression. In this case, the intracranial space-occupying lesion was a mixed cystic and solid enhancing pineal region mass measuring approximately 16.9 × 12.2 × 15.5 mm. The patient remitted from depression with 36 sessions of dorsolateral prefrontal cortex rTMS treatments over a 6-week period. During the rTMS treatment course, patient's medication list included bupropion that potentially can increase the risk for a seizure and topiramate that potentially can reduce the risk for seizure associated with the treatment. The patient tolerated the rTMS treatment well, reporting only transient headache and discomfort at the site of stimulation after the treatment. She tolerated the procedure well and had no incidental seizure activity throughout her treatment sessions.",
"affiliations": "From the Department of Psychiatry and Health Behavior, Medical College of Georgia, Georgia Regents University, Augusta, GA.",
"authors": "Surya|Sandarsh|S|;Rosenquist|Peter B|PB|;McCall|W Vaughn|WV|",
"chemical_list": "D000927:Anticonvulsants; D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion; D000077236:Topiramate; D005632:Fructose",
"country": "United States",
"delete": false,
"doi": "10.1097/YCT.0000000000000245",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1095-0680",
"issue": "32(1)",
"journal": "The journal of ECT",
"keywords": null,
"medline_ta": "J ECT",
"mesh_terms": "D000927:Anticonvulsants; D018687:Antidepressive Agents, Second-Generation; D001932:Brain Neoplasms; D016642:Bupropion; D003865:Depressive Disorder, Major; D005260:Female; D005632:Fructose; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D010871:Pinealoma; D012008:Recurrence; D000077236:Topiramate; D050781:Transcranial Magnetic Stimulation",
"nlm_unique_id": "9808943",
"other_id": null,
"pages": "62-4",
"pmc": null,
"pmid": "25945969",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12738425;1821269;9144111;9474057;16957531;17493877;24051073;19833552;20539835;20633447;22708257;23485014;17573044",
"title": "Repetitive Transcranial Magnetic Stimulation for the Treatment of Major Depression in a Patient With an Intracranial Space-Occupying Lesion: A Case Report of Safety.",
"title_normalized": "repetitive transcranial magnetic stimulation for the treatment of major depression in a patient with an intracranial space occupying lesion a case report of safety"
} | [
{
"companynumb": "US-CIPLA LTD.-2016US02510",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DULOXETINE"
},
"drugadditional": null,
... |
{
"abstract": "Exstrophy of the urinary bladder is a rare congenital anomaly which if untreated causes bladder carcinoma and intestinal tumours noted if urinary diversion is performed. It is seen that 50% of all persons afflicted with exstrophy are dead by their tenth year and 66-67% are dead by their twentieth year. It is thus a great rarity to see a case of ectopia vesicae in adulthood. Still more uncommon is to see a case of exstrophy complicated by carcinoma. Here, we report a case of papillary adenocarcinoma of ectopic urinary bladder in a 42-year-old male patient. In view of locally advanced disease, patient was given neoadjuvant chemotherapy. The case is being reported on account of its rarity to sensitise clinicians about rising incidence of carcinoma if mismanaged due to lack of protocol in oncological screening.",
"affiliations": "Junior Resident, Department of Radiotherapy, MGMMC , Indore, India .;Senior Resident, Department of Surgery, ESIC Model Hospital , Indore, India .;Junior Resident, Department of Radiotherapy, MGMMC , Indore, India .;Assistant Professor, Department of Radiotherapy, MGMMC , Indore, India .;Professor and HOD, Department of Radiotherapy, MGMMC , Indore, India .",
"authors": "Shwetha|S|S|;Ghalige|Hemanth S|HS|;Goyal|Love|L|;Jain|Preety|P|;Fakhruddin|||",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2015/12352.6467",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "9(9)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Adenocarcinoma; Bladder cancer; Ectopia vesicae",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "XD04-XD05",
"pmc": null,
"pmid": "26500998",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports",
"references": "16807437;5906001;15310979;19239457;22906645;534827;11350401",
"title": "Oncologic Concerns in An Exstrophied Urinary Bladder - An Indian Scenario.",
"title_normalized": "oncologic concerns in an exstrophied urinary bladder an indian scenario"
} | [
{
"companynumb": "IN-SA-2015SA143148",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Murine model suggests programmed cell death-1 (PD-1), an immune checkpoint not only plays role in tumor escape but is also a tumor suppressor for T-cells. But until, no reports of secondary T-cell lymphoma postuse of immune checkpoint inhibitors (ICIs) has been reported. Herein, we present a hitherto unreported phenomenon of secondary T-cell lymphoma when PD-1 inhibitor was used in a patient diagnosed with a tumor of epithelial origin.\n\n\n\nA man in mid-70s presented with biopsy-proven metastatic tumor of epithelial origin. Patient received carboplatin in combination with paclitaxel for four cycles leading to partial remission. The patient was subsequently switched to pembrolizumab due to persistent disease in the mediastinum. After four cycles of PD-1 inhibitor, patient presented with progression of disease and was diagnosed with biopsy-proven peripheral T-cell lymphoma-not otherwise specified. Based on the reported tumor suppressor function of PD-1 in murine models, we hypothesized that the use of PD-1 inhibitor caused clonal proliferation of abnormal T-cell clone leading to T-cell lymphoma. T-cell receptor (TCR) sequencing was performed by TCRβ sequencing and T-cell clones from pre-ICI treatment specimen were compared with post-ICI treatment specimens. We show that one of the T-cell clones present in pre-ICI treatment specimen at a low frequency of had massive expansion to become most dominant clone in post-ICI treatment specimens leading to lymphoma. Moreover, targeted exome sequencing revealed a new TET2 mutation in the clone representing the lymphoma.Next, we retrospectively reviewed the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS), the pharmacovigilance database from 2012 to 2018 to find the reported incidence of this phenomenon and calculated the reporting OR (ROR) for disproportionality analysis for risk of T-cell lymphoma due to checkpoint inhibitors compared with other drugs. In FAERS, the incidence of T-cell lymphoma post-ICIs (pembrolizumab, nivolumab and ipilimumab) was found to be 0.02% with 17% mortality. The ROR probability of risk of T-cell lymphoma compared with other drugs in pharmacovigilance database was increased at 1.91.\n\n\n\nT-cell lymphoma is a rare sequela of ICIs with high mortality. Larger studies with long-term follow-up of patients receiving ICIs is needed.",
"affiliations": "Houston Methodist Cancer Center, Houston, Texas, USA kartikanand88@gmail.com spiyer@mdanderson.org.;Houston Methodist Research Institute, Houston, Texas, USA.;Houston Methodist Cancer Center, Houston, Texas, USA.;University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Houston Methodist Cancer Center, Houston, Texas, USA.;University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Houston Methodist Cancer Center, Houston, Texas, USA.;University of Texas MD Anderson Cancer Center, Houston, Texas, USA kartikanand88@gmail.com spiyer@mdanderson.org.",
"authors": "Anand|Kartik|K|0000-0003-4480-1443;Ensor|Joe|J|;Pingali|Sai Ravi|SR|;Hwu|Patrick|P|;Duvic|Madeleine|M|;Chiang|Stephen|S|;Miranda|Roberto|R|;Zu|Youli|Y|;Iyer|Swaminathan|S|0000-0002-1646-813X",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D016190:Carboplatin; C582435:pembrolizumab; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1136/jitc-2019-000104",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\n32114498\njitc-2019-000104\n10.1136/jitc-2019-000104\nCase Report\n1506\nT-cell lymphoma secondary to checkpoint inhibitor therapy\nhttp://orcid.org/0000-0003-4480-1443Anand Kartik 1 Ensor Joe 2 Pingali Sai Ravi 1 Hwu Patrick 34 Duvic Madeleine 3 Chiang Stephen 1 Miranda Roberto 3 Zu Youli 1 http://orcid.org/0000-0002-1646-813XIyer Swaminathan 3 \n1 \nHouston Methodist Cancer Center, Houston, Texas, USA\n\n\n2 \nHouston Methodist Research Institute, Houston, Texas, USA\n\n\n3 \nUniversity of Texas MD Anderson Cancer Center, Houston, Texas, USA\n\n\n4 \nDivision of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA\n\nCorrespondence to Dr Kartik Anand; kartikanand88@gmail.com; Dr Swaminathan Iyer; spiyer@mdanderson.org\n2020 \n28 2 2020 \n8 1 e00010416 12 2019 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.Background\nMurine model suggests programmed cell death-1 (PD-1), an immune checkpoint not only plays role in tumor escape but is also a tumor suppressor for T-cells. But until, no reports of secondary T-cell lymphoma postuse of immune checkpoint inhibitors (ICIs) has been reported. Herein, we present a hitherto unreported phenomenon of secondary T-cell lymphoma when PD-1 inhibitor was used in a patient diagnosed with a tumor of epithelial origin.\n\nCase report\nA man in mid-70s presented with biopsy-proven metastatic tumor of epithelial origin. Patient received carboplatin in combination with paclitaxel for four cycles leading to partial remission. The patient was subsequently switched to pembrolizumab due to persistent disease in the mediastinum. After four cycles of PD-1 inhibitor, patient presented with progression of disease and was diagnosed with biopsy-proven peripheral T-cell lymphoma-not otherwise specified. Based on the reported tumor suppressor function of PD-1 in murine models, we hypothesized that the use of PD-1 inhibitor caused clonal proliferation of abnormal T-cell clone leading to T-cell lymphoma. T-cell receptor (TCR) sequencing was performed by TCRβ sequencing and T-cell clones from pre-ICI treatment specimen were compared with post-ICI treatment specimens. We show that one of the T-cell clones present in pre-ICI treatment specimen at a low frequency of had massive expansion to become most dominant clone in post-ICI treatment specimens leading to lymphoma. Moreover, targeted exome sequencing revealed a new TET2 mutation in the clone representing the lymphoma.\n\nNext, we retrospectively reviewed the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS), the pharmacovigilance database from 2012 to 2018 to find the reported incidence of this phenomenon and calculated the reporting OR (ROR) for disproportionality analysis for risk of T-cell lymphoma due to checkpoint inhibitors compared with other drugs. In FAERS, the incidence of T-cell lymphoma post-ICIs (pembrolizumab, nivolumab and ipilimumab) was found to be 0.02% with 17% mortality. The ROR probability of risk of T-cell lymphoma compared with other drugs in pharmacovigilance database was increased at 1.91.\n\nConclusions\nT-cell lymphoma is a rare sequela of ICIs with high mortality. Larger studies with long-term follow-up of patients receiving ICIs is needed.\n\nlymphomaimmunologyHouston Methodist HospitalInnovation grantspecial-featureunlocked\n==== Body\nBackground\nImmune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 to overcome tumor immune escape have greatly improved outcomes in many cancer subtypes.1 2 However, ICIs are not without toxicity due to off target effects of immune stimulation known as immune-related adverse events (AEs),3 which can be potentially life threatening such as myocarditis.4 As ICIs are relatively newer class of antineoplastic drugs full extent of toxicity is not known. Immune checkpoint PD-1 not only plays a role in tumor escape through inactivation of T-cell when bound by its ligand programmed cell death ligand 1/2 (PD-L1/2) on tumor cells through PI3K pathway5 but is a tumor suppressor for T-cells itself. Wartewig et al\n6 discovered the previously unknown role of PD-1 being tumor suppressor when they investigated in a syngeneic mouse model carrying itk-syk oncogenic driver mutation that treatment with PD-1 inhibitor caused massive proliferation of abnormal T-cells carrying oncogenic driver mutation leading to T-cell lymphogenesis. Until now no case of secondary T-cell lymphoma post-treatment with PD-1 inhibitor has been described. Herein, we present a case of secondary T-cell lymphoma in a patient treated with PD-1 inhibitor for tumor of epithelial origin. We also retrospectively queried FDA Adverse Events Reporting System (FAERS) from 2012 to 2018 to find out incidence of this AE and performed disproportionality signal analysis using reporting OR (ROR).\n\nCase presentation\nA man in mid-70s with history of stage T1 transitional cell carcinoma of bladder 14 years prior (treated at that time with intravesical BCG vaccine and intravesical instillation of doxorubicin for vaccine failure) presented to the hospital with shortness of breath. Complete blood count (CBC) and complete metabolic panel were within normal limits. Workup revealed left-sided pleural effusion (figure 1A). Incisional biopsy of left pleura was performed which on immunohistochemistry (IHC) was positive for cytokeratin (CK) and negative for CD45 and anaplastic lymphoma kinase (ALK) consistent with undifferentiated carcinoma of epithelial origin (see online supplementary figure 1). PD-L1 staining on the tumor was 5%. Targeted next-generation sequencing (NGS) was performed, which showed low tumor mutation burden of five mutations/megabase with mutation involving TP53 being most predominant; variant allele frequency (VAF)=31% (see online supplementary table 1 for all mutations detected). Patient received chemotherapy with standard dose carboplatin in combination with paclitaxel every 3 weeks. After four cycles, the patient had partial response to therapy (figure 1B) and treatment was switched to pembrolizumab (a PD-1 inhibitor) 200 mg intravenously every 3 weeks due to persistent disease in the mediastinum. After four cycles of pembrolizumab, the patient had fever, weight loss along with left cervical, bilateral axillary and inguinal lymphadenopathy (figure 1C). CBC revealed marked lymphocytosis with eosinophilia. Biopsy of left cervical lymph node which on IHC was positive for CD3, CD5, CD30, CD45 and negative for CK, CD20, ALK was consistent with peripheral T-cell lymphoma; not otherwise specified (PTCL;NOS) (online supplementary figure 2). Bone marrow staging biopsy showed the same findings as lymph node confirming Stage IV disease. Targeted exome NGS showed TET2 mutation; VAF=26% (c.5127T>A or p.Cys1709Ter, a nonsense mutation in exon 11 of TET2). Unfortunately, the patient developed cerebral venous thrombosis, which led family to decline any further therapy for lymphoma and decided to pursue hospice and patient died shortly thereafter. Based on the reported tumor suppressor function of PD-1 in murine models, we hypothesized that anti PD-1 therapy caused monoclonal expansion of TET2 mutated T-cell clone causing T-cell lymphoma. To prove our hypothesis after obtaining informed consent from the patient family, we performed T-cell receptor (TCR) sequencing (TCRβ sequencing by Immunoseq assay) and compared pre-ICI to post-ICI biopsy sample. TCR sequencing revealed clonal expansion of T-cell clone (CASTADGSSNTGELFF) from 0.008% in lung (pre-ICI sample) to 11% in bone marrow and 41% in the lymph node (post-ICI samples) which is suspected to be the TET2 mutated clone, hence supporting our hypothesis (figure 2) (online supplementary figure 3). Next to find out incidence of this AE, we retrospectively queried FAERS for AEs secondary to ICIs namely ‘nivolumab’, ‘ipilimumab’ and ‘pembrolizumab’ from 1 January 2012 to 31 December 2018. FAERS quarterly files were downloaded and all T-cell-related neoplasm reactions due to ICIs were searched, six were found to be present namely ‘T-cell lymphoma’, ‘mycosis fungoides’, ‘adult T-cell lymphoma/leukemia’, ‘T-cell type acute leukemia’, ‘anaplastic large-cell lymphoma’ and ‘PTCL unspecified’. To compare risk of T-cell-related neoplasm in ICI treated cases versus cases treated by all other drugs in the database, a disproportionality signal analysis was conducted using ROR. ROR is a measure of the magnitude of association between an exposure to a pharmaceutical and odds of a specific outcome occurring.7 It is considered significant when lower limit of 95% CI is >1. We found 12 cases of T-cell-related neoplasm out of 50 445 AEs reported due to ICIs, with incidence of 0.02% (table 1). Seventy-five per cent were men, median age of the whole cohort was 65 years and 50% were reported in 2018. Half of the cases were secondary to nivolumab, followed by pembrolizumab, nivolumab +ipilimumab and ipilimumab involved in 3, 2 and 1, respectively. Most common indication for ICI use was lung cancer, followed by malignant melanoma, Hodgkin disease, oesophageal carcinoma and renal cancer. Median time to AE was 10.5 months with 17% (2/12) cases with outcome of death. ROR for ICIs causing T-cell lymphoma was elevated at 1.91 (95% CI 1.08 to 3.37) (online supplementary table 2). The analysis of FAERS has limitations, this study is retrospective, actual incidence of T-cell lymphoma post-ICI use cannot be determined because it is possible not all the events are reported within FAERS and time of event for all cases was not available. It is critical that any hypotheses generated by using pharmacovigilance databases are validated through prospective studies.\n\n10.1136/jitc-2019-000104.supp1Supplementary data \n\n\n\n Figure 1 Serial PET scans. (A) Initial PET scan showing increased 18 fludeoxyglucose uptake. (B) PET scan post four cycles of carboplatin plus paclitaxel showing partial remission. (C) PET scan post-PD-1 inhibitor therapy. PD-1, programmed cell death-1.\n\nFigure 2 TCRβ sequencing. T-cell clone by TCRβ sequencing before PD-1 inhibitor therapy in lung was 0.008%, which expanded to 11% in bone marrow and 41% in lymph node (post-treatment samples). Amino acid sequence of T-cell clone was CASTADGSSNTGELFF. ICI, immune checkpoint inhibitor; PD-1, programmed cell death-1; TCR, T-cell receptor.\n\nTable 1 Review of Food and Drug Administration adverse events reporting (pharmacovigilance database)\n\nTotal adverse events (nivolumab, pembrolizumab, ipilimumab)\t50445\t\nTotal T-cell related neoplasm AE\t12\t\nSex\t\t\n Male\t8\t\n Female\t4\t\nMedian age, years; no of patients for whom data was available\tn=9\t\nRange (minimum/maximum)\t65 (51-87)\t\nCPI used\t\t\n Nivolumab\t6\t\n Pembrolizumab\t3\t\n Nivolumab+ipilimumab\t2\t\n Ipilimumab\t1\t\nIndication for CPI use\t\t\n Lung cancer\t5\t\n Malignant melanoma\t3\t\n Hodgkin disease\t2\t\n Esophageal carcinoma\t1\t\n Renal cancer\t1\t\nTime to AE, months; no of patients for whom data were available\tn=7\t\nRange (minimum/maximum)\t10.5 (1.33-121.5)\t\nOutcome\t\t\n Death\t2\t\n Life threatening\t2\t\n Other outcome\t8\t\nYear event reported\t\t\n 2012\t1\t\n 2015\t1\t\n 2016\t1\t\n 2017\t3\t\n 2018\t6\t\nCountry where event occurred\t\t\n USA\t5\t\n Japan\t3\t\n Hong Kong\t1\t\n Spain\t1\t\n Brazil\t1\t\n Canada\t1\t\nAE, adverse event; CPI, checkpoint inhibitor.\n\nDiscussion\nThis study reports, to our knowledge, the first report of secondary malignancy with use of ICIs. We report a case of PTCL, NOS in a patient where PD-1 inhibitor was used for undifferentiated carcinoma of epithelial origin. We also review FAERS database to show increased reports of incidence of T-cell-related neoplasm with ICIs, particularly PD-1 inhibitors. TCR signaling on T-cells expressing PD-1 can be inactivated when engaged by its ligand PDL-1/2 on tumor cells through PI3K pathway.5 Addition of ICI normally overcomes this PD-1-PD-L1-mediated T-cell anergy and promotes T-cell proliferation with enhanced antitumor T-cell responses. Wartewig et al\n6 discovered a previously unknown role of PD-1 of being a tumor suppressor. They used a syngeneic mouse model of T-cell lymphoma carrying itk-syk oncogenic driver mutation. In presence of PD-1 expansion of T-cells expressing itk-syk was diminished, while in absence of PD-1 the mice (with biallelic PD-1 deletion) had to be euthanized rapidly due to unregulated expansion and accumulation of T-cells expressing itk-syk. Next they treated syngeneic mice with itk-syk oncogenic driver mutation with PD-1 inhibitor and found massive lymphoproliferation and hyperprogression of lymphoma as in itk-syk carrying mice with PD-1 deletion. Rapid progression of T-cell lymphoma has also been described when nivolumab (a PD-1 inhibitor) was used for adult T-cell lymphoma.8 Another clinical trial evaluating pembrolizumab for relapsed/refractory T-cell lymphoma was stopped prematurely due to futility; at initial restaging scan more than 50% had disease progression.9 T-cell lymphoma as a complication of ICI treatment for other malignancies has not been described. Our patient developed TET2-mutated T-cell lymphoma when pembrolizumab was used to treat the epithelial tumor, closely resembling the process in the itk-syk model. We demonstrate this by finding of massive clonal expansion using the Immunoseq TCR sequencing that tracks the T-cell clone from the lung biopsy specimen at very low frequency to the dominant one in the bone marrow and lymph node. Furthermore, targeted exome NGS revealed a TET2 mutation in exon 1110 and this was not detected previously on targeted exome NGS in the lung specimen. Mutations in TET2 gene have been reported in higher frequency in T-cell lymphomas,11–13 for example, more than one-third of PTCL-NOS cases harbor TET2 mutations.13 Studies have shown genomic disruption of TET2 alone is not enough for overt oncogenesis.12 14 Disruption of TET2 can lead to altered differentiation of T-lymphocyte as demonstrated by Fraietta et al,\n15 which reported a patient with B cell chronic lymphocytic leukemia treated with anti CD19 chimeric antigen receptor therapy (CAR-T) wherein the CAR-T lentivirus was randomly integrated into the TET2 gene leading to disruption on one allele and patient already had exon 11 mutation on second TET2 allele. They show that TET2 mutation affecting exon 11 only leads to hypofunctioning of gene. They noted that one CAR +T-cells which had this disruption of TET2 gene on both alleles was able to proliferate massively becoming the dominant T-cell clone in the blood leading to durable remission. TET2 disrupted CAR +T-cells were even detected in peripheral circulation 4 years later with concern of patient developing T-cell malignancy. In our patient, the use of pembrolizumab lead to ‘second hit’ with the loss of PD-1 tumor suppressor function and the clonal proliferation of this TET2 mutant, culminating in the transformation to the T-cell lymphoma. The observed clinical phenomenon is supported by our query into FAERS, which demonstrates this likelihood of this complication at 0.02%. The ROR for T-cell lymphoma post-ICI use was increased at 1.91. T-cell lymphoma post ICI is indeed an emerging but a rare complication with a relatively high mortality.\n\nConclusion\nT-cell lymphoma is a rare complication of ICIs with high mortality. Long-term follow-up of patients receiving ICIs particularly PD-1 inhibitors is needed.\n\nAuthors acknowledge the family of patient for donating tissue for research. The manuscript was previously presented in part as a poster presentation at ASCO-SITC Immuno Oncology symposium in 2019 and KA was awarded ASCO Cancer Conqueror Merit award. We acknowledge grant support (SI- Dottie and Jimmy Adair Foundation; YZ (PI) and SI (Co-PI)- 5R01CA224304-02 from National Institutes of Health).\n\nTwitter: @DrSwami_Iyer\n\nContributors: Contribution conceptualisation: KA. SI: methodology. KA, SI and JE: statistical analysis. JE: radiological review. SC: pathological review. YZ: writing original draft preparation. KA and SI. Writing review and editing: all authors.\n\nFunding: This study was funded by Houston Methodist Hospital.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Not required.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 \nReck M , Rodríguez-Abreu D , Robinson AG , et al \nPembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer\n. N Engl J Med \n2016 ;375 :1823 –33\n.10.1056/NEJMoa1606774 \n27718847 \n2 \nCoit DG , Thompson JA , Albertini MR , et al \nCutaneous melanoma, version 2.2019, NCCN clinical practice guidelines in oncology\n. J Natl Compr Canc Netw \n2019 ;17 :367 –402\n.10.6004/jnccn.2019.0018 \n30959471 \n3 \nBrahmer JR , Lacchetti C , Schneider BJ , et al \nManagement of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of clinical oncology clinical practice guideline\n. J Clin Oncol \n2018 ;36 :1714 –68\n.10.1200/JCO.2017.77.6385 \n29442540 \n4 \nJohnson DB , Balko JM , Compton ML , et al \nFulminant myocarditis with combination immune checkpoint blockade\n. N Engl J Med \n2016 ;375 :1749 –55\n.10.1056/NEJMoa1609214 \n27806233 \n5 \nSharpe AH , Pauken KE \nThe diverse functions of the PD1 inhibitory pathway\n. Nat Rev Immunol \n2018 ;18 :153 –67\n.10.1038/nri.2017.108 \n28990585 \n6 \nWartewig T , Kurgyis Z , Keppler S , et al \nPD-1 is a haploinsufficient suppressor of T cell lymphomagenesis\n. Nature \n2017 ;552 :121 –5\n.10.1038/nature24649 \n29143824 \n7 \nRothman KJ , Lanes S , Sacks ST \nThe reporting odds ratio and its advantages over the proportional reporting ratio\n. Pharmacoepidemiol Drug Saf \n2004 ;13 :519 –23\n.10.1002/pds.1001 \n15317031 \n8 \nRatner L , Waldmann TA , Janakiram M , et al \nRapid progression of adult T-cell leukemia-lymphoma after PD-1 inhibitor therapy\n. N Engl J Med \n2018 ;378 :1947 –8\n.10.1056/NEJMc1803181 \n29768155 \n9 \nBarta SK , Zain J , MacFarlane AW , et al \nPhase II study of the PD-1 inhibitor pembrolizumab for the treatment of relapsed or refractory mature T-cell lymphoma\n. Clin Lymphoma Myeloma Leuk \n2019 ;19 :356 –64\n.10.1016/j.clml.2019.03.022 \n31029646 \n10 \nKopanos C , Tsiolkas V , Kouris A , et al \nVarSome: the human genomic variant search engine\n. Bioinformatics \n2019 ;35 :1978 –80\n.10.1093/bioinformatics/bty897 \n30376034 \n11 \nCouronné L , Bastard C , Bernard OA \nTet2 and Dnmt3a mutations in human T-cell lymphoma\n. N Engl J Med \n2012 ;366 :95 –6\n.10.1056/NEJMc1111708 \n22216861 \n12 \nQuivoron C , Couronné L , Della Valle V , et al \nTet2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis\n. Cancer Cell \n2011 ;20 :25 –38\n.10.1016/j.ccr.2011.06.003 \n21723201 \n13 \nLemonnier F , Couronné L , Parrens M , et al \nRecurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters\n. Blood \n2012 ;120 :1466 –9\n.10.1182/blood-2012-02-408542 \n22760778 \n14 \nZang S , Li J , Yang H , et al \nMutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis\n. J Clin Invest \n2017 ;127 :2998 –3012\n.10.1172/JCI92026 \n28691928 \n15 \nFraietta JA , Nobles CL , Sammons MA , et al \nDisruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells\n. Nature \n2018 ;558 :307 –12\n.10.1038/s41586-018-0178-z \n29849141\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2051-1426",
"issue": "8(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "immunology; lymphoma",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002295:Carcinoma, Transitional Cell; D006801:Humans; D007167:Immunotherapy; D016399:Lymphoma, T-Cell; D008297:Male; D016609:Neoplasms, Second Primary; D017239:Paclitaxel; D010997:Pleural Neoplasms; D011379:Prognosis; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "101620585",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32114498",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "29442540;22216861;29143824;29849141;30959471;22760778;21723201;31029646;27806233;15317031;29768155;27718847;28691928;28990585;30376034",
"title": "T-cell lymphoma secondary to checkpoint inhibitor therapy.",
"title_normalized": "t cell lymphoma secondary to checkpoint inhibitor therapy"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-243162",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"dru... |
{
"abstract": "Patients with castration-resistant prostate cancer still need a urologist or radiation oncologist for treatment of local complications. Symptomatic progression will be reduced with treatment of the primary tumour.",
"affiliations": "Department of Urology, VU University Medical Centre, Amsterdam, The Netherlands. Electronic address: rja.vanmoorselaar@vumc.nl.",
"authors": "van Moorselaar|R Jeroen A|RJA|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.euf.2016.06.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2405-4569",
"issue": "2(5)",
"journal": "European urology focus",
"keywords": null,
"medline_ta": "Eur Urol Focus",
"mesh_terms": null,
"nlm_unique_id": "101665661",
"other_id": null,
"pages": "476-477",
"pmc": null,
"pmid": "28723510",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Case Presentation: Fit Patient with Nonmetastatic Castration-resistant Prostate Cancer, Lower Urinary Tract Symptoms, and Severe Recurrent Haematuria.",
"title_normalized": "case presentation fit patient with nonmetastatic castration resistant prostate cancer lower urinary tract symptoms and severe recurrent haematuria"
} | [
{
"companynumb": "NL-IPCA LABORATORIES LIMITED-IPC201704-000435",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
"... |
{
"abstract": "Intracranial solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a rare mesenchymal tumor with a propensity to recur and metastasize extracranially years after treatment. Accordingly, there are no reported cases of a patient presenting with a simultaneous intracranial primary and extracranial metastases. We present the case of a patient presenting with an intracranial SFT/HPC and simultaneous liver metastases and propose a treatment paradigm.\nA 74-year-old male smoker presented with confusion. An MRI of the brain revealed a heterogeneously enhancing left frontal extra-axial mass. Systemic workup revealed multiple small liver lesions concerning for metastases. The patient underwent gross total resection (GTR) of the intracranial lesion with adjuvant CyberKnife stereotactic radiotherapy to the resection cavity. Pathology was consistent with a WHO Grade III SFT/HPC (previously known as anaplastic HPC). The liver lesions were biopsied and confirmed to be metastases. They were subsequently treated with stereotactic body radiation therapy, temozolomide, and bevacizumab. Eighteen months postoperatively, the patient is alive with no evidence of intracranial malignancy and regression of the hepatic lesions.\nSeveral studies support GTR and adjuvant radiotherapy to treat intracranial SFT/HPC. The role of adjuvant chemotherapy is less clear. Metastatic disease is typically detected several years after the initial diagnosis, and there is no consensus regarding the optimal treatment strategy. We propose that the rare presentation of intracranial SFT/HPC with simultaneous extracranial metastases should be treated in a multidisciplinary fashion with surgical resection, adjuvant radiotherapy, and chemotherapy.",
"affiliations": "Departments of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, United States.;Departments of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, United States.;Departments of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States.;Departments of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, United States.;Departments of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States.;Departments of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, United States.;Departments of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, United States.",
"authors": "Reddy|Sumanth|S|;Plitt|Aaron|A|;Raisanen|Jack|J|;Patel|Ankur R|AR|;Gopal|Purva|P|;Timmerman|Robert|R|;Patel|Toral R|TR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.25259/SNI_111_2019",
"fulltext": "\n==== Front\nSurg Neurol IntSurg Neurol IntSurgical Neurology International2229-50972152-7806Scientific Scholar USA SNI-10-14810.25259/SNI_111_2019Case ReportIntracranial anaplastic hemangiopericytoma presenting with simultaneous extra-cranial metastases: A case report and review of the literature Reddy Sumanth 1sumanth.reddy@utsouthwestern.eduPlitt Aaron 1aaron.plitt@phhs.orgRaisanen Jack 2jack.raisanen@utsouthwestern.eduPatel Ankur R. 1ankur.patel@phhs.orgGopal Purva 2purva.gopal@utsouthwestern.eduTimmerman Robert 3robert.timmerman@utsouthwestern.eduPatel Toral R. 1toral.patel@utsouthwestern.edu1 Departments of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, United States.2 Departments of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States.3 Departments of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, United States.* Corresponding author: Toral R. Patel, MD., Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States. toral.patel@utsouthwestern.edu2019 26 7 2019 10 14817 2 2019 06 6 2019 Copyright: © 2019 Surgical Neurology International2019This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background:\nIntracranial solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a rare mesenchymal tumor with a propensity to recur and metastasize extracranially years after treatment. Accordingly, there are no reported cases of a patient presenting with a simultaneous intracranial primary and extracranial metastases. We present the case of a patient presenting with an intracranial SFT/HPC and simultaneous liver metastases and propose a treatment paradigm.\n\nCase Description:\nA 74-year-old male smoker presented with confusion. An MRI of the brain revealed a heterogeneously enhancing left frontal extra-axial mass. Systemic workup revealed multiple small liver lesions concerning for metastases. The patient underwent gross total resection (GTR) of the intracranial lesion with adjuvant CyberKnife stereotactic radiotherapy to the resection cavity. Pathology was consistent with a WHO Grade III SFT/HPC (previously known as anaplastic HPC). The liver lesions were biopsied and confirmed to be metastases. They were subsequently treated with stereotactic body radiation therapy, temozolomide, and bevacizumab. Eighteen months postoperatively, the patient is alive with no evidence of intracranial malignancy and regression of the hepatic lesions.\n\nConclusion:\nSeveral studies support GTR and adjuvant radiotherapy to treat intracranial SFT/HPC. The role of adjuvant chemotherapy is less clear. Metastatic disease is typically detected several years after the initial diagnosis, and there is no consensus regarding the optimal treatment strategy. We propose that the rare presentation of intracranial SFT/HPC with simultaneous extracranial metastases should be treated in a multidisciplinary fashion with surgical resection, adjuvant radiotherapy, and chemotherapy.\n\nExtracranial metastasisHemangiopericytomaIntracranialSimultaneousSolitary fibrous tumorSynchronous\n==== Body\nINTRODUCTION\nIntracranial solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a rare tumor of mesenchymal origin.[21] Analysis of the Surveillance, Epidemiology, and End Results Program data reveals an age-adjusted incidence of 3.77 per 10,000,000 people.[23] Evaluation of the National Cancer Database demonstrates that SFT/HPC comprises 0.22% of all intracranial tumors.[39] Before the updated WHO 2016 classification of central nervous system tumors, intracranial SFT and HPC were classified as two separate pathological entities. SFTs were designated as WHO Grade I lesions, while HPCs were designated as WHO Grade II or III lesions. Recently, whole- exome sequencing has revealed a unique NAB2-STAT6 fusion gene common to both SFTs and HPCs.[11] In recognition of this common molecular pathophysiology, the 2016 WHO classification combined these two tumors into a single entity known as SFT/HPC, with three distinct grades.[26]\n\nGrade I SFT/HPC is characterized by low cellularity and dense collagen deposition, which corresponds to the prior diagnosis of SFT. Grade II SFT/HPC is characterized by “staghorn” vasculature and increased cellularity. The presence of at least five mitoses per 10 high-power fields denotes a Grade III SFT/HPC, previously recognized as an anaplastic HPC.[11,26] More recent data have revealed that, with time, even low-grade SFT/HPCs can undergo malignant transformation.[2]\n\nIntracranial SFT/HPCs metastasize to extracranial locations at a rate of 11.6 to 69% within 10 years of initial diagnosis, most commonly to the lung/pleura, liver, and bone.[34] In the published literature, the reported time frame from diagnosis of the primary tumor to the diagnosis of extracranial metastases is wide and ranges from 3 to 372 months.[34] High-grade SFT/HPCs (WHO Grade III) are significantly more likely to develop extracranial metastases than low-grade tumors.[34] The typical clinical course consists of the initial identification of a solitary intracranial lesion, followed by the discovery of extracranial metastases during a long-term surveillance period. There are no reported cases describing the simultaneous diagnosis of an intracranial SFT/HPC and an extracranial metastasis.\n\nIn this report, we detail the case of a patient presenting with a symptomatic anterior cranial fossa WHO Grade III SFT/HPC and synchronous liver metastases. We will describe the patient’s clinical course and briefly review the literature in an effort to provide a rational treatment approach to this unusual clinical scenario.\n\nCASE DESCRIPTION\nA 74-year-old, right-handed, male smoker was taken to an outside hospital after he became confused at a gas station. This episode was preceded by 1 month of cognitive decline, personality changes, and urinary incontinence, as well as self- reported clear rhinorrhea while eating. His neurologic exam was notable for a flat affect and a relative paucity of speech.\n\nA head computed tomography (CT) was obtained and demonstrated a large, hyperdense left frontal extra- axial mass along the floor of the anterior cranial fossa, with bony erosion into the frontal sinus [Figure 1]. A subsequent magnetic resonance imaging (MRI) revealed a 7.0 cm×5.0 cm×4.9 cm heterogeneously enhancing mass with intrinsic T1 shortening, suggestive of prior hemorrhage, and subacute blood products posterior to the tumor margin, abutting the frontal horn of the left lateral ventricle. T1 postcontrast imaging revealed a dural tail and T2-weighted images demonstrated a partial cerebrospinal fluid cleft around the periphery of the lesion; both findings suggested that the mass was extra-axial in origin [Figure 2]. Given the aggressive appearance of the lesion and the patient’s smoking history, there was a concern that the lesion was a dural-based metastasis from an unknown primary. Therefore, a metastatic workup was completed, including a contrasted CT of the chest, abdomen, and pelvis. The CT scans revealed multiple small, hypodense liver lesions concerning for metastases [Figure 3] as well as pulmonary emboli.\n\nFigure 1: CT head without contrast demonstrates a hyperdense left frontal mass with the erosion of the inner table of the frontal sinus, near midline.\n\nFigure 2: MRI brain. (a) T1 noncontrast and (b) T1 postcontrast sequences demonstrate a 7.0 cm×5.0 cm×4.9 cm heterogeneously enhancing left frontal mass with T1 shortening at the posterior aspect of the lesion, suggestive of prior hemorrhage. (c) T1 postcontrast sequences also reveal a dural tail and (d) T2-weighted sequences demonstrate a partial cerebrospinal fluid cleft around the periphery of the lesion; both findings suggest that the mass is extra- axial in origin.\n\nFigure 3: CT abdomen/pelvis demonstrates a hypodense hepatic lesion (arrow) concerning for metastatic disease.\n\nAn inferior vena cava filter was placed, and the patient was subsequently taken to the operating room for resection of the intracranial tumor. A two-piece bifrontal craniotomy was performed since the tumor was noted to invade both the frontal sinus and the superior sagittal sinus on the preoperative imaging. The lesion was of mixed consistency, with both firm and soft components. There was significant hypervascularity, which was controlled with bipolar electrocautery. The involved portions of the superior sagittal sinus and frontal sinus were removed. The frontal sinus was subsequently obliterated with an abdominal fat graft and reconstructed with a combination of methyl methacrylate and titanium plates. Intraoperative frozen section analysis was consistent with a high-grade neoplasm (SFT/HPC vs. anaplastic meningioma vs. metastasis). A gross total resection (GTR) was achieved. The patient tolerated the procedure well; his speech and affect improved postoperatively. A postoperative MRI confirmed GTR.\n\nThe pathological assessment revealed that the left frontal tumor was a SFT/HPC. The tumor was histologically characterized by a proliferation of relatively small cells with round to oval nuclei, some with small nucleoli, and scant or indistinguishable cytoplasm. The cells were arranged haphazardly among staghorn-like vessels. There were >5 mitotic figures in 10 high-power microscopic fields and foci of tumor necrosis, and thus, the neoplasm was designated as anaplastic (WHO Grade III). Immunoperoxidase stains demonstrated nuclear expression of STAT6 by many of the neoplastic cells indicating fusion of the NAB2 and STAT6 genes [Figure 4]. Three weeks postoperatively, a CT-guided biopsy of one of the liver lesions was performed. Histologic sections revealed neoplastic cells that were morphologically similar to those in the intracranial tumor specimen and immunohistochemistry confirmed the NAB2/STAT6 fusion [Figure 5].\n\nFigure 4: (a) Histologic sections of the left frontal mass demonstrate a high-grade SFT/HPC. Note the four mitotic figures in the mid-upper right (red arrows). (H & E, 200×). (b) Nuclei of the neoplastic cells express STAT6, indicating a fusion of the NAB2 and STAT6 genes (Diaminobenzidine, 100×).\n\nFigure 5: (a) Metastatic hemangiopericytoma in liver core biopsy (H & E, 200×). (b) Expression of STAT6 by the neoplastic cells (Diaminobenzidine, 100×).\n\nThe patient underwent adjuvant CyberKnife stereotactic radiation therapy to the intracranial resection cavity. He received a total dose of 50 Gy (in 25 fractions). In addition, stereotactic body radiation therapy (SBRT) was used to treat the liver lesions: a segment 6 liver lesion was treated with 40 Gy in one fraction and a segment eight liver lesion was treated with 60 Gy in five fractions.\n\nSequential surveillance MRIs of the brain and abdomen were obtained following the completion of radiation treatment. MRIs of the brain remained stable, with no evidence of disease recurrence at 18 months postoperatively [Figure 6]. An MRI of the abdomen obtained 6 weeks following liver SBRT demonstrated mild growth of the previously noted lesions. These were initially observed; subsequent MRI 2 months later demonstrated persistent, but stable hepatic tumors. Given the abdominal MRI findings, the patient was offered additional treatment with chemotherapy. Two regimens were discussed: (1) pazopanib (800 mg daily) versus (2) temozolomide (150 mg/m2 on days 1–7 and 15–21/28-day cycle) and bevacizumab (5 mg/kg on days 8- and 22/28-day cycle). The patient ultimately opted to proceed with temozolomide and bevacizumab, and he completed 6 cycles and was then placed on observation. Follow-up abdominal MRIs over the next 6 months have demonstrated partial regression of the liver lesions. The patient is now 18 months from initial diagnosis and is alive and doing well, with no evidence of disease progression. He is on observation, with surveillance MRIs of the brain and abdomen obtained every 3 months.\n\nFigure 6: Postoperative surveillance MRI brain (T1 postcontrast) demonstrates no evidence of residual or recurrent disease.\n\nDISCUSSION\nSurgical resection remains the primary treatment for SFT/HPCs. Numerous studies have demonstrated that GTR improves both overall survival (OS) and progression- free survival (PFS) in patients with SFT/HPC, as compared to subtotal resection (STR).[6,7,10,28,33,41] A meta-analysis of 277 patients with intracranial SFT/HPC found that GTR prolonged OS by 3.25 years, compared to STR.[35] Importantly, the authors noted this benefit was independent of adjuvant radiotherapy.\n\nThe role of adjuvant radiotherapy for treatment of intracranial SFT/HPC remains controversial. Some studies have found that postoperative radiotherapy prolongs PFS, but that it does not provide a survival benefit.[22,28,35,39] Other studies have found an increase in OS in patients receiving postoperative radiotherapy.[12,15,36] Our own institutional experience suggests that postoperative radiotherapy does not improve PFS or OS in patients who undergo GTR.[32] However, it is worth noting that each of these studies included a heterogeneous cohort of patients, with both low- and high- grade SFT/HPCs. Thus, it is difficult to generalize these results to patients with the WHO grade III SFT/HPC. The largest study of patients with anaplastic SFT/HPCs followed 52 patients for a mean of 36.8 months and determined that postoperative radiotherapy did improve both PFS and OS. The 5-year PFS was 66.3% in patients who received postoperative radiotherapy versus 38.3% in patients who did not. Furthermore, the 5-year OS was 90% in patients who received postoperative radiotherapy versus 47.1% in patients who did not.[41] The standard treatment dose for adjuvant radiotherapy in this setting is 50 Gy.[4,13,15,35]\n\nThere is a paucity of published literature addressing the role of adjuvant systemic chemotherapy for SFT/HPC. In general, treatment with traditional cytotoxic chemotherapeutic agents has yielded disappointing results.[3,41,42] The use of targeted chemotherapies for the management of SFT/HPC remains an area of interest and is emerging. Pazopanib is a tyrosine kinase inhibitor that acts as an antiangiogenic agent by binding to vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR).[37] A case report of two patients with recurrent intracranial SFT/HPC treated with pazopanib demonstrated excellent radiographic results, with decreases in tumor volume of 84% and 43% after 3 months of therapy.[1] Genomic analyses have revealed increased expression of several tyrosine kinase sequences targeted by pazopanib in intracranial SFT/HPC, as compared to systemic SFT/HPC. This difference may explain the increased efficacy of pazopanib in treating intracranial SFT/HPC versus systemic SFT/HPC, although this observation is based on limited case studies. The primary limitations of pazopanib therapy are hepatotoxicity and thrombosis.[9]\n\nOf note, a Phase II trial of sunitinib (another tyrosine kinase inhibitor, which targets VEGFR, PDGFR, and c-KIT) for atypical and anaplastic meningioma included an exploratory cohort of six patients with SFT/HPC. Three patients discontinued therapy due to toxicity, two withdrew, and one had a progression of disease at 1.6 months.[18] An additional potential target is programmed death-ligand 1 (PD-L1), an immune checkpoint molecule that allows tumor cells to evade the host immune response by inactivating host T-cells. Kamamoto et al. have recently demonstrated that PD-L1 is commonly expressed in intracranial SFT/HPCs and that increased PD-L1 expression is associated with earlier extracranial metastases.[19] Further research into the use of PD-L1 inhibitors for the treatment of SFT/HPC is necessary.\n\nFinally, combination therapy with temozolomide and bevacizumab has been shown to be effective in the treatment of patients with refractory disease, although it is unclear if this benefit is from temozolomide, bevacizumab, or a synergistic response. A case series of 14 patients, with a median follow-up of 34 months, demonstrated either partial response (11 patients) or stable disease (2 patients) in all but one patient. For those patients with a partial response, the treatment effect was observed after 2 to 4 cycles of therapy, at a median of 2.5 months. Median PFS was 9.67 months and 78.6% of patients were progression-free at 6 months. Five patients had a PFS of at least 20 months.[31]\n\nExtracranial metastases are a relatively common finding in patients with SFT/HPC. A recent large case review found that 28% of all patients with intracranial SFT/HPC will develop extracranial metastases, most commonly to the bone, lung, or liver.[34] Approximately 17% of all extracranial SFT/HPC metastases occur in the liver.[34] Proposed treatment strategies for hepatic metastases include surgical resection, radiotherapy, radiofrequency ablation, transarterial embolization, and chemotherapy. Although various combinations of these treatment modalities have been described [Table 1], there is no consensus regarding the optimal approach, and clinical outcomes vary widely.\n\nTable 1: Treatment modalities and outcomes for intracranial SFT/HPC with liver metastases*.\n\nGiven that our patient had an excellent performance status and GTR of his intracranial disease, we felt that the aggressive treatment of his liver metastases was indicated. Due to his recent intracranial surgery and the preoperative pulmonary emboli, the decision was made to initially treat the hepatic lesions with SBRT alone. In addition, given the WHO Grade III histology, we also opted to treat the intracranial resection cavity with adjuvant CyberKnife stereotactic radiosurgery. When follow-up imaging demonstrated the mild progression of the liver metastases, systemic chemotherapy was advised. Two different regimens were offered: pazopanib alone versus combination temozolomide and bevacizumab. Given the hepatic location of the metastases and the history of pulmonary emboli, the decision was made to treat with temozolomide and bevacizumab. The patient completed 6 cycles and his subsequent MRIs demonstrated improvement in his disease burden. He is now 18 months from initial diagnosis and is being observed with surveillance MRIs of the brain and abdomen every 3 months. If future imaging studies demonstrate disease progression, evaluation of his original tumor specimens (brain and liver) for expression of pazopanib-targeted tyrosine kinase sequences and/or PD-L1 activity would be of particular utility to guide the selection of salvage therapies.\n\nCONCLUSION\nThe average time from diagnosis of a primary intracranial SFT/HPC to the detection of metastatic disease is approximately 7.5 years.[14] There are no reported cases of a patient presenting with an intracranial primary and synchronous extracranial metastasis. We believe that our patient may have a particularly aggressive SFT/HPC, given the WHO Grade III histology and presence of metastatic disease at presentation. In addition, the tumor’s infiltration of the superior sagittal sinus may have provided it with early access to the venous system, thus increasing the risk of hematogenous metastases. We present this rare case to provide clinical guidance to others who may encounter a similar patient. We believe that this type of patient should be treated in a multidisciplinary fashion, with initial maximal safe surgical resection, followed by a combination of radiotherapy and chemotherapy, tailored specifically to the patient’s systemic disease burden.\n\nHow to cite this article: Reddy S, Plitt A, Raisanen J, Patel AR, Gopal P, Timmerman R, et al. Intracranial anaplastic hemangiopericytoma presenting with simultaneous extracranial metastases: A case report and review of the literature. Surg Neurol Int 2019;10:148.\n\nDeclaration of patient consent\nThe authors certify that they have obtained IRB approval for this retrospective review and that all appropriate patient consent forms have been obtained. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Apra C Alentorn A Mokhtari K Kalamarides M Sanson M Pazopanib efficacy in recurrent central nervous system hemangiopericytomas J Neurooncol 2018 139 369 72 29700673 \n2 Apra C Mokhtari K Cornu P Peyre M Kalamarides M Intracranial solitary fibrous tumors/hemangiopericytomas: First report of malignant progression J Neurosurg 2018 128 1719 24 28644098 \n3 Bassiouni H Asgari S Hübschen U König HJ Stolke D Intracranial hemangiopericytoma: Treatment outcomes in a consecutive series Zentralbl Neurochir 2007 68 111 8 17665341 \n4 Bastin KT Mehta MP Meningeal hemangiopericytoma: Defining the role for radiation therapy J Neurooncol 1992 14 277 87 1460491 \n5 Chakravarty BJ Munn S Lane MR Hepatic metastasis from a meningeal haemangiopericytoma Aust N Z J Med 1991 21 884 5 1818550 \n6 Chen H Zeng XW Wu JS Dou YF Wang Y Zhong P Solitary fibrous tumor of the central nervous system: A clinicopathologic study of 24 cases Acta Neurochir (Wien) 2012 154 237 48 21938461 \n7 Chen LF Yang Y Yu XG Gui QP Xu BN Zhou DB Multimodal treatment and management strategies for intracranial hemangiopericytoma J Clin Neurosci 2015 22 718 25 25744076 \n8 De Martin E Coilly A Guettier C Samuel D Liver metastases from meningeal hemangiopericytoma Liver Int 2015 35 2337 25913235 \n9 Ebata T Shimoi T Bun S Miyake M Yoshida A Shimomura A Efficacy and safety of pazopanib for recurrent or metastatic solitary fibrous tumor Oncology 2018 94 340 4 29614488 \n10 Fargen KM Opalach KJ Wakefield D Jacob RP Yachnis AT Lister JR The central nervous system solitary fibrous tumor: A review of clinical, imaging and pathologic findings among all reported cases from 1996 to 2010 Clin Neurol Neurosurg 2011 113 703 10 21872387 \n11 Fritchie K Jensch K Moskalev EA Caron A Jenkins S Link M The impact of histopathology and NAB2-STAT6 fusion subtype in classification and grading of meningeal solitary fibrous tumor/hemangiopericytoma Acta Neuropathol 2019 137 307 19 30584643 \n12 Ghia AJ Allen PK Mahajan A Penas-Prado M McCutcheon IE Brown PD Intracranial hemangiopericytoma and the role of radiation therapy: A population based analysis Neurosurgery 2013 72 203 9 23149953 \n13 Ghia AJ Chang EL Allen PK Mahajan A Penas-Prado M McCutcheon IE Intracranial hemangiopericytoma: Patterns of failure and the role of radiation therapy Neurosurgery 2013 73 624 30 23839520 \n14 Ghose A Guha G Kundu R Tew J Chaudhary R CNS hemangiopericytoma: A systematic review of 523 patients Am J Clin Oncol 2017 40 223 7 25350465 \n15 Guthrie BL Ebersold MJ Scheithauer BW Shaw EG Meningeal hemangiopericytoma: Histopathological features, treatment, and long-term follow-up of 44 cases Neurosurgery 1989 25 514 22 2797389 \n16 Hukill PB Lowman RM Visceral metastasis from a meningioma: Report of a case Ann Surg 1960 152 804 8 13716736 \n17 Iwamuro M Nakamura S Shiraha H Kobayashi Y Fukatsu H Yamamoto K A case of primary intracranial hemangiopericytoma with hepatic metastases: Successful treatment with radiofrequency ablation and transcatheter arterial chemoembolization Clin J Gastroenterol 2009 2 30 5 26191805 \n18 Kaley TJ Wen P Schiff D Ligon K Haidar S Karimi S Phase II trial of sunitinib for recurrent and progressive atypical and anaplastic meningioma Neuro Oncol 2015 17 116 21 25100872 \n19 Kamamoto D Ohara K Kitamura Y Yoshida K Kawakami Y Sasaki H Association between programmed cell death ligand-1 expression and extracranial metastasis in intracranial solitary fibrous tumor/hemangiopericytoma J Neurooncol 2018 139 251 9 29675794 \n20 Kaneko T Harada A Isshiki K Murakami H Nakao A Nonami T Hemangiopericytomatous meningioma metastasized to the liver: Report of a case and review of the literature Surg Today 1993 23 644 8 8369618 \n21 Kim BS Kim Y Kong DS Nam DH Lee JI Suh YL Clinical outcomes of intracranial solitary fibrous tumor and hemangiopericytoma: Analysis according to the 2016 WHO classification of central nervous system tumors J Neurosurg 2018 129 1384 96 29372881 \n22 Kim JH Jung HW Kim YS Kim CJ Hwang SK Paek SH Meningeal hemangiopericytomas: Long-term outcome and biological behavior Surg Neurol 2003 59 47 53 12633961 \n23 Kinslow CJ Bruce SS Rae AI Sheth SA McKhann GM Sisti MB Solitary-fibrous tumor/hemangiopericytoma of the central nervous system: A population-based study J Neurooncol 2018 138 173 82 29427152 \n24 Lee SJ Kim ST Park SH Choi YL Park JB Kim SJ Successful use of pazopanib for treatment of refractory metastatic hemangiopericytoma Clin Sarcoma Res 2014 4 13 25276340 \n25 Lo RC Suriawinata AA Rubin BP Liver metastasis of meningeal hemangiopericytoma: A study of 5 cases Clin Mol Hepatol 2016 22 188 91 27044772 \n26 Louis DN Perry A Reifenberger G von Deimling A Figarella-Branger D Cavenee WK The 2016 world health organization classification of tumors of the central nervous system: A summary Acta Neuropathol 2016 131 803 20 27157931 \n27 Manatakis DK Delis SG Ptohis N Korkolopoulou P Dervenis C Multidisciplinary approach to hepatic metastases of intracranial hemangiopericytoma: A case report and review of the literature Case Rep Oncol Med 2015 2015 214306 26090247 \n28 Melone AG D’Elia A Santoro F Salvati M Delfini R Cantore G Intracranial hemangiopericytoma our experience in 30 years: A series of 43 cases and review of the literature World Neurosurg 2014 81 556 62 24239740 \n29 Nickerson TP Fahy AS Bingener J Laparoscopic resection of intra-abdominal metastasis from intracranial hemangiopericytoma Int J Surg Case Rep 2015 15 50 3 26318126 \n30 Niwa M Kobayashi T Kuchiwaki H Furuse M A case of hemangiopericytoma with multiple extracranial metastasis: A case report No Shinkei Geka 1998 26 241 5 9558656 \n31 Park MS Patel SR Ludwig JA Trent JC Conrad CA Lazar AJ Activity of temozolomide and bevacizumab in the treatment of locally advanced, recurrent, and metastatic hemangiopericytoma and malignant solitary fibrous tumor Cancer 2011 117 4939 47 21480200 \n32 Patel AR Flores BC Ban VS Hatanpaa KJ Mickey BE Barnett SL Intracranial hemangiopericytomas: Recurrence, metastasis, and radiotherapy J Neurol Surg B Skull Base 2017 78 324 30 28725519 \n33 Ramakrishna R Rostomily R Sekhar L Rockhill J Ferreira M Hemangiopericytoma: Radical resection remains the cornerstone of therapy J Clin Neurosci 2014 21 612 5 24231562 \n34 Ratneswaren T Hogg FR Gallagher MJ Ashkan K Surveillance for metastatic hemangiopericytoma-solitary fibrous tumors-systematic literature review on incidence, predictors and diagnosis of extra-cranial disease J Neurooncol 2018 138 447 67 29551003 \n35 Rutkowski MJ Sughrue ME Kane AJ Aranda D Mills SA Barani IJ Predictors of mortality following treatment of intracranial hemangiopericytoma J Neurosurg 2010 113 333 9 20367074 \n36 Schiariti M Goetz P El-Maghraby H Tailor J Kitchen N Hemangiopericytoma: Long-term outcome revisited. Clinical article J Neurosurg 2011 114 747 55 20672899 \n37 Schutz FA Choueiri TK Sternberg CN Pazopanib: Clinical development of a potent anti-angiogenic drug Crit Rev Oncol Hematol 2011 77 163 71 20456972 \n38 Spatola C Privitera G Recurrent intracranial hemangiopericytoma with extracranial and unusual multiple metastases: Case report and review of the literature Tumori 2004 90 265 8 15237597 \n39 Trifiletti DM Mehta GU Grover S Sheehan JP Clinical management and survival of patients with central nervous system hemangiopericytoma in the national cancer database J Clin Neurosci 2017 44 169 74 28711294 \n40 Yoshida K Yamazaki S Ota K Makuuchi M Hasegawa H Takayasu K A case report of meningioma with multiple liver metastases Kanzo 1988 29 1528 34 \n41 Zhang GJ Zhang LW Li D Wu Z Zhang JT Analysis of prognostic factors, survival rates, and treatment in anaplastic hemangiopericytoma World Neurosurg 2017 104 795 801 28552736 \n42 Zweckberger K Jung CS Mueller W Unterberg AW Schick U Hemangiopericytomas grade II are not benign tumors Acta Neurochir (Wien) 2011 153 385 94 21104099\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2152-7806",
"issue": "10()",
"journal": "Surgical neurology international",
"keywords": "Extracranial metastasis; Hemangiopericytoma; Intracranial; Simultaneous; Solitary fibrous tumor; Synchronous",
"medline_ta": "Surg Neurol Int",
"mesh_terms": null,
"nlm_unique_id": "101535836",
"other_id": null,
"pages": "148",
"pmc": null,
"pmid": "31528483",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "12633961;13716736;1460491;15237597;17665341;1818550;20367074;20456972;20672899;21104099;21480200;21872387;21938461;23149953;23839520;24231562;24239740;25100872;25276340;25350465;25744076;25913235;26090247;26191805;26318126;27044772;27157931;2797389;28552736;28644098;28711294;28725519;29372881;29427152;29551003;29614488;29675794;29700673;30584643;8369618;9558656",
"title": "Intracranial anaplastic hemangiopericytoma presenting with simultaneous extra-cranial metastases: A case report and review of the literature.",
"title_normalized": "intracranial anaplastic hemangiopericytoma presenting with simultaneous extra cranial metastases a case report and review of the literature"
} | [
{
"companynumb": "US-009507513-2108USA004131",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nFollowing severe burn injury, patients undergo profound metabolic changes, including insulin resistance and hyperglycemia. Hyperglycemia has been linked to impaired wound healing, increased risk of skin graft loss, increased muscle catabolism, increased infections, and mortality. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that improves glycemic control by slowing the inactivation of incretin hormones, increasing insulin synthesis and release from pancreatic beta cells and lowering glucagon secretion from pancreatic alpha cells. The objective of this study was to describe our institution's experience with using sitagliptin to help mitigate insulin resistance after burn injury.\n\n\nMETHODS\nThis was a retrospective chart review that included 22 adult burn patients. Burn patients were prescribed sitagliptin regardless of their previous medical history of type 2 diabetes mellitus. Patients were included in this analysis if they were adults admitted for burn injury during a 13-month period and received at least 3 consecutive doses of sitagliptin. Patients were excluded if they did not have insulin use data 3 days pre- and 3 days post-sitagliptin initiation. The first day of sitagliptin initiation was considered day 0; data from day 0 were not included in either the pre- or post-sitagliptin analysis.\n\n\nRESULTS\nIn the 3 days prior to sitagliptin initiation, patients received a median of 114.3 units per day (IQR 49.1, 228) in an attempt to maintain a blood glucose goal of less than 180 mg/dL. In the 3 days after sitagliptin was started, exogenous insulin requirements significantly decreased to a median to 36.3 units per day (IQR 11.7, 95) (P=0.009). Seven patients were on insulin infusions at the time of sitagliptin initiation. After sitagliptin was started, it took a median of 3 days (IQR 2, 3.25) to be liberated from the insulin infusion. In terms of safety, there were two episodes of hypoglycemia (BG<70 mg/dL) after sitagliptin initiation, compared to three episodes prior to sitagliptin initiation (P=0.7).\n\n\nCONCLUSIONS\nThe addition of sitagliptin to burn patients' medication regimens significantly reduced insulin requirements over a 3-day period and allowed liberation from insulin drips.",
"affiliations": "US Army Institute of Surgical Research 3698 Chambers Pass, JBSA Fort Sam Houston, TX 78234, The United States.;US Army Institute of Surgical Research 3698 Chambers Pass, JBSA Fort Sam Houston, TX 78234, The United States.;Methodist Hospital 7700 Floyd Curl Drive, San Antonio, TX 78229, The United States.;US Army Institute of Surgical Research 3698 Chambers Pass, JBSA Fort Sam Houston, TX 78234, The United States.",
"authors": "Pruskowski|Kaitlin A|KA|;Shields|Beth A|BA|;Ainsworth|Craig R|CR|;Cancio|Leopoldo C|LC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2160-2026",
"issue": "10(5)",
"journal": "International journal of burns and trauma",
"keywords": "Insulin resistance; hyperglycemia; sitagliptin",
"medline_ta": "Int J Burns Trauma",
"mesh_terms": null,
"nlm_unique_id": "101581623",
"other_id": null,
"pages": "237-245",
"pmc": null,
"pmid": "33224612",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "12634538;16385293;21841493;20739853;31543976;11535907;30253968;23056044;24074819;23164767;18695610;26691869;14559958;19503020;15650645;18847648;16868220;19770742;29408836;18182920;30517046;19318384;23890278",
"title": "Evaluation of the use of sitagliptin for insulin resistance in burn patients.",
"title_normalized": "evaluation of the use of sitagliptin for insulin resistance in burn patients"
} | [
{
"companynumb": "US-009507513-2012USA000018",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SITAGLIPTIN PHOSPHATE"
},
"drugadditional": ... |
{
"abstract": "This article investigates everyday experiences and practises that are associated with processes of pharmaceuticalization and with practices of 'drug diversion'--that is, the illicit exchange and non-medical use of prescription drugs. It reports results from a qualitative study that was designed to examine the everyday dimensions of non-medical prescription stimulant use among students on an American university campus, which involved 38 semi-structured interviews with individuals who used prescription stimulants as a means of improving academic performance. While discussions of drug diversion are often framed in terms of broad, population-level patterns and demographic trends, the present analysis provides a complementary sociocultural perspective that is attuned to the local and everyday phenomena. Results are reported in relation to the acquisition of supplies of medications intended for nonmedical use. An analysis is provided which identifies four different sources of diverted medications (friends; family members; black-market vendors; deceived clinicians), and describes particular sets of understandings, practices and experiences that arise in relation to each different source. Findings suggest that at the level of everyday experience and practice, the phenomenon of prescription stimulant diversion is characterised by a significant degree of complexity and heterogeneity.",
"affiliations": "Department of Social Science, Health and Medicine, King's College London, Strand, London WC2R 2LS, UK. Electronic address: scott.vrecko@kcl.ac.uk.",
"authors": "Vrecko|Scott|S|",
"chemical_list": "C090411:Adderall; D000662:Amphetamines; D000697:Central Nervous System Stimulants; D055553:Prescription Drugs; D008774:Methylphenidate",
"country": "England",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nSoc Sci MedSoc Sci MedSocial Science & Medicine (1982)0277-95361873-5347Pergamon S0277-9536(14)00662-510.1016/j.socscimed.2014.10.016ArticleEveryday drug diversions: A qualitative study of the illicit exchange and non-medical use of prescription stimulants on a university campus Vrecko Scott scott.vrecko@kcl.ac.ukDepartment of Social Science, Health and Medicine, King's College London, Strand, London WC2R 2LS, UK1 4 2015 4 2015 131 297 304 © 2014 The Author2014This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).This article investigates everyday experiences and practises that are associated with processes of pharmaceuticalization and with practices of ‘drug diversion’—that is, the illicit exchange and non-medical use of prescription drugs. It reports results from a qualitative study that was designed to examine the everyday dimensions of non-medical prescription stimulant use among students on an American university campus, which involved 38 semi-structured interviews with individuals who used prescription stimulants as a means of improving academic performance. While discussions of drug diversion are often framed in terms of broad, population-level patterns and demographic trends, the present analysis provides a complementary sociocultural perspective that is attuned to the local and everyday phenomena. Results are reported in relation to the acquisition of supplies of medications intended for nonmedical use. An analysis is provided which identifies four different sources of diverted medications (friends; family members; black-market vendors; deceived clinicians), and describes particular sets of understandings, practices and experiences that arise in relation to each different source. Findings suggest that at the level of everyday experience and practice, the phenomenon of prescription stimulant diversion is characterised by a significant degree of complexity and heterogeneity.\n\nHighlights\n• Reports original research on non-medical stimulant use among university students.\n\n• Explores mechanisms of drug diversion from the perspective of everyday users.\n\n• Offers empirical insight on local organisation of illicit pharmaceutical markets.\n\n• Furthers understandings of everyday dimensions of ‘pharmaceuticalization’.\n\n\n\nKeywords\nUnited StatesPharmaceuticalsDrug diversionPharmaceuticalizationNon-medical drug usePrescription medicationEnhancementAdderall\n==== Body\n1 Introduction\nALEXIS: We were in the same class; she lived down the hall, so we worked a lot together. I was done, but she wanted me to stay. She was actually wanting me to study with her, and I was just, ‘I'm tired’. It doesn't take me that long to do my part, and she had a little bit more trouble, and it took her a little bit longer. So she was, ‘all right, well—you can take an Adderall and just stay up with me in the library!’ And at first, when she said it, I was: ‘no, I'm not taking Adderall. I'm just going to go to sleep, and I'll help you tomorrow.’\n\nBecause of the phobia of its being a pill, you automatically assume that you're going to get an out-of-body experience, you're doing something wrong, and it's just … I've never been prescribed anything, so it just didn't feel right. But then on the other hand, I didn't have any hesitation [in relation to concerns about whether taking the pill] would hurt me because I knew so many other people that were taking it at time, more frequently. So I just was, ‘all right, I’ll help you out’, and popped it. I ended up taking it just because she was really struggling in the class. And once I took it, I was, ‘oh, this isn't that bad.’ And it didn't bother me, and I didn't feel like I was doing anything wrong.\n\n\n\nAlexis is a third-year undergraduate science major who regularly uses Adderall—a stimulant medication composed of mixed amphetamine salts that is produced by Shire Pharmaceuticals and approved for use in the treatment of Attention Deficit and Hyperactivity Disorder (ADHD) and narcolepsy—to help her study more effectively. Above, she is telling me about how she came to try the drug for the first time, during a study session with one of her classmates. After several hours of studying, Alexis had finished her work, was tired, and was ready to call it a day; however, when her friend offers her a tablet of Adderall to help her get over any tiredness she might feel, Alexis accepts the offer. And though she tells me that at the time she considered herself to be someone who ‘would never do that sort of thing’, she subsequently begins to use the pills as regularly as she can obtain them, which she does by ‘dropping hints’ to her friend.\n\nAlexis's non-medical use of Adderall is part of a trend that has been identified by a range of scholars: the increasing use of pharmaceuticals approved for therapeutic purposes as a means to enhance the mental capacities of ‘normal’ individuals, i.e. those who are not ill (Kramer, 1992; Parens, 1998; Quintero and Nichter, 2011). While a wide range of prescription medications are consumed for unapproved, non-therapeutic purposes, the use of stimulant medications by individuals—particularly researchers and university students—seeking to boost their abilities to concentrate and focus on academic work has become one of the main areas of focus within discussions of enhancement (Arria, 2008; Elnicki, 2013; Maher, 2008). This phenomenon raises a number of ethical and policymaking questions that have received attention from bioethicists, such as whether pharmaceutical enhancement constitutes a form of cheating and whether individuals who do not use pharmaceutical enhancers might experience coercion (S. Bell et al., 2013; Farah et al., 2004; Greely et al., 2008; Rudski, 2014). It also raises significant issues that have been examined by social scientists, from political–economic concerns about the scientific and commercial choices involved in the development of medications that blur the boundary between normal and pathological cognition (Bond, 2009; Moreira et al., 2009; Whitehouse et al., 2005), to transformations in medical practice and patient expectations associated with increasing medicalization (Conrad and Leiter, 2004; Coveney et al., 2011).\n\nA growing body of empirical research provides useful insight into non-medical prescription stimulant use, particularly in the form of regional and national surveys that examine broad demographic patterns and social attitudes (Hotze et al., 2011; Maher, 2008; Pilkinton and Cannatella, 2012; Teter et al., 2006). In the US context, significant levels of non-medical prescription stimulant use have been found among university students, with estimates of lifetime prevalence rates as high as 6.9% (McCabe et al., 2005). At the same time, variations have been reported across different regions of the country and among different groups of academic institutions: for example, lifetime prevalence rates of non-medical prescription stimulant use are reported to be as high as 25% at institutions located in the American north-east, with more competitive admissions standards (Loe, 2008; Wilens et al., 2008). Further variations appear among student subpopulations, with greater prevalence of use among white male students, and members of fraternities and sororities (Hall et al., 2005; McCabe et al., 2005).\n\nSurvey findings such as those above are crucial for revealing significant demographic and historical trends about non-medical prescription stimulant use. However, they are limited in their ability to produce detailed information on the lived experiences and daily practices of actual users (Loe and Cuttino, 2008; Singh et al., 2010). It is increasingly recognized that qualitative research has the capacity to offer distinctive insight in this respect (Lucke, 2012), and although empirical data on the experiences and practices of everyday users remains somewhat limited (Singh and Kelleher, 2010; Varga, 2012), findings from several studies have been published in recent years (Loe, 2008; Loe and Cuttino, 2008; Partridge et al., 2013; Vrecko, 2013). This article aims to contribute to this emerging body of work, presenting findings from a qualitative study designed to further understandings of the everyday dimensions of non-medical prescription stimulant use among university students seeking to improve their academic performance.\n\n1.1 Pharmaceutical leakage: drug diversion and everyday life\nQualitative research on prescription stimulant use among university students to date has largely focused on exploring the subjective views and experiences of this population. For example, Loe and Cuttino (2008)'s study of students diagnosed with ADHD focuses on forms of identity management and self-conception associated with medication use, while Partridge et al. (2013) examine perceptions of drug efficacy and safety, and Vrecko (2013) reports on non-medical users' accounts of experiences of studying while on prescription stimulants. This article takes a rather different focus, however, exploring processes associated with prescription drug ‘diversion’, that is, the movement of medications away from those to whom they have been prescribed legally, to those who obtain and use them illegally and for non-therapeutic purposes.\n\nIn recent decades, the non-medical use of prescription drugs has been identified as a significant and growing phenomenon, and has received increasing attention from public health experts, medical practitioners, and government agencies involved in law enforcement and drug abuse prevention. While there is some emerging data on national trends in stimulant drug diversion (McCabe et al., 2014; Varga, 2012), relatively little is known about the transactions that arise as prescription stimulants enter into and circulate within networks of non-medical users (Fischer et al., 2010; Wilens et al., 2008). Much of existing research and commentary relating to drug diversion has been oriented towards population-level analyses that are linked to forms of epidemiologic inquiry, and survey-based data findings. In comparison, relatively few studies have explored non-medical prescription drug use and processes of drug diversion in terms of the smaller-scale social and interpersonal dynamics underlying these broad patterns of consumption. The present analysis is based on the hypothesis that fine-grained sociocultural approaches may be valuable for understanding the local particularities and processes from which population-level trends arise (Quintero et al., 2006).\n\nAn example of such a socio-cultural approach is provided by the anthropologist Anne Lovell and her ethnographic analysis of the ‘pharmaceutical leakage’ (2006) that arises in relation to buprenorphine diversion in France. While predominantly oriented toward the specific case of buprenorphine use and exchange among her informants, Lovell's study may be taken—as it is here—as a starting point for considering how patterns of national drug diversion can be investigated at the micro level as a social and interactive phenomenon. For example, Lovell suggests that pharmaceutical diversion might be described as a process that ‘connects the doctor's office or the pharmacy with networks of drug users who can diffuse the product and knowledge about it’ (2006: 156). While Lovell fully recognizes that local actors' activities are tied to broad cultural dynamics and political-economic systems, one of her most crucial findings is that macro-level patterns cannot be fully understood without an account of the everyday beliefs and actions of individuals who seek, receive, and distribute diverted pharmaceuticals: the different practices and strategies associated with acquiring medications, as well as the intersubjective understandings and local knowledges that circulate with them. The novelty of such a perspective, in comparison to many other analyses of drug diversion, is that it places emphasis on developing an empirical account of the everyday practices that arise as pharmaceutical products ‘leak’ out from the legalised flows of industrial production and medically-condoned distribution, to the illicit realm of black-market distribution and non-medical use.\n\nThe analysis below takes inspiration from sociocultural analyses such as Lovell's insofar as it approaches drug diversion as a social process to be explained, rather than as an epidemiological pattern to be measured. Exploring the mechanisms through which prescription psychostimulants are acquired and exchanged among students on an elite American university campus, it focuses in particular on what Lovell describes as ‘the pharmaco-associative’, that is, ‘the indigenous transmission and elaboration of knowledge about psychoactive substances and the ongoing interaction and ensuing social organization of the drug users themselves’ (2006: 156). After providing an account of research methods and data analysis, it presents results which may be considered as representations of different forms of ‘pharmaco-association’ that appear among users, as these relate to individuals' strategies for obtaining Adderall for illicit, non-medical purposes. A subsequent discussion further considers how the everyday circumstances, shared meanings and social practices that are reported may be linked to ‘translocal’ processes, including those associated with contemporary configurations of medical knowledge and clinical practice, national regulatory apparatuses, and commercial pharmaceutical enterprise.\n\nBeyond developing insights on the specific case of illicit, nonmedical use of prescription stimulants, a subsidiary aim of the current paper is to contribute to fine-grained, micro-level studies of ‘pharmaceuticalization’ that explore the social, personal and everyday dynamics that arise as pharmaceutical products come to be put to work in the management of an increasingly wide array of problems and experiences. In line with contemporary empirically-oriented approaches, pharmceuticalization is understood here as a ‘dynamic and complex heterogeneous socio-technical process’ (Williams et al., 2011: 721) linked to increasing rates of pharmaceutical consumption (Bell and Figert, 2012; Busfield, 2010); and I suggest that qualitative approaches attuned to everyday consumer practices hold significant potential for contributing to understandings of how individuals and consumer experiences intersect with broader political and economic dynamics (Fox et al., 2005; Jones, 2008; Stevenson et al., 2008).\n\n1.2 Methods and data analysis\nFindings presented here were generated from a qualitative investigation conducted by the author over a three-year period (2009–2011). Data was collected over 5 months of fieldwork at an elite US university, involving thirty-eight semi-structured interviews designed to elicit informal conversation about the beliefs, practices, and experiences of non-medical users (17 women, 21 men) of prescription stimulants. Initial subjects were recruited through posters placed in student areas on the university campus, and through a call for participants circulated via an email listserv run by the university; snowball sampling was also subsequently used, as participants informed friends, acquaintances, and colleagues about the study. Research and consent procedures were reviewed and approved by the university's IRB.\n\nRecruitment materials requested participants who had experience using Ritalin, Adderall, or other medications as ‘study aids’, and to be included in the dataset used for the following analysis participants had to: (1) be a former or current university student; (2) have experience using prescription stimulants as a means of improving academic performance, over a period of at least 3 months; and (3) not self-identify as having ADHD or any other psychiatric condition associated with impaired academic performance. Interviews were recorded and transcribed in full, and transcripts were imported into the qualitative analysis software Nvivo (Bazeley, 2007). Consonant with a grounded theory approach (Charmaz, 2006), data were coded and analytic induction used to identify key themes. Informants reported using a number of different medications, including Ritalin, Concerta, and Dexedrine, but the analysis below focuses on one particular product—namely Adderall—as this was what the overwhelming majority of subjects reported experiences with. In order to ensure anonymity, pseudonyms have been used for all informants' names.\n\n2 Results\nAs a result of preliminary analysis of data, variation in the sources from which individuals obtained Adderall was identified as a significant theme, relating to differences in informants' practises and experiences with the drug. Subsequent analysis identified four different sources, each of which was in turn associated with different ‘acquisition strategies’ that individuals employed in order to obtain medication for non-therapeutic use. Two of the strategies involved gift-like exchanges of Adderall, in which medication was obtained from friends or family members without any financial payment. Another two strategies involved the procurement of Adderall in relation to commercial transactions, either through involvement in local black markets, or by accessing legal pharmaceutical markets after having fraudulently obtained a doctor's prescription. Every one of the individuals interviewed reported experiences relating to one or more of these four themes.\n\n2.1 Acquisition from friends\nThe most common way that informants reported obtaining Adderall for non-medical use involved receiving pills from someone known personally to them, and well enough to be described as a friend. More than three-quarters of individuals (n29) reported such transactions, in which a recipient would typically be given a small supply of pills without expectation of a monetary payment or other financial exchange. Such gifts would usually, although not always, come from individuals who themselves had a prescription for the medication; and they would normally consist of no more than a few pills—often, only one or two which would be expected to be consumed on a single occasion.\n\nThe fact that pills were provided only a few at a time meant that regular use depended on continuous offerings being made to an individual. At the same time, however, direct requests for Adderall were largely avoided, as these were considered likely to give rise to uncomfortable situations—for example, a person making an explicit request might be perceived as greedy or presumptuous, or might risk putting a friend in the awkward position of having to refuse an appeal for help. Thus, more circumspect tactics were considered to be called for, particularly if one was hoping to receive pills on a regular basis.\n\nDuring a discussion of how he acquires his medications, Jas, an undergraduate science major, offers a typical account of such a pattern of exchange, and alludes to ‘scrounging’ behaviours that are involved:JAS: That first time, a friend gave me five 10-mg pills and I broke them in half, so it was ten days' worth and went from there.\n\nINTERVIEWER: And that's how you get them now, the same way?\n\nJAS: Well, I don't ask, like I did then. It's more scrounging around from the friends that I know have lots of extras. Like I said, people get prescribed significantly more than they actually use.\n\nIV: So you don't normally ask them?\n\nJAS: No. Asking all the time, that would be … I just make sure, I do what I can so that it’ll be offered.\n\n\n\nIndividuals reported a variety of similar ‘scrounging’ practices, directed towards individuals known to have supplies that might be shared, and performed in the hopes of yielding an offer of medication. Most commonly, informants reported dropping hints in conversations that could be picked up on by a receptive interlocutor. For example, Estelle explains the efforts she made after having received Adderall from a friend for the first time:ESTELLE: What I did was, afterwards, I made it very clear that I was open to more. ‘Oh, you know, it was amazing, it made things so much easier—thank you so much! And you get to use it all the time, I'm so jealous!’ And she got the message. It was pretty obvious.\n\nIV: But not as obvious as, say, just asking her?\n\nESTELLE: No. I didn't do that. I didn't know how she would feel, you know? And even now [after regular, ongoing exchanges], I just wouldn't. I just let her know, keep on telling her how great she is—and how great it is!\n\n\n\nIn addition to discussing benefits derived from Adderall, and voicing appreciation of gifts, individuals might also emphasize stresses or worries about difficult workloads. Anna explains how she does this deliberately, when attempting to elicit an offer from a friend:ANNA: I'll just steer the conversation toward that, and say something like, ‘I don't know what to do, in the next 3 weeks I've got a paper for English, one for History, a report for Bio; and three killer finals, too. It's soooo much …’\n\n\n\nIn a similar vein, Jeff explains how to present an account of one's academic troubles in a manner likely to lead to an offer of assistance in the form of medication:JEFF: You just make it clear that you’re in over your head, like, ‘I'm in deep shit here!’, and you drive it home. Eventually, if he's got some, he’ll feel bad keeping it to himself, when he knows he can help you out. If he can manage, he’ll offer you some. Or, at least, he'll say ‘sorry man, I've only got enough for me right now’, and then you know, you can move on and try elsewhere.\n\n\n\nWhile the deliberate management of conversational exchanges was the most commonly reported scrounging strategy, some individuals described practices oriented toward fostering emotional and/or spatial closeness between donor and recipient. For example, Aiden tells me that he makes a point of being present with a friend at times when she is likely to be taking Adderall herself. Physical co-presence, a shared social experience, and feelings of togetherness among ‘study buddies’ leads to Adderall exchanging hands:AIDEN: I don't ask, or even hint much, really. I just, I know the days she tends to be on it; and so I'm like, ‘Oh, hey, I'm going to hit the books today—what, you are too? Well, we should hang out!’ And when she's going to take some, she’ll just look at me and smile, and look at the bottle. And I'll shrug, sort of to say, ‘well, ok, sure I guess.’\n\n\n\nDespite variations in these different tactics, this group of friendship-oriented, gift-seeking practices share in common significant features that are captured by Jas's felicitous use of the term ‘scrounging,’ above. They involve attempts to identify and subtly manipulate sources from which medication can be obtained for free; they are associated with a sense of uncertainty that is experienced in the face of a more or less unreliable supply; and they tend to reflect a dependence on the beneficence of others that must be actively encouraged. Moreover, informants often acknowledged that however subtle such strategies might be, they involved a manipulation of one's friends. While seldom relished, this was considered a necessary part of what needed to be done to obtain the pills that were sought.\n\n2.2 Acquisition from family members\nA related though less common set of practices (reported by nine participants) involved the acquisition of Adderall from family members or intimate partners. Exchanges of Adderall through family connections resembled gift transactions among friends, insofar as they took place in the absence of monetary exchange. However, family-oriented strategies often involved practices that would be regarded as unsuitable or unthinkable if directed toward friends. Most notably, informants indicated that the sort of explicit request for Adderall that was difficult to make to a friend could be made with relative ease to a family member.\n\nIn response to a question about how he obtains Adderall from a brother who uses it as a prescribed treatment for ADHD, for example, James explains why he feels able to make requests directly:IV: So you just ask him for it, and he gives it to you?\n\nJAMES: Yeah, of course. I mean, he has plenty, and it's not like he would be like, ‘no—it’s mine!’ He just wouldn't, we’re not like that. And it's his prescription, ok, but it's like, my Dad's insurance is what pays for it.\n\nIV: And he doesn't have any problem … You know, even though you don't have ADHD?\n\nJAMES: No. I mean, he knows that he takes it and it helps him with school. And he knows that if he gives it to me, it helps me with my stuff, too. What does it matter, who's got the diagnosis? It's like: you’ve got something, it helps, can help me. Of course you’re going to share.\n\n\n\nFor James, Adderall appears to be considered something akin to a collectively owned, family good. James suggests that even if the pills he receives are, in one sense, a gift from his brother, they are at the same time not really his brother's to give, since they are paid for by his family's medical plan. Moreover, as our conversation continued, it became apparent that James' receipt of Adderall was not accompanied by any significant sense of gratitude or reciprocal obligation. Sharing between family members was expected as a matter of course.\n\nOther informants indicated that family members with legitimate prescriptions could be less willing to share than was James' brother; in fact, some even resisted demands placed upon them. However, in such cases the nature of the close ties between seeker and potential supplier seemed to allow direct strategies of manipulation to be used, without giving rise to the negative feelings associated with scrounging from friends. For example, Adam, a social science undergraduate, tells me that it's not a big deal for him to ‘guilt-trip’ his girlfriend of several years into giving up some of her prescribed supply. ‘She does get a little weirded out by it [a direct request], but she’ll eventually go along’, he says as he explains a typical situation in which he asks for some Adderall to help him through an end-of-semester crunch. ‘I’ll be, “Look, don't you want me to do well? I need it, I need to ace these. It's my future we’re talking about here.” And she’ll be, “Ok …”.’\n\nPerhaps the clearest indication of the distinct quality of family-oriented acquisition strategies was the fact that practices extending beyond emotional manipulation could be entertained as options—including behaviours reported by two individuals that might be considered theft. Frieda, for instance, tells me that she obtains her study pills while returning to her family home during holidays or other breaks. During such visits, she surreptitiously goes into the family medicine cabinet and ‘skims’ pills from bottles of medication that are intended for her ADHD-diagnosed little sister. Although she does confess feeling guilty about such behaviour, Frieda nevertheless feels able to obtain Adderall from her sister in a way that she insists she would never consider in relation to a friend. When I ask her whether she has ‘skimmed’ pills from a friend's medicine cabinet, she appears shocked at the suggestion, emphatically telling me: “No way, I would never—that would be stealing. I mean, for real.” Similar to James, Frieda appears to regard a family member's supply of medication as something akin to communal property, a share of which one might more or less rightfully expect.\n\n2.3 Acquisition from black market sources\nEight individuals reported paying cash for pills from those willing to sell them on what was, in essence, a black market existing within and around the university campus. Practices oriented to these sources diverged from those outlined above, insofar as they involved monetary exchange, and tended to involve more impersonal interactions as are generally associated with market-oriented transactions. This was especially apparent in cases that involved buying Adderall from individuals described as campus-based ‘drug dealers’: While the main trade of such dealers consisted of recreational street drugs such as marijuana and cocaine, they could also provide Adderall and other prescription drugs, through transactions that were almost entirely business-like in terms of their impersonality.\n\nHowever, distinctions between market and non-market exchanges appeared much less clear-cut in relation to the most frequently reported black-market transactions; these (reported by seven individuals) involved the purchase of Adderall not from ‘dealers’, but from students who were situated within a buyer's extended social networks. Such suppliers tended to be described in familiar and relatively informal terms, for example as someone that one ‘sort of knows’, or as a ‘friend-of-a-friend.’ At the same time, however, the distance between exchanging partners was such that the employment of strategies used for acquiring Adderall as a gift would not be considered viable. Whereas friends might be approached with the hope of receiving pills for free, receipt of Adderall from acquaintances could only be expected in exchange for payment.\n\nThe acquisition of black market Adderall from acquaintances was not always easy, as connections to sellers were most often made through mutual friends. This meant that locating acquaintance-based sources would usually depend on the ability of a potential buyer to mobilise personal networks, as Jeff, indicates when explaining the strategy he uses when he is unable to obtain pills for free:JEFF: I'll just ask around, ‘hey, I want to stock up a bit for end of term–do you know anyone who's got some that they'd be willing to part with?’ And they'll ask how much I'm willing to pay, and then ask around, if they know anyone who has it’\n\n\n\nThe nature of resulting transactions was somewhat ambiguous, insofar as these blurred distinctions between market and gift relations. Reliance upon friends who were willing to help find a source meant that buyers often experienced uncertainty about the reliability of their supplies; moreover, to the extent that successful acquisition were dependent upon the goodwill of connection-making friends, it might call for interpersonal efforts akin to those involved when scrounging gifts. At the same time, pills obtained from acquaintances could usually be purchased more cheaply than those bought from a dealer, with prices sometimes so low—for example, just enough to cover the costs that an acquaintance would have incurred at a pharmacy—as to be almost gift-like.\n\nA notable feature of market-oriented acquisition strategies was their association with particular beliefs and understandings about what purchased Adderall might reveal about its users. While one might expect market-oriented exchanges to be a preferred means of acquisition, to the extent that they could offer more impersonal transactions and increased reliability of supplies, most individuals expressed a strong preference for gifted Adderall. Rather than being linked to concerns about financial cost, this preference was usually articulated in connection with the belief that someone who would go so far as buying pills might be too dependent on them; the implicit expectation being that one ought to be able to take Adderall or leave it, and only take it when it came for free. Purchased Adderall also tended to be associated with subtle but significant meanings that differentiated it from Adderall received as a gift: when purchased, it was something that seemed more like a ‘drug,’ with connotations of street use, danger, and outright illegality, and less like a ‘medication,’ which by comparison was perceived as relatively safe and socially accepted. Moreover, those who had never paid for the medication often emphasised that fact, in such a way as to imply a significant distinction between themselves and others who had.\n\n2.4 Acquisition from deceived clinicians\nA separate set of market-oriented acquisition strategies involved the extraction of Adderall for non-medical use from legal pharmaceutical markets, through means of clinical deception. Four individuals reported obtaining Adderall as a result of carefully-planned, fraudulent encounters with healthcare providers. These involved strategies oriented toward deliberately manipulating physicians in a way that would lead toward a (false) diagnosis of ADHD, which in turn would result in a prescription for the desired medication.\n\nOne such encounter was described by Lucy, a second-year undergraduate who explained to me how her plans had developed out of a visit to her doctor, regarding what she believed to be depression. Lucy had reported several psychiatric symptoms relating to low mood, but also one which led her clinician to raise the possibility of prescribing a stimulant medication:LUCY: I told her about the problem, of feeling really down, and sometimes crying and stuff. But I also mentioned that I was having concentration problems—and she said, ‘oh it might be ADD [Attention-Deficit Disorder]. But, you know, we’re going to put you on anti-depressants first.’\n\n\n\nAlthough Lucy did not consider there to be any chance that she actually had ADD, she had in fact already been using gifted Adderall to help her study. She thus seized upon her doctor's mention of ADD as an opportunity to access a new, more reliable source of Adderall. After a few months on antidepressants, she returned to her doctor with this plan in mind. ‘I just used that’, she explained, referring to the physician's prior speculation about ADD. ‘I said, oh yeah, well, you know, that anti-depressants are really working, but I'm still having trouble concentrating on my work.’ Believing it would ‘play better’ if she did not appear too eager, Lucy describes feigning resistance in response to the clinician's suggestion that her antidepressant be supplemented with an ADHD medication:LUCY: I just played into the whole fact of being like [… ] nervous about taking the medication. And, you know, she kept soothing me and saying, “no, no, no, like, you know, lots of people take medication for it, it's absolutely fine, you know, we're just going to start you off low, we’ll see how it goes, and you know, see how you responded, you might not respond to it at first so if you need to increase it, you know, that's fine, we’ll talk about that—come back next week.”\n\n\n\nInforming me that this was ‘exactly what I wanted’, Lucy went on to explain how, over a series of subsequent appointments, she successfully executed plans that resulted in a tripling of her initially prescribed dosage. This provided her with more pills than she herself regularly used, and thus with a surplus that she could sell to others on campus, in order to recoup the costs she incurred when paying to have her prescription filled at her pharmacy.\n\nThree other individuals described similar approaches involving deliberate deception, although without any prior discussion of ADHD or stimulant medications with their doctors. Aaron, for example, told me about a strategy he developed after hearing ‘good things’ about non-medical Adderall use from those around him on campus. Feeling uncomfortable about requesting the drug from his friends, he conducted research online that led him to decide to try ‘faking’ ADHD symptoms. Preparations for deceiving his doctor included studying ADHD diagnosis criteria, and using a pen to scrawl a variety of notes and reminders on his hands immediately before his appointment, in the hope that these would be noticed as a symptom—he had learned that ‘people with ADD or whatever have trouble keeping track of stuff, they forget a lot.’ Following a successful encounter, Aaron left his doctor's office with an initial prescription for a month's supply, which was subsequently renewed on a regular basis.\n\nWhile only four individuals engaged in this strategy, it is notable that they all reported using Adderall on a more frequent basis than did those who acquired the medication from other sources. No respondents reported taking Adderall on a daily basis for more than a few consecutive days, when receiving it as a gift or purchasing black market supplies. Yet all four of the individuals who obtained their own prescriptions did: two reported having previously taken the medication everyday for several weeks in a row before establishing their current patterns of intermittent use, while two reported patterns of daily use that had been maintained for more than three months. One reason for this tendency toward more regular use appeared to relate to the fact these individuals found themselves with a steady and ample supply of the medication. An illustration of the significance of reliability associated with prescription-sourced Adderall was provided by Marcus, who describes how his everyday decision-making process changed as he switched from acquiring Adderall irregularly from friends to obtaining it via his own prescription: ‘Before, it had been “should I take some today, or may be save it when I’ll need it more?” But now, it's more like, I ask myself: “why not take it?” Once a prescription holder, Marcus did not experience anxieties relating to medication scarcity that arose when scrounging for Adderall from friends, and felt able to take pills freely, without a need to consider rationing his supplies.\n\n3 Discussion\nThe preceding analysis provides insights into the experiences, practices and perspectives of non-medical Adderall users, and results suggest that the means through which non-medical users obtain their supplies of medication are characterised by a significant degree of complexity and heterogeneity. This diversity is particularly striking if non-medical acquisition strategies are compared to the simplicity of how Adderall is obtained when legally prescribed to patients as a therapeutic intervention. Legitimately prescribed patients would generally proceed along a predictable pathway, taking a prescription obtained in the clinic to a pharmacy, where it would be exchanged for medication. In contrast, practices of drug acquisition among non-medical users of Adderall appear to be much less standardized, varying considerably in relation to the particular social and everyday circumstances in which individuals find themselves. Moreover, the use of different strategies for non-medical Adderall acquisition appears to correspond to subtle but significant differences in users' perceptions and experiences: Adderall bought from a ‘drug dealer,’ for example, is likely to be perceived differently from that received from a friend for free or from a doctor that has been tricked into providing it; and each different source of the medication is associated with a slightly different set of practical and ethical challenges with which an individual might be required to engage.\n\nFindings of such diversity among different users is certainly consonant with well-established scholarship that indicates that the choices, behaviours and experiences of individual drug users vary according to the particular circumstances and local conditions within which individuals find themselves (Fraser and Moore, 2011). They also offer support for recent suggestions that prescription drug diversion is a complex and multi-faceted phenomenon, involving considerable variation between different classes of medication, and between different subpopulations of users (Fischer et al., 2010; Quintero et al., 2006). Moreover, such insights into the experiences, practices and perspectives of nonmedical stimulant users as provided above would seem necessary for developing an empirically-grounded understanding of the circulation and use of prescription stimulants among ‘healthy’ university students: It would be difficult to understand the relatively free movement and use of nonmedical Adderall among my informants, for example, without taking into account the practical strategies that make the substance accessible, and the particular understandings held by students that make the drug appear as something more or less acceptable to illicitly acquire and consume.\n\nAt the same time that the preceding results and analysis have explored the significance of local and everyday phenomena associated with drug diversion, it is important to note that the everyday beliefs and actions of individuals who seek, receive, and distribute unprescribed medications such as Adderall are also connected to larger cultural and political-economic dynamics—including those associated with the provision of national healthcare, scientific enterprise, and legal pharmaceutical markets. For example, as Lovell (2006) observes in relation to her study of buprenorphine diversion, the existence of medications as black market goods depends upon the medical knowledges and regulatory mechanisms that allow for the legal production and provision of those substances: these are required to make a pharmaceutical product's very existence possible, and in their absence there would be no legitimate commodity to divert from a legal market.\n\nIn relation to Adderall, the pharmaceutical markets that exist for the legal circulation of stimulant drugs can be considered to provide one of the most basic necessary conditions for students' illegal trades. Moreover, empirical evidence of a close interrelationship between legal markets and illicit use is suggested by recent research that has begun to identify correlations between the overall size of legal markets for prescription stimulants and rates of non-medical use of such drugs. Poulin (2007), for example, reports population-level findings from Canada that suggested that patterns of medical and non-medical use of prescription stimulants were closely connected with one another. Further support is also provided by findings of longitudinal survey research conducted by McCabe et al. (2014), which demonstrate that a decade-long increase in reports of medical use of prescription stimulants to treat ADHD correlated with a comparable increase in reported diversion behaviours and non-medical use.\n\nIt thus seems reasonable to suggest that the experiences and practises of the individuals reported above are intertwined with broader commercial and professional dynamics that studies of pharmaceuticalization have identified in relation to the growth of markets for ADHD drugs. These would include the economic and regulatory factors that have shaped ADHD as a clinical entity, and have produced a ‘diagnostic expansion’ in recent years that has allowed a wider range of individuals to qualify for legal access to prescription stimulants (Conrad and Potter, 2000). Within the US, they would also include the influence of Direct-to-Consumer advertisements, forms of consumer-group activism, and other initiatives financed by pharmaceutical companies that may directly or indirectly promote medication use, and also reinforce perceptions of psycho-stimulant pharmaceuticals as relatively safe, health-enhancing substances (Cohen, 2006; Loe and Cuttino, 2008).\n\n3.1 Limitations of current study\nThe findings presented above reflect limitations that often arise in relation to qualitative and naturalistic research, particularly when conducted on a relatively small scale. While providing rich information pertaining to understandings of and interactions between individuals, the fact that research was conducted on only one university campus make it difficult to stake convincing claims about generalizability of results in relation to other contexts, both within and beyond the US. Moreover, use of semi-structured interviews raises the potential for unintended interview effects, whereby informants may offer what they consider to be socially desirable responses, rather than truthful ones. Finally, the use of non-randomised sampling procedures means that the population under study cannot be taken as representative of all students at the university where the study took place, and also raises the possibility of self-selection bias.\n\n4 Conclusion\nThis article has presented findings that add to existing knowledge about prescription drug diversion, by elucidating some of the everyday practises and understandings that arise in relation to the non-medical use of stimulant medications among university students—a population that has been associated with particularly pronounced levels of such use (Quintero et al., 2006). It has shown that significant divergences in users' practices and experiences of nonmedical stimulant use arise in relation to acquisition strategies employed by individuals, as these relate to the four sources of illicit medication supplies that were most commonly reported (i.e., friends; family members; black market dealers; deceived clinicians). It has further shown that different acquisition strategies correspond to variations in how individuals think and feel about their nonmedical drug usage. Combined, the reported findings suggest that how and why prescription stimulants are used may vary significantly between individuals, even when they might superficially appear to constitute a single, homogenous population (e.g., university students consuming stimulants for the non-medical purpose of improving academic performance). Such findings are significant because they indicate that nonmedical prescription stimulant is a phenomenon that involves a greater degree of complexity than might be apparent from consideration of statistical or population-level data.\n\nWhile findings relating to the particularities of users' everyday experiences and practises might be dismissed as relatively unimportant details by those experts and agencies that seek to address public health issues associated with nonmedical prescription drug use, such a dismissal would be misguided. Indeed, if social circumstances and individual contingencies do in fact constitute significant factors in determining how and why students come to take prescription stimulants, then a better understanding of these would be helpful in relation to the consideration of ethical, regulatory, and public health questions arising in relation to nonmedical stimulant use. As Quintero et al. (2006) note, surveillance data and media reports suggest significant trends in prescription drug misuse among university students, yet little is known about social and cultural factors that shape individuals' practices. This dearth of knowledge is significant, because detailed understandings of how drug diversion happens within different groups of users might be of significant value in relation to education and prevention initiatives that seek to change individual behaviours, particularly if these are best developed in such a way that takes individual-level variations into account (Wilens et al., 2008). For example, findings above might be useful in devising initiatives that are specifically oriented to different practices of drug diversion that arise in relation to different sources of supply and related acquisition strategies.\n\nIt is worth reiterating that the study reported here was conducted at a single university, and therefore provides findings that are limited in their generalizability. Nevertheless, results suggest fruitful avenues for further research on non-medical prescription stimulant use. Future studies might pursue more systematically the findings reported above that suggest that divergences in the acquisition strategies that are employed by individuals correspond to differences in how users think and feel about Adderall. More broadly, findings above suggest that further use of sociocultural research strategies could increase understandings of how drug diversion happens among the individuals and groups who actively engage in the illicit use and exchange of pharmaceutical products.\n\nA further avenue for research would involve exploring in more detail the potential of Lovell's concept of ‘pharmaceutical leakage’ for contributing to studies of ‘pharmaceuticalization’ that examine the expanding usage of medications within a wide range of personal and socio-medical contexts (Bell and Figert, 2012)—and particularly those which seek to understand pharmceuticalization as a complex, multi-faceted social and medical process (Williams et al., 2011). Lovell develops her ideas exclusively in relation to buprenorphine users in France, with little discussion of other medications. However, the analysis above suggests that her framework has applicability to cases beyond that of buprenorphine; it may be particularly useful in extending analyses of how individual and consumer experiences intersect with broader political and economic dynamics (Fox et al., 2005; Jones, 2008; Stevenson et al., 2008). It has been suggested that recent studies of pharmaceutical research, development and commerce (e.g., Petryna, 2009; Pollock, 2012; Wahlberg and McGoey, 2007) indicate that the pharmaceutical industry is a complex and multi-faceted entity akin to a massive elephant whose form can only be grasped in parts at a time (Dumit, 2012: 18). With its orientation toward investigating how globally produced and marketed products enter into the circuits of everyday use, and how effects and meanings of pharmaceuticals are mediated by the personal and social circumstances of individual who consume them, Lovell's approach might allow for the dynamics of pharmaceutical industry to be understood in even greater complexity, as extending down into the everyday worlds of those who consume the industry's products.\n\nAcknowledgements\nResearch reported in this article was generously supported by a research grant from the Wellcome Trust (award number 079529/Z/06/Z). The author is grateful to Martha Farah for advice and support that made the study possible, and for helpful feedback received from Linsey McGoey, and from members of the Culture, Medicine and Power research group at King's College London.\n==== Refs\nReferences\nArria A.M. Nonmedical use of prescription stimulants and analgesics: associations with social and academic behaviors among college students J. Drug Issues 28 2008 156 \nBazeley P. Qualitative Data Analysis with NVivo 2007 Sage Publications Ltd \nBell S. Partridge B. Lucke J. Hall W. Australian university students' attitudes towards the acceptability and regulation of pharmaceuticals to improve academic performance Neuroethics 6 2013 197 205 \nBell S.E. Figert A.E. Medicalization and pharmaceuticalization at the intersections: looking backward, sideways and forward Soc. Sci. Med. 75 2012 775 783 22633161 \nBond J. Stages in cognitive impairment: boundary issues and the biomedicalisation of later life Gerontologist 49 2009 87–87 \nCharmaz K. Constructing Grounded Theory: A Practical Guide through Qualitative Analysis 2006 Sage Publications Ltd \nCohen D. Critiques of the ‘ADHD’enterprise Lloyd G. Stead J. Cohen D. Critical New Perspectives on ADHD 2006 Routledge New York, NY 12 33 \nConrad P. Leiter V. Medicalization, markets and consumers J. Health Soc. Behav. 2004 158 176 15779472 \nConrad P. Potter D. From hyperactive children to ADHD adults: observations on the expansion of medical categories Soc. Probl. 2000 559 582 \nCoveney C. Gabe J. Williams S. The sociology of cognitive enhancement: medicalisation and beyond Health Sociol. Rev. 20 2011 381 393 \nDumit J. Drugs for Life: How Pharmaceutical Companies Define Our Health 2012 Duke University Press Durhma, NC \nElnicki D.M. Cognitive enhancement drug use among medical students and concerns about medical student well-being J. General Intern. Med. 28 2013 984 985 \nFarah M.J. Illes J. Cook-Deegan R. Gardner H. Kandel E. King P. Neurocognitive enhancement: what can we do and what should we do? Nat. Rev. Neurosci. 5 2004 421 425 15100724 \nFischer B. Bibby M. Bouchard M. The global diversion of pharmaceutical drugsnon-medical use and diversion of psychotropic prescription drugs in North America: a review of sourcing routes and control measures Addiction 105 2010 2062 2070 20840172 \nFox N.J. Ward K.J. O'Rourke A.J. The ‘expert patient’: empowerment or medical dominance? The case of weight loss, pharmaceutical drugs and the Internet Soc. Sci. Med. 60 2005 1299 1309 15626525 \nFraser S. Moore D. The Drug Effect: Health, Crime and Society 2011 Cambridge University Press Cambridge \nGreely H. Sahakian B. Harris J. Kessler R.C. Gazzaniga M. Campbell P. Towards responsible use of cognitive-enhancing drugs by the healthy Nature 456 2008 702 705 19060880 \nHall K.M. Irwin M.M. Bowman K.A. Frankenberger W. Jewett D.C. Illicit use of prescribed stimulant medication among college students J. Am. Coll. Health 53 2005 167 174 15663065 \nHotze T.D. Shah K. Anderson E.E. Wynia M.K. “Doctor, would you prescribe a pill to help me…?” A national survey of physicians on using medicine for human enhancement Am. J. Bioeth. 11 2011 3 13 21240795 \nJones K. In whose interest? Relationships between health consumer groups and the pharmaceutical industry in the UK Sociol. Health Illn. 30 2008 929 943 18761512 \nKramer P.D. Listening to Prozac 1992 Viking New York, N.Y \nLoe M. The prescription of a new generation Contexts 7 2008 46 49 \nLoe M. Cuttino L. Grappling with the medicated self: the case of ADHD college students Symb. Interact. 31 2008 303 323 \nLovell A.M. Addiction markets: the case of high-dose buprenorphine in France Petryna A. Lakoff A. Kleinman A. Global Pharmaceuticals: Ethics, Markets, Practices 2006 Duke University Press 136 170 \nLucke J.C. Empirical research on attitudes toward cognitive enhancement is essential to inform policy and practice guidelines AJOB Prim. Res. 3 2012 58 60 \nMaher B. Poll results: look who's doping Nature 452 2008 674 675 18401370 \nMcCabe S.E. Knight J.R. Teter C.J. Wechsler H. Non-medical use of prescription stimulants among US college students: prevalence and correlates from a national survey Addiction 100 2005 96 106 15598197 \nMcCabe S.E. West B.T. Teter C.J. Boyd C.J. Trends in medical use, diversion, and nonmedical use of prescription medications among college students from 2003 to 2013: connecting the dots Addict. Behav. 39 2014 1176 1182 24727278 \nMoreira T. May C. Bond J. Regulatory objectivity in action: mild cognitive impairment and the collective production of uncertainty Soc. Stud. Sci. 39 2009 665 690 \nParens E. Enhancing Human Traits : Ethical and Social Implications 1998 Georgetown University Press Washington, D.C. \nPartridge B. Bell S. Lucke J. Hall W. Australian university students' attitudes towards the use of prescription stimulants as cognitive enhancers: perceived patterns of use, efficacy and safety Drug alcohol Rev. 32 2013 295 302 23121045 \nPetryna A. When Experiments Travel: Clinical Trials and the Global Search for Human Subjects 2009 Princeton University Press Princeton \nPilkinton M. Cannatella A. Nonmedical use of prescription stimulants: age, race, gender, and educational attainment patterns J. Hum. Behav. Soc. Environ. 22 2012 409 420 \nPollock A. Medicating Race: Heart Disease and Durable Preoccupations with Difference 2012 Duke University Press Books \nPoulin C. From attention-deficit/hyperactivity disorder to medical stimulant use to the diversion of prescribed stimulants to non-medical stimulant use: connecting the dots Addiction 102 2007 740 751 17506151 \nQuintero G. Nichter M. Generation RX: anthropological research on pharmaceutical enhancement, lifestyle regulation, self-medication and recreational drug use Singer M. Erickson P.I. A Companion to Medical Anthropology 2011 Wiley 339 355 \nQuintero G. Peterson J. Young B. An exploratory study of socio-cultural factors contributing to prescription drug misuse among college students J. Drug Issues 36 2006 903 931 \nRudski J.M. A comparison of attitudes toward pharmacological treatment versus enhancement under competitive and noncompetitive conditions AJOB Empir. Bioeth. 5 2014 80 90 \nSingh I. Kelleher K.J. Neuroenhancement in young people: proposal for research, policy, and clinical management AJOB Neurosci. 1 2010 3 16 22247810 \nSingh I. Kendall T. Taylor C. Mears A. Hollis C. Batty M. Young people's experience of ADHD and stimulant medication: a qualitative study for the NICE guideline Child Adolesc. Ment. health 15 2010 186 192 \nStevenson F.A. Leontowitsch M. Duggan C. Over-the-counter medicines: professional expertise and consumer discourses Sociol. Health Illn. 30 2008 913 928 18761511 \nTeter C.J. McCabe S.E. LaGrange K. Cranford J.A. Boyd C.J. Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration Pharmacotherapy 26 2006 1501 1510 16999660 \nVarga M.D. Adderall abuse on college campuses: a comprehensive literature review J. Evidence-Based Soc. Work 9 2012 293 313 \nVrecko S. Just how cognitive is “cognitive enhancement”? On the significance of emotions in university students' experiences with study drugs AJOB Neurosci. 4 2013 4 12 23486311 \nWahlberg A. McGoey L. An elusive evidence base: the construction and governance of randomized controlled trials Biosocieties 2 2007 1 10 \nWhitehouse P. Gaines A.D. Lindstrom H. Graham J.E. Anthropological contributions to the understanding of age-related cognitive impairment Lancet Neurol. 4 2005 320 326 15847845 \nWilens T.E. Adler L.A. Adams J. Sgambati S. Rotrosen J. Sawtelle R. Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature J. Am. Acad. Child Adolesc. Psychiatry 47 2008 21 31 18174822 \nWilliams S.J. Martin P. Gabe J. The pharmaceuticalisation of society? A framework for analysis Sociol. health & Illn. 33 2011 710 725\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0277-9536",
"issue": "131()",
"journal": "Social science & medicine (1982)",
"keywords": "Adderall; Drug diversion; Enhancement; Non-medical drug use; Pharmaceuticalization; Pharmaceuticals; Prescription medication; United States",
"medline_ta": "Soc Sci Med",
"mesh_terms": "D000293:Adolescent; D000662:Amphetamines; D000697:Central Nervous System Stimulants; D008192:Deception; D064423:Drug Trafficking; D005260:Female; D006801:Humans; D007406:Interview, Psychological; D008297:Male; D008774:Methylphenidate; D064226:Prescription Drug Diversion; D000067490:Prescription Drug Overuse; D055553:Prescription Drugs; D036301:Qualitative Research; D013334:Students; D019966:Substance-Related Disorders; D055815:Young Adult",
"nlm_unique_id": "8303205",
"other_id": null,
"pages": "297-304",
"pmc": null,
"pmid": "25455480",
"pubdate": "2015-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15100724;15598197;15626525;15663065;15779472;15847845;16999660;17506151;18174822;18401370;18761511;18761512;19060880;20414361;20840172;21240795;21371048;22633161;22694135;23121045;23486311;23595922;24727278;27702218",
"title": "Everyday drug diversions: a qualitative study of the illicit exchange and non-medical use of prescription stimulants on a university campus.",
"title_normalized": "everyday drug diversions a qualitative study of the illicit exchange and non medical use of prescription stimulants on a university campus"
} | [
{
"companynumb": "GB-JNJFOC-20151225975",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Targeted therapies such as the BRAF inhibitors vemurafenib and dabrafenib are highly effective in the treatment of systemic metastatic melanoma and have been shown to be effective in controlling solid brain metastases; however, limited data exist on their activity in leptomeningeal spread. Here, we present a case of a 60-year-old woman who developed leptomeningeal carcinomatosis from melanoma after resection and stereotactic radiotherapy of melanoma brain metastases, with poor performance status, who received vemurafenib as first-line treatment, resulting in significant clinical and imaging response as well as prolonged survival.",
"affiliations": "aDepartment of Internal Medicine, Maimonides Medical Center bDivision of Hematology and Oncology, Maimonides Cancer Center, Brooklyn, New York, USA.",
"authors": "Floudas|Charalampos S|CS|;Chandra|Abhinav B|AB|;Xu|Yiqing|Y|",
"chemical_list": "D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib",
"country": "England",
"delete": false,
"doi": "10.1097/CMR.0000000000000257",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-8931",
"issue": "26(3)",
"journal": "Melanoma research",
"keywords": null,
"medline_ta": "Melanoma Res",
"mesh_terms": "D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D007211:Indoles; D008545:Melanoma; D055756:Meningeal Carcinomatosis; D008875:Middle Aged; D012189:Retrospective Studies; D013449:Sulfonamides; D016019:Survival Analysis; D000077484:Vemurafenib",
"nlm_unique_id": "9109623",
"other_id": null,
"pages": "312-5",
"pmc": null,
"pmid": "26974967",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vemurafenib in leptomeningeal carcinomatosis from melanoma: a case report of near-complete response and prolonged survival.",
"title_normalized": "vemurafenib in leptomeningeal carcinomatosis from melanoma a case report of near complete response and prolonged survival"
} | [
{
"companynumb": "US-ROCHE-1730152",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "VEMURAFENIB"
},
"drugadditional": null,
"dru... |
{
"abstract": "JC polyomavirus (JCPyV)-associated nephropathy (JCPyVAN) is a severe, but rare complication in adult renal transplant (RTx) recipients. Related data in pediatric patients are scarce.\n\n\n\nBased on the CERTAIN Registry, we therefore performed a multi-center, retrospective study on the JCPyV antibody status, prevalence of JCPyV replication, and its associated disease in 139 pediatric RTx recipients (mean age, 8.5 ± 5.3 years). JCPyV DNA in plasma and/or urine was measured by quantitative PCR at a median time of 3.2 (IQR, 0.3-8.1) years post-transplant.\n\n\n\n53.2% of patients were JCPyV-seronegative prior to transplantation; younger age was associated with JCPyV seronegativity. 34/139 (24.5%) patients post-transplant showed active JCPyV replication in either urine (22.0%), plasma (13.4%), or both (7.6%). JCPyV viremia occurred significantly (p < 0.001) more often in patients with viruria (34.6%) than in those without (7.6%), but 7/118 (5.9%) had isolated viremia. High-level viruria (> 107 copies/mL) was found in 29.6% of viruric patients. A higher net state of immunosuppression constituted an independent risk factor for JCPyV replication both in urine and plasma (OR 1.2, p < 0.02). Male patients tended to have a higher risk of JCPyV viremia than females (OR 4.3, p = 0.057). There was one male patient (0.7%) with JCPyVAN 7 years post-transplant, which resolved after reduction of immunosuppressive therapy. No patient exhibited progressive multifocal leukoencephalopathy.\n\n\n\nThis first multi-center study on JCPyV in pediatric renal transplant recipients shows that JCPyV replication is common (24.5%), with strong immunosuppression being a significant risk factor, but associated nephropathy is rare.",
"affiliations": "Department of Pediatrics I, University Children's Hospital, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany. britta.hoecker@med.uni-heidelberg.de.;Department of Pediatrics I, University Children's Hospital, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.;Department of Pediatrics I, University Children's Hospital, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.;Department of Pediatric Nephrology, University Children's Hospital, Martinistr. 52, 20246, Hamburg, Germany.;Department of Pediatric Nephrology, University Children's Hospital, Martinistr. 52, 20246, Hamburg, Germany.;Hanover Medical School, Carl-Neuberg-Str. 1, 30625, Hanover, Germany.;Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.;Faculty of Medicine, Department of Pediatric Nephrology, Hacettepe University, Ankara, Turkey.;Department of General Pediatrics, University Children's Hospital Münster, Waldeyerstraße 22, 48149, Münster, Germany.;Department of Pediatric Nephrology, University Children's Hospital Marburg, Baldingerstraße, 35043, Marburg, Germany.;1st Pediatric Department, Aristotle University of Thessaloniki, Thessaloniki, Greece.;Department of Pediatric Nephrology, Tepecik Teaching and Research Hospital, 1140/1 Sk No: 1, 35180 Yenisehir, İzmir, Turkey.;Department of Pediatrics I, University Children's Hospital, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.;Department of Pediatrics I, University Children's Hospital, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.;Institute of Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany.;Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.;Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.;Department of Infectious Diseases, Virology, University Hospital Heidelberg, Im Neuenheimer Feld 324, 69120, Heidelberg, Germany.;Transplantation & Clinical Virology, Department Biomedicine, University of Basel, Petersplatz 10, 4009, Basel, Switzerland.;Department of Pediatrics I, University Children's Hospital, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.",
"authors": "Höcker|Britta|B|0000-0003-4131-2273;Tabatabai|Julia|J|;Schneble|Lukas|L|;Oh|Jun|J|;Thiel|Florian|F|;Pape|Lars|L|;Rusai|Krisztina|K|;Topaloglu|Rezan|R|;Kranz|Birgitta|B|;Klaus|Günter|G|;Printza|Nikoleta|N|;Yavascan|Onder|O|;Fichtner|Alexander|A|;Krupka|Kai|K|;Bruckner|Thomas|T|;Waldherr|Rüdiger|R|;Pawlita|Michael|M|;Schnitzler|Paul|P|;Hirsch|Hans H|HH|;Tönshoff|Burkhard|B|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-018-4029-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-041X",
"issue": "33(12)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": "JC polyomavirus; JC virus; Nephropathy; Pediatric kidney transplantation; Pediatric renal transplantation; Polyomavirus",
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007165:Immunosuppression Therapy; D007577:JC Virus; D007674:Kidney Diseases; D016030:Kidney Transplantation; D008297:Male; D027601:Polyomavirus Infections; D015995:Prevalence; D012042:Registries; D012189:Retrospective Studies; D066027:Transplant Recipients; D014766:Viremia",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "2343-2352",
"pmc": null,
"pmid": "30058047",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "26262348;27251361;24472190;23465010;23042966;27989013;26736017;27842264;23967139;23538701;16164661;24476010;23726585;21511831;25091177;21299772;4104715;28127886;26923352;12858417;17700156;19474265;15367285;29500631;22533698;12402171;23424601;17315193;15947078;29322328;23781977;14981772;14702550;25359127;17999891;14301897;19158356;13227587;27704725;19434930;26923930;20550458;19220823;15648074;191404",
"title": "JC polyomavirus replication and associated disease in pediatric renal transplantation: an international CERTAIN Registry study.",
"title_normalized": "jc polyomavirus replication and associated disease in pediatric renal transplantation an international certain registry study"
} | [
{
"companynumb": "PHHY2018DE070012",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
"druga... |
{
"abstract": "A 38-year-old female patient with well-controlled type 2 diabetes mellitus treated with canagliflozin underwent ureteral stent placement for obstructive renal calculi. Ten days following ureteroscopy and ureteral stenting, she developed fevers and blood cultures grew Candida glabrata (C. glabrata). The patient was successfully treated with an extended course of broad-spectrum antibiotics and antifungal agents. The clinical presentation of candidemia is indistinguishable from bacteremia resulting in delay in diagnosis and treatment. Candiduria is commonly seen in patients with type 2 diabetes, however it rarely leads to candidemia in an otherwise healthy person following a relatively simple urologic procedure. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors act by its glycosuric effect and further increases the risk of genitourinary candida infection. Urologic procedures may lead to bloodstream entry of the genitourinary fungal organisms and result in life-threatening fungemia. Our case emphasizes the importance of awareness of the increased risk of potentially life threatening fungemia in patients using SGLT-2 inhibitors to avoid delay in diagnosis and treatment.",
"affiliations": "Department of Endocrinology, Diabetes and Metabolism, University of Kentucky, Lexington, KY, United States.;Department of Medicine, University of Kentucky, Lexington, KY, United States.;Department of Hematology and Oncology, University of Kentucky, Lexington, KY, United States.;Department of Endocrinology, Diabetes and Metabolism, University of Kentucky, Lexington, KY, United States.",
"authors": "Raj|Rishi|R|;Hendrie|Jon|J|;Jacob|Aasems|A|;Adams|Derick|D|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fendo.2019.00020",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)Front Endocrinol (Lausanne)Front. Endocrinol.Frontiers in Endocrinology1664-2392Frontiers Media S.A. 10.3389/fendo.2019.00020EndocrinologyCase ReportCandidemia Following Ureteric Stent Placement in a Patient With Type 2 Diabetes Treated With Canagliflozin Raj Rishi 1*Hendrie Jon 2Jacob Aasems 3Adams Derick 11Department of Endocrinology, Diabetes and Metabolism, University of Kentucky, Lexington, KY, United States2Department of Medicine, University of Kentucky, Lexington, KY, United States3Department of Hematology and Oncology, University of Kentucky, Lexington, KY, United StatesEdited by: Elias S. Siraj, Eastern Virginia Medical School, United States\n\nReviewed by: Javier Ena, Hospital Marina Baixa, Spain; Jose Mario Franco De Oliveira, Universidade Federal Fluminense, Brazil\n\n*Correspondence: Rishi Raj rishiraj91215@gmail.comThis article was submitted to Diabetes, a section of the journal Frontiers in Endocrinology\n\n30 1 2019 2019 10 2015 10 2018 14 1 2019 Copyright © 2019 Raj, Hendrie, Jacob and Adams.2019Raj, Hendrie, Jacob and AdamsThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.A 38-year-old female patient with well-controlled type 2 diabetes mellitus treated with canagliflozin underwent ureteral stent placement for obstructive renal calculi. Ten days following ureteroscopy and ureteral stenting, she developed fevers and blood cultures grew Candida glabrata (C. glabrata). The patient was successfully treated with an extended course of broad-spectrum antibiotics and antifungal agents. The clinical presentation of candidemia is indistinguishable from bacteremia resulting in delay in diagnosis and treatment. Candiduria is commonly seen in patients with type 2 diabetes, however it rarely leads to candidemia in an otherwise healthy person following a relatively simple urologic procedure. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors act by its glycosuric effect and further increases the risk of genitourinary candida infection. Urologic procedures may lead to bloodstream entry of the genitourinary fungal organisms and result in life-threatening fungemia. Our case emphasizes the importance of awareness of the increased risk of potentially life threatening fungemia in patients using SGLT-2 inhibitors to avoid delay in diagnosis and treatment.\n\ncandidemiacandiduriasodium-glucose co-transporter 2 inhibitorscanagliflozindiabetes mellitusureteral stent\n==== Body\nBackground\nAccording to the most recent Centers for Disease Control and Prevention (CDC) data, ~46,000 healthcare-associated candida infections occur in the United States each year (1). Invasive Candida infections can be fatal, with a 30-day all-cause mortality of 30% and high rates of morbidity (2). Although, there are at least 15 distinct Candida species, more than 90% of the invasive diseases are caused by the five most common pathogens, C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei (3). SGLT-2 inhibitors are known to increase the incidence of urogenital infections however, there have been no reported cases of invasive candidemia associated with SGLT-2 inhibitor use. Although these agents can potentiate the urinary colonization of candida, it is unknown whether this colonization is a preceding factor for the development of candidemia following urologic procedures. With our literature review, we propose that patient with type 2 diabetes treated with canagliflozin could be at a higher risk of candidemia following urological procedures like ureteral stent placement by bloodstream entry of the organism.\n\nCase Presentation\nA 38-year-old Caucasian female presented to the emergency department with 3 days of left lower quadrant abdominal pain rated 6/10 with radiation to the left lower back. She also reported a high-grade fever (103°F) with associated nausea and vomiting. She denied dysuria or hematuria. Medical history was significant for well-controlled type II diabetes mellitus, hypertension, and hyperlipidemia. She was taking canagliflozin 100 mg daily, lisinopril 20 mg daily, and atorvastatin 80 mg daily. She has been on canagliflozin (SGLT-2 inhibitor) for type 2 diabetes mellitus for 14 months prior to the current presentation. She denied any history of urinary tract infections or renal stones. On presentation, her blood pressure was 172/86 mmHg, heart rate 94 beats per minute and temperature 102°F. BMI was 46.61 kg/m2. Physical examination revealed tenderness to palpation in the left lower quadrant and left flank. The rest of the examination was unremarkable. Urinalysis (Table 1) revealed pyuria, bacteriuria, and nitrites. Hemoglobin A1C was 7.5% (59 mmol/mol). CT abdomen and pelvis without contrast showed an obstructive 4–5 mm left distal ureteral stone associated with mild hydroureteronephrosis. She was diagnosed with obstructing nephrolithiasis complicated by pyelonephritis and was empirically treated with intravenous ceftriaxone 1 gram every 24 h. Cystoscopy with retrograde pyelography was done and a left 6-French × 24 cm double-J ureteral stent was placed. Placement was confirmed with fluoroscopy and cystoscopy. Intraoperative urine cultures obtained from the left renal pelvis and bladder showed no growth. She was discharged home on cefdinir 300 mg twice a day for 14 days and tamsulosin 0.4 mg daily for 30 days with a urology follow-up appointment in 2 weeks.\n\nTable 1 Laboratory studies.\n\nTest (Units)\tReferences range\t1ST admission\t2ND admission\t\nWBC count (k/uL)\t3.7–10.3\t7.4\t12.1\t\nHemoglobin (g/dL)\t11.2–15.7\t13.8\t13.6\t\nGlucose level (mg/dL)\t74-99\t286\t161\t\nUrea nitrogen, blood (mg/dL)\t7–21\t9\t9\t\nCreatinine level (mg/dL)\t0.60–1.10\t0.69\t0.60\t\nAlanine aminotransferase (U/L)\t8–33\t43\t41\t\nAspartate aminotransferase (U/L)\t11–32\t46\t28\t\nAlkaline phosphatase (U/L)\t35–104\t135\t113\t\nURINALYSIS WITH MICROSCOPY\t\nSpecific gravity\t1.001–1.030\t≥1.030\t1.025\t\npH\t4.5–8.0\t5.0\t5.0\t\nProtein (mg/dL)\t–\t30\t≥300\t\nGlucose (mg/dL)\t–\t≥1,000\tNegative\t\nKetone\t–\tTrace\tTrace\t\nBlood\t–\tSmall\tLarge\t\nNitrite\t–\tPositive\tPositive\t\nLeukocyte esterase\t–\tNegative\tSmall\t\nWBC (/HPF)\t0–5\t16–30\t>50\t\nRBC (/HPF)\t0–3\t3\t>50\t\nBacteria\t–\tPresent\tPresent\t\nCulture\t–\t10,000–100,000 CFU/ml mixed urogenital flora\t>100,000 CFU/ml Klebsiella pneumoniae\t\nTen days later, she presented again with intermittent low-grade fever (100.5°F) and left flank pain. She was hypotensive (96/58 mmHg), tachycardic (104 bpm) and febrile with temperature of 102.8°F. Physical examination revealed severe tenderness to palpation in the left lower quadrant extending to the suprapubic area. Laboratory workup (Table 1) showed worsening leukocytosis, pyuria, bacteriuria, positive urinary nitrites, and small leukocyte esterase. A repeat CT scan of the abdomen and pelvis with renal stone protocol confirmed the position of the left ureteral stent and absence of previously seen stone. She was diagnosed with sepsis secondary to acute pyelonephritis in the setting of recent stent placement and started on aggressive intravenous hydration and Piperacillin-Tazobactam. Urine culture from the day of admission grew Klebsiella pneumoniae with >100 k CFU/ml however blood cultures remained negative. Despite appropriate antibiotics, she remained febrile even after 48 h. Two days later, the anaerobic blood cultures became positive for C. glabrata. She was started on intravenous micafungin 100 mg every 24 h and antibiotic was narrowed down based on culture sensitivities. Repeat cystoureteroscopy with retrograde pyelogram revealed partial contrast uptake in the left kidney due to an impacted ureteral stone in the mid ureter. The presence of fungal elements and cloudy urine were also found in the left kidney. The previously placed left ureteral stent was removed and a new double-J ureteral stent was placed. Urine from the left renal pelvis and bladder were cultured for a second time which grew C. glabrata susceptible to Fluconazole. On the 4th day of admission, blood cultures from both anaerobic and aerobic samples grew C. glabrata. Dilated fundus examination was negative for fungal ocular involvement and transthoracic echocardiogram was unremarkable for valvular vegetations. Blood cultures after antifungal initiation remained negative. She was eventually discharged on oral fluconazole 800 mg daily for 2 weeks and cefazolin 2 g every 8 h for 7 days.\n\nDiscussion and Review of Literature\nCanagliflozin, the first sodium-glucose co-transporter 2 (SGLT-2) inhibitor introduced in the USA was FDA approved in March 2013. Since then, SGLT-2 inhibitors have become popular in the management of type 2 diabetes mellitus as monotherapy (in the event of metformin intolerance), dual, or triple therapy. Although, it increases the incidence of urogenital infections, there is no report of candidemia associated with its use. We hereby discuss possible association of candiduria leading to candidemia following urologic procedure in a patient with diabetes on SGLT-2 inhibitors with current evidence from literature.\n\nCandiduria is frequently encountered among patients with diabetes and is even higher in presence of certain underlying risk factors like female gender, indwelling urinary catheter, prior use of antibiotics, and acidic urine. However, it rarely results in candidemia. Ang et al. analyzed 249 cases of candidemia and reported 26 cases of candidemia originating from a urinary source in a retrospective review. However, most of the patients who developed candidemia from urinary source had some underlying risk factors like urinary tract abnormalities (88%), use of antibiotics within 1 week (85%), underlying malignancies (73%), urinary tract obstruction (73%), and prior urologic procedure within 2 weeks (73%), which put them at an increased risk of fungemia (4). Other similar studies also have not found any direct evidence of association between candiduria leading to candidemia without any of the underlying high risk factors (5–9). Candiduria, however is linked with increased mortality and is therefore considered as an independent marker of higher mortality (8, 10, 11). In a randomized control trial, Binelli et al. however found that candida isolates from urine and blood were different in 52% of patients with simultaneous candiduria and candidemia implying alternate source (12). Patients with diabetes are inherently at increased risk of candiduria due to glycosuria, immune dysfunction associated with hyperglycemia, and increased virulence of Candida (13, 14). Various studies have found candida to be third or fourth most commonly isolated organisms from the urine among hospitalized patients (7, 15, 16). A cross-sectional study on 305 patient with type 2 diabetes in an ambulatory setting showed presence of candiduria in 12.5% of patients, majority (95%) being in female (17). Nosocomial candiduria has even a higher prevalence ranging from 10 to 89% (7). Apart from uncontrolled diabetes, female gender, old age, presence of indwelling urinary catheter, prior use of antibiotics, and acidic urine pH are other known risk factors for urinary candida colonization (6, 7, 16–21).\n\nUrologic procedure like ureteral stent placement may lead to bacterial (68–90%) and candidal (10–40%) colonization of urinary tract and is attributed to formation of a biofilm (22–25). Dariane et al. found candiduria to be frequently associated with ureteral stent placement, most commonly due to C. albicans (19–72%) followed by C. glabrata (15.6–49.4%) (25, 26). Two cases of candidemia was reported in elderly patients following ureteric stent placement for nephrolithiasis. Both patients had a positive candidal urine cultures at the time of procedure, prior broad-spectrum antibiotic use, and one of them was diabetic (27). Two cases of candidemia following ureteroscopy with stone manipulation was reported in patients with cirrhosis who underwent ureteric stent placement for obstructing stone and developed candidemia at the time of stent removal at 60 and 35 days (28). The mechanism of candidemia following ureteroscopy or ureteral stenting is proposed to be direct bloodstream seeding through microscopic lacerations in the presence of increased intra-ureteral pressure during ureteroscopy resulting in pyelovenous and pyelolymphatic reflux (25).\n\nOur patient developed candidemia within 2 weeks following ureteric stent placement while on SGLT-2 inhibitor, raising concern about association of SGLT-2 inhibitor with increased risk of candidemia following ureteric stent placement. SGLT-2 inhibitors result in glycosuria up to 70–120 g per day (29). This pharmacologically-induced glycosuria may be implicated in the increased urogenital candida colonization in patients on SGLT2 inhibitors compared to placebo (10–31 vs. 3–14%) (30, 31). A recent study on adverse drug reports (ADRs) with SGLT-2 inhibitors (dapagliflozin, canagliflozin, and empagliflozin) in Spain over a period of 3.5-year showed increased reporting of urogenital tract infections (32).\n\nAlthough, candida colonization is mostly asymptomatic and does not require treatment, Infectious Diseases Society of America (IDSA) recommends performing urine culture and to treat any positive urine culture prior to urological procedure (3, 25). When indicated, oral fluconazole, 400 mg (6 mg/kg) daily, OR Amphotericin B deoxycholate, 0.3–0.6 mg/kg daily is considered to be drug of choice (3). However, the duration of antifungal therapy required to achieve sterilization of urine is not well-established and current practice varies from 48 h to 3 weeks before stent exchange (25). Furthermore, several days of antifungal agents may not be practically feasible especially in situations where patient might require acute urologic interventions, e.g., ureteral stent placement for stone or obstruction.\n\nOur case highlights a rare and unusual adverse event of canagliflozin in patient with diabetes who underwent ureteric stent placement. With increasing use of SGLT-2 inhibitors, more patients will be at risk of urinary tract colonization with candida, which might result in increased incidences of candida colonization related complications (e.g., symptomatic candiduria or candidemia following urologic surgery). Large comparative studies are required to address the necessity of antifungal therapy and its duration in preventing candidemia in patient with type 2 diabetes on SGLT-2 inhibitors undergoing urologic procedures. We also recommend discontinuation of SGLT-2 inhibitors prior to non-emergent/elective urologic interventions in order to decrease the colonization by candida, but more studies are needed to establish the exact duration of drug discontinuation required to result in appropriate urinary tract decolonization and optimal time for reinitiation.\n\nConclusion\nIn summary, candida colonization of ureteral stents is common and can rarely lead to subsequent candidemia following urologic procedures especially in presence of risk factors. Due to the risk of urogenital candida infections in patients with diabetes treated with SGLT-2 inhibitors, urine culture and treatment of urinary colonization is advised before performing any urological procedures.\n\nPatient Consent\nWritten informed consent was obtained from the participant for publication of this case report.\n\nAuthor Contributions\nJH contributed in preparing the case presentation. RR and AJ prepared the discussion of the manuscript. DA reviewed the manuscript in detail.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1. CDC \nAntibiotic Resistance Threats in the United States . Atlanta, GA : CDC (2013 ).\n2. Cleveland AA Farley MM Harrison LH Stein B Hollick R Lockhart SR . Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, 2008–2011 . Clin Infect Dis . (2012 ) 55 :1352 –61 . 10.1093/cid/cis697 22893576 \n3. Pappas PG Kauffman CA Andes DR Clancy CJ Marr KA Ostrosky-Zeichner L \nClinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America . Clin Infect Dis . (2016 ) 622016 \ne1 –50 . 10.1093/cid/civ933 \n4. Ang BS Telenti A King B Steckelberg JM Wilson WR . Candidemia from a urinary tract source: microbiological aspects and clinical significance . Clin Infect Dis . (1993 ) 17 :662 –6 . 8268347 \n5. Alvarez-Lerma F Nolla-Salas J Leon C Palomar M Jorda R Carrasco N . Candiduria in critically ill patients admitted to intensive care medical units . Intens Care Med . (2003 ) 29 :1069 –76 . 10.1007/s00134-003-1807-y 12756441 \n6. Chen SC Tong ZS Lee OC Halliday C Playford EG Widmer F . Clinician response to Candida organisms in the urine of patients attending hospital . Eur J Clin Microbiol Infect Dis . (2008 ) 27 :201 –8 . 10.1007/s10096-007-0427-9 18060438 \n7. Kauffman CA Vazquez JA Sobel JD Gallis HA McKinsey DS Karchmer AW . Prospective multicenter surveillance study of funguria in hospitalized patients. The National Institute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group . Clin Infect Dis . (2000 ) 30 :14 –8 . 10.1086/313583 10619726 \n8. Paul N Mathai E Abraham OC Michael JS Mathai D . Factors associated with candiduria and related mortality . J Infect . (2007 ) 55 :450 –5 . 10.1016/j.jinf.2007.06.010 17706785 \n9. Simpson C Blitz S Shafran SD . The effect of current management on morbidity and mortality in hospitalised adults with funguria . J Infect . (2004 ) 49 :248 –52 . 10.1016/j.jinf.2003.08.008 15337343 \n10. Safdar N Slattery WR Knasinski V Gangnon RE Li Z Pirsch JD . Predictors and outcomes of candiduria in renal transplant recipients . Clin Infect Dis . (2005 ) 40 :1413 –21 . 10.1086/429620 15844063 \n11. Viale P . Candida colonization and candiduria in critically ill patients in the intensive care unit . Drugs (2009 ) 69 (Suppl. 1 ):51 –7 . 10.2165/11315640-000000000-00000 19877735 \n12. Binelli CA Moretti ML Assis RS Sauaia N Menezes PR Ribeiro E . Investigation of the possible association between nosocomial candiduria and candidaemia . Clin Microbiol Infect . (2006 ) 12 :538 –43 . 10.1111/j.1469-0691.2006.01435.x 16700702 \n13. Geerlings S Fonseca V Castro-Diaz D List J Parikh S . Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria . Diabetes Res Clin Prac . (2014 ) 103 :373 –81 . 10.1016/j.diabres.2013.12.052 24529566 \n14. Hirji I Andersson SW Guo Z Hammar N Gomez-Caminero A . Incidence of genital infection among patients with type 2 diabetes in the UK General Practice Research Database . J Diabetes Complicat . (2012 ) 26 :501 –5 . 10.1016/j.jdiacomp.2012.06.012 22840886 \n15. Bouza E San Juan R Munoz P Voss A Kluytmans J \nA European perspective on nosocomial urinary tract infections I. Report on the microbiology workload, etiology and antimicrobial susceptibility (ESGNI-003 study). European Study Group on Nosocomial Infections . Clin Microbiol Infect . (2001 ) 7 :523 –31 . 10.1046/j.1198-743x.2001.00326.x 11683792 \n16. Sobel JD Fisher JF Kauffman CA Newman CA . Candida urinary tract infections–epidemiology . Clin Infect Dis . (2011 ) 52 (Suppl. 6 ):S433 –6 . 10.1093/cid/cir109 21498836 \n17. Falahati M Farahyar S Akhlaghi L Mahmoudi S Sabzian K Yarahmadi M . Characterization and identification of candiduria due to Candida species in diabetic patients . Curr Med Mycol . (2016 ) 2 :10 –4 . 10.18869/acadpub.cmm.2.3.10 28681023 \n18. Esmailzadeh A Zarrinfar H Fata A Sen T . High prevalence of candiduria due to non-albicans Candida species among diabetic patients: a matter of concern? \nJ. Clin Lab Anal . (2018 ) 32 :e22343 . 10.1002/jcla.22343 29076587 \n19. Achkar JM Fries BC . Candida infections of the genitourinary tract . Clin Microbiol Rev . (2010 ) 23 :253 –73 . 10.1128/CMR.00076-09 20375352 \n20. Kobayashi CC de Fernandes OF Miranda KC de Sousa ED Silva Mdo R . Candiduria in hospital patients: a study prospective . Mycopathologia (2004 ) 158 :49 –52 . 10.1023/B:MYCO.0000038436.51918.d9 15487320 \n21. Fraisse T Crouzet J Lachaud L Durand A Charachon S Lavigne JP . Candiduria in those over 85 years old: a retrospective study of 73 patients . Intern Med . (2011 ) 50 :1935 –40 . 10.2169/internalmedicine.50.5560 21921372 \n22. Paick SH Park HK Oh SJ Kim HH . Characteristics of bacterial colonization and urinary tract infection after indwelling of double-J ureteral stent . Urology (2003 ) 62 :214 –7 . 10.1016/S0090-4295(03)00325-X 12893321 \n23. Tenke P Köves B Nagy K Hultgren SJ Mendling W Wullt B . Update on biofilm infections in the urinary tract . World J Urol . (2012 ) 30 :51 –7 . 10.1007/s00345-011-0689-9 21590469 \n24. Kehinde EO Rotimi VO Al-Hunayan A Abdul-Halim H Boland F Al-Awadi KA . Bacteriology of urinary tract infection associated with indwelling J ureteral stents . J Endourol . (2004 ) 18 :891 –6 . 10.1089/end.2004.18.891 15659928 \n25. Dariane C Cornu JN Esteve E Cordel H Egrot C Traxer O . Fungal infections and ureteral material: how to manage? \nProg Urol. (2015 ) 25 :306 –11 . 10.1016/j.purol.2015.01.015 25724861 \n26. Kauffman CA . Diagnosis and management of fungal urinary tract infection . Infect Dis Clin North Am . (2014 ) 28 :61 –74 . 10.1016/j.idc.2013.09.004 24484575 \n27. Gross M Winkler H Pitlik S Weinberger M . Unexpected candidemia complicating ureteroscopy and urinary stenting . Eur J Clin Microbiol Infect Dis . (1998 ) 17 :583 –6 . 9796660 \n28. Beck SM Finley DS Deane LA . Fungal urosepsis after ureteroscopy in cirrhotic patients: a word of caution . Urology (2008 ) 72 :291 –3 . 10.1016/j.urology.2008.01.005 18468666 \n29. Chao EC . SGLT-2 Inhibitors: a new mechanism for glycemic control . Clin Diabetes (2014 ) 32 :4 –11 . 10.2337/diaclin.32.1.4 26246672 \n30. Nyirjesy P Zhao Y Ways K Usiskin K . Evaluation of vulvovaginal symptoms and Candida colonization in women with type 2 diabetes mellitus treated with canagliflozin, a sodium glucose co-transporter 2 inhibitor . Curr Med Res Opin . (2012 ) 28 :1173 –8 . 10.1185/03007995.2012.697053 22632452 \n31. Kushner P . Benefits/risks of sodium-glucose co-transporter 2 inhibitor canagliflozin in women for the treatment of Type 2 diabetes . Womens Health (2016 ) 12 :379 –88 . 10.2217/whe-2016-0001 26928259 \n32. Esteban-Jimenez O Navarro-Peman C Urieta-Gonzalez L . [Safety of SGLT2 inhibitors. A review of the adverse drug reactions registered in a national database] . Semergen (2018 ) 44 :23 –9 . 10.1016/j.semerg.2017.10.003 29183654\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2392",
"issue": "10()",
"journal": "Frontiers in endocrinology",
"keywords": "canagliflozin; candidemia; candiduria; diabetes mellitus; sodium-glucose co-transporter 2 inhibitors; ureteral stent",
"medline_ta": "Front Endocrinol (Lausanne)",
"mesh_terms": null,
"nlm_unique_id": "101555782",
"other_id": null,
"pages": "20",
"pmc": null,
"pmid": "30761087",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10619726;11683792;12756441;12893321;15337343;15487320;15659928;15844063;16700702;17706785;18060438;18468666;19877735;20375352;21498836;21590469;21921372;22632452;22840886;22893576;24484575;24529566;25724861;26246672;26679628;26928259;28681023;29076587;29183654;8268347;9796660",
"title": "Candidemia Following Ureteric Stent Placement in a Patient With Type 2 Diabetes Treated With Canagliflozin.",
"title_normalized": "candidemia following ureteric stent placement in a patient with type 2 diabetes treated with canagliflozin"
} | [
{
"companynumb": "US-TEVA-2019-US-1049675",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe use of autologous hematopoietic stem cell transplantation (AHSCT) for autoimmune diseases has become the first indication for transplant in nonmalignant disease. Mucormycosis is a rare invasive infection with increasing incidence in patients treated with AHSCT. We report the first case of pulmonary mucormycosis following AHSCT for systemic sclerosis (SSc).\nA 24-year-old woman with rapidly progressive diffuse cutaneous SSc presented with an acute respiratory distress syndrome 6 days after AHSCT.\nThe results of clinical and computed tomography scan were consistent with pulmonary mucormycosis and the diagnosis was confirmed by a positive Mucorales Polymerase Chain Reaction on a peripheral blood sample.\n\n\nRESULTS\nEarly antifungal therapy by intravenous amphotericin B provided rapid improvement within 4 days and sustained recovery after 2 years of follow-up.\n\n\nCONCLUSIONS\nWith the progressively increasing use of AHSCT and other stem cell therapy for treatment of severe SSc and other autoimmune diseases, the potential onset of rare post-transplant fungal infections, such as mucormycosis, requires careful patient monitoring and better awareness of early initiation of adequate therapy.",
"affiliations": "Department of Internal Medicine.;Department of infectious and tropical diseases, Toulouse University Hospital.;Hematology Department.;Hematology Department.;Hematology Department.;Hematology Department.;Department of Internal Medicine, Institut Universitaire du Cancer de Toulouse - Oncopole.;Department of Nephrology and Organ Transplantation.;Department of Internal Medicine.;Department of Internal Medicine.;Department of Internal Medicine.;Department of Internal Medicine.;Department of Internal Medicine.;Department of Internal Medicine.;Unité de Médecine Interne: Maladies Auto-immunes et Pathologie Vasculaire (UF 04), Hôpital St-Louis, AP-HP, 1 Avenue Claude Vellefaux.;Department of Internal Medicine.",
"authors": "Boumaza|Xavier|X|;Lelièvre|Lucie|L|;Guenounou|Sarah|S|;Borel|Cécile|C|;Huynh|Anne|A|;Beziat|Guillaume|G|;Delavigne|Karen|K|;Guinault|Damien|D|;Garric|Marie|M|;Piel-Julian|Marie|M|;Paricaud|Kim|K|;Moulis|Guillaume|G|;Astudillo|Leonardo|L|;Sailler|Laurent|L|;Farge|Dominique|D|;Pugnet|Grégory|G|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000021431",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\nMD-D-19-06055\n10.1097/MD.0000000000021431\n21431\n4900\nResearch Article\nClinical Case Report\nPulmonary mucormycosis following autologous hematopoietic stem cell transplantation for rapidly progressive diffuse cutaneous systemic sclerosis\nA case reportBoumaza Xavier Medical Residenta∗ Lelièvre Lucie MDb Guenounou Sarah MDc Borel Cécile MDc Huynh Anne MDc Beziat Guillaume Medical Residentc Delavigne Karen MDd Guinault Damien MDe Garric Marie MDa Piel-Julian Marie MDa Paricaud Kim MDa Moulis Guillaume MD, PhDafg Astudillo Leonardo MD, PhDa Sailler Laurent MD, PhDafg Farge Dominique MD, PhDhijk Pugnet Grégory MD, PhDafg∗ Saranathan. Maya a Department of Internal Medicine\nb Department of infectious and tropical diseases, Toulouse University Hospital\nc Hematology Department\nd Department of Internal Medicine, Institut Universitaire du Cancer de Toulouse - Oncopole\ne Department of Nephrology and Organ Transplantation\nf Clinical Investigation Center, Toulouse University Hospital\ng UMR 1027 INSERM, University of Toulouse, Toulouse\nh Unité de Médecine Interne: Maladies Auto-immunes et Pathologie Vasculaire (UF 04), Hôpital St-Louis, AP-HP, 1 Avenue Claude Vellefaux\ni Centre de Référence des Maladies auto-immunes Systémiques Rares d’Ile-de-France\nj EA 3518, Université Denis Diderot, Paris, France\nk Department of Internal Medicine, McGill University, Montréal, Canada.\n∗ Correspondence: Xavier Boumaza, Grégory Pugnet, Department of Internal Medicine, Toulouse University Hospital, Toulouse, France (e-mail: boumaza.xavier@gmail.com, pugnet.g@chu-toulouse.fr).\n31 7 2020 \n31 7 2020 \n99 31 e2143119 8 2019 12 6 2020 25 6 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nThe use of autologous hematopoietic stem cell transplantation (AHSCT) for autoimmune diseases has become the first indication for transplant in nonmalignant disease. Mucormycosis is a rare invasive infection with increasing incidence in patients treated with AHSCT. We report the first case of pulmonary mucormycosis following AHSCT for systemic sclerosis (SSc).\n\nPatient concerns:\nA 24-year-old woman with rapidly progressive diffuse cutaneous SSc presented with an acute respiratory distress syndrome 6 days after AHSCT.\n\nDiagnoses:\nThe results of clinical and computed tomography scan were consistent with pulmonary mucormycosis and the diagnosis was confirmed by a positive Mucorales Polymerase Chain Reaction on a peripheral blood sample.\n\nInterventions and Outcomes:\nEarly antifungal therapy by intravenous amphotericin B provided rapid improvement within 4 days and sustained recovery after 2 years of follow-up.\n\nLessons:\nWith the progressively increasing use of AHSCT and other stem cell therapy for treatment of severe SSc and other autoimmune diseases, the potential onset of rare post-transplant fungal infections, such as mucormycosis, requires careful patient monitoring and better awareness of early initiation of adequate therapy.\n\nKeywords\nautologous stem cellsmucormycosissystemic sclerosisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nMucormycosis is a rare severe invasive fungal infection, caused by filamentous fungi of the class zygomycetes order Mucorales, primarily encountered in transplanted or diabetic patients.[1–4] This severe disease occurs in highly immunosuppressed patients and is associated with a mortality rate ranging from 35% to 60%, depending on the associated comorbidities.[5]\n\nOver the past 20 years the use of autologous hematopoietic stem cell transplantation (AHSCT) to treat severe rapidly progressive systemic sclerosis (SSc) has expanded progressively and this procedure is now recommended as a first-line option,[6–8] on condition that the procedure is performed in an expert center, according to European Society for Blood and Marrow Transplantation guidelines.[9–12] In such circumstances, careful patient pretransplant evaluation and close posttransplant follow-up are recommended,[11,12] especially during the first 2 years after transplant while progressive immune reconstitution occurs. Mucormycosis has never been reported following AHSCT for autoimmune diseases or in SSc patients.\n\nIn this article we report on the first case of pulmonary mucormycosis after AHSCT for rapidly progressive diffuse cutaneous SSc.\n\n2 Case\nA 24-year-old woman diagnosed with SSc 2 years ago and who had no other past medical history, was initially treated with low-dose corticosteroids and mycophenolate mofetil for 9 months then with methotrexate for 6 months and 2 courses of rituximab. She was then referred for AHSCT due to a rapidly progressive disease with extensive skin fibrosis (modified Rodnan skin score 25/51) and pulmonary involvement [decreased diffusing capacity of the lung for carbon monoxide at 56% of the theoretical values on lung function tests and the presence of ground-glass infiltrate and diffuse bronchial wall thickening on chest computerized tomography (CT) scan]. Right heart catheterization with fluid overload, echocardiography, cardiac magnetic imaging, and myocardial scintigraphy were all normal.\n\nPeripheral blood hematopoietic stem cells (PBSCs) were mobilized with intravenous (IV) cyclophosphamide (CPM) (total of 2 g/m2 administered over 2 consecutive days), and filgrastim (10 μ/kg/day for 7 days), allowing collection of 25 × 106 CD34+ cells/kg in 2 cytaphereses.\n\nForty days later, a conditioning regimen with a total dose of 200 mg/kg IV CPM over 4 consecutive days with 2 L of 0.9% IV saline/day, plus IV rabbit antithymocyte globulins (2.5 mg/kg/day for 5 consecutive days) was administered followed by a reinjection of non-selected PBSC (day 0).\n\nOn day 0, the patient had leukopenia of less than 0.1 g/L and aplasia was sustained until day 12. She experienced her first febrile peak (39°C) the day after PBSC reinfusion while physical examination was otherwise normal and peripheral and port-a-cath blood cultures remained sterile. An empiric IV antibiotic therapy by piperacillin-tazobactam and amikacin was started. The patient remained afebrile until day 4 after PBSC reinjection, when she had a new onset of fever with a progressive increase in C-reactive protein level (278 mg/L). Repeated peripheral and port-a-cath blood cultures were sterile. The IV antibiotic therapy was switched to meropenem, ciprofloxacin, and vancomycin.\n\nThe patient remained febrile (39°C) and 2 days later developed a dry cough. The chest CT scan revealed massive bilateral pleural effusion, upper right lobe condensation, and less extensive upper left lobe condensation (Fig. 1).\n\nFigure 1 Pulmonary mucormycosis appearing as a mass with the halo sign on computerized tomography (CT) in 24-year-old woman after autologous hematopoietic stem cell transplantation for rapidly progressive diffuse cutaneous systemic sclerosis. A, CT scan on day 6, showing a bilateral parenchymatous condensation within the right upper lobe the reverse halo sign. B, CT scan on day 20 showing showed a nearly complete regression of bilateral parenchymatous condensation and disappearance of the reverse halo sign.\n\nOn day 6, an acute respiratory distress syndrome with hypoxemia at 60 mm Hg required endotracheal intubation and mechanical ventilation. Acyclovir (10 mg/kg/dose/8 h IV) and amphotericin B (5 mg/kg/dose/24 h IV) were added. Repeated CT scan showed bilateral parenchymal condensation with a focal ground-glass opacity surrounded by a consolidation ring in the right upper lobe, consistent with the reverse halo sign (Fig. 1A).\n\nBronchoalveolar lavage (BAL) was performed and tests for cytomegalovirus, herpes simplex virus 1, herpes simplex virus 2, varicella zoster virus, adenovirus, other respiratory viruses, as well as for Aspergillus sp and mucormycoses (species tested for were Mucor sp., Rhizopus sp., Lichtheimia sp, and Rhizomucor sp.) by polymerase chain reaction (PCR) were all negative. Blood, Aspergillus antigenemia was negative, whereas Mucor sp. and/or Rhizopus sp PCR were positive.\n\nThe diagnosis of pulmonary mucormycosis was established on day 10 after AHSCT, and IV amphotericin B, increased to 7.5 mg/kg, with the addition of isavuconazole (200 mg/dose/8 h IV for 48 h and then 200 mg/24 h) were started. Antibiotics were discontinued and sulfamethoxazole-trimethoprim and valacyclovir were resumed at prophylactic doses. Rapid clinical improvement was observed, the patient was extubated on day 14 and oxygen therapy was stopped on day 17. Blood PCR for mucormycosis was negative on day 18.\n\nThe follow-up chest CT scan (on day 20) showed almost complete regression of bilateral alveolar parenchymal condensation and resolution of the reverse halo sign (Fig. 1B). Isavuconazole was stopped on day 21. Amphotericin B was discontinued on day 22 because of refractory hypokalemia due to tubular injury and loss of potassium. Maintenance therapy with posaconazole per os was administered from day 21 until day 28 (patient's decision) and the patient was discharged on day 22 after AHSCT.\n\nAfter 1 year of follow-up, the patient is still in clinical and CT scan remission from mucormycosis.\n\n3 Discussion\nInvasive mucormycosis has a high mortality rate of 76% and the lungs are the second most commonly reported site after the sinuses.[5] The clinical features of pulmonary mucormycosis are nonspecific and cannot be distinguished from pulmonary aspergillosis. High-grade fever and a nonproductive cough are the most common symptoms.[5]\n\nMost of the signs of pulmonary mucormycosis on CT scan are indistinguishable from other invasive pulmonary fungal infections, with the presence of infiltrates, consolidation, nodules, cavitations, atelectasis, effusion, posterior tracheal band thickening and hilar or mediastinal lymphadenopathies. Only the reversed halo sign, a focal round area of ground-glass attenuation surrounded by a ring of consolidation, appears more specific and is highly suggestive of pulmonary mucormycosis.[13]\n\nEvidence of mucormycosis on cultures or on histopathological examination is required for a definitive diagnosis.[14] PCR detection of Mucorales DNA in blood samples is now recognized as the earliest biological indication of mucormycoses[15–17] and could even precede the diagnosis of proven mucormycosis by an average of 9 days.[16]\n\nMucormycosis tends to occur late in autologous stem cells recipients for various diseases (median interval, 412 days; range, 190–2254 days).[18] In this case, the patient presented with acute respiratory distress only 6 days after PBSC reinjection, which underscores the crucial role of prior immunosuppression, especially prolonged use of corticosteroids, which was the case for our patient.\n\nManagement guidelines suggest amphotericin B as the first-line treatment (daily dose 5 mg/kg) combined with a surgical procedure, when necessary, and then a switch to posaconazole as a maintenance treatment.[19] Even so, mortality rates are still high (61%).[20]\n\nEarly antifungal therapy is essential, as soon as the diagnosis is suspected, without waiting for biological evidence. In fact, Chamilos et al[21] showed that delaying the administration of amphotericin B–based regimens by 5 days is associated with a 2-fold increase in mortality.\n\nIn hematological patients, the risk of mucormycosis after stem cell transplantation is well-documented, with a postallograft incidence estimated at 0.3%,[3] which represents approximately 8% of the postallograft invasive fungal infections.[18] Less data is available on the occurrence of mucormycosis after AHSCT, but the incidence appears to be lower with 7.8% of the post-autograft invasive fungal infections.[4] In systemic autoimmune diseases, the onset of mucormycosis remains uncommon and appears to be related to the use of corticosteroids.[5,22] In a series of 24 cases of autoimmune disease patients with mucormycosis,[23] 83% had systemic lupus erythematosus. All the subjects had been exposed to corticosteroids and 6 had received additional CPM. In autoimmune diseases, mucormycosis symptoms can mimic a flare of the underlying disease.\n\nIn France, between 1996 and 2018, 75 AHSCT for severe SSc were performed[11] with no report of increased risk for post-transplantation invasive fungal infection. In the various other trials, which showed the benefit of AHSCT in SSc patients,[6–8] a higher proportion of viral infections were described but no increased risk for fungal infection has been noted.\n\n4 Conclusion\nIn light of the increase in the availability of AHSCT for severe SSc clinicians should be aware of this rare post-transplant fungal infection and that early initiation of adequate therapy for patients with clinical and radiological features consistent with mucormycosis could change the outcome.\n\nAuthor contributions\nConceptualization: Grégory Pugnet.\n\nSupervision: Grégory Pugnet.\n\nValidation: Grégory Pugnet.\n\nWriting – original draft: Xavier Boumaza.\n\nWriting – review & editing: Xavier Boumaza, Lucie Lelievre, Sarah Guenounou, Cécile Borel, Anne Huynh, Guillaume Beziat, Karen Delavigne, Damien Guinault, Marie Garric, Marie Piel-Julian, Kim Paricaud, Guillaume Moulis, Leonardo Astudillo, Laurent Sailler, Dominique Farge, Grégory Pugnet.\n\nAbbreviations: AHSCT = autologous hematopoietic stem cell transplantation, CPM = cyclophosphamide, CT = computerized tomography, EBMT = European Society for Blood and Marrow Transplantation, IV = intravenous, PBSC = peripheral blood hematopoietic stem cell, PCR = polymerase chain reaction, SSc = systemic sclerosis, VZV = varicella zoster virus.\n\nHow to cite this article: Boumaza X, Lelièvre L, Guenounou S, Borel C, Huynh A, Beziat G, Delavigne K, Guinault D, Garric M, Piel-Julian M, Paricaud K, Moulis G, Astudillo L, Sailler L, Farge D, Pugnet G. Pulmonary mucormycosis following autologous hematopoietic stem cell transplantation for rapidly progressive diffuse cutaneous systemic sclerosis: a case report. Medicine. 2020;99:31(e21431).\n\nThe authors have no funding and conflicts of interest to disclose.\n\nPatient has provided informed consent for publication of the case.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n[1] Pappas PG Alexander BD Andes DR \nInvasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET)\n. Clin Infect Dis \n2010 ;50 :1101 –11\n.20218876 \n[2] Robin C Alanio A Cordonnier C \nMucormycosis: a new concern in the transplant ward?\n\nCurr Opin Hematol \n2014 ;21 :482 –90\n.25295745 \n[3] Lanternier F Sun H-Y Ribaud P \nMucormycosis in organ and stem cell transplant recipients\n. Clin Infect Dis \n2012 ;54 :1 –8\n.22109950 \n[4] Neofytos D Horn D Anaissie E \nEpidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of multicenter Prospective Antifungal Therapy (PATH) Alliance Registry\n. Clin Infect Dis \n2009 ;48 :265 –73\n.19115967 \n[5] Petrikkos G Skiada A Lortholary O \nEpidemiology and clinical manifestations of mucormycosis\n. Clin Infect Dis \n2012 ;54 : suppl_1 : S23 –34\n.22247442 \n[6] Burt RK Shah SJ Dill K \nAutologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial\n. Lancet \n2011 ;378 :498 –506\n.21777972 \n[7] Van Laar JM Farge D Sont JK \nAutologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial\n. JAMA \n2014 ;311 :2490 –8\n.25058083 \n[8] Sullivan KM Goldmuntz EA Keyes-Elstein L \nMyeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma\n. N Engl J Med \n2018 ;378 :35 –47\n.29298160 \n[9] Kowal-Bielecka O Fransen J Avouac J \nUpdate of EULAR recommendations for the treatment of systemic sclerosis\n. Ann Rheum Dis \n2017 ;76 :1327 –39\n.27941129 \n[10] Snowden JA Saccardi R Allez M \nHaematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation\n. Bone Marrow Transplant \n2012 ;47 :770 –90\n.22002489 \n[11] Pugnet G Castilla-Llorente C Puyade M \nIndications and follow-up for autologous hematopoietic stem cell transplantation in autoimmune and autoinflammatory diseases: guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)\n. Bull Cancer \n2017 ;104 :S169 –80\n.29173974 \n[12] Farge D Burt RK Oliveira M-C \nCardiopulmonary assessment of patients with systemic sclerosis for hematopoietic stem cell transplantation: recommendations from the European Society for Blood and Marrow Transplantation Autoimmune Diseases Working Party and collaborating partners\n. Bone Marrow Transplant \n2017 ;52 :1495 –503\n.28530671 \n[13] Legouge C Caillot D Chrétien ML \nThe reversed halo sign: pathognomonic pattern of pulmonary mucormycosis in leukemic patients with neutropenia?\n\nClin Infect Dis \n2014 ;58 :672 –8\n.24352351 \n[14] Cornely OA Arikan-Akdagli S Dannaoui E \nESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013\n. Clin Microbiol Infect \n2014 ;20 : Suppl 3 : 5 –26\n.\n[15] Millon L Larosa F Lepiller Q \nQuantitative polymerase chain reaction detection of circulating DNA in serum for early diagnosis of mucormycosis in immunocompromised patients\n. Clin Infect Dis \n2013 ;56 :e95 –101\n.23420816 \n[16] Millon L Herbrecht R Grenouillet F \nEarly diagnosis and monitoring of mucormycosis by detection of circulating DNA in serum: retrospective analysis of 44 cases collected through the French Surveillance Network of Invasive Fungal Infections (RESSIF)\n. Clin Microbiol Infect \n2016 ;22 :810.e1 –8\n.26706615 \n[17] Dadwal SS Kontoyiannis DP \nRecent advances in the molecular diagnosis of mucormycosis\n. Expert Rev Mol Diagn \n2018 ;18 :1 –0\n.28954554 \n[18] Park BJ Pappas PG Wannemuehler KA \nInvasive non-Aspergillus mold infections in transplant recipients, United States, 2001-2006\n. Emerg Infect Dis \n2011 ;17 :1855 .22000355 \n[19] Tissot F Agrawal S Pagano L \nECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients\n. Haematologica \n2017 ;102 :433 –44\n.28011902 \n[20] Roden MM Zaoutis TE Buchanan WL \nEpidemiology and outcome of zygomycosis: a review of 929 reported cases\n. Clin Infect Dis \n2005 ;41 :634 –53\n.16080086 \n[21] Chamilos G Lewis RE Kontoyiannis DP \nAmphotericin B–based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis\n. Clin Infect Dis \n2008 ;47 :503 –9\n.18611163 \n[22] Ribes JA Vanover-Sams CL Baker DJ \nZygomycetes in human disease\n. Clin Microbiol Rev \n2000 ;13 :236 –301\n.10756000 \n[23] Royer M Puéchal X \nMucormycosis in systemic autoimmune diseases\n. Joint Bone Spine \n2014 ;81 :303 –7\n.24603011\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "99(31)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000208:Acute Disease; D061605:Administration, Intravenous; D000359:Aftercare; D000666:Amphotericin B; D000935:Antifungal Agents; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008172:Lung Diseases, Fungal; D009090:Mucorales; D009091:Mucormycosis; D012128:Respiratory Distress Syndrome; D045743:Scleroderma, Diffuse; D012595:Scleroderma, Systemic; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e21431",
"pmc": null,
"pmid": "32756151",
"pubdate": "2020-07-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pulmonary mucormycosis following autologous hematopoietic stem cell transplantation for rapidly progressive diffuse cutaneous systemic sclerosis: A case report.",
"title_normalized": "pulmonary mucormycosis following autologous hematopoietic stem cell transplantation for rapidly progressive diffuse cutaneous systemic sclerosis a case report"
} | [
{
"companynumb": "FR-MYLANLABS-2020M1076350",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
"drugadditional": "3",
... |
{
"abstract": "Heart retransplant is a treatment option for some patients with graft failure. With heart donor short-age, it is important to assess candidates carefully for cardiac retransplant. An adult patient had a successful urgent heart retransplant due to severe toxic cardiomyopathy (anthracycline-induced) after posttransplant lymphoproliferative disease that was a diffuse large B-cell lymphoma.",
"affiliations": "University of Zagreb School of Medicine, University Hospital Centre Zagreb, Zagreb, Croatia.",
"authors": "Samardzic|Jure|J|;Skoric|Bosko|B|;Cikes|Maja|M|;Ljubas-Macek|Jana|J|;Baricevic|Zeljko|Z|;Milicic|Davor|D|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2014.0077",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "13(6)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000293:Adolescent; D009202:Cardiomyopathies; D016027:Heart Transplantation; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D012086:Reoperation; D014184:Transplantation, Homologous",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "593-5",
"pmc": null,
"pmid": "25654316",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Urgent Heart Retransplant in an Adult Patient With Anthracycline-Induced Cardiomyopathy After Diffuse Large B-Cell Lymphoma - Case Report.",
"title_normalized": "urgent heart retransplant in an adult patient with anthracycline induced cardiomyopathy after diffuse large b cell lymphoma case report"
} | [
{
"companynumb": "HR-MYLANLABS-2016M1002343",
"fulfillexpeditecriteria": "1",
"occurcountry": "HR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": n... |
{
"abstract": "Acetaminophen is a common cause of poisoning and liver injury worldwide; however, patient stratification is suboptimal. We aimed to assess the contribution of admission plasma procalcitonin concentration (PCT) to better identify acetaminophen-poisoned patients likely to develop liver injury.\n\n\n\nWe conducted a prospective observational cohort study including all acetaminophen-poisoned patients requiring N-acetylcysteine admitted in a toxicological intensive care unit between 2012 and 2017. Multivariate analysis was performed using a Cox regression model to investigate factors associated with liver injury, defined as an increase in alanine aminotransferase (ALT) >100 IU/L.\n\n\n\nOne hundred seventeen patients (age, 32 years (21-53), median [25th-75th percentiles]) were included after self-ingesting 16 g (9-30) acetaminophen and received N-acetylcysteine infusion administered within a median 6 h-delay (4-12) from exposure. Co-ingestions were reported in 77% of patients. Rumack-Matthew nomogram was non-interpretable in 47% cases. Liver injury occurred in 38 patients (32%) with a median peak ALT of 2020 IU/L (577-4248). In liver injury patients, admission PCT was significantly increased in comparison to patients without liver injury (21.5 ng/ml (3.2-44.9) versus 0.1 ng/ml (0-0.4), respectively, p < 0.01). The increase in PCT preceded the increase in ALT by 33 h (10-74). In a multivariate analysis, PCT > 1 ng/ml was significantly associated with liver injury (hazard ratio, 7.2 [95% confidence interval, 2.3-22.6; p < 0.001]). PCT (area under the receiver-operating characteristics curve, 0.91 [95%CI: 0.84-0.97]) predicted liver injury with sensitivity, specificity, negative, and positive predictive values of 0.92, 0.84, 0.96, and 0.73, respectively.\n\n\n\nPCT on admission is associated with liver injury in acetaminophen poisoning. PCT might be used as a predictive tool of liver injury to improve clinical decision-making.",
"affiliations": "Department of Medical and Toxicological Critical Care, APHP, Lariboisière Hospital, Paris University, INSERM UMRS-1144, Paris, France.;Department of Medical and Toxicological Critical Care, APHP, Lariboisière Hospital, Paris University, INSERM UMRS-1144, Paris, France.;Department of Medical and Toxicological Critical Care, APHP, Lariboisière Hospital, Paris University, INSERM UMRS-1144, Paris, France.;Department of Epidemiology, APHP, Biostatistics and Clinical Research, Fernand-Widal Hospital, Paris University, Paris, France.;Department of Medical and Toxicological Critical Care, APHP, Lariboisière Hospital, Paris University, INSERM UMRS-1144, Paris, France.;Department of Medical and Toxicological Critical Care, APHP, Lariboisière Hospital, Paris University, INSERM UMRS-1144, Paris, France.;APHP, Laboratory of Toxicology, Lariboisière Hospital, Paris University, INSERM UMRS-1144, Paris, France.;Department of Medical and Toxicological Critical Care, APHP, Lariboisière Hospital, Paris University, INSERM UMRS-1144, Paris, France.;Department of Epidemiology, APHP, Biostatistics and Clinical Research, Fernand-Widal Hospital, Paris University, Paris, France.;Department of Medical and Toxicological Critical Care, APHP, Lariboisière Hospital, Paris University, INSERM UMRS-1144, Paris, France.;Department of Medical and Toxicological Critical Care, APHP, Lariboisière Hospital, Paris University, INSERM UMRS-1144, Paris, France.",
"authors": "Nuzzo|Alexandre|A|0000-0002-8952-7620;Salem|Shireen|S|;Malissin|Isabelle|I|;Diallo|Abdourahmane|A|;Deye|Nicolas|N|;Goury|Antoine|A|;Gourlain|Hervé|H|;Péron|Nicolas|N|;Vicaut|Eric|E|;Voicu|Sebastian|S|;Mégarbane|Bruno|B|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ueg2.12093",
"fulltext": "\n==== Front\nUnited European Gastroenterol J\nUnited European Gastroenterol J\n10.1002/(ISSN)2050-6414\nUEG2\nUnited European Gastroenterology Journal\n2050-6406\n2050-6414\nJohn Wiley and Sons Inc. Hoboken\n\n34181312\n10.1002/ueg2.12093\nUEG212093\nOriginal Article\nHepatobiliary\nPlasma procalcitonin may be an early predictor of liver injury in acetaminophen poisoning: A prospective cohort study\nNuzzo Alexandre https://orcid.org/0000-0002-8952-7620\n1 2\nSalem Shireen 1\nMalissin Isabelle 1\nDiallo Abdourahmane 3\nDeye Nicolas 1\nGoury Antoine 1\nGourlain Hervé 4\nPéron Nicolas 1\nVicaut Eric 3\nVoicu Sebastian 1\nMégarbane Bruno 1 bruno.megarbane@lrb.aphp.fr\n\n1 Department of Medical and Toxicological Critical Care APHP Lariboisière Hospital Paris University INSERM UMRS‐1144 Paris France\n2 Department of Gastroenterology APHP Beaujon Hospital Paris University INSERM UMRS‐1148 Clichy France\n3 Department of Epidemiology APHP Biostatistics and Clinical Research Fernand‐Widal Hospital Paris University Paris France\n4 APHP Laboratory of Toxicology Lariboisière Hospital Paris University INSERM UMRS‐1144 Paris France\n* Correspondence\nBruno Mégarbane, Department of Medical and Toxicological Critical Care, Lariboisière Hospital, 2 Rue Ambroise Paré, Paris 75010, France.\nEmail: bruno.megarbane@lrb.aphp.fr\n\n28 6 2021\n6 2021\n9 5 10.1002/ueg2.v9.5 571580\n02 3 2021\n26 4 2021\n© 2021 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nBackground and Aims\n\nAcetaminophen is a common cause of poisoning and liver injury worldwide; however, patient stratification is suboptimal. We aimed to assess the contribution of admission plasma procalcitonin concentration (PCT) to better identify acetaminophen‐poisoned patients likely to develop liver injury.\n\nMethods\n\nWe conducted a prospective observational cohort study including all acetaminophen‐poisoned patients requiring N‐acetylcysteine admitted in a toxicological intensive care unit between 2012 and 2017. Multivariate analysis was performed using a Cox regression model to investigate factors associated with liver injury, defined as an increase in alanine aminotransferase (ALT) >100 IU/L.\n\nResults\n\nOne hundred seventeen patients (age, 32 years (21–53), median [25th–75th percentiles]) were included after self‐ingesting 16 g (9–30) acetaminophen and received N‐acetylcysteine infusion administered within a median 6 h‐delay (4–12) from exposure. Co‐ingestions were reported in 77% of patients. Rumack–Matthew nomogram was non‐interpretable in 47% cases. Liver injury occurred in 38 patients (32%) with a median peak ALT of 2020 IU/L (577–4248). In liver injury patients, admission PCT was significantly increased in comparison to patients without liver injury (21.5 ng/ml (3.2–44.9) versus 0.1 ng/ml (0–0.4), respectively, p < 0.01). The increase in PCT preceded the increase in ALT by 33 h (10–74). In a multivariate analysis, PCT > 1 ng/ml was significantly associated with liver injury (hazard ratio, 7.2 [95% confidence interval, 2.3–22.6; p < 0.001]). PCT (area under the receiver‐operating characteristics curve, 0.91 [95%CI: 0.84–0.97]) predicted liver injury with sensitivity, specificity, negative, and positive predictive values of 0.92, 0.84, 0.96, and 0.73, respectively.\n\nConclusion\n\nPCT on admission is associated with liver injury in acetaminophen poisoning. PCT might be used as a predictive tool of liver injury to improve clinical decision‐making.\n\nacetaminophen\nacute liver injury\nbiomarker\ndrug‐induced liver injury\nhepatotoxicity\nparacetamol\nPCT\npoisoning\npredictive tool\nprocalcitonin\nsource-schema-version-number2.0\ncover-dateJune 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:06.07.2021\n==== Body\nINTRODUCTION\n\nAcetaminophen, one of the most commonly prescribed drugs worldwide, is the leading cause of acute poisoning and liver injury (LI) in the developed countries. 1 , 2 , 3 For more than 4 decades, a nomogram has been used to predict acetaminophen‐induced hepatotoxicity, helping physicians deciding whether to treat the poisoned patient with N‐acetylcysteine (NAC) or not. 4 Nevertheless, evaluating the risk of LI using the nomogram has not been validated in several common scenarios, including (1) chronic overdose, (2) co‐ingested drugs slowing gastrointestinal absorption, (3) unknown time from ingestion to presentation, and (4) presentation >24 h post‐ingestion. 4 , 5 Interestingly, about 3.9%–5.2% of vulnerable acetaminophen‐poisoned patients have been shown to develop LI despite NAC administration. 5 , 6 , 7 In contrast, other patients at lower risk of hepatotoxicity may receive NAC by excess, resulting in a significant increase in bed occupancy and potentially preventable NAC‐related adverse events. 5 , 8 , 9 To date, the identification of such patients cannot be achieved based on the nomogram only.Key points\n\n1. Summarize the established knowledge on this subject\n\nFor decades, a nomogram has been used to predict acetaminophen‐induced hepatotoxicity\n\nNevertheless, using the nomogram has not been validated in several common scenarios, including chronic overdose or when time from ingestion to presentation is unknown\n\nNew biomarkers that would complement the nomogram for patient stratification are needed\n\n2. What are the significant and/or new findings of this study?\n\nIn 117 prospective patients, plasma procalcitonin on admission was associated to liver injury with excellent accuracy and negative predictive value\n\nThe rise of plasma procalcitonin preceded that of alanine aminotransferase by a median of 33 h\n\nPlasma procalcitonin on admission may help in early identification of patients at higher or lower risk of ALI in whom personalized management may be used\n\nTherefore, asides from the nomogram, predictive biomarkers are needed to early identify, among acetaminophen‐poisoned patients receiving NAC, those at risk of LI. 5 , 10 These patients may consequently benefit from closer clinical and laboratory monitoring, prolonged or higher doses of NAC, and earlier decision of liver transplantation if needed. Conversely, decision against NAC treatment or a short regimen, as well as rapid discharge, may be safely proposed in patients at lower risk of LI. For this purpose, novel biomarkers have been developed, such as acetaminophen protein adducts and liver micro‐RNAs (miR‐122) or proteins (HMGB1, keratin 18, and GLDH). 5 , 11 , 12 However, further evaluation is needed and these biomarkers are still not available in routine practice. 5 , 10 , 12\n\nThe liver has been suggested as a potential source of production of procalcitonin (PCT), 13 a readily and commonly used validated biomarker of bacterial infection 14 , 15 . We sought to investigate its contribution to identifying, upon admission, acetaminophen‐poisoned patients likely to develop LI.\n\nPATIENTS & METHODS\n\nThis study was performed in accordance with the ethical standards of the Ethics Committee of the French Society of Intensive Care Medicine (FICS) and reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. 16 The study protocol was declared to the National Commission on Informatics and Liberty (CNIL) and approved by the FICS Ethics Committee (CE SRLF 18‐14). Participating patients were informed, but written consent was waived due to the observational methodology of the study.\n\nPatient population and poisoning management\n\nIn this prospective observational cohort study, we included all consecutive acetaminophen‐poisoned patients admitted to the toxicological intensive care unit of a University Hospital in Paris, France, between January 2012 and December 2017.\n\nPlasma PCT, C‐reactive protein (CRP), liver and coagulation tests, blood lactate, and plasma acetaminophen concentrations were systematically measured on admission. As part of routine clinical follow‐up, subsequent blood tests were performed at the discretion of the treating physician. Plasma PCT was measured using a Cobase® automated analyzer (Roche, normal, <0.05 ng/ml). Plasma acetaminophen concentration was measured using a spectrophotometric method (therapeutic range, 5–25 mg/L). Acetaminophen‐induced LI was defined as the peak increase in alanine aminotransferase (ALT) >100 IU/L, corresponding to the French indication for continuing NAC therapy after completion of the initial regimen at the time of the study. Patients were considered for referral to the liver transplantation unit of a neighboring hospital in case of acute liver failure (ALF). ALF was defined as the association of severe LI with encephalopathy and international normalized ratio (INR) >1.5 at any time. 17 , 18\n\nNAC was administered in all patients as per French recommendations: (1) baseline plasma acetaminophen concentration above the cutoff (starting at 150 mg/L at the fourth hour post‐ingestion according to the Rumack–Matthew nomogram); 4 (2) increased plasma ALT > 50 IU/L; or (3) nonvalidity of the nomogram due to unknown overdose timing, time from ingestion out of the 4–24 h range, chronic overdose or presence of co‐ingested toxicants delaying gastrointestinal absorption. All patients received intravenous NAC with a 150 mg/kg loading dose during the first hour, followed by 50 mg/kg and 100 mg/kg during the next 4 and 16 h, respectively. Then, a daily infusion of 300 mg/kg NAC was given until plasma acetaminophen concentration was undetectable and significant liver function improvement was obtained.\n\nData collection\n\nThe following demographic, clinical, biological, and outcome variables were prospectively collected in a dedicated registry: age, gender, weight, history of ethanol abuse and suicide attempt, history of liver, kidney and psychiatric diseases, body temperature, abdominal pain, nausea/vomiting, cardiovascular failure defined as mean arterial pressure <65 mmHg requiring catecholamine administration, Glasgow coma score, and clinical suspicion of associated infection. Toxicological data collected included the presumed ingested acetaminophen dose and time of ingestion whenever available, the type of overdose (acute ingestion or chronic overdose), and the presumed co‐ingestions (ethanol, codeine, tramadol, nonsteroidal anti‐inflammatory drugs, psychotropic, and cardiotoxic drugs). The baseline acetaminophen concentration was considered not interpretable in case of co‐ingestion of drugs potentially delaying acetaminophen gastrointestinal absorption such as codeine and tramadol. Time to NAC administration was defined as the delay from the presumed time of acetaminophen ingestion to the time of NAC administration. Laboratory data collected on admission included plasma CRP, PCT acetaminophen, ethanol, liver function and coagulation tests, serum creatinine, and blood lactate. The time course of ALT, PCT, CRP, INR, and lactate values were recorded if available. Management and follow‐up data collected included charcoal administration, mechanical ventilation, length of ICU stay, referral to the liver transplantation unit, and death.\n\nStatistical analysis\n\nQuantitative data were reported as medians (interquartile range). Normally distributed quantitative data were analyzed using Student t‐tests. The Mann–Whitney U‐tests or Wilcoxon Sum‐Rank tests were used otherwise. Qualitative data were reported as the number of patients (percentages) and compared using Pearson χ2 tests or Fisher exact tests, depending on the sample size. The value of PCT on admission for the diagnosis of LI was assessed using the receiver‐operating characteristics (ROC) curve, sensitivity, specificity, accuracy, negative, and positive predictive value. The estimated area under the ROC curve (95% confidence interval [CI]) was computed. The Youden index was used to determine the optimal threshold of PCT concentration in terms of sensitivity and specificity. PCT variable was then dichotomized for testing in univariate and multivariate analysis.\n\nMultivariate analysis of the association between PCT levels and LI was performed using a Cox proportional‐hazards regression model including all variables with p‐values <0.10 in univariate analysis. Age, history of chronic liver disease, delay to NAC administration, and clinical suspicion of infection were planned to be included in the Cox regression model to adjust on potential confounding factors. Results of the multivariate analysis are shown as hazard ratio (HR) with their 95%CI. Incidence of LI according to admission PCT value was presented as Kaplan Meier curves.\n\nAll tests were two‐sided. Missing data were not analyzed or estimated. p‐values <0.05 were considered to be significant. Analyses were performed using SAS software, version 9.4 (SAS Institute).\n\nRESULTS\n\nPatient characteristics\n\nA total of 117 consecutive patients (86 female [74%]/31 male [26%]; age, 32 years [21–53]) were included after the ingestion of a median amount of 16 g (9–30) of acetaminophen. Baseline and follow‐up patient characteristics are described in Table 1. Poisoning resulted from suicide attempt in 110 patients (94%). Poisoning involved co‐ingested drugs in 90 cases (77%), including benzodiazepines in 35 (30%), codeine in 34 (29%), tramadol in 18 (10%), nonsteroidal anti‐inflammatory drugs in 16 (14%), and other psychotropic drugs in 48 (41%) patients. The nomogram was considered as noninterpretable in 55 patients (47%) due to unknown or >24 h time of ingestion in 36/55 (65%), chronic overdose in 7/55 (13%), or tramadol/codeine co‐ingestion in 12/55 (22%) patients. The delay from ingestion to NAC administration was 6 h (4–12) (available data, N = 88). Biochemical tests on presentation included serum ALT of 29 IU/L (14–99), bilirubin of 9 µmol/L (6–17), serum ALP of 68 IU/L (52–87), serum GGT of 24 IU/L (16–49), INR of 1.2 (1.1–1.4), and serum creatinine of 62 µmol/L (53–82).\n\nTABLE 1 Characteristics of the 117 acetaminophen‐poisoned patients\n\n\tLiver injury\tNo liver injury\tOverall population\tp‐value\t\nn = 38 (%)\tn = 79 (%)\tn = 117 (%)\t\nAge, years a\t41 (24–55)\t28 (20–49)\t32 (21–53)\t0.04\t\nFemale\t29 (76)\t57 (72)\t86 (74)\t0.63\t\nWeight, kg a\t68 (56–75)\t67 (59–78)\t68 (59–76)\t0.77\t\nHistory of chronic diseases\t\t\t\t\t\nAlcohol abuse\t5 (13)\t7 (9)\t12 (10)\t0.52\t\nLiver disease\t2 (5)\t1 (1)\t3 (3)\t0.25\t\nPsychiatric illness\t28 (74)\t58 (73)\t86 (74)\t0.98\t\nAcetaminophen overdose\t\t\t\t\t\nPresumed ingested dose, g a\t24 (13–31)\t16 (8–30)\t16 (9–30)\t0.12\t\nSuicide attempt\t34 (90)\t76 (96)\t110 (94)\t0.21\t\nDelay to NAC administration, h a , b\t15 (8–23)\t5 (4–8)\t6 (4–12)\t<0.01\t\nCo‐ingested drugs\t29 (76)\t61 (77)\t90 (77)\t0.91\t\nNomogram uninterpretable\t18 (47)\t37 (47)\t55 (47)\t0.40\t\nClinical data\t\t\t\t\t\nAbdominal pain\t10 (26)\t12 (15)\t22 (19)\t0.15\t\nNausea/Vomiting\t15 (40)\t33 (42)\t48 (41)\t0.81\t\nCardiovascular failure\t13 (34)\t9 (11)\t22 (19)\t<0.01\t\nGlasgow coma score <8\t14 (37)\t18 (23)\t32 (27)\t0.11\t\nSuspicion of infection on admission\t16 (20)\t12 (32)\t28 (24)\t0.18\t\nBiological data a\t\t\t\t\t\nAdmission acetaminophen, mg/ml\t41 (12–133)\t53 (22–137)\t51 (21–133)\t0.35\t\nAdmission creatinine, µmol/L\t77 (56–127)\t61 (51–73)\t62 (53–82)\t<0.01\t\nAdmission ALT, IU/L\t297 (99–1433)\t18 (12–32)\t29 (14–99)\t<0.001\t\nPeak ALT, IU/L\t2020 (577–4248)\t21 (15–36)\t33 (18–555)\t<0.001\t\nAdmission bilirubin, µmol/L\t13 (8–34)\t8 (6–14)\t9 (6–17)\t0.001\t\nAdmission ALP, IU/L\t78 (63–106)\t61 (48–81)\t68 (52–87)\t0.005\t\nAdmission GGT, IU/L\t44 (20–134)\t22 (14–38)\t24 (16–49)\t0.002\t\nAdmission INR\t1.5 (1.3–2.7)\t1.1 (1.1–1.3)\t1.1 (1.2–1.4)\t<0.001\t\nAdmission C‐reactive protein, mg/L\t7 (4–23)\t4 (4–4)\t4 (4–8)\t<0.01\t\nAdmission lactate, mmol/L\t2.1 (1.2–6.6)\t2.0 (1.1–2.8)\t2.0 (1.2–3.3)\t0.10\t\nAdmission PCT, ng/ml\t21.5 (3.0–45.3)\t0.1 (0.0–0.4)\t0.2 (0.1–10.8)\t<0.001\t\nAdmission PCT > 1 ng/ml, n (%)\t33 (87)\t13 (17)\t46 (39)\t<0.01\t\nICU management\t\t\t\t\t\nActivated charcoal\t6 (16)\t14 (18)\t20 (17)\t0.79\t\nMechanical ventilation\t10 (26)\t8 (10)\t18 (15)\t0.02\t\nLength of ICU stay, days a\t5 (2–9)\t2 (1–3)\t2 (1.5–4.5)\t<0.01\t\nNon‐survivors\t8 (21)\t1 (1)\t9 (8)\t<0.01\t\nAbbreviations: ALT, alanine aminotransferase; ICU, intensive care unit; INR, international normalized ratio; NAC, N‐acetylcysteine; PCT, procalcitonin.\n\na Median (interquartile range).\n\nb Delay to NAC administration was calculated from the time of ingestion if known (N = 88).\n\nOn admission, 32 patients (27%) were comatose and 22 (19%) patients presented with cardiovascular failure, due to ALF in seven patients or due to co‐ingested drugs otherwise. Bacterial infection was suspected in 28 patients (24%) upon admission, consisting of 23 aspiration pneumonia, 4 urinary tract infections, and 1 colitis with no significant difference in patients with or without LI. Infection was eventually confirmed during the follow‐up in 23 of them, with microbiology diagnosis obtained in six patients only. Mechanical ventilation was required in 18 patients (15%) with a median duration of 3 days (0.8–6). The median length of ICU stay was 2 days (1.5–4.5). Nine patients (8%) died. The reason for death was ALF in eight patients and cardiogenic shock in one patient.\n\nPredictive value of admission PCT for the diagnosis of LI\n\nLI occurred in 38 patients (32%) including 27 patients on admission and 11 during the follow‐up period, with a median peak serum ALT of 2020 IU/L (577–4248). In 29 patients (25%), LI progressed to ALF, with complete recovery during the follow‐up in 18/29 (62%) patients, liver transplantation request in 3/29 (10%), and death in 8/29 (28%) patients. Median plasma PCT concentration on admission was 0.2 ng/ml (0.1–10.5) and was significantly higher in patients with LI (21.5 ng/ml [3.2–44.9] versus 0.1 ng/ml [0–0.4], p < 0.001); Figure 1). ROC analysis of the plasma PCT concentration on admission to discriminate between LI and non‐LI patients showed AUC of 0.91 (95%CI: 0.84 to 0.97) (Figure 2). The optimal threshold value for PCT was 0.96 ng/ml, with sensitivity, specificity, accuracy, negative, and positive predictive values of 92%, 84%, 86%, 96%, and 73%, respectively.\n\nFIGURE 1 Plasma PCT concentrations on admission according to the onset of liver injury in 117 acetaminophen‐poisoned patients. log, logarithmic; ng/ml, nanograms per milliliters; PCT, procalcitonin\n\nFIGURE 2 Value of plasma PCT concentration on admission in the diagnosis of liver injury in the acetaminophen‐poisoned patient (receiver‐operating characteristics curve). AUC, area under the ROC curve; CI, confidence interval; NPV, negative predictive value; PCT, procalcitonin; PPV, positive predictive value\n\nLegend tablePCT best cutoff value\tSensitivity (95%CI)\tSpecificity (95%CI)\tAccuracy (95%CI)\tPPV (95%CI)\tNPV (95%CI)\tYouden index (95%CI)\tAUC (95%CI)\t\n0.96 ng/ml\t0.92 (0.79–0.98)\t0.84 (0.74–0.90)\t0.86 (0.78–0.92)\t0.73 (0.58–0.85)\t0.96 (0.88–0.99)\t0.76 (0.64–0.88)\t0.91 (0.84–0.97)\t\n\nBased on univariate analyses, age (p = 0.04), delay to NAC administration (p < 0.01), cardiovascular failure (p < 0.01), serum creatinine (p < 0.01), plasma CRP (p < 0.01), and plasma PCT > 1 ng/ml (p < 0.01) were significantly associated with increased incidence of LI (Table 1). Despite slight elevation (2.0 mmol/L [1.2–3.3]; N: 0.5–1.6), no significant association was found between blood lactate concentration on admission and LI (p = 0.10). Among the 16 patients who had blood lactate concentration >3 mmol/L on admission, none of them progressed to LI or cardiovascular failure and lactate returned to normal values within 12 h delay (10–30).\n\nAfter adjustment in the Cox regression model (Table 2), admission PCT concentration >1 ng/ml was independently associated with increased onset of LI (HR: 7.2 [95%CI: 2.3–22.6]; p < 0.001; Figure 3), as was the delay to NAC administration (HR: 1.03 [95%CI: 1.0–1.1]; p = 0.04). Among the 11/38 patients who developed LI during the follow‐up despite NAC, the increase in PCT > 1 ng/ml preceded the increase in ALT by 33 h (10–74; Figure 4). In the subgroup of 38 patients with LI, median PCT was 21.6 (4.5–42.5) ng/ml in patients with LI + ALF versus 9.2 (0.4–50.4) ng/ml in patients with LI alone (p = 0.49).\n\nTABLE 2 Risk of liver injury in 117 acetaminophen‐poisoned patients based on a multivariate Cox proportional hazard model\n\n\tMultivariate analysis a\t\np‐value\tHR\t95%CI\t\nAge, years\t0.94\t‐\t‐\t\nHistory of liver disease\t0.06\t‐\t‐\t\nDelay to NAC administration, h2\t0.04\t1.03\t1.0–1.1\t\nCardiovascular failure\t0.79\t‐\t‐\t\nClinical suspicion of infection\t0.45\t‐\t‐\t\nPlasma C‐reactive protein, mg/L\t0.56\t‐\t‐\t\nSerum creatinine, µmol/L\t0.71\t‐\t‐\t\nPlasma procalcitonin >1 ng/ml\t<0.001\t7.2\t2.3–22.6\t\nNote: Bold values indicate significant results.\n\nAbbreviations: CI, confidence interval; HR, hazard ratio; NAC, N‐acetylcysteine.\n\na The multivariate analysis included 83 complete cases.\n\nb Delay to NAC administration was calculated from the time of ingestion if known (available data N = 88).\n\nFIGURE 3 Probability of acetaminophen‐induced liver injury according to admission PCT concentration (Kaplan–Meier curves, p < 0.001). PCT, procalcitonin\n\nFIGURE 4 Time course of plasma PCT and ALT concentrations in an acetaminophen‐poisoned patient. This 90‐year‐old woman was admitted 16 h post‐ingestion of an unknown dose of paracetamol. On admission, she presented with high acetaminophen plasma levels 136 mg/ml, high procalcitonin levels 27 ng/ml, and normal liver tests. ALT, alanine aminotransferase; PCT, procalcitonin\n\nAdmission PCT significantly correlated with peak serum ALT (rs = 0.58, p < 0.001) and the delay to NAC administration (rs = 0.54, p < 0.001).\n\nDISCUSSION\n\nIn this observational cohort including 117 acetaminophen‐poisoned patients treated by NAC, with 38 cases of LI, we suggest that plasma PCT concentration on admission may be an early independent predictor of LI with an excellent accuracy and negative predictive value. The rise in PCT in acetaminophen‐induced LI patients was particularly high (median value, 21.5 ng/ml), much greater than the 1–2 ng/ml cutoff commonly used to identify bacterial infections. 14 Such elevated values are generally observed in septic shock. 19 Interestingly, the rise in PCT tended to be higher in patients with LI + ALF (median 21.6 ng/ml) than in patients with LI alone (median 9.2 ng/ml). However, the difference did not reach statistical significance.\n\nOur findings support a remarkable association between PCT and acetaminophen‐related LI. First and foremost, despite the increasing clinical interest for PCT in the setting of sepsis, 14 , 20 its tissue production source remains poorly understood. Although primarily identified in thyroid‐C‐cells and neuroendocrine cells, 21 , 22 data suggest that the liver is a potential source of sepsis‐related PCT production, as PCT mRNAs have been found to be highly expressed in the hepatic tissue. 13 Second, in an attempt to better predict bacterial infection in the setting of liver disease, recent investigations with plasma PCT monitoring reported uncommonly elevated PCT concentrations in numerous LI and ALF patients, with no or poor cutoff values for the diagnosis of infection. 23 , 24 , 25 , 26 , 27 , 28 , 29 These findings suggested a strong association between PCT increase and LI, while hampering its diagnostic value for sepsis in this setting. 29 Consistent with our results, Jackson et al. found high PCT concentrations in acetaminophen‐induced ALF [median value, 9.4 ng/ml (0.9–123.8)]. 30 Similar cases were recently published. 31 Moreover, Mallet et al. reported significantly higher PCT concentrations in acetaminophen‐induced ALF than in any other causes (10.6 vs. 0.8 ng/ml p < 0.0001), irrespective of any concurrent infection (10.3 vs. 10.7 ng/ml, p = 0.7). 32 In a pediatric cohort study, Tschiedel et al. observed that paracetamol intoxication led to a marked increase in PCT serum levels, correlating with ALT but not correlating with the INR or paracetamol blood levels, consistent with our findings. 33\n\nInterestingly in our study, the rise of PCT levels preceded that of ALT by a median of 33 h in patients with normal ALT on admission. Moreover, the association between PCT levels and LI was independent from and stronger than the delay to NAC administration, which is the most recognized risk factor for the development of hepatotoxicity and mortality in the setting of acetaminophen poisoning. 4 , 5 , 34 Plasma PCT concentrations could be even more useful when the nomogram is not interpretable, as the ingestion time is frequently unknown or unreliable. 35 Over the years, several prognostic tools have been developed to identify patients more likely to die without liver transplantation. In this regard, the King's College Hospital and Clichy Criteria have been validated and used worldwide in combination with blood lactate >3 mmol/L. However, they are only useful once ALF is established. 36 , 37 Interestingly, at the early stages of poisoning, we observed a slight increase in blood lactate but no significant association with LI or cardiovascular failure and a rapid normalization within a median delay of 12 h. None of the patients with baseline lactate >3 mmol/L progressed to LI or ALF. This observation is consistent with studies suggesting a direct inhibitory toxic effect of acetaminophen on cellular respiration in mitochondria 38 , 39 and with other reports of severe overdose presenting early with lactic acidosis without overt signs of hepatic damage or shock. 39 , 40 , 41\n\nAcetaminophen poisoning is a common etiology for emergency room admission resulting in significant bed occupancy (around 47,000 bed days per year in the United Kingdom). 12 , 42 Management is only based on the interpretation of admission acetaminophen concentration on the nomogram. As a result, numerous patients may be over‐treated with a time‐consuming and potentially harmful antidote, especially since the toxic threshold has been recently lowered in some countries such as the United Kingdom. 5 Minor adverse reactions to NAC have been reported in 15%–45% of treated patients, mainly including nausea, vomiting, and anaphylactoid reactions. Additionally, although rare, some fatalities have been reported. 8 , 9 On the other hand, patients at higher risk of LI may be undertreated, with a small subgroup of patients that will develop liver toxicity despite appropriate therapy. 5 Therefore, the burden of overdose and limitations of current management have led to a particular interest in new biomarkers that would complement the nomogram for the early identification and discrimination of patients at high or low risk of LI. High‐risk patients may benefit from closer monitoring, earlier recognition of ALF, and appropriate listing for liver transplantation. Conversely, low‐risk patients may safely be offered abbreviated NAC regimen or early discharge. 5 , 12 However, and contrary to PCT which can be rapidly and accurately measured by point‐of‐care testing, none of the promising biomarkers recently highlighted is readily available in daily clinical practice. 5 , 12\n\nSome limitations of our study should be underlined. First, our primary outcome was an increase in ALT > 100 IU/L. Although lower than the threshold used in the published definition of drug‐induced LI, ALT > 100 IU/L is commonly used in toxicological risk stratification studies of acetaminophen‐poisoned patients. 12 , 43 Besides, this cutoff is widely used in the French and UK clinical guidelines (www.toxbase.org) to indicate the need for further NAC treatment, based on evidence that substantial LI is unlikely if serum ALT is <100 IU/L. 7 Green et al. showed that 97% of the patients with peak serum ALT > 1000 IU/L exhibited ALT > 100 IU/L at the end of the 21 h NAC treatment. 7 Second, an important proportion of our patients ingested other drugs that may have caused specific hepatotoxicity, interactions with acetaminophen metabolism, or systemic consequences (such as cardiovascular failure, kidney injury, systemic inflammation or infections) affecting both ALT and PCT levels. However, this heterogeneity reflects the real‐life clinical epidemiology of acetaminophen poisoning in France, and the multivariate analysis adjusted on these potential confounding factors. Besides, high rates of drug co‐ingestions were reported in a large recent US cohort of 1162 patients with acetaminophen‐induced LI. 44 Third, the delay from the PCT rise to the ALT rise was only evaluated in the 29% of LI patients who had presented with normal liver tests and developed hepatotoxicity during follow‐up. Finally, given our findings are based on a monocentric and tertiary care cohort study, interpretation should be cautious. More studies are required to confirm the added value of PCT in the setting of acetaminophen poisoning as well as in other causes of LI.\n\nCONCLUSION\n\nOur results suggest that high plasma PCT on admission is independently associated with LI and may be an early predictor of LI in the setting of acetaminophen poisoning. PCT measurement may help in earlier identification of patients at higher or lower‐risk of LI in whom personalized management and adapted NAC regimen may be used. Our findings should be validated in future prospective large‐cohort studies.\n\nCONFLICT OF INTEREST\n\nNone.\n\nAUTHOR CONTRIBUTION\n\nStudy concept and design: Alexandre Nuzzo, Eric Vicaut, and Bruno Mégarbane. Acquisition of data: Alexandre Nuzzo, Shireen Salem, Hervé Gourlain, and Bruno Mégarbane. Analysis and interpretation of data: Alexandre Nuzzo, Abdourahmane Diallo, Eric Vicaut, Sebastian Voicu, and Bruno Mégarbane. Drafting of the manuscript: Alexandre Nuzzo and Bruno Mégarbane. Critical revision of the manuscript for important intellectual content: Antoine Goury, Isabelle Malissin, Nicolas Deye, Nicolas Péron, Eric Vicaut, Sebastian Voicu, and Bruno Mégarbane. Statistical analysis: Abdourahmane Diallo and Eric Vicaut. Study supervision: Bruno Mégarbane.\n\nACKNOWLEDGMENT\n\nAlexandre Nuzzo received PhD grant from Fondation de l’Avenir and SNFGE.\n\nDATA AVAILABILITY STATEMENT\n\nResearch data are not shared.\n\nAPPENDIX A STROBE Statement—Checklist of items that should be included in reports of cohort studies\n\n\tItem no\tRecommendation\t\nTitle and abstract\t1\t(a) Indicate the study's design with a commonly used term in the title or the abstract\t\n(b) Provide in the abstract an informative and balanced summary of what was done and what was found\t\nIntroduction\t\nBackground/rationale\t2\tExplain the scientific background and rationale for the investigation being reported\t\nObjectives\t3\tState specific objectives, including any prespecified hypotheses\t\nMethods\t\nStudy design\t4\tPresent key elements of study design early in the paper\t\nSetting\t5\tDescribe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow‐up, and data collection\t\nParticipants\t6\t(a) Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow‐up\t\n(b) For matched studies, give matching criteria and number of exposed and unexposed\t\nVariables\t7\tClearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable\t\nData sources/measurement\t8*\tFor each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group\t\nBias\t9\tDescribe any efforts to address potential sources of bias\t\nStudy size\t10\tExplain how the study size was arrived at\t\nQuantitative variables\t11\tExplain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why\t\nStatistical methods\t12\t(a) Describe all statistical methods, including those used to control for confounding\t\n(b) Describe any methods used to examine subgroups and interactions\t\n(c) Explain how missing data were addressed\t\n(d) If applicable, explain how loss to follow‐up was addressed\t\n(e) Describe any sensitivity analyses\t\nResults\t\nParticipants\t13*\t(a) Report numbers of individuals at each stage of study—for example, numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow‐up, and analyzed\t\n(b) Give reasons for non‐participation at each stage\t\n(c) Consider use of a flow diagram\t\nDescriptive data\t14*\t(a) Give characteristics of study participants (e.g., demographic, clinical, social) and information on exposures and potential confounders\t\n(b) Indicate number of participants with missing data for each variable of interest\t\n(c) Summarize follow‐up time (e.g., average and total amount)\t\nOutcome data\t15*\tReport numbers of outcome events or summary measures over time\t\nMain results\t16\t(a) Give unadjusted estimates and, if applicable, confounder‐adjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included\t\n(b) Report category boundaries when continuous variables were categorized\t\n(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period\t\nOther analyses\t17\tReport other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses\t\nDiscussion\t\nKey results\t18\tSummarize key results with reference to study objectives\t\nLimitations\t19\tDiscuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias\t\nInterpretation\t20\tGive a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence\t\nGeneralizability\t21\tDiscuss the generalizability (external validity) of the study results\t\nOther information\t\nFunding\t22\tGive the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based\t\nNote: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at http://www.strobe‐statement.org.\n\n*Give information separately for exposed and unexposed groups.\n==== Refs\nREFERENCES\n\n1 Bernal W , Wendon J . Acute liver failure. N Engl J Med. 2013;369 :2525‐34.24369077\n2 Bateman DN , Carroll R , Pettie J , Yamamoto T , Elamin MEMO , Peart L , et al. Effect of the UK's revised paracetamol poisoning management guidelines on admissions, adverse reactions and costs of treatment. Br J Clin Pharmacol. 2014;78 :610‐8.24666324\n3 Mowry JB , Spyker DA , Cantilena LR, Jr , Spyker DA , Brooks DE , Dibert KW , et al. Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 31st annual report. Clin Toxicol (Phila) 2014. 2013;52 :1032‐283.\n4 Rumack BH , Matthew H . Acetaminophen poisoning and toxicity. Pediatrics. 1975;55 :871‐6.1134886\n5 Wong A , Graudins A . Risk prediction of hepatotoxicity in paracetamol poisoning. Clin Toxicol (Phila). 2017;55 :879‐92.28447858\n6 Doyon S , Klein‐Schwartz W . Hepatotoxicity despite early administration of intravenous N‐acetylcysteine for acute acetaminophen overdose. Acad Emerg Med. 2009;16 :34‐9.19007345\n7 Green TJ , Sivilotti ML , Langmann C , Yarema M , Juurlink D , Burns MJ , et al. When do the aminotransferases rise after acute acetaminophen overdose? Clin Toxicol (Phila). 2010;48 :787‐92.20969501\n8 Kerr F , Dawson A , Whyte IM , Buckley N , Murray L , Graudins A , et al. The Australasian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of N‐acetylcysteine. Ann Emerg Med. 2005;45 :402‐8.15795719\n9 Waring WS , Stephen AF , Robinson OD , Dow MA , Pettie JM . Lower incidence of anaphylactoid reactions to N‐acetylcysteine in patients with high acetaminophen concentrations after overdose. Clin Toxicol (Phila). 2008;46 :496‐500.18584360\n10 Howell LS , Ireland L , Park BK , Goldring CE . MiR‐122 and other microRNAs as potential circulating biomarkers of drug‐induced liver injury. Expert Rev Mol Diagn. 2018;18 :47‐54.29235390\n11 Dear JW , Antoine DJ . Stratification of paracetamol overdose patients using new toxicity biomarkers: current candidates and future challenges. Expet Rev Clin Pharmacol. 2014;7 :181‐9.\n12 Antoine DJ , Dear JW , Lewis PS , Platt V , Coyle J , Masson M , et al. Mechanistic biomarkers provide early and sensitive detection of acetaminophen‐induced acute liver injury at first presentation to hospital. Hepatology. 2013;58 :777‐87.23390034\n13 Russwurm S , Stonans I , Stonane E , Wiederhold M , Luber A , Zipfel PF , et al. Procalcitonin and CGRP‐1 mrna expression in various human tissues. Shock. 2001;16 :109‐12.11508861\n14 Wacker C , Prkno A , Brunkhorst FM , Schlattmann P . Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta‐analysis. Lancet Infect Dis. 2013;13 :426‐35.23375419\n15 Bouadma L , Luyt CE , Tubach F , Cracco C , Alvarez A , Schwebel C , et al. Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet. 2010;375 :463‐74.20097417\n16 von Elm E , Altman DG , Egger M , Pocock SJ , Gøtzsche PC , Vandenbroucke JP , et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370 :1453‐7.18064739\n17 European Association for the Study of the Liver . Electronic address eee, Clinical practice guidelines p, Wendon J, et al. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66 :1047‐81.28417882\n18 Polson J , Lee WM , American Association for the Study of Liver Disease . AASLD position paper: the management of acute liver failure. Hepatology. 2005;41 :1179‐97.15841455\n19 Harbarth S , Holeckova K , Froidevaux C , Pittet D , Ricou B , Grau GE , et al. Diagnostic value of procalcitonin, interleukin‐6, and interleukin‐8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med. 2001;164 :396‐402.11500339\n20 Huang DT , Yealy DM , Filbin MR , Pearse D , Pantle H , Masterson M , et al. Procalcitonin‐guided use of antibiotics for lower respiratory tract infection. N Engl J Med. 2018;379 :236‐49.29781385\n21 Rosenfeld MG , Mermod JJ , Amara SG , Swanson LW , Sawchenko PE , Rivier J , et al. Production of a novel neuropeptide encoded by the calcitonin gene via tissue‐specific RNA processing. Nature. 1983;304 :129‐35.6346105\n22 Sabate MI , Stolarsky LS , Polak JM , Bloom SR , Varndell IM , Ghatei MA , et al. Regulation of neuroendocrine gene expression by alternative RNA processing. Colocalization of calcitonin and calcitonin gene‐related peptide in thyroid C‐cells. J Biol Chem. 1985;260 :2589‐92.2982827\n23 Bolia R , Srivastava A , Marak R , Yachha SK , Poddar U , Role of procalcitonin and C‐reactive protein as biomarkers of infection in children with liver disease. J Pediatr Gastroenterol Nutr. 2016;63 :406‐11.26933799\n24 Bota DP , Van Nuffelen M , Zakariah AN , Vincent J . Serum levels of C‐reactive protein and procalcitonin in critically ill patients with cirrhosis of the liver. J Lab Clin Med. 2005;146 :347‐51.16310518\n25 Qu J , Feng P , Luo Y , Lü X . Impact of hepatic function on serum procalcitonin for the diagnosis of bacterial infections in patients with chronic liver disease: a retrospective analysis of 324 cases. Medicine (Baltimore). 2016;95 :e4270.27472699\n26 Cousin VL , Lambert K , Trabelsi S , Galetto‐Lacour A , Posfay‐Barbe KM , Wildhaber BE , et al. Procalcitonin for infections in the first week after pediatric liver transplantation. BMC Infect Dis. 2017;17 :149.28201980\n27 Eyraud D , Ben Ayed S , Tanguy ML , Vézinet C , Siksik J , Bernard M , et al. Procalcitonin in liver transplantation: are high levels due to donors or recipients?. Crit Care. 2008;12 :R85.18601732\n28 Meisner M , Tschaikowsky K , Hutzler A , Schick C , Schüttler J . Postoperative plasma concentrations of procalcitonin after different types of surgery. Intensive Care Med. 1998;24 :680‐4.9722037\n29 Rule JA , Hynan LS , Attar N , Sanders C , Korzun WJ , Lee WM , et al. Procalcitonin identifies cell injury, not bacterial infection, in acute liver failure. PLoS One. 2015;10 :e0138566.26393924\n30 Jackson N , Batouche S , Sherwood R , Wendon J . Serial plasma procalcitonin levels in patients requiring admission to liver ITU with paracetamol induced acute liver failure. Br J Anaesth. 2000;84 :692.\n31 Ahn JH , Cho YS , Cho GC . Elevated procalcitonin levels in patients with acetaminophen intoxication: two case reports: a CARE‐compliant article. Medicine (Baltimore). 2020;99 :e18882.32049787\n32 Mallet M , Haq M , Tripon S , Bernard M , Benosman H , Thabut D , et al. Elevated procalcitonin is associated with bacterial infection during acute liver failure only when unrelated to acetaminophen intoxication. Eur J Gastroenterol Hepatol. 2017;29 :811‐6.28272093\n33 Tschiedel E , Assert R , Felderhoff‐Muser U , Kathemann S , Witzke O , Hoyer P , et al. Undue elevation of procalcitonin in pediatric paracetamol intoxication is not explained by liver cell injury alone. Ann Hepatol. 2018;17 :631‐7.29893707\n34 Schmidt LE , Dalhoff K , Poulsen HE . Acute versus chronic alcohol consumption in acetaminophen‐induced hepatotoxicity. Hepatology. 2002;35 :876‐82.11915034\n35 Remien CH , Adler FR , Waddoups L , Box TD , Sussman NL . Mathematical modeling of liver injury and dysfunction after acetaminophen overdose: early discrimination between survival and death. Hepatology. 2012;56 :727‐34.22331703\n36 Bernal W , Donaldson N , Wyncoll D , Wendon J . Blood lactate as an early predictor of outcome in paracetamol‐induced acute liver failure: a cohort study. Lancet. 2002;359 :558‐63.11867109\n37 Hadem J , Stiefel P , Bahr MJ , Tillmann HL , Rifai K , Klempnauer J , et al. Prognostic implications of lactate, bilirubin, and etiology in German patients with acute liver failure. Clin Gastroenterol Hepatol. 2008;6 :339‐45.18328438\n38 Gray TA , Buckley BM , Vale JA . Hyperlactataemia and metabolic acidosis following paracetamol overdose. Q J Med. 1987;65 :811‐21.3449887\n39 Esterline RL , Ji S . Metabolic alterations resulting from the inhibition of mitochondrial respiration by acetaminophen in vivo. Biochem Pharmacol. 1989;38 :2390‐2.2751701\n40 Flanagan RJ , Mant TG . Coma and metabolic acidosis early in severe acute paracetamol poisoning. Hum Toxicol. 1986;5 :179‐82.3710495\n41 Zezulka A , Wright N . Severe metabolic acidosis early in paracetamol poisoning. Br Med J (Clin Res Ed). 1982;285 :851‐2.\n42 Nourjah P , Ahmad SR , Karwoski C , Willy M . Estimates of acetaminophen (Paracetomal)‐associated overdoses in the United States. Pharmacoepidemiol Drug Saf. 2006;15 :398‐405.16294364\n43 Dear JW , Clarke JI , Francis B , Allen L , Wraight J , Shen J , et al. Risk stratification after paracetamol overdose using mechanistic biomarkers: results from two prospective cohort studies. Lancet Gastroenterol Hepatol. 2018;3 :104‐13.29146439\n44 Rubin JB , Hameed B , Gottfried M , Lee WM , Sarkar M . Acetaminophen‐induced acute liver failure is more common and more severe in women. Clin Gastroenterol Hepatol. 2018;16 :936‐46.29199145\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-6406",
"issue": "9(5)",
"journal": "United European gastroenterology journal",
"keywords": "PCT; acetaminophen; acute liver injury; biomarker; drug-induced liver injury; hepatotoxicity; paracetamol; poisoning; predictive tool; procalcitonin",
"medline_ta": "United European Gastroenterol J",
"mesh_terms": null,
"nlm_unique_id": "101606807",
"other_id": null,
"pages": "571-580",
"pmc": null,
"pmid": "34181312",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "2751701;16294364;26393924;18601732;23375419;28272093;29199145;29146439;20097417;20969501;2982827;9722037;1134886;3449887;29893707;15795719;24369077;27472699;11915034;29235390;18064739;25559822;26933799;18584360;11500339;6346105;28201980;11508861;28447858;16310518;6811039;23390034;11867109;3710495;18328438;15841455;28417882;19007345;24450481;29781385;24666324;22331703;32049787",
"title": "Plasma procalcitonin may be an early predictor of liver injury in acetaminophen poisoning: A prospective cohort study.",
"title_normalized": "plasma procalcitonin may be an early predictor of liver injury in acetaminophen poisoning a prospective cohort study"
} | [
{
"companynumb": "FR-VISTAPHARM, INC.-VER202107-001661",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN\\HYDROCODONE"
},
"dr... |
{
"abstract": "Diazoxide is a peripheral vasodilator that has been used for intravenous treatment of hypertensive emergencies. However, it is currently used mainly for hyperinsulinemic hypoglycemia in lower dose orally, and its major side effects are edema and pulmonary hypertension. Herein, we report the first association between periventricular leukomalacia (PVL) and intractable hypotension due to diazoxide. A Japanese female premature infant showed hypoglycemia concomitant with hyperinsulinemia. She was diagnosed with congenital hyperinsulinism, and oral diazoxide was started. Six days after starting diazoxide, she suddenly showed peripheral coldness, oliguria, and severe hypotension. The hypotension was refractory to general vasopressor therapies and persisted even after the discontinuation of diazoxide. Cranial echography showed periventricular echodensities followed by cystic PVL. Low-dose vasopressin effectively treated the hypotension. This single case reminds us the serious adverse events of diazoxide that have been forgotten, especially in premature neonates.",
"affiliations": "Department of Pediatrics, Saiseikai Shimonoseki General Hospital, Shimonoseki, Yamaguchi, Japan.;Department of Pediatrics, Saiseikai Shimonoseki General Hospital, Shimonoseki, Yamaguchi, Japan.;Department of Pediatrics, Saiseikai Shimonoseki General Hospital, Shimonoseki, Yamaguchi, Japan.;Department of Pediatrics, Saiseikai Shimonoseki General Hospital, Shimonoseki, Yamaguchi, Japan.;Department of Pediatrics, Saiseikai Shimonoseki General Hospital, Shimonoseki, Yamaguchi, Japan.;Department of Pediatrics, Saiseikai Shimonoseki General Hospital, Shimonoseki, Yamaguchi, Japan.;Department of Pediatrics, Saiseikai Shimonoseki General Hospital, Shimonoseki, Yamaguchi, Japan.",
"authors": "Okada|Seigo|S|0000-0002-9150-1913;Fukunaga|Shinnosuke|S|;Ohta|Haruka|H|;Furuta|Takashi|T|;Hirano|Reiji|R|;Motonaga|Takahiro|T|;Ishikawa|Yuichi|Y|",
"chemical_list": "D014665:Vasodilator Agents; D003981:Diazoxide",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0039-3400975",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0174-304X",
"issue": "51(3)",
"journal": "Neuropediatrics",
"keywords": null,
"medline_ta": "Neuropediatrics",
"mesh_terms": "D044903:Congenital Hyperinsulinism; D003981:Diazoxide; D005260:Female; D006801:Humans; D007022:Hypotension; D007231:Infant, Newborn; D007234:Infant, Premature; D007969:Leukomalacia, Periventricular; D011247:Pregnancy; D059285:Pregnancy, Twin; D014665:Vasodilator Agents",
"nlm_unique_id": "8101187",
"other_id": null,
"pages": "211-214",
"pmc": null,
"pmid": "31777044",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cerebral Insufficiency Caused by Diazoxide in a Premature Neonate with Congenital Hyperinsulinism.",
"title_normalized": "cerebral insufficiency caused by diazoxide in a premature neonate with congenital hyperinsulinism"
} | [
{
"companynumb": "JP-TEVA-2020-JP-1796801",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Systemic rheumatologic and inflammatory disorders can affect almost any organ system, including the heart. The cardiac valves, conduction system, myocardium, endocardium, pericardium, and coronary arteries may be affected. Intracardiac masses may develop as part of the disease process or a consequence of their therapy, such as methotrexate-associated nodulosis. Optimal therapy in these cases is not known, since many patients are asymptomatic and the potential benefit of surgical excision must be weighed against its associated morbidity and mortality. Importantly, these inflammatory masses must be differentiated from thrombus, infection, and primary and metastatic tumors. We present three cases of inflammatory cardiac masses associated with rheumatoid arthritis and Wegener's granulomatosis, which were successfully treated conservatively, and propose a management algorithm. The benefits of such an approach must be individualized and weighed against the risks of systemic embolization, stroke and obstruction.",
"affiliations": "Section of Cardiology, Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, MA 02118, USA.;Section of Cardiology, Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, MA 02118, USA.",
"authors": "Karnik|Ankur A|AA|;Awtry|Eric H|EH|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.14740/cr801",
"fulltext": "\n==== Front\nCardiol ResCardiol ResElmer PressCardiology Research1923-28291923-2837Elmer Press 10.14740/cr801Case ReportManagement of Inflammatory Cardiac Masses Inflammatory Cardiac MassesKarnik Ankur A. abAwtry Eric H. aa Section of Cardiology, Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, MA 02118, USAb Corresponding Author: Ankur A. Karnik, Collamore 8, Division of Cardiovascular Medicine, Boston Medical Center, 88 East Newton Street, Boston, MA 02118, USA. Email: Ankur.karnik@bmc.org12 2018 7 12 2018 9 6 400 406 26 10 2018 12 11 2018 Copyright 2018, Karnik et al.2018This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Systemic rheumatologic and inflammatory disorders can affect almost any organ system, including the heart. The cardiac valves, conduction system, myocardium, endocardium, pericardium, and coronary arteries may be affected. Intracardiac masses may develop as part of the disease process or a consequence of their therapy, such as methotrexate-associated nodulosis. Optimal therapy in these cases is not known, since many patients are asymptomatic and the potential benefit of surgical excision must be weighed against its associated morbidity and mortality. Importantly, these inflammatory masses must be differentiated from thrombus, infection, and primary and metastatic tumors. We present three cases of inflammatory cardiac masses associated with rheumatoid arthritis and Wegener’s granulomatosis, which were successfully treated conservatively, and propose a management algorithm. The benefits of such an approach must be individualized and weighed against the risks of systemic embolization, stroke and obstruction.\n\nCardiac massInflammatoryRheumatoid arthritisWegener’s granulomatosis\n==== Body\nIntroduction\nPrimary cardiac tumors are extremely rare and are seen in 0.001% to 0.3% of individuals based on autopsy series; 75% are non-malignant [1]. Taken together, primary tumors and tumor-like conditions vary widely in appearance, location, size, number, and age at presentation [2]. Many of these tumors arise in the setting of genetic syndromes [2]. While recommendations for surgical excision depend on presumed etiology and presence of symptoms or obstructive physiology, some tumors such as hemangiomas [3] and inflammatory myofibroblastic tumors (IMT) [4-6] have been known to regress either spontaneously or after treatment with steroids. There are several prior reports of cardiac masses associated with systemic disorders such as Wegner’s granulomatosis [7, 8], sarcoidosis [9, 10], Behcet’s disease [11, 12] and rheumatoid arthritis [13-15]; however, owing to the rarity of these masses, there is currently no consensus regarding management. We present three cases of patients with cardiac masses occurring in association with systemic inflammatory disease whose lesions significantly diminished with conservative therapy, review the English language literature regarding such an approach, and suggest an algorithm for management of these types of masses. Given a sample size of three, this case series was exempt from review by the Boston University Institutional Review Board.\n\nCase Reports\nCase 1\nA 63-year-old woman with breast cancer status post lumpectomy and radiation, rheumatoid arthritis, and paroxysmal atrial fibrillation, presented with diplopia and was found to have multiple embolic strokes. She had multiple flares of her rheumatoid arthritis in the past, including an inflammatory pericardial effusion, but it was currently in remission on methotrexate and certolizumab. Brain magnetic resonance imaging (MRI) revealed thalamic and cerebellar infarcts. Transesophageal echocardiography (TEE) demonstrated sessile masses in the left atrium (LA) and right atrium (RA) that were contiguous with the interatrial septum, as well as a pedunculated mass in RA (Fig. 1a, b) (Supplementary Videos 1a, b) (www. cardiologyres.org). Cardiac MRI confirmed biatrial masses with a heterogenous enhancement pattern suggesting vascularization, most consistent with an inflammatory or neoplastic process and not a thrombus. Surgical resection was not felt to be feasible because of the multiple locations of these lesions, which suggested a systemic process. She was started on warfarin (goal INR 2 - 3) with a heparin bridge given a history of paroxysmal atrial fibrillation with multiple embolic strokes, treated with prednisone for rheumatoid arthritis-related tenosynovitis, and her methotrexate was stopped. Repeat TEE 2 months later revealed near-complete resolution of the atrial masses (Fig. 1c). Cardiac MRI 2 years later showed a mobile avascular echodensity in the RA most consistent with thrombus (different from prior study). She was lost to follow-up so it is unknown if she was still on warfarin at that time.\n\nFigure 1 (a, b) TEE of sessile masses in the LA and RA (arrow heads) as well as a pedunculated mass in the RA (arrow with tail) in a patient with rheumatoid arthritis. (c) TEE 2 months after initiation of warfarin, prednisone, and cessation of methotrexate shows near-complete resolution of the atrial masses.\n\nCase 2\nA 75-year-old woman with rheumatoid arthritis and paroxysmal atrial fibrillation presented with dysarthria and inattention and was found to have multiple embolic lesions or infarcts on head computerized tomography (CT). Brain MRI revealed infarcts of the subcortical white matter, pons, and cerebellum. TEE demonstrated a 6 mm mobile, irregularly-shaped echodensity associated with the atrial surface of the mitral valve extending from the base of the interatrial septum to the intervalvular fibrosa (Fig. 2a). She was diagnosed with paroxysmal atrial fibrillation in the hospital, and warfarin (goal INR 2 - 3) was initiated; however repeat TEE 1 month later revealed a new 1.7 × 1.1 cm pedunculated echodense mass within the RA arising from the posterior RA free wall and extending through the interatrial septum (Fig. 2b) (Supplementary Video 2a) (www. cardiologyres.org).\n\nFigure 2 TEE of echodensities associated with the atrial surface of the mitral valve (a) and the posterior RA free wall (b). TEE 1 month following surgical resection shows new pedunculated masses in the RA and on the mitral and tricuspid valves (c, d).\n\nShe underwent surgery under cardiopulmonary bypass. A right atrial incision perpendicular to the AV groove was made, exposing a 2 × 1.5 cm pedunculated mass between the coronary sinus and septal leaflet of the tricuspid valve. It was excised with a small remnant of the posterior wall. A posterior left atrial incision was made and exposed a 0.5 × 0.5 cm polypoid mass on the anterior leaflet of the mitral valve near the annulus, which was then excised. The interatrial septum was not involved. There were no postoperative events. Her etanercept was discontinued following surgery and her prednisone was reduced to 5 mg. Surgical pathology of her masses showed focal areas of fibrinoid necrosis surrounded by palisading histiocytes, chronic inflammatory cells, and giant cells which was diagnostic for rheumatoid nodules (Fig. 3). One month later she presented with a recurrent cerebrovascular accident despite a therapeutic INR; repeat TEE revealed new pedunculated masses in the RA and on the mitral and tricuspid valves, which did not have the appearance of thrombus (Fig. 2c, d) (Supplementary Videos 2b, c) (www. cardiologyres.org). Her etanercept was restarted and repeat TEE 3 months later showed persistent 6 × 8 mm mobile echodensities on the mitral valve; however, the previously seen masses in the RA and on the tricuspid valve had resolved. She was lost to follow-up and expired 4 years later from urosepsis.\n\nFigure 3 Surgical pathology images of right atrial mass. Lesional area showing necrosis (black arrow) containing eosinophilic debris surrounded by histiocytes, lymphocytes, plasma cells, and giant cells (box). These changes are compatible with rheumatoid nodule.\n\nCase 3\nA 66-year-old woman presented with fevers and night sweats and was found to have new first degree atrioventricular block. Transthoracic echocardiogram (TTE) revealed an aortic root mass; TEE demonstrated a large complex mass invading the intraatrial septum, encasing the aortic root and extending into the right ventricular outflow tract (Fig. 4a). Blood cultures were negative. Inflammatory markers were consistent with Wegener’s granulomatosis (+MPO ANCA). She developed high degree atrioventricular heart block and a dual chamber pacemaker was implanted. Cyclophosphamide and prednisone were started and serial TTEs showed progressive regression of the aortic mass. On repeat TEE the following year, the aortic mass was much smaller (Fig. 4b) (Supplementary Video 3) (www.cardiologyres.org). She underwent an aortic valve replacement with a 19 mm Carpentier-Edwards bioprosthetic valve soon afterwards due to development of severe aortic regurgitation; intense inflammatory-type tissue was noted below the non-coronary leaflet extending into the annulus and into the anterior leaflet of the mitral valve, essentially encompassing the fibrous trigone. Biopsy showed myxoid changes and chronic inflammation (Fig. 5). She continues to do well 6 years post surgery and most recent echocardiogram showed well functioning bioprosthetic aortic valve without recurrent mass.\n\nFigure 4 (a) TEE of a large complex mass invading the intaatrial septum and encasing the aortic root. Cyclophosphamide and prednisone were started and serial TTEs showed progressive regression of the aortic mass. (b) Follow-up TEE the following year shows near resolution.\n\nFigure 5 Surgical pathology images of valvular tissue: valvular tissue with myxoid changes (red arrow), focal chronic inflammation (black arrow), and fibrosis (green star). These changes could represent changes compatible with previously active vasculitis.\n\nDiscussion\nThe therapeutic approach to the management of cardiac masses depends on the nature of the mass. Surgical treatment for primary cardiac malignancies (predominantly sarcomas) and metastatic disease to the heart is often limited by the poor prognosis associated with these conditions; however, surgical resection is the treatment of choice for all benign cardiac tumors and in those malignant tumors which are potentially curable or can result in significant palliation. These tumors must, however, be differentiated from vegetation, thrombus and inflammatory pseudotumor (IP).\n\nThe term IP has been applied to a variety of inflammatory masses, including IMT. IMT is a rare lesion that usually presents as an intrapulmonary mass in children but may occur in adults. It is thought to arise from a benign tissue proliferative response and is composed of mesenchymal and polyclonal inflammatory cells. It commonly occurs in the lung, stomach, and orbit, but is rare in the heart [6]. Cardiac IMT is pathologically distinguishable from cardiac fibromas, myxomas, and sarcomas [16]; and may be biologically distinct from extracardiac IMT as evidenced by its usual lack of locally aggressive behavior [17]. Although there is no consensus on optimal therapy, there are four reported cases of cardiac IMT regressing either spontaneously [5] or following steroid treatment [4, 6]. However, the recurrence rate has been reported at 13 to 37% [18]. Furthermore, recent data suggests that IMT may be pathologically distinct from other forms of IP, and those associated with a chromosomal translocation in the ALK-1 tyrosine kinase have malignant potential [19].\n\nSystemic inflammatory diseases are a family of autoimmune conditions that share common pathogenetic mechanisms and can be subclassified into vasculitides, connective tissue diseases, and miscellaneous disorders [20]. These conditions may involve multiple organ systems including the heart, and all components of the heart may be affected, including the valves, coronary arteries, conduction system, myocardium, endocardium or pericardium [21]. Furthermore, there have been several prior reports of IP developing in patients with disorders such as Wegener’s granulomatosis [7, 8], sarcoidosis [9, 10], Behcet’s disease [11, 12], and rheumatoid arthritis [13-15]. These IPs may arise in the presence of a known systemic inflammatory disease or may be an isolated finding, and are likely pathologically distinct from IMT. Indeed, pathological examination of cardiac IP in patients with a known systemic inflammatory disease has been found to be histologically consistent with their systemic process [7-15].\n\nThe optimal treatment of masses associated with systemic inflammatory disease is not well established; however, recurrence after surgical resection and regression after steroid therapy has been reported. For instance, subcutaneous rheumatoid nodules may recur after initial excision but often regress after conventional systemic treatment for rheumatoid arthritis or direct injection of corticosteroids [22]. Joffe et al [10] describe a patient who presented with palpitations and lightheadedness and was found to have right atrial and biventricular masses with biopsy consistent with sarcoidosis. High dose prednisone therapy resulted in significant reduction in size of the atrial mass and resolution of the ventricular mass. A similar therapeutic response was seen in the cases presented above. In case 1 there was near complete resolution of the IP after initiation of prednisone for rheumatoid arthritis, and in case 3 there was marked reduction in the size of the intracardiac masses with institution of prednisone and cyclophosphamide for Wegener’s granulomatosis. Furthermore, in case 2, the rheumatoid nodules recurred after initial surgical resection, but regressed significantly after re-initiation of etanercept. It is, therefore, reasonable to postulate that in patients with IP associated with systemic inflammatory disease, treatment of the systemic condition may ameliorate cardiac manifestations as well, and a conservative non-surgical approach to the initial management of these lesions could be considered.\n\nCareful evaluation of a patient’s medications may identify another potential etiology of cardiac masses, as illustrated in case 1. Accelerated nodulosis, indistinguishable from rheumatoid nodules, typically occurs on hands or feet but may affect the heart or lung [23]. A number of drugs used to treat inflammatory diseases have been implicated including methotrexate, anti-tumor necrosis factor alpha drugs, and leflunomide [22]. While no clear consensus exists, management usually involves stopping the offending medication and/or adding an alternative anti-rheumatologic agent [24].\n\nBefore embarking on conservative management of a cardiac mass, the differential diagnosis needs to be carefully considered, including thrombus, infection, primary cardiac tumors, and metastatic lesions. Cardiac imaging can be useful to differentiate among these. Echocardiography is often the initial modality with which the mass is discovered. Echo contrast enhancement is a surrogate for vascularity; whereas thrombi have none, myxomas have partial, and malignant or highly vascular tumors have significant enhancement. Attachment of the mass at an area of wall motion abnormality make tumor more likely. Three-dimensional echo allows for volumetric assessment and analysis of various aspects of the mass [25]. On cardiac MRI, thrombi tend to be smaller, more heterogeneous and have a pattern of hyperintensity/isointensity compared to tumors. Malignant tumors tend to be larger and more often exhibit late gadolinium enhancement and contrast first-pass perfusion compared to benign tumors [26]. The role of catheter-based endomyocardial biopsy (EMB) for cardiac tumors is uncertain. Per the 2007 American College of Cardiology, American Heart Association, and European Society of Cardiology guidelines on EMB in management of cardiovascular disease, EMB is a class IIa indication if: 1) The diagnosis cannot be made with non-invasive modalities or non-cardiac biopsy; 2) Tissue diagnosis can be expected to alter the direction of therapy; 3) Chances of successful biopsy are reasonably high; 4) The procedure is performed by an experienced operator. Guidance with TEE or cardiac MRI is advised [27].\n\nThrombus should be suspected in patients with multiple or prolonged indwelling central lines, recent structural cardiac surgery, hypercoagulable states, and atrial fibrillation/flutter, especially those with subtherapeutic levels of anticoagulation [28]. Even large atrial thrombi may resolve following 6 - 8 weeks of anticoagulation with warfarin or low molecular weight heparin [29-32]. Therefore, in most cases it is reasonable to initiate a trial of oral anticoagulation as this can be curative. Furthermore, systemic anticoagulation should always be considered for mobile lesions to diminish risk of stroke, as inflammatory masses may have superimposed thrombus [33]. A case series of 22 patients with Behcet disease demonstrated that intracardiac thrombus can resolve with systemic immunosuppressive alone, presumably by reversing the hypercoagulable state responsible for the thrombus [34]. However, the sample size is too small to recommend universally withholding anticoagulation. Duration of anticoagulation is unclear as the inflammatory disease process may recur, putting the patient at risk for repeat thrombus. However, those with prior stroke or high CHA2DS2-VASc score would be candidates for long-term anticoagulation. Infection should be identified and treated. There are two reports of large right atrial masses consistent with tuberculomas on biopsy that completely resolved following 6 - 12 months of anti-tuberculous therapy [35, 36]. In addition, IP has also been reported in association with other infections including Listeria monocytogenes [37, 38] and Mycobacterium avium-intracellulare [39]. Primary cardiac tumors are often suspected by their appearance on imaging studies and the primary source of metastatic disease to the heart is usually obvious on review of history, examination, and laboratory testing.\n\nThe potential pitfalls of a conservative approach to therapy include pulmonary or systemic embolization, stroke, and mechanical obstruction. The alternative to medical management is surgical excision via a traditional sternotomy with its attendant risks. Nonetheless, as illustrated by case 2, these masses may recur after initial surgical resection. A multi-modality and multi-disciplinary management strategy with input from cardiologists, cardiac surgeons, and imaging specialists is prudent. Based on our experience, we propose a treatment algorithm for suspected inflammatory cardiac masses (Fig. 6). First, infection should be ruled out. Thrombus and malignant and benign tumors can be differentiated with cardiac MRI and contrast echocardiography. Surgical excision is the treatment of choice for benign and some malignant tumors based on prognosis and symptoms. If thrombus is suspected, a trial of 2 months of therapeutic anticoagulation followed by repeat imaging is reasonable. If there is no response or the patient suffers stroke or obstructive symptoms, surgical excision is indicated. If neither tumor nor thrombus is present, evaluation for accelerated nodulosis should be performed and offending drugs removed. IMT would be the last remaining diagnosis for which immunosuppressive therapy may be trialed. If there is no response or the patient suffers stroke or obstructive symptoms, surgical excision is indicated.\n\nFigure 6 Proposed management strategy for suspected inflammatory cardiac masses.\n\nConclusions\nIn summary, systemic inflammatory diseases are associated with a variety of cardiac manifestations including intracardiac masses. We present three such cases that were successfully treated with a conservative strategy and present an algorithmic approach for patients with suspected inflammatory cardiac masses. After excluding infection and primary or metastatic tumors, an initial trial of anticoagulation is reasonable for patients in whom thrombus is suspects, as even a large thrombus may readily respond. If there is no response to anticoagulation or thrombus is not suspected, therapy targeted at the underlying inflammatory disease is indicated and serial imaging studies should be obtained to assess the response. While the risk of systemic embolization, stroke, and cardiac obstructive syndromes exists with this approach, extirpation of intracardiac masses is by no means curative and recurrent lesions may form as seen in case 2. Ultimately, the approach to complex intracardiac masses must be individualized; the risks of surgery and the potential for tumor recurrence must be weighed against the risks of a conservative approach on a case-by-case basis.\n\nWe wish to thank Dr. Josenia Tan for providing pathology images and for Dr. Harold Lazar for reviewing the manuscript.\n\nDeclaration\nNone.\n\nAbbreviations\nIMTinflammatory myofibroblastic tumor\n\nMRImagnetic resonance imaging\n\nTEEtransesophageal echocardiogram\n\nLAleft atrium\n\nRAright atrium\n\nCTcomputerized tomography\n\nIPinflammatory pseudotumor\n\nEMBendomyocardial biopsy\n==== Refs\nReferences\n1 Reynen K Frequency of primary tumors of the heart Am J Cardiol 1996 77 1 107 10.1016/S0002-9149(97)89149-7 8540447 \n2 Jain D Maleszewski JJ Halushka MK Benign cardiac tumors and tumorlike conditions Ann Diagn Pathol 2010 14 3 215 230 10.1016/j.anndiagpath.2009.12.010 20471569 \n3 Palmer TE Tresch DD Bonchek LI Spontaneous resolution of a large, cavernous hemangioma of the heart Am J Cardiol 1986 58 1 184 185 10.1016/0002-9149(86)90273-0 3728325 \n4 Ferbend P Abramson LP Backer CL Mavroudis C Webb CL Doll JA Junewick JJ et al Cardiac plasma cell granulomas: response to oral steroid treatment Pediatr Cardiol 2004 25 4 406 410 10.1007/s00246-003-0269-x 15054564 \n5 Pearson PJ Smithson WA Driscoll DJ Banks PM Ehman RL Inoperable plasma cell granuloma of the heart: spontaneous decrease in size during an 11-month period Mayo Clin Proc 1988 63 10 1022 1025 10.1016/S0025-6196(12)64918-0 3172851 \n6 Tomiyama M Nakatani S Ishibashi-Ueda H Yutani C Yamagishi M Inflammatory pseudotumor of the heart Ann Intern Med 2007 147 5 351 352 10.7326/0003-4819-147-5-200709040-00023 17785499 \n7 Singh R Rosen S Tumor of the heart in a young woman; a rare manifestation of Wegener granulomatosis Hum Pathol 2012 43 2 289 292 10.1016/j.humpath.2011.04.020 21803397 \n8 Herbst A Padilla MT Prasad AR Morales MC Copeland JG Cardiac Wegener's granulomatosis masquerading as left atrial myxoma Ann Thorac Surg 2003 75 4 1321 1323 10.1016/S0003-4975(02)04662-3 12683590 \n9 Abrishami B O'Connel C Sharma O Cardiac sarcoidosis with presentation of large left atrial mass Curr Opin Pulm Med 2004 10 5 397 400 10.1097/01.mcp.0000136403.32451.aa 15316439 \n10 Joffe, II, Lampert C Jacobs LE Owen AN Ioli A Kotler MN Cardiac sarcoidosis masquerading as a metastatic tumor: the role of transthoracic and transesophageal echocardiography J Am Soc Echocardiogr 1995 8 6 933 937 10.1016/S0894-7317(05)80020-3 8611296 \n11 Yao FJ Liu D Zhang Y Yin S Inflammatory pseudotumor of the right ventricle in a 35-year-old woman with Behcet's disease: a case report Echocardiography 2012 29 6 E134 136 10.1111/j.1540-8175.2011.01644.x 22329544 \n12 Leitao B Machado F Soares F Souza H Queiroz AC Santiago MB Myocardial inflammatory pseudotumor and multiple thromboses as a manifestation of Behcet disease J Clin Rheumatol 2009 15 5 252 253 10.1097/RHU.0b013e3181b082a0 19654491 \n13 Abbas A Byrd BF 3rd Right-sided heart failure due to right ventricular cavity obliteration by rheumatoid nodules Am J Cardiol 2000 86 6 711 712 10.1016/S0002-9149(00)01063-8 10980235 \n14 Suriani RJ Lansman S Konstadt S Intracardiac rheumatoid nodule presenting as a left atrial mass Am Heart J 1994 127 2 463 465 10.1016/0002-8703(94)90147-3 8296724 \n15 Webber MD Selsky EJ Roper PA Identification of a mobile intracardiac rheumatoid nodule mimicking an atrial myxoma J Am Soc Echocardiogr 1995 8 6 961 964 10.1016/S0894-7317(05)80027-6 8611303 \n16 Obikane H Ariizumi K Yutani C Mitsumata M Inflammatory pseudotumor (inflammatory myofibroblastic tumor) of the mitral valve of the heart Pathol Int 2010 60 7 533 537 10.1111/j.1440-1827.2010.02556.x 20594277 \n17 Burke A Li L Kling E Kutys R Virmani R Miettinen M Cardiac inflammatory myofibroblastic tumor: a \"benign\" neoplasm that may result in syncope, myocardial infarction, and sudden death Am J Surg Pathol 2007 31 7 1115 1122 10.1097/PAS.0b013e31802d68ff 17592279 \n18 Sunbul M Cagac O Birkan Y A rare case of inflammatory pseudotumor with both involvement of lung and heart Thorac Cardiovasc Surg 2013 61 7 646 648 23250846 \n19 Gleason BC Hornick JL Inflammatory myofibroblastic tumours: where are we now? J Clin Pathol 2008 61 4 428 437 10.1136/jcp.2007.049387 17938159 \n20 Sherman BM Haspel KL Inflammatory diseases and the heart Int Anesthesiol Clin 2012 50 2 173 204 10.1097/AIA.0b013e3182516ee8 22481562 \n21 Sitia S Atzeni F Sarzi-Puttini P Di Bello V Tomasoni L Delfino L Antonini-Canterin F et al Cardiovascular involvement in systemic autoimmune diseases Autoimmun Rev 2009 8 4 281 286 10.1016/j.autrev.2008.08.004 18817899 \n22 Garcia-Patos V Rheumatoid nodule Semin Cutan Med Surg 2007 26 2 100 107 10.1016/j.sder.2007.02.007 17544962 \n23 Rau R Herborn G Benefit and risk of methotrexate treatment in rheumatoid arthritis Clin Exp Rheumatol 2004 22 5 Suppl 35 S83 94 15552520 \n24 Patatanian E Thompson DF A review of methotrexate-induced accelerated nodulosis Pharmacotherapy 2002 22 9 1157 1162 10.1592/phco.22.13.1157.33525 12222551 \n25 Mankad R Herrmann J Cardiac tumors: echo assessment Echo Res Pract 2016 3 4 R65 R77 10.1530/ERP-16-0035 27600455 \n26 Pazos-Lopez P Pozo E Siqueira ME Garcia-Lunar I Cham M Jacobi A Macaluso F et al Value of CMR for the differential diagnosis of cardiac masses JACC Cardiovasc Imaging 2014 7 9 896 905 10.1016/j.jcmg.2014.05.009 25129516 \n27 Cooper LT Baughman KL Feldman AM Frustaci A Jessup M Kuhl U Levine GN et al The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Circulation 2007 116 19 2216 2233 10.1161/CIRCULATIONAHA.107.186093 17959655 \n28 Al-Ebrahim KE Right atrial mass: the dilemma of diagnosis and when not to operate Ann Thorac Surg 2009 87 6 2005 author reply 2005 \n29 Floris N Gabriel L Marchandise B Successful anticoagulation for treatment of a giant left atrial thrombus Acta Cardiol 2010 65 6 713 715 10.1080/AC.65.6.2059874 21302683 \n30 Senturk T Kaderli AA Yesilbursa D Resolution of a giant atrial thrombus following anticoagulation therapy Cardiovasc J Afr 2008 19 1 28 30 18320084 \n31 Marcu CB Kramer C Donohue TJ Giant left atrial thrombus successfully treated with anticoagulation Heart Lung Circ 2007 16 1 55 56 10.1016/j.hlc.2006.05.006 17045526 \n32 Chrzanowski L Lipiec P Kasprzak JD Rapid resolution of large right atrial mass after anticoagulant therapy Eur Heart J 2006 27 17 2087 10.1093/eurheartj/ehi767 16923743 \n33 Kang H Baron M Embolic complications of a mitral valve rheumatoid nodule J Rheumatol 2004 31 5 1001 1003 15124265 \n34 Emmungil H Yasar Bilge NS Kucuksahin O Kilic L Okutucu S Gucenmez S Kalyoncu U et al A rare but serious manifestation of Behcet's disease: intracardiac thrombus in 22 patients Clin Exp Rheumatol 2014 32 4 Suppl 84 S87 92 25068833 \n35 Rao VR Jagannath K Sunil PK Madhusudana N A rare disappearing right atrial mass Interact Cardiovasc Thorac Surg 2012 15 2 290 291 10.1093/icvts/ivs129 22535544 \n36 Goyal NK Saxena A Chopra P Complete resolution of a large intracardiac mass with medical treatment: an echocardiographic follow up Heart 2005 91 8 1046 10.1136/hrt.2004.055160 16020593 \n37 Adler A Fimbres A Marcinak J Johnson A Zheng X Hasegawa S Shulman ST Inflammatory pseudotumor of the heart caused by Listeria monocytogenes infection J Infect 2009 58 2 161 163 10.1016/j.jinf.2008.12.007 19203798 \n38 Uehara Yonekawa A Iwasaka S Nakamura H Fukata M Kadowaki M Uchida Y Odashiro K et al Infective endocarditis caused by Listeria monocytogenes forming a pseudotumor Intern Med 2014 53 9 1029 1032 10.2169/internalmedicine.53.1925 24785898 \n39 Wood C Nickoloff BJ Todes-Taylor NR Pseudotumor resulting from atypical mycobacterial infection: a \"histoid\" variety of Mycobacterium avium-intracellulare complex infection Am J Clin Pathol 1985 83 4 524 527 10.1093/ajcp/83.4.524 2984921\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1923-2829",
"issue": "9(6)",
"journal": "Cardiology research",
"keywords": "Cardiac mass; Inflammatory; Rheumatoid arthritis; Wegener’s granulomatosis",
"medline_ta": "Cardiol Res",
"mesh_terms": null,
"nlm_unique_id": "101557543",
"other_id": null,
"pages": "400-406",
"pmc": null,
"pmid": "30627294",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports",
"references": "10980235;12222551;12683590;15054564;15124265;15316439;15552520;16020593;16923743;17045526;17544962;17592279;17785499;17938159;17959655;18320084;18817899;19203798;19463656;19654491;20471569;20594277;21302683;21803397;22329544;22481562;22535544;23250846;24785898;25068833;25129516;27600455;2984921;3172851;3728325;8296724;8540447;8611296;8611303",
"title": "Management of Inflammatory Cardiac Masses.",
"title_normalized": "management of inflammatory cardiac masses"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-21-03122",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"... |
{
"abstract": "Pulmonary embolism (PE) is a common clinical problem affecting 600,000 patients per year in the United States. Although the diagnosis can be easily confirmed by imaging techniques, such as computed tomographic angiography of the chest, the identification of underlying mechanism leading to PE is important for appropriate duration of anticoagulation, and prevention of subsequent episodes. The differential diagnosis of underlying mechanism is broad and must include careful review of medication history. Drug-related thromboembolic disease can be easily missed and may have catastrophic consequences. The identification of the culprit drug is important for prevention of subsequent episodes and choosing appropriate duration of anticoagulation. We report a case of a middle-aged man who developed PE after administration of intravenous immunoglobulin.",
"affiliations": "Department of Internal Medicine, University of Arizona, Tucson, AZ.",
"authors": "Bilal|Jawad|J|;Riaz|Irbaz B|IB|;Hill|Jennifer L|JL|;Zangeneh|Tirdad T|TT|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000288",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "23(4)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D003937:Diagnosis, Differential; D006801:Humans; D017099:IgG Deficiency; D016756:Immunoglobulins, Intravenous; D008297:Male; D008875:Middle Aged; D011655:Pulmonary Embolism; D020246:Venous Thrombosis",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e1074-7",
"pmc": null,
"pmid": "26164024",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intravenous Immunoglobulin-Induced Pulmonary Embolism: It Is Time to Act!",
"title_normalized": "intravenous immunoglobulin induced pulmonary embolism it is time to act"
} | [
{
"companynumb": "US-OCTA-LIT14616US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drugadditional": null,
... |
{
"abstract": "Stereotactic radiosurgery (SRS) is a proven treatment modality for inoperable arteriovenous malformations (AVMs). However, the rate of radiation-induced necrosis (RIN) is as high as 10%. A 6-year-old female patient presented with severe headache, emesis, and syncope, and workup revealed a Spetzler-Martin grade 4 AVM with intraventricular hemorrhage and hydrocephalus. The patient underwent a right frontal ventriculostomy followed by a linear accelerator-based SRS of 16.9 Gy. At 19 years, she developed progressive neurological symptoms. Diagnostic magnetic resonance imaging (MRI) revealed a recurrent parietal AVM nidus. We delivered the linear accelerator-based SRS of 18.5 Gy to the AVM nidus. Within 9 months, she experienced episodic headaches and left-sided weakness and spasticity; symptoms were initially managed with dexamethasone. Follow-up MRI was notable for edema and nondetectable blood flow, consistent with RIN and AVM obliteration. The second course of steroids did not provide the symptom control. Persistent RIN was noted on MRI, and she had stigmata of steroid toxicity (centripetal obesity, depression, and sleep disorder). Two infusions of bevacizumab (5 mg/kg) were administered concurrently with a tapering dose of dexamethasone. The patient noted a near immediate improvement in her headaches, and 2 months following the second bevacizumab infusion, she reported a near-complete resolution of her symptoms and displayed improved ambulation. The development of RIN remains a noteworthy concern post-SRS of AVMs. While steroids aid with initial management of RIN, for persistent and recurrent symptoms, bevacizumab infusions serve as a viable treatment course, with the added benefit of reducing the likelihood of adverse effects resulting from prolonged steroid therapy.",
"affiliations": "School of Medicine, Oregon Health & Science University, Portland, Oregon, USA.;Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA.;Department of Diagnostic Radiology, Oregon Health & Science University, Portland, Oregon, USA.;Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA.;Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA.;Department of Radiation Oncology, Indiana University, Indianapolis, Indiana, USA.;Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA.",
"authors": "Kwong|Forrest|F|;Scarpelli|Daphne B|DB|;Barajas|Ramon F|RF|;Monaco|Debra|D|;Tanyi|James A|JA|;McClelland|Shearwood|S|;Jaboin|Jerry J|JJ|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000513560",
"fulltext": "\n==== Front\nCase Rep Neurol\nCase Rep Neurol\nCRN\nCase Reports in Neurology\n1662-680X\nS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com\n\n10.1159/000513560\ncrn-0013-0297\nSingle Case − General Neurology\nResolution of Radiation-Induced Necrosis in Arteriovenous Malformation with Bevacizumab: A Case Report and Review of Current Literature\nKwong Forrest a\nScarpelli Daphne B. b\nBarajas Ramon F. cde\nMonaco Debra b\nTanyi James A. b\nMcClelland Shearwood f\nJaboin Jerry J. b*\naSchool of Medicine, Oregon Health & Science University, Portland, Oregon, USA\nbDepartment of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA\ncDepartment of Diagnostic Radiology, Oregon Health & Science University, Portland, Oregon, USA\ndAdvanced Imaging Research Center, Oregon Health & Science University, Portland, Oregon, USA\neKnight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA\nfDepartment of Radiation Oncology, Indiana University, Indianapolis, Indiana, USA\n*Jerry J. Jaboin, jaboin@ohsu.edu\nMay-Aug 2021\n27 5 2021\n27 5 2021\n13 2 297304\n22 10 2020\n29 11 2020\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.\nStereotactic radiosurgery (SRS) is a proven treatment modality for inoperable arteriovenous malformations (AVMs). However, the rate of radiation-induced necrosis (RIN) is as high as 10%. A 6-year-old female patient presented with severe headache, emesis, and syncope, and workup revealed a Spetzler-Martin grade 4 AVM with intraventricular hemorrhage and hydrocephalus. The patient underwent a right frontal ventriculostomy followed by a linear accelerator-based SRS of 16.9 Gy. At 19 years, she developed progressive neurological symptoms. Diagnostic magnetic resonance imaging (MRI) revealed a recurrent parietal AVM nidus. We delivered the linear accelerator-based SRS of 18.5 Gy to the AVM nidus. Within 9 months, she experienced episodic headaches and left-sided weakness and spasticity; symptoms were initially managed with dexamethasone. Follow-up MRI was notable for edema and nondetectable blood flow, consistent with RIN and AVM obliteration. The second course of steroids did not provide the symptom control. Persistent RIN was noted on MRI, and she had stigmata of steroid toxicity (centripetal obesity, depression, and sleep disorder). Two infusions of bevacizumab (5 mg/kg) were administered concurrently with a tapering dose of dexamethasone. The patient noted a near immediate improvement in her headaches, and 2 months following the second bevacizumab infusion, she reported a near-complete resolution of her symptoms and displayed improved ambulation. The development of RIN remains a noteworthy concern post-SRS of AVMs. While steroids aid with initial management of RIN, for persistent and recurrent symptoms, bevacizumab infusions serve as a viable treatment course, with the added benefit of reducing the likelihood of adverse effects resulting from prolonged steroid therapy.\n\nKeywords\n\nArteriovenous malformation\nStereotactic radiosurgery\nBevacizumab\nRadiation-induced necrosis\n==== Body\nIntroduction\n\nStereotactic radiosurgery (SRS) is a proven treatment modality for inoperable high-risk arteriovenous malformations (AVM) [1]. However, SRS administration has been associated with late toxicities, such as radiation-induced necrosis (RIN), which can present symptomatically in 2–14% of patients and neuroradiologically in ≤46% [2]. Steroid therapy is the primary mean for managing RIN, while the efficacy of bevacizumab, an angiogenesis inhibitor, is currently under investigation. This case report highlights the occurrence of RIN post-SRS administration in AVM and the resolution of symptoms using bevacizumab.\n\nCase Report\n\nA 6-year-old patient presented with a history of headaches and acute presentations of severe headache, emesis, and syncope. Computed tomography (CT) showed intraventricular hemorrhage with hydrocephalus. Magnetic resonance imaging (MRI) revealed a large right parietal AVM. Cerebral angiogram confirmed a parietal parasagittal angiomatous-type AVM, which due to its nidus size (>5 cm), eloquent cortex involvement (sensorimotor), and deep venous drainage (draining into the superior sagittal sinus) met the criteria for a Spetzler-Martin grade 4 AVM [3].\n\nBased on the Spetzler-Martin grade, this AVM was deemed a suboptimal embolization and surgery candidate; a right frontal ventriculostomy was placed, resulting in a resolution of hydrocephalus. The ventriculostomy was removed, and the patient was discharged without residual deficits. Due to a lack of medical insurance, she received a linear accelerator-based SRS of 16.9 Gy approximately a year later. Three months post-SRS, she developed left-sided weakness and episodic partial motor seizures, initiating dexamethasone 1 mg/day and Keppra management. MRI revealed edema in the right cerebral hemisphere, leading to prolonged dexamethasone management and slow stabilization of her left-sided motor function with physical therapy. Five years post-SRS, she experienced 2 months of worsening occipital area headaches, 2–3 times a day and increased left-sided weakness with left upper extremity contracture. MRI indicated enhancing vessels into the previous SRS site with stable encephalomalacia and gliosis of the right posterior medial frontal and anterior medial parietal lobes. She underwent renewed physical and occupational therapy. At 19 years, her neuroangiogram indicated a 1.6-cm parietal AVM with 2 residual pericallosal and interhemispheric draining veins consistent with a Spetzler-Martin grade 3 lesion, which was treated with the linear accelerator-based SRS. The nidus was delineated with 18.5 Gy prescribed to at least 95% of the target volume in 1 fraction (shown in Fig. 1a). All dose constraints were met as illustrated in Figure 1b [1].\n\nOver the 9 months following her second SRS, she developed episodic headaches, and left-sided spasticity and weakness; symptoms were managed on intermittent treatment with dexamethasone. While initially, symptoms were controlled on dexamethasone, after tapering off of dexamethasone, her spasticity, headaches, and other general symptoms would return each time with varying latency. She suffered depression and anxiety attacks related to her symptoms, impairing her quality of life and contributing to delays in her education.\n\nNine months post-SRS, MRI demonstrated edema consistent with RIN and AVM obliteration (as shown in Fig. 2). Steroids were recommended, but considering that her swelling likely peaked, the clinical team focused on the symptom management as she had the stigmata of steroid toxicity (facial/neck plethora, increased centripetal weight, fatigue, and disrupted sleep). However, at 12 months post-SRS, she demonstrated no improvement and her MRI showed persistent RIN. Given her history of dexamethasone tapers, steroid toxicity, and the negative impact on her quality of life, the patient was evaluated for bevacizumab. Two bevacizumab infusions (5 mg/kg) were started 14 months post-SRS, 2 weeks apart. Bevacizumab was administered with 2 mg dexamethasone ongoing at every other day since her prior emergency room visit for RIN-related symptoms. Her symptoms improved within the first 24 hours. Five weeks from the last bevacizumab infusion, the extent of both the enhancement and associated surrounding T2 FLAIR hyperintensity mildly decreased without evidence of acute hemorrhage or intracranial mass. The patient noted subjective improvements in mood, sleep, light sensitivity, and ability to rise from a seated position without orthostatic hypotension. Her headaches and weakness nearly resolved 2 months after the final bevacizumab infusion, and the patient reported walking and running. One adverse symptom our patient continues to notice is episodes of hypertonicity, which is treated with dantrolene. This, however, is preferred to her years of flaccidity in this extremity, and she continues to be happy with her current outcomes. She has returned to school and has not had a bout of major depression since infusion.\n\nDiscussion\n\nHigh-radiation dose has been well documented to increase AVM obliteration rates but must be cautiously selected to minimize the risk of hemorrhage and adverse radiation effects, such as RIN [1, 4]. In a single-institution study of 1,400 AVM patients who proceeded with gamma knife surgery, Yen et al. [5] calculated an annual hemorrhage rate after an AVM diagnosis of 6.6%. This rate was observed to decline to 2.5% post-radiosurgery and 0% with confirmed angiographic obliteration. Potts et al. [6] reported that a pediatric cohort treated with ≥18 Gy had a significantly higher rate of 3-year angiographic obliteration (52%, p = 0.015) and lower occurrence of post-SRS hemorrhage (3%, p = 0.0003) than the patients treated with <18 Gy of 16%. Similarly, Miyawaki et al. [7] observed obliteration rates of 60% and 9%, respectively, in patients who received 18 Gy and ≤14 Gy. Increased risk of post-SRS hemorrhage was also associated with decreased minimum dose (p = 0.05) and treatment volume (p = 0.001). However, RIN requiring resection was noted to occur in 22% of the patients treated with ≥16 Gy for AVM of >14 cm3 [7]. Additional studies have identified treatment dose-volume to significantly increase the risk for post-SRS complications [1, 4]. Pollock et al. [4] highlighted the potential benefits of volume-staged SRS, especially in cases with large AVM (>14 cm3). Volume-staged SRS allows for high-radiation dose delivery to the entire AVM lesion over several sessions while minimizing radiation exposure to adjacent anatomical structures. In our institution, we separated the AVM volume to ≤10 cm3 per treatment session to increase the overall obliteration rates and reduce risks of posttreatment toxicity. This approach has been associated with 28–68% complete or near-complete obliteration rates in AVM treated with ≥17 Gy and decreased risk for permanent adverse radiation effects at 6.6% [4].\n\nRIN affects 10% of the patients who undergo SRS for AVM [1]. Symptomatic RIN depends on the anatomic location of AVM and may include headache, paralysis, and ataxia. While steroid treatment is the first-line therapy, steroid-refractory RIN remains a challenge to treat and requires further research. A randomized double-blind clinical trial by Levin et al. [8] aimed to test the efficacy of bevacizumab in patients with RIN who underwent SRS for the head and neck cancer, meningioma, or low-mid grade glioma. This study showed reduction of necrosis among all the patients within the treatment arm and no reduction in the control group. Furthermore, all the patients treated with bevacizumab experienced improved neurological symptoms contrary to the outcomes in the control group. While the previous clinical trial did not examine RIN post-SRS for AVM, the results suggest that bevacizumab could be a viable treatment for patients with steroid-resistant RIN. Drawbacks to this study include mixed results when comparing bevacizumab and the control groups with cognitive improvement tests. Furthermore, of the 11 patients treated with bevacizumab, 3 developed serious adverse effects (pneumonia, superior sagittal sinus thrombosis, and DVT with related PE). Patients treated with bevacizumab should be monitored for potential toxicities including but not limited to hypertension, proteinuria, gastrointestinal perforation, and hemorrhage. Hypertension and proteinuria can typically be managed with traditional approaches. Even minor gastrointestinal symptoms should be examined suspiciously for a perforation [9]. Bevacizumab is a risk factor for hemorrhage which is especially concerning in a patient with a history of brain AVM, however, in oncological settings, studies have shown that the CNS-specific hemorrhages are not at increased risk [10, 11].\n\nPrevious examples of the anti-vascular endothelial growth factor medication, bevacizumab, have shown to variably reduce RIN (as shown in Table 1). Williams et al. [12] was the first case report of using bevacizumab for steroid-refractory RIN in a patient who underwent SRS for AVM. Williams et al. [12] reported improvement in symptoms − including reduction of headaches and increased strength − and a reduction in T2 FLAIR. Preuss et al. [13] supplied examples of using bevacizumab in pediatric patients with mixed results. Both the patients experienced marked reduction in T2 FLAIR but with only initial symptom improvement that proved marginal long-term. Dashti et al. [14] gave bevacizumab following hyperosmotic blood-brain-barrier disruption to minimize the dose of bevacizumab given. The results from Dashti et al. [14] showed reduction or resolution of severe headaches and over a 70% reduction in T2 FLAIR in both the patients. Turner et al. [2] reported full recovery from steroid-refractory RIN post-SRS for AVM, including complete resolution of severe headaches and hemiparesis with bevacizumab. Uysal et al. [15] reported a patient with steroid-resistant RIN post-SRS for AVM who experienced improvement in headache, hemiparesis, and ambulation along with significant resolution of perilesional edema on computed tomography [15].\n\nConclusion\n\nAVMs are extremely dangerous with previously ruptured malformations having as high as a 4–8% annual risk of hemorrhage. For inoperable lesions, SRS is a mainstay of treatment with variations in efficacy and technique based on the nidus size and Spetzler-Martin grade. Even SRS to a small AVM nidus can result in RIN. This risk is even higher in a previously irradiated region. Symptomatic management with steroids can be highly effective and is the mainstay of early management. For steroid treatment greater than 28 days in duration, the risks of adrenal insufficiency, myalgias, thermal dysregulation, and cerebrovascular accidents all increase significantly. Additionally, the poor control of radiation-induced necrosis can result in permanent neurologic dysfunction. After one month of steroid use, if not contraindicated, infusion of bevacizumab should be considered to manage RIN.\n\nStatement of Ethics\n\nThe authors state that they have followed the principles outlined in the Declaration of Helsinki for all human experimental investigation. Written informed consent was obtained from the patient for publication of this case report and any accompanying images involved.\n\nConflict of Interest Statement\n\nDr. McClelland III reports grants from the Indianapolis Public Transportation Corporation; outside the submitted work. Dr. Barajas reports grants from K08 CA237809-01A1, outside the submitted work. Other authors have nothing to disclose.\n\nFunding Sources\n\nNo funding was received.\n\nAuthor Contributions\n\nConception and design: Jerry. J. Jaboin. Data collection: Jerry J. Jaboin and Forrest Kwong. Data analysis and interpretation: Ramon F. Barajas Jr., Debra Monaco, James A. Tanyi, and Jerry J. Jaboin. Manuscript writing: Forrest Kwong, Daphne B. Scarpelli, and Jerry J. Jaboin. The final approval of the manuscript: Forrest Kwong, Daphne B. Scarpelli, Ramon F. Barajas Jr., Debra Monaco, James A. Tanyi, Shearwood McClelland III, and Jerry J. Jaboin.\n\nFig. 1 Linear accelerator-based SRS was performed using a high-resolution MLC system (HD-MLC; 2.5 mm at isocenter; Novalis Tx, Brainlab/Varian Medical Systems, Palo Alto, CA, USA). Volumetric On-Board Imager (OBI, Varian Medical System, Palo Alto, CA, USA) and ExacTrac X-ray 6 degree-of-freedom system (ExacTrac, BrainLab, Munich, Germany) were used for patient positioning, positional verification, and the intrafraction motion assessment. A custom-fit thermoplastic mask (Orfit, OrfitIndustries, Wijnegem, Belgium) was used for cranial immobilization. MRI data plus a reference planning CT were imported into Eclipse v.15.1 (Varian Medical Systems, Inc., Palo Alto, CA, USA) for target delineation and dose computation with Acuros, respectively. Four volumetric modulated arcs were used to deliver a prescription (Rx) dose 18.5 Gy to at least 95% of the irregularly shaped AVM nidus. a Axial/sagittal/coronal views, respectively, through the isocenter of the AVM nidus with corresponding IDL on the legend. b Key dosimetric data and planning constraints. AVM, arteriovenous malformations; SRS, stereotactic radiosurgery; MRI, magnetic resonance imaging; CT, computed tomography; IDL, isodose lines.\n\nFig. 2 AVM Radiation Necrosis. Pre-therapeutic MRA (top left column) demonstrates a vascular nidus (red arrow) with flow-related enhancement surrounded by T2 signal hyperintensity (bottom left column) consistent with vasogenic edema. Follow-up MRA 6 months after the radiation therapy demonstrates resolution of the vascular nidus (top middle left column) with contrast enhancement involving the radiation field (middle left column). Upon 12 months follow-up imaging, the contrast enhancing focus (middle right column, arrow head) was noted to enlarge and develop central necrosis concurrent with marked increased vasogenic edema on T2-weighted imaging (bottom middle right column, star) without evidence of recurrent vascular nidus that was felt to be consistent with therapy-induced radiation necrosis. Serial follow-up MRI following bevacizumab therapy demonstrates a diminished central necrosis and vasogenic edema. AVM, arteriovenous malformations; MRA, magnetic resonance angiography.\n\nTable 1 Current literature on RIN treated with bevacizumab\n\nStudy\tPatient characteristics\tDose X frequency\tAVM status\tSymptom improvement\tRadiological improvement\t\nWilliams et al. [12]\t20 yr female\t2.5 mg/kg initial dose., then 7.5 mg/kg two weeks later (single dose)\tObliterated\tHeadaches down to occasional (down from severe) and improved strength (4+/5 from\tImprovement of RIN (decrease in T2 FLAIR)\t\n\t\nPreuss et al. [13]\t9 yr male\t5 mg/kg 4 cycles every 2 weeks\tObliterated\tInitial clinical improvement but long-term overall minimal improvement. Identical manual ability classification system (MACS) pre-/posttreatment\tCerebral edema reduction (via T2 FLAIR)\t\n\t\nPreuss et al. [13]\t9 yr female\t5 mg/kg 4 cycles every 2 weeks (+7 additional cycles after steroid cessation)\tObliterated\tInitial clinical improvement but long-term overall minimal improvement. Identical MACS pre-/posttreatment\tCerebral edema reduction (via T2 FLAIR)\t\n\t\nDashti et al. [14]\t12 yr female\t2.5 mg/kg following hyperosmotic BBBD\tN/A\tHeadache down to 5/10 (from 10/10 severe), strength improved to walking with help of electronic boot (from 0/5 R hand/foot strength)\t78% decrease in T2 FLAIR\t\n\t\nDashti et al. [14]\t11 yr female\t2.5 mg/kg following hyperosmotic BBBD\tN/A\tComplete resolution of headaches (from intractable headaches + N/V)\t74% decrease in T2 FLAIR\t\n\t\nTurner et al. [2]\t43 yr male\t7.5 mg/kg × tri-weekly (×3 wk)\tObliterated\tCompletely resolution of symptoms\tFull recovery from RIN\t\n\t\nUysal et al. [15]\t41 yr male\tInitial 2.5 mg/kg, then (2 wk later) 7.5 mg/kg every 2 weeks for 4 cycles\tObliterated\tHemiparesis improved to $$ (from $$), headache improvement, and ambulatory improvement\tPerilesional edema significantly resolved (via cranial CT)\t\n\t\nKwong et al. [2020]\t22 yr female\t5 mg/kg, 2 cycles 2 weeks apart\tObliterated\tImprovement in headache, hypertonicity, and ambulatory ability\tMild decrease in T2 FLAIR\t\nAVM, arteriovenous malformations; RIN, radiation-induced necrosis; CT, computed tomography.\n==== Refs\nReferences\n\n1 Blonigen BJ Steinmetz RD Levin L Lamba MA Warnick RE Breneman JC Irradiated volume as a predictor of brain radionecrosis after linear accelerator stereotactic radiosurgery Int J Radiat Oncol Biol Phys. 2010 Jul 15 77 (4) 996 1001 19783374\n2 Turner RC Lucke-Wold BP Josiah D Gonzalez J Schmidt M Tarabishy AR Stereotactic radiosurgery planning based on time-resolved CTA for arteriovenous malformation: a case report and review of the literature Acta Neurochir. 2016 8 158 (8) 1555 62 27334738\n3 Spetzler RF Martin NA A proposed grading system for arteriovenous malformations J Neurosurg. 1986 10 65 (4) 476 83 3760956\n4 Pollock BE Link MJ Stafford SL Lanzino G Garces YI Foote RL Volume-staged stereotactic radiosurgery for intracranial arteriovenous malformations: outcomes based on an 18-year experience Neurosurgery. 2017 Apr 1 80 (4) 543 50 28362923\n5 Yen CP Schlesinger D Sheehan JP Natural history of cerebral arteriovenous malformations and the risk of hemorrhage after radiosurgery Prog Neurol Surg. 2013 27 5 21 23258505\n6 Potts MB Sheth SA Louie J Smyth MD Sneed PK McDermott MW Stereotactic radiosurgery at a low marginal dose for the treatment of pediatric arteriovenous malformations: obliteration, complications, and functional outcomes J Neurosurg Pediatr. 2014 7 14 (1) 1 11\n7 Miyawaki L Dowd C Wara W Goldsmith B Albright N Gutin P Five year results of LINAC radiosurgery for arteriovenous malformations: outcome for large AVMS Int J Radiat Oncol Biol Phys. 1999 Jul 15 44 (5) 1089 106 10421543\n8 Levin VA Bidaut L Hou P Kumar AJ Wefel JS Bekele BN Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system Int J Radiat Oncol Biol Phys. 2011 Apr 1 79 (5) 1487 95 20399573\n9 Randall LM Monk BJ Bevacizumab toxicities and their management in ovarian cancer Gynecol Oncol. 2010 6 117 (3) 497 504 20363017\n10 Gressett SM Shah SR Intricacies of bevacizumab-induced toxicities and their management Ann Pharmacother. 2009 Mar 43 (3) 490 501 19261963\n11 Yang L Chen CJ Guo XL Wu XC Lv BJ Wang HL Bevacizumab and risk of intracranial hemorrhage in patients with brain metastases: a meta-analysis J Neurooncol. 2018 Mar 137 (1) 49 56 29170906\n12 Williams BJ Park DM Sheehan JP Bevacizumab used for the treatment of severe, refractory perilesional edema due to an arteriovenous malformation treated with stereotactic radiosurgery J Neurosurg. 2012 May 116 (5) 972 7 22324417\n13 Preuss M Hirsch W Hoffmann KT Bernhard MK Siekmeyer M Kiess W Effectiveness of bevacizumab for radiation-induced cerebral necrosis in children Pediatr Neurosurg. 2013 49 (2) 81 5 24435068\n14 Dashti SR Spalding A Kadner RJ Yao T Kumar A Sun DA Targeted intraarterial anti-VEGF therapy for medically refractory radiation necrosis in the brain J Neurosurg Pediatr. 2015 Jan 15 (1) 20 5 25360851\n15 Uysal E Baskurt O Avci I Peker HO Celik SE Late recovery of stereotactic radiosurgery induced perilesional edema of an arteriovenous malformation after bevacizumab treatment Br J Neurosurg. 2020 Mar 27 1 5\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-680X",
"issue": "13(2)",
"journal": "Case reports in neurology",
"keywords": "Arteriovenous malformation; Bevacizumab; Radiation-induced necrosis; Stereotactic radiosurgery",
"medline_ta": "Case Rep Neurol",
"mesh_terms": null,
"nlm_unique_id": "101517693",
"other_id": null,
"pages": "297-304",
"pmc": null,
"pmid": "34177536",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "19783374;20363017;24435068;32216590;25360851;3760956;28362923;10421543;22324417;27334738;20399573;23258505;24766309;19261963;29170906",
"title": "Resolution of Radiation-Induced Necrosis in Arteriovenous Malformation with Bevacizumab: A Case Report and Review of Current Literature.",
"title_normalized": "resolution of radiation induced necrosis in arteriovenous malformation with bevacizumab a case report and review of current literature"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2022SP004732",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugaddition... |
{
"abstract": "Most antidepressant agents have the potential to cause liver injury, even at therapeutic doses. Nevertheless, drug-induced liver injury (DILI) from antidepressant agents is a rare event. There is no way to prevent idiopathic DILI, but the severity of the reaction may be minimized with prompt recognition and early withdrawal of the agent. We describe a rare case of a 63-year-old man presenting with acute liver failure after 3 months of trazodone and diazepam administration at normal therapeutic doses, requiring liver transplantation. This report should increase physicians' awareness of this complication and call attention to the regular monitoring of liver tests in patients taking trazodone, in order to prevent life-threatening complications.",
"affiliations": "Gastroenterology and Hepatology Department, Hospital de Santa Maria, Centro Hospitalar de Lisboa Norte, Lisbon, Portugal.;Intensive Care Unit, Hospital Curry Cabral, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Intensive Care Unit, Hospital Curry Cabral, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Intensive Care Unit, Hospital Curry Cabral, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Transplantation Unit, Hospital Curry Cabral, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Transplantation Unit, Hospital Curry Cabral, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.",
"authors": "Carvalhana|Sofia|S|;Oliveira|Ana|A|;Ferreira|Pedro|P|;Resende|Margarida|M|;Perdigoto|Rui|R|;Barroso|Eduardo|E|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000450878",
"fulltext": "\n==== Front\nGE Port J GastroenterolGE Port J GastroenterolPJGGE Portuguese Journal of Gastroenterology2341-45452387-1954S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000450878pjg-0024-0040Clinical Case StudyAcute Liver Failure due to Trazodone and Diazepam Insuficiência Hepática Aguda Induzida pela Trazodona e Diazepam Carvalhana Sofia a*Oliveira Ana bFerreira Pedro bResende Margarida bPerdigoto Rui cBarroso Eduardo caGastroenterology and Hepatology Department, Hospital de Santa Maria, Centro Hospitalar de Lisboa Norte, Lisbon, PortugalbIntensive Care Unit, Hospital Curry Cabral, Centro Hospitalar de Lisboa Central, Lisbon, PortugalcTransplantation Unit, Hospital Curry Cabral, Centro Hospitalar de Lisboa Central, Lisbon, Portugal*Dr. Sofia Carvalhana, Departamento de Gastrenterologia, Hospital de Santa Maria, Av. Prof. Egas Moniz, PT-1649-028 Lisbon (Portugal), E-Mail sofiacarvalhana@msn.com1 2017 16 11 2016 16 11 2016 24 1 40 42 10 5 2016 10 8 2016 Copyright © 2016 by Sociedade Portuguesa de Gastrenterologia Published by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.Most antidepressant agents have the potential to cause liver injury, even at therapeutic doses. Nevertheless, drug-induced liver injury (DILI) from antidepressant agents is a rare event. There is no way to prevent idiopathic DILI, but the severity of the reaction may be minimized with prompt recognition and early withdrawal of the agent. We describe a rare case of a 63-year-old man presenting with acute liver failure after 3 months of trazodone and diazepam administration at normal therapeutic doses, requiring liver transplantation. This report should increase physicians' awareness of this complication and call attention to the regular monitoring of liver tests in patients taking trazodone, in order to prevent life-threatening complications.\n\nResumo\nA maioria dos antidepressivos tem o potencial de causar lesão hepática, mesmo em doses terapêuticas. Contudo, a hepatite tóxica por antidepressivos é um evento raro. Não existe forma de prevenir a hepatite tóxica, mas a sua gravidade pode ser minimizada com o diagnóstico precoce e a retirada antecipada do fármaco. Apresentamos um caso raro de um homem de 63 anos com insuficiência hepática aguda após 3 meses de terapêutica com trazodona e diazepam em doses terapêuticas, com necessidade de transplante hepático. Com este caso pretende-se alertar os clínicos para a possibilidade desta entidade e da necessidade de monitorização regular das provas hepáticas em doentes sob tratamento com trazodona, de forma a prevenir morbilidade e mortalidade.\n\nKeywords\nAntidepressive agentsDiazepamLiver failure, acute/chemically inducedTrazodone\n==== Body\nIntroduction\nTrazodone is a second-generation, nontricyclic antidepressant that has been linked to rare cases of hepatic injury. The onset of injury is usually several months after continuous ingestion and the presentation pattern is commonly one of hepatocellular serum enzyme elevation, although cases with a shorter latency and with a mixed or cholestatic form have also been described [1]. There is no way to prevent idiopathic drug-induced liver injury (DILI), but the severity of the reaction may be minimized with prompt recognition and early withdrawal of the agent. We describe a rare case of acute liver failure (ALF) after 3 months of trazodone and diazepam administration at normal therapeutic doses, requiring liver transplantation.\n\nClinical Case\nA 57-year-old man with no previous medical history was started on diazepam (5 mg/day) and trazodone (200 mg/day) for depression. Three months later, he developed increased jaundice and was admitted. Laboratory test results included marked elevations in serum aminotransferase levels (ALT 4,638 U/L, AST 2,745 U/L), with increases in GGT (603 U/L), alkaline phosphatase (122 U/L), bilirubin levels (12.7 mg/dL), and international normalized ratio (1.84). His liver enzymes were known to be normal in the past. All medications were stopped. Over the next week, he developed encephalopathy, his international normalized ratio (2.37) and bilirubin (25.2 mg/dL) increased, and his factor V fell (from 51 to 29%). He was transferred to a liver transplant center and was listed for urgent liver transplantation. Test results for hepatitis A, B, and C were negative, as were serologic tests for acute cytomegalovirus, herpes simplex, and Epstein-Barr virus infection. Iron and copper studies were normal and autoantibodies were negative. An abdominal ultrasound ruled out biliary obstruction and occlusion of the liver vessels. A liver biopsy showed confluent necrosis involving most of the liver parenchyma, intrahepatic cholestasis, modest inflammation, and evidence of feathery degeneration and ballooning of hepatocytes in parenchyma, but no fat or fibrosis, compatible with toxic ALF (Fig. 1). In order to evaluate the causality between liver manifestation and drug treatment, the Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method (CIOMS/RUCAM) scale has been used. The CIOMS/RUCAM scale indicated a “probable” relationship for trazodone and a “possible” relationship for diazepam in causing hepatotoxicity. While the patient was waiting for liver transplantation, encephalopathy worsened requiring mechanical ventilation. He underwent liver transplantation 2 weeks after medication stoppage and he fully recovered.\n\nDiscussion\nTrazodone- and diazepam-induced ALF diagnosis was supported by (1) the development of hepatocellular liver injury 3 months after the introduction of trazodone and diazepam, (2) hepatotoxicity as a known adverse side effect of each of the drugs, (3) liver biopsy findings, especially confluent necrosis with inflammatory activity, which is the most common pattern seen in idiosyncratic adverse drug reactions complicated with ALF [2], and (4) exclusion of other etiologies of liver injury. Furthermore, when we assessed the causality by the CIOMS/RUCAM scale for trazodone, the score was in the category of “possible” cause of liver injury.\n\nDILI is a well-recognized problem that accounts for up to 10% of all adverse drug reactions. Two main mechanisms of DILI have been proposed: predictable injury (intrinsic hepatotoxins) and unpredictable injury (idiosyncratic reactions). In our case, an idiosyncratic reaction is likely to be the case. A literature review revealed that both drugs have been known to be implicated in DILI. Trazodone may cause alteration of liver enzyme levels at normal doses, but elevations are usually modest and usually do not require dose modification or discontinuation. Rare instances of ALF and death from trazodone have been described. The onset of liver toxicity may occur a few days or months after drug ingestion and even after the drug has been stopped. The pattern of liver injury is usually hepatocellular, but mixed or cholestatic forms have also been described. Contrarily, increases in liver enzymes during therapy with diazepam are rare and significant hepatotoxicity is uncommon. Only a few cases have been reported and none developed ALF [3]. The onset of injury has ranged from 1 to 6 months, and the pattern of serum enzyme elevations has typically been cholestatic or mixed [3]. The mechanism by which trazodone causes liver damage is unknown. Liver injury from benzodiazepines is probably due to a rarely produced intermediate metabolite.\n\nThis case is of special interest for its rarity. To our knowledge, only two other ALF cases associated with trazodone have been reported. Hull et al. [4] reported a 72-year-old woman who developed ALT elevations (107 U/L) 10 weeks after starting trazodone, trifluoperazine, and lithium, developing jaundice at 18 weeks and dying 2 months later. Postmortem liver biopsy revealed acute hepatic necrosis with cholestasis and portal inflammation [4]. The second case occurred in a 48-year-old woman who developed fulminant liver failure after 4 months of trazodone and venlafaxine therapy, requiring liver transplantation [5].\n\nThis report should increase physicians' awareness of this complication and call attention to the regular monitoring of liver tests in patients taking trazodone, especially if taken in concomitant therapy such as with other antidepressants or antipsychotics, in order to prevent life-threatening complications.\n\nStatement of Ethics\nThis study did not require informed consent nor review/approval by the appropriate ethics committee.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nAcknowledgements\nAll authors contributed equally. They thank Dr. Ana Carvalho for the liver biopsy pictures.\n\nFig. 1 Photomicrographs of liver biopsy in hematoxylin and eosin staining showing confluent necrosis involving most of the liver parenchyma (a, magnification ×40), modest inflammation and evidence of feathery degeneration and ballooning of hepatocytes in parenchyma (b, ×400), and intrahepatic cholestasis (c, ×400).\n==== Refs\nReferences\n1 Fernandes NF Martin RR Schenker S Trazodone-induced hepatotoxicity: a case report with comments on drug-induced hepatotoxicity Am J Gastroenterol 2000 95 532 535 10685763 \n2 Ramachandran R Kakar S Histological patterns in drug-induced liver disease J Clin Pathol 2009 62 481 492 19474352 \n3 Larrey D Ripault MP Kaplowitz N DeLeve LD Benzodiazepines. Hepatotoxicity of psychotropic drugs and drugs of abuse Drug-Induced Liver Disease 2013 ed 3 Amsterdam Elsevier 455 \n4 Hull M Jones R Bendall M Fatal hepatic necrosis associated with trazodone and neuroleptic drugs BMJ 1994 309 378 \n5 Detry O Delwaide J De Roover A Hans MF Delbouille MH Monard J Honoré P Fulminant hepatic failure induced by venlafaxine and trazodone therapy: a case report Transplant Proc 2009 41 3435 3436 19857765\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2387-1954",
"issue": "24(1)",
"journal": "GE Portuguese journal of gastroenterology",
"keywords": "Antidepressive agents; Diazepam; Liver failure, acute/chemically induced; Trazodone",
"medline_ta": "GE Port J Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101685861",
"other_id": null,
"pages": "40-42",
"pmc": null,
"pmid": "28848778",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports",
"references": "10685763;19474352;19857765;7915924",
"title": "Acute Liver Failure due to Trazodone and Diazepam.",
"title_normalized": "acute liver failure due to trazodone and diazepam"
} | [
{
"companynumb": "PT-TEVA-742720ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "OBJECTIVE\nDrug-induced gynecomastia accounts for up to 25% of cases of gynecomastia. The objective of the present study was to provide a comprehensive overview of drug-induced gynecomastia on the basis of spontaneously reported adverse drug reactions (ADRs) in the French national pharmacovigilance database (FPVD).\n\n\nMETHODS\nWe performed a case - noncase study of drug-induced gynecomastia. Cases corresponded to reports of gynecomastia recorded in the FPVD between 1 January 2008 and 31 December 2015. The noncases corresponded to all other spontaneously reported ADRs recorded in the FPVD during the same period. Data were expressed as the reporting odds ratio (ROR) and its 95% confidence interval.\n\n\nRESULTS\nOf the 255,354 ADRs recorded in the FPVD between 1 January 2008 and 31 December 2015, 327 (0.31%) of relevant cases of gynecomastia and 106,800 noncases were analyzed. The RORs were statistically significant for 54 active compounds mentioned 429 times in cases of gynecomastia. A single drug was involved in 59% of cases. The most frequently implicated drug classes were antiretrovirals (23.5%), diuretics (15.5%), proton pump inhibitors (11.9%), HMG-CoA reductase inhibitors (9.1%), neuroleptics and related drugs (6.5%), calcium channel blockers (6.3%), and 5-alpha reductase inhibitors (4%).\n\n\nCONCLUSIONS\nA comprehensive analysis of a national pharmacovigilance database highlighted the main drug classes suspected of inducing gynecomastia. A physiopathological mechanism (a hormone imbalance with elevated estrogen levels) is known or suspected for most of the drugs involved in gynecomastia. However, we noticed a lack of harmonization in the summary of product characteristics for original vs. generic medicines.",
"affiliations": "Centre régional de pharmacovigilance, CHU Amiens Sud, avenue René Laënnec, 80054 Amiens cedex 1, France. Electronic address: batteux.benjamin@chu-amiens.fr.;Centre régional de pharmacovigilance, CHU Amiens Sud, avenue René Laënnec, 80054 Amiens cedex 1, France.;Centre régional de pharmacovigilance, hôpital civil, 67091 Strasbourg, France.;Centre régional de pharmacovigilance, CHU Grenoble, 38043 Grenoble, France.;Centre régional de pharmacovigilance, CHU Amiens Sud, avenue René Laënnec, 80054 Amiens cedex 1, France.;Centre régional de pharmacovigilance, CHU Amiens Sud, avenue René Laënnec, 80054 Amiens cedex 1, France.;Centre régional de pharmacovigilance, CHU Amiens Sud, avenue René Laënnec, 80054 Amiens cedex 1, France.;Centre régional de pharmacovigilance, CHU Amiens Sud, avenue René Laënnec, 80054 Amiens cedex 1, France.",
"authors": "Batteux|Benjamin|B|;Llopis|Benoît|B|;Muller|Charlotte|C|;Khouri|Charles|C|;Moragny|Julien|J|;Liabeuf|Sophie|S|;Masmoudi|Kamel|K|;Gras|Valérie|V|;|||",
"chemical_list": "D004364:Pharmaceutical Preparations",
"country": "France",
"delete": false,
"doi": "10.1016/j.therap.2019.06.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-5957",
"issue": "75(3)",
"journal": "Therapie",
"keywords": "Chemically-induced disorders; Gynecomastia; Pharmacovigilance",
"medline_ta": "Therapie",
"mesh_terms": "D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D016022:Case-Control Studies; D016208:Databases, Factual; D064420:Drug-Related Side Effects and Adverse Reactions; D005602:France; D006177:Gynecomastia; D006801:Humans; D008297:Male; D008875:Middle Aged; D004364:Pharmaceutical Preparations; D060735:Pharmacovigilance",
"nlm_unique_id": "0420544",
"other_id": null,
"pages": "225-238",
"pmc": null,
"pmid": "31471065",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The drugs that mostly frequently induce gynecomastia: A national case - noncase study.",
"title_normalized": "the drugs that mostly frequently induce gynecomastia a national case noncase study"
} | [
{
"companynumb": "FR-JNJFOC-20200611123",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOMPERIDONE"
},
"drugadditional": "3",
... |
{
"abstract": "Gastroparesis is a chronic condition of delayed gastric emptying in the absence of mechanical outlet obstruction. We report a 47-year-old African American woman with diabetic gastroparesis who presented with intractable nausea, vomiting, and decreased oral intake with electrolyte disturbances. The patient's symptoms were difficult to control with antiemetic and conventional prokinetic agents, and she was started on mirtazapine 15 mg nightly. She experienced an almost complete symptom relief and was able to tolerate solid food within 24-48 hours. We highlight the role of mirtazapine, a 5-HT1a agonist, as an effective therapy for refractory gastroparesis.",
"affiliations": "Department of Medicine, University of Tennessee Health Science Center, Memphis, TN.;Department of Gastroenterology and Hepatology, University of Tennessee Health Science Center, Memphis, TN.;Department of Gastroenterology and Hepatology, University of Tennessee Health Science Center, Memphis, TN.",
"authors": "Marella|Hemnishil K|HK|;Saleem|Nasir|N|;Olden|Kevin|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14309/crj.0000000000000256",
"fulltext": "\n==== Front\nACG Case Rep JACG Case Rep JACGCRJACGCRJAC9ACG Case Reports Journal2326-3253Wolters Kluwer Maryland, MD ACGCR-19-053510.14309/crj.000000000000025600024Case ReportFunctional GI DisordersMirtazapine for Refractory Gastroparesis Marella Hemnishil K. DO1Saleem Nasir MD2Olden Kevin MD21 Department of Medicine, University of Tennessee Health Science Center, Memphis, TN2 Department of Gastroenterology and Hepatology, University of Tennessee Health Science Center, Memphis, TNCorrespondence: Hemnishil K. Marella, DO, Department of Medicine, University of Tennessee Health Science Center, 956 Court Ave Suite H314, Memphis TN 38163 (hmarella@uthsc.edu).10 2019 22 10 2019 6 10 e0025609 7 2019 11 9 2019 © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.2019This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.ABSTRACT\nGastroparesis is a chronic condition of delayed gastric emptying in the absence of mechanical outlet obstruction. We report a 47-year-old African American woman with diabetic gastroparesis who presented with intractable nausea, vomiting, and decreased oral intake with electrolyte disturbances. The patient's symptoms were difficult to control with antiemetic and conventional prokinetic agents, and she was started on mirtazapine 15 mg nightly. She experienced an almost complete symptom relief and was able to tolerate solid food within 24–48 hours. We highlight the role of mirtazapine, a 5-HT1a agonist, as an effective therapy for refractory gastroparesis.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nGastroparesis causes delayed gastric emptying in the absence of gastric outlet obstruction. Common causes of gastroparesis include diabetes mellitus (DM), gastrointestinal infection, surgical intervention, and idiopathic.1 DM is the most frequent systemic disease associated with gastroparesis. In a population-based, historical cohort study, the cumulative proportions of patients developing gastroparesis over a 10-year time period were 5.2% in type 1 DM, 1.0% in type 2 DM, and 0.2% in controls.2 The symptoms of gastroparesis include nausea, vomiting, upper abdominal pain, postprandial fullness, and bloating, which may lead to multiple frequent hospital admissions.3 The gold standard for diagnosis is solid-phase gastric scintigraphy; gastric retention of >10% at 4 hours is diagnostic.4\n\nMedical therapy is primarily focused on a combination of prokinetic agents that work on dopamine receptors (metoclopramide and domperidone) and antiemetic agents (ondansetron, promethazine, and prochlorperazine).1,3 Metoclopramide, a commonly used prokinetic, has a “black box” warnings from the US Food and Drug Agency because of the risk of extrapyramidal side effects.5 Erythromycin has the potential for diarrhea and QT-prolongation and is commonly associated with tachyphylaxis. Implantation of a gastric electrical stimulator is recommended after failure of conventional medical therapy for 1 year, but results have been inconsistent.6 Despite these therapeutic options, many patients still experience debilitating symptoms. Mirtazapine, a tetracyclic antidepressant with 5-HT1a receptor agonist activity in the central and peripheral nervous system, has been used to alleviate symptoms of gastroparesis.7–12 We describe a patient with refractory gastroparesis secondary to DM who had symptomatic relief after starting mirtazapine 15 mg nightly. In contrast to previous reports describing the use of mirtazapine in patients with idiopathic, postsurgical, postinfectious, neurological, or multifactorial gastroparesis, our patient had gastroparesis attributed only to DM.\n\nCASE REPORT\nA 47-year-old African American woman with insulin-requiring type 2 DM complicated by gastroparesis, retinopathy, and neuropathy presented with a 2-day history of intractable nausea and vomiting, diffuse crampy abdominal pain, and postprandial fullness. She had no psychiatric problems. She had multiple hospitalizations over the preceding 6–12 months for similar episodes, and an esophagogastroduodenoscopy performed during one of these hospitalizations had ruled out gastric obstruction. A gastric emptying study performed within the preceding year, while she was off narcotic and anticholinergic medications and her blood glucose was in the normal range, showed 60% retention after 4 hours. She was instructed to eat small frequent meals, and appropriate dietary modifications were tried with minimal response. Her DM was well controlled (HbA1C 6.0%; fasting blood glucose 75–138 mg/dL) with basal and prandial insulin. The patient had previously been treated with intravenous and oral ondansetron, promethazine, and prochlorperazine. Before her current hospitalization, she had been taking metoclopramide 5 mg 3 times daily but had remained symptomatic with nausea and vomiting.\n\nDuring the current admission, laboratory studies were unremarkable except for potassium level 3.2, which was appropriately corrected, and an abdominal x-ray was unremarkable. She was started on intravenous metoclopramide 30 mg daily and ondansetron 4 mg every 6 hour. Owing to uncontrolled symptoms and lack of response to metoclopramide, she was started on mirtazapine 15 mg nightly, and metoclopramide and ondansetron were discontinued. Within 2 days, she reported dramatic improvement of nausea and vomiting and was able to tolerate liquid diet followed by solid food. She reported drowsiness in the morning after starting mirtazapine, which improved after being given earlier in the evening around 6 pm. The patient was discharged on mirtazapine 15 mg nightly and ondansetron 4 mg as needed for nausea and vomiting.\n\nDISCUSSION\nBecause refractory gastroparesis can be debilitating, it is important to identify potential new therapies. Mirtazapine acts on multiple 5-hydroxytryptamine (5-HT; serotonin) receptor subtypes, including 5-HT1A, 5-HT2A, 5-HT2C, and 5-HT3.13 In functional dyspepsia, it acts on central and peripheral 5-HT1A receptors, leading to gastric fundus relaxation, better symptom control, and improved quality of life.14 It is also an antagonist at 5-HT3 receptors, which may account for its antiemetic effect.15\n\nIn a single-center prospective, open-label trial of 30 patients with refractory gastroparesis, mirtazapine significantly (P < 0.001) improved nausea and vomiting at 2 and 4 weeks compared with baseline. This cohort included 4 patients with DM, all of whom responded. However, the presence or absence of psychiatric disease was not taken into account when enrolling patients; this is a potential limitation because the improvement of mood could have altered the observed effect.11 Kim et al reported a patient with depression and type 1 DM who had refractory gastroparesis for 7 months and had complete resolution of symptoms with mirtazapine.9 Similarly, Kundu et al reported a patient with postinfectious gastroparesis in whom symptoms improved with mirtazapine.10 Mirtazapine also reduces tube feed residuals and postoperative gastroparesis.7,8 A randomized, double-blind study evaluated gastric emptying, satiation, and postprandial symptoms following a nutrient load in healthy volunteers after 14 days of mirtazapine or nortriptyline. It did not show statistically significant effects of mirtazapine or nortriptyline on gastric emptying compared with placebo (P = 0.34).16 However, this study evaluated healthy volunteers, not patients with gastroparesis, and used a nutrient drink test to induce symptoms. It also used the [13C]-octanoic acid breath test to measure gastric emptying rather than gastric scintigraphy.\n\nMirtazapine has been used in idiopathic, postsurgical, postinfectious, and neurological and diabetic gastroparesis with or without comorbid neurological or psychiatric conditions. A population-based cohort study from Olmsted County, Minnesota, estimated the prevalence of psychiatric illnesses including anxiety, depression, and eating disorders in patients with gastroparesis at 30%.17 Mirtazapine's antidepressant properties could have led to symptomatic improvement observed in previous case reports. By contrast, our patient had no history of psychiatric/central neurological illnesses and no other apparent cause of gastroparesis except DM. Therefore, we believe the beneficial effect of mirtazapine in our patient was independent of its antidepressant effect. This case highlights the use of mirtazapine as a treatment for refractory diabetic gastroparesis.\n\nAs mirtazapine is “off-label” for gastroparesis, Malamood et al showed that it could only be used in a select number of patients because of side effects of drowsiness and lethargy.11 Based on our experience, we suggest that patients be followed up weekly for at least the first 2 months after initiation of treatment to monitor adverse effects. Large-scale, comparative, and controlled studies are required to further elucidate the safety and efficacy of mirtazapine in patients with gastroparesis.\n\nDISCLOSURES\nAuthor contributions: HK Marella and N. Saleem wrote and revised the manuscript, and K. Olden revised the manuscript and approved the final version. HK Marella is the article guarantor.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n1. Camilleri M Parkman HP Shafi MA Abell TL Gerson L ; American College of Gastroenterology . Clinical guideline: Management of gastroparesis . Am J Gastroenterol . 2013 ;108 (1 ):18 –37 .23147521 \n2. Choung RS Locke GR IIISchleck CD Zinsmeister AR Melton LJ IIITalley NJ \nRisk of gastroparesis in subjects with type 1 and 2 diabetes in the general population . Am J Gastroenterol. \n2012 ;107 (1 ):82 –8 .22085818 \n3. Liu N Abell T \nGastroparesis updates on pathogenesis and management . Gut Liver . 2017 ;11 (5 ):579 –89 .28535580 \n4. Tougas G Eaker EY Abell TL \nAssessment of gastric emptying using a low fat meal: Establishment of international control values . Am J Gastroenterol. \n2000 ;95 (6 ):1456 –62 .10894578 \n5. Rao AS Camilleri M \nReview article: Metoclopramide and tardive dyskinesia . Aliment Pharmacol Ther. \n2010 ;31 (1 ):11 –9 .19886950 \n6. Shada A Nielsen A Marowski S \nWisconsin's enterra therapy experience: A multi-institutional review of gastric electrical stimulation for medically refractory gastroparesis . Surgery . 2018 ;164 (4 ):760 –5 .30072246 \n7. Gooden JY Takahashi PY \nMirtazapine treatment of diabetic gastroparesis as a novel method to reduce tube-feed residual: A case report . J Med Case Rep. \n2013 ;7 :38 .23388206 \n8. Johnstone M Buddhdev P Peter M Diggory R \nMirtazapine: A solution for postoperative gastroparesis? \nBMJ Case Rep. \n2009 ;2009 :bcr0220091579. \n9. Kim SW Shin IS Kim JM \nMirtazapine for severe gastroparesis unresponsive to conventional prokinetic treatment . Psychosomatics . 2006 ;47 (5 ):440 –2 .16959934 \n10. Kundu S Rogal S Alam A Levinthal DJ \nRapid improvement in post-infectious gastroparesis symptoms with mirtazapine . World J Gastroenterol. \n2014 ;20 (21 ):6671 –4 .24914393 \n11. Malamood M Roberts A Kataria R Parkman HP Schey R \nMirtazapine for symptom control in refractory gastroparesis . Drug Des Devel Ther. \n2017 ;11 :1035 –41 .\n12. Song J Lin N Tian F Li Y Li Y \nSuccessful treatment of gastroparesis with the antidepressant mirtazapine: A case report . J Nippon Med Sch. \n2014 ;81 (6 ):392 –4 .25744484 \n13. Anttila SA Leinonen EV \nA review of the pharmacological and clinical profile of mirtazapine . CNS Drug Rev. \n2001 ;7 (3 ):249 –64 .11607047 \n14. Tack J Ly HG Carbone F \nEfficacy of mirtazapine in patients with functional dyspepsia and weight loss . Clin Gastroenterol Hepatol. \n2016 ;14 (3 ):385 –92.e384 .26538208 \n15. Kast RE Foley KF \nCancer chemotherapy and cachexia: Mirtazapine and olanzapine are 5-HT3 antagonists with good antinausea effects . Eur J Cancer Care (Engl). \n2007 ;16 (4 ):351 –4 .17587360 \n16. Choung RS Cremonini F Thapa P Zinsmeister AR Talley NJ \nThe effect of short-term, low-dose tricyclic and tetracyclic antidepressant treatment on satiation, postnutrient load gastrointestinal symptoms and gastric emptying: A double-blind, randomized, placebo-controlled trial . Neurogastroenterol Motil. \n2008 ;20 (3 ):220 –7 .18031471 \n17. Jung HK Choung RS Locke GR III \nThe incidence, prevalence, and outcomes of patients with gastroparesis in Olmsted County, Minnesota, from 1996 to 2006 . Gastroenterology . 2009 ;136 (4 ):1225 –33 .19249393\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2326-3253",
"issue": "6(10)",
"journal": "ACG case reports journal",
"keywords": null,
"medline_ta": "ACG Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101638398",
"other_id": null,
"pages": "e00256",
"pmc": null,
"pmid": "31832475",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports",
"references": "19886950;23147521;28535580;23388206;21847421;11607047;18031471;24914393;25744484;19249393;28408802;22085818;30072246;26538208;16959934;17587360;10894578",
"title": "Mirtazapine for Refractory Gastroparesis.",
"title_normalized": "mirtazapine for refractory gastroparesis"
} | [
{
"companynumb": "US-APOTEX-2020AP008105",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "INSULIN NOS"
},
"drugadditional": null,
... |
{
"abstract": "An 86-year-old woman underwent mastectomy with sentinel lymph node biopsy for cStage ⅡA breast cancer. The subtype of tumor was triple negative breast cancer. Pulmonary metastasis was found 1 month after surgery. Chemotherapy was done because of her good performance status(PS)and her hope. Administration of S-1 produced SD status of tumor for 8 months. However, NCC-ST-439 was increased and tumor size was enlarged. Therefore, the second line of chemotherapy by low-dose- biweekly paclitaxel and bevacizumab was planned because of her high age and good PS. Thereafter, tumor maker levels dramatically decreased and lung metastasis turned to be small. This therapy had been continued without any severe adverse events for 9 months. Unfortunately, this therapy was failed because of proteinuria, but pulmonary metastasis kept favorable efficacy during administration. Biweekly low-dose paclitaxel and bevacizumab therapy can be safe and effective therapy even for elderly patient with recurrent and metastatic breast cancer.",
"affiliations": "Dept. of Surgery, Kanazawa Medical Center.",
"authors": "Munemoto|Masayoshi|M|;Kano|Shunsuke|S|;Ishikawa|Satoko|S|;Makita|Naoki|N|;Yagi|Yasumichi|Y|;Oonishi|Ichiro|I|;Kayahara|Masato|M|",
"chemical_list": "D000068258:Bevacizumab; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "47(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D008408:Mastectomy; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2038-2040",
"pmc": null,
"pmid": "33468793",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Chemotherapy with Low-Dose Paclitaxel and Bevacizumab for Elderly Recurrent Breast Cancer Patient.",
"title_normalized": "a case of chemotherapy with low dose paclitaxel and bevacizumab for elderly recurrent breast cancer patient"
} | [
{
"companynumb": "JP-PFIZER INC-2021132502",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSystemic artery to pulmonary artery fistulas (SA-PAFs), are extremely rare in people without congenital heart disease. In this group of patients pulmonary arterial hypertension was reported in the single case. Then, we describe a case of multiple SA-PAFs, which were the cause of severe nonreversible arterial pulmonary hypertension in a patient who had a right-sided pneumothorax 35 years earlier.\n\n\nMETHODS\n52-year-old male Caucasian patient with echocardiographically confirmed pulmonary hypertension (PH) was admitted to cardiology department due to exertional dyspnea and signs of right ventricle failure. Routine screening for causes of secondary PH was negative. Right heart catheterization (RHC) confirmed a high degree arterial PH [mean pulmonary artery pressure (mPAP); 50,6 mmHg, pulmonary wedge pressure (PWP); 11,3 mmHg, pulmonary vascular resistance (PVR); 11,9 Wood's units (WU)] irreversible in the test with inhaled nitric oxide. Oxygen saturation (SaO2) of blood samples obtained during the first RHC ranged from 69.3 to 73.2%. Idiopathic pulmonary arterial hypertension was diagnosed. Treatment with inhaled iloprost and sildenafil was initiated. Control RHC, performed 5 months later showed values of mPAP (59,7 mmHg) and PVR (13,4 WU) higher in comparison to the initial measurement, SaO2 of blood obtained during RHC from upper lobe artery of the right lung was elevated and amounted 89.7%. Then, pulmonary arteriography was performed. Lack of contrast in the right upper lobe artery with the evidence of retrograde blood flow visible as a negative contrast in the right pulmonary artery was found. Afterwards, right subclavian artery arteriography detected a huge vascular malformation communicating with right upper lobe artery. Following computed tomography angiogram (angio-CT) additionally revealed the enlargement of bronchial arteries originated fistulas to pulmonary artery of right upper lobe. In spite of intensive pharmacological treatment, including the therapy of pulmonary hypertension and percutaneous embolisation of the fistulas, the patient's condition continued to deteriorate further. He died three months after embolisation due to severe heart failure complicated by pneumonia.\n\n\nCONCLUSIONS\nNon-congenital SA-PAFs are extremely rare, however, they should be excluded in patients with pulmonary arterial hypertension and history of inflammatory or infectious disease of the lung and pleura, pneumothorax, cancer or Takayashu's disease and after chest trauma.",
"affiliations": "2nd Department of Cardiology, School of Medicine with Dentistry Division in Zabrze, Medical University of Silesia, 10 Curie-Sklodowska str, 41-808, Zabrze, Poland. wjachec@interia.pl.;2nd Department of Cardiology, School of Medicine with Dentistry Division in Zabrze, Medical University of Silesia, 10 Curie-Sklodowska str, 41-808, Zabrze, Poland.;Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre Otwock, 14/18 Borowa str, 05-400, Otwock, Poland.;Department of Radiography Medical, University of Lublin, Staszica 11 str., 20-081, 20-954, Lublin, Poland.;Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre Otwock, 14/18 Borowa str, 05-400, Otwock, Poland.;Department of Radiology and Nuclear Medicine, School of Medicine with Dentistry Division in Zabrze, Medical University of Silesia, 13-15 3-go Maja str, 41-800, Zabrze, Poland.;2nd Department of Cardiology, School of Medicine with Dentistry Division in Zabrze, Medical University of Silesia, 10 Curie-Sklodowska str, 41-808, Zabrze, Poland.;2nd Department of Cardiology, School of Medicine with Dentistry Division in Zabrze, Medical University of Silesia, 10 Curie-Sklodowska str, 41-808, Zabrze, Poland.",
"authors": "Jacheć|Wojciech|W|http://orcid.org/0000-0002-1091-9788;Tomasik|Andrzej|A|;Kurzyna|Marcin|M|;Pietura|Radosław|R|;Torbicki|Adam|A|;Głowacki|Jan|J|;Nowalany-Kozielska|Ewa|E|;Wojciechowska|Celina|C|",
"chemical_list": "D000068677:Sildenafil Citrate; D016285:Iloprost",
"country": "England",
"delete": false,
"doi": "10.1186/s12890-019-0832-8",
"fulltext": "\n==== Front\nBMC Pulm MedBMC Pulm MedBMC Pulmonary Medicine1471-2466BioMed Central London 83210.1186/s12890-019-0832-8Case ReportThe multiple systemic artery to pulmonary artery fistulas resulting in severe irreversible pulmonary arterial hypertension in patient with previous history of pneumothorax http://orcid.org/0000-0002-1091-9788Jacheć Wojciech wjachec@interia.pl 1Tomasik Andrzej tomasik@poczta.onet.pl 1Kurzyna Marcin marcin.kurzyna@ecz-otwock.pl 2Pietura Radosław radoslawpietura@poczta.onet.pl 3Torbicki Adam adam.torbicki@ecz-otwock.pl 2Głowacki Jan j.glowacki@sccs.pl 4Nowalany-Kozielska Ewa ewakozielska@wp.pl 1Wojciechowska Celina wojciechowskac@wp.pl 11 0000 0001 2198 0923grid.411728.92nd Department of Cardiology, School of Medicine with Dentistry Division in Zabrze, Medical University of Silesia, 10 Curie-Sklodowska str, 41-808 Zabrze, Poland 2 Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre Otwock, 14/18 Borowa str, 05-400 Otwock, Poland 3 Department of Radiography Medical, University of Lublin, Staszica 11 str., 20-081, 20-954 Lublin, Poland 4 0000 0001 2198 0923grid.411728.9Department of Radiology and Nuclear Medicine, School of Medicine with Dentistry Division in Zabrze, Medical University of Silesia, 13-15 3-go Maja str, 41-800 Zabrze, Poland 16 4 2019 16 4 2019 2019 19 809 9 2018 13 3 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nSystemic artery to pulmonary artery fistulas (SA-PAFs), are extremely rare in people without congenital heart disease. In this group of patients pulmonary arterial hypertension was reported in the single case. Then, we describe a case of multiple SA-PAFs, which were the cause of severe nonreversible arterial pulmonary hypertension in a patient who had a right-sided pneumothorax 35 years earlier.\n\nCase presentation\n52-year-old male Caucasian patient with echocardiographically confirmed pulmonary hypertension (PH) was admitted to cardiology department due to exertional dyspnea and signs of right ventricle failure. Routine screening for causes of secondary PH was negative. Right heart catheterization (RHC) confirmed a high degree arterial PH [mean pulmonary artery pressure (mPAP); 50,6 mmHg, pulmonary wedge pressure (PWP); 11,3 mmHg, pulmonary vascular resistance (PVR); 11,9 Wood’s units (WU)] irreversible in the test with inhaled nitric oxide. Oxygen saturation (SaO2) of blood samples obtained during the first RHC ranged from 69.3 to 73.2%. Idiopathic pulmonary arterial hypertension was diagnosed. Treatment with inhaled iloprost and sildenafil was initiated.\n\nControl RHC, performed 5 months later showed values of mPAP (59,7 mmHg) and PVR (13,4 WU) higher in comparison to the initial measurement, SaO2 of blood obtained during RHC from upper lobe artery of the right lung was elevated and amounted 89.7%.\n\nThen, pulmonary arteriography was performed. Lack of contrast in the right upper lobe artery with the evidence of retrograde blood flow visible as a negative contrast in the right pulmonary artery was found. Afterwards, right subclavian artery arteriography detected a huge vascular malformation communicating with right upper lobe artery. Following computed tomography angiogram (angio-CT) additionally revealed the enlargement of bronchial arteries originated fistulas to pulmonary artery of right upper lobe.\n\nIn spite of intensive pharmacological treatment, including the therapy of pulmonary hypertension and percutaneous embolisation of the fistulas, the patient’s condition continued to deteriorate further. He died three months after embolisation due to severe heart failure complicated by pneumonia.\n\nConclusion\nNon-congenital SA-PAFs are extremely rare, however, they should be excluded in patients with pulmonary arterial hypertension and history of inflammatory or infectious disease of the lung and pleura, pneumothorax, cancer or Takayashu’s disease and after chest trauma.\n\nKeywords\nSystemic artery to pulmonary artery fistulasPulmonary arterial hypertensionPneumothoraxMedical University of SilesiaKNW-1-174 / K / 8 / KTomasik Andrzej issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nSystemic artery to pulmonary artery fistulas (SA-PAFs) are known to develop in patients with congenital heart diseases, which are combined with right ventricular outflow or pulmonary artery obstruction and in many cases it may be the only blood supply to pulmonary circulation [1].\n\nSA-PAFs are extremely rare in people with normal pulmonary circulation. They can be congenital and non-congenital. Non-congenital fistulas can develop in patients with inflammatory or infectious disease of the lung and pleura, cancer, Takayasu’s disease, or after trauma [2–4]. Congenital SA-PAFs can be detected in patients without any of the above-mentioned risk factors [5].\n\nSA-PAF can be single or multiple and connect pulmonary vascular bed with left internal mammary artery, left subclavian artery, pericardiacophrenic branch of left inferior phrenic artery, left bronchial artery, gastric arteries or others [5, 6]. SA-PAFs are usually asymptomatic. Some patients complained about dyspnea, hemoptysis or symptoms of congestive heart failure [7–11]. The natural outcome of SA-PAFs is not well-known yet. SA-PAFs may be managed by embolisation, resection, or observation [1].\n\nOnly in two reported cases of congenital SA-PAFs mild elevated systolic pulmonary artery pressure (to 37 mmHg) was detected [5] and severe pulmonary arterial hypertension was reported in one case of congenital SA-PAFs [12].\n\nWe describe a case of non-congenital multiple SA-PAFs which were the cause of severe precapillary pulmonary hypertension in a patient who had right-sided pneumothorax thirty years earlier.\n\nCase presentation\nA 52-year-old male patient with initial diagnosis of pulmonary arterial was admitted to the Department of Cardiology for medical assessment and decision on further treatment. The patient had a history of right-sided spontaneous pneumothorax, treated with thoracentesis and vacuum drainage 35 years earlier. The patient felt increasing dyspnea on exertion. He also complained about signs of right ventricle failure and cyanosis. Four years earlier the patient was hospitalized three times for paroxysmal atrial fibrillation that was converted to sinus rhythm by electric cardioversion besides electrocardiographic examination was normal.\n\nIn the same year coronary angiography indicated normal coronary arteries. Echocardiography revealed mild pulmonary hypertension with calculated right ventricle systolic pressure of 36 mmHg without right ventricle dilation.\n\nIn the following years, progressive heart failure with increasing pulmonary artery pressure in echocardiography has been observed. Angio-CT was performed on two occasions and chronic thromboembolic pulmonary hypertension was excluded each time. High-resolution computed tomography has excluded interstitial pulmonary pathology. Spirometry was normal. Screening for autoimmune diseases and HIV infection was negative (Table 1).Table 1 Timeline – history, course of the disease, diagnosis and treatment\n\n1976\tright-hand pneumothorax\t\n2007\tHospitalized three times for atrial fibrillation and heart failure echocardiography, cardioversion, coronarography were performed. Every time discharged from the departments with diagnosis: Atrial fibrillation, Heart failure, NYHA class II.\t\n2010–2011\tIncreasing growing shortness of breath and symptoms of heart failure. Patient was hospitalized 3 times. Indirect features of pulmonary hypertension in echocardiography were detected. Three times chest-CT examination was performed; pulmonary embolism or chronic thromboembolic pulmonary arterial hypertension (2 x angio-CT) or pulmonary fibrosis (high resolution computer tomography) was excluded.\nDiagnosis of pulmonary hypertension was established, WHO class III.\t\nDEC-2011\tAdmission to cardiology clinic – echocardiography (TTE, TEE), 6-min walking test, NT-proBNP, right heart catheterisation, pulmonary vasoreactivity test.\nDiagnosis of irreversible arterial pulmonary hypertension was established.\nTreatment with the illoprost and sildenafil has started\t\nJAN-2012\tcontrol visit – improvement in WHO class, decrease of NT-proBNP concentration and increase of 6-min test distance\t\nMAY-2012\tControl RHC. SaO2 of blood samples obtained during RHC from upper lobe artery of the right lung amounted 87%.\nAngiographic diagnostic of pulmonary arteries revealed PAH fistulas between subclavian and upper lobe of right lung arteries\t\nJUN 2012\tangio-CT of systemic arteries revealed additional presence of bronchial artery fistulas to upper lobe of right lung arteries\t\nIII-2013\tEmbolisation of fistulas\t\nVI-2013\tDeath as a result of worsening of heart failure combined with pneumonia.\t\n\n\nAt admission to our clinic functional class of patient was assessed as WHO III, In physical examination the second heart sound (S2) was accentuated with widened split S2. Moreover, heart auscultation indicated holosystolic murmur of tricuspid regurgitation. The auscultation of the chest did not show a vascular murmur. Peripheral and central cyanosis was marked. Hepatomegaly, peripheral edema and varicose veins bilaterally were examined.\n\nSaO2 obtained by pulse oximetry method was reduced to 88%. Electrocardiography revealed atrial fibrillation, right axis deviation and negative T wave in precordial leads v1-v3. Additional tests were as follows: NT-proBNP concentration – 3383 pg/ml, six-minute walking test distance - 373 m with 7/10 points in Borg dyspnea score.\n\nEchocardiography showed features of severe pulmonary hypertension: right ventricle enlargement to 44 mm (four chamber view), with depressed function of right ventricle TAPSE 9 mm, right atrium area enlargement to 40 cm2, severe tricuspid valve regurgitation (++++), increased calculated RVSP to 112 mmHg, shortened pulmonary artery acceleration time to 60 ms and mild pericardial effusion. There was no interventricular septum defect. Trans-esophageal echocardiography did not show a defect in the atrial septum too, which was confirmed later by angio-CT (Fig. 1).Fig. 1 “Angio-CT - preserved continuity of the atrial septum, high degree enlargement of right atrium and ventricle”. RA right atrium, RV right ventricle, LA left atrium, LV left ventricle\n\n\n\nSaO2 of blood obtained from radial artery was reduced to 87,8%. Right heart catheterization was performed. SaO2 of blood samples obtained during RHC from vena cava superior, vena cava inferior, right atrium, pulmonary trunk, middle lobe artery of the right lung and left pulmonary artery amounted respectively: 64,8%; 77,4%; 73,2%; 70,2%, 69,3%; 71,2% and did not indicate the presence of a left-to-right shunt.\n\nHemodynamic measurements showed severe precapillary pulmonary hypertension, irreversible in vasoreactivity testing with inhaled nitric oxide (80 ppm) and a combination of oral sildenafil (50 mg) and inhaled nitric oxide (80 ppm) [13] (Table 2).Table 2 Results of pulmonary arterial hypertension reversibility test\n\n\tPAPs/PAPd (mPAP)\n[mm Hg]\tABPs/ABPd (mABP)\n[mm Hg]\tPWP\n[mm Hg]\tPVR\n[WU]\tSVR\n[WU]\tRA\n[mm Hg]\tCI\n[l/min./m2]\tSaO2\n[%]\t\nBaseline\t69,8/41,0 (50,6)\t104,0/80,0 (88,3)\t12,3\t11,9\t24,4\t10,0\t1,5\t87,8\t\nNO/O2 (80 ppm)\t63,0/35,6 (44,7)\t101,0/74,0 (83)\t12,0\t9,1\t20,8\t8,0\t1,7\t99,0\t\nSildenafil (50 mg)\t68,0/37,6 (47,7)\t99,5/70,0 (79,8)\t12,0\t8,1\t16,3\t8,0\t2,0\t84,0\t\nNO/O2 (80 ppm)\t62,0/34,4 (43,6)\t98,0/72,0 (80,3)\t12,5\t6,9\t16,2\t8,0\t2,1\t95,2\t\nControl RHC\t75,4/51,8 (59,7)\t104,0/78,0 (86,7)\t13,5\t13,4\t21,7\t12,0\t1,6\t90,1\t\nPAPs systolic pulmonary artery pressure, PAPd diastolic pulmonary artery pressure, mPAP mean pulmonary artery pressure, ABPs systolic arterial blood pressure, ABPd diastolic arterial blood pressure, mABP mean arterial blood pressure, PWP pulmonary wedge pressure, PVR pulmonary vascular resistance, SVR systemic vascular resistance, RAP right atrium pressure, CI cardiac index, SaO2 systemic blood oxygenation, NO nitric oxide, O2 oxygen, ppm parts per million, RHC right heart catheterization\n\n\n\nBased on the whole clinical data and the results of RHC, a diagnosis of idiopathic irreversible pulmonary hypertension was established.\n\nTreatment with inhaled iloprost (Ventavis) 6 × 5 μg and sildenafil (Revatio) orally 3 × 20 mg was initiated. Moreover, digoxin (0,1 mg daily), warfarin (INR range: 2–3), furosemide (40 mg orally daily) and spironolactone (100 mg daily) were administered.\n\nNoninvasive follow up was performed one month later – the patient reported improved physical capacity, class II WHO, NT-proBNP concentration: 1014 pg/ml. Six-minute walking test distance - 471 m.\n\nInvasive assessment was done five months later. RHC showed higher than in initial measurements values of PAP [75,4/51,8 (59,7) mm Hg] and PVR (13,4 WU) (Table 2 – control RHC).\n\nOxygen saturation of blood samples obtained during RHC from upper lobe artery of the right lung was elevated and amounted 89.7%.\n\nIn the pulmonary angiography reduction of peripheral vascular drawing typical of pulmonary arterial hypertension and the lack of contrast of the right upper lobe artery were detected. Additionally the evidence of retrograde blood flow visible as a negative contrast in right pulmonary artery was found (Fig. 2 a-d). Afterwards, right subclavian artery arteriography was performed and a huge vascular malformation communicating with right upper lobe artery (Fig. 2e-k) was detected.Fig. 2 “Pulmonary angiography results. Retrograde filling of the right pulmonary artery is seen, representing fistulas between the subclavian and bronchial arteries and pulmonary artery”. a – right pulmonary artery; no contrast of the upper lobe arteries (arrow), b – left pulmonary artery, c, d – selective angiography of the upper lobe artery, visible contrast leaching (arrow) and lack of venous phase, e – selective angiography of the right subclavian artery, visible vascular malformation (arrow), f, g, h – selective angiography of fistula between left subclavian artery and pulmonary upper lobe artery, i, j – occlusion of fistula by balloon (5.0 20 mm), with subsequent selective angiography of the upper lobe artery, still visible contrast leaching (arrow) and lack of venous phase, k – selective angiography of the right subclavian artery, visible second vascular malformation (arrow), l – pulmonary angiography with contrast injected into an enlarged bronchial artery. Retrograde filling of the right pulmonary artery is seen, representing a fistula between the bronchial artery and pulmonary artery\n\n\n\nAngio-CT of systemic arteries confirmed presence of previously described fistulas and revealed additional presence of bronchial artery fistulas to upper lobe of right lung arteries (Fig. 3).Fig. 3 Systemic artery to pulmonary artery fistulas, CT angiography reconstruction; bronchial arteries fistulas (narrower arrows) and subclavian artery fistulas (thicker arrow)\n\n\n\nSelective embolisation of fistulas was performed (50% mixture of Lipiodol and monomeric n-butyl-2-cyanoacrylate glue). Embolisation did not bring any clinical change in the patient’s condition.\n\nDiscussion and conclusions\nA case of 52-year-old male patient with high-grade pulmonary arterial hypertension leading to severe right ventricle failure that was irreversible in vasoreactivity testing with inhaled nitric oxide and sildenafil was reported. Patient had a right-sided pneumothorax 35 years earlier.\n\nMultiple artery-to-artery fistulas between systemic and pulmonary circulation, existing despite normal morphologic development of pulmonary circulation were the cause leading to severe pulmonary hypertension.\n\nDuring the last four years of his life, the patient presenting with cyanosis and echocardiographic evidence of pulmonary hypertension and had normal spirometry results, HRCT and angio-CT of pulmonary arteries.\n\nMild to moderate hypoxemia is common in arterial pulmonary hypertension patients [14, 15].\n\nIt may be possibly related to ventilation/perfusion mismatch [16], low diffusion capacity, low mixed venous PvO2 [16, 17], and sometimes existing right-to-left shunting, which is classically considered to arise from the reopening of patent foramen ovale [14, 18]. In this case normal chest radiographs, HRCT of the chest, and lack of pulmonary edema during vasodilatatory therapy excluded pulmonary veno-occlusive disease as the cause of hypoxemia [19].\n\nWe believe that in this case the probable cause of pulmonary hypertension are multiple systemic to pulmonary artery fistulas which initially cause left-to-right shunt, induce an increase in pulmonary vascular resistance which leads to an increase in pulmonary vascular resistance which eventually results in reversal of the direction of the shunt. It was responsible for the proper perfusion of the upper lobe of right lung during first two angio-CT.\n\nIn contrast, in the first RHC the ratio of mean pulmonary to systemic pressure was about 5/8, which clearly indicates the left-to-right direction of the shunt. This may be related to worsening function of right ventricle.\n\nAt the stage of the first RHC, we had no premises to extend the diagnosis towards systemic-pulmonary shunt. Moreover, unfortunately, the blood sample for the SaO2 was taken from the middle lobe artery of the right lung. After establishing the diagnosis of idiopathic pulmonary arterial hypertension, we included PAH treatment in accordance with the ESC standards. Control RHC has become a contribution to the diagnosis of multiple system-pulmonary fistulas. Only then did the patient inform us about a right-sided pneumothorax 35 years earlier.\n\nThe course of changes in pulmonary hemodynamics can be compared to changes in congenital heart defects leading to the development of the Eisenmenger syndrome but due to the observed clinical improvement, we did not decide to replace iloprost and sildenafil for the recommended endothelin-receptor antagonist [20]. Furthermore, co-occurrence of idiopathic pulmonary arterial hypertension and systemic pulmonary fistulas can’t be clearly excluded.\n\nFinally after many discussions within the heart team, selective embolisation of fistulas was performed. Unfortunately, despite effective embolization, changes in pulmonary circulation were so advanced that removal of the cause of pulmonary hypertension did not improve the patient’s condition. In addition, closure of the fistulas blocked the “potentially” beneficial effect of right ventricular decompression in the event of a re-growth of pulmonary artery pressure to super systemic values.\n\nIn spite of intensive pharmacological treatment, including the therapy of pulmonary hypertension the patient’s condition deteriorated further. He died three months later due to severe heart failure complicated by pneumonia.\n\nJi-Feng Li et al. described a similar case of multiple fistulas between systemic and pulmonary arteries of right lung, which were of congenital origin. They resulted in moderate pulmonary hypertension with mean PAP value = 37 mmHg. The right ventricle function was not seriously depressed; TAPSE = 18,5 mm. Embolisation of the largest fistula resulted in a gradual drop of mPAP in six-month follow-up despite the lack of PDE5-I, ARB or prostanoids in concomitant therapy [12].\n\nTake home message\nNon congenital SA-PAFs are extremely rare, but still the diagnosis should be considered when a shunt is suspected during the diagnostic work up of pulmonary arterial hypertension, especially in patients with risk factors.\n\nAbbreviations\nABPdDiastolic arterial blood pressure\n\nABPsSystolic arterial blood pressure\n\nAngio-CTComputed tomography angiography\n\nCOCardiac output\n\nHIVHuman immunodeficiency virus\n\nHRCTHigh-resolution computed tomography\n\nINRInternational normalized ratio\n\nmABPMean arterial blood pressure\n\nmgMilligram\n\nmPAPMean pulmonary artery pressure\n\nNONitric oxide\n\nNT-proBNPN-terminal pro-brain natriuretic peptide\n\nO2Oxygen\n\nPAPdDiastolic pulmonary artery pressure\n\nPAPsSystolic pulmonary artery pressure\n\nPHPulmonary hypertension\n\nppmParts per million\n\nPvO2Venous blood oxygen saturation\n\nPVRIPulmonary vascular resistance index\n\nPWPPulmonary artery wedge pressure\n\nRAPRight atrium pressure\n\nRHCRight heart catheterization\n\nRVSPRight ventricle systolic pressure\n\nSaO2Systemic blood oxygenation\n\nSA-PAFsSystemic artery to pulmonary artery fistulas\n\nSVRISystemic vascular resistance index\n\nTAPSETricuspid annular plane systolic excursion\n\nTEETransesophageal echocardiography\n\nTTETransthoracic echocardiography\n\nWHOWorld health organization\n\nAcknowledgements\nNot applicable.\n\nFunding\nThe design of the case report, analysis, and interpretation of data and writing of the manuscript had no funding. If the case report is accepted for publication, the Medical University of Silesia will cover the related costs.\n\nAvailability of data and materials\nAll data presented come from the patient’s medical records and after their disclosure individual privacy of patient could be compromised.\n\nAll data generated or analyzed during this study are included in this published article.\n\nAuthors’ contributions\n“WJ” performed all right heart catheterizations, diagnosed fistulas between subclavian artery and pulmonary artery and analyzed and co-interpreted the patient data regarding pulmonary circulation, hypertension and pulmonary hypertension reversibility test results. In addition to diagnostics, he conducted pharmacological treatment of the patient and was a major contributor to the writing of the manuscript. “AT” participated in right heart catheterization and analyzed and co-interpreted the patient data regarding pulmonary circulation and hypertension. He was a contributor to the writing of the manuscript. “MK” analyzed and co-interpreted the patient data regarding pulmonary circulation and hypertension. He was a contributor to the writing of the manuscript. “RP” analyzed and co-interpreted the patient data regarding pulmonary circulation and he performed procedure of fistulas embolisation. He was a contributor to the writing of the manuscript. “JG”diagnosed additional fistulas between aorta and pulmonary artery, analyzed and co-interpreted the patient data regarding pulmonary circulation. He was a contributor to the writing of the manuscript. “ATor” analyzed and co-interpreted the patient data regarding pulmonary circulation and hypertension. “ENK” analyzed and co-interpreted the patient data regarding pulmonary hypertension. “CW” participated in right heart catheterizations, she co-diagnosed fistulas between subclavian artery and pulmonary artery and analyzed and co-interpreted the patient data regarding pulmonary hypertension and pulmonary hypertension reversibility test results. She performed echocardiography examinations. In addition to diagnostics, she conducted pharmacological treatment of the patient and was a contributor to the writing of the manuscript. All authors read and approved the final manuscript.”\n\nAuthors’ information\n“WJ” – cardiologist, pulmonary hypertension specialist, deputy head of the 2nd Department of Cardiology and head of cardiac cath-lab of the 2nd Department of Cardiology of School of Medicine with Dentistry Division in Zabrze, Medical University of Silesia, 10 Ci-Sklodowska str., 41–808 Zabrze, Poland.\n\n“AT” – cardiologist, pulmonary hypertension specialist, deputy head of cardiac cath-lab of the 2nd Department of Cardiology of School of Medicine with Dentistry Division in Zabrze, Medical University of Silesia, 10 Ci-Sklodowska str., 41–808 Zabrze, Poland.\n\n“MK” – cardiologist, pulmonary circulation and hypertension specialist, deputy head of the Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre Otwock, 14/18 Borowa str, 05–400 Otwock, Poland. Polish Society of Cardiology expert.\n\n“RP” – interventional radiologist, head of Department of Interventional Radiology, Department of Radiography Medical, University of Lublin, Staszica 11 str., 20–081, 20–954 Lublin, Poland.\n\n“JG” – radiologist, lecturer of Department of Radiology and Nuclear Medicine, School of Medicine with Dentistry Division in Zabrze, Medical University of Silesia, 13–15 3-go Maja str., 41–800 Zabrze, Poland.\n\n“ATor” – cardiologist, pulmonary circulation and hypertension specialist, head of the Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre Otwock, 14/18 Borowa str, 05–400 Otwock, Poland. European Society of Cardiology expert.\n\n“ENK” – cardiologist, head of the 2nd Department of Cardiology of School of Medicine with Dentistry Division in Zabrze, Medical University of Silesia, 10 Ci-Sklodowska str., 41–808 Zabrze, Poland.\n\n“CW” – cardiologist, pulmonary hypertension specialist, head of echocardiography laboratory of the 2nd Department of Cardiology of School of Medicine with Dentistry Division in Zabrze, Medical University of Silesia, 10 Ci-Sklodowska str., 41–808 Zabrze, Poland.\n\nEthics approval and consent to participate\nPresented case report was reviewed by the Bioethics Committee of the Medical University of Silesia, reference number; KNW/0022/KB/7/8.\n\nConsent for publication\nManuscript does not contain any individual person’s data in any form. During life, the patient gave consent for a case report publication. Because the patient died, written consent for the use of medical records was obtained from the wife of the patient.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Maeda E Akahane M Kato N Hayashi N Koga H Yamada H Kato H Ohtomo K Assessment of major aortopulmonary collateral arteries with multidetector-row computed tomography Radiat Med 2006 24 5 378 383 10.1007/s11604-006-0037-y 16958418 \n2. Hearne SF Burbank MK Internal mammary artery to-pulmonary artery fistulas Circulation 1980 62 1131 1135 10.1161/01.CIR.62.5.1131 7418166 \n3. Yan Y Tweddale BA Trerotola SO Internal mammary artery–to–pulmonary artery and vein fistula acquired after video-assisted thoracoscopic surgery and Pleurodesis J of Vasc Intervnet Radiol 2013 24 11 1759 1761 10.1016/j.jvir.2013.05.063 \n4. Rieh G Chaffanjon P Frey G Sessa C Brichon P-Y Postoperative systemic artery to pulmonary vessel fistula: analysis of three cases Ann Thorac Surg 2003 76 1873 1877 10.1016/S0003-4975(03)01056-7 14667603 \n5. Itano H Lee S Kulick DM Iannettoni MD Williams DM Mark B Orringer nontraumatic Chest Wall systemic-to-pulmonary artery fistula Ann Thorac Surg 2005 79 29 31 10.1016/j.athoracsur.2005.01.035 15620909 \n6. Lee J-K Park J-H Kim J Kim SJ Lee A-R Lee CH Young-ho so mbolization of multiple systemic artery to pulmonary artery fistula with recurrent hemoptysis Tuberc Respir Dis 2013 75 120 124 10.4046/trd.2013.75.3.120 \n7. Voll A Marstrander F Wexels P Systemic-pulmonary shunt Dis Chest 1966 45 396 401 10.1378/chest.45.4.396 \n8. Tadavarthy SM Klugman J Castaneda-Zuniga WR Systemic-to-pulmonary collaterals in pathological states Radiology 1982 144 55 59 10.1148/radiology.144.1.7089266 7089266 \n9. Gallet B Bayet G Saudemont JP Fistule syste’mopulmonaire acquise apre` s pleurectomie responsable d’un souffle thoracique continu Cardiol Angeiol 1988 37 305 308 \n10. Saito T Matsuda M Yamaguchi T A case of a traumatic systemic-pulmonary arteriovenous fistula Jpn Heart J 1975 16 196 203 10.1536/ihj.16.196 1121144 \n11. VanDerPloeg DG BS WRS Krohmer SJ O’Connor WN Martin JT Congenital bronchial artery to pulmonary artery fistula presenting as hemoptysis Ann Thorac Surg 2015 99 19 20 10.1016/j.athoracsur.2014.10.057 \n12. Li J-F Zhai Z-G Kuang T-G Liu M Ma Z-H Li Y-D Yang Y-H A case of pulmonary hypertension due to fistulas between multiple systemic arteries and the right pulmonary artery in an adult discovered for occulted Dyspnoea Heart, Lung and Circulation 2017 26 e54 e58 10.1016/j.hlc.2016.12.018 \n13. Jan Wodniecki, Wojciech Jacheć, Lech Poloński, Andrzej R. Tomasik, Celina Wojciechowska, Ala Foremny. Sildenafil obniża ciśnienie i opory płucne oraz zwiększa wrażliwość tętnic płucnych na tlenek azotu w pierwotnym nadciśnieniu płucnym. Przegląd Lekarski 2005 T.62 nr 2 s. 135–138.\n14. Rich S Dantzker D Ayres S Bergofsky E Brundage B Detre K Fishman A Goldring R Groves B Koerner S Primary pulmonary hypertension: a national prospective study Ann Int Med 1987 107 216 223 10.7326/0003-4819-107-2-216 3605900 \n15. Hoeper MM Pletz MW Golpon H Welte T Prognostic value of blood gas analyses in patients with idiopathic pulmonary arterial hypertension Eur Respir J 2007 29 944 950 10.1183/09031936.00134506 17301100 \n16. Melot C Naeije R Mols P Vandenbossche JL Denolin H Effects of nifedipine on ventilation/perfusion matching in primary pulmonary hypertension Chest 1983 83 203 207 10.1378/chest.83.2.203 6822102 \n17. Dantzker DR Bower JS Mechanisms of gas exchange abnormality in patients with chronic obliterative pulmonary vascular disease J Clin Invest 1979 64 1050 1055 10.1172/JCI109542 479367 \n18. Chen WJ Chen JJ Lin SC Hwang JJ Lien WP Detection of cardiovascular shunts by transesophageal echocardiography in patients with pulmonary hypertension of unexplained cause Chest 1995 107 8 13 10.1378/chest.107.1.8 7813317 \n19. Montani D Price LC Dorfmuller P Achouh L Jaïs X Yaïci A Sitbon O Musset D Simonneau G Humbert M Pulmonary veno-occlusive disease Eur Respir J 2009 33 189 200 10.1183/09031936.00090608 19118230 \n20. Galie N Hoeper MM Humbert M Torbicki A Vachiery J-L Barbera JA Beghetti M Corris P Gaine S Simon Gibbs J Gomez-Sanchez MA Jondeau G Klepetko W Opitz C Rubin APL Zellweger M Simonneau G Guidelines for the diagnosis and treatment of pulmonary hypertension: the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by: International Society for Heart and Lung Transplantation (ISHLT) Eur Heart J 2009 30 2493 2537 10.1093/eurheartj/ehp297 19713419\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2466",
"issue": "19(1)",
"journal": "BMC pulmonary medicine",
"keywords": "Pneumothorax; Pulmonary arterial hypertension; Systemic artery to pulmonary artery fistulas",
"medline_ta": "BMC Pulm Med",
"mesh_terms": "D001159:Arterio-Arterial Fistula; D006328:Cardiac Catheterization; D000072226:Computed Tomography Angiography; D065627:Familial Primary Pulmonary Hypertension; D017809:Fatal Outcome; D006333:Heart Failure; D006801:Humans; D016285:Iloprost; D008168:Lung; D008297:Male; D008875:Middle Aged; D011030:Pneumothorax; D011651:Pulmonary Artery; D011669:Pulmonary Wedge Pressure; D000068677:Sildenafil Citrate; D014655:Vascular Resistance",
"nlm_unique_id": "100968563",
"other_id": null,
"pages": "80",
"pmc": null,
"pmid": "30991994",
"pubdate": "2019-04-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1121144;14136626;14667603;15854915;16095162;16958418;17301100;19118230;19713419;24101937;24160836;25555983;28314671;3044247;3605900;479367;6822102;7089266;7418166;7813317",
"title": "The multiple systemic artery to pulmonary artery fistulas resulting in severe irreversible pulmonary arterial hypertension in patient with previous history of pneumothorax.",
"title_normalized": "the multiple systemic artery to pulmonary artery fistulas resulting in severe irreversible pulmonary arterial hypertension in patient with previous history of pneumothorax"
} | [
{
"companynumb": "PL-PFIZER INC-2019204647",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SPIRONOLACTONE"
},
"drugadditional": null,
... |
{
"abstract": "Molecular profiling of urothelial cancers for therapeutic and prognostic potential has been very limited due to the absence of cancer-specific targeted therapies. We describe here 2 clinical cases with a histological diagnosis of an invasive sarcomatoid and a poorly differentiated carcinoma favoring urothelial with some neuroendocrine differentiation, two of the rarer types of urothelial cancers, which were evaluated for mutations in 212 genes for single-nucleotide variants and copy-number variants and 53 genes for fusions associated with solid tumors. In both cases, we identified variants in 2 genes, ARID1A and CDKN2A, indicative of the role of dysregulation of chromatin remodeling and cell cycle control as being common features of bladder cancer, consistent with the proposed model of tumorigenesis in these rare, highly aggressive pathological subtypes. The presence of a KRAS mutation in the poorly differentiated cancer and a TP53 mutation in the sarcomatoid tumor is indicative of a distinctive profile and adds a potential layer of molecular stratification to these rarer histological subtypes. We present a comparative analysis of the histological, clinical, and molecular profile of both cases and discuss the potential to delineate these tumors at the molecular level keeping in mind the possible therapeutic implications.",
"affiliations": "The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.;Pen Bay Medical Center, Rockport, Maine, USA.;New England Cancer Specialists, Scarborough, Maine, USA.;Mid Coast Hospital, Brunswick, Maine, USA.;Department of Pathology, Maine Medical Center, Portland, Maine, USA.;The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.;The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.;The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.;The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.;The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.;The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.;The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.;The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.;The Maine Cancer Genomics Initiative, The Jackson Laboratory, Augusta, Maine, USA.;The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.",
"authors": "Hesse|Andrew N|AN|;Fabricius|William|W|;Thomas|Christian A|CA|;Gaindh|Ramesh|R|;Christman|Robert|R|;Selvam|Pavalan|P|;Prego|Matthew|M|;Lewis|Gregory|G|;Uvalic|Jasmina|J|;Bergeron|Daniel|D|;Burns|Shelbi|S|;Sisson|Bridgette|B|;Kelly|Kevin|K|;Rueter|Jens|J|;Reddi|Honey V|HV|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000487882",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000487882cro-0011-0196Case ReportGenomic Profiling of Two Histologically Distinct Rare Urothelial Cancers in a Clinical Setting to Identify Potential Therapeutic Options for Treatment and Management of Disease Hesse Andrew N. aFabricius William bThomas Christian A. cGaindh Ramesh dChristman Robert eSelvam Pavalan aPrego Matthew aLewis Gregory aUvalic Jasmina aBergeron Daniel aBurns Shelbi aSisson Bridgette aKelly Kevin aRueter Jens fReddi Honey V. a*aThe Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USAbPen Bay Medical Center, Rockport, Maine, USAcNew England Cancer Specialists, Scarborough, Maine, USAdMid Coast Hospital, Brunswick, Maine, USAeDepartment of Pathology, Maine Medical Center, Portland, Maine, USAfThe Maine Cancer Genomics Initiative, The Jackson Laboratory, Augusta, Maine, USA*Honey V. Reddi, PhD, FACMG, 10 Discovery Drive, Farmington, CT 06032 (USA), E-Mail honey.reddi@jax.orgA.N. Hesse, W. Fabricius, C.A. Thomas, R. Gaindh, and R. Christman contributed equally to this work. J. Rueter and H.V. Reddi: equal contribution.\n\nJan-Apr 2018 27 3 2018 27 3 2018 11 1 196 205 22 2 2018 22 2 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Molecular profiling of urothelial cancers for therapeutic and prognostic potential has been very limited due to the absence of cancer-specific targeted therapies. We describe here 2 clinical cases with a histological diagnosis of an invasive sarcomatoid and a poorly differentiated carcinoma favoring urothelial with some neuroendocrine differentiation, two of the rarer types of urothelial cancers, which were evaluated for mutations in 212 genes for single-nucleotide variants and copy-number variants and 53 genes for fusions associated with solid tumors. In both cases, we identified variants in 2 genes, ARID1A and CDKN2A, indicative of the role of dysregulation of chromatin remodeling and cell cycle control as being common features of bladder cancer, consistent with the proposed model of tumorigenesis in these rare, highly aggressive pathological subtypes. The presence of a KRAS mutation in the poorly differentiated cancer and a TP53 mutation in the sarcomatoid tumor is indicative of a distinctive profile and adds a potential layer of molecular stratification to these rarer histological subtypes. We present a comparative analysis of the histological, clinical, and molecular profile of both cases and discuss the potential to delineate these tumors at the molecular level keeping in mind the possible therapeutic implications.\n\nKeywords\nGenomic profilingNext-generation sequencingUrothelial cancer\n==== Body\nIntroduction\nBladder cancer is the most common malignancy involving the urinary system and the ninth most common malignancy worldwide [1], responsible for ∼150,000 deaths per year worldwide and about 5% of all new cancers in the US [2]. Invasive urothelial carcinoma involving the urinary bladder is very well known for divergent differentiation [3], with transitional cell carcinoma being the most common histological type accounting for 90% of cases. Sarcomatoid carcinomas of the bladder are rare (0.6% of bladder cancers – SEER Statistics) with only about 24 cases reported so far [4]. Similarly, neuroendocrine tumors of the bladder are equally rare (< 0.5% of all bladder cancer malignancies) with ∼12 cases being reported [5]. Prognosis with both variant morphologies is poor with an aggressive clinical course and rapid onset of metastatic disease. Given the rarity of the 2 variant morphotypes presented in the current analysis, it is difficult to draw any conclusions about the optimal treatment strategy or prognostic markers due to the small number of reported cases.\n\nHere we present 2 cases (initial pathology, genomic findings, and clinical follow-up) of the rare pathological subtypes of urothelial cancer, a sarcomatoid tumor and a poorly differentiated urothelial carcinoma (PDUC) with some neuroendocrine differentiation. To our knowledge, this is the first report of these rare variant morphologies of urothelial carcinomas being described with clinical genomic profiling to identify potential targeted therapeutic approaches.\n\nCase Reports\nPDUC with Some Neuroendocrine Differentiation\nA 70-year-old man with a diagnosis of invasive PDUC of the right lateral wall of the bladder was initially noted by his primary care provider to have persistent microscopic hematuria. However, cystoscopy conducted 2 months later did not identify any tumors. CT scans of the abdomen and pelvis with contrast were negative for metastatic disease. Three months later, he developed macroscopic hematuria and anemia and a new 3–4 cm broad-based nodular lesion was identified in the right lateral wall of the bladder on repeat cystoscopy. Transurethral resection of these lesions and several clots in the bladder were noted during that procedure and were removed, resulting in resolution of his gross hematuria. Pathology of these lesions noted a high-grade, muscle-invasive PDUC with some neuroendocrine differentiation of the right lateral wall of the bladder (Fig. 1a, b). He was clinically staged as stage II, cT2 cN0 cM0. A PET/CT scan done at the same time showed no evidence of regional or distant metastatic disease.\n\nInvasive Sarcomatoid Urothelial Carcinoma\nA 69-year-old man with a family history of pancreatic cancer in his mother and a brother initially underwent an evaluation for hematuria followed by a partial cystectomy when a cystoscopy identified a bladder diverticulum. Histological examination identified a high-grade bladder tumor with sarcomatoid features (Fig. 1c, d). Associated lymph nodes were negative for malignancy. The tumor had been resected with negative margins and no further treatment was advised at that time. After 9 months of surveillance, a repeat cystoscopy revealed the possibility of recurrent disease and restaging MRI scan of the abdomen performed at the same time revealed the presence of bulky pelvic and retroperitoneal adenopathy. A transurethral resection of a recurrent tumor in the trigone area showed invasive sarcomatoid urothelial carcinoma, which locally progressed as confirmed on CT scans 1 month later. Chemotherapy with gemcitabine and cisplatin was initiated, but after a brief period of clinical improvement, a repeat staging CT scan after about 2.5 months of treatment revealed progression of his pelvic and retroperitoneal disease. Given a high PD-L1 score of 95%, treatment with atezolizumab was initiated but the patient progressed clinically after 2 cycles of treatment and then expired.\n\nGenomic Analyses and Clinical Interpretation\nUltrasound-guided core-needle biopsies were histologically evaluated for diagnosis of malignancy (Fig. 2) and formalin-fixed paraffin-embedded (FFPE) samples were shipped to The Jackson Laboratory for Genomic Medicine (JAX) CLIA lab by the ordering physicians (W.F. and C.A.T.) to be processed using a clinically validated (CLIA/CAP) assay called the ActionSeq PlusTM. The assay included a DNA-based panel comprising 212 cancer-related genes for which all coding exons are sequenced (to allow for detection of somatic single-nucleotide variants, indels, and copy-number variants) and a RNA-based panel for 53 genes known to form fusions. Data were analyzed to identify variants of actionability, i.e., those with therapeutic, prognostic, or diagnostic relevance.\n\nTwo genes were mutated in both cases; actionable variants were identified in ARID1A (p.Q1172* – PDUC and p. H782Tfs*51 – sarcomatoid) and CDKN2A (p. N42Kfs*77 – PDUC and p. W110* – sarcomatoid). Additionally, we identified an actionable KRAS (p.G12D) variant in the PDUC and 2 actionable variants in the tumor suppressors TP53 (p. R273C) and FBXW7 (p. R465C) in the sarcomatoid cancer. While no variants of uncertain significance were identified in the PDUC, we did identify 1 variant of uncertain significance in NFE2L2 (p.E82V) in the sarcomatoid tumor (Table 1). No actionable copy-number variants or fusions were identified in either case. A comprehensive summary of the potential therapies, variant classification, FDA-approved therapies and potential clinical trials identified for the patient-specific mutational profile is listed in Table 2. While there were no FDA-approved targeted therapies identified for urothelial tumors in any of the relevant drug classes, FDA-approved drugs for these mutations in other cancers (metastatic or locally advanced solid tumors) were listed in the genomic testing report as potential options for off-label use, consistent with the AMP/ASCO guidelines for reporting of somatic variants [6].\n\nTreatment Outcomes\nPDUC with Some Neuroendocrine Differentiation\nThe patient was initially started on neoadjuvant chemotherapy with cisplatin-etoposide (i.v. cisplatin 80 mg/m2 on day 1, i.v. etoposide 80 mg/m2 on days 1, 2, and 3). This was planned for 4 cycles. During the completion of this first cycle, a revision of his pathology stated that the neuroendocrine component of his tumor was minimal, with scant evidence of neuroendocrine cells and very weak stain synaptophysin, thus favoring the diagnosis of PDUC. After a multidisciplinary discussion, the patient's neoadjuvant chemotherapy regimen was changed to dose-dense methotrexate-vinblastin-doxorubicin-cisplatin (ddMVAC) (i.v. cisplatin 70 mg/m2, i.v. methotrexate 30 mg/m2, i.v. vinblastin 3 mg/m2, I.V. doxorubicin 30 mg/m2 on day 1 every 2 weeks), a category 1 NCCN guideline recommendation.\n\nThe patient completed 3 cycles of neoadjuvant ddMVAC without serious complications except for moderate cytopenia, fatigue, poor appetite, and nausea. Two weeks after completion of that regimen, restaging CT scans of the abdomen, pelvis, and chest showed no radiological evidence of disease. The plan is now to perform a radical cystectomy, to be followed likely by active monitoring for development of metastatic disease. There remains a significant risk for metastatic disease recurrence and having the next-generation sequencing test results may help identify future treatment options or clinical trials if the patient develops metastatic disease.\n\nSarcomatoid Urothelial Carcinoma\nThe patient passed away in the interim during genomic testing and was unable to benefit from the results of genomic testing.\n\nDiscussion\nPrecision medicine aims to identify novel targets for treating rare and difficult-to-treat cancers. To advance the field and identify novel treatment options for patients, broad molecular profiling is needed. Here we describe the molecular profiling results of 2 cases with urothelial cancers that identified potential treatment options for the patients. We identified some interesting profiles which offer the opportunity to identify new treatment options and may support novel molecular disease classifications in the future.\n\nMutations in 2 genes, ARID1A and CDKN2A, were identified in both our cases and they have been shown to occur in 25 and 5% of urothelial carcinomas, respectively, indicative of the role of dysregulation of chromatin remodeling and cell cycle control in these rare, highly aggressive pathological subtypes. Evaluation of 347 cases across a broad complement of cancers demonstrated that CDKN2A was more likely to be independently associated with ARID1A in a multivariate analysis (OR D 3.98, 95% CI: 1.36–11.8, p D 0.01, p = 0.01).\n\nIn addition, we identified a mutation in KRAS in 1 of the 2 cases (PDUC). Mutations in the RAS oncogenes (HRAS, KRAS, and NRAS) are found in ∼11–13% of bladder tumors and occur in all stages and grades, with mutations in KRAS being the least frequent [7]. Profiling of urothelial cancers across multiple studies have not identified co-occurrence of KRAS with CDKN2A mutations [8], however, a single study has reported the co-occurrence of a KRAS substitution with an ARID1A truncation mutation in a stage IV high-grade urothelial carcinoma in a 51-year-old male [9] indicative of the rarity of this genomic profile. The co-occurrence of the ARID1A and KRAS mutation in the PDUC could therefore possibly account for the aggressive and poorly differentiated nature of the tumor. In contrast to the PDUC, the sarcomatoid urothelial carcinoma had actionable mutations in 3 other genes (TP53, FBXW7, and NFE2L2) known to harbor aberration in bladder cancer. TP53 is the most commonly mutated gene in bladder cancer observed at a frequency of ∼15% in non-muscle-invasive tumors as is the sarcomatoid tumor. Mutations in TP53 have been shown to co-occur with either ARID1A or CDKN2A [9] with aberration in the CDK pathway genes being the second most common mutation across most cancers next to TP53 [10]. Mutations in FBXW7 are observed in 10% of bladder cancers across all stages [7] and mutations in NFE2L2 are observed in ∼8–11% of bladder tumors [11], particularly the basal subtype [12], based on samples in TCGA suggesting a potential role for the oxidative stress pathway in progression of bladder cancer. While co-occurrence of FBXW7 mutations with TP53 has been reported in a single case report, of a high-grade, advanced-stage tumor from a 71-year-old woman, from the lymph node metastasis specimen which had a micropapillary architecture [9], mutations in NFE2L2 have not been shown to co-occur with TP53 mutations [12] across a comprehensive study evaluating ∼400 bladder cancers, contributing to the novelty of this genomic profile and providing further insight into the possible genomic changes involved in the development and evolution of sarcomatoid urothelial carcinoma.\n\nThere are currently no molecularly targeted agents approved for the treatment of bladder cancer despite a significant amount of effort in recent times to profile bladder tumors. By following the AMP/CAP/ASCO guidelines on reporting actionability of cancer-specific genes, we were able to identify potential drug classes for clinical consideration (Table 2). These included FDA-approved drugs (for a different indication) as well as some experimental therapies. In addition, we were able to identify a number of clinical trials for each one of the patients based on their genomic profile, although all of the trials were recruiting patients broadly across solid tumors. Most noteworthy is a trial listed for the ARID1A and KRAS mutations (NCT02576444) which is a phase II study of the PARP inhibitor olaparib (AZD2281) alone and in combination with AZD1775, AZD5363, or AZD2014 in advanced solid tumors across different molecular profiles including any mutation in ARID1A, as well as protocol-defined mutations in KRAS and TP53. The TP53 mutation identified in the sarcomatoid case did not fit inclusion criteria, but the mutations in ARID1A and KRAS were eligible, resulting in the inclusion of this trial in the genomic testing report. All in all, molecular profiling has identified a number of genomic-marker-driven treatment approaches for patients with urothelial cancers, but these treatments should be accessed through clinical trial enrollment rather than off-label use of drugs.\n\nThough the ARID1A and CDKN2A genes identified in our cases are amongst those known to be commonly associated with urothelial carcinoma, to our knowledge this study is the first clinical case report comparing and identifying unique genomic profiles in 2 rare pathological subtypes of urothelial cancer. The identification of the co-occurring combinations of ARID1A/KRAS in the PDUC and the TP53/FBXW7 in the sarcomatoid subtype adds a layer of potential stratification across these two histological subtypes. Further, our documentation of these rare co-occurrences in high-grade urothelial carcinomas adds an additional case report to the existing literature of single cases currently reported for each combination, amplifying the potential of broad-based targeted clinical trials. In addition, given the rarity of these tumors, with only 24 clinical cases of sarcomatoid tumors [4] and ∼12 cases of urothelial carcinoma with neuroendocrine component [5] being reported, our evaluation also adds to the knowledgebase of these rare urothelial carcinoma morphologies, both from a genomic profile perspective as well as identification of potential targeted therapies and trials since there are currently no targeted FDA-approved therapies specific for urothelial cancer.\n\nStatement of Ethics\nPatient specimens were sent to the CLIA/CAP-accredited laboratory at The Jackson Laboratory for Genomic Medicine as part of the patients' routine care and management for genomic testing. Informed written consent was obtained by the ordering physician from the patient for tumor profiling using the JAX ActionSeq PlusTM assay. The use of data sets is allowed for research reports and scientific publications.\n\nDisclosure Statement\nThe authors declare that there are no conflicts of interest.\n\nAcknowledgment\nWe gratefully acknowledge the participation of the patients. The authors are grateful for the funding support from the Harold Alfond® Foundation that facilitated the genomic testing in collaboration with The Jackson Laboratory as part of the Maine Cancer Genomics Initiative (MCGI) led by J.R.\n\nFig. 1 a, b Pathology sections of a poorly differentiated urothelial carcinoma: ×4 (a), ×40 (b). c, d Pathology sections of a sarcomatoid carcinoma: ×20 (c), ×40 (d).\n\nFig. 2 Immunostained sections of the tumors: synaptophysin (poorly differentiated urothelial carcinoma) (a), GATA3 (sarcomatoid) (b), and CAM5.2 (sarcomatoid) (c).\n\nTable 1 Variants reported in both cases\n\nHistology\tGene\tProtein change\tcDNA\tTranscript\tCoordinate\tVariant type\tPredicted effect\t\nCase 1\t\nPDUC with areas of neuroendocrine differentiation\tARID1A\tp.Q1172*\tc.3514C>T\tNM_006015.4\tchr1:26772607\tTransition\tMissense\t\n\tCDKN2A\tp.N42Kfs77*\tc.126_127delTA\tNM_000077.4\tchr9:21974700\tDeletion\tFS/truncation\t\n\tKRAS\tp.G12D\tc.35G>A\tNM_033360.3\tchr12:25245350\tTransition\tMissense\t\n\t\nCase 2\t\nSarcomatoid urothelial carcinoma\tARID1A\tp.H782Tfs*51\tc.2343delA\tNM_006015.4\tchr1:26762242\tDeletion\tFS/truncation\t\n\tCDKN2A\tp.W110*\tc.330G>A\tNM_000077.4\tchr9:21971029\tTransition\tNonsense\t\n\tFBXW7\tp.R465C\tc.1393C>T\tNM_033632.3\tchr4:152328233\tTransition\tMissense\t\n\tTP53\tp.R273C\tc.817C>T\tNM_000546.5\tchr17:7673803\tTransition\tMissense\t\nPDUC, poorly differentiated urothelial carcinoma; FS, frameshift mutation.\n\nTable 2 Clinically significant variants with potential therapies and clinical trials listed in genomic testing reports\n\nHistology\tGene\tClassification\tDrug classes\tFDA approved for tumor type\tFDA approved for other indications\tPotential clinical trials\t\nCase 1\t\nPDUC with areas of neuroendocrine differentiation\tARID1A\nc.3514C>T\tTier II\t√ PARP inhibitor\tNone\tOlaparib1\nNiraparib2\nRucaparib2\tNCT02576444\t\n\t\t\tO AKT inhibitor\tN/A\tN/A\tNCT02576444\t\n\t\t\n\tCDKN2A\nc.126_127delTA\tTier II\t√ CDK4/6 inhibitor\tNone\tPalbociclib1\nRibociclib2\nAbemaciclib2\tNCT02693535, NCT02334527\t\n\t\t\tO Multikinase inhibitor\tN/A\tN/A\tNCT02478320, NCT02540876\t\n\t\t\n\tKRAS\nc.35G>A\tTier II\t√ MEK inhibitor\tNone\tCobimetinib Trametinib\tNCT01827384, NCT02022982\nNCT03108131, NCT02079740\nNCT03162627\t\n\t\t\tO ERK inhibitor\tN/A\tN/A\tNCT02857270, NCT03051035\t\n\t\t\tO KRAS ASO inhibitor\tN/A\tN/A\tNCT03101839\t\n\t\nCase 2\t\nSarcomatoid urothelial carcinoma\tARID1A\nc.2343delA\tTier II\t√ PARP inhibitor\tNone\tOlaparib1\nNiraparib2\nRucaparib2\tNCT02576444\t\t\n\t\t\tO AKT inhibitor\tN/A\tN/A\tNCT02576444\t\n\t\t\n\tCDKN2A\nc.330G>A\tTier II\t√ CDK4/6 inhibitor\tNone\tPalbociclib1\nRibociclib2\nAbemaciclib2\tNCT02693535, NCT02334527\t\n\t\t\tO Multikinase inhibitor\tN/A\tN/A\tNCT02478320, NCT02540876\t\n\t\t\n\tFBXW7\nc.1393C>T\tTier II\tO CHK1 inhibitor\tN/A\tN/A\tNCT02873975\t\n\t\t\n\tTP53\nc.817C>T\tTier II\tO P53 gene therapy\tN/A\tN/A\tNCT02842125\t\nO P53 vaccine\tN/A\tN/A\tNCT02432963\t\n\t\t\tO WEE1 inhibitor\tN/A\tN/A\tNCT02576444\t\nPDUC, poorly differentiated urothelial carcinoma; √, approved therapies; O, experimental therapies; Tier I, strong clinical significance; Tier II, potential clinical significance; Tier III, unknown clinical significance.\n\n1 Currently being investigated in a clinical trial.\n\n2 Additional “in-class” drug not currently under active investigation in a clinical trial.\n==== Refs\nReferences\n1 Ploeg M Aben KK Kiemeney LA The present and future burden of urinary bladder cancer in the world World J Urol 2009 Jun 27 (3) 289 93 19219610 \n2 Andreassen BK Aagnes B Gislefoss R Andreassen M Wahlqvist R Incidence and Survival of urothelial carcinoma of the urinary bladder in Norway 1981–2014 BMC Cancer 2016 Oct 16 (1) 799 27737647 \n3 Humphrey PA Moch H Cubilla AL Ulbright TM Reuter VE The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part B Prostate and Bladder Tumours Eur Urol 2016 Jul 70 (1) 106 19 26996659 \n4 Lu W Wang Y Li Y Cao Y Han H Zhou F Sarcomatoid urothelial carcinoma with chondrosarcomatous differentiation of the ureter A case report and review of the literature Oncol Lett 2017 Mar 13 (3) 1331 7 28454257 \n5 Amin MB Histological variants of urothelial carcinoma diagnostic, therapeutic and prognostic implications Mod Pathol 2009 Jun 22 (S2 Suppl 2) S96 118 19494856 \n6 Li MM Datto M Duncavage EJ Kulkarni S Lindeman NI Roy S Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists J Mol Diagn 2017 Jan 19 (1) 4 23 27993330 \n7 Kompier LC Lurkin I van der Aa MN van Rhijn BW van der Kwast TH Zwarthoff EC FGFR3 NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy PLoS One 2010 Nov 5 (11) e13821 21072204 \n8 Grivas P Zargar H Ercole CE Kovac E Remer EM Karim W Assessment of sarcopenia as predictor of response and outcome after neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC) J Clin Oncol 2015 33 (15_suppl) e15512 \n9 Ross JS Wang K Al-Rohil RN Nazeer T Sheehan CE Otto GA Advanced urothelial carcinoma next-generation sequencing reveals diverse genomic alterations and targets of therapy Mod Pathol 2014 Feb 27 (2) 271 80 23887298 \n10 Kato S Schwaederle M Daniels GA Piccioni D Kesari S Bazhenova L Cyclin-dependent kinase pathway aberrations in diverse malignancies clinical and molecular characteristics Cell Cycle. 2015 14 (8) 1252 9 25695927 \n11 Real FX Boutros PC Malats N Next-generation sequencing of urologic cancers next is now Eur Urol 2014 Jul 66 (1) 4 7 24731787 \n12 Kim J Akbani R Creighton CJ Lerner SP Weinstein JN Getz G Invasive Bladder Cancer: Genomic Insights and Therapeutic Promise Clin Cancer Res 2015 Oct 21 (20) 4514 24 26473186\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "11(1)",
"journal": "Case reports in oncology",
"keywords": "Genomic profiling; Next-generation sequencing; Urothelial cancer",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "196-205",
"pmc": null,
"pmid": "29681821",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "19219610;28454257;26473186;23887298;24731787;27737647;19494856;25695927;21072204;26996659;27993330",
"title": "Genomic Profiling of Two Histologically Distinct Rare Urothelial Cancers in a Clinical Setting to Identify Potential Therapeutic Options for Treatment and Management of Disease.",
"title_normalized": "genomic profiling of two histologically distinct rare urothelial cancers in a clinical setting to identify potential therapeutic options for treatment and management of disease"
} | [
{
"companynumb": "US-PFIZER INC-2018235333",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Imatinib mesylate and the newer BCR-ABL tyrosine kinase inhibitors are the standard therapy for chronic myeloid leukemia. Although these are remarkably effective drugs, some mechanisms of resistance have been identified including drug-to-drug interactions. Here we present the case of a chronic myeloid leukemia patient with an inadequate response to imatinib due to concurrent phenytoin administration. Conspicuously low imatinib plasma trough levels were documented. Imatinib dose was increased from 400 to 800 mg with good response. In conclusion, drug-to-drug interactions should be ruled out in cases of resistance to tyrosine kinase inhibitor treatment. Potent inducers of cytochrome P450 isoenzyme CYP3A4, as phenytoin, could induce inadequate responses due to increased imatinib clearance and low imatinib trough plasma levels. Thus, this interaction should be avoided. When this is not possible, dose escalation of imatinib and measurement of plasma levels, if available, is recommended.",
"affiliations": "1 Hematology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;2 Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.;1 Hematology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;1 Hematology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;2 Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.;1 Hematology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.",
"authors": "Osorio|S|S|;Escudero-Vilaplana|V|V|https://orcid.org/0000-0003-4417-8321;Gómez-Centurión|I|I|;González-Arias|E|E|;García-González|X|X|;Díez|J L|JL|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D010672:Phenytoin; D000068877:Imatinib Mesylate; D051544:Cytochrome P-450 CYP3A",
"country": "England",
"delete": false,
"doi": "10.1177/1078155217743565",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(3)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Drug–drug interaction; imatinib; pharmacokinetic; phenytoin",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D051544:Cytochrome P-450 CYP3A; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D010672:Phenytoin; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "694-698",
"pmc": null,
"pmid": "29199506",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Inadequate response to imatinib treatment in chronic myeloid leukemia due to a drug interaction with phenytoin.",
"title_normalized": "inadequate response to imatinib treatment in chronic myeloid leukemia due to a drug interaction with phenytoin"
} | [
{
"companynumb": "ES-PFIZER INC-2018000907",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugadditional": null,
... |
{
"abstract": "Neuropathy exacerbated by exposure to cold is a dose-limiting toxicity of oxaliplatin. The incidence of this side effect is claimed to dependent on infusion rate and therefore a 2-h infusion is often recommended. For practical reasons and for the convenience of the patient, we used XELOX (Xeloda 2000 mg/m2 orally on days 1-14 and oxaliplatin 130 mg/m2 as a 30-min infusion on day 1) in patients with advanced colorectal cancer resistant to irinotecan and 5-fluorouracil. Thirty-four consecutive patients received a median of 5 courses of XELOX. Nine patients obtained partial response (PR) (response rate (RR) 26%), 11 patients no change (NC), 7 patients disease progression (PD) and 7 patients were not evaluable. Median time to progression was 4.7 (2.6-7.6) months and median survival was 7.4 (6.0-11.3) months. Sixteen patients had neuropathy grade 1, four patients grade 2 and two patients grade 3. Short-time infusion of oxaliplatin and capecitabine is an active and convenient second-line regimen with a safety profile similar to that of other oxaliplatin schedules.",
"affiliations": "Department of Oncology, Odense University Hospital, Denmark. per.pfeiffer@ouh.fyns-amt.dk",
"authors": "Pfeiffer|Per|P|;Hahn|Pernille|P|;Jensen|Helle Anita|HA|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1080/02841860310015894",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0284-186X",
"issue": "42(8)",
"journal": "Acta oncologica (Stockholm, Sweden)",
"keywords": null,
"medline_ta": "Acta Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D015179:Colorectal Neoplasms; D003841:Deoxycytidine; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases; D012189:Retrospective Studies",
"nlm_unique_id": "8709065",
"other_id": null,
"pages": "832-6",
"pmc": null,
"pmid": "14968944",
"pubdate": "2003",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Short-time infusion of oxaliplatin (Eloxatin) in combination with capecitabine (Xeloda) in patients with advanced colorectal cancer.",
"title_normalized": "short time infusion of oxaliplatin eloxatin in combination with capecitabine xeloda in patients with advanced colorectal cancer"
} | [
{
"companynumb": "DK-CIPLA LTD.-2015DK01475",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null,
... |
{
"abstract": "The authors have presented a case of ochronosis, as the incidental finding during the autopsy of a female patient, aged 59 years. It was the case of suicidal drug poisoning. Ochronosis is a rare disease, with chronic benign course, but frequently followed by complications. Histopathological criteria for the diagnosis of this disease are described in detail.",
"affiliations": null,
"authors": "Kostov|M|M|;Stanković|Z|Z|;Tatić|V|V|;Spasić|P|P|;Zdravković|M|M|",
"chemical_list": "D007328:Insulin; D011433:Propranolol; D003975:Diazepam",
"country": "Serbia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0042-8450",
"issue": "56(1)",
"journal": "Vojnosanitetski pregled",
"keywords": null,
"medline_ta": "Vojnosanit Pregl",
"mesh_terms": "D003975:Diazepam; D005260:Female; D006801:Humans; D007328:Insulin; D008875:Middle Aged; D009794:Ochronosis; D011041:Poisoning; D011433:Propranolol; D013405:Suicide",
"nlm_unique_id": "21530700R",
"other_id": null,
"pages": "89-92",
"pmc": null,
"pmid": "10230339",
"pubdate": "1999",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Ochronosis--an autopsy case report.",
"title_normalized": "ochronosis an autopsy case report"
} | [
{
"companynumb": "RS-ROCHE-1605969",
"fulfillexpeditecriteria": "1",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": null,
"druga... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.