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{
"abstract": "BACKGROUND\nVascular hemangiomas are considered to be a common finding among neonates and infants. The presence of five or more cutaneous hemangiomas may carry a higher incidence of multiple organ involvement\n\n\nMETHODS\nAn eleven week old female infant with high cardiac output heart failure and multiple cutaneous hemangiomas was referred to our clinic. Soon after birth she failed to gain weight and developed breathlessness. There was partial response to Captopril and Frusemide therapy, with development of a progressive cough. Echocardiogram and liver and brain ultrasound scans revealed heart chamber enlargement, multiple liver hemangiomas and an isolated cerebellar arterio-venous malformation (AVM). Supportive treatment for congestive heart failure combined with propranolol therapy resulted in rapid clinical response and recovery.\n\n\nCONCLUSIONS\nThe diagnosis of Diffuse Neonatal Hemangiomatosis in infants with failure to thrive and symptoms of heart failure raises the possibility of internal organ involvement. Augmentation of propranolol in such cases may cause regression of Hemangiomatosis with patient clinical improvement.\n\n\nCONCLUSIONS\nWe report our experience with a single patient of Hemangiomatosis induced heart failure which responded to propranolol combined with medication to control heart failure and failure to thrive prevention. This treatment should be further evaluated with special attention to potential adverse effects, tolerance and compliance.",
"affiliations": "Department of Pediatric Cardiology and Adults with Congenital Heart Disease, Meyer Children's Hospital, Rambam Health Care Campus, Haifa, Israel.",
"authors": "Dotan|Moshe|M|;Lorber|Avraham|A|",
"chemical_list": null,
"country": "Norway",
"delete": false,
"doi": "10.1111/apa.12184",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0803-5253",
"issue": "102(5)",
"journal": "Acta paediatrica (Oslo, Norway : 1992)",
"keywords": null,
"medline_ta": "Acta Paediatr",
"mesh_terms": "D001165:Arteriovenous Malformations; D005260:Female; D006333:Heart Failure; D006391:Hemangioma; D006801:Humans; D007223:Infant; D008113:Liver Neoplasms",
"nlm_unique_id": "9205968",
"other_id": null,
"pages": "e232-8",
"pmc": null,
"pmid": "23432737",
"pubdate": "2013-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Congestive heart failure with diffuse neonatal hemangiomatosis--case report and literature review.",
"title_normalized": "congestive heart failure with diffuse neonatal hemangiomatosis case report and literature review"
} | [
{
"companynumb": "IL-MYLANLABS-2015M1001863",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PROPRANOLOL\\PROPRANOLOL HYDROCHLORIDE"
},
"d... |
{
"abstract": "BACKGROUND\nAn increasing number of end-stage heart failure patients are supported with left ventricular assist device (LVAD) implantation and must be maintained on consistent anticoagulation. These patients are experiencing prolonged survival and, in some, there is development of new biliary disease. However, safety and outcomes of this procedure in this unique patient group is not well reported.\n\n\nMETHODS\nThis was a retrospective single-center review. All adult patients supported on an implanted, continuous flow LVAD from 2007 to 2016 were screened. Baseline characteristics, laboratory values, and operative details were collected through retrospective chart review and an institutional LVAD registry.\n\n\nRESULTS\nOf the 798 patients screened, 5 (0.63%) underwent laparoscopic cholecystectomy after LVAD implantation. In 4 patients (80%), the indication for surgery was symptomatic cholelithiasis and 1 patient (20%) had symptomatic acalculous cholecystitis. The average time from LVAD implantation to laparoscopic cholecystectomy was 254 ± 158 days. Average (corrected) preoperative international normalized ratio (INR) was 1.34 ± 0.30. Average preoperative hemoglobin was 11.28 ± 2.41 g/dL. All patients were on warfarin preoperatively and admitted before their operations for bridging with a heparin drip. Average postoperative change in hemoglobin was -1.16 ± 1.97 g/dL. The only major postoperative complication in this cohort was the development of an abdominal wall hematoma in 1 patient requiring operative evacuation. The average length of stay was 13.2 ± 4.6 days. Three patients (60%) took an average of 12 days to reach therapeutic INR.\n\n\nCONCLUSIONS\nLaparoscopic cholecystectomies can be performed safely in LVAD patients. Prolonged hospital stay is mainly owing to time required to reach a therapeutic INR postoperatively.\n\n\nMETHODS\nII, prognostic.",
"affiliations": "1 School of Medicine, Duke University Medical Center, Durham, North Carolina.;2 Division of Cardiothoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina.;2 Division of Cardiothoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina.;3 Division of Cardiothoracic Anesthesiology, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina.;4 Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.;2 Division of Cardiothoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina.;2 Division of Cardiothoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina.;5 Division of Acute Care Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina.",
"authors": "Suresh|Visakha|V|;Bishawi|Muath|M|;Bryner|Benjamin|B|;Manning|Michael|M|;Patel|Chetan|C|;Milano|Carmelo|C|;Schroder|Jacob|J|;Sommer|Courtney|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/lap.2018.0431",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1092-6429",
"issue": "29(4)",
"journal": "Journal of laparoendoscopic & advanced surgical techniques. Part A",
"keywords": "LVAD; laparoscopic cholecystectomy; patient outcomes",
"medline_ta": "J Laparoendosc Adv Surg Tech A",
"mesh_terms": "D000368:Aged; D017081:Cholecystectomy, Laparoscopic; D005260:Female; D005705:Gallbladder Diseases; D006333:Heart Failure; D006353:Heart-Assist Devices; D006801:Humans; D007902:Length of Stay; D008297:Male; D012042:Registries; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "9706293",
"other_id": null,
"pages": "441-444",
"pmc": null,
"pmid": "30452314",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcomes of Laparoscopic Cholecystectomy in Patients Supported with a Left Ventricular Assist Device.",
"title_normalized": "outcomes of laparoscopic cholecystectomy in patients supported with a left ventricular assist device"
} | [
{
"companynumb": "US-TEVA-2019-US-1055694",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "The difference in coagulation state during the periprocedural period of atrial fibrillation (AF) ablation among patients with uninterrupted anticoagulation has not been fully elucidated.\n\n\n\nThe purpose of this study was to compare periprocedural trends in coagulation markers among patients on uninterrupted anticoagulation for AF ablation.\n\n\n\nIn total, 275 consecutive patients who underwent AF ablation were evaluated. These patients were divided according to the anticoagulant they received into the dabigatran group (DG) (n = 64); rivaroxaban group (RG) (n = 62); apixaban group (AG) (n = 60); edoxaban group (EG) (n = 59); and warfarin group (WG) (n = 30). The trends in coagulation markers and the rate of silent stroke (SS) confirmed by postoperative magnetic resonance imaging were evaluated.\n\n\n\nThe fibrin monomer complex (FMC) level on postoperative day 1 and the prothrombin fragment 1+2 (PF1+2) levels on the operative day and postoperative day 1 were higher in DG than in the other groups (P <.05, <.001, and <.001, respectively). The incidence of SS in DG (17%) was significantly higher than in RG (6%), AG (3%, EG (7%), or WG (4%) (P <.05). Dabigatran use independently predicted the occurrence of SS (odds ratio 4.12; 95% confidence interval 1.37-12.7; P <.05).\n\n\n\nFMC and PF1+2 levels during the periprocedural period of AF ablation were higher in DG than in the other groups. Dabigatran use independently predicted the occurrence of SS.",
"affiliations": "Department of Cardiology, Chubu Rosai Hospital, Nagoya, Japan. Electronic address: cyphernation@yahoo.co.jp.;Department of Cardiology, Chubu Rosai Hospital, Nagoya, Japan.;Department of Cardiology, Chubu Rosai Hospital, Nagoya, Japan.;Department of Cardiology, Chubu Rosai Hospital, Nagoya, Japan.;Department of Cardiology, Chubu Rosai Hospital, Nagoya, Japan.;Department of Cardiology, Chubu Rosai Hospital, Nagoya, Japan.;Department of Cardiology, Chubu Rosai Hospital, Nagoya, Japan.;Department of Cardiology, Chubu Rosai Hospital, Nagoya, Japan.;Department of Cardiology, Chubu Rosai Hospital, Nagoya, Japan.;Department of Cardiology, Chubu Rosai Hospital, Nagoya, Japan.;Department of Cardiology, Aichi-Medical University, Nagakute, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.",
"authors": "Nagao|Tomoyuki|T|;Higo|Sayaka|S|;Suzuki|Hitomi|H|;Teshima|Yuto|Y|;Matsunaga|Syun|S|;Harada|Kazuhiro|K|;Shinoda|Norihiro|N|;Harada|Ken|K|;Kato|Masataka|M|;Marui|Nobuyuki|N|;Amano|Tetsuya|T|;Inden|Yasuya|Y|;Murohara|Toyoaki|T|",
"chemical_list": "D000925:Anticoagulants; D015415:Biomarkers",
"country": "United States",
"delete": false,
"doi": "10.1016/j.hrthm.2019.10.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1547-5271",
"issue": "17(3)",
"journal": "Heart rhythm",
"keywords": "Atrial fibrillation; Catheter ablation; Coagulation markers; Direct oral anticoagulant; Silent stroke",
"medline_ta": "Heart Rhythm",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D015415:Biomarkers; D001777:Blood Coagulation; D017115:Catheter Ablation; D005260:Female; D006801:Humans; D008297:Male; D059035:Perioperative Period; D011379:Prognosis; D011446:Prospective Studies; D020521:Stroke",
"nlm_unique_id": "101200317",
"other_id": null,
"pages": "391-397",
"pmc": null,
"pmid": "31606462",
"pubdate": "2020-03",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Prospective comparison of periprocedural coagulation markers among uninterrupted anticoagulants for atrial fibrillation ablation.",
"title_normalized": "prospective comparison of periprocedural coagulation markers among uninterrupted anticoagulants for atrial fibrillation ablation"
} | [
{
"companynumb": "JP-JNJFOC-20191134006",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": "1",
... |
{
"abstract": "To describe retinal manifestations seen in patients associated with COVID-19 infection at a multi-specialty tertiary care hospital in Southern India.\nIn this retrospective chart review, all consecutive cases presenting to the Retina-Uveitis service from May 2020 to January 2021 with retinal manifestations associated with COVID-19 infection or its sequelae or as a result of treatment given for COVID-19 were included.\n: Of the 7 patients, 3 were female, and 4 were male. Four patients had onset of symptoms during the active phase of COVID-19 infection. Four had bilateral and three had unilateral involvement. The manifestations ranged from mild to vision threatening. Vision threatening manifestations included infections: endogenous endophthalmitis, candida retinitis and tubercular choroidal abscess and bilateral pre-foveal hemorrhages. Milder manifestations included paracentral acute middle maculopathy, central serous chorio-retinopathy and voriconazole induced visual symptoms. Final visual acuity was 6/36 or better in the four severe cases and 6/9 or better in the mild cases.\nThis study highlights the retinal manifestations associated with COVID-19 infection and its sequelae. As these patients presented with an association with COVID-19 (either during or after recovery), ophthalmologists should be vigilant and screen for such entities in case of complaints of visual symptoms or in the presence of systemic sepsis. The outcomes can be good with prompt and aggressive management.",
"affiliations": "Retina-Uveitis Service, Department of Ophthalmology, Apollo Health City, Hyderabad, Telangana, India.;Uveitis Service, L. V. Prasad Eye Institute, Hyderabad, Telangana, India.;Retina-Uveitis Service, Department of Ophthalmology, Apollo Health City, Hyderabad, Telangana, India.",
"authors": "Goyal|Mallika|M|;Murthy|Somasheila I|SI|;Annum|Sridhar|S|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijo.IJO_403_21",
"fulltext": "\n==== Front\nIndian J Ophthalmol\nIndian J Ophthalmol\nIJO\nIndian Journal of Ophthalmology\n0301-4738\n1998-3689\nWolters Kluwer - Medknow India\n\n33913876\nIJO-69-1275\n10.4103/ijo.IJO_403_21\nExpedited Publication, Original Article\nRetinal manifestations in patients following COVID-19 infection: A consecutive case series\nGoyal Mallika\nMurthy Somasheila I 1\nAnnum Sridhar\nRetina-Uveitis Service, Department of Ophthalmology, Apollo Health City, Hyderabad, Telangana, India\n1 Uveitis Service, L. V. Prasad Eye Institute, Hyderabad, Telangana, India\nCorrespondence to: Dr. Mallika Goyal, Senior Consultant, Retina-Vitreous and Uveitis, Apollo Health City Campus, Jubilee Hills, Hyderabad, Telangana, India. E-mail: drmallikagoyal1@gmail.com\n5 2021\n30 4 2021\n69 5 12751282\n17 2 2021\n27 2 2021\n04 3 2021\nCopyright: © 2021 Indian Journal of Ophthalmology\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nPurpose:\n\nTo describe retinal manifestations seen in patients associated with COVID-19 infection at a multi-specialty tertiary care hospital in Southern India.\n\nMethods:\n\nIn this retrospective chart review, all consecutive cases presenting to the Retina-Uveitis service from May 2020 to January 2021 with retinal manifestations associated with COVID-19 infection or its sequelae or as a result of treatment given for COVID-19 were included.\n\nResults:\n\nOf the 7 patients, 3 were female, and 4 were male. Four patients had onset of symptoms during the active phase of COVID-19 infection. Four had bilateral and three had unilateral involvement. The manifestations ranged from mild to vision threatening. Vision threatening manifestations included infections: endogenous endophthalmitis, candida retinitis and tubercular choroidal abscess and bilateral pre-foveal hemorrhages. Milder manifestations included paracentral acute middle maculopathy, central serous chorio-retinopathy and voriconazole induced visual symptoms. Final visual acuity was 6/36 or better in the four severe cases and 6/9 or better in the mild cases.\n\nConclusion:\n\nThis study highlights the retinal manifestations associated with COVID-19 infection and its sequelae. As these patients presented with an association with COVID-19 (either during or after recovery), ophthalmologists should be vigilant and screen for such entities in case of complaints of visual symptoms or in the presence of systemic sepsis. The outcomes can be good with prompt and aggressive management.\n\nCOVID-associated mycoses\nCOVID 19\nendophthalmitis\nocular manifestations\nparacentral acute middle maculopathy\nretinal manifestations\n==== Body\nThe coronavirus disease 2019 (COVID-19) which is caused by the newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global pandemic.[1] Apart from severe systemic disease, various ophthalmic manifestations have been reported, ranging from anterior segment involvement such as conjunctivitis, severe keratitis and acute angle closure; retinal such as microangiopathy, cotton wool spots, hemorrhages and retinal vascular occlusions; and neuro-ophthalmic manifestations including optic neuritis, extra-ocular muscle palsies and idiopathic intracranial hypertension with papilledema.[123] These are attributed to: 1) a direct result of the viral infection and its cytopathological effects; 2) adverse effects of the pharmacological therapy administered for COVID-19 infection; 3) manifestations related to prolonged hospitalization and intensive care (such as nosocomial infections) 4) and lastly due to alterations in the host immune response. Systemic immunosuppression by decreased production of CD4 + T and CD8 + T cells and stimulation of cytokines is known to occur in COVID-19 infection thus predisposing to secondary opportunistic infections (especially fungal) during the middle and late stage of the disease.[45] This state of immunosuppression is further augmented by the use of systemic steroids and other immunosuppressives that are necessary in the management of COVID-19 infection.[6]\n\nWhile previous publications have reported retinal involvement occurring mainly as vascular-related phenomenon,[7] with central retinal arterial occlusion and central retinal vein occlusion[8910] being the severe ones reported so far, there are very few reports on other retinal findings. Herein we report a series of cases of retinal manifestations in patients associated with COVID-19 infection, ranging from mild to vision threatening conditions.\n\nMethods\n\nThis was a retrospective case series, approved by the institutional review board and the research adhered to the tenets of the Declaration of Helsinki. Those patients presenting to either to the out-patient retina-uveitis department or were hospitalized and identified with retinal problems associated with COVID-19 infection or sequelae or treatment, seen between May 2020 to January 2021 were included. All patients had positive real-time reverse transcription-polymerase chain reaction (RT-PCR) for SARS-CoV-2 from a nasopharyngeal swab during the active phase of the COVID-19 infection. The details of the COVID-19 infection such as the use of systemic steroids and presence of co-morbid conditions as well as detailed ocular history were noted when available. Ambulatory patients underwent a complete eye examination which included visual acuity test, slit-lamp examination, non-contact tonometry and binocular indirect ophthalmoscopy and imaging as applicable {B-scan ultrasonography (B-scan), spectral domain optical coherence tomography (OCT) and Humphrey visual fields analysis (HVF)}. Cases where physical consultation or clinical documentation of the condition was not available (such as teleconsultation diagnosis) or poor quality of clinical photographs that would hinder the assessment of clinical course were excluded from this series.\n\nResults\n\nThere were four male and three female patients, with age ranging from 23 to 75 years. Three of seven patients were admitted at initial examination, of which two were in intensive care. Diagnosis was divided as severe manifestations which included: fungal endophthalmitis, candida retinitis, tubercular choroiditis and pre-foveal hemorrhages and mild manifestations: acute macular neuro-retinopathy, central serous chorioretinopathy and voriconazole-induced transient visual disturbance. 4/7 had unilateral involvement. 3/7 developed symptoms during active COVID-19 infection and 4/7 received systemic steroids as part of therapy for COVID-19. Co-morbid conditions were present in 6/7 cases and included: steroid-induced diabetes mellitus in two patients, one patient had three factors: history of renal transplant, diabetes mellitus and systemic aspergillosis; candidemia with renal infection in one patient, Pseudomonas septicaemia with thrombocytopenia in one and splenic abscess in one. At last follow-up, all patients had improvement in visual recovery ranging from 6/36 to 6/9. Table 1 lists the demographic, co-morbid factors and ocular details of each patient.\n\nTable 1 Clinical characteristics of the seven patients\n\nCase\tAge/Gender\tEye\tCOVID Infection timeline\tUse of steroids\tSystemic disease, status, investigations\tOnset and duration of symptoms\tVision\tExamination\tDiagnosis\tTreatment\tFinal outcome\t\n1\t42/M\tRE\t6 weeks prior to ocular symptoms\tIntravenous steroids for five days\tSteroid induced diabetes\tOnset: while on COVID treatment 4 weeks duration\tHand movements\tConjunctival congestion, cells 3+, hypopyon, dense vitreous exudates, fungal balls\tFungal endophthalmitis (microbiology negative)\tPars plana vitrectomy + intravitreal antifungals followed by oral antifungals for 6 weeks\tResolved with 6/9 vision\t\n2\t75/M\tRE\tNot available\tNot available\tCandida septicemia, and candida renal infection during COVID 19, blood and urine cultures positive. Generalized compromised status\tNot noticed by the patient\tCounting fingers at 2 meters\t2+cells, 1+vitreous cells three retinitis lesions\tCandida retinitis\tOral fluconazole and voriconazole for 6 weeks, followed by intravitreal Amphotericin B and voriconazole\t6/36, slow response\t\n3\t59/F\tRE\tCOVID-19 infection two months prior\tOral steroids used for 4 weeks\tNocturnal pyrexia, whole body imaging revealed splenic abscesses\t4 weeks\t6/9\t1+ vit cells, choroidal abscess with scarring of edges and miliary lesions\tIntraocular tuberculosis\tAnti-tubercular therapy, lesions resolving over 6 weeks\t6/6\t\n4\t32/M\tBoth eyes\tCOVID 4 months ago\tNo\tNil\t3 days\t6/6\tBilateral greyish white retinal lesions\tAcute Macular Neuroretinopathy (AMN) and Paracentral Acute Middle Maculopathy (PAMM)\tObservation\t6/6\t\n5\t27.F\tLE\tCOVID-19 infection two weeks prior\tOn oral steroids for one week\tNil\tOne week\t6/18\tSerous detachment of macula\tCSCR\tNIL\t6/6\t\n6\t32/F\tBES\tCOVID infection 6 weeks prior\tYes\tPseudomonas sepsis and thrombocytopenia, admitted in intensive care unit\tOne month\tCounting fingers at 4 meters\tBilateral prefoveal hemorrhages\tRetinal hemorrhages\tNIL\t6/18 and 6/36\t\n7\t40/M\tBES\tCOVID infection 6 weeks prior\tYes\tIntensive care unit admission for systemic aspergillosis, status post renal transplant and Diabetes mellitus\t3 weeks\t6/6\tNormal examination, visual fields: normal\tVoriconazole induced transient visual disturbance\tDecreasing the dose of voriconazole, recovery for one week followed by relapse after resuming therapy\t6/6\t\n\nCase Reports\n\nCase 1: Presumed fungal endogenous endophthalmitis\n\nA 46-year-old man presented with a 4-week history of right eye (RE) ocular pain, redness and visual loss. He was diagnosed and treated for COVID-19 infection two weeks before onset of symptoms and had received home therapy of intravenous steroids for five days as a result of which he had developed steroid-induced diabetes. At presentation, visual acuity was hand motions; examination showed ciliary congestion, anterior chamber showed 2 + cells and 1 mm hypopyon and there were dense vitreous exudates [Fig. 1a]. B-scan revealed vitreous echoes and attached retina. A diagnosis of endogenous endophthalmitis was made and he underwent pars plans vitrectomy with injection of intravitreal vancomycin 1.0 mg, amikacin 300 ug, amphotericin-B 5 ug and voriconazole 100 ug. On table the vitreous exudates appeared dry with snowball like accumulations suggesting fungal infection [Fig. 1b and c]. Thick sheets of pre-retinal exudates were seen in the inferior periphery. The vitreous biopsy samples were sent for microbiological processing for smears (Grams and KOH), and aerobic and anerobic cultures by plating on blood and chocolate agar and fungal cultures by plating on Sabouraud dextrose agar. All were negative. Oral voriconazole was continued for 6 weeks. The infection resolved rapidly with visual recovery to 6/9 six weeks later [Fig. 1d].\n\nFigure 1 (a) Intraoperative photograph of the right eye shows severe ciliary congestion and hypopyon. (b) Intra-operative photograph during pars plana vitrectomy shows dense and dry vitreous lesions (asterisk) (c) Snowball like opacities noted in the inferior periphery (d) Same eye shows compete resolution with clear media and normal fundus at 6 weeks\n\nCase 2: Candida retinitis\n\nA 57-year-old male, diabetic and hypertensive, was hospitalized for severe Candida septicemia, with renal infection during COVID-19 infection. Blood and urine cultures were positive for Candida tropicalis. The patient did not complain of loss of vision but on testing, his visual acuity had dropped to counting fingers at 2 meters in his RE. LE was normal. RE showed 2 + cells and flare and 1+ vitreous cells and three well-circumscribed retinitis lesions in his RE, one involving the center of macula [Fig. 2a and b]. He was switched from systemic fluconazole to intra-venous voriconazole 200 mg twice daily due to the superior ocular bioavailability of the latter. After two weeks, the retinitis appeared to be resolving [Fig. 2c] but subsequently worsened [Fig. 2d and e]. Intravitreal amphotericin-B 5 ug and voriconazole 100 ug were given. Ten days later, there was increase in the vitreous haze, but the original retinitis lesions were resolving [Fig. 2f and g]. As he was not systemically fit to undergo surgery, intervention was deferred and the ocular condition was closely monitored. Four weeks after the intravitreal injection, the vitreous inflammation persisted but retinitis showed early signs of resolution [Fig. 2h and i]. Systemic voriconazole was continued for the renal and ocular infection and 3 months following the intravitreal injection his visual acuity improved to 6/36 with complete resolution of the vitreous inflammation and retinitis [Fig. 2j-l]. He was advised to continue oral voriconazole for a further 4 weeks.\n\nFigure 2 (a-k) Creamy-white candida retinitis lesions at presentation (a), macular involvement (b) Two weeks after voriconazole (c) Six weeks later: increasing activity (d and e) 10 days after intravitreal injections new vitreous exudates are noted (f); older retinitits lesions show some resolution (g)The lesions and vitreous exudates persist with some resolution after 4 weeks of injections. 3 months review: complete resolution of vitreous inflammation and retinitis, (j-l) with scarring noted at the site of the original lesions\n\nCase 3: Choroidal abscess\n\nA 59-year-old lady presented with complaint of RE visual deterioration and nocturnal low-grade fever for 4 weeks. Symptoms had started 2 months ago during COVID-19 infection, for which systemic steroids were given for 4 weeks. Locally she had undergone Magnetic Resonance Imaging (MRI) of the whole body for her pyrexia, which had revealed abdominal abscesses and she had received systemic antibiotics for the same with no response. On examination, visual acuity was 6/9 and 6/6 in the RE and LE respectively. LE was normal. RE showed 1 + vitreous cells and a large choroidal abscess supero-temporal to the macula [Fig. 3a]. The abscess showed central activity, scarring at its edges and multiple discrete yellow miliary lesions around it [Fig. 3b and c]. OCT revealed vitreous traction over the lesion [Fig. 3d]. Serological investigations to look for possible etiological causes which included: complete blood picture, Mantoux skin test, Quantiferon-TB gold test, Venereal disease research laboratory test, Treponema pallidum hemagglutinin assay and blood and urine cultures, were negative. Whole body Positive Emission Tomography/Computed tomography (PET/CT) scan revealed multiple hypodense lesions in the spleen, the largest being 43 millimeters in diameter, low for hypermetabolic activity. Based on the clinical appearance of the chorio-retinal lesions, a provisional diagnosis of tuberculosis was considered. After discussion with her internist, a therapeutic trial of 4-drug anti-tubercular therapy (ATT) was started, with the intention of considering vitreous biopsy in case of worsening. She was closely followed up every week and the lesions showed improvement. Six-weeks after initiating ATT the choroidal abscess and the miliary lesions had resolved significantly [Fig. 3e and f]. The splenic abscesses had also started showing resolution. She was continued on 4-drug ATT for the first two months with the intention to continue 2-drug ATT for 10 months.\n\nFigure 3 (a) Large choroidal abscess with active appearing center and resolving activity at edges supero-temporal to the right macula. (b and c) Multiple miliary lesions around the choroidal abscess in temporal and inferotemporal fundus. Lesions are larger and irregular closer to the abscess, becoming smaller, punctate with smoother edges further from it. (d) OCT showing epiretinal membrane and vitreous traction over the choroidal abscess. (e and f) Significant resolution of choroidal abscess and miliary lesions 6 weeks after initiating anti-tubercular therapy\n\nCase 4. Acute macular neuroretinopathy (AMN) and paracentral acute middle maculopathy (PAMM)\n\nA 32-year-old man presented with 3-day onset of paracentral and triangular negative scotoma in RE infero-temporal visual field. He had recovered from COVID-19 infection 4 months prior. LE was asymptomatic. He had undergone a complete health check-up including serological investigations a month prior which were normal. RE fundus revealed a triangular deeper retinal greyish-white lesion located supero-nasal to center of macula [Fig. 4a]. OCT over the corresponding area showed disruption in the outer retinal layers [Fig. 4b], hyper-reflective lesions in superficial retinal layers with shadowing of deeper retina [Fig. 4c and d]. The entire inner retinal surface just inferior to foveal center showed hyper-reflectivity [Fig. 4e]. LE fundus revealed small greyish-white lesion nasal to the foveal center and multiple similar lesions inferonasal and temporal to the center [Fig. 4f]. OCT revealed a single hyper-reflective lesion in the superficial retina with underlying shadowing temporal to the center [Fig. 4g] and hyper-reflectivity of the entire inner retinal surface [Fig. 4h]. Based on the characteristic symptoms, the fundus lesions and OCT findings he was diagnosed as post COVID-19 RE symptomatic AMN, and bilateral asymptomatic PAMM. He was placed under observation.\n\nFigure 4 (a) Triangular greyish-white lesion (asterisk) of AMN (b) Corresponding OCT shows disruption of external retinal layers (c and d) Focal areas of hyper-reflectivity with deeper shadowing of PAMM. (e) OCT right eye: diffuse hyper-reflectivity of entire inner retinal surface (f) Small greyish-white lesions in superficial retina nasal, inferonasal and temporal to the foveal center in left eye. (g) Corresponding OCT shows hyper-reflective lesion with underlying shadowing (h) OCT left eye showing diffuse hyper-reflectivity of the inner retinal surface\n\nCase 5: Central serous chorioretinopathy (CSCR)\n\nA 27-year-old female patient presented with central vision deterioration in LE of 10-days duration. She had recovered from COVID-19 infection two weeks prior for which she had been on oral steroids. RE was normal; left eye visual acuity was 6/18. Examination showed no signs of inflammation. Fundus examination revealed serous detachment of the macula and was confirmed by OCT [Fig. 5]. She was observed and the symptoms resolved spontaneously a few weeks later.\n\nFigure 5 OCT left eye of a young female treated with oral steroids for COVID-19 showing serous macular detachment\n\nCase 6: Post-COVID-19 sepsis related bilateral pre-foveal hemorrhages\n\nA 32-year-old lady in the ICU complained of rapid loss of central vision in both eyes (one month after COVID-19 infection). She was admitted with fever and Pseudomonas sepsis while still on treatment for COVID-19 infection. She had severe anemia (hemoglobin 6.8 gm%), leukocytosis (total leucocyte count 13000/mm3) and thrombocytopenia (platelets 72,000/mm3). Vision was counting fingers at 4 meters. Fundus examination showed bilateral pre-foveal hemorrhages. Four weeks later she followed up in the outpatient department and reported no improvement. Her visual acuity was recorded as 6/18 in and 6/36 in the RE and LE respectively. Bilateral retinal hemorrhages were noted as before. The corresponding OCT showed pre-foveal location with underlying shadowing [Fig. 6a-d]. A month later her visual acuity had improved to 6/6 and 6/9 in the RE and LE respectively. The pre-foveal heme had resolved almost completely [Fig. 6e and f] although the RE OCT showed residual paracentral pre-foveal heme and the LE OCT now revealed some intraretinal heme [Fig. 6g and h]. She was advised to follow-up after 3 months.\n\nFigure 6 Bilateral pre-foveal hemorrhage of the right (a) and left eye (b) in a young lady with post COVID-19 sepsis. OCT of the right eye (c) and left eye (d) showing pre-foveal location of the hemorrhage with underlying shadowing. One month later, there is almost complete resolution of the pre-foveal heme in the RE (e) and LE (f) Corresponding optical coherence tomography scans show residual paracentral pre-foveal heme in the RE (g) and intra-retinal heme in the LE (h)\n\nCase 7: Voriconazole-induced transient visual disturbance\n\nA 40-year-old gentleman complained of multiple non-specific but distressing visual symptoms including severe visual blur and extreme brightness and flashes of light for 3 weeks. He was admitted in ICU with invasive systemic aspergillosis and was on intravenous voriconazole (300 mg twice daily) for 4 weeks as microbiology isolates had shown sensitivity only to voriconazole. The systemic aspergillosis had been diagnosed during his COVID-19 infection, which he had developed 6 weeks prior. History was significant for renal transplant 3 years back and diabetes mellitus for 2 months (onset after recovery from COVID-19 infection). He was also on tablet augmentin 1 gram twice daily; oral mycophenolate mofetil 360 mg twice daily; oral prednisolone 5 mg daily; tacrolimus 0.5 mg twice daily; and subcutaneous insulin. The BCVA was 6/6 BES. Color vision (using Ishihara charts), pupil response to light, anterior segment and fundus evaluation were within normal limits in both eyes each eye. Perimetry (Humphrey’s visual field analysis central 24-2 program) was normal. A review of all the medications that the patient was on was done and based on the onset of his symptoms, a possibility of voriconazole-induced visual symptoms was made. The dose of voriconazole was reduced with improvement in symptoms within a week. However, the drug had to be stepped up in view of his systemic condition of invasive aspergillosis and the patient again reported recurrence of his visual symptoms.\n\nDiscussion\n\nWe have described a series of cases with retinal manifestations, which were associated with COVID-19 infection, with symptoms that started either during the infection or soon after resolution. Of the three cases of intra ocular infection in our series, in the case of presumed endogenous endophthalmitis the systemic focus of infection could not be detected. The patient had a complete recovery with surgery and antifungals. We postulate that the severe infection in our otherwise healthy patient could be as a result of immunosuppression caused by COVID-19 infection, and the steroids used for its management.\n\nThe second case which was retinal candidiasis in COVID-19 infection has not yet been reported. Contrary to the first case, the source was obvious as this patient had invasive candidemia. The patient was also diabetic, which no doubt contributed to the risk. It is recommended that surveillance for systemic fungal infections should be done in severe COVID-19 infection.[4511]\n\nOur third case of intra-ocular infection was a diagnostic challenge. Systemic tuberculosis associated with COVID-19 has been reported,[121314] however, choroidal abscess due to tuberculosis, in association with recent COVID-19 has not. Our patient tested negative for both Mantoux test and interferon gamma assay which could indicate miliary tuberculosis. The value of PET scan imaging in tuberculosis has been well documented. It has been used to detect tubercular granulomas and assess disease activity.[15] In our case, while the splenic lesions could be ruled as non-malignant, confirmatory diagnosis for tuberculosis would necessitate a tissue biopsy. On the other hand, ocular choroidal lesions with their pattern of peripheral scarring in our case leaned towards a diagnosis of ocular tuberculosis.[16] The patient was not keen to undergo any invasive diagnostic evaluation either systemically or ocular and thus we resorted to a therapeutic trial, following which the patient had improvement in both the ocular and systemic condition. One more feature in our case was the presence of yellowish inflammatory deposits around the chorio-retinal lesions, which have been described with syphilitic retinitis.[17] However, the relevant investigations were negative for syphilis and the clinical picture appeared to be consistent with tuberculosis.\n\nWe had a case of strikingly remarkable pre-foveal hemorrhages. This was secondary to thrombocytopenia in systemic Pseudomonas sepsis. Sepsis and signs of multi-organ injury typical of sepsis occur in approximately 2-5% of those with COVID-19 after approximately 8-10 days.[1819] Thrombocytopenia is a known complication of sepsis.[20] While bilateral simultaneous pre-foveal hemorrhage as a complication of post COVID-19 sepsis has not been reported, bilateral premacular sub-hyaloid hemorrhage unmasking COVID-19 infection has been reported.[21]\n\nWe had one case of PAMM/AMN. These are rare conditions characterized by the sudden onset of single or multiple paracentral scotomas, which persist indefinitely or may resolve partially over months.[2223] Most scotomas spare the fixation by being perifoveal and often do not cause significant visual loss in the affected eye.[24] The exact etiology is not clear although microvascular abnormality of the retina is hypothesized as well as altered coagulation status[2224] We did not advice inflammatory markers or coagulation profile markers due to affordability for our patient. There was a typical abrupt onset of a paracentral scotoma corresponding to a triangular greyish-white lesion in the RE fundus and an area of disruption of the external retinal layers on OCT suggesting symptomatic AMN. In addition, presence of other asymptomatic parafoveal greyish lesions in left eye fundus and bilateral OCT features of hyper- reflective lesions in superficial retinal layers suggested bilateral asymptomatic PAMM. Both PAMM and AMN have been reported following viral illness in as high as 47.5%. of cases[22] In association with COVID-19, there are only two reports so far, one representing post-infectious complication[25] and another where PAMM was associated with acute myeloid leukemia and co-existing COVID-19 infection.[26]\n\nWe also had retinal manifestations due to the adverse effects of medication used for the management of COVID-19 infection or its sequelae. CSCR is a recognized complication of steroid use[27] and hence its association with COVID-19 management is of course anticipated. However, there are no specific case reports of CSCR in patients with COVID-19 infection.\n\nVoriconazole is known to cause reversible visual symptoms in 18-30% patients including altered light perception, photopsia, photophobia, blurred vision, or color vision changes[28] but this often remains a diagnosis of exclusion. The retina is believed to be the site of the visual disturbances because reversible decreases in the amplitude of the electroretinogram (ERG) have been documented in voriconazole-treated humans.[29] Fortunately, these effects are completely reversible, and are not reported with the other azoles such as fluconazole and itraconazole.[28] In our patient, the best corrected visual acuity, color vision, ocular findings and perimetry were normal ruling out any ocular or visual pathways lesion accounting for the visual symptoms. Considering the association of systemic fungal infections with COVID-19 infection, voriconazole-induced visual symptoms must remain as one of the possible causes of inexplicable visual symptoms in a setting of normal ocular examination in a COVID-19 patient, as it is the easiest to reverse by simply decreasing or stopping the medication.\n\nConclusion\n\nWhile there are isolated case reports of COVID-19 related retinal manifestations, this is the first single large case series of diverse retinal manifestations of COVID-19 infection, some of these not reported, ranging from medication related mild adverse effects and post viral complications like PAMM and pre-foveal hemorrhages to grave sight-threatening ocular infections such as endophthalmitis, candida retinitis & tubercular choroidal abscess. Even in the severe cases, we could institute therapy promptly and our patients were able to recover well, suggesting an overall good prognosis in this subset of patients.\n\nDeclaration of patient consent\n\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand 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\n\nFunding provided by Hyderabad Eye Research Foundation, Hyderabad, India for Dr Somasheila I. Murthy. The funders had no role in the preparation, review or approval of the manuscript.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\n1 Bertoli F Veritti D Danese C Samassa F Sarao V Rassu N Ocular findings in COVID-19 patients:A review of direct manifestations and indirect effects on the eye J Ophthalmol 2020 2020 4827304 doi:10.1155/2020/4827304 32963819\n2 Douglas KA Douglas VP Moschos MM Ocular manifestations of COVID-19 (SARS-CoV-2):A critical review of current literature In Vivo 2020 34 3 Suppl 1619 28 32503820\n3 Lani-Louzada R Ramos CdVF Cordeiro RM Sadun AA Retinal changes in COVID-19 hospitalized cases PLoS One 2020 15 e0243346 33270751\n4 Song G Liang G Liu W Fungal co-infections associated with global COVID-19 pandemic:A clinical and diagnostic perspective from China Mycopathologia 2020 7 1 8\n5 Lei Y Song Y Shu Y Zhao Y Huo X Wang H Fungal antigenemia in patients with severe Coronavirus disease 2019 (COVID-19):The facts and challenges J Microbiol Immunol Infect 2020 53 657 9 32482367\n6 Sanders JM Monogue ML Jodlowski TZ Cutrell JB Pharmacologic treatments for coronavirus disease 2019 (COVID-19):A review JAMA 2020 323 1824 36 32282022\n7 Pereira LA Soares LC Nascimento PA Cirillo LR Sakuma HT da Veiga GL Retinal findings in hospitalized patients with severe COVID-19 Br J Ophthalmol 2020 doi:10.1136/bjophthalmol-2020-317576\n8 Montesel A Bucolo C Mouvet V Moret E Eandi CM Case report:Central retinal artery occlusion in a covid-19 patient Front Pharmacol 2020 11 588384 doi:10.3389/fphar. 2020.588384 33424598\n9 Acharya S Diamond M Anwar S Glaser A Tyagi P Unique case of central retinal artery occlusion secondary to COVID-19 disease ID Cases 2020 21 e00867 doi:10.1016/j.idcr. 2020.e00867 32572363\n10 Yahalomi T Pikkel J Arnon R Pessach Y Central retinal vein occlusion in a young healthy COVID-19 patient:A case report Am J Ophthalmol Case Rep 2020 20 100992 doi:10.1016/j.ajoc. 2020.100992 33225111\n11 Antinori S Bonazzetti C Gubertini G Capetti A Pagani C Morena V Tocilizumab for cytokine storm syndrome in COVID-19 pneumonia:An increased risk for candidemia? Autoimmun Rev 2020 19 102564 doi:10.1016/j.autrev. 2020.102564 32376396\n12 Stochino C Villa S Zucchi P Parravicini P Gori A Raviglione MC Clinical characteristics of COVID-19 and active tuberculosis co-infection in an Italian reference hospital Eur Respir J 2020 56 2001708 doi:10.1183/13993003.01708-2020 32482787\n13 Tadolini M Codecasa LR García-García JM Blanc FX Borisov S Alffenaar JW Active tuberculosis, sequelae and COVID-19 co-infection:First cohort of 49 cases Eur Respir J 2020 56 2001398 doi:10.1183/13993003.01398-2020 32457198\n14 Crisan-Dabija R Grigorescu C Pavel CA Artene B Popa IV Cernomaz A Tuberculosis and COVID-19:Lessons from the past viral outbreaks and possible future outcomes Can Respir J 2020 2020 1401053 doi:10.1155/2020/1401053 32934758\n15 Ankrah AO van der Werf TS de Vries EF Dierckx RA Sathekge MM Glaudemans AW PET/CT imaging of Mycobacterium tuberculosis infection Clin Transl Imaging 2016 4 131 44 27077068\n16 Gupta A Sharma A Bansal R Sharma K Classification of intraocular tuberculosis Ocul Immunol Inflamm 2015 23 7 13 25314361\n17 Pathengay A Kaza H Tyagi M Patel A Pappuru RR Agrawal H Miliary retinal lesions in ocular syphilis:Imaging characteristics and outcomes Ocul Immunol Inflamm 2019 5 1 5\n18 Colantuoni A Martini R Caprari P Ballestri M Capecchi PL Gnasso A COVID-19 sepsis and microcirculation dysfunction Front Physiol 2020 11 747 32676039\n19 Beltrán-García J Osca-Verdegal R Pallardó FV Ferreres J Rodríguez M Mulet S Sepsis and coronavirus disease 2019:Common features and anti-inflammatory therapeutic approaches Crit Care Med 2020 48 1841 4 32826431\n20 Venkata C Kashyap R Farmer JC Afessa B Thrombocytopenia in adult patients with sepsis:Incidence, risk factors, and its association with clinical outcome J Intensive Care 2013 1 9 25810916\n21 Kumar A Kumar P Singh A Srujana D Kaushik J Bilateral premacular sub-hyaloid hemorrhage-unmasking COVID-19 induced pancytopenia J Med Virol 2020 12 1 5\n22 Bhavsar KV Lin S Rahimy E Joseph A Freund KB Sarraf D Acute macular neuroretinopathy:A comprehensive review of the literature Surv Ophthalmol 2016 61 538 65 26973287\n23 Casalino G Arrigo A Romano F Munk MR Bandello F Parodi MB Acute macular neuroretinopathy:Pathogenetic insights from optical coherence tomography angiography Br J Ophthalmol 2019 103 410 4 29844084\n24 Sarraf D Rahimy E Fawzi AA Sohn E Barbazetto I Zacks DN Paracentral acute middle maculopathy:A new variant of acute macular neuroretinopathy associated with retinal capillary ischemia JAMA Ophthalmol 2013 131 1275 87 23929382\n25 Virgo J Mohamed M Paracentral acute middle maculopathy and acute macular neuroretinopathy following SARS-CoV-2 infection Eye 2020 34 2352 3 32620843\n26 Zamani G Ataei Azimi S Aminizadeh A Shams Abadi E Kamandi M Mortazi H Acute macular neuroretinopathy in a patient with acute myeloid leukemia and deceased by COVID-19:A case report J Ophthalmic Inflamm Infect 2021 10 39 33415590\n27 Liu B Deng T Zhang J Risk factors for central serous chorioretinopathy:A systematic review and meta-analysis Retina 2016 36 9 19 26710181\n28 Eiden C Peyrière H Cociglio M Djezzar S Hansel S Blayac JP Adverse effects of voriconazole:Analysis of the French pharmacovigilance database Ann Pharmacother 2007 41 755 63 17456542\n29 Kinoshita J Iwata N Ohba M Kimotsuki T Yasuda M Mechanism of voriconazole-induced transient visual disturbance:Reversible dysfunction of retinal ON-bipolar cells in monkeys Invest Ophthalmol Vis Sci 2011 52 5058 63 21436272\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0301-4738",
"issue": "69(5)",
"journal": "Indian journal of ophthalmology",
"keywords": "COVID 19; COVID-associated mycoses; endophthalmitis; ocular manifestations; paracentral acute middle maculopathy; retinal manifestations",
"medline_ta": "Indian J Ophthalmol",
"mesh_terms": "D000086382:COVID-19; D005260:Female; D006801:Humans; D007194:India; D008297:Male; D012160:Retina; D012189:Retrospective Studies; D000086402:SARS-CoV-2",
"nlm_unique_id": "0405376",
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"pages": "1275-1282",
"pmc": null,
"pmid": "33913876",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": "32482787;33415590;33067361;32737747;32376396;26710181;25314361;25810916;32503820;33270751;29844084;23929382;33225111;32826431;32676039;32457198;32963819;32620843;31580177;32572363;21436272;33424598;33368339;27077068;32482367;32934758;26973287;32282022;17456542",
"title": "Retinal manifestations in patients following COVID-19 infection: A consecutive case series.",
"title_normalized": "retinal manifestations in patients following covid 19 infection a consecutive case series"
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"abstract": "BACKGROUND\nPeripheral neuropathic pain is a highly disabling condition for patients and a challenge for neurologists and pain physicians. Although many drugs have been assessed in scientific studies, few have demonstrated a clear clinical efficacy against neuropathic pain. Moreover, the paucity of data regarding their safety raised the question on the benefit-risk ratio when used in patients experiencing peripheral neuropathies.\nThe authors conducted a review of double-blind, placebo-controlled, randomized clinical trials to assess the safety of medications used to treat neuropathic pain. This first review was focused on antidepressant and antiepileptic medications. The aim was to provide an overview of the treatment-emergent adverse events (≥10%) and the serious adverse effects described in clinical trials.\nAmong antiepileptics and antidepressants, duloxetine appeared to have the most detailed safety for the treatment of peripheral neuropathic pain. Over all studies, the most commonly reported adverse effects were dizziness, drowsiness, nausea, and constipation. Only 20.0% of the included studies (N = 90) presented a good description of adverse effects that included a statistical comparison vers usa placebo group. Important methodological improvements must be made to improve the assessment of medication safety in future clinical trials.",
"affiliations": "Université Clermont Auvergne, CHU Clermont-Ferrand, Service de chirurgie digestive, INSERM, NEURO-DOL , Clermont-Ferrand, France.;Université Clermont Auvergne, INSERM NEURO-DOL , Clermont-Ferrand, France.;Université Clermont Auvergne, CHU Clermont-Ferrand, Service de pharmacologie médicale, INSERMNEURO-DOL, Institut Analgesia , Clermont-Ferrand, France.;Université Clermont Auvergne, INSERM NEURO-DOL , Clermont-Ferrand, France.;Université Clermont Auvergne, INSERM NEURO-DOL , Clermont-Ferrand, France.;Université Clermont Auvergne, CHU Clermont-Ferrand, Délégation à la recherche clinique et à l'innovation, INSERM, NEURO-DOL , Clermont-Ferrand, France.",
"authors": "Selvy|Marie|M|https://orcid.org/0000-0001-5897-6434;Cuménal|Mélissa|M|;Kerckhove|Nicolas|N|https://orcid.org/0000-0003-2223-1240;Courteix|Christine|C|;Busserolles|Jérôme|J|https://orcid.org/0000-0001-7542-9520;Balayssac|David|D|https://orcid.org/0000-0002-6126-6588",
"chemical_list": "D000927:Anticonvulsants; D000928:Antidepressive Agents; D000068736:Duloxetine Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1080/14740338.2020.1764934",
"fulltext": null,
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"issn_linking": "1474-0338",
"issue": "19(6)",
"journal": "Expert opinion on drug safety",
"keywords": "Drug-related side effects and adverse reactions; neuropathic pain; peripheral nervous system diseases; randomized controlled trials",
"medline_ta": "Expert Opin Drug Saf",
"mesh_terms": "D000927:Anticonvulsants; D000928:Antidepressive Agents; D000068736:Duloxetine Hydrochloride; D006801:Humans; D010523:Peripheral Nervous System Diseases; D016032:Randomized Controlled Trials as Topic",
"nlm_unique_id": "101163027",
"other_id": null,
"pages": "707-733",
"pmc": null,
"pmid": "32363948",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "The safety of medications used to treat peripheral neuropathic pain, part 1 (antidepressants and antiepileptics): review of double-blind, placebo-controlled, randomized clinical trials.",
"title_normalized": "the safety of medications used to treat peripheral neuropathic pain part 1 antidepressants and antiepileptics review of double blind placebo controlled randomized clinical trials"
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"activesubstancename": "DULOXETINE HYDROCHLORIDE"
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"abstract": "This study aimed to explore whether peak serum methotrexate concentration (Cmax) correlated with adverse events, overall survival (OS) and event-free survival (EFS) in patients with primary extremity osteosarcoma.\n\n\n\nPatients with extremity osteosarcoma who were treated at our center between 2005 and 2015 were retrospectively studied. All the patients were Enneking stage II and had received standard perioperative chemotherapy composed of high-dose methotrexate, doxorubicin, cisplatin and ifosfamide. Cmax and treatment-associated toxicities of each cycle were recorded. OS and EFS were estimated and compared by Kaplan-Meier survival analysis, and Cox regression models were performed for univariate comparisons.\n\n\n\nIn total, 567 patients were followed for an average of 53 months (24-104 months). The estimated 3- and 5-year EFS were 71.7 and 63.1%, and the 3- and 5-year OS were 78.2 and 72.9%, respectively. Cmax ranged from 527 to 2495 µmol/L with a mean value of 931 ± 106 µmol/L. No significant differences in EFS and OS (p = 0.18 and p = 0.28) were observed among patients with a mean Cmax > 1500, > 1000, > 700 and < 700 µmol/L. However, patients with a mean Cmax > 1500 µmol/L had significantly increased rates of grade 3-5 toxicity. In the univariate analysis, Cmax was not a prognostic factor for EFS (p = 0.08) or OS (p = 0.16).\n\n\n\nCmax did not correlate significantly with the oncologic prognosis of non-metastatic extremity osteosarcoma patients treated by multi-agent chemotherapy; however, Cmax correlated closely with toxicities and complications. The persistent inclusion of methotrexate in classical multidisciplinary chemotherapy was questioned and should be examined in future trials.",
"affiliations": "Musculoskeletal Oncology Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China.;Musculoskeletal Oncology Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China.;Musculoskeletal Oncology Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China.;Musculoskeletal Oncology Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China.;Musculoskeletal Oncology Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China.;Musculoskeletal Oncology Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China.;Musculoskeletal Oncology Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China. shenjingnan@126.com.",
"authors": "Wang|Bo|B|0000-0001-9177-5175;Yao|Hao|H|;Xie|Xianbiao|X|;Yin|Junqiang|J|;Zou|Changye|C|;Huang|Gang|G|;Shen|Jingnan|J|",
"chemical_list": "D004317:Doxorubicin; D002945:Cisplatin; D007069:Ifosfamide; D008727:Methotrexate",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-018-3592-x",
"fulltext": null,
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"issue": "82(2)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Chemotherapy; Methotrexate; Osteosarcoma; Peak concentration; Pharmacokinetic",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D002945:Cisplatin; D018572:Disease-Free Survival; D004317:Doxorubicin; D005121:Extremities; D005260:Female; D006801:Humans; D007069:Ifosfamide; D008297:Male; D008727:Methotrexate; D012516:Osteosarcoma; D019990:Perioperative Care; D011379:Prognosis; D012189:Retrospective Studies",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "221-227",
"pmc": null,
"pmid": "29808416",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Relationship of peak serum methotrexate concentration to prognosis and drug tolerance in non-metastatic extremity osteosarcomas.",
"title_normalized": "relationship of peak serum methotrexate concentration to prognosis and drug tolerance in non metastatic extremity osteosarcomas"
} | [
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"companynumb": "CN-SILVERGATE PHARMACEUTICALS, INC.-2018SIL00030",
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"activesubstancename": "IFOSFAMIDE"
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"abstract": "Atypical hemolytic uremic syndrome (aHUS) has been described as an uncommon complication of gemcitabine. In this review, we discuss the diagnosis of gemcitabine-induced aHUS (GiHUS) and the published experience with therapeutic plasma exchange (TPE). To illustrate GiHUS, we present a patient who developed hypertension and peripheral edema while receiving gemcitabine and subsequently was found to have thrombocytopenia, hemolytic anemia, renal failure, and normal ADAMTS-13 activity. Although laboratory parameters improved on suspending gemcitabine, they worsened after reinstitution of the drug. Thrombocytopenia and hemolysis ceased once the drug was permanently discontinued without therapeutic plasma exchange (TPE). The pathological characteristics of GiHUS suggest damage of the glomeruli endothelial lining, leading to occlusion by fibrin-rich thrombi. Among 26 patients described in the literature not treated with TPE, 56% recovered from GiHUS, whereas only 30% of 18 patients treated with TPE did. The difference in recovery rate may have been confounded by the severity of GiHUS as suggested by the rate of dialysis in each group: 10/26 (38%) patients who did not receive TPE were dialyzed compared with 11/18 (61%) of those who had plasma exchange. Thus, although the currently available evidence is not decisive for use or non use of TPE, we suggest that the most important therapeutic intervention in GiHUS is discontinuation of the drug. Apheresis medicine specialists should be aware of this specific type of aHUS and provide treatment advice based on the currently available evidence.",
"affiliations": "University of South Alabama College of Medicine, Mobile, Alabama, USA.",
"authors": "Gore|Ethan McCaleb|EM|;Jones|Benjamin Scott|BS|;Marques|Marisa B|MB|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "United States",
"delete": false,
"doi": "10.1002/jca.20213",
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"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D001943:Breast Neoplasms; D003841:Deoxycytidine; D005260:Female; D006463:Hemolytic-Uremic Syndrome; D006801:Humans; D008875:Middle Aged; D010951:Plasma Exchange",
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"title": "Is therapeutic plasma exchange indicated for patients with gemcitabine-induced hemolytic uremic syndrome?",
"title_normalized": "is therapeutic plasma exchange indicated for patients with gemcitabine induced hemolytic uremic syndrome"
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"abstract": "We report about a 43-year-old woman with polyvalent drug addiction (i.e. alcohol, nicotine, methadone maintenance program with parallel consumption of heroin) who presented to the emergency department with peripheral edema, generalized weakness, and arthralgia. Laboratory findings revealed, among others, proteinuria, hyperlipoproteinemia and hypoproteinemia defining nephrotic syndrome. Computed tomography of the abdomen and iliocavography further revealed compression of left renal vein between aorta and superior mesenteric artery with distention of left ovarian vein as a possible cause of nephrotic syndrome (i. e. nutcracker syndrome). After excluding other possible causes of nephrotic syndrome, we decided against an interventional procedure due to poor compliance of the patient and potential risk of secondary stent dislocation. Instead, we opted for a surgical approach (i. e. veno-venous bypass, meaning transposition of left vena ovarica on vena cava inferior). The operative and postoperative course was uneventful. Postoperatively, proteinuria, microhematuria, arthralgia and edema receded.",
"affiliations": "Klinik für Gastroenterologie und Diabetologie, Vivantes Humboldt-Klinikum, Am Nordgraben 2, 13509, Berlin, Deutschland. norman.schoeffel@vivantes.de.;Klinik für Gastroenterologie und Diabetologie, Vivantes Humboldt-Klinikum, Am Nordgraben 2, 13509, Berlin, Deutschland.;Klinik für Gefäßmedizin, Vivantes Humboldt-Klinikum, Am Nordgraben 2, 13509, Berlin, Deutschland.;Klinik für Radiologie und interventionelle Therapie, Vivantes Humboldt-Klinikum, Am Nordgraben 2, 13509, Berlin, Deutschland.;Klinik für Gastroenterologie und Diabetologie, Vivantes Humboldt-Klinikum, Am Nordgraben 2, 13509, Berlin, Deutschland.",
"authors": "Schöffel|N|N|;Liehr|R-M|RM|;Bünger|C|C|;Krüger|K|K|;Rubin|D|D|",
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"issue": "59(6)",
"journal": "Der Internist",
"keywords": "Hematuria; Nephrotic syndrome; Opiate substitution treatment, methadone; Proteinuria; Renal nutcracker syndrome",
"medline_ta": "Internist (Berl)",
"mesh_terms": "D000328:Adult; D005260:Female; D006417:Hematuria; D006801:Humans; D017538:Mesenteric Artery, Superior; D009404:Nephrotic Syndrome; D059228:Renal Nutcracker Syndrome; D012082:Renal Veins; D013577:Syndrome; D014682:Vena Cava, Inferior",
"nlm_unique_id": "0264620",
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"title": "Nephrotic syndrome and microhematuria in a patient with nutcracker syndrome: Report of a case and review of the literature.",
"title_normalized": "nephrotic syndrome and microhematuria in a patient with nutcracker syndrome report of a case and review of the literature"
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"abstract": "Eltrombopag is a thrombopoietin agonist and has been used in aplastic anemia and post-transplantation thrombocytopenia. The c-MPL receptor is present on hematopoietic stem cells. There are no reports of eltrombopag utilization for improving poor graft function in the post-transplant setting. Here were report a case of a young female with post-transplant poor graft function as evident from the low absolute neutrophil count, anemia, and thrombocytopenia on day 60. Eltrombopag was started on day 72 and resulted in improvement in all 3 cell lines. The counts continued to be stable even after eltrombopag was discontinued. The patient tolerated the drug without significant side effects for 1 year.",
"affiliations": "Division of Hematology and Oncology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.;Division of Hematology and Oncology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.;Division of Hematology and Oncology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.;Division of Hematology and Oncology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.;Division of Hematology and Oncology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.",
"authors": "Master|Samip|S|;Dwary|Ashish|A|;Mansour|Richard|R|;Mills|Glenn M|GM|;Koshy|Nebu|N|",
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"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 10.1159/000487229cro-0011-0191Case ReportUse of Eltrombopag in Improving Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation Master Samip Dwary Ashish Mansour Richard Mills Glenn M. Koshy Nebu *Division of Hematology and Oncology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA*Nebu Koshy, MD, Division of Hematology and Oncology, Louisiana State University Health Sciences Center, Feist-Weiller Cancer Center, Shreveport, Louisiana 71130 (USA), E-Mail nkoshy@lsuhsc.eduJan-Apr 2018 27 3 2018 27 3 2018 11 1 191 195 29 1 2018 29 1 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.Eltrombopag is a thrombopoietin agonist and has been used in aplastic anemia and post-transplantation thrombocytopenia. The c-MPL receptor is present on hematopoietic stem cells. There are no reports of eltrombopag utilization for improving poor graft function in the post-transplant setting. Here were report a case of a young female with post-transplant poor graft function as evident from the low absolute neutrophil count, anemia, and thrombocytopenia on day 60. Eltrombopag was started on day 72 and resulted in improvement in all 3 cell lines. The counts continued to be stable even after eltrombopag was discontinued. The patient tolerated the drug without significant side effects for 1 year.\n\nKeywords\nAcute myeloid leukemiaStem cell transplantationEltrombopagAllogenic transplant\n==== Body\nIntroduction\nEltrombopag is a c-MPL receptor agonist drug [1, 2, 3]. Murine studies have shown that the thrombopoietin (TPO)/c-MPL receptor system is present in early hematopoiesis and hematopoietic stem cells (HSCs) [4]. There are few case reports of TPO agonist use in post-transplantation thrombocytopenia. Also, TPO agonist use has been suggested in the management of severe aplastic anemia. Here we report a case of eltrombopag utilization in the treatment of trilineage graft failure.\n\nCase Report\nA 26-year-old female with acute myeloid leukemia developed marrow hypoplasia after 1 cycle of consolidation with high-dose cytarabine. This resulted in severe pancytopenia causing transfusion dependence for both red blood cells and platelets. Following persistence of pancytopenia for almost 5 months, she underwent a matched related (brother) allogeneic hematopoietic stem cell transplant using fludarabine/melphalan conditioning and alemtuzumab/tacrolimus as graft versus host disease prophylaxis. The patient had delayed engraftment as the absolute neutrophil count stayed below 1,000/µL (with granulocyte colony-stimulating factor support), hemoglobin was less than 8 g/dL, and the platelet count was less than 20,000/µL even at day 60. Bone marrow biopsy done on days 30 and 60 as well as at 1 year showed adequate cellularity, no evidence of relapse, and cytogenetics showed normal male karyotype. Chimerism studies showed 100% donor cells in myeloid lineage (CD33+) at days 30 and 60. Eltrombopag was started at 50 mg orally daily on day 72 to promote poor graft function. As shown in Figure 1, all 3 cell lines responded. The patient tolerated eltrombopag without any significant side effects. The patient was on eltrombopag for 1 year, and after that, it was stopped. Blood counts continued to be stable after discontinuing eltrombopag.\n\nDiscussion\nBinding of TPO to the c-MPL receptor on megakaryocytes is the principal step that results in platelet maturation and release [1]. c-MPL is also expressed on the surface of HSCs [2, 3, 4]. Previous studies have shown that the addition of recombinant TPO leads to expansion of the pool of HSCs in culture [4]. In vitro models using knockout mice have shown that deficiency of c-MPL receptor [5, 6] or the TPO ligand leads to a reduced number of HSCs. Eventually, multilineage bone marrow failure develops [7]. These observations suggest that stimulation of c-MPL-signaling pathways may overcome depletion of HSCs and progenitor cells in aplastic anemia. Previous studies were done on cytokines like erythropoietin, and granulocyte colony-stimulating factor in aplastic anemia did not show a benefit because HSCs did not have receptors for these cytokines on them [8].\n\nRomiplostim is a peptide TPO mimetic which activates the TPO receptor by binding to the distal hematopoietic receptor domain. Eltrombopag is a non-peptide TPO mimetic that activates the TPO receptor by binding to the transmembrane domain [9]. While romiplostim is given subcutaneously, eltrombopag can be given orally [9]. While romiplostim is only FDA approved for immune thrombocytopenia [10], eltrombopag is FDA approved for immune thrombocytopenia, hepatitis C-related thrombocytopenia, and severe aplastic anemia [11].\n\nPrevious studies have shown that both are useful in post-transplantation thrombocytopenia anemia [12, 13, 14] and aplastic anemia [15, 16]. To our knowledge, this is the first case of eltrombopag use for the treatment of trilineage graft failure after allogeneic stem cell transplant [17]. Our case highlights the use of eltrombopag as a very effective medication with minimal side effects to promote poor graft function after allogeneic hematopoietic stem cell transplant. Repeat biopsy done after 1 year did not show any signs of myelodysplasia, recurrent acute myeloid leukemia, or myelofibrosis. Like previous studies on aplastic anemia [6], in our patient, the response continued even after eltrombopag was stopped.\n\nThere is evidence that eltrombopag might be stimulating hematopoiesis in noncompetitive activation of c-MPL. In immune thrombocytopenia, TPO levels are at the upper end of average, while in aplastic anemia they are significantly elevated [18]. Eltrombopag binds outside the ligand-binding pocket at the membrane, spanning a region of c-MPL. It activated signaling by JAK-STAT (Janus-associated kinase-signal transducers and activators of transcription) and MAPK (mitogen-activated protein kinase) pathways [19].\n\nUmbilical cord blood is emerging as a promising source of stem cells for allogeneic stem cell transplant, but it is challenged by low stem cell yield. In a previous study done on umbilical cord blood, eltrombopag enhanced expansion of HSCs in vivo and in vitro [5]. Also, eltrombopag favored earlier HSC populations which differed from recombinant TPO [20].\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFig. 1 Three graphs showing the response to eltrombopag. The x axis shows the days after transplant.\n==== Refs\nReferences\n1 Kaushansky K Historical review megakaryopoiesis and thrombopoiesis Blood 2008 Feb 111 (3) 981 6 18223171 \n2 Kaushansky K Lin N Grossmann A Humes J Sprugel KH Broudy VC Thrombopoietin expands erythroid and megakaryocytic progenitor cells in normal and myelosuppressed mice Exp Hematol 1996 Feb 24 (2) 265 9 8641351 \n3 Qian H Buza-Vidas N Hyland CD Jensen CT Antonchuk J Månsson R Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells Cell Stem Cell 2007 Dec 1 (6) 671 84 18371408 \n4 Zeigler FC de Sauvage F Widmer HR Keller GA Donahue C Schreiber RD In vitro megakaryocytopoietic and thrombopoietic activity of c-mpl ligand (TPO) on purified murine hematopoietic stem cells Blood 1994 Dec 84 (12) 4045 52 7527664 \n5 Alexander WS Roberts AW Nicola NA Li R Metcalf D Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl Blood 1996 Mar 87 (6) 2162 70 8630375 \n6 Kimura S Roberts AW Metcalf D Alexander WS Hematopoietic stem cell deficiencies in mice lacking c-Mpl the receptor for thrombopoietin Proc Natl Acad Sci USA 1998 Feb 95 (3) 1195 200 9448308 \n7 Geddis AE Congenital amegakaryocytic thrombocytopenia Pediatr Blood Cancer 2011 Aug 57 (2) 199 203 21337678 \n8 Gurion R Gafter-Gvili A Paul M Vidal L Ben-Bassat I Yeshurun M Hematopoietic growth factors in aplastic anemia patients treated with immunosuppressive therapy-systematic review and meta-analysis Haematologica 2009 May 94 (5) 712 9 19336743 \n9 Kuter DJ Thrombopoietin and thrombopoietin mimetics in the treatment of thrombocytopenia Annu Rev Med 2009 60 (1) 193 206 19642221 \n10 Nplate package insert FDA 2011 \n11 Promacta package insert FDA 2015 \n12 Hartranft ME Clemmons AB DeRemer DL Kota V Evaluation of romiplostim for the treatment of secondary failure of platelet recovery among allogeneic hematopoietic stem cell transplant patients J Oncol Pharm Pract 2017 Jan 23 (1) 10 7 26471738 \n13 Poon LM Di Stasi A Popat U Champlin RE Ciurea SO Romiplostim for delayed platelet recovery and secondary thrombocytopenia following allogeneic stem cell transplantation Am J Blood Res 2013 Aug 3 (3) 260 4 23997988 \n14 Olnes MJ Scheinberg P Calvo KR Desmond R Tang Y Dumitriu B Eltrombopag and improved hematopoiesis in refractory aplastic anemia N Engl J Med 2012 Jul 367 (1) 11 9 22762314 \n15 Lee JW Jang JH Lee SE Jung CW Park S Oh IH Efficacy and Safety of Romiplostim in Patients with Aplastic Anemia Refractory to Immunosuppressive Therapy 1-Year Interim Analysis of Phase 2 Clinical Trial Blood 2016 128 (22) 3910 \n16 Gill H Leung GM Lopes D Kwong YL The thrombopoietin mimetics eltrombopag and romiplostim in the treatment of refractory aplastic anaemia Br J Haematol 2017 Mar 176 (6) 991 4 27097929 \n17 Dyba J Tinmouth A Bredeson C Matthews J Allan DS Eltrombopag after allogeneic haematopoietic cell transplantation in a case of poor graft function and systematic review of the literature Transfus Med 2016 Jun 26 (3) 202 7 27046441 \n18 Emmons RV Reid DM Cohen RL Meng G Young NS Dunbar CE Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction Blood 1996 May 87 (10) 4068 71 8639762 \n19 Erickson-Miller CL Delorme E Tian SS Hopson CB Landis AJ Valoret EI Preclinical activity of eltrombopag (SB-497115) an oral nonpeptide thrombopoietin receptor agonist Stem Cells 2009 Feb 27 (2) 424 30 19038790 \n20 Sun H Tsai Y Nowak I Liesveld J Chen Y Eltrombopag a thrombopoietin receptor agonist enhances human umbilical cord blood hematopoietic stem/primitive progenitor cell expansion and promotes multi-lineage hematopoiesis Stem Cell Res (Amst) 2012 Sep 9 (2) 77 86\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "11(1)",
"journal": "Case reports in oncology",
"keywords": "Acute myeloid leukemia; Allogenic transplant; Eltrombopag; Stem cell transplantation",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "191-195",
"pmc": null,
"pmid": "29681820",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "19642221;8630375;9448308;8641351;7527664;23997988;19038790;18371408;19336743;21337678;27046441;26471738;22762314;18223171;27097929;8639762;22683680",
"title": "Use of Eltrombopag in Improving Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation.",
"title_normalized": "use of eltrombopag in improving poor graft function after allogeneic hematopoietic stem cell transplantation"
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"abstract": "Flexible bronchoscopy, therapeutic bronchoscopy and other procedures requiring anesthesia are generally avoided in pregnancy and postponed until after delivery if possible. We report a case of a parturient with an abnormal chest radiograph and mild obstructive symptoms of unknown etiology. At bronchoscopy, a tumor associated with post-obstructive suppuration was found and excised using electrocautery snare and cryotherapy, for restoration of airway patency. Coordination between pulmonary, obstetric, anesthesia, neonatology and thoracic surgery services was essential in ensuring success and the safety of the mother and fetus.",
"affiliations": "Department of Anesthesiology, Baylor College of Medicine, Houston, TX, USA.;Department of Pulmonology, Baylor College of Medicine, Houston, TX, USA.;Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA.;Department of Pulmonology, Baylor College of Medicine, Houston, TX, USA.;Department of Pulmonology, Baylor College of Medicine, Houston, TX, USA.;Department of Pulmonology, Baylor College of Medicine, Houston, TX, USA.;Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA.;Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA.;Department of Anesthesiology, Baylor College of Medicine, Houston, TX, USA. Electronic address: umunnur@bcm.edu.",
"authors": "Falce|K|K|;Guy|E|E|;Hyman|D|D|;Hotze|T|T|;Lazarus|D|D|;Bandi|V|V|;Parchem|J|J|;Davidson|C|C|;Munnur|U|U|",
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"journal": "International journal of obstetric anesthesia",
"keywords": "Benign respiratory tumor; Bronchoscopy; Endobronchial leiomyoma; Pregnancy",
"medline_ta": "Int J Obstet Anesth",
"mesh_terms": "D000328:Adult; D001984:Bronchial Neoplasms; D001999:Bronchoscopy; D005260:Female; D006340:Heart Rate, Fetal; D006801:Humans; D007889:Leiomyoma; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D014134:Tracheal Neoplasms",
"nlm_unique_id": "9200430",
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"title": "Bronchoscopic resection of a tracheobronchial leiomyoma in a pregnant patient.",
"title_normalized": "bronchoscopic resection of a tracheobronchial leiomyoma in a pregnant patient"
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"abstract": "Use of biologic agents in generalized myasthenia gravis is generally limited to therapy-refractory cases; benefit in new-onset disease is unknown.\n\n\n\nTo assess rituximab in refractory and new-onset generalized myasthenia gravis and rituximab vs conventional immunotherapy in new-onset disease.\n\n\n\nA retrospective cohort study with prospectively collected data was conducted on a county-based community sample at Karolinska University Hospital, Stockholm, Sweden. Participants included 72 patients with myasthenia gravis, excluding those displaying muscle-specific tyrosine kinase antibodies, initiating rituximab treatment from January 1, 2010, to December 31, 2018, and patients with new-onset disease initiating conventional immunotherapy from January 1, 2003, to December 31, 2012, with 12 months or more of observation time. The present study was conducted from March 1, 2019, to January 31, 2020.\n\n\n\nTreatment with low-dose rituximab (most often 500 mg every 6 months) or conventional immunosuppressants.\n\n\n\nTime to remission (main outcome) as well as use of rescue therapies or additional immunotherapies and time in remission (secondary outcomes).\n\n\n\nOf the 72 patients included, 31 patients (43%) were women; mean (SD) age at treatment start was 60 (18) years. Twenty-four patients had received rituximab within 12 months of disease onset and 48 received rituximab at a later time, 34 of whom had therapy-refractory disease. A total of 26 patients (3 [12%] women; mean [SD] age, 68 [11] years at treatment start) received conventional immunosuppressant therapy. Median time to remission was shorter for new-onset vs refractory disease (7 vs 16 months: hazard ratio [HR], 2.53; 95% CI, 1.26-5.07; P = .009 after adjustment for age, sex, and disease severity) and for rituximab vs conventional immunosuppressant therapies (7 vs 11 months: HR, 2.97; 95% CI, 1.43-6.18; P = .004 after adjustment). In addition, fewer rescue therapy episodes during the first 24 months were required (mean [SD], 0.38 [1.10] vs 1.31 [1.59] times; mean difference, -1.26; 95% CI, -1.97 to -0.56; P < .001 after adjustment), and a larger proportion of patients had minimal or no need of additional immunotherapies (70% vs 35%; OR, 5.47; 95% CI, 1.40-21.43; P = .02 after adjustment). Rates of treatment discontinuation due to adverse events were lower with rituximab compared with conventional therapies (3% vs 46%; P < .001 after adjustment).\n\n\n\nClinical outcomes with rituximab appeared to be more favorable in new-onset generalized myasthenia gravis, and rituximab also appeared to perform better than conventional immunosuppressant therapy. These findings suggest a relatively greater benefit of rituximab earlier in the disease course. A placebo-controlled randomized trial to corroborate these findings is warranted.",
"affiliations": "Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.;Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.;Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.;Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.;Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.;Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.",
"authors": "Brauner|Susanna|S|;Eriksson-Dufva|Ann|A|;Hietala|Max Albert|MA|;Frisell|Thomas|T|;Press|Rayomand|R|;Piehl|Fredrik|F|",
"chemical_list": "D007155:Immunologic Factors; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1001/jamaneurol.2020.0851",
"fulltext": null,
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"issn_linking": "2168-6149",
"issue": "77(8)",
"journal": "JAMA neurology",
"keywords": null,
"medline_ta": "JAMA Neurol",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis; D017063:Outcome Assessment, Health Care; D012042:Registries; D012189:Retrospective Studies; D000069283:Rituximab; D013548:Sweden; D013997:Time Factors",
"nlm_unique_id": "101589536",
"other_id": null,
"pages": "974-981",
"pmc": null,
"pmid": "32364568",
"pubdate": "2020-08-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "27640924;25698678;29309484;28801338;26376969;31875994;31048702;29925992;27038238;11435471;21555250;30410033;27893014;14576843;29066163;25251578;25308632;27386504;27103470;18059039;30173916;17925487;21828201;31118245;21321193;27358333;30649616;30573759;26276965;28762877;24389034;10993912;29381221;27760868;31589278;24183642",
"title": "Comparison Between Rituximab Treatment for New-Onset Generalized Myasthenia Gravis and Refractory Generalized Myasthenia Gravis.",
"title_normalized": "comparison between rituximab treatment for new onset generalized myasthenia gravis and refractory generalized myasthenia gravis"
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"abstract": "A 54-year-old man who was previously found to be COVID-19 positive received two doses of mRNA-1273 (Moderna) vaccine 4 weeks apart, as recommended by the manufacturer. He was brought to the emergency department 1 day after second dose of the vaccine with altered mental status, headache and high fever. The patient was hospitalised for 2 days and managed with supportive care. He completely recovered with return of mental status to baseline and resolution of fever.",
"affiliations": "Internal Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA patrick.hilaire@med.wmich.edu.;Internal Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA.;Internal Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA.;Internal Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, Michigan, USA.",
"authors": "Hilaire|Patrick Shamell|PS|;Tito|Emmanuel|E|;Muthukumarasamy|Nirmal|N|;Schauer|Mark|M|",
"chemical_list": "D000086663:COVID-19 Vaccines; D012333:RNA, Messenger",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-244119",
"fulltext": null,
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"issue": "14(9)",
"journal": "BMJ case reports",
"keywords": "COVID-19; infectious diseases",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000086382:COVID-19; D000086663:COVID-19 Vaccines; D005334:Fever; D006801:Humans; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger; D000086402:SARS-CoV-2",
"nlm_unique_id": "101526291",
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"title": "Altered mental status and pronounced febrile response after second mRNA-1273 (Moderna) COVID-19 vaccine administration in a patient with previously documented COVID-19 infection.",
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"abstract": "Barium studies are commonly used to rule out gastrointestinal (GI) pathologies and sometimes they are associated with complications such as barium aspiration with heterogeneity in clinical features ranging from mild to severe symptoms. We present a case of large volume barium aspiration in a 73-year-old male with past medical history of dysphagia diagnosed with diffuse esophageal spasm. Barium is an inert material commonly used for GI tract study. Although complications associated with barium studies are rare, aspiration of barium can have dramatic findings resulting in mild to severe symptoms. Clinically patient had very minimal symptoms but radiographic studies appeared dramatic. Therefore, a clinical and radiographic paradox must be kept in mind when evaluating patients and reviewing large volume barium aspiration imaging. Our case remained asymptomatic and had no respiratory complaints, nor did he develop any respiratory distress post barium aspiration.",
"affiliations": "Internal Medicine, Interfaith Medical Center, Brooklyn, USA.;Internal Medicine, Interfaith Medical Center, Brooklyn, USA.;Internal Medicine, Interfaith Medical Center, Brooklyn, USA.;Internal Medicine, Interfaith Medical Center, Brooklyn, USA.;Internal Medicine, Interfaith Medical Center, Brooklyn, USA.",
"authors": "Pata|Ramakanth|R|;Dolkar|Tsering|T|;Patel|Meet J|MJ|;Nway|Nway|N|;Aung|Htun M|HM|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.12557\nRadiology\nGastroenterology\nPulmonology\nClinical and Radiological Dissociation in Massive Barium Aspiration\nMuacevic Alexander Adler John R Pata Ramakanth 1 Dolkar Tsering 1 Patel Meet J 1 Nway Nway 1 Aung Htun M 1 \n1 \nInternal Medicine, Interfaith Medical Center, Brooklyn, USA \n\nRamakanth Pata cookybrey1@gmail.com\n7 1 2021 \n1 2021 \n13 1 e125577 1 2021 Copyright © 2021, Pata et al.2021Pata 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/48300-clinical-and-radiological-dissociation-in-massive-barium-aspirationBarium studies are commonly used to rule out gastrointestinal (GI) pathologies and sometimes they are associated with complications such as barium aspiration with heterogeneity in clinical features ranging from mild to severe symptoms. We present a case of large volume barium aspiration in a 73-year-old male with past medical history of dysphagia diagnosed with diffuse esophageal spasm. Barium is an inert material commonly used for GI tract study. Although complications associated with barium studies are rare, aspiration of barium can have dramatic findings resulting in mild to severe symptoms. Clinically patient had very minimal symptoms but radiographic studies appeared dramatic. Therefore, a clinical and radiographic paradox must be kept in mind when evaluating patients and reviewing large volume barium aspiration imaging. Our case remained asymptomatic and had no respiratory complaints, nor did he develop any respiratory distress post barium aspiration.\n\nbarium aspirationThe 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\nBarium is an inert material commonly used for gastrointestinal (GI) tract study. We present a case of large volume barium aspiration in a 73-year-old male with past medical history of dysphagia diagnosed with diffuse esophageal spasm. Although complications associated with barium studies are rare, aspiration of barium can have dramatic findings resulting in mild to severe symptoms. Clinically patient had very minimal symptoms but radiographic studies appeared dramatic.\n\nCase presentation\nA 73-year-old male presented to emergency department due to presyncope with an episode of loss of consciousness for three minutes. He also complained of productive cough with whitish sputum. Vital signs were normal and physical examination was benign. Chest X-ray (CXR) showed evidence of consolidation, which was followed by a computed tomography (CT) chest that revealed a dilated esophagus (Figure 1). Barium swallow was done for optimal evaluation of dilated esophagus (Figure 2). Post-procedure CXR revealed interval development of complete opacification of left hemithorax and retained barium in the left upper chest (Figure 3). CT chest was followed, which revealed retained barium within the upper to the mid-thoracic esophagus. Complete left lung atelectasis was noted, likely related to the obstructing filling defect within the left main bronchus (Figure 4). Subsequently, the CXR showed persistently retained contrast within the esophagus and improved left lobar airspace disease with moderate to large pleural effusion (Figure 5). However, bedside sonogram showed predominantly consolidation. The patient had no symptoms and was clinically stable to be discharged. He was advised to follow up as an outpatient at the chest clinic in six weeks.\n\nFigure 1 CT chest without contrast revealed fluid-filled dilated esophagus, which was suboptimally evaluated due to lack of contrast. The patient also had left lower lobe consolidation consistent with pneumonia.\nFigure 2 A barium study was done, which revealed diffuse esophageal spasm and akinesis of the mid-thoracic esophagus.\nFigure 3 Chest X-ray revealed interval development of complete opacification of left hemithorax and retained barium in the left upper chest.\nFigure 4 CT chest revealed retained barium within the upper to the mid-thoracic esophagus. Complete left lung atelectasis was noted, likely related to the obstructing filling defect within the left main bronchus.\nFigure 5 Subsequently, a chest x-ray showed persistently retained contrast within the esophagus and improved left lobar airspace disease with moderate to large pleural effusion.\nDiscussion\nBarium studies are regularly performed to rule out GI lumen pathologies. Despite the risk of barium aspiration, which is present, the complications are rare [1,2]. We present a case of large volume barium aspiration which was clinically asymptomatic with dramatic radiographic findings. In most cases, patients remain largely asymptomatic despite the paradoxical radiographic findings [3]. However, mechanical obstruction leading to atelectasis as well as uncommon acute inflammatory reactions have been reported [3-5].\n\nThere are few articles published reporting mild cases of large volume barium aspiration [1]. Most patients do not develop severe symptoms as seen on the imaging, which is alarming. Our case remained asymptomatic and neither had any respiratory complaints nor did he develop any respiratory distress post barium aspiration. CT chest revealed complete left lung atelectasis, which subsequently improved within days, revealing moderate pleural effusion. Although there was a pleural effusion on the CXR, a bedside sonogram of the lung revealed a predominant consolidation pattern. The patient was kept under observation. A 6-minute walk test was carried out and no desaturation or symptoms were noted. Steroids or antibiotics were not used and bronchoscopy was not performed due to the risk of spreading the contrast to unaffected areas [4]. The patient was asked to follow up in the pulmonary clinic six weeks post-discharge.\n\nWe prefer to classify patients based on radiographic, physiologic, and clinical parameters: positive radiographic findings and no change in physiological findings; positive radiographic findings and altered ventilation/perfusion (V/Q) ratio [6]; positive radiographic findings with shunt effect [7]; and positive radiographic findings with inflammatory response [8]. Most patients are completely asymptomatic after aspiration and treatment remains observation [2]. Aspiration pneumonia should be suspected whenever a patient complains of dysphagia and radiographic evidence of consolidation. Nevertheless, the risk of aspirations and complications remains high in patients with dysphagia or the elderly [1,9]. Treatment strategies vary depending on the underlying baseline comorbidities in patients with severe respiratory complications, although bronchoscopy and suctioning have been tried [10]. Furthermore, if gastric contents are aspirated along with barium, antibiotics have been used [11].\n\nMost patients appear to recover completely one-year post aspiration. High-resolution CT has reported subtle evidence of early fibrosis even one-year post aspiration, although limited data is available on patient outcome years after aspiration [3]. The clinical significance of such findings remains unknown.\n\nConclusions\nAlthough barium aspiration has dramatic radiographic findings, most patients are asymptomatic. Therefore, a clinical and radiographic paradox must be kept in mind when evaluating the patients and reviewing large volume barium aspiration imaging. We recommend longer follow-ups to check for delayed developments post barium aspiration.\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 Large-volume barium aspiration Proc (Bayl Univ Med Cent) Hundemer G Kumar V Vaduganathan M 183 184 28 2015 25829647 \n2 Barium aspiration QJM Varatharaj A Roome C Allsup S 903 904 105 2012 21865311 \n3 Inhalation bronchography Chest Shook CD Felson B 333 337 58 1970 5506625 \n4 Severe barium sulfate aspiration into the lung: clinical presentation, prognosis, and therapy Respiration Tamm I Kortsik C 81 84 66 1999 9973698 \n5 Aspiration of high-density barium contrast medium causing acute pulmonary inflammation—report of two fatal cases in elderly women with disordered swallowing Clin Radiol Gray C Sivaloganathan S Simpkins KC 397 400 40 1989 2758750 \n6 Barium sulfate aspiration: is early bronchioalveolar lavage a life-saving procedure? Turk J Emerg Med Kumar A Kumar A Kumar N Sinha C Singh J 50 20 2020 32355903 \n7 Massive aspiration of barium sulfate during an upper gastrointestinal examination in a child with dysphagia Int J Pediatr Otorhinolaryngol Chiu CY Wong KS Tsai MH 541 544 69 2005 15763294 \n8 Aspiration of high-density barium contrast medium causing acute pulmonary inflammation: report of two fatal cases in elderly women with disordered swallowing Clin Radiol Gray C Sivaloganathan S Simpkins CK 397 400 40 1989 2758750 \n9 Late changes in barium sulfate aspiration: HRCT features Eur Radiol Voloudaki A Ergazakis N Gourtsoyiannis N 2226 2229 13 2003 https://link.springer.com/article/10.1007/s00330-002-1687-5 12928969 \n10 Images in clinical medicine. A deadly examination N Engl J Med Fruchter O Dragu R 1016 348 2003 12637611 \n11 Barium sulfate aspiration Lancet Kaira K Takise A Goto T Horie T Mori M 2220 364 2004 15610809\n\n",
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"publication_types": "D002363:Case Reports",
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"title": "Clinical and Radiological Dissociation in Massive Barium Aspiration.",
"title_normalized": "clinical and radiological dissociation in massive barium aspiration"
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"abstract": "We investigated the combination of midostaurin and azacitidine (AZA) in patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). Patients received AZA 75 mg m(-2) on days 1-7 and midostaurin 25 mg bid (in cohort 1 of phase I) or 50 mg bid (in cohort 2 of Phase I and in Phase II) orally on day 8-21 during the first cycle and continuously thereafter. Fourteen patients were enrolled in the phase I and 40 in the phase II. Overall response rate was 26%. The median remission duration (RD) was 20 weeks and was significantly longer in patients with FLT3 mutations not previously exposed to other FLT3 inhibitors (P = 0.05) and in patients not previously transplanted (P = 0.01). Thirty-two (59%) patients have died, all of complications related to disease progression. G3-4 nonhematological toxicity was reported in 38 (70%) patients, most frequently infections (56%), ejection fraction reduction (11%), and diarrhea or nausea/vomiting (9% each). The combination of midostaurin and AZA is an effective and safe regimen in patients with AML and high-risk MDS. Patients with FLT3 mutations but not previously exposed to other FLT3 inhibitors and patients not previously transplanted derived the greatest benefit. Further studies with this combination are warranted.",
"affiliations": "Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.",
"authors": "Strati|Paolo|P|;Kantarjian|Hagop|H|;Ravandi|Farhad|F|;Nazha|Aziz|A|;Borthakur|Gautam|G|;Daver|Naval|N|;Kadia|Tapan|T|;Estrov|Zeev|Z|;Garcia-Manero|Guillermo|G|;Konopleva|Marina|M|;Rajkhowa|Trivikram|T|;Durand|Menda|M|;Andreeff|Michael|M|;Levis|Mark|M|;Cortes|Jorge|J|",
"chemical_list": "C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D019311:Staurosporine; C059539:midostaurin; D001374:Azacitidine",
"country": "United States",
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"journal": "American journal of hematology",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes; D019311:Staurosporine; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3",
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"pubdate": "2015-04",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "24487412;23798029;11281740;12036858;12123403;12124173;14673054;14604974;2475589;8946930;15345597;15746041;15632409;16609072;16857987;17315155;17488484;17341661;17965322;18379012;18398735;18450602;19357394;19808698;20212254;19878996;20733134;20952518;21314823;21263155;22504184;22571445;22627678;22504140;23071272;24149914;23631653;24737502;23530930;23613521;24002496;23959811;11230495",
"title": "Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome.",
"title_normalized": "phase i ii trial of the combination of midostaurin pkc412 and 5 azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome"
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"abstract": "We report a case of a 76-year-old female who presented with non-ST elevation myocardial infarction and developed a 22-second ventricular pause with ticagrelor that did not recur after shifting to clopidogrel. Based on the Naranjo algorithm, the likelihood that our patient's prolonged ventricular pause was due to ticagrelor exposure was probable.\nTicagrelor use is associated with prolonged ventricular pauses, warranting close monitoring, particularly during the first week of therapy.",
"affiliations": "Pharmacy Department Heart Hospital Hamad Medical Corporation Doha Qatar.;Pharmacy Department Heart Hospital Hamad Medical Corporation Doha Qatar.;Internal Medicine Department, Hamad General Hospital Hamad Medical Corporation Doha Qatar.;Cardiology Department, Heart Hospital Hamad Medical Corporation Doha Qatar.;Cardiology Department, Heart Hospital Hamad Medical Corporation Doha Qatar.",
"authors": "Rahhal|Alaa|A|https://orcid.org/0000-0002-2631-0184;Aljundi|Amer|A|;Ibrahim Mohamed|Sara Saeed|SS|;Arif|Muhammad Awais|MA|;Arabi|Abdul Rahman|AR|",
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"doi": "10.1002/ccr3.5017",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.5017\nCCR35017\nCase Report\nCase Report\nProlonged ventricular pause associated with ticagrelor use: A case report\nRAHHAL et al.\nRahhal Alaa https://orcid.org/0000-0002-2631-0184\n1 arahhal1@hamad.qa\n\nAljundi Amer 1\nIbrahim Mohamed Sara Saeed 2\nArif Muhammad Awais 3\nArabi Abdul Rahman 3\n1 Pharmacy Department Heart Hospital Hamad Medical Corporation Doha Qatar\n2 Internal Medicine Department, Hamad General Hospital Hamad Medical Corporation Doha Qatar\n3 Cardiology Department, Heart Hospital Hamad Medical Corporation Doha Qatar\n* Correspondence\nAlaa Rahhal, Heart Hospital, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.\nEmail: arahhal1@hamad.qa\n\n25 10 2021\n10 2021\n9 10 10.1002/ccr3.v9.10 e0501731 8 2021\n02 7 2021\n07 10 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\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\nCase\n\nWe report a case of a 76‐year‐old female who presented with non‐ST elevation myocardial infarction and developed a 22‐second ventricular pause with ticagrelor that did not recur after shifting to clopidogrel. Based on the Naranjo algorithm, the likelihood that our patient's prolonged ventricular pause was due to ticagrelor exposure was probable.\n\nConclusion\n\nTicagrelor use is associated with prolonged ventricular pauses, warranting close monitoring, particularly during the first week of therapy.\n\nTicagrelor use is associated with prolonged ventricular pauses, warranting close monitoring, particularly during the first week of therapy.\n\nadverse drug reaction\nticagrelor\nventricular pause\nsource-schema-version-number2.0\ncover-dateOctober 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.8 mode:remove_FC converted:25.10.2021\nRahhal A , Aljundi A , Ibrahim Mohamed SS , Arif MA , Arabi AR . Prolonged ventricular pause associated with ticagrelor use: A case report. Clin Case Rep. 2021;9 :e05017. 10.1002/ccr3.5017\n\nFunding information\n\nOpen access funding provided by Qatar National Library. The funders had no role in the design, planning, or the preparation of this manuscript. The content is the sole responsibility of the authors\n==== Body\npmc1 BACKGROUND\n\nTicagrelor is an oral reversible antagonist of adenosine diphosphate P2Y12 receptor which is approved by FDA in the management of acute coronary syndromes (ACS); unstable angina pectoris, ST‐segment elevation myocardial infarction (STEMI) or non‐STEMI, including those managed medically or with percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG). 1\n\nIn the PLATO (Ticagrelor versus clopidogrel in patients with acute coronary syndromes) trial, 2 treatment with ticagrelor compared with clopidogrel significantly reduced the composite endpoint of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding. Among safety outcomes, ventricular pauses ≥3 s during the first week of therapy were significantly more frequent with ticagrelor than clopidogrel. However, ventricular pauses ≥5 s difference did not reach statistical significance. Following the PLATO trial, there have been emerging case reports of ticagrelor‐associated bradyarrhythmias. 3 , 4 Unlike previous cases, we report a case of prolonged ticagrelor‐associated pause (22 s) within 1 h of ticagrelor initiation in a patient without a baseline conduction abnormalities, which required ticagrelor discontinuation and shifting to clopidogrel.\n\n2 CASE DESCRIPTION\n\nA 76‐year‐old female without a past history of conduction diseases and confirmed past medical history significant for type 2 diabetes mellitus, hypertension, and coronary artery disease post PCI to right coronary artery (RCA) in 2018, treated with aspirin 100 mg, atorvastatin 20 mg, metoprolol tartrate 50 mg, isosorbide mononitrate 20 mg, and basal‐bolus insulin, presented to our hospital emergency department with a 5‐day history of shortness of breath that was increasing in severity and associated with central chest pain radiating to throat that started 6 h prior to admission. Her vital signs were as follows: blood pressure = 115/73 mmHg, heart rate = 106 beats per minute, temperature = 36.5 C, and oxygen saturation = 95% on room air. Her first 2 sets of troponin T were 104 ng/L and 135 ng/L (normal <14 ng/L), and her transthoracic echocardiogram showed left ventricular regional wall motion abnormalities with an ejection fraction of 38%. Her initial electrocardiogram (ECG) showed T wave inversion in anterolateral leads (V3–V6 leads) as shown in Figure 1. Therefore, a diagnosis of non‐STEMI was made, and she was planned for in‐patient coronary angiography (CAG) and hence started on aspirin 300 mg then 100 mg enteric coated (EC) daily, clopidogrel 300 mg then 75 mg daily, and enoxaparin 1 mg/Kg subcutaneous every 12 h.\n\nFIGURE 1 T wave inversion in anterolateral leads (V3–V6)\n\nOn the second day of admission, she underwent CAG and was found to have 95% stenosis in proximal left anterior descending (LAD) artery, and a patent drug‐eluting stent (DES) in the mid‐RCA. A DES (3.0 × 33 mm) was placed in the proximal to mid LAD. After the PCI, she was on aspirin 100 mg EC, clopidogrel 150 mg daily, bisoprolol 5 mg, atorvastatin 40 mg, lisinopril 5 mg, spironolactone 12.5 mg daily, furosemide 40 mg intravenous twice daily, and insulin (basal glargine and bolus aspart). Two days after the PCI, it was decided to start the patient on ticagrelor 180 mg as a loading dose followed by 90 mg twice daily and to stop clopidogrel.\n\nOne hour after receiving ticagrelor loading dose, the patient started to develop dyspnea followed by an episode of unresponsiveness. The review of the telemetry monitoring strips showed bradycardia followed by a sinus pause of 22 s during the episode of unresponsiveness as shown in Figure 2. Therefore, she was transferred immediately to our cardiac intensive care unit (CICU) where she underwent transvenous pacemaker insertion, which was kept for 2 days, and ticagrelor was switched back to clopidogrel after 24 h of receiving ticagrelor loading dose, by giving a loading dose of 600 mg followed by 75 mg daily. After the removal of the pacemaker, metoprolol 12.5 mg twice daily was started, and she was observed for 2 days and remained stable without any further episodes of bradycardia or sinus pause with a heart rate ranging from 65–75 beats per minute. After which, she was discharged and then seen in the outpatient clinic within 20 days of discharge and had no complaints.\n\nFIGURE 2 A 22‐s pause on telemetry\n\n3 DISCUSSION\n\nVentricular pauses are defined as absence of a QRS complex that lasts for more than 2.5 s. 5 It can be caused by sinoatrial (SA) node dysfunction or atrioventricular (AV) node dysfunction or other causes. 6\n\nIn the phase IIb trial (DISPERSE‐2) that compared 2 regimens of ticagrelor (90 mg twice daily and 180 mg twice daily) to clopidogrel, dose‐related ventricular pauses were more common among patients receiving ticagrelor. Pauses of more than 2.5 s occurred in 4.3%, 5.5%, and 9.9% for clopidogrel, ticagrelor 90 mg [p = 0.58], and ticagrelor 180 mg [p = 0.0.014], respectively. Pauses of more than 5 s occurred in 0.3%, 1.6% [p = 0.22], and 2.1% [p = 0.06], respectively. 5\n\nBecause of this observation, the investigator of PLATO trial excluded patients at increased risk for symptomatic bradyarrhythmias (such as patients with known sick sinus syndrome, second‐degree or third‐degree AV block, or previous syncope likely to be due to bradycardia unless a pacemaker was in place) and included a prospectively designed continuous ECG monitoring to determine the incidence of ventricular pauses with ticagrelor and identify any associated symptoms. During the first week of treatment, ventricular pauses of 3 s or more occurred in 5.8% of patients on ticagrelor compared with 3.6% of patients on clopidogrel (RR: 1.61; 95% CI: 1.14–2.26), and pauses of 5 s or more occurred in 2.0% of patients on ticagrelor compared with 1.2% of patients on clopidogrel (RR: 1.66; 95% CI: 0.92–3.01). The difference was mainly due to an excess in sinoatrial (SA) node pauses in ticagrelor group. Ventricular pauses were mostly asymptomatic and nocturnal. 6\n\nCompared with clopidogrel, ticagrelor has been shown to increase adenosine plasma concentration in acute coronary syndrome patients by inhibiting adenosine uptake by erythrocytes. 7 Adenosine is known to suppress the automaticity of cardiac pacemaker cells. 8 This could explain the potential of ticagrelor to cause adenosine‐mediated effects including ventricular pauses. 6 , 9\n\nIn the present case, ticagrelor caused 22‐second ventricular pause within the first day of initiation. Although ventricular pauses can be attributed to coronary artery disease itself, we believe that ticagrelor was the main cause of these pauses for several reasons; first, the longer pause of 22 s occurred 2 days after successful revascularization; second, the pause did not recur after shifting to clopidogrel. Moreover, the use of the Naranjo algorithm also indicated a probable relationship between the administration of ticagrelor and the development of prolonged ventricular pause (score of 7). 10\n\nA challenging decision in our case was whether a loading dose of clopidogrel is required or not in a patient who had received a loading dose of ticagrelor. Following the SWAP‐4 (switching From ticagrelor to clopidogrel in patients with coronary artery disease) trial that compared 3 different strategies of clopidogrel dosing (600 mg loading dose 12 h after last ticagrelor dose followed by 75 mg daily, 600 mg loading dose 24 h after last ticagrelor dose followed by 75 mg daily, and 75 mg daily without a loading dose), 600 mg clopidogrel was given 12 h after the last dose of ticagrelor followed by clopidogrel 75 mg daily. 11\n\nIn comparison to previously reported cases of ticagrelor‐induced pauses, our patient who was already tolerating beta‐blocker prior to admission, developed a longer pause after a very short time of ticagrelor initiation. Nicol et al. reported an 8‐s ventricular pause in a 39‐year‐old male with STEMI within 1 h of receiving ticagrelor loading dose and atenolol 25 mg. 3 And Low et al. reported that a 59‐year‐old female who presented with non‐STEMI developed four pauses, the longest was 18.5 s in duration, within 3 h of initiating ticagrelor. 4\n\n4 CONCLUSION\n\nTicagrelor use is associated with prolonged ventricular pauses. Thus, patients who are receiving ticagrelor should be monitored closely, particularly during the first week of therapy. If ticagrelor‐induced ventricular pauses occur and a decision is made to shift to clopidogrel, a loading dose of 600 mg should be administered to maintain an acceptable level of platelet inhibition and prevent major cardiovascular events.\n\nACKNOWLEDGEMENTS\n\nOpen access funding provided by Qatar National Library.\n\nCONFLICT OF INTEREST\n\nThe authors declare that there is no conflict of interest.\n\nAUTHOR CONTRIBUTIONS\n\nAR contributed to study design conception, literature review, acquisition of relevant data, writing the first draft of the manuscript, and approving the final version of the manuscript; AA contribute to the literature review, acquisition of relevant data, and approving the final version of the manuscript; SSIM contributed to writing the case description and approving the final version of the manuscript; MAA and ARA contributed to study design conception and approving the final draft of the manuscript.\n\nCONSENT\n\nA written informed consent for publishing patient's information and images was obtained from the patient.\n\nDATA AVAILABILITY STATEMENT\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n==== Refs\nREFERENCES\n\n1 Deeks ED . Ticagrelor: a review of its use in the management of acute coronary syndromes. Drugs. 2011;71 (7 ):909‐933. 10.2165/11206850-000000000-00000 21568367\n2 Wallentin L , Becker RC , Budaj A , et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361 (11 ):1045‐1057. 10.1056/NEJMoa0904327 19717846\n3 Nicol M , Deblaise J , Choussat R , Dubourg O , Mansencal N . Side effects of ticagrelor: sinus node dysfunction with ventricular pause. Int J Cardiol. 2015;15 (191 ):56‐57. 10.1016/j.ijcard.2015.04.198\n4 Low A , Leong K , Sharma A , Oqueli E . Ticagrelor‐associated ventricular pauses: a case report and literature review. Eur Heart J Case Rep. 2018;3 (1 ):yty156. 10.1093/ehjcr/yty156 31020232\n5 Cannon CP , Husted S , Harrington RA , et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non‐ST‐segment elevation acute coronary syndrome: primary results of the DISPERSE‐2 tri. J Am Coll Cardiol. 2007;50 (19 ):1844‐1851. 10.1016/j.jacc.2007.07.053 17980250\n6 Scirica BM , Cannon CP , Emanuelsson H , et al. The incidence of bradyarrhythmias and clinical bradyarrhythmic events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) trial: results of the continuous electrocardiogr. J Am Coll Cardiol. 2011;57 (19 ):1908‐1916. 10.1016/j.jacc.2010.11.056 21545948\n7 Bonello L , Laine M , Kipson N , et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol. 2014;63 (9 ):872‐877. 10.1016/j.jacc.2013.09.067 24291273\n8 Belardinelli L , Shryock JC , Song Y , Wang D , Srinivas M . Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes. FASEB J. 1995;9 (5 ):359‐365.7896004\n9 Cattaneo M , Schulz R , Nylander S . Adenosine‐mediated effects of ticagrelor: evidence and potential clinical relevance. J Am Coll Cardiol. 2014;63 (23 ):2503‐2509. 10.1016/j.jacc.2014.03.031 24768873\n10 Naranjo CA , Busto U , Sellers EM , et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30 :239‐245.7249508\n11 Franchi F , Rollini F , Rivas Rios J , et al. Pharmacodynamic effects of switching from ticagrelor to clopidogrel in patients with coronary artery disease: results of the SWAP‐4 study. Circulation. 2018;137 (23 ):2450‐2462. 10.1161/CIRCULATIONAHA.118.033983 29526833\n\n",
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"abstract": "Unusual forms of pulmonary hypertension include pulmonary hypertension related to mediastinal fibrosis and the use of serotonergic drugs. Here, we describe a patient with diffuse mediastinal fibrosis and pulmonary hypertension while she was on dopamine agonist therapy. A young woman, who was treated with cabergoline and bromocriptine for hyperprolactinemia, presented with progressive dyspnea over several months. Based on the clinical investigation results, in particular, elevated pulmonary arterial pressures and significant perfusion defects on computed tomography (CT) pulmonary angiography and ventilation/perfusion (V/Q) scintigraphy, chronic thromboembolic pulmonary hypertension (CTEPH) was initially considered the most plausible diagnosis. However, during an attempted pulmonary endarterectomy, loose fibrous tissues were observed in the mediastinum and cryosection of the right pulmonary artery showed fibrosis and chronic inflammation. Subsequent investigations revealed that diffuse mediastinal fibrosis with concurrent pulmonary hypertension, and not CTEPH, was the most likely diagnosis and cabergoline and bromocriptine may have triggered the fibrotic changes. Both drugs are ergot-derived dopamine agonists, which are known to cause cardiac valve fibrosis and less frequently, non-cardiac fibrotic changes. The underlying mechanism is attributed to their interactions with serotonin receptors. There is much evidence that serotonin, a potent vasoconstrictor and mitogen, is involved in the pathogenesis of pulmonary hypertension. In conclusion, as CT and V/Q scintigraphy findings can occasionally be deceptive, physicians should be particularly aware of differential diagnoses in patients without obvious history of venous thromboembolism that are suspected of having chronic thromboembolic pulmonary hypertension.",
"affiliations": "Department of Biomedicine and Pharmacology, Aarhus UniversityAarhus, Denmark.;Department of Biomedicine and Pharmacology, Aarhus UniversityAarhus, Denmark.;Department of Cardiology, RigshospitaletCopenhagen, Denmark.;Department of Cardiology, Aarhus University HospitalAarhus, Denmark.",
"authors": "Su|Junjing|J|;Simonsen|Ulf|U|;Carlsen|Jørn|J|;Mellemkjaer|Soren|S|",
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"doi": "10.3389/fphar.2017.00492",
"fulltext": "\n==== Front\nFront PharmacolFront PharmacolFront. Pharmacol.Frontiers in Pharmacology1663-9812Frontiers Media S.A. 10.3389/fphar.2017.00492PharmacologyCase ReportPulmonary Artery Occlusion and Mediastinal Fibrosis in a Patient on Dopamine Agonist Treatment for Hyperprolactinemia Su Junjing 1*Simonsen Ulf 1Carlsen Jørn 2Mellemkjaer Soren 31Department of Biomedicine and Pharmacology, Aarhus University\nAarhus, Denmark2Department of Cardiology, Rigshospitalet\nCopenhagen, Denmark3Department of Cardiology, Aarhus University Hospital\nAarhus, DenmarkEdited by: Nicolau Beckmann, Novartis Institutes for BioMedical Research, United States\n\nReviewed by: Lohit Garg, Lehigh Valley Health Network, United States; Nenad Petrovic, University of South Australia, Australia\n\n*Correspondence: Junjing Su, junjing.su@biomed.au.dkThis article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal Frontiers in Pharmacology\n\n20 7 2017 2017 8 49223 5 2017 10 7 2017 Copyright © 2017 Su, Simonsen, Carlsen and Mellemkjaer.2017Su, Simonsen, Carlsen and MellemkjaerThis 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) or licensor 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.Unusual forms of pulmonary hypertension include pulmonary hypertension related to mediastinal fibrosis and the use of serotonergic drugs. Here, we describe a patient with diffuse mediastinal fibrosis and pulmonary hypertension while she was on dopamine agonist therapy. A young woman, who was treated with cabergoline and bromocriptine for hyperprolactinemia, presented with progressive dyspnea over several months. Based on the clinical investigation results, in particular, elevated pulmonary arterial pressures and significant perfusion defects on computed tomography (CT) pulmonary angiography and ventilation/perfusion (V/Q) scintigraphy, chronic thromboembolic pulmonary hypertension (CTEPH) was initially considered the most plausible diagnosis. However, during an attempted pulmonary endarterectomy, loose fibrous tissues were observed in the mediastinum and cryosection of the right pulmonary artery showed fibrosis and chronic inflammation. Subsequent investigations revealed that diffuse mediastinal fibrosis with concurrent pulmonary hypertension, and not CTEPH, was the most likely diagnosis and cabergoline and bromocriptine may have triggered the fibrotic changes. Both drugs are ergot-derived dopamine agonists, which are known to cause cardiac valve fibrosis and less frequently, non-cardiac fibrotic changes. The underlying mechanism is attributed to their interactions with serotonin receptors. There is much evidence that serotonin, a potent vasoconstrictor and mitogen, is involved in the pathogenesis of pulmonary hypertension. In conclusion, as CT and V/Q scintigraphy findings can occasionally be deceptive, physicians should be particularly aware of differential diagnoses in patients without obvious history of venous thromboembolism that are suspected of having chronic thromboembolic pulmonary hypertension.\n\ndopamine agonistserotoninpulmonary hypertensionmediastinal fibrosisadverse drug reaction\n==== Body\nIntroduction\nPulmonary hypertension, defined as an increase in resting mean pulmonary arterial pressure (≥ 25 mmHg) as assessed by right heart catheterization, is a serious condition that can lead to right heart failure (Galie et al., 2016). Several forms of pulmonary hypertension exist, including chronic thromboembolic pulmonary hypertension (CTEPH), which is caused by obstruction of the large pulmonary arteries typically following an episode or recurrent episodes of pulmonary embolism. The treatment of choice for CTEPH is pulmonary endarterectomy, which is potentially curative (Jamieson et al., 2003). It is therefore imperative to identify patients that are eligible for surgery.\n\nOther unusual forms of pulmonary hypertension include pulmonary hypertension related to mediastinal fibrosis (Seferian et al., 2015) and the use of serotonergic drugs (Seferian et al., 2013). Mediastinal fibrosis (fibrosing mediastinitis) is a rare condition characterized by proliferation of fibrous tissues in the mediastinum often associated with granulomatous diseases, such as histoplasmosis, tuberculosis and sarcoidosis and other fibro-inflammatory and autoimmune diseases (Rossi et al., 2016). It can be induced iatrogenically in relation to previous mediastinal irradiation and treatment with methysergide maleate (Graham et al., 1966), an ergot-derived serotonin antagonists previously used in the treatment of migraine. Mediastinal fibrosis can cause compression and obliteration of vital mediastinal structures, i.e., the airways, esophagus and great vessels (Sherrick et al., 1994). Thin-walled vessels with low intraluminal pressure, such as superior vena cava and less frequently, the pulmonary arteries, are especially subjected to compression by mediastinal masses resulting in increased intravascular pressure. Due to its extended course through the mediastinum, the right pulmonary artery is more susceptible to mediastinal processes compared to the left pulmonary artery.\n\nSerotonin is a potent vasoconstrictor and mitogen that causes smooth muscle cell hyperplasia and hypertrophy. There is much evidence that it is involved in the pathogenesis of pulmonary hypertension (Egermayer et al., 1999). In addition, an association between the appetite suppressants, fenfluramine derivatives, and pulmonary hypertension is well-established. Fenfluramine derivatives cause increased serotonin levels by acting as serotonin uptake inhibitors and induce transport-mediated serotonin release (Seferian et al., 2013). However, whether other serotonergic drugs, such as ergot-derived dopamine agonists, are associated with an increased risk of developing pulmonary hypertension remains unclear. Here, we describe a patient on ergot-derived dopamine agonist therapy for hyperprolactinemia that had diffuse mediastinal fibrosis and pulmonary hypertension mimicking CTEPH.\n\nCase Presentation\nA 36-year-old woman, who presented with progressive exertional dyspnea over 6 months, was referred to us as a potential candidate for pulmonary endarterectomy with a presumptive diagnosis of CTEPH, for which she was receiving anticoagulation treatment. She did not report any chest pain or episodes of syncope. She was diagnosed with a microprolactinoma after experiencing galactorrhoea 7 years earlier, for which she received low-dose cabergoline treatment (0.5 mg/week) for a year before switching to bromocriptine (2.5 mg/day) when she wished to become pregnant. She took bromocriptine for a year until she became pregnant and the treatment was paused. Shortly after a non-problematic pregnancy and childbirth, low-dose cabergoline treatment (0.5 mg/week) was resumed. In total, the patient had received ∼160 mg cabergoline and ∼900 mg bromocriptine and her prolactin level remained within normal range on treatment. She was a non-smoker and was on birth control pills for several years. The medical history on the father’s side was unknown and there was nothing remarkable on the mother’s side.\n\nClinical examination of the patient revealed a systolic murmur and reduced breath sound in the right lung. The 6-min-walk-distance was reduced to 259 m. An electrocardiogram showed T-wave inversion in leads V3 and V4. Creatine kinase MB isoenzyme and troponin T levels were within normal range. However, the level of the NT-proBNP was elevated to 2899 ng/L. Transthoracic echocardiography revealed a moderately dilated right ventricle with impaired function and moderate tricuspid regurgitation with a gradient of 92 mmHg. Subsequent right heart catheterization showed severe pre-capillary pulmonary hypertension with a mean pulmonary arterial pressure of 52 mmHg and pulmonary vascular resistance of 880 dyn.s/cm5 (a summary of main findings are listed in Table 1). HRCT showed significantly thickened left and right pulmonary arteries, elevated right hemidiaphragm and non-specific infiltrates in the right lower lung. There was no evidence of mediastinal lymphadenopathy. CT pulmonary angiography revealed near-complete occlusion of the right pulmonary artery and severe, short-segment stenosis as well as wall irregularities in the left lobar and segmental pulmonary arteries. Similar findings were observed during digital subtraction angiography (Figure 1). PET-CT did not show any pathological FDG-uptake. V/Q scintigraphy revealed absent perfusion to the right lung that was not matched to the ventilation and several segmental and sub-segmental mismatched perfusion defects in the left lung. Spirometry showed reduced lung function of a restrictive pattern. Biochemical and serological screening for thrombophilia, autoimmune diseases and systemic connective tissue diseases were all negative. Based on results from the above-mentioned investigations, CTEPH as a consequence of previous subclinical pulmonary embolism was initially considered the most plausible diagnosis.\n\nTable 1 Summary of main findings.\n\nVital signs\tHeart rate: 97 min-1, blood pressure: 125/80 mmHg, temperature: 37.6°C, saturation: 95%\t\n6-min walk distance\t259 m\t\nElectrocardiography\tSinus rhythm, T-wave inversion in V3 and V4\t\nTransthoracic echocardiography\tNormal sized left atrium, normal left ventricular dimensions and function, moderately dilated right atrium and ventricle, TAPSE: 1.4 cm, -moderate tricuspid regurgitation with a gradient of 92 mmHg, dilated IVC with absent respiratory variation\t\nRight heart catheterization\tCI (thermodilution): 1.8 L/min/m2, right atrial pressure: 19 mmHg, PAPm: 52 mmHg, PAWP: 13 mmHg, PVR: 880 dyn.s/cm5\t\nCoronary angiography\tNormal\t\nHRCT\tThickened pulmonary arteries, elevated right hemidiaphragm, nonspecific infiltrates in the right lower lung\t\nPET-CT\tNo pathological FDG-uptake\t\nCTPA and DSA\tSee Figure 1\t\nV/Q scintigraphy\tAbsent perfusion to the right lung, segmental and sub-segmental mismatched perfusion defects in the left lung\t\nSpirometry\tFEV1: 1.36 (42% predicted), FVC: 1.79 (48% predicted), FEV1/FVC: 76%\t\nHistology\tSee Figure 2\t\nBronchoscopy with EBUS\tNo evidence of malignant cells or granulomatous inflammation in the endobronchial biopsy, bronchoalveolar lavage fluid and transbronchial needle aspiration biopsy from lower paratracheal and subcarinal lymph nodes.\t\nBlood test\tNormal blood count, normal liver and kidney function tests, C-reactive protein: 26 mg/L, erythrocyte sedimentation rate: 14 mm/hr, prolactin: 288 mIU/L (on cabergoline treatment), NT-proBNP: 2899 ng/L, troponin-T: below limit of detection, negative screening for thrombophilia, autoimmune and connective tissue diseases\t\nBronchoscopy results were obtained after the attempted pulmonary endarterectomy, while the rest of the results were obtained prior to or during the procedure. CI, cardiac index; CT, computed tomography; CTPA, CT pulmonary angiography; DSA, digital subtraction angiography; EBUS, endobronchial ultrasound; FDG, fluorodeoxyglucose; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; HRCT, high resolution CT; IVC, inferior vena cava; NT-proBNP, terminal pro-B-type natriuretic peptide; PAPm, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; PET, positive emission tomography; TAPSE, tricuspid annular plane systolic excursion; V/Q, ventilation/perfusion.FIGURE 1 Pulmonary artery occlusion. CT pulmonary angiography (A) showed near-complete occlusion of the right pulmonary artery without any flow and elevated right hemidiaphragm. There was severe thickening of the left lobar pulmonary arteries and short-segment stenosis (white triangles) and wall irregularities (white arrow) in the left lobar and segmental pulmonary arteries. Similar findings were observed during digital subtraction angiography (B).\n\nPulmonary endarterectomy was attempted 7 months later, during which, loose fibrous tissues were observed around the aorta, main pulmonary artery and superior vena cava. The right pulmonary artery appeared stiff and cryosection of the artery showed fibrosis and chronic inflammation. In light of the new findings, which were not compatible with CTEPH, pulmonary endarterectomy was aborted. Cabergoline treatment was discontinued immediately after the attempted endarterectomy as it was suspected to have caused the fibrotic changes and anticoagulation therapy was discontinued a few days later. Histologic examination of the right pulmonary artery biopsy (Figure 2) confirmed the cryosection results. Immunohistochemical screening for overexpression of MUM1, a lymphocyte-specific transcription factor associated with a wide range of hematolymphoid neoplasms (Natkunam et al., 2001), and IgG4, which can be associated with idiopathic fibro-inflammatory disorders (Rossi et al., 2016), were negative. Subsequent bronchoscopy showed no endobronchial abnormalities. Endobronchial biopsy and transbronchial needle aspiration biopsy showed nonspecific changes with no evidence of malignancy or granulomatous inflammation. Repeat HRCT showed pleural thickening and no evidence of retroperitoneal fibrosis. Repeat PET-CT showed hypermetabolic activity around the lung hila and aortic arch and in the right lung. Based on the clinical findings, histopathology and after ruling out other possible diseases, a diagnosis of mediastinal and pleuropulmonary fibrosis was made.\n\nFIGURE 2 Right pulmonary artery biopsy. Histologic examination (hematoxylin and eosin stain) of the right pulmonary artery biopsy revealed fibrotic connective tissue (A) infiltrated by inflammatory cells consisting of lymphocytes and macrophages (B,C). Immunohistochemistry was carried out for the leukocyte common antigen CD45 (D,E), immunoglobulin subclass IgG4 (F,J) and a lymphocyte specific transcriptional factor: multiple MUM1 (H,I). Total magnification of 40× (A) and 400× (B–I).\n\nIn the year that followed, the patient was monitored biweekly. Her prolactin level remained within normal range without dopamine agonist treatment. She received immunosuppressive therapy, prednisolone, methotrexate and mycophenolate mofetil, as well as pulmonary hypertension treatment, sildenafil, spironolactone and bumetanide. However, her symptoms deteriorated despite radiological signs of disease regression. She was hospitalized several times due to hemoptysis and opportunistic infections. Endovascular stenting of the right pulmonary artery was considered unsafe due to a high risk of arterial rupture. Double lung transplantation was assessed to be technically feasible and after much deliberation and detailed discussions at multidisciplinary meetings, it was considered the only option and the patient was admitted for the procedure. Upon sternotomy, the right lung appeared fibrotic and atelectic. It was adhered to the inner chest wall and appeared to be receiving part of its blood supply from the chest wall. Sadly, although the donor lungs were transplanted, the patient died on the operating table due to uncontainable bleeding from the chest wall and intercostal arteries.\n\nDiscussion\nWe have presented an unusual complex case of pulmonary hypertension. It remains unclear whether this is a case of pulmonary hypertension complicating mediastinal fibrosis or multi-organ affection with concurrent fibrotic changes in the mediastinum, pulmonary artery, right lung, and pleura. It is debatable whether there is an association with the ergot-derived dopamine agonists, cabergoline and bromocriptine, that the patient had received.\n\nPulmonary hypertension complicating mediastinal fibrosis shares many similarities with proximal CTEPH including perfusion defects on CTPA and V/Q scintigraphy (Seferian et al., 2015), both of which have a high sensitivity for the diagnosis of CTEPH (Galie et al., 2016). The most common pattern of mediastinal fibrosis on CT is large, localized soft tissue masses with or without calcifications, while diffuse homogeneous soft tissue processes are less common (Sherrick et al., 1994; Worrell et al., 2007). Hence, the lack of clear radiological evidence of mediastinal masses, lymphadenopathy and/or extrinsic compression and encasement of the pulmonary arteries by neighboring tissues (Seferian et al., 2015) and the nonspecific lung parenchymal affection in this patient led to the incorrect diagnosis of CTEPH. Due to the variable etiologies and clinical presentations, there is no standard therapy for mediastinal fibrosis. Pharmacology treatment is often ineffective. However, there are reports of successful treatment with corticosteroids and mycophenolate mofetil (Lal et al., 2005; Ikeda et al., 2007; Witschi et al., 2009). Pulmonary hypertension related to mediastinal fibrosis is associated with a poor prognosis. Invasive interventions include endovascular stenting and bypassing or reconstructing an obstructed pulmonary artery (Brown et al., 2009; Seferian et al., 2015). In the current patient case, as pharmacological treatment was unsuccessful and direct manipulation of the right pulmonary artery was associated with a high risk of artery rupture due to the extensive fibrotic changes, lung transplantation was considered the only option. To the best of our knowledge, this is the first described case of attempted lung transplantation in a patient with mediastinal fibrosis, which, regrettably, was unsuccessful.\n\nErgot-derived dopamine agonists, such as cabergoline, pergolide and bromocriptine, can induce cardiac valve fibrosis and less frequently, non-cardiac fibrotic changes, such as pleuropulmonary and retroperitoneal fibrosis, especially in patients on long-term high-dose treatment for Parkinson’s disease, usually a cumulative dose >2000 mg in the case of cabergoline. The underlying mechanism is attributed to their interaction with serotonin receptors (Schade et al., 2007; Zanettini et al., 2007; Andersohn and Garbe, 2009). Low-dose treatment for hyperprolactinemia is not associated with an increased risk of clinically significant cardiac valvulopathy. However, mild to moderate tricuspid regurgitation and subclinical fibrotic lesions appear to be more prevalent during cabergoline and bromocriptine treatment and pulmonary arterial pressure, obtained on transthoracic echocardiography, was reported to be higher, but within normal range, in patients receiving bromocriptine (Elenkova et al., 2012; De Vecchis et al., 2013).\n\nSeveral previous case reports that suggest a possible link between low-dose ergot-derived dopamine agonist treatment and clinically significant fibrotic changes are relevant to summarize here. Severe mitral regurgitation caused by cabergoline therapy (cumulative dose: ∼250 mg) was reported in a patient with hyperprolactinemia (Cawood et al., 2009). After daily low-dose cabergoline treatment (cumulative dose: ∼180 mg), a patient with acromegaly developed severe tricuspid regurgitation and dilated right ventricle with impaired function (Izgi et al., 2010). In a Parkinson patient, enlarged pulmonary artery, severe pulmonary hypertension, pleural effusion and mediastinal lymphadenopathy occurred after just one year of cabergoline treatment (cumulative dose: ∼730 mg) (Haro-Estarriol et al., 2009). Finally, constrictive pericarditis was diagnosed in a hyperprolactinemia patient treated with bromocriptine (cumulative dose: 14600 mg) and cabergoline (cumulative dose: 320 mg) (Londahl et al., 2008).These cases illustrate individual variations in susceptibility to the fibrotic side effects of ergot-derived dopamine agonists.\n\nDrug-induced pulmonary hypertension is well-recognized. The best documented are the sympathomimetic anorexigens, aminorex, benfluorex and other fenfluramine derivatives, that have direct and indirect serotonergic effects (Seferian et al., 2013). However, there is no clear evidence of a causal relationship between ergot-derived dopamine agonists and pulmonary hypertension. Pergolide and methyseride, both of which are ergot-derivatives, are possibly associated with pulmonary hypertension (Egermayer et al., 1999; Seferian et al., 2013). Cabergoline and bromocriptine display agonist properties at several serotonin receptors, including 5-HT1B, 5-HT2A, and 5-HT2B (bromocriptine is a 5-HT2B antagonist, however) (Newman-Tancredi et al., 2002), all of which are implicated in the development of pulmonary hypertension. 5-HT1B receptors mediate serotonin-induced pulmonary vasoconstriction and vascular smooth muscle hypertrophy and hyperplasia, 5-HT2A receptors induce pulmonary arterial adventitial fibroblast proliferation and 5-HT2B receptors are involved in right ventricular fibrosis (MacLean and Dempsie, 2010; Janssen et al., 2015). Consistent with this, macroscopic and microscopic structural changes were observed in the right pulmonary artery of our patient suggesting that pulmonary hypertension was caused by direct pulmonary artery affection possibly in addition to extrinsic compression caused by mediastinal fibrosis.\n\nConcluding Remarks\nIt remains undetermined whether cabergoline and/or bromocriptine treatment was the cause of mediastinal fibrosis and pulmonary hypertension in this patient. Further investigations are required to elucidate whether there is an association between ergot-derived dopamine agonists and mediastinal fibrosis and pulmonary hypertension. In conclusion as CT and V/Q scintigraphy findings can occasionally be deceptive, physicians should be particularly aware of differential diagnoses in patients without obvious history of venous thromboembolism that are suspected of having chronic thromboembolic pulmonary hypertension.\n\nEthics Statement\nOur submission is a case report. Data was collected during the routine clinical care of the patient. Prior to her death, the patient had given written informed consent to participate in a research study conducted by our group that was approved by The National Committee on Health Research Ethics (reference M-2013-278-13), including permission to collect and publish clinical data in anonymized form. Confidentiality of the data has been ensured in accordance to the ICMJE guidelines.\n\nAuthor Contributions\nSM and JC were involved in the care of the patient. JS, SM, and JC collected the data and all the authors (JS, US, JC, and SM) contributed to the interpretation of the data. JS drafted the manuscript and all the authors have revised it critically for important intellectual content and approved the final version of the manuscript and this submission.\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\nFunding. JS is receiving funding from Aarhus University Graduate School.\n\nWe thank Dr. Steen Bærentzen, Department of Pathology, Aarhus University Hospital, for providing the images of histological sections.\n\nAbbreviations\nCIcardiac index\n\nCTcomputed tomography\n\nCTEPHchronic thromboembolic pulmonary hypertension\n\nCTPACT pulmonary angiography\n\nDSAdigital subtraction angiography\n\nEBUSendobronchial ultrasound\n\nFDGfluorodeoxyglucose\n\nFEV1forced expiratory volume in the first second\n\nFVCforced vital capacity\n\nHRCThigh resolution CT\n\nIVCinferior vena cava\n\nMUM1myeloma oncogene 1\n\nNT-proBNPterminal pro-B-type natriuretic peptide\n\nPAPmmean pulmonary arterial pressure\n\nPAWPpulmonary arterial wedge pressure\n\nPETpositive emission tomography\n\nPVRpulmonary vascular resistance\n\nTAPSEtricuspid annular plane systolic excursion\n\nV/Qventilation/perfusion.\n==== Refs\nReferences\nAndersohn F. Garbe E. (2009 ). 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Pleural effusion and pulmonary hypertension in a patient with Parkinson disease treated with cabergoline. \nArch. Bronconeumol. \n45 \n100 –102 . 10.1016/j.arbres.2008.01.003 19232272 \nIkeda K. Nomori H. Mori T. Kobayashi H. Iwatani K. Yoshimoto K. (2007 ). Successful steroid treatment for fibrosing mediastinitis and sclerosing cervicitis. \nAnn. Thorac. Surg. \n83 \n1199 –1201 . 10.1016/j.athoracsur.2006.09.034 17307498 \nIzgi C. Feray H. Cevik C. Saltan Y. Mansuroglu D. Nugent K. (2010 ). Severe tricuspid regurgitation in a patient receiving low-dose cabergoline for the treatment of acromegaly. \nJ. Heart Valve Dis. \n19 \n797 –800 .21214109 \nJamieson S. W. Kapelanski D. P. Sakakibara N. Manecke G. R. Thistlethwaite P. A. Kerr K. M. (2003 ). Pulmonary endarterectomy: experience and lessons learned in 1,500 cases. \nAnn. Thorac. Surg. \n76 \n1457 –1462 . 10.1016/S0003-4975(03)00828-2 14602267 \nJanssen W. Schymura Y. Novoyatleva T. Kojonazarov B. Boehm M. Wietelmann A. (2015 ). 5-HT2B receptor antagonists inhibit fibrosis and protect from RV heart failure. \nBiomed Res. Int. \n2015 :438403 \n10.1155/2015/438403 \nLal C. Weiman D. Eltorky M. Pugazhenthi M. (2005 ). Complete resolution of fibrosing mediastinitis with corticosteroid therapy. \nSouth Med. J. \n98 \n749 –750 . 10.1097/01.smj.0000168656.75306.24 16108250 \nLondahl M. Nilsson A. Lindgren H. Katzman P. (2008 ). A case of constrictive pericarditis during cabergoline treatment for hyperprolactinaemia. \nEur. J. Endocrinol. \n158 \n583 –585 . 10.1530/EJE-07-0584 18362307 \nMacLean M. R. Dempsie Y. (2010 ). The serotonin hypothesis of pulmonary hypertension revisited. \nAdv. Exp. Med. Biol. \n661 \n309 –322 . 10.1007/978-1-60761-500-2_20 20204739 \nNatkunam Y. Warnke R. A. Montgomery K. Falini B. van De R. M. (2001 ). Analysis of MUM1/IRF4 protein expression using tissue microarrays and immunohistochemistry. \nMod. Pathol. \n14 \n686 –694 . 10.1038/modpathol.3880373 11455001 \nNewman-Tancredi A. Cussac D. Quentric Y. Touzard M. Verriele L. Carpentier N. (2002 ). Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT(1) and 5-HT(2), receptor subtypes. \nJ. Pharmacol. Exp. Ther. \n303 \n815 –822 . 10.1124/jpet.102.039883 12388668 \nRossi G. M. Emmi G. Corradi D. Urban M. L. Maritati F. Landini F. (2016 ). Idiopathic mediastinal fibrosis: a systemic immune-mediated disorder. A case series and a review of the literature. \nClin. Rev. Allergy Immunol. \n52 \n446 –459 . 10.1007/s12016-016-8584-1 \nSchade R. Andersohn F. Suissa S. Haverkamp W. Garbe E. (2007 ). Dopamine agonists and the risk of cardiac-valve regurgitation. \nN. Engl. J. Med. \n356 \n29 –38 . 10.1056/NEJMoa062222 17202453 \nSeferian A. Chaumais M. C. Savale L. Gunther S. Tubert-Bitter P. Humbert M. (2013 ). Drugs induced pulmonary arterial hypertension. \nPresse Med. \n42 \ne303 –e310 . 10.1016/j.lpm.2013.07.005 23972547 \nSeferian A. Steriade A. Jais X. Planche O. Savale L. Parent F. (2015 ). Pulmonary hypertension complicating fibrosing mediastinitis. \nMedicine \n94 :e1800 \n10.1097/MD.0000000000001800 \nSherrick A. D. Brown L. R. Harms G. F. Myers J. L. (1994 ). The radiographic findings of fibrosing mediastinitis. \nChest \n106 \n484 –489 . 10.1378/chest.106.2.484 7774324 \nWitschi M. Gugger M. Nicod L. P. (2009 ). Treatment of mediastinal fibrosis with mycophenolate mofetil. \nRespiration \n78 \n330 –333 . 10.1159/000209508 19295189 \nWorrell J. A. Donnelly E. F. Martin J. B. Bastarache J. A. Loyd J. E. (2007 ). Computed tomography and the idiopathic form of proliferative fibrosing mediastinitis. \nJ. Thorac. Imaging \n22 \n235 –240 . 10.1097/01.rti.0000213589.29472.18 17721332 \nZanettini R. Antonini A. Gatto G. Gentile R. Tesei S. Pezzoli G. (2007 ). Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. \nN. Engl. J. Med. \n356 \n39 –46 . 10.1056/NEJMoa054830 17202454\n\n",
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"title": "Pulmonary Artery Occlusion and Mediastinal Fibrosis in a Patient on Dopamine Agonist Treatment for Hyperprolactinemia.",
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"abstract": "Anaphylaxis is a severe, systemic hypersensitivity reaction that can be potentially life-threatening. Anaphylaxis during oral food challenge is not uncommon and can usually be effectively managed with intramuscular adrenaline as first line treatment. Although very rare, fatal anaphylaxis during in-hospital food challenge has been reported.\n\n\n\nWe describe our experience of cases of refractory anaphylaxis at in-hospital challenge and propose a framework for escalation of treatment in such cases using intravenous infusion of adrenaline which has been adopted for widespread use elsewhere.\n\n\n\nWe present four patients who all experienced severe life-threatening anaphylaxis, refractory to intramuscular adrenaline treatment, during supervised oral food challenges. Patient data were collected from contemporaneous notes, and patient consent was obtained.\n\n\n\nIn all four cases, the anaphylaxis reactions were amenable to treatment with low-dose intravenous adrenaline, with no reported adverse effects.\n\n\n\nThese cases demonstrate the need for clinicians undertaking higher risk allergen challenges to be able to manage cases of severe anaphylaxis refractory to intramuscular adrenaline, and to consider a framework for managing these reactions. While peripheral intravenous adrenaline infusions should always be initiated only in conjunction with expert input, the protocol suggested is simple enough to be undertaken within the hospital environment while more experienced support is obtained.",
"affiliations": "Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK.;National Heart & Lung Institute, Imperial College London, London, UK.;Royal Berkshire NHS Foundation Trust, Reading, UK.;Royal Berkshire NHS Foundation Trust, Reading, UK.;Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK.;National Heart & Lung Institute, Imperial College London, London, UK.;Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK.",
"authors": "Alviani|Cherry|C|0000-0003-1527-0495;Burrell|Sarah|S|;Macleod|Abigail|A|;Edees|Susan|S|;Roberts|Graham|G|0000-0003-2252-1248;Turner|Paul J|PJ|;Erlewyn-Lajeunesse|Michel|M|0000-0003-1982-1397",
"chemical_list": "D000485:Allergens; D018926:Anti-Allergic Agents; D004837:Epinephrine",
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"journal": "Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology",
"keywords": "adrenaline; allergy; anaphylaxis; food allergy; oral food challenge",
"medline_ta": "Clin Exp Allergy",
"mesh_terms": "D000293:Adolescent; D000485:Allergens; D000707:Anaphylaxis; D018926:Anti-Allergic Agents; D002648:Child; D004351:Drug Resistance; D004837:Epinephrine; D005260:Female; D005512:Food Hypersensitivity; D006801:Humans; D007159:Immunologic Tests; D007262:Infusions, Intravenous; D007273:Injections, Intramuscular; D008297:Male; D011237:Predictive Value of Tests; D016896:Treatment Outcome",
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"title": "Anaphylaxis Refractory to intramuscular adrenaline during in-hospital food challenges: A case series and proposed management.",
"title_normalized": "anaphylaxis refractory to intramuscular adrenaline during in hospital food challenges a case series and proposed management"
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"abstract": "BACKGROUND\nExcessive dynamic airway collapse (EDAC) is an uncommon cause of high airway pressure during mechanical ventilation. However, EDAC is not widely recognized by anesthesiologists, and therefore, it is often misdiagnosed as asthma.\n\n\nMETHODS\nA 70-year-old woman with a history of asthma received anesthesia with sevoflurane for a laparotomic cholecystectomy. Under general anesthesia, she developed wheezing, high inspiratory pressure, and a shark-fin waveform on capnography, which was interpreted as an asthma attack. However, treatment with a bronchodilator was ineffective. Bronchoscopy revealed the collapse of the trachea and main bronchi upon expiration. We reviewed the preoperative computed tomography scan and saw bulging of the posterior membrane into the airway lumen, leading to a diagnosis of EDAC.\n\n\nCONCLUSIONS\nAlthough both EDAC and bronchospasm present as similar symptoms, the treatments are different. Bronchoscopy proved useful for distinguishing between these two entities. Positive end-expiratory pressure should be applied and bronchodilators avoided in EDAC.",
"affiliations": "Department of Anesthesiology, Shuto General Hospital, Kogaisaku 1000-1, Yanai, Yamaguchi, 742-0032, Japan. m076eb@gmail.com.;Department of Anesthesiology, Shuto General Hospital, Kogaisaku 1000-1, Yanai, Yamaguchi, 742-0032, Japan.;Department of Anesthesiology, Japan Community Healthcare Organization Tokuyama Central Hospital, Kodacho 1-1, Shunan, Yamaguchi, 745-8522, Japan.;Department of Anesthesiology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan.;Department of Anesthesiology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan.",
"authors": "Murakami|Shunichi|S|http://orcid.org/0000-0002-4594-4553;Tsuruta|Shunsuke|S|;Ishida|Kazuyoshi|K|;Yamashita|Atsuo|A|;Matsumoto|Mishiya|M|",
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"fulltext": "\n==== Front\nJA Clin Rep\nJA Clinical Reports\n2363-9024 Springer Berlin Heidelberg Berlin/Heidelberg \n\n380\n10.1186/s40981-020-00380-1\nCase Report\nExcessive dynamic airway collapse during general anesthesia: a case report\nhttp://orcid.org/0000-0002-4594-4553Murakami Shunichi m076eb@gmail.com 1 Tsuruta Shunsuke 1 Ishida Kazuyoshi 2 Yamashita Atsuo 3 Matsumoto Mishiya 3 1 grid.415872.d0000 0004 1781 5521Department of Anesthesiology, Shuto General Hospital, Kogaisaku 1000-1, Yanai, Yamaguchi, 742-0032 Japan \n2 Department of Anesthesiology, Japan Community Healthcare Organization Tokuyama Central Hospital, Kodacho 1-1, Shunan, Yamaguchi, 745-8522 Japan \n3 grid.268397.10000 0001 0660 7960Department of Anesthesiology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi, 755-8505 Japan \n28 9 2020 \n28 9 2020 \n12 2020 \n6 7316 8 2020 16 9 2020 22 9 2020 © The Author(s) 2020Open 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/.Background\nExcessive dynamic airway collapse (EDAC) is an uncommon cause of high airway pressure during mechanical ventilation. However, EDAC is not widely recognized by anesthesiologists, and therefore, it is often misdiagnosed as asthma.\n\nCase presentation\nA 70-year-old woman with a history of asthma received anesthesia with sevoflurane for a laparotomic cholecystectomy. Under general anesthesia, she developed wheezing, high inspiratory pressure, and a shark-fin waveform on capnography, which was interpreted as an asthma attack. However, treatment with a bronchodilator was ineffective. Bronchoscopy revealed the collapse of the trachea and main bronchi upon expiration. We reviewed the preoperative computed tomography scan and saw bulging of the posterior membrane into the airway lumen, leading to a diagnosis of EDAC.\n\nConclusions\nAlthough both EDAC and bronchospasm present as similar symptoms, the treatments are different. Bronchoscopy proved useful for distinguishing between these two entities. Positive end-expiratory pressure should be applied and bronchodilators avoided in EDAC.\n\nKeywords\nExcessive dynamic airway collapseAsthmaBronchoscopyGeneral anesthesiaPositive end-expiratory pressureissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nHigh-inspiratory airway pressure is sometimes encountered during general anesthesia with endotracheal intubation and is usually caused by an asthma attack or chronic obstructive pulmonary disease. However, there are some uncommon causes of this phenomenon, one of which is expiratory central airway collapse. In adults, expiratory central airway collapse occurs because of tracheobronchomalacia (TBM), excessive dynamic airway collapse (EDAC), or both [1]. TBM is characterized by weakness of the tracheobronchial cartilaginous structures and manifests as circumferential flaccidity. In contrast, EDAC results from degeneration of the smooth muscle of the posterior membrane of the tracheobronchial tree and is characterized by excessive bulging of the posterior membranes into the airway lumen without collapse of the cartilage [1].\n\nHere, we report a case in which EDAC was incidentally diagnosed during abdominal surgery under general anesthesia. We obtained written informed consent from the patient and her family for publication of this case report.\n\nCase presentation\nA 70-year-old woman (height 145 cm, weight 65 kg, body mass index 31 kg/m2) was transferred to our hospital with fever, abdominal pain, and elevated liver enzymes. Computed tomography (CT) revealed calculous cholecystitis and paralytic ileus. Therefore, an emergent laparotomic cholecystectomy was planned. She had tachypnea but no wheeze or cough. Arterial blood gas analysis showed pH of 7.47, PaO2 of 65 mmHg, and PaCO2 of 36 mmHg under nasal tube oxygen at 1 L/min. Chest radiography revealed an elevation of the right hemidiaphragm and right-sided pleural effusion (Fig. 1a). Her medical history included schizophrenia, dementia, atrial fibrillation, diabetes mellitus, and untreated asthma. She had no previous history of abdominal or thoracic surgery.\nFig. 1 Chest radiographs a before surgery and b after extubation. a Elevation of the right hemidiaphragm, right-sided pleural effusion, and dilated bowel were shown. b An increase in the right lung volume was shown\n\n\n\nGeneral anesthesia was induced with fentanyl 75 μg, propofol 60 mg, and rocuronium bromide 50 mg under standard monitoring. After endotracheal intubation, anesthesia was maintained with sevoflurane, fentanyl, and rocuronium bromide. Volume-controlled mechanical ventilation was started consisting of 8 mL/kg predicted body weight (respiratory rate 10 breaths per minute with an inspiratory to expiratory ratio of 1:2) without positive end-expiratory pressure (PEEP). Forty-five minutes after induction of anesthesia, we noticed a high peak inspiratory pressure (PIP) of 30 cmH2O, bilateral expiratory wheeze, and a shark-fin waveform on capnography without a decrease in percutaneous arterial blood oxygen saturation. There was minimal secretion in the trachea and no kinks in the endotracheal tube. Given the patient’s history of untreated asthma, we assumed she was having an asthma attack and administered 40 μg of procaterol via the endotracheal tube. However, the abnormal waveform and high airway pressure persisted. Although we re-administered procaterol and increased the concentration of inhalational sevoflurane from 1.5 to 2.0%, airway pressure increased further, fluctuating between 27 cmH2O and 35 cmH2O with each ventilation. Fortunately, she did not develop hypoxia or hypercapnia. Bronchoscopy revealed the collapsed trachea and main bronchi during expiration, indicating expiratory central airway collapse. The addition of PEEP (5 cmH2O) and extension of the exhalation time improved her condition promptly. Although the shark fin waveform remained on capnography, the highest PIP decreased from 35 cmH2O to 27 cmH2O. The surgeons then changed the procedure from cholecystectomy to gallbladder drainage because it was difficult to dissect the gallbladder from the liver bed. Despite lessening of the severity of her condition, peak airway pressure remained high and she was admitted to the postsurgical care unit after surgery without extubation. Operating time was 1 h 26 min and anesthesia time was 2 h 45 min.\n\nAfter the surgery, we noticed that preoperative non-dynamic CT had captured bulging of the posterior membranes of the trachea and main bronchi into the airway lumen without collapse of the cartilage (Fig. 2). We therefore diagnosed EDAC.\nFig. 2 Computed tomography scan of the chest. Computed tomography scan of the chest taken before surgery showing bulging of the posterior membrane (allow) into the airway lumen without collapse of the cartilage at the aortic arch level. An arrowhead indicates the esophagus\n\n\n\nThe patient was mechanically ventilated using volume-controlled synchronized intermittent mandatory ventilation with PEEP of 5 cmH2O postoperatively. Neither bronchodilators nor corticosteroids were administrated. The airway pressure started to decrease gradually on postoperative day (POD) 5. The patient was extubated after the ventilation mode was changed to continuous positive airway pressure of 5 cmH2O on POD 11 (Fig. 1b). The patient did not need further mechanical respiratory support.\n\nDiscussion\nEDAC can become unexpectedly severe such that mechanical ventilation becomes difficult and the resulting hypoxia and hypercapnia are life-threatening. Smoking, chronic inflammation, administration of steroids or beta-agonists, and ischemia (caused, for example, by introducing the endotracheal tube, tracheostomy, thyroid tumor, or vascular anomaly) can lead to degeneration of the smooth muscle fibers in the posterior membrane of the tracheobronchial tree [1, 2]. As air travels in the direction of the larynx, the intraluminal pressure decreases from alveolus toward the larynx during expiration. Because the smooth muscle of the trachea and main bronchi is affected with atrophies in EDAC patient, the posterior membrane bulges toward the anterior wall at the part where the intraluminal pressure is below the intrathoracic pressure [1]. One study found the prevalence of EDAC defined by expiratory airway collapse ≥ 75 to be 1.6% (1/62) in non-smokers without obstructive lung disease and 30.7% (62/202) in non-smokers with asthma [3]. Our patient may have been prone to EDAC because of her untreated asthma. The same study also reported the prevalence of EDAC to be 6.8% in a mild asthma group and 69.2% in a severe asthma group [3], indicating that patients with more severe asthma are at higher risk of EDAC.\n\nHowever, EDAC is not widely recognized by anesthesiologists, probably because it is not clinically serious unless there is a significant narrowing of the airway. The symptoms of airway narrowing are paroxysmal cough, wheeze, and stridor [4]. Those symptoms are also common in asthma and chronic obstructive pulmonary disease. Given the slow progression of EDAC, patients may not notice airway narrowing in everyday life. Although our patient did not have symptoms suggesting airway collapse before surgery during spontaneous breathing, general anesthesia with neuromuscular blockade seemed to cause an increase in intrathoracic pressure, leading to worsening of airway collapse. Furthermore, the choice of sevoflurane and administration of a bronchodilator might have worsened the EDAC by causing relaxation of the smooth muscle.\n\nThere has been another report of expiratory central airway collapse after induction of general anesthesia with isoflurane [5]. However, in that case, collapse affected in a limited portion of the trachea, as demonstrated by immediate improvement after the endotracheal tube was advanced 3 cm further down the trachea. In contrast, our case had more severe collapse, extending from the trachea to the main bronchi, as evident from our review of the preoperative CT scans. Our patient was extubated on POD 11. We speculate that improvement in the ileus and a return to spontaneous breathing may have helped reduce the intrathoracic pressure, leading to the improvement of EDAC.\n\nDynamic bronchoscopy or paired inspiratory-dynamic expiratory CT is often used for the diagnosis of expiratory central airway collapse [4]. In our case, we first detected the airway collapse using bronchoscopy. This incident diagnosis of EDAC was also supported by preoperative non-dynamic CT findings. Non-dynamic CT scans are usually acquired during breath-holding in the end-inspiratory phase, so images of expiratory airway collapse would not usually be obtained. However, the patient’s chest might have been scanned during the expiratory phase due to tachypnea and cognitive decline. Harada et al. [6] also reported incidental detection of EDAC with non-dynamic CT.\n\nPEEP can serve as a useful pneumatic stent if EDAC is suspected during general anesthesia, as in our case. Lyaker et al. [7] reported a case in which EDAC consistently worsened soon after extubation. In severe cases, noninvasive positive pressure ventilation might be necessary after extubation; this was not needed in our patient after extubation, probably because we continued mechanical ventilation until she had recovered satisfactorily. Some reports describe the use of PEEP of 6–10 cmH2O as treatment for EDAC not related to anesthesia [6, 8]. In another study, expiratory flow in children with TBM improved at noninvasive positive expiratory pressures of 5, 10, and 15 cmH2O but worsened at 20 cmH2O [9]. Although these were not cases of intraoperative EDAC, PEEP of 5–15 cmH2O may be adequate to improve EDAC that occurs during general anesthesia. In our case, we carefully added PEEP of 5 cmH2O and were able to decrease the PIP. However, it is possible that a higher PEEP could have further improved the airway obstruction. If a mechanical ventilator has a function of displaying flow-volume loops, the lowest PEEP value that can get the highest maximum expiratory flow will be a suitable setting. Considering the patient had already presented a hypoxia and a pleural effusion before the operation, we probably should have applied PEEP when mechanical ventilation was initiated.\n\nConclusion\nEDAC is likely to develop in patients with asthma. Both bronchospasm and worsening EDAC should be considered in a patient with a chronic lung condition such as asthma who develops increased airway pressure, wheezing, and a shark fin waveform on capnography during general anesthesia. Bronchoscopy provides useful for distinguishing between these two entities. As demonstrated in our case, bronchodilators should be avoided in patients with EDAC; instead, it is preferable to increase PEEP and have the patient breathe spontaneously when possible. Finally, it is worth keeping in mind that the preoperative CT scan can occasionally provide useful information about EDAC in patients with a chronic lung condition.\n\nAbbreviations\nEDACExcessive dynamic airway collapse\n\nTBMTracheobronchomalacia\n\nCTComputed tomography\n\nPEEPPositive end-expiratory pressure\n\nPIPPeak inspiratory pressure\n\nPODPostoperative day\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\nSM wrote the manuscript and prepared the images. ST assisted in the preparation of the manuscript. KI, AY, and MM revised the manuscript. The authors read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient and patient’s family for publication of this case report and accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Diaz Milian R Foley E Bauer M Martinez-Velez A Castresana MR Expiratory central airway collapse in adults: anesthetic implications (Part 1) J Cardiothorac Vasc Anesth 2019 33 2546 2554 10.1053/j.jvca.2018.08.205 30279064 \n2. Murgu SD Colt HG Tracheobronchomalacia and excessive dynamic airway collapse Respirology. 2006 11 388 406 10.1111/j.1440-1843.2006.00862.x 16771908 \n3. Dal Negro RW Tognella S Guerriero M Micheletto C Prevalence of tracheobronchomalacia and excessive dynamic airway collapse in bronchial asthma of different severity Multidiscip Respir Med 2013 8 32 10.1186/2049-6958-8-32 23673082 \n4. Murgu S Colt H Tracheobronchomalacia and excessive dynamic airway collapse Clin Chest Med 2013 34 527 555 10.1016/j.ccm.2013.05.003 23993822 \n5. Katoh H Saitoh S Takiguchi M Yamasaki Y Yamamoto M A case of tracheomalacia during isoflurane anesthesia Anesth Analg 1995 80 1051 1053 7726407 \n6. Harada Y Kondo T Excessive dynamic airway collapse detected using nondynamic CT Intern Med 2016 55 1477 1479 10.2169/internalmedicine.55.5621 27250056 \n7. Lyaker MR Davila VR Papadimos TJ Excessive dynamic airway collapse: an unexpected contributor to respiratory failure in a surgical patient Case Rep Anesthesiol 2015 2015 596857 26167306 \n8. Bastos HN Teixeira N Redondo M Goncalves M Sucena M Mechanical ventilation for the treatment of severe excessive dynamic airway collapse Respir Care 2015 60 e90 e91 10.4187/respcare.03972 25841047 \n9. Sirithangkul S Ranganathan S Robinson PJ Robertson CF Positive expiratory pressure to enhance cough effectiveness in tracheomalacia J Med Assoc Thai 2010 93 Suppl 6 S112 S118 21280523\n\n",
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"issue": "6(1)",
"journal": "JA clinical reports",
"keywords": "Asthma; Bronchoscopy; Excessive dynamic airway collapse; General anesthesia; Positive end-expiratory pressure",
"medline_ta": "JA Clin Rep",
"mesh_terms": null,
"nlm_unique_id": "101682121",
"other_id": null,
"pages": "73",
"pmc": null,
"pmid": "32989528",
"pubdate": "2020-09-28",
"publication_types": "D016428:Journal Article",
"references": "26167306;27250056;30279064;16771908;23673082;23993822;21280523;7726407;25841047",
"title": "Excessive dynamic airway collapse during general anesthesia: a case report.",
"title_normalized": "excessive dynamic airway collapse during general anesthesia a case report"
} | [
{
"companynumb": "JP-ALVOGEN-2020-ALVOGEN-115007",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
... |
{
"abstract": "Recent reports have described a rare but severe complication of coronavirus disease 2019 (COVID-19) in nonpregnant adults that is associated with extrapulmonary organ dysfunction and appears to be secondary to a hyperinflammatory state.\n\n\n\nA multiparous woman at 28 weeks of gestation, diagnosed with COVID-19 4 weeks prior, was admitted with chest pain. Evaluation indicated myocarditis and marked elevations of inflammatory markers consistent with multisystem inflammatory syndrome in adults. The patient developed cardiogenic shock and required mechanical ventilation. Treatment with intravenous immunoglobulin and high-dose corticosteroids was associated with a favorable maternal and fetal outcome.\n\n\n\nMultisystem inflammatory syndrome in adults associated with COVID-19 in pregnancy is a critical illness, presenting several weeks after initial infection. Treatment with intravenous immunoglobin and corticosteroids was associated with a favorable outcome.",
"affiliations": "Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, the Department of Cardiology, the Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, and the Department of Anesthesiology, North Shore University Hospital-Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York.",
"authors": "Gulersen|Moti|M|;Staszewski|Cara|C|;Grayver|Evelina|E|;Tam Tam|Hima|H|;Gottesman|Eric|E|;Isseroff|Donnie|D|;Rochelson|Burton|B|;Bonanno|Clarissa|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/AOG.0000000000004256",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-7844",
"issue": "137(3)",
"journal": "Obstetrics and gynecology",
"keywords": null,
"medline_ta": "Obstet Gynecol",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D000086742:COVID-19 Testing; D016638:Critical Illness; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011256:Pregnancy Outcome; D018746:Systemic Inflammatory Response Syndrome",
"nlm_unique_id": "0401101",
"other_id": null,
"pages": "418-422",
"pmc": null,
"pmid": "33278275",
"pubdate": "2021-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Coronavirus Disease 2019 (COVID-19)-Related Multisystem Inflammatory Syndrome in a Pregnant Woman.",
"title_normalized": "coronavirus disease 2019 covid 19 related multisystem inflammatory syndrome in a pregnant woman"
} | [
{
"companynumb": "US-BEH-2020126316",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Everolimus is an immunosuppressant agent used in organ transplantation and, more recently, in cancer therapy. It has demonstrated beneficial effects in breast cancer, renal cancer, and neuroendocrine tumours. However, the treatment is not without side effects, some of which are still little known. We report the case of a 56 year-old man with a diagnosis of neuroendocrine tumour who developed a complex regional pain syndrome (CRPS) secondary to treatment with everolimus. CRPS has been linked to treatments with everolimus in renal and breast cancer patients as well as in renal transplant patients. To our knowledge, this is the first case of CRPS in a neuroendocrine tumour patient on everolimus treatment.",
"affiliations": "Pharmacy Department, Son Llàtzer Hospital, Palma de Mallorca, Spain.;Pharmacy Department, Son Llàtzer Hospital, Palma de Mallorca, Spain.;Pharmacy Department, Son Llàtzer Hospital, Palma de Mallorca, Spain.;Oncology Department, Son Llàtzer Hospital, Palma de Mallorca, Spain.",
"authors": "Pérez de Amezaga-Tomás|Luis|L|https://orcid.org/0000-0003-1286-0836;Oliver-Noguera|Aina|A|;Rodríguez-Camacho|Juan Manuel|JM|;Fernández-Rodríguez|Teresa|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/10781552211021485",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "28(1)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Complex regional pain syndrome (CRPS); bone marrow; reflex sympathetic dystrophy (RSD)",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "228-231",
"pmc": null,
"pmid": "34082632",
"pubdate": "2022-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Complex regional pain syndrome in a patient with neuroendocrine tumour under treatment with everolimus.",
"title_normalized": "complex regional pain syndrome in a patient with neuroendocrine tumour under treatment with everolimus"
} | [
{
"companynumb": "ES-NOVARTISPH-NVSC2021ES297622",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
"drugadditional": "1",
... |
{
"abstract": "Mucous membrane pemphigoid (MMP) encompasses a group of autoantibody-mediated, subepithelial blistering diseases, which primarily affect mucosal surfaces including oral, ocular, skin, genital, nasopharyngeal and oesophageal sites. We present a first description of laryngoceles as a manifestation of mucous membrane pemphigoid resulting in dynamic airway closure. Mucosal injury at other sites had previously resulted in pathergy and localised cicatrisation. We discuss successful combined medical and transcutaneous surgical intervention designed to avoid tracheostomy and minimise iatrogenic laryngeal cicatrisation.",
"affiliations": "Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.;Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.;Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.;Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.",
"authors": "Wijaya|Carolyn|C|http://orcid.org/0000-0002-2769-5055;Morgan|Lucy|L|;Novakovic|Daniel|D|;Riminton|Sean|S|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D000069283:Rituximab; D009173:Mycophenolic Acid",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-225316",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "ear, nose and throat/otolaryngology; immunology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000402:Airway Obstruction; D000903:Antibiotics, Antineoplastic; D006801:Humans; D059608:Laryngocele; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D010390:Pemphigoid, Benign Mucous Membrane; D000069283:Rituximab",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30021739",
"pubdate": "2018-07-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21365194;28491985;21422323;12071170;22064820;11004612;23237497;16810295;9182819;21925010;25502268;3180497;11902988",
"title": "Laryngoceles with airway compromise complicating mucous membrane pemphigoid.",
"title_normalized": "laryngoceles with airway compromise complicating mucous membrane pemphigoid"
} | [
{
"companynumb": "AU-SAMSUNG BIOEPIS-SB-2020-01296",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "3"... |
{
"abstract": "We describe the first case of treatment failure of gonorrhoea with a third generation cephalosporin, cefotaxime 1g intramuscularly, in the Netherlands. The case was from a high-frequency transmitting population (men having sex with men) and was caused by the internationally spreading multidrug-resistant gonococcal NG-MAST ST1407 clone. The patient was clinically cured after treatment with ceftriaxone 500 mg intramuscularly and this is the only third generation cephalosporin that should be used for first-line empiric treatment of gonorrhoea. Increased awareness of failures with third generation cephalosporins, enhanced monitoring and appropriate verification of treatment failures including more frequent test-of-cures, and strict adherence to regularly updated treatment guidelines are essential globally.",
"affiliations": "Public Health Laboratory, Cluster of Infectious Diseases, Amsterdam Health Service, Amsterdam, The Netherlands Department of Microbiology, Onze Lieve Vrouwe Gasthuis General Hospital, Amsterdam, The Netherlands.;Department of Microbiology, Onze Lieve Vrouwe Gasthuis General Hospital, Amsterdam, The Netherlands.;Department of Laboratory Medicine, Clinical Microbiology, WHO Collaborating Centre for Gonorrhoea and Other STIs, Örebro University Hospital, Örebro, Sweden.;Integral Physician Practice West, Amsterdam, The Netherlands.;STI Outpatient Department, Cluster of Infectious Diseases, Amsterdam Health Service, Amsterdam, The Netherlands Centre for Infections and immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.;Department of Laboratory Medicine, Clinical Microbiology, WHO Collaborating Centre for Gonorrhoea and Other STIs, Örebro University Hospital, Örebro, Sweden.",
"authors": "van Dam|Alje P|AP|;van Ogtrop|Marc L|ML|;Golparian|Daniel|D|;Mehrtens|Jan|J|;de Vries|Henry J C|HJ|;Unemo|Magnus|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D002439:Cefotaxime",
"country": "England",
"delete": false,
"doi": "10.1136/sextrans-2014-051552",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1368-4973",
"issue": "90(7)",
"journal": "Sexually transmitted infections",
"keywords": "ANTIBIOTIC RESISTANCE; GAY MEN; GONORRHOEA; NEISSERIA GONORRHOEA; URETHRITIS",
"medline_ta": "Sex Transm Infect",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D002439:Cefotaxime; D002443:Ceftriaxone; D024901:Drug Resistance, Multiple, Bacterial; D006069:Gonorrhea; D018451:Homosexuality, Male; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D008826:Microbial Sensitivity Tests; D009344:Neisseria gonorrhoeae; D009426:Netherlands; D017211:Treatment Failure",
"nlm_unique_id": "9805554",
"other_id": null,
"pages": "513-4",
"pmc": null,
"pmid": "25114322",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Verified clinical failure with cefotaxime 1g for treatment of gonorrhoea in the Netherlands: a case report.",
"title_normalized": "verified clinical failure with cefotaxime 1g for treatment of gonorrhoea in the netherlands a case report"
} | [
{
"companynumb": "NL-LUPIN PHARMACEUTICALS INC.-2014-01475",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFOTAXIME\\CEFOTAXIME SODIUM"
},
... |
{
"abstract": "Pediatric intractable autoimmune hepatitis is rare and may be responsible for acute liver failure. Mutations in the itchy E3 ubiquitin protein ligase (ITCH) gene (located on chromosome 20q11.22) can lead to a deficiency of the encoded protein, resulting in increased T-cell activity with lack of immune tolerance and manifestation of a complex systemic autoimmune disease. A 1-year-old girl of consanguineous parents received a liver transplant (LT) because of acute liver failure attributed to a drug-induced hypereosinophilic syndrome with positive liver-kidney-mikrosome-2 antibodies. Notable findings were syndromic features, dystrophy, short stature, psychomotor retardation, and muscular hypotonia. Later, we saw corticosteroid-sensitive rejections as well as a systemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia). Histologically, liver cirrhosis with lobular inflammatory infiltrates, giant-cell hepatitis, and ductopenia was verified in chronic cholestasis. Shortly after a second LT, a comparable liver histology could be detected, and viral, bacterial, and mycotic infections deteriorated the general health condition. Because of refractory pancytopenia related to portal hypertension and hypersplenism, a posttransplant lymphoproliferative disorder was excluded. One year after the second LT, epidural and subdural bleeding occurred. Three months afterward, the girl died of sepsis. Postmortem, whole-exome sequencing revealed a homozygous mutation in the ITCH gene. A biallelic mutation in ITCH can cause a severe syndromic multisystem autoimmune disease with the above phenotypic characteristics and acute liver failure because of autoimmune hepatitis. This case reveals the importance of ubiquitin pathways for regulation of the immune system.",
"affiliations": "Departments of Pediatrics, Gastroenterology, and Hepatology and.;Department of Pediatrics, University of Heidelberg, Heidelberg, Germany; and.;Departments of Pediatrics, Gastroenterology, and Hepatology and.;Human Genetics, University of Duisburg-Essen, Essen, Germany.;Institute of Human Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.;Institute of Human Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.;Departments of Pediatrics, Gastroenterology, and Hepatology and elke.lainka@uk-essen.de.",
"authors": "Kleine-Eggebrecht|Nicola|N|;Staufner|Christian|C|;Kathemann|Simone|S|;Elgizouli|Magdeldin|M|;Kopajtich|Robert|R|;Prokisch|Holger|H|;Lainka|Elke|E|",
"chemical_list": "D012097:Repressor Proteins; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2018-1554",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "143(2)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D001483:Base Sequence; D002675:Child, Preschool; D017809:Fatal Outcome; D005260:Female; D019693:Hepatitis, Autoimmune; D006801:Humans; D007223:Infant; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D009154:Mutation; D012097:Repressor Proteins; D044767:Ubiquitin-Protein Ligases",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30705142",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Mutation in ITCH Gene Can Cause Syndromic Multisystem Autoimmune Disease With Acute Liver Failure.",
"title_normalized": "mutation in itch gene can cause syndromic multisystem autoimmune disease with acute liver failure"
} | [
{
"companynumb": "DE-CELLTRION INC.-2019DE019273",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Cardiopulmonary arrest during pregnancy is a devastating event necessitating rapid intervention from experienced practitioners to reduce the incidence and severity of adverse maternal and fetal outcomes. Perimortem cesarean delivery is rarely performed within the recommended time frame to meet these goals. We describe a case of a successful perimortem cesarean delivery after the \"4-minute rule\" in a morbidly obese parturient with goiter and preeclampsia.",
"affiliations": "From the Department of Anesthesiology, North Shore/LIJ Health System, New Hyde Park, New York.",
"authors": "Aronsohn|Judith|J|;Danzer|Brett|B|;Overdyk|Frank|F|;Roseman|Adam|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000116",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-7237",
"issue": "4(4)",
"journal": "A & A case reports",
"keywords": null,
"medline_ta": "A A Case Rep",
"mesh_terms": "D000328:Adult; D000402:Airway Obstruction; D016887:Cardiopulmonary Resuscitation; D002585:Cesarean Section; D015897:Comorbidity; D005260:Female; D006042:Goiter; D006323:Heart Arrest; D006801:Humans; D009767:Obesity, Morbid; D011225:Pre-Eclampsia; D011247:Pregnancy; D012307:Risk Factors; D013997:Time Factors; D061665:Time-to-Treatment; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "41-3",
"pmc": null,
"pmid": "25689359",
"pubdate": "2015-02-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Perimortem cesarean delivery in a pregnant patient with goiter, preeclampsia, and morbid obesity.",
"title_normalized": "perimortem cesarean delivery in a pregnant patient with goiter preeclampsia and morbid obesity"
} | [
{
"companynumb": "PHHY2016US006116",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MAGNESIUM"
},
"drugadditional": null,
"drug... |
{
"abstract": "Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos-XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT).\n\n\n\nData from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used.\n\n\n\nFifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC (P = .006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P = .45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved.\n\n\n\nRIC HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.",
"affiliations": "Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.;Dr. von Hauner University Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.;Immunology and Hematopoietic Stem Cell Transplantation Department, Federal Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia.;Dr. von Hauner University Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.;Stem Cell Transplant Unit, Department of Hematology and Oncology, Ospedale Pediatrico Bambino Gesù, Rome, Italy.;Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.;Infection, Immunity, Inflammation, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.;Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway.;Duke University School of Medicine, Departments of Pediatrics and Immunology, Duke University Medical Center, Durham, NC.;Paediatric BMT Unit, Robert Debre Hospital, Paris, France.;Immunology and Hematopoietic Stem Cell Transplantation Department, Federal Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia.;Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland.;Center for International Blood and Marrow Transplant Research, Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wis.;Department of Haematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany.;Department of Systems Medicine, University of Rome \"Tor Vergata\", Unit of Immune and Infectious Diseases, Children's Hospital Bambino Gesù, Rome, Itlay.;Infection, Immunity, Inflammation, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.;Infection, Immunity, Inflammation, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; Division of Pediatric Stem Cell Therapy, Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Düsseldorf, Germany.;Joseph M. Sanzari Children's Hospital, Hackensack University Medical Center, Hackensack, NJ.;Immunodeficiencies, Hematology & Oncology Unit, Pediatrics, Hospital 12 Octubre, and Universidad Complutense, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.;Division of Immunology and Allergy, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.;Division of Stem Cell Transplantation, University Children's Hospital Zürich, Zürich, Switzerland.;BørneUngeKlinikken, Copenhagen, Denmark.;Paediatric Research Center, University Hospital of Tampere, Tampere, Finland.;Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.;Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Pediatric Hematology, Oncology and BMT, Wroclaw Medical University, Wroclaw, Poland.;Department of Dermatology, Wakayama Medical University, Wakayama, Japan.;Bahcesehir University Faculty of Medicine, Göztepe Medicalpark Hospital Pediatric Stem Cell Transplantation Unit, Istanbul, Turkey.;Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.;Immunology and Hematopoietic Stem Cell Transplantation Department, Federal Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia.;Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences / Lower Silesian Center for Cellular Transplantation, Wrocław, Poland.;French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Immuno-Hematology Unit, Necker Children's Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.;Division of Pediatric Stem Cell Therapy, Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Düsseldorf, Germany.;Immuno-Hematology Unit, Necker Children's Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.;Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Duke University School of Medicine, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, NC.;Mother and Child Health Institute, Medical Faculty, University of Belgrade, Belgrade, Serbia.;Dr. von Hauner University Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.;Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.;Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.;Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital and Child and Family Research Institute, Vancouver, British Columbia, Canada.;Department of Oncology, Children's Hospital at Westmead, Westmead, Australia.;Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.;Department of Pediatric Hematology Oncology, Hannover Medical, Hannover, Germany.;Department of Hematology and Oncology, Wakayama Medical University, Wakayama, Japan.;Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Helsinki University Hospital, Helsinki, Finland.;Paediatric Haematology & Oncology, Kinderklinik der Technische Universität München, Krankenhaus München-Schwabing, Munich, Germany.;Department of Immunology, Children's Memorial Health Institute, Warsaw, Poland.;Allergy Immunology and Blood and Marrow Transplant Division, University of California San Francisco Benioff Children's Hospital, San Francisco, Calif.;Immuno-Hematology Unit, Necker Children's Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.;Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address: a.r.gennery@ncl.ac.uk.",
"authors": "Slack|James|J|;Albert|Michael H|MH|;Balashov|Dmitry|D|;Belohradsky|Bernd H|BH|;Bertaina|Alice|A|;Bleesing|Jack|J|;Booth|Claire|C|;Buechner|Jochen|J|;Buckley|Rebecca H|RH|;Ouachée-Chardin|Marie|M|;Deripapa|Elena|E|;Drabko|Katarzyna|K|;Eapen|Mary|M|;Feuchtinger|Tobias|T|;Finocchi|Andrea|A|;Gaspar|H Bobby|HB|;Ghosh|Sujal|S|;Gillio|Alfred|A|;Gonzalez-Granado|Luis I|LI|;Grunebaum|Eyal|E|;Güngör|Tayfun|T|;Heilmann|Carsten|C|;Helminen|Merja|M|;Higuchi|Kohei|K|;Imai|Kohsuke|K|;Kalwak|Krzysztof|K|;Kanazawa|Nubuo|N|;Karasu|Gülsün|G|;Kucuk|Zeynep Y|ZY|;Laberko|Alexandra|A|;Lange|Andrzej|A|;Mahlaoui|Nizar|N|;Meisel|Roland|R|;Moshous|D|D|;Muramatsu|Hideki|H|;Parikh|Suhag|S|;Pasic|Srdjan|S|;Schmid|Irene|I|;Schuetz|Catharina|C|;Schulz|Ansgar|A|;Schultz|Kirk R|KR|;Shaw|Peter J|PJ|;Slatter|Mary A|MA|;Sykora|Karl-Walter|KW|;Tamura|Shinobu|S|;Taskinen|Mervi|M|;Wawer|Angela|A|;Wolska-Kuśnierz|Beata|B|;Cowan|Morton J|MJ|;Fischer|Alain|A|;Gennery|Andrew R|AR|;|||;|||;|||;|||",
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"keywords": "Ataxia-telangiectasia; Cernunnos-XLF deficiency; DNA ligase IV deficiency; DNA repair disorders; Nijmegen breakage syndrome; hematopoietic stem cell transplantation",
"medline_ta": "J Allergy Clin Immunol",
"mesh_terms": "D000293:Adolescent; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D049914:DNA Repair-Deficiency Disorders; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D009154:Mutation; D011379:Prognosis; D016896:Treatment Outcome; D014777:Virus Diseases; D055815:Young Adult",
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"references": "12604777;23761151;18845326;16357942;11336668;23264593;19729196;23433795;24780557;23722905;12569164;16358361;20926771;26271390;23103677;19067926;8810255;24144642;21535335;26172957;16549504;23751955;24161820;13130311;16439204;23721719;24630899;19684627;19896087;16585603;8547667;25985449;25523867;22354567;17224058;19075392;24144640;20673987;11779494;26055221",
"title": "Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders.",
"title_normalized": "outcome of hematopoietic cell transplantation for dna double strand break repair disorders"
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"abstract": "Levetiracetam is a widely used, effective and usually well-tolerated anti-epileptic medicine. It is mostly excreted by kidneys and requires dose adjustment according to the glomerular filtration rate. Very few case reports have been published in the literature about levetiracetam causing acute kidney injury (AKI). We present a case of a 26-year-old male with a seizure disorder on levetiracetam, presented with status epilepticus requiring intubation for airway protection. He received 4 g of intravenous levetiracetam as a loading dose and continued with a maintenance dose of 750 mg intravenous every 12 hours. He had signs of AKI on day two and creatinine eventually reached a maximum level of 12.2 mg/dL. His kidney function improved to his new baseline in a period of 30 days without requiring renal replacement therapy. He did not have significant rhabdomyolysis and his kidney function started improving right after his anti-epileptic therapy was switched to valproic acid pointing towards levetiracetam as the primary cause of kidney injury. Clinicians should be aware that levetiracetam can cause AKI on patients with a seizure disorder, especially when administered in high doses. Kidney function should be monitored closely and patients should be treated aggressively with intravenous fluids when they have any signs of rhabdomyolysis to prevent further kidney damage.",
"affiliations": "Internal Medicine, Brookdale University Hospital Medical Center, Brooklyn, USA.;Internal Medicine, Brookdale University Hospital Medical Center, Brooklyn, USA.;Internal Medicine, Brookdale University Hospital Medical Center, Brooklyn, USA.;Internal Medicine, Brookdale University Hospital Medical Center, Brooklyn, USA.;Internal Medicine, Brookdale University Hospital Medical Center, Brooklyn, USA.",
"authors": "Erdinc|Burak|B|;Ghanta|Snigdha|S|;Andreev|Alexander|A|;Elkholy|Karim O|KO|;Sahni|Sonu|S|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.8814\nInternal Medicine\nNeurology\nNephrology\nAcute Kidney Injury Caused by Levetiracetam in a Patient With Status Epilepticus\nMuacevic Alexander Adler John R Erdinc Burak 1 Ghanta Snigdha 1 Andreev Alexander 1 Elkholy Karim O 1 Sahni Sonu 123 \n1 \nInternal Medicine, Brookdale University Hospital Medical Center, Brooklyn, USA \n\n2 \nResearch Medicine, New York Institute of Technology College of Osteopathic Medicine, New York, USA \n\n3 \nPrimary Care, Touro College of Osteopathic Medicine, New York, USA \n\nBurak Erdinc berdinc@icloud.com\n24 6 2020 \n6 2020 \n12 6 e88148 6 2020 24 6 2020 Copyright © 2020, Erdinc et al.2020Erdinc 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/33880-acute-kidney-injury-caused-by-levetiracetam-in-a-patient-with-status-epilepticusLevetiracetam is a widely used, effective and usually well-tolerated anti-epileptic medicine. It is mostly excreted by kidneys and requires dose adjustment according to the glomerular filtration rate. Very few case reports have been published in the literature about levetiracetam causing acute kidney injury (AKI). We present a case of a 26-year-old male with a seizure disorder on levetiracetam, presented with status epilepticus requiring intubation for airway protection. He received 4 g of intravenous levetiracetam as a loading dose and continued with a maintenance dose of 750 mg intravenous every 12 hours. He had signs of AKI on day two and creatinine eventually reached a maximum level of 12.2 mg/dL. His kidney function improved to his new baseline in a period of 30 days without requiring renal replacement therapy. He did not have significant rhabdomyolysis and his kidney function started improving right after his anti-epileptic therapy was switched to valproic acid pointing towards levetiracetam as the primary cause of kidney injury. Clinicians should be aware that levetiracetam can cause AKI on patients with a seizure disorder, especially when administered in high doses. Kidney function should be monitored closely and patients should be treated aggressively with intravenous fluids when they have any signs of rhabdomyolysis to prevent further kidney damage.\n\nlevetiracetamacute kidney injurystatus epilepticusThe 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\nLevetiracetam is currently one of the most commonly used anti-epileptic drugs (AEDs). Due to its mechanism of action not binding it to plasma proteins and not being dependent on the cytochrome p450 system, its pharmacokinetic interactions are minimal. Primary elimination of levetiracetam occurs through renal excretion and dose adjustments are necessary for patients with moderate to severe kidney impairment [1-3]. The most commonly reported side effects of levetiracetam are somnolence, asthenia, dizziness, headache, and rarely behavioral adverse effects [4]. Despite its mechanism of action and renal excretion, there has been scant literature of acute kidney injury (AKI) secondary to levetiracetam use [5-8]. On the other hand, a retrospective population-based cohort study involving 3,980 patients on levetiracetam treatment reported no significant risk of developing AKI within 180 days [9]. Herein we report a case of AKI caused by levetiracetam, which was administered with a high loading dose in a critical unit setting.\n\nCase presentation\nA 26-year-old Hispanic male with a past medical history only significant for epilepsy was witnessed by family members to have five episodes of tonic-clonic seizures without regaining consciousness between seizure episodes. As per emergency medical services (EMS) reported, the patient was found lying on the floor with fecal and urinary incontinence. Initial vital signs by EMS showed a blood pressure (BP) of 183/108 mmHg, heart rate (HR) of 103 beats per minute (bpm), and blood glucose of 302 mg/dL. He was able to mumble some answer verbally but remained disoriented. As the patient was being transferred to the ambulance, he became aggressive and combative. He was administered 10 mg midazolam intramuscularly and brought in the ED at Brookdale University Hospital Medicine Center. Prior to the presentation, home medications included levetiracetam 750 mg tablets twice daily with which he was not fully compliant as per his family. Chart review revealed multiple ED visits for seizures due to non-compliance with the medication. In the ED, he received another dose of midazolam, 4 mg to terminate the residual seizure activity and also received haloperidol and ketamine due to agitation with combativeness after his initial seizure episode. Vital signs in the ED were within normal limits except a HR of 142 bpm. Electrocardiogram showed sinus tachycardia. The patient remained afebrile, but it was noted that his BP began to rise and was recorded at 133/109 mmHg. Soon thereafter, the patient was noticed to be in a phase of status epilepticus and eventually was intubated for airway protection.\n\nPhysical examination revealed the patient to be intubated and sedated, equal-sized pupils reactive to light, intact brainstem reflexes, no signs of major trauma on his body. He received 4 g of intravenous levetiracetam as a loading dose and was continued with 1000 mg of levetiracetam intravenously every 12 hours thereafter. Initial laboratory investigations revealed an elevated lactic acid level of >12 mmol/L, creatinine level of 0.9 mg/dL and creatinine kinase level of 1004 U/L. Clinical laboratory data has been shown in Table 1. His baseline creatinine level was within normal limits at 0.9 mg/dL about four years ago and he did not have any previous history of kidney disease. Venous blood gas showed a pH of 7.07 and bicarbonate level of 14.4 mmol/L indicating metabolic acidosis most likely due to prolonged seizure activity. Urine toxicology was positive for cannabinoids. CT imaging of the head was negative for acute pathology.\n\nTable 1 Initial laboratory investigations\nTest\tReference Range\tResult\t\nWhite Blood Cell Count\t4.10 - 10.10 10x3/uL\t25.90 (H)\t\nHemoglobin\t12.9 - 16.7 g/dL\t14.8\t\nPlatelets\t153 - 328 10x3/uL\t416 (H)\t\nNeutrophils, Absolute\t1.40 - 6.80 10x3/uL\t22.50 (H)\t\nLymphocytes, Absolute\t1.10 - 2.90 10x3/uL\t2.6\t\nMonocytes, Absolute\t0.20 - 1.00 10x3/uL\t0.7\t\nEosinophils, Absolute\t0.00 - 0.40 10x3/uL\t0.1\t\nBasophils, Absolute\t0.00 - 0.10 10x3/uL\t0.1\t\nGlucose\t74 - 106 mg/dL\t145 (H)\t\nBlood Urea Nitrogen\t9.0 - 20.0 mg/dL\t16\t\nCreatinine\t0.66 - 1.25 mg/dL\t1.22\t\nSodium\t133 - 145 mEq/L\t137\t\nPotassium\t3.5 - 5.1 mEq/L\t4.5\t\nChloride\t98 - 107 mEq/L\t109 (H)\t\nBicarbonate\t22 - 30 mEq/L\t19 (L)\t\nCalcium\t8.4 - 10.2 mg/dL\t10.8 (H)\t\nAnion Gap\t8-12 mEq/L\t9\t\nProtein, Total\t6.3 - 8.2 g/dL\t9.5 (H)\t\nAlbumin\t3.5 - 5.0 g/dL\t5.3 (H)\t\nBilirubin, Total\t0.2 - 1.3 mg/dL\t1\t\nAlanine transaminase (ALT)\t21 - 72 U/L\t72\t\nAspartate transaminase (AST)\t17 - 59 U/L\t43\t\nLactate\t0.70 - 2.10 mmol/L\t>12 (H)\t\nCreatinine Kinase (CPK)\t55 - 170 U/L\t1004 (H)\t\nUrine sodium\t30.0 - 90.0 mEq/L\t96.0 (H)\t\nUrine potassium\tmEq/L\t22.2\t\nUrine protein\t5.0 - 11.0 mg/dL\t95.0 (H)\t\nUrine creatinine\tmg/dL\t127.2\t\nUrine urea nitrogen\tmg/dL\t87\t\nThe patient was transferred to the intensive care unit and repeat laboratory testing the next day showed blood urea nitrogen of 17 mg/dL and significant elevation in creatinine level to 3.27 mg/dL without a significant increase in creatinine kinase 1377 U/L (reference value: 55-170 U/L). Urine electrolytes were obtained to investigate the acute rise in creatinine (Table 1) and FeNa (fraction excretion of sodium) was calculated at 8%. Initial urinalysis showed large blood but only 0-3 red blood cells on high power field microscopy, The patient also had iso-osmotic urine with a specific gravity of 1.010 and high urine sodium (96 mEq/L). He did not receive any intravenous contrast, had any other medications with known nephrotoxicity or had any episodes of hypotension, which might compromise kidney perfusion and cause AKI. \n\nThe patient was assessed by a neurologist and valproic acid 500 mg twice daily was added to the anti-epileptic regimen to control seizures and levetiracetam was stopped since it was thought to be the culprit for AKI. Urine output was noted to decrease to 60 cc per hour and then the patient entered an oliguric phase. The patient received intravenous furosemide to keep him in non-oliguric and also received half normal saline interchangeably with 5% dextrose in water for volume expansion. The patient soon began to undergo brisk diuresis (up to 4L of urine per day) in the recovery phase of acute tubular necrosis (ATN). Creatinine levels continued trending down. Ultrasound of the retro-peritoneal organs showed normal kidneys without any signs of hydronephrosis. The patient’s urine output was monitored closely and he received large amounts of intravenous fluids in the recovery phase. His creatinine level came back to its new baseline level of 1.36 mg/dL after 20 days without requiring renal replacement therapy. Blood urea nitrogen, creatinine, and CPK trends have been shown in Figures 1-3, respectively. The patient was extubated successfully after 12 days, remained seizure-free and discharged home with outpatient follow-up. The patient has remained seizure-free and renal function has remained stable 30 days after discharge.\n\nFigure 1 Blood urea nitrogen trend\nFigure 2 Creatinine trend\nFigure 3 Creatinine kinase trend\nDiscussion\nDue to its favorable safety profile, levetiracetam is a widely used and well-tolerated medication for different types of seizure disorders with minimal side effects. However, due to its renal excretion, there is a possibility of renal side effects and there remains a paucity in the literature about levetiracetam causing AKI. Our case demonstrates that levetiracetam may cause AKI, especially when it is administered with high loading doses.\n\nLevetiracetam is a highly effective anti-epileptic medication with a high therapeutic index and good bioavailability. It minimally binds to proteins in the blood and reaches steady-state concentrations rapidly. Its interaction with liver-metabolized medications is limited since it is not dependent on the cytochrome p450 enzyme system. Levetiracetam is mostly (60%) excreted in the urine with no modifications and a fraction (24%) of it gets inactivated in the circulatory system before being excreted in the urine. Due to primarily being excreted in the urine, its dose should be adjusted according to creatinine clearance [1].\n\nThe most common adverse reactions secondary to levetiracetam use are fatigue, dizziness, headache and somnolence [4,10,11]. In a large, open-label, community study on safety and efficacy of levetiracetam, 1,030 patients being treated for partial-onset seizures showed no evidence of kidney injury [4]. In another open label, multi-center, single-arm study on 99 patients who were treated with 1000-3000 mg/day levetiracetam for refractory partial-onset seizures, patients' blood chemistry was followed up while on therapy. They reported no significant changes in patient’s blood urea nitrogen and creatinine levels, except they found blood in the urine of 10 patients, of whom nine were women who were perimenstrual [11].\n\nMoreover, levetiracetam induced kidney injury has been reported in very few cases. In a case of a previously healthy 23-year-old woman who presented with new-onset seizures and was started levetiracetam 500 mg twice daily, on day two of therapy she had a rise in her blood urea nitrogen (20 mg/dL) and creatinine (2.48 mg/dL) levels from a normal baseline. Levetiracetam therapy was stopped and she started taking phenytoin for seizure prevention. Her kidney function improved to her baseline on follow-up physical examination two months after discharge [5]. Another case of a 17-year-old female who was started on levetiracetam (250 mg twice daily) for new-onset partial complex seizures, presented to a local ED 10 days later with gastrointestinal side effects. She was found to have elevated creatinine of 3.3 mg/dL from a normal baseline and also had +3 blood and +3 protein in her dipstick urine test. Subsequent kidney biopsy confirmed the diagnosis of interstitial nephritis. Her kidney function recovered completely after 10 days of initiating oral prednisone treatment and switching levetiracetam to oxcarbazepine for seizure prevention [7]. A third case of a 16-year-old, previously healthy male, who presented with generalized tonic-clonic seizures and was started levetiracetam therapy (750 mg twice daily) had a rise in his creatinine level (2.2 mg/dL) on day two from a normal baseline. The patient also complained of muscle pain and labs were significant for rhabdomyolysis with peak creatinine kinase level of 15,111 U/l, primarily contributing to AKI. Levetiracetam therapy was stopped on day five of his treatment and the patient was switched to divalproex sodium therapy for seizure prevention and received intravenous fluid resuscitation. His creatinine level normalized on day seven and the patient was safely discharged home [8]. A fourth case of a previously healthy 45-year-old male who started taking levetiracetam (starting dose was 500 mg twice daily which later gradually increased to 3000 mg/day) for seizure prevention due to newly discovered astrocytoma. He experienced progressively worsening gastrointestinal symptoms (mainly intractable nausea) and had an increased serum creatinine to 3.59 mg/dL from a normal baseline. Levetiracetam was the only medication he received during over the two month period and his fractional excretion of sodium (FeNa) was calculated more than 1%, indicating intrinsic causes of kidney injury rather than pre-renal AKI from dehydration. Levetiracetam was tapered off and he started taking lacosamide for seizure prevention. His creatinine level normalized to 1.34 mg/dL over one month [6].\n\nConclusions\nTo summarize, levetiracetam can cause AKI on patients with a seizure disorder, more commonly when used in high doses as was seen in our case. In addition, rhabdomyolysis might contribute to kidney injury in patients with prolonged seizure activity. In these circumstances, levetiracetam therapy should be stopped immediately and patients should continue their treatment with an alternative anti-epileptic medication for seizure prevention, along with intravenous fluid resuscitation and motorization of kidney function. Kidney function usually recovers in a period of seven days to 30 days with appropriate therapy and follow-up according to previously reported case reports.\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 Pharmacokinetic profile of levetiracetam: toward ideal characteristics Pharmacol Ther Patsalos PN 77 85 85 2000 10722121 \n2 The pharmacokinetic characteristics of levetiracetam Methods Find Exp Clin Pharmacol Patsalos PN 123 129 25 2003 12731458 \n3 Levetiracetam pharmacokinetics in Japanese subjects with renal impairment Clin Drug Investig Yamamoto J Toublanc N Kumagai Y Stockis A 819 828 34 2014 \n4 The KEEPER trial: levetiracetam adjunctive treatment of partial-onset seizures in an open-label community-based study Epilepsy Res Morrell MJ Leppik I French J Ferrendelli J Han J Magnus L 153 161 54 2003 12837566 \n5 Levetiracetam as a possible contributor to acute kidney injury Clin Ther Spengler DC Montouris GD Hohler AD 1303 1306 36 2014 \n6 Levetiracetam-induced interstitial nephritis in a patient with glioma J Clin Neurosci Mahta A Kim RY Kesari S 177 178 19 2012 22071460 \n7 Levetiracetam induced interstitial nephritis and renal failure Pediatr Neurol Hurwitz KA Ingulli EG Krous HF 57 58 41 2009 19520278 \n8 Rhabdomyolysis in a hospitalized 16-year-old boy: a rarely reported underlying cause Case Rep Pediatr Singh R Patel DR Pejka S 7873813 2016 2016 27895953 \n9 Population-based study of risk of AKI with levetiracetam Clin J Am Soc Nephrol Yau K Burneo JG Jandoc R 17 26 14 2019 30538089 \n10 An open-label study of levetiracetam at individualised doses between 1000 and 3000 mg day(-1) in adult patients with refractory epilepsy Seizure Abou-Khalil B Hemdal P Privitera MD 141 149 12 2003 12651078 \n11 Efficacy and safety of levetiracetam 1000-3000 mg/day in patients with refractory partial-onset seizures: a multicenter, open-label single-arm study Epilepsy Res Beran RG Berkovic SF Black AB Danta G Hiersemenzel R Schapel GJ Vajda FJ 1 9 63 2005 15716083\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(6)",
"journal": "Cureus",
"keywords": "acute kidney injury; levetiracetam; status epilepticus",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e8814",
"pmc": null,
"pmid": "32742830",
"pubdate": "2020-06-24",
"publication_types": "D002363:Case Reports",
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"title": "Acute Kidney Injury Caused by Levetiracetam in a Patient With Status Epilepticus.",
"title_normalized": "acute kidney injury caused by levetiracetam in a patient with status epilepticus"
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"abstract": "Drug-induced liver injury (DILI) is often caused by innate and adaptive host immune responses. Characterization of inflammatory infiltrates in the liver may improve understanding of the underlying pathogenesis of DILI. This study aimed to enumerate and characterize leucocytes infiltrating liver tissue from subjects with acute DILI (n = 32) versus non-DILI causes of acute liver injury (n = 25). Immunostains for CD11b/CD4 (Kupffer and T helper cells), CD3/CD20 (T and B cells) and CD8/CD56 [T cytotoxic and natural killer (NK) cells] were evaluated in biopsies from subjects with acute DILI, either immunoallergic (IAD) or autoimmune (AID) and idiopathic autoimmune (AIH) and viral hepatitis (VH) and correlated with clinical and pathological features. All biopsies showed numerous CD8(+) T cells and macrophages. DILI cases had significantly fewer B lymphocytes than AIH and VH and significantly fewer NK cells than VH. Prominent plasma cells were unusual in IAD (three of 10 cases), but were associated strongly with AIH (eight of nine) and also observed in most with AID (six of nine). They were also found in five of 10 cases with VH. Liver biopsies from subjects with DILI were characterized by low counts of mature B cells and NK cells in portal triads in contrast to VH. NK cells were found only in cases of VH, whereas AIH and VH both showed higher counts of B cells than DILI. Plasma cells were associated most strongly with AIH and less so with AID, but were uncommon in IAD.",
"affiliations": "Departments of Medicine, Surgery, Pathology, the Liver-Biliary-Pancreatic Center, Immune Monitoring Core Laboratory, Dickson Center for Advanced Analytics, Carolinas HealthCare System, Charlotte, USA.",
"authors": "Foureau|D M|DM|;Walling|T L|TL|;Maddukuri|V|V|;Anderson|W|W|;Culbreath|K|K|;Kleiner|D E|DE|;Ahrens|W A|WA|;Jacobs|C|C|;Watkins|P B|PB|;Fontana|R J|RJ|;Chalasani|N|N|;Talwalkar|J|J|;Lee|W M|WM|;Stolz|A|A|;Serrano|J|J|;Bonkovsky|H L|HL|",
"chemical_list": "D015703:Antigens, CD",
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"issue": "180(1)",
"journal": "Clinical and experimental immunology",
"keywords": "autoimmunity; drug-induced liver injury; inflammation; viral hepatitis",
"medline_ta": "Clin Exp Immunol",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D001402:B-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D005260:Female; D019693:Hepatitis, Autoimmune; D006525:Hepatitis, Viral, Human; D006801:Humans; D007694:Killer Cells, Natural; D007728:Kupffer Cells; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "0057202",
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"pages": "40-51",
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"publication_types": "D003160:Comparative Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D052060:Research Support, N.I.H., Intramural; D013485:Research Support, Non-U.S. Gov't",
"references": "8021510;14986274;18354374;11812920;24879983;17486048;24037963;7560864;20512999;22351677;19826970;18713872;11132456;8446908;20564754;9625135;16276416;18025181;10807503;18955056;19132805;25043597;10385655;15040956;12547408;23298212;21674554;12362578",
"title": "Comparative analysis of portal hepatic infiltrating leucocytes in acute drug-induced liver injury, idiopathic autoimmune and viral hepatitis.",
"title_normalized": "comparative analysis of portal hepatic infiltrating leucocytes in acute drug induced liver injury idiopathic autoimmune and viral hepatitis"
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"abstract": "BACKGROUND\nMedullary thyroid carcinoma accounts for approximately 1 to 2 % of all thyroid carcinoma cases. The most common route of dissemination is to locoregional lymph nodes. Distant metastases commonly affect bones, lungs, and liver. We present a case of a white woman with a 25-year history of medullary thyroid carcinoma on multiple medications including tyrosine kinase inhibitor therapy for the last 11 months, who exhibited unusual diffuse infiltration of advanced stage medullary thyroid carcinoma to her gastric mucosa.\n\n\nMETHODS\nA 53-year-old white woman presented with increasing fatigue, loss of appetite, and severe epigastric pain radiating to her back. She had a history of medullary thyroid carcinoma (pT2pN1b), diagnosed 25 years ago and treated by complete thyroidectomy and repeated bilateral cervical lymph node dissection. Medical therapy included octreotide 20 mg every 4 weeks, which was switched to the tyrosine kinase inhibitor vandetanib 300 mg/day 11 months ago when computed tomography scanning revealed progressive mediastinal lymph node and diffuse and symptomatic pulmonary metastases. Of note, she demonstrated macroscopically stable pulmonary and mediastinal lymph node metastases; however, her calcitonin serum levels dramatically increased. Computed tomography scanning revealed a single new intrahepatic lesion (4 mm) as well as multiple (>10) new supraclavicular lesions suggestive of medullary thyroid carcinoma progress. As proven by gastric biopsy and immunohistochemical evaluation, her epigastric pain was explained by a diffuse infiltration of her gastric mucosa by metastatic medullary thyroid carcinoma. Subsequently, she rapidly deteriorated and died.\n\n\nCONCLUSIONS\nThe current case report shows for the first time an unusual metastatic infiltration of the gastric mucosa by medullary thyroid carcinoma. When treating these patients, it is important to include this differential diagnosis during follow-up.",
"affiliations": "Department of Internal Medicine III, Giessen University Hospital, Klinikstrasse 33, 35392, Gießen, Germany. thomas.karrasch@innere.med.uni-giessen.de.;Central Interdisciplinary Endoscopy Unit (ZIVE), Giessen University Hospital, 35392 Gießen, Germany.;Department of Radiology, Giessen University Hospital, 35392 Gießen, Germany.;Department of Internal Medicine III, Giessen University Hospital, Klinikstrasse 33, 35392, Gießen, Germany.;Department of Pathology, Giessen University Hospital, 35392 Gießen, Germany.;Department of Pathology, Giessen University Hospital, 35392 Gießen, Germany.",
"authors": "Karrasch|T|T|http://orcid.org/0000-0001-6850-588X;Doppl|W|W|;Roller|F C|FC|;Schäffler|A|A|;Schäffer|R|R|;Gattenlöhner|S|S|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 98110.1186/s13256-016-0981-9Case ReportUnusual gastric mucosal infiltration by a medullary thyroid carcinoma: a case report http://orcid.org/0000-0001-6850-588XKarrasch T. 0049-641-985-42751thomas.karrasch@innere.med.uni-giessen.de 1Doppl W. wilhelm.e.doppl@innere.med.uni-giessen.de 2Roller F. C. fritz.c.roller@radiol.med.uni-giessen.de 3Schäffler A. andreas.schaeffler@innere.med.uni-giessen.de 1Schäffer R. raimund.schaeffer@patho.med.uni-giessen.de 4Gattenlöhner S. stefan.gattenloehner@patho.med.uni-giessen.de 41 Department of Internal Medicine III, Giessen University Hospital, Klinikstrasse 33, 35392 Gießen, Germany 2 Central Interdisciplinary Endoscopy Unit (ZIVE), Giessen University Hospital, 35392 Gießen, Germany 3 Department of Radiology, Giessen University Hospital, 35392 Gießen, Germany 4 Department of Pathology, Giessen University Hospital, 35392 Gießen, Germany 27 7 2016 27 7 2016 2016 10 2086 4 2016 28 6 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. 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\nMedullary thyroid carcinoma accounts for approximately 1 to 2 % of all thyroid carcinoma cases. The most common route of dissemination is to locoregional lymph nodes. Distant metastases commonly affect bones, lungs, and liver. We present a case of a white woman with a 25-year history of medullary thyroid carcinoma on multiple medications including tyrosine kinase inhibitor therapy for the last 11 months, who exhibited unusual diffuse infiltration of advanced stage medullary thyroid carcinoma to her gastric mucosa.\n\nCase presentation\nA 53-year-old white woman presented with increasing fatigue, loss of appetite, and severe epigastric pain radiating to her back. She had a history of medullary thyroid carcinoma (pT2pN1b), diagnosed 25 years ago and treated by complete thyroidectomy and repeated bilateral cervical lymph node dissection. Medical therapy included octreotide 20 mg every 4 weeks, which was switched to the tyrosine kinase inhibitor vandetanib 300 mg/day 11 months ago when computed tomography scanning revealed progressive mediastinal lymph node and diffuse and symptomatic pulmonary metastases. Of note, she demonstrated macroscopically stable pulmonary and mediastinal lymph node metastases; however, her calcitonin serum levels dramatically increased. Computed tomography scanning revealed a single new intrahepatic lesion (4 mm) as well as multiple (>10) new supraclavicular lesions suggestive of medullary thyroid carcinoma progress. As proven by gastric biopsy and immunohistochemical evaluation, her epigastric pain was explained by a diffuse infiltration of her gastric mucosa by metastatic medullary thyroid carcinoma. Subsequently, she rapidly deteriorated and died.\n\nConclusions\nThe current case report shows for the first time an unusual metastatic infiltration of the gastric mucosa by medullary thyroid carcinoma. When treating these patients, it is important to include this differential diagnosis during follow-up.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s13256-016-0981-9) contains supplementary material, which is available to authorized users.\n\nKeywords\nEpigastric painMedullary thyroid carcinomaDistant metastasisGastric mucosaTyrosine kinase inhibitorsCase reportissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nThyroid cancer overall represents a rare tumor entity, however, the incidence of thyroid cancer has recently been constantly increasing [1, 2]. Within this heterogeneous group of tumors, differentiated thyroid cancer represents the majority (approximately 90 %) of all newly diagnosed thyroid cancer cases [3]. Medullary thyroid carcinoma (MTC) accounts for approximately 1 to 2 % of all thyroid carcinoma cases, and at diagnosis 7 to 23 % of all patients demonstrate metastatic disease [1, 4]. Overall, 10-year disease-specific survival rates average approximately 75 % with a strong dependency on tumor stage (averaging 21 % in stage IV tumors). Metastases are commonly found in the lymph nodes, while distant metastatic disease is found in lungs, bone, and liver, and, more rarely, in brain, skin, and breast [5, 6]. Therapeutically, the recent introduction of tyrosine kinase inhibitor therapy (vandetanib, cabozantinib) has led to a significant improvement of the prognosis in patients with rapidly progressive and advanced stage MTC [7].\n\nCase presentation\nA 53-year-old white woman presented with increasing fatigue, loss of appetite, and severe epigastric pain radiating to her back. She had a history of MTC (pT2pN1b), diagnosed 25 years ago and treated by complete thyroidectomy and bilateral cervical lymph node dissection, followed by repeated surgical resection of lymph node metastases 19 and 12 years ago. No further specific treatment modalities (for example radiotherapy) had been employed. No genetic analysis had been performed for germline or somatic RET proto-oncogene mutations, nor for other somatic mutations (HRAS, KRAS, NRAS). On clinical examination, however, there was no indication of other manifestations of multiple endocrine neoplasia type 2 (MEN2), especially no clinical signs of pheochromocytoma. Since data on the RET proto-oncogene status have been missing in our patient, no risk category (moderate, high, highest) according to the revised American Thyroid Association Guidelines for the management of MTC [1] had been assigned. However, based on the American Joint Committee on Cancer (AJCC) TNM-Classification, the MTC had been a stage IV A tumor (pT2pN1b) at the time of the initial complete thyroidectomy in our patient. Post complete thyroidectomy, she had hypoparathyroidism, which was treated with calcium and calcitriol. She received levothyroxine replacement therapy. Repeated biochemical and clinical evaluations during the course of the disease did not demonstrate any signs of paraneoplastic adrenocorticotropic hormone (ACTH) and/or corticotropin-releasing hormone (CRH) secretion. Medical therapy of the MTC included octreotide 20 mg every 4 weeks, which was switched to the tyrosine kinase inhibitor vandetanib 300 mg/day 11 month ago when computed tomography (CT) scanning revealed progressive mediastinal lymph node and diffuse and symptomatic pulmonary metastases.\n\nStandard laboratory tests in our patient revealed moderate leukocytosis (18.3 G/l) as well as slightly elevated serum CRP levels (12.58 mg/l); her serum lactate was 5.5 mmol/l. Pancreatitis was ruled out because her serum amylase and lipase levels were within normal range. An upper endoscopy was performed and demonstrated multiple centrally ulcerated lesions in her gastric mucosa of up to 4 mm in size (Fig. 1a, b). Two-phase contrast-enhanced multi-detector CT of her chest and abdomen revealed stable pulmonary and mediastinal lymph node metastases; however, there was a single new intrahepatic lesion of 4 mm size suspicious for liver metastasis. Contrast-enhanced multi-detector CT of her neck revealed multiple, new, centrally hypodense supraclavicular lesions up to 12 mm in size suggestive of lymph node metastases. In addition, multiple noduli within her stomach wall were apparent (Fig. 1c, I–III). Three-phase bone scintigraphy showed no evidence of bone metastasis.Fig. 1 \na, b Endoscopic view of the gastric corpus mucosa. c Computed tomography demonstrating multiple small noduli within the stomach wall: I overview, noduli marked by white circle; II, III magnification, noduli marked by white arrows. d–h Histologic and immunohistochemical staining of gastric biopsy specimen. d Hematoxylin-eosin, overview. e Hematoxylin-eosin, detail. f Immunohistochemical staining for chromogranin A. g Immunohistochemical staining for calcitonin. h Immunohistochemical staining for carcinoembryonic antigen (CEA). Remarkably, histology reveals intact non-neoplastic gastric gland structures (marked by *) in between infiltrating cells\n\n\n\nAdditional laboratory tests revealed a dramatic increase in her basal serum calcitonin levels from 563 pg/ml to 6487 pg/ml within 2 months, indicative of rapid tumor progress of the underlying MTC. Of interest, at the same time she had rather stable carcinoembryonic antigen (CEA) serum levels of 40.7 ng/ml (from 62.3 ng/ml 14 months earlier). Histologic and immunohistochemical analyses of gastric biopsy specimen demonstrated diffuse mucosal infiltration of MTC (Fig. 1d–h) with a KI-67 index of up to 40 %, proving metastatic disease of MTC to the gastric mucosa. Of note, while immunohistochemical analysis of calcitonin was strongly positive (Fig. 1g), staining for CEA demonstrated merely focal and weak staining (Fig. 1h); staining for thyroglobulin remained completely negative (data provided in Additional file 1). She rapidly deteriorated and died due to multiorgan failure before third-line treatment could be initiated.\n\nConclusions\nMTC is sporadic in origin in 60 to 75 % of all patients with MTC, while the others exhibit germline mutations in the RET proto-oncogene, namely patients with multiple endocrine neoplasia type 2A (MEN2A), multiple endocrine neoplasia type 2B (MEN2B), and familial MTC syndrome (FMTC). The most common sites for metastatic disease in MTC are locoregional lymph nodes; these metastases often occur early in the disease process [8]. This was also the case in our patient, who initially presented with a pT2pN1b tumor stage, and who received repeated resection of cervical lymph node metastases during the following years.\n\nHowever, in advanced MTC, distant metastases have been described. In one report, 74 % of patients demonstrated metastatic disease to the bone [9], other groups found small hepatic metastases in 25 % of patients with advanced MTC [10], as well as lung metastases in 35 % of patients with MTC with persistently elevated calcitonin levels after initial treatment [5]. In addition, cases of cutaneous [11, 12], brain [13], and breast [14, 15] metastases of MTC have been described.\n\nMetastatic disease to the stomach overall is a rare incidence in all cancer types, and data in the literature are based on case reports as well as small case series [16–18]. The most common primary tumors reported to spread to the stomach are melanoma, breast, lung, and esophageal carcinoma as well as renal cell cancer [17]. On clinical examination, gastric metastases present with epigastric pain, nausea, vomiting, as well as gastrointestinal hemorrhage. Mostly solitary lesions within the gastric mucosa are observed, although multiple metastatic lesions have been reported as well [17]. To the best of our knowledge, metastatic disease to the gastric mucosa of a MTC has not yet been reported in the literature.\n\nOur patient had MTC with a follow-up history of 25 years and presented with severe epigastric pain. Multiple lesions within her gastric mucosa were histologically proved to be a diffuse metastatic infiltration of the MTC. Of note, CT scans of her chest and abdomen revealed stable pulmonary and mediastinal lymph node metastases; however, multiple supraclavicular lesions as well as a single new intrahepatic lesion were suggestive of MTC progress. Remarkably, a sharp rise in calcitonin levels was indicative of rapid tumor progression as well, while her serum levels of CEA remained rather stable.\n\nThe current case report should raise awareness of unusual gastrointestinal metastatic disease of MTC in advanced disease states, especially with the increasing prognosis of these tumors due to molecular-targeted oncologic therapies (for example tyrosine kinase inhibitors). In treating these patients, it is important to include this generally uncommon differential diagnosis for unspecific patient complaints during follow-up.\n\nAbbreviations\nACTH, adrenocorticotropic hormone; AJCC, American Joint Committee on Cancer; CEA, carcinoembryonic antigen; CRH, corticotropin-releasing hormone; CT, computed tomography; FMTC, familial medullary thyroid carcinoma syndrome; MEN2, multiple endocrine neoplasia type 2; MEN2A, multiple endocrine neoplasia type 2A; MEN2B, multiple endocrine neoplasia type 2B; MTC, medullary thyroid carcinoma\n\nAdditional file\nAdditional file 1: Immunohistochemical staining of gastric biopsy specimen for thyroglobulin remained completely negative. (TIF 1120 kb)\n\n\n\nAcknowledgements\nWe thank the Department of Radiology, Giessen University Hospital, for preparation of the computed tomography scans presented in our manuscript.\n\nFunding\nNo funding agency was involved in our patient’s treatment or our preparation of the manuscript.\n\nAvailability of data and materials\nThe dataset supporting the conclusions of this case report is included within the case report (images and laboratory parameters).\n\nAuthors’ contributions\nAcquisition, analysis, and interpretation of the data: TK, WD, FCR, AS, RS, and SG. Manuscript preparation: TK and AS. Critical revision and significant intellectual contribution to the manuscript: TK, WD, FCR, AS, RS, and SG. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s next-of-kin 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\nEthics approval and consent to participate\nNot applicable.\n==== Refs\nReferences\n1. Wells SA Jr Asa SL Dralle H Elisei R Evans DB Gagel RF Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma Thyroid 2015 25 6 567 610 10.1089/thy.2014.0335 25810047 \n2. Radespiel-Troger M Batzler WU Holleczek B Luttmann S Pritzkuleit R Stabenow R Rising incidence of papillary thyroid carcinoma in Germany Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2014 57 1 84 92 10.1007/s00103-013-1884-1 24357177 \n3. American Thyroid Association Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer Cooper DS Doherty GM Haugen BR Kloos RT Lee SL Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer Thyroid 2009 19 11 1167 214 10.1089/thy.2009.0110 19860577 \n4. Schlumberger M Bastholt L Dralle H Jarzab B Pacini F Smit JW 2012 European Thyroid Association guidelines for metastatic medullary thyroid cancer Eur Thyroid J 2012 1 1 5 14 10.1159/000336977 24782992 \n5. Giraudet AL Vanel D Leboulleux S Auperin A Dromain C Chami L Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels J Clin Endocrinol Metab 2007 92 11 4185 90 10.1210/jc.2007-1211 17726071 \n6. Pacini F Castagna MG Cipri C Schlumberger M Medullary thyroid carcinoma Clin Oncol 2010 22 6 475 85 10.1016/j.clon.2010.05.002 \n7. Cabanillas ME Hu MI Jimenez C Medullary thyroid cancer in the era of tyrosine kinase inhibitors: to treat or not to treat – and with which drug – those are the questions J Clin Endocrinol Metab 2014 99 12 4390 6 10.1210/jc.2014-2811 25238206 \n8. Maxwell JE Sherman SK O’Dorisio TM Howe JR Medical management of metastatic medullary thyroid cancer Cancer 2014 120 21 3287 301 10.1002/cncr.28858 24942936 \n9. Mirallie E Vuillez JP Bardet S Frampas E Dupas B Ferrer L High frequency of bone/bone marrow involvement in advanced medullary thyroid cancer J Clin Endocrinol Metab 2005 90 2 779 88 10.1210/jc.2004-1500 15572422 \n10. Tung WS Vesely TM Moley JF Laparoscopic detection of hepatic metastases in patients with residual or recurrent medullary thyroid cancer Surgery 1995 118 6 1024 9 10.1016/S0039-6060(05)80109-6 7491518 \n11. Nashed C Sakpal SV Cherneykin S Chamberlain RS Medullary thyroid carcinoma metastatic to skin J Cutan Pathol 2010 37 12 1237 40 10.1111/j.1600-0560.2009.01365.x 19615004 \n12. Ordonez NG Samaan NA Medullary carcinoma of the thyroid metastatic to the skin: report of two cases J Cutan Pathol 1987 14 4 251 4 10.1111/j.1600-0560.1987.tb01343.x 3305613 \n13. Borcek P Asa SL Gentili F Ezzat S Kiehl TR Brain metastasis from medullary thyroid carcinoma BMJ case reports 2010 2010 bcr0920103301 10.1136/bcr.09.2010.3301 22802478 \n14. Marcy PY Thariat J Peyrottes I Dassonville O Bilateral breast involvement in medullary thyroid carcinoma Thyroid 2009 19 2 197 9 10.1089/thy.2008.0383 19191751 \n15. Mandanas S Margaritidou E Christoforidou V Karoglou E Geranou C Chrisoulidou A Breast metastasis from medullary thyroid carcinoma in a male patient: case report and review of the literature Rare Tumors 2015 7 2 5765 10.4081/rt.2015.5765 26266011 \n16. De Palma GD Masone S Rega M Simeoli I Donisi M Addeo P Metastatic tumors to the stomach: clinical and endoscopic features World J Gastroenterol 2006 12 45 7326 8 10.3748/wjg.v12.i45.7326 17143949 \n17. Namikawa T Hanazaki K Clinicopathological features and treatment outcomes of metastatic tumors in the stomach Surg Today 2014 44 8 1392 9 10.1007/s00595-013-0671-9 23896636 \n18. Weigt J Malfertheiner P Metastatic disease in the stomach Gastrointestinal tumors 2015 2 2 61 4 10.1159/000431304 26674003\n\n",
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"mesh_terms": "D018278:Carcinoma, Neuroendocrine; D017809:Fatal Outcome; D005260:Female; D005753:Gastric Mucosa; D006801:Humans; D008875:Middle Aged; D016609:Neoplasms, Second Primary; D013274:Stomach Neoplasms; D013964:Thyroid Neoplasms",
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"title": "Unusual gastric mucosal infiltration by a medullary thyroid carcinoma: a case report.",
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"abstract": "We present an illustrative case of a 62-year-old woman with small cell lung cancer who developed progressive worsening of pre-existing anti-Hu antibody associated sensory neuronopathy after treatment with programmed cell death-1 (PD-1) inhibitor, nivolumab. We review the literature and identify 6 reported cases to understand the clinical outcomes of patients with anti-Hu paraneoplastic neurologic syndrome (PNS) treated with anti-PD-1 treatment. The PNS clinical spectrum comprised of encephalitis, a combination of sensory neuronopathy and anti-NMDAR encephalitis, isolated sensory neuronopathy, and encephalomyelitis. Immune checkpoint inhibitor have the potential to worsen pre-existing anti-Hu PNS and may promote the development of anti-Hu PNS.",
"affiliations": "Division of Neurology, Lahey Hospital & Medical Center, Burlington, MA, United States of America; Tufts University School of Medicine, Boston, MA, United States of America. Electronic address: pooja.raibagkar@lahey.org.;Division of Neurology, Lahey Hospital & Medical Center, Burlington, MA, United States of America; Tufts University School of Medicine, Boston, MA, United States of America.;Tufts University School of Medicine, Boston, MA, United States of America; Division of Oncology, Lahey Hospital & Medical Center, Burlington, MA, United States of America.;Division of Neurology, Lahey Hospital & Medical Center, Burlington, MA, United States of America; Tufts University School of Medicine, Boston, MA, United States of America.",
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"title": "Worsening of anti-Hu paraneoplastic neurological syndrome related to anti-PD-1 treatment: Case report and review of literature.",
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"abstract": "Actinomycosis is a subacute-to-chronic bacterial infection caused by gram-positive, filamentous, non-acid-fast, facultative anaerobic bacteria. It is a normal commensal bacterium found in the oral cavity and the lower reproductive tract of women. We present a case of primary actinomycosis of the breast. A postmenopausal woman, complicated by penicillin allergy, presented with a left breast lump clinically simulating malignancy. The first line of treatment for actinomycosis is penicillin. Due to a penicillin allergy, the patient was initially treated with doxycycline. However, doxycycline was discontinued due to tremors, and was replaced by clindamycin. The patient had a good clinical response with resolution of the abscess.",
"affiliations": "Family and Community Medicine, Texas Tech University Health Sciences Center School of Medicine Permian Basin, Odessa, Texas, USA.;Family and Community Medicine, Texas Tech University Health Sciences Center School of Medicine Permian Basin, Odessa, Texas, USA.;Family and Community Medicine, Texas Tech University Health Sciences Center School of Medicine Permian Basin, Odessa, Texas, USA.;Family and Community Medicine, Texas Tech University Health Sciences Center School of Medicine Permian Basin, Odessa, Texas, USA vani.selvan@ttuhsc.edu.",
"authors": "de Leoz|Josephine B|JB|;Suravajjala|Devi|D|;Rafeek|Hashmi|H|;Selvan|Vani|V|",
"chemical_list": "D000900:Anti-Bacterial Agents; D010406:Penicillins; D002981:Clindamycin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-235883",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "breast cancer; drugs: infectious diseases; general practice / family medicine; general surgery; ultrasonography",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000196:Actinomycosis; D000900:Anti-Bacterial Agents; D002981:Clindamycin; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D010406:Penicillins",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34257106",
"pubdate": "2021-07-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary mammary actinomycosis challenged with penicillin allergy.",
"title_normalized": "primary mammary actinomycosis challenged with penicillin allergy"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-21-03656",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PENICILLIN"
},
"d... |
{
"abstract": "This is, to our knowledge, the first reported case of secondary Plasma Cell Leukemia that was successfully by pomalidomide plus fixed low-dose dexamethasone. Pomalidomide at a dosage of 4 mg orally on days 1-21 of repeated 28-day cycles associated with fixed low-dose dexamethasone (40 mg on days 1, 8, 15 and 22 of each 28-day cycle), outside of the clinical trials, was started as a final attempt. After the fourth course, the patient achieved an interesting response that included a significant reduction of circulating plasma cells from the peripheral blood, a very important decrease of the M-component, and normalization of haematological value. The toxicities were acceptable. The time to best response was 4 months.",
"affiliations": "Haematology and BMT Unit-\"Antonio Perrino\" Hospital, 72100 Brindisi, Italy. Electronic address: giuseppemele2007@gmail.com.;Haematology and BMT Unit-\"Antonio Perrino\" Hospital, 72100 Brindisi, Italy.;Haematology and BMT Unit-\"Antonio Perrino\" Hospital, 72100 Brindisi, Italy.;Haematology and BMT Unit-\"Antonio Perrino\" Hospital, 72100 Brindisi, Italy.;Haematology and BMT Unit-\"Antonio Perrino\" Hospital, 72100 Brindisi, Italy.",
"authors": "Mele|Giuseppe|G|;Coppi|Maria Rosaria|MR|;Guaragna|Gianluca|G|;Spina|Alessandro|A|;Melpignano|Angela|A|",
"chemical_list": "D013792:Thalidomide; D003907:Dexamethasone; C467566:pomalidomide",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-2126",
"issue": "40()",
"journal": "Leukemia research",
"keywords": "Dexamethasone; Pomalidomide; Secondary plasma cell leukemia",
"medline_ta": "Leuk Res",
"mesh_terms": "D000368:Aged; D003907:Dexamethasone; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007952:Leukemia, Plasma Cell; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "7706787",
"other_id": null,
"pages": "30-2",
"pmc": null,
"pmid": "26626205",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Response to pomalidomide plus fixed low-dose dexamethasone in a case of secondary plasma cell leukaemia.",
"title_normalized": "response to pomalidomide plus fixed low dose dexamethasone in a case of secondary plasma cell leukaemia"
} | [
{
"companynumb": "IT-CELGENEUS-ITA-2015117700",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "POMALIDOMIDE"
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... |
{
"abstract": "N-acetylcysteine (NAC) is the antidote for acetaminophen (APAP)-induced hepatotoxicity. Both intravenous (IV) and oral (PO) NAC formulations are available with equal efficacy. Adverse events from either preparation are rare. We describe a hand compartment syndrome after extravasation of NAC requiring emergent fasciotomy during phase three of treatment for suspected APAP toxicity. Extravasation injuries leading to compartment syndrome are rare. It is unclear whether IV NAC induced a direct tissue-toxic insult, or functioned as a space-occupying lesion to cause a compartment syndrome. Compartment syndrome from extravasation of NAC is possible. In cases where IV access is difficult, PO NAC is an alternative.",
"affiliations": "Long Island Jewish Medical Center, Northwell Health, New Hyde Park, Department of Emergency Medicine, New Hyde Park, New York.;Long Island Jewish Medical Center, Northwell Health, New Hyde Park, Department of Emergency Medicine, New Hyde Park, New York.;Staten Island University Hospital, Northwell Health, Department of Emergency Medicine, Staten Island, New York.;Long Island Jewish Medical Center, Northwell Health, New Hyde Park, Department of Emergency Medicine, New Hyde Park, New York.;Long Island Jewish Medical Center, Northwell Health, New Hyde Park, Department of Emergency Medicine, New Hyde Park, New York.",
"authors": "Thoppil|Joby|J|;Berman|Adam|A|;Kessler|Benjamin|B|;Sud|Payal|P|;Nogar|Joshua|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5811/cpcem.2017.9.35152",
"fulltext": "\n==== Front\nClin Pract Cases Emerg MedClin Pract Cases Emerg MedClinical Practice and Cases in Emergency Medicine2474-252XUniversity of California Irvine, Department of Emergency Medicine publishing Western Journal of Emergency Medicine 10.5811/cpcem.2017.9.35152cpcem-01-377Case ReportHand Compartment Syndrome Due to N-acetylcysteine Extravasation Thoppil Joby MD, PhD*Berman Adam MD*Kessler Benjamin MD†Sud Payal MD*Nogar Joshua MD*‡\n* Long Island Jewish Medical Center, Northwell Health, New Hyde Park, Department of Emergency Medicine, New Hyde Park, New York\n† Staten Island University Hospital, Northwell Health, Department of Emergency Medicine, Staten Island, New York\n‡ North Shore University Hospital, Northwell Health, Department of Emergency Medicine, Manhasset, New YorkAddress for Correspondence: Joby Josekutty Thoppil, MD, PhD, Long Island Jewish Medical Center, Northwell Health, New Hyde Park, Department of Emergency Medicine, 270-05 76th Ave, Queens, NY 11040. Email: joby.josekutty@gmail.com.11 2017 18 10 2017 1 4 377 379 09 6 2017 07 9 2017 22 9 2017 © 2017 Thoppil et al.2017This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/N-acetylcysteine (NAC) is the antidote for acetaminophen (APAP)-induced hepatotoxicity. Both intravenous (IV) and oral (PO) NAC formulations are available with equal efficacy. Adverse events from either preparation are rare. We describe a hand compartment syndrome after extravasation of NAC requiring emergent fasciotomy during phase three of treatment for suspected APAP toxicity. Extravasation injuries leading to compartment syndrome are rare. It is unclear whether IV NAC induced a direct tissue-toxic insult, or functioned as a space-occupying lesion to cause a compartment syndrome. Compartment syndrome from extravasation of NAC is possible. In cases where IV access is difficult, PO NAC is an alternative.\n==== Body\nINTRODUCTION\nAcetaminophen (APAP) is one of the most widely used antipyretic and analgesic medications available without a prescription. It is also the leading cause of drug-induced acute liver failure in the United States.2–4. N-acetylcysteine (NAC) is an acetyl derivative of the amino acid cysteine known for its antioxidant properties, and is used worldwide as a well-tolerated and safe antidote for APAP toxicity.1 In overdose, APAP depletes endogenous hepatic stores of the anti-oxidant glutathione (GSH), whereas NAC, a GSH precursor, can replete GSH levels.1,4 NAC either rapidly binds to or detoxifies the highly reactive electrophilic intermediates of APAP metabolism, or it may enhance the reduction of the toxic intermediate of APAP, N-acetyl-p-benzoquinone imine (NAPQI).5 It is most effective in preventing acetaminophen-induced liver injury when given early. It may also be beneficial in reducing the severity of liver injury later in intoxication by several proposed mechanisms, such as improving blood flow and oxygen delivery to the liver, modifying cytokine production and scavenging free radicals.5 Therefore, it may also be used empirically when the severity of ingestion is unknown or serum concentrations are not immediately available.5\n\nNAC can be administered either orally (PO) or intravenously (IV), with most data demonstrating that they are equally efficacious.1–4 Some studies go as far as suggesting that PO NAC results in better outcomes than IV NAC by avoiding first-pass hepatic metabolism.1,4 However, IV NAC is preferentially ordered over the PO form due to practical concerns: 1) PO NAC smells like rotten eggs, which may limit patient adherence; 2) sedation and airway considerations frequently accompany the overdosed patient, thereby rendering PO medications unsafe; 3) the duration of IV NAC therapy is much shorter than the PO dosing scheme (21 hours vs. 72 hours, respectively).1–4 There are, however, some concerns with the administration of IV NAC, such as rate-related anaphylactoid reactions.1,4 In this case report, we describe a rare complication of IV NAC.\n\nCASE REPORT\nA 26-year-old male with a psychiatric history significant for polysubstance abuse, undifferentiated psychosis and depression with multiple suicide attempts presented to the emergency department (ED) 12 hours after a suicide attempt. He admitted to an overdose of approximately 55 tablets of aripiprazole (20 mg tabs), diphenhydramine (25 mg tabs), benztropine (1 mg tabs), haloperidol (5 mg tabs) and paroxetine (40 mg tabs). He denied any other ingestions. The patient reported a recent upper respiratory infection. Initial vital signs included a temperature of 98.1° F, pulse of 81 beats per minute, respirations of 18 breaths per minute and a blood pressure of 112/60 mmHg. Upon initial evaluation, the patient was asymptomatic, fully alert and oriented, with an unremarkable physical exam.\n\nThe electrocardiogram (ECG) had a normal sinus rate, rhythm and intervals. A 20-gauge IV was placed in the right hand. A complete blood count demonstrated an elevated white blood count (21.6 K/ul, 80.8% neutrophils, 14% lymphocytes). A complete metabolic panel was unremarkable except for a mildly elevated aspartate aminotransferase level of 41 IU/L. Surrogate markers of liver function, such as total protein, bilirubin and PT/INR were also within normal limits. No other metabolic abnormalities were noted. The serum toxicology screen resulted in an APAP level of 15.7 mcg/ml. The bedside toxicology service was consulted due to the elevated APAP level. Despite the patient’s report of ingestion as 12 hours prior to presentation, given the history of multiple suicide attempts and elevated APAP level, IV NAC was administered due to the possibility of a late-presenting acetaminophen overdose. A standard infusion pump was used to control the rate of infusion using standard pressure alarm settings at the appropriate rate for phase of infusion.\n\nDuring phase three of NAC therapy, the patient began complaining of pain and swelling around the IV site. Exam showed tense swelling of the right hand to mid forearm, pain with passive movement, paresthesias, and a faint but palpable radial pulse. The patient also noted sensation deficits with light touch to the distal fingers as compared to the left hand. Hand surgery was immediately consulted for evaluation of possible compartment syndrome. Compartment pressures were measured as high as 45 mmHg with a delta pressure of 17 mmHg.\n\nThe patient underwent an emergent fasciotomy, and the surgical team noted a “rotten egg” odor upon compartment release. The patient was started on broad-spectrum antibiotics due to concerns for infection due to the rotten-egg odor noted during surgery. He was given one dose of vancomycin (1 gram) and piperacillin/tazobactam (3.375 grams). Antibiotics were discontinued once the surgical team was made aware that this odor is characteristic of NAC. No complications were noted post-operatively, and pain, paresthesias, sensory deficits, swelling and range of motion improved over the following two days. The patient continued to improve and was eventually deemed medically stable for transfer to a psychiatric care facility.\n\nDISCUSSION\nExtravasation injury is the inadvertent leakage of a solution into the extravascular space. If the solution leaks into a confined space, it can result in elevated tissue pressures and decreased vascular flow. Specifically, vesicant solutions that extravasate may cause tissue inflammation, ischemia and possible necrosis that may lead to the accumulation of edema fluid in a confined space.5–7 Acute compartment syndrome develops when the tissue pressure within the fascial sheath surrounding a group of muscles rises to within 30 mmHg of aortic diastolic pressure.8 Once compartment pressure reaches this level, microvascular compression results in progressive muscle and nerve ischemia.8\n\nCPC-EM Capsule\nWhat do we already know about this clinical entity?\n\nThere are no documented reports of N-acetylcysteine (NAC)-induced compartment syndrome.\n\nWhat makes this presentation of disease reportable?\n\nWe preferentially use IV formulations of NAC when oral (PO) formulations are just as efficacious. It may be prudent to consider PO formulations when indicated.\n\nWhat is the major learning point?\n\nNAC is considered a relatively benign medication. However, even benign medications can still cause harm.\n\nHow might this improve emergency medicine practice?\n\nOur goal is to have physicians think more carefully about the decision to use intravenous vs. PO formulations when indicated.\n\nIn our case, IV NAC likely acted to cause compartment syndrome of the right hand and forearm secondary to extravasation of a large volume of fluid into a confined compartment, as opposed to vesicant injury. This is evidenced by the lack of tissue destruction/inflammation/necrosis in the surgical report after fasciotomy. Despite the use of an infusion pump to control rate, fluid still extravasated into the extravascular space. There were no nursing reports of any malfunction of the pump or any alarms to our knowledge. Furthermore, it is unlikely that the patient could have sabotaged his own infusion, given that he was under constant observation because of the suicide attempt. Progression of care occurred due to symptom presentation and concern for compartment syndrome.\n\nExtravasation injuries resulting in compartment syndromes are rare. However, there have been reports of extravasation injuries complicated by compartment syndromes from contrast dye, chemotherapeutic agents or mannitol. In these instances, it was postulated that the compartment syndromes developed secondary to a combination of excess volume and vesicant tissue injury.6–9\n\nTo our knowledge, no case reports in the literature identify IV NAC as a cause of compartment syndrome. It is still unclear whether the compartment syndrome was due to a volume injury, a vesicant property of NAC, or both. Post-operative reports did not indicate any obvious signs of tissue destruction, suggesting the cause of increased compartmental pressure was a consequence of increased volume in a confined space, as opposed to vesicant injury. In addition, at least one study suggests that the anti-oxidant effect of NAC may prove to be beneficial in limiting injury associated with compartment syndrome.8\n\nCONCLUSION\nMonitoring IV sites during antidotal infusions is important to avoid significant extravasation injuries. Although likely very rare, compartment syndrome due to NAC extravasation is a concern with difficult IV access. Oral NAC is a safe, cheap and efficacious alternative to IV NAC in cases where IV access is difficult and no potential contraindications exist. If NAC extravasation does cause compartment syndrome, normal odor characteristics of NAC should be communicated to surgical teams caring for affected patients.\n\nSection Editor: Rick A. McPheeters, DO\n\nFull text available through open access at http://escholarship.org/uc/uciem_cpcem\n\nConflicts of Interest: By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.\n==== Refs\nREFERENCES\n1 Khayyat A Tobwala S Hart M N-acetylcysteine amide, a promising antidote for acetaminophen toxicity Toxicol Lett 2016 241 133 42 26602168 \n2 Janssen J Singh-Saluja S How much did you take? Reviewing acetaminophen toxicity Can Fam Physician 2015 61 4 347 9 25873702 \n3 Lancaster EM Hiatt JR Zarrinpar A Acetaminophen hepatotoxicity: an updated review Arch Toxicol 2015 89 2 193 9 25537186 \n4 Koppen A van Riel A de Vries I Recommendations for the paracetamol treatment nomogram and side effects of N-acetylcysteine Neth J Med 2014 72 5 251 7 24930458 \n5 Nelson LS Lewin NA Howland MA Chapter A4: Antidotes in Depth Goldfrank’s Toxicologic Emergencies 9th ed NYC NY 2011 \n6 Loubani OM Green RS A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters J Crit Care 2015 30 3 653.e9 17 \n7 Le A Patel S Extravasation of noncytotoxic drugs: a review of the literature Ann Pharmacother 2014 48 7 870 86 24714850 \n8 Kearns SR O’Briain DE Sheehan KM N-acetylcysteine protects striated muscle in a model of compartment syndrome Clin Orthop Relat Res 2010 468 8 2251 9 20309660 \n9 Kreidieh FY Moukadem HA El Saghir NS Overview, prevention and management of chemotherapy extravasation World J Clin Oncol 2016 7 1 87 97 26862492\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2474-252X",
"issue": "1(4)",
"journal": "Clinical practice and cases in emergency medicine",
"keywords": null,
"medline_ta": "Clin Pract Cases Emerg Med",
"mesh_terms": null,
"nlm_unique_id": "101718968",
"other_id": null,
"pages": "377-379",
"pmc": null,
"pmid": "29849372",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports",
"references": "25537186;25669592;26602168;26862492;25873702;24930458;20309660;24714850",
"title": "Hand Compartment Syndrome Due to N-acetylcysteine Extravasation.",
"title_normalized": "hand compartment syndrome due to n acetylcysteine extravasation"
} | [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETYLCYSTEINE"
},
"drugaddi... |
{
"abstract": "Gastropleural and gastropericardial fistulas are abnormal communications between the stomach and the pleural cavity or pericardium. They are rare and life-threatening complications, which require prompt surgical intervention. We report the case of a gastro-pleuro-pericardial fistula that developed in a patient treated with radiotherapy and then Sunitinib (Sutent(®)), a novel tyrosine-kinase inhibitor, for lung metastases from renal cell carcinoma. To our knowledge, this is the first case of a gastro-pleuro-pericardial fistula developing as a consequence of combined radiation and chemotherapy.",
"affiliations": "Section of General Surgery and Surgical Oncology, Department of Human Pathology and Oncology, University of Siena, viale Bracci, Policlinico \"Le Scotte\", 53100, Siena, Italy.",
"authors": "Neri|Alessandro|A|;Lambert|Youdel|Y|;Marrelli|Daniele|D|;Di Mare|Giulio|G|;Mastrogiacomo|Doralba|D|;Corso|Giovanni|G|;Volterrani|Luca|L|;Roviello|Franco|F|",
"chemical_list": "D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D011758:Pyrroles; D011505:Protein-Tyrosine Kinases; D000077210:Sunitinib",
"country": "Japan",
"delete": false,
"doi": "10.1007/s00595-012-0475-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-1291",
"issue": "43(12)",
"journal": "Surgery today",
"keywords": null,
"medline_ta": "Surg Today",
"mesh_terms": "D000970:Antineoplastic Agents; D002292:Carcinoma, Renal Cell; D059248:Chemoradiotherapy; D004791:Enzyme Inhibitors; D005402:Fistula; D005747:Gastric Fistula; D006331:Heart Diseases; D006801:Humans; D007211:Indoles; D007680:Kidney Neoplasms; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D010496:Pericardium; D010995:Pleural Diseases; D011505:Protein-Tyrosine Kinases; D011758:Pyrroles; D000077210:Sunitinib; D016896:Treatment Outcome",
"nlm_unique_id": "9204360",
"other_id": null,
"pages": "1457-60",
"pmc": null,
"pmid": "23307297",
"pubdate": "2013-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14421290;20204363;17332278;4851856;17227905;8611135;8303639;19545786;14717523;10049427;19581144;3282969;12522538;20118139;15333561;4835195;2179244;22127535;20663167;16314617;18932293",
"title": "Gastro-pleuro-pericardial fistula following combined radiation and chemotherapy for lung metastases from renal cell carcinoma: report of a case.",
"title_normalized": "gastro pleuro pericardial fistula following combined radiation and chemotherapy for lung metastases from renal cell carcinoma report of a case"
} | [
{
"companynumb": "IT-PFIZER INC-2013030442",
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"occurcountry": "IT",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SUNITINIB MALATE"
},
"drugadditional": "3",
... |
{
"abstract": "We present a case of Cryptococcus neoformans pericarditis in a cardiac transplant recipient. This article reviews the diagnosis, treatment, and complications of cryptococcosis specifically in transplant patients. While pericarditis is a rare manifestation of Cryptococcus infection, this case highlights that cryptococcosis should be considered in the differential diagnosis for solid organ transplant and immunocompromised patients presenting with pericardial effusions.",
"affiliations": "Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA.;Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA.;Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado, USA.;Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA.;Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA.;Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA.;Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado, USA.;Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado, USA.;Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA.;Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA.;Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA.",
"authors": "Mann|Sarah|S|https://orcid.org/0000-0003-3852-1760;Tobolowsky|Farrell|F|;Purohit|Suneet|S|;Henao-Martínez|Andres|A|;Bajrovic|Valida|V|;Ramanan|Poornima|P|https://orcid.org/0000-0002-0249-4361;Wolfel|Eugene|E|;Khazanie|Prateeti|P|;Barron|Michelle|M|;Madinger|Nancy|N|;Benamu|Esther|E|",
"chemical_list": "D000935:Antifungal Agents; D015725:Fluconazole",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13366",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "22(6)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nCryptococcus neoformans\n; heart transplant; pericarditis",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D003453:Cryptococcosis; D003455:Cryptococcus neoformans; D004452:Echocardiography; D005260:Female; D015725:Fluconazole; D016027:Heart Transplantation; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D020519:Pericardiocentesis; D010493:Pericarditis; D016896:Treatment Outcome",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13366",
"pmc": null,
"pmid": "32533755",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Cryptococcal pericarditis in a heart transplant recipient.",
"title_normalized": "cryptococcal pericarditis in a heart transplant recipient"
} | [
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"companynumb": "US-DRREDDYS-USA/USA/21/0131803",
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"activesubstancename": "PREDNISONE"
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... |
{
"abstract": "The first reported human anaphylactic death is considered to be the Pharaoh Menes death, caused by a wasp sting. Currently, anaphylactic cardiovascular events represent one of most frequent medical emergencies. Rapid diagnosis, prompt and appropriate treatment can be life saving. The main concept beyond anaphylaxis lies to myocardial damage and ventricular dysfunction, thus resulting in cardiovascular collapse. Cardiac output depression due to coronary hypoperfusion from systemic vasodilation, leakage of plasma and volume loss due to increased vascular permeability, as well as reduced venous return, are regarded as the main causes of cardiovascular collapse. Clinical reports and experiments indicate that the human heart, in general, and the coronary arteries, in particular, could be the primary target of the released anaphylactic mediators. Coronary vasoconstriction and thrombosis induced by the released mediators namely histamine, chymase, tryptase, cathepsin D, leukotrienes, thromboxane and platelet activating factor (PAF) can result to further myocardial damage and anaphylaxis associated acute coronary syndrome, the so-called Kounis syndrome. Kounis syndrome with increase of cardiac troponin and other cardiac biomarkers, can progress to heart failure and cardiovascular collapse. In experimental anaphylaxis, cardiac reactions caused by the intracardiac histamine and release of other anaphylactic mediators are followed by secondary cardiovascular reactions, such as cardiac arrhythmias, atrioventricular block, acute myocardial ischemia, decrease in coronary blood flow and cardiac output, cerebral blood flow, left ventricular developed pressure (LVdp/dtmax) as well as increase in portal venous and coronary vascular resistance denoting vascular spasm. Clinically, some patients with anaphylactic myocardial infarction respond satisfactorily to appropriate interventional and medical therapy, while anti-allergic treatment with antihistamines, corticosteroids and fluid replacement might be ineffective. Therefore, differentiating the decrease of cardiac output due to myocardial tissue hypoperfusion from systemic vasodilation and leakage of plasma, from myocardial tissue due to coronary vasoconstriction and thrombosis might be challenging during anaphylactic cardiac collapse. Combined antiallergic, anti-ischemic and antithrombotic treatment seems currently beneficial. Simultaneous measurements of peripheral arterial resistance and coronary blood flow with newer diagnostic techniques including cardiac magnetic resonance imaging (MRI) and myocardial scintigraphy may help elucidating the pathophysiology of anaphylactic cardiovascular collapse, thus rendering treatment more rapid and effective.",
"affiliations": "Department of Cardiology University of Patras Medical School, Rion, Patras, Achaia, Greece.;Emergency Department, Academic Hospital of Parma, Parma, Italy.;Department of Electrophysiology, Queen Elizabeth Hospital, Birmingham, England.;Emergency Department, Academic Hospital of Parma, Parma, Italy.;Hemodialysis Unit, Kyanos Stavros, Patras, Greece.;Division of Pneumology, Department of Internal Medicine, General Hospital of Pirgos, Pirgos, Greece.;Department of Internal Medicine, Division of Infectious Diseases, University of Patras Medical School, Patras, Greece.;Department of Vascular Surgery, University of Patras Medical School, Patras, Greece.;Department of Vascular Surgery, University of Patras Medical School, Patras, Greece.;Department of Cardiology, \"Saint Andrews State General Hospital\", Patras, Achaia, Greece.;Department of Vascular Surgery, University of Patras Medical School, Patras, Greece.",
"authors": "Kounis|Nicholas G|NG|;Cervellin|Gianfranco|G|;Koniari|Ioanna|I|;Bonfanti|Laura|L|;Dousdampanis|Periklis|P|;Charokopos|Nikolaos|N|;Assimakopoulos|Stelios F|SF|;Kakkos|Stavros K|SK|;Ntouvas|Ioannis G|IG|;Soufras|George D|GD|;Tsolakis|Ioannis|I|",
"chemical_list": null,
"country": "China",
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"doi": "10.21037/atm.2018.09.05",
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"issn_linking": "2305-5839",
"issue": "6(17)",
"journal": "Annals of translational medicine",
"keywords": "Anaphylaxis; Kounis syndrome; anaphylactic shock; cardiovascular collapse; coronary vasoconstriction",
"medline_ta": "Ann Transl Med",
"mesh_terms": null,
"nlm_unique_id": "101617978",
"other_id": null,
"pages": "332",
"pmc": null,
"pmid": "30306071",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "26715167;15461609;20543887;24535927;23591563;5336448;23641382;2869715;21110234;28780941;19741149;19867490;22335765;29454395;23092000;28523173;1793697;2218074;5842873;11529214;24282744;26677363;23812218;16916722;14789736;14529065;19867320;22527679;25572555;15448540;30047352;20920770;23141553;26005807;23490289;21429602;29348253;9152651;27270180;17493496;26597331;26792237;63338;7648649;11150362;25252221;21690110;28958381;15985820;25849705;23079098;26005172;26156319;24920969;26708221;18227290;9013989;16875994;22050066;6017121;7648650;8417633;24915548;26512841;9826306;28153536;15238794;28400926;17706964;22814288;23809391;16249041;7270959;27914212;30057169;26120516;20542582;24404540;23580866;14775022;28882329;11408772;12032577;23677729;2557156;15703419",
"title": "Anaphylactic cardiovascular collapse and Kounis syndrome: systemic vasodilation or coronary vasoconstriction?",
"title_normalized": "anaphylactic cardiovascular collapse and kounis syndrome systemic vasodilation or coronary vasoconstriction"
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"abstract": "Background: In patients with lung adenocarcinoma and leptomeningeal metastases, it remains unknown whether non-classical mutations in the epidermal growth factor receptor (EGFR) gene can be detected in the cerebrospinal fluid (CSF) and how it may be used to design directed therapy. Methods: On April 18, 2018, the Interventional Department of Tianjin Huanhu Hospital admitted a 34-years-old male patient with lung adenocarcinoma and leptomeningeal metastasis. An emergency lateral ventriculoperitoneal shunt was performed to relieve the clinical symptoms of intracranial hypertension. Next-generation sequencing (NGS) of the CFS specimens revealed a mutation in EGFR exon 18 p.G719A, and afatinib was administered. Follow-up showed significantly relieved headache, with significantly reduced soft leptomeningeal abnormal enhancement as revealed by enhanced magnetic resonance imaging and significantly smaller tumors in the left lung by chest computed tomography. Carcinoembryonic antigens (CEAs) in cerebrospinal fluid and peripheral blood were significantly reduced. The patient responded well to afatinib, with mild adverse complications. The patient died on October 27, 2019 from respiratory failure as a result of lung infection unrelated to cancer progression. The overall survival (OS) using afatinib was 530 days. Conclusion: CSF can be used as a liquid biopsy for NGS gene detection in patients with lung adenocarcinoma and leptomeningeal metastases. Afatinib exhibits a beneficial effect in patients with lung adenocarcinoma and leptomeningeal metastases harboring the EGFR exon 18 p.G719A mutation.",
"affiliations": "Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Disease, Department of Intervention, Tianjin Huanhu Hospital, Tianjin, China.;Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Disease, Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, China.;Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Disease, Department of Intervention, Tianjin Huanhu Hospital, Tianjin, China.;Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Disease, Department of Intervention, Tianjin Huanhu Hospital, Tianjin, China.;Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Disease, Department of Intervention, Tianjin Huanhu Hospital, Tianjin, China.;Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Disease, Department of Intervention, Tianjin Huanhu Hospital, Tianjin, China.;Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Disease, Department of Intervention, Tianjin Huanhu Hospital, Tianjin, China.",
"authors": "Ma|Chunhua|C|;Wang|Shuyuan|S|;Mu|Ning|N|;Li|Jinduo|J|;Liu|Mei|M|;Li|Lin|L|;Jiang|Rong|R|",
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"doi": "10.3389/fonc.2020.01635",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.01635\nOncology\nCase Report\nEffective Treatment With Afatinib of Lung Adenocarcinoma With Leptomeningeal Metastasis Harboring the Exon 18 p.G719A Mutation in the EGFR Gene Was Detected in Cerebrospinal Fluid: A Case Report\nMa Chunhua 1† Wang Shuyuan 2† Mu Ning 1 Li Jinduo 1 Liu Mei 1 Li Lin 1 Jiang Rong 1* 1Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Disease, Department of Intervention, Tianjin Huanhu Hospital, Tianjin, China\n2Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Disease, Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, China\nEdited by: Sumei Wang, Guangdong Provincial Hospital of Chinese Medicine, China\n\nReviewed by: Timothy F. Burns, University of Pittsburgh, United States; Sheng-Kai Liang, National Taiwan University Hospital Hsin-Chu Branch, Taiwan\n\n*Correspondence: Rong Jiang jiangrong1999@126.comThis article was submitted to Thoracic Oncology, a section of the journal Frontiers in Oncology\n\n†These authors have contributed equally to this work\n\n\n08 9 2020 \n2020 \n10 163516 12 2019 27 7 2020 Copyright © 2020 Ma, Wang, Mu, Li, Liu, Li and Jiang.2020Ma, Wang, Mu, Li, Liu, Li and JiangThis 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.Background: In patients with lung adenocarcinoma and leptomeningeal metastases, it remains unknown whether non-classical mutations in the epidermal growth factor receptor (EGFR) gene can be detected in the cerebrospinal fluid (CSF) and how it may be used to design directed therapy.\n\nMethods: On April 18, 2018, the Interventional Department of Tianjin Huanhu Hospital admitted a 34-years-old male patient with lung adenocarcinoma and leptomeningeal metastasis. An emergency lateral ventriculoperitoneal shunt was performed to relieve the clinical symptoms of intracranial hypertension. Next-generation sequencing (NGS) of the CFS specimens revealed a mutation in EGFR exon 18 p.G719A, and afatinib was administered. Follow-up showed significantly relieved headache, with significantly reduced soft leptomeningeal abnormal enhancement as revealed by enhanced magnetic resonance imaging and significantly smaller tumors in the left lung by chest computed tomography. Carcinoembryonic antigens (CEAs) in cerebrospinal fluid and peripheral blood were significantly reduced. The patient responded well to afatinib, with mild adverse complications. The patient died on October 27, 2019 from respiratory failure as a result of lung infection unrelated to cancer progression. The overall survival (OS) using afatinib was 530 days.\n\nConclusion: CSF can be used as a liquid biopsy for NGS gene detection in patients with lung adenocarcinoma and leptomeningeal metastases. Afatinib exhibits a beneficial effect in patients with lung adenocarcinoma and leptomeningeal metastases harboring the EGFR exon 18 p.G719A mutation.\n\nlung neoplasmsleptomeningeal metastasiscerebrospinal fluidnon-classical mutations of EGFRG719A mutation\n==== Body\nIntroduction\nThe incidence of leptomeningeal metastasis in patients with non-small cell lung cancer (NSCLC) is about 3.4–3.8% (1), with unfavorable prognosis and median survival in untreated patients of merely 4–6 weeks (2). Lung adenocarcinoma is the pathological type with the highest risk of brain and leptomeningeal metastases. About 43.0–70.5% of lung adenocarcinomas are associated with a sensitive mutation in the epidermal growth factor receptor (EGFR) gene. These patients can receive EGFR tyrosine kinase inhibitors (TKIs) treatment and then exhibit significantly prolonged survival (3), highlighting the importance of determining the mutation status of the EGFR gene. Previous work has shown that the cerebrospinal fluid (CSF) is an effective specimen to complement gene detection in patients with lung adenocarcinoma and leptomeningeal metastasis, from whom pathological tissue samples are not readily accessible for gene detection (4, 5).\n\nThe non-classical point mutation G719X is the most common mutation type in the exon 18 of the EGFR gene. Previous work showed that the second generation of EGFR-TKIs are effective in treating lung adenocarcinoma with the EGFR exon 18 p.G719X point mutation (6). In this paper, we report a patient with lung adenocarcinoma and leptomeningeal metastasis after multiple cycles of chemotherapy. The EGFR exon18 p.G719A gene mutation was detected in the CSF (Lizhu Gene, NGS), and a beneficial clinical effect was observed after afatinib treatment. The current findings, therefore, provide a reference for the treatment of lung adenocarcinoma with leptomeningeal metastasis harboring the EGFR exon 18 p.G719A mutation.\n\nCase Report\nThis was reviewed and approved by the ethics committee of Tianjin Huanhu Hospital. Written informed consent was obtained from the patient for publication of this case report and any potentially identifying information and images.\n\nA 34-years-old man with an intractable headache for 6 months and blindness for 3 weeks visited our hospital on April 18, 2018. The patient was hospitalized in May 2016 at another hospital for chest tightness, and computed tomography (CT) revealed space-occupying lesions in the left lower lung, indicative of peripheral lung cancer, and this was confirmed as lung adenocarcinoma by subsequent bronchoscopy. Genetic testing of the tumor specimen was performed, and it was found that the EGFR G719A mutation had an abundance of 0.12%. No targeted therapy was given, and six cycles of intravenous docetaxel combined with cisplatin were administered, leading to partial remission. In April 2017, chest CT suggested progression of the left lung tumor, and 10 cycles of intravenous pemetrexed combined with carboplatin were administered, with the last dose in December 2017. During chemotherapy, the patient developed intractable dizziness with nausea and vomiting.\n\nMagnetic resonance imaging (MRI) in June 2017 suggested leptomeningeal metastasis, with tumor cells detected in CSF cytology. Combined with oral temozolomide, whole-brain radiotherapy (WBRT) was performed at a dose of 2 Gy/15 f, for a total of 30 Gy. Peripheral blood mutation detection (microdrip digital PCR assay) was performed in September 2017, but no sensitive mutations of the EGFR gene were detected. In October 2017, the patient suffered from dizziness and severe headache, and the dose of intravenous mannitol was increased gradually to 250 ml q 6 h (drip) with bevacizumab and semustine, but the headache and nausea were not relieved. Three weeks before admission, the patient developed blindness and was admitted to the hospital with a diagnosis of lung adenocarcinoma with leptomeningeal metastasis. The patient was normal since the disease onset in terms of mentality, sleep, poor diet, and feces, with a weight loss of 10 kg. The patient had no previous smoking or alcohol drinking history or family members with tumor history. After admission, the patient showed disorganized consciousness and poor mental status, with the eyes showing no light reflex and a bilateral pupil at about 5 mm. The leptomeningeal stimulation sign was positive. Palpation of the left clavicle area revealed many 1-cm swollen lymph nodes with poor movement and unclear boundaries. There was also a rale sound when the patient breathed. Limb muscle strength was level IV. The patient was diagnosed with stage IV left pulmonary peripheral lung cancer, T3N3M1c (leptomeningeal and lymph node metastasis), and Eastern Collaborative Oncology Group (ECOG) performance status rating of 4. Lung biopsy could not be performed at that time because of the poor condition of the patient.\n\nCT examination on April 19, 2018 showed expansion of the supratentorial ventricle system and widening of the sulcus cerebri and cistern. Chest CT on April 19, 2018 revealed an irregular solid mass in the lower lobe of the left lung, about 4.0 × 1.9 cm in size, considered as peripheral lung cancer (Figure 1A). Blood carcinoembryonic antigen (CEA) was 716.8 ng/ml. The CSF examination pressure of lumbar puncture was 272 mmH2O (1 mmH2O = 9.81 × 10−3 kPa, normal reference value of 80–180 mmH2O). A right lateral ventriculoperitoneal shunt (VPS) was performed under general anesthesia on April 21, 2018. Lumbar puncture was performed on April 25, 2018. CSF pressure was 240 mmH2O. The patient had an intractable headache. Symptoms of limb convulsions were alleviated earlier. After intrathecal chemotherapy (methotrexate 8 mg and dexamethasone 1 ml added to 9 ml of normal saline) on May 8, 2018, the CSF pressure was 109 mmH2O.\n\nFigure 1 (A) Chest computed tomography (CT) pulmonary window on April 19, 2018 showed an irregular solid mass in the lower lobe of the left lung of about 4.0 × 1.9 cm in size. (B) Chest CT pulmonary window on July 25, 2018 showed the tumor in the lower lobe of the left lung with an irregular shape and uneven density at about 3.5 × 1.1 cm. (C) Chest CT pulmonary window on September 18, 2019 showed an irregular solid mass striated shadow in the lower lobe of the left lung at 2.1 × 0.4 cm in size.\n\nFor the liquid biopsy, 10 ml of CSF was slowly drained using a puncture needle, and 10 ml of peripheral blood was drawn. Both specimens were examined for mutations using next-generation sequencing (NGS). CSF CEA levels were 9,470 ng/ml, and, together with grade 3 bone marrow suppression, intrathecal chemotherapy was terminated. On May 10, 2018, an enhanced MRI scan showed abnormal high-signal images of the medulla oblongata, pontine, ventral midbrain, and dorsal lateral lineaments, indicative of leptomeningeal metastasis (Figure 2A). On May 15, 2018, the EGFR exon 18 p.G719A mutation was identified in CSF specimens, with a frequency of 55.6%. No EGFR gene sensitive mutation was detected in the peripheral blood. The cell-free DNA (cfDNA) platform can also detect EGFR p.G873R, FLT3 p.K602R, KIT p.I841T, NRAS p.G12V, and TP53 p.M243V, but they were all negative. The patient received afatinib 30 mg/day. One week later, the headache symptoms were significantly relieved, but the binocular blindness remained. An ophthalmologist was consulted, who considered this as optic nerve injury that was not recoverable. Afatinib 30 mg/day was continued.\n\nFigure 2 (A) Magnetic resonance imaging (MRI) T2 fluid-attenuated inversion recovery (FLAIR) enhanced scan on May 10, 2018 showed abnormally high signal shadows in the medulla oblongata, pons, and ventral and dorsolateral line of the midbrain, suggesting soft leptomeningeal metastasis. (B) MRI T2 FLAIR enhanced scan on July 31, 2018 showed medulla oblongata, pons, midbrain ventral, and dorsolateral line abnormally high signal shadows, with no significant changes compared with the MRI results on May 10, 2018. (C) MRI T2 FLAIR enhanced scan on September 18, 2019 showed medulla oblongata, pons, midbrain ventral, and dorsal lateral abnormally high signal shadows.\n\nOn July 25, 2018, CT examination showed that the lower lobe of the left lung was irregular in shape and uneven in density with a size of about 3.50 × 1.1 cm (Figure 1B). Enhanced MRI scan on July 31, 2018 showed a high signal shadow of the medulla oblongata, pontine, ventral midbrain, and dorsal lateral lineation, with no significant changes compared with the previous one (Figure 2B). The CEA levels in peripheral blood and CSF were 126.7 and 2,111.0 ng/ml, respectively. On August 10, 2018, the re-examination of the CSF showed the EGFR exon 18 p.G719A mutation with a frequency of 22.2%. The patient was considered as partial remission (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. No major adverse drug reactions were observed, except mild facial skin rash. The headache symptoms were significantly alleviated, with ECOG at 2. Afatinib was increased to 40 mg/day, and no intolerant drug adverse reactions occurred. After that, the tumor size was stable when examined every 8 weeks. On November 20, 2018, the EGFR exon 18 p.G719A mutation frequency in the CSF was 23.1%. The CEA levels were 92.99 ng/ml in the peripheral blood and 1,590.0 ng/ml in CSF.\n\nThe last re-examination was on September 18, 2019. Chest CT showed an irregular solid mass in the lower lobe of the left lung, about 2.1 × 0.4 cm in size (Figure 1C). An enhanced MRI scan showed an abnormally high signal shadow on the ventral and dorsal side of the medulla oblongata, pontine, and midbrain. The abnormal signal showed no significant change compared with the previous one (Figure 2C). Genetic examination of the CSF on September 21, 2019 showed the EGFR exon 18 p.G719A mutation with a frequency of 25.5% (Table 1). The CEA levels in the peripheral blood and CSF were 42.95 and 1,717.5 ng/ml, respectively (Figure 3). The patient continued to be treated with afatinib 40 mg/day.\n\nTable 1 Genetic mutations detected by liquid biopsy of cerebrospinal fluid (CSF).\n\nDate\tGene\tAmino acid site\tAllele frequency\t\n2018/5/8\tEGFR\tExon18 p.G719A\t55.6%\t\n2018/8/10\tEGFR\tExon18 p.G719A\t22.2%\t\n2018/11/20\tEGFR\tExon18 p.G719A\t23.1%\t\n2019/9/21\tEGFR\tExon18 p.G719A\t25.5%\t\nFigure 3 The carcinoembryonic antigen (CEA) levels from the cerebrospinal fluid (CSF) and peripheral blood were significantly decreased.\n\nOn October 27, 2019, the patient died of respiratory failure due to lung infection unrelated to tumor progression. The progression-free survival (PFS) of the patient upon afatinib treatment was 530 days.\n\nDiscussion\nLeptomeningeal metastases are serious lesions caused by malignant tumor cells that enter the bloodstream, the lymphatic system, and the CSF and implant themselves into the leptomeninges. Alternatively, adjacent tumors may directly invade the leptomeninges. In both cases, this leads to clinical damage to the brain parenchyma, the brain nerves, and the spinal cord. The clinical manifestations are overall complex and varied, and early diagnosis is difficult using the routine examination. Current treatments for lung cancer with leptomeningeal metastases include WBRT, surgery, drug chemotherapy, and molecular targeted drug therapy (3). The primary objective is to improve or stabilize the central nervous system functions and relieve the symptoms. Nevertheless, the clinical outcomes of those treatment strategies remain unsatisfactory, with a median survival time of only 4–6 months. In this study, given the intractable dizziness symptoms with nausea and vomiting, enhanced MRI revealed abnormal enhancement of the leptomeninges, and CSF cytology identified tumor cells, indicative of lung adenocarcinoma with leptomeningeal metastasis. Pemetrexed combined with temozolomide, WBRT, and other comprehensive treatment led to a stable clinical condition for only 4 months. The clinical symptoms aggravated again, although mannitol dehydration was used to reduce intracranial pressure. Bevacizumab, semustine, and other drugs were also tried, but the beneficial effect was modest. When admitted to our emergency department, the clinical condition of the patient was poor, with intractable headache, binocular blindness, limb convulsion, consciousness loss, and ECOG performance status rating of 4. The expected survival time was <4 weeks. CT scan upon admission showed significant ventricular dilatation, cerebral stroma edema, and significantly increased CSF pressure (272 mmH2O) that required an acute right lateral ventriculoperitoneal shunt. Subsequent re-examination showed gradually decreasing CSF pressure. The intractable headache became gradually alleviated. A lateral ventricle–peritoneal shunt can improve encephalopathy resulting from hydrocephalus by effectively draining CSF and lowering CSF pressure in patients with significantly elevated CSF pressure (7, 8).\n\nEGFR-TKIs hold promise for patients with central nervous system metastases from lung adenocarcinoma with a sensitive mutation in the EGFR gene. EGFR-TKIs are fat-soluble, small molecular weight drugs with a capacity to penetrate the blood–brain barrier. In patients with leptomeningeal metastases from non-small cell lung cancer with EGFR gene-sensitive mutations, beneficial results can be obtained using EGFR-TKIs (9, 10). EGFR gene mutations are found mainly in exons 18, 19, 20, and 21, among which the frequency of the deletion in exon 19 and the L858R point mutation in exon 21 is 90%. They are considered as classic sensitive mutation, while the others are considered as non-classical mutation (6, 11). About 3.6% of EGFR mutations are exon 18 mutations, especially for the G719X.719 mutation where the glycine is substituted for an alanine (G719A), cysteine (G719C), or serine (G719S). Prior studies have shown that this mutation increases the distance between residual L718 and G796, making ATP-binding pockets more open and thus easier to bind to TKIs (11, 12). In vitro studies showed that exon 18, a driver mutation, was more sensitive to second-generation EGFR-TKIs than to the second and third generations (13). Patients with the G719X mutation treated with second-generation EGFR-TKIs exhibited a median PFS >12 months and an objective response rate of 78% (6). Fan et al. (4) demonstrated consistent information of EGFR gene mutation when using primary tumor vs. CSF specimens from 11 patients with lung adenocarcinoma and leptomeningeal metastasis, suggesting that CSF liquid biopsies are an effective complement for gene mutation detection when pathological specimens are not readily accessible. Li et al. (5) compared the CSF cell-free DNA (cfDNA), CSF precipitate, and plasma samples from 26 patients with lung adenocarcinoma and leptomeningeal metastases using NGS and found that the sensitivity of driving gene mutation was 100% (26/26), 84.6% (22/26), and 73.1% (19/26), respectively. Compared with plasma and primary tumor tissue, CSF cfDNA exhibits unique gene profiles. Leptomeningeal metastasis from non-small cell lung cancer is considered to be the most representative fluid biopsy in which EGFR gene-sensitive mutations can be identified. The 2018 Consensus for Diagnosis and Treatment of Brain (Leptomeningeal) Metastasis of Lung Cancer in China recommends that CSF gene detection be performed in patients with lung adenocarcinoma and leptomeningeal metastases. In the case reported here, the patient was in a highly unfavorable condition when admitted, and intrathecal chemotherapy had to be terminated due to bone marrow suppression. Consequently, mutation detection from CSF and blood was performed. The results indicated the EGFR exon 18 p.G719A mutation with a mutation frequency of 55.6% in CSF, but the results from the blood samples were negative. Bai et al. (14) showed that intravenous chemotherapy reduced the frequency of EGFR gene mutations. The patient underwent two lines of platinum-containing intravenous chemotherapy, oral temozolomide, and semustine chemotherapy, and the lung lesions were stable, but leptomeningeal metastasis showed progression. We, therefore, speculate that the negative gene test results of the blood sample may stem from the patient's multicycle chemotherapy history and the effective control of the lung lesions. Nevertheless, because of the blood–brain barrier and the progression of the leptomeningeal metastasis, the mutation could be detected in CSF specimens. Gene detection using CSF and peripheral blood in patients with lung adenocarcinoma and leptomeningeal metastasis was demonstrated by Huang et al. (15), who also suggested a higher positive detection rate using CSF than peripheral blood.\n\nWe found for the first time that the mutation frequency of the EGFR G719A mutation in CSF remained the same (Table 1), although the clinical symptoms improved significantly during afatinib treatment. We believe that in patients with leptomeningeal metastases from lung adenocarcinoma, CSF NGS bears the following characteristics. Foremost, because of the blood–brain barrier that restricts the value of plasma cfDNA or circulating tumor cells in evaluating intracranial lesions, the use of CSF specimens better reflects the gene spectrum of brain tumor lesions. Second, cfDNA from tumor source in plasma could exhibit background interference, whereas this interference is smaller in CSF. The high mutation frequency can be detected by NGS. Third, CSF gene detection may be used to dynamically monitor tumor load in leptomeningeal metastases, thereby revealing the efficacy and prognosis for EGFR-TKIs. Therefore, CSF NGS may have advantages over the unique gene spectrum of the reactive intracranial lesions, and this will help determine whether lung adenocarcinoma patients with leptomeningeal metastases can be treated with EGFR-TKIs or not.\n\nCSF liquid biopsy for the detection of driver mutation in NSCLC leptomeningeal metastases is relatively novel. The clinical significance of uncommon EGFR mutations on the development of leptomeningeal metastases from NSCLC and their response to treatment remains unclear. CSF liquid biopsy has emerged recently as a novel tool for assessing EGFR mutations in intracranial metastases. A recent study showed that in patients with NSCLC and leptomeningeal metastasis, the rate of uncommon EGFR mutation was high and that the brain metastases with uncommon EGFR mutations seem to respond to EGFR-TKI treatment (16). CSF liquid biopsy could reveal the EGFR genetic profile of the BM and help guide treatment using small-molecule TKI. Molecular testing of CSF could be helpful in guiding treatment and tracking treatment response. Indeed, previous studies reported that the EGFR mutations found in the NSCLC primary lesions are not consistent with those found in the intracranial metastases (17–19). Indeed, a primary tumor is composed of multiple different clones (20, 21), and not all of them will have the abilities to spread in circulation, cross the blood–brain barrier, survive in the brain microenvironment, and invade brain tissues (22, 23). Those characteristics require specific sets of factors and mutations, and uncommon mutations might be considered as participating in the process of brain metastases of NSCLC. CSF liquid biopsy could be a new tool for the management of NSCLC, especially in the context where afatinib is able to cross the blood–brain barrier in sufficient amounts to induce an antitumor effect (24, 25).\n\nGuided by the CSF NGS results, the patient received oral afatinib therapy. The intractable headaches were significantly relieved, with no intolerable adverse drug reactions. A chest CT examination showed a significant reduction in lung lesions. An enhanced MRI scan of the head showed the reduced intensity of leptomeningeal lesions and CEA in both CSF and peripheral blood. The patient died of respiratory failure due to lung infection unrelated to tumor progression. The OS was 530 days after starting apatinib, suggesting a beneficial clinical effect for afatinib on leptomeningeal metastasis resulting from lung adenocarcinoma and harboring the EGFR exon 18 p.G719A mutation.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by Tianjin Huanhu Hospital. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\nCM and SW carried out the studies, participated in collecting the data, and drafted the manuscript. RJ performed the statistical analysis and participated in its design. NM, JL, ML, and LL helped draft the manuscript. All authors read and approved the final manuscript.\n\nConflict of Interest\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\nThe authors would like to thank the bio-information team at Livzongene LLC for their excellent guidance in bioinformatics analysis to improve our study output. The team was not directly involved with any aspect of the study.\n==== Refs\nReferences\n1. Jiang BY Li YS Guo WB Zhang XC Chen ZH Su J . Detection of driver and resistance mutations in leptomeningeal metastases of NSCLC by next-generation sequencing of cerebrospinal fluid circulating tumor cells\n. Clin Cancer Res. (2017 ) 23 :5480 –8\n. 10.1158/1078-0432.Ccr-17-0047 28606923 \n2. Ma C Jiang R Li J Wang B Sun L Lv Y . Research progress of lung cancer with leptomeningeal metastasis\n. Zhongguo Fei Ai Za Zhi. (2014 ) 17 :695 –700\n. 10.3779/j.issn.1009-3419.2014.09.10 25248713 \n3. Xu Y Li L Wang M . Diagnosis and treatment of leptomeningeal metastasis in non-small cell lung cancer\n. Zhongguo Fei Ai Za Zhi. (2015 ) 18 :626 –32\n. 10.3779/j.issn.1009-3419.2015.10.05 26483335 \n4. Fan Y Zhu X Xu Y Lu X Xu Y Wang M . Cell-cycle and DNA-damage response pathway is involved in leptomeningeal metastasis of non-small cell lung cancer\n. Clin Cancer Res. (2018 ) 24 :209 –16\n. 10.1158/1078-0432.Ccr-17-1582 29030356 \n5. Li YS Jiang BY Yang JJ Zhang XC Zhang Z Ye JY . Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung cancer: a new medium of liquid biopsy\n. Ann Oncol. (2018 ) 29 :945 –52\n. 10.1093/annonc/mdy009 29346604 \n6. Yang JC Sequist LV Geater SL Tsai CM Mok TS Schuler M . Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6\n. Lancet Oncol. (2015 ) 16 :830 –8\n. 10.1016/s1470-2045(15)00026-1 26051236 \n7. Lee SH Kong DS Seol HJ Nam DH Lee JI . Ventriculoperitoneal shunt for hydrocephalus caused by central nervous system metastasis\n. J Neurooncol. (2011 ) 104 :545 –51\n. 10.1007/s11060-010-0512-2 21274592 \n8. Lee SJ Lee JI Nam DH Ahn YC Han JH Sun JM . Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors\n. J Thorac Oncol. (2013 ) 8 :185 –91\n. 10.1097/JTO.0b013e3182773f21 23328548 \n9. Yi HG Kim HJ Kim YJ Han SW Oh DY Lee SH \nEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for leptomeningeal metastasis from non-small cell lung cancer patients with sensitive EGFR mutation or other predictive factors of good response for EGFR TKI\n. Lung Cancer. (2009 ) 65 :80 –4\n. 10.1016/j.lungcan.2008.10.016 19059670 \n10. Lee E Keam B Kim DW Kim TM Lee SH Chung DH . Erlotinib versus gefitinib for control of leptomeningeal carcinomatosis in non-small-cell lung cancer\n. J Thorac Oncol. (2013 ) 8 :1069 –74\n. 10.1097/JTO.0b013e318294c8e8 23804027 \n11. Wang Y Li M Hu CP \nRare mutation and targeted therapy of EGFR gene in non-small cell lung cancer\n. Natl Med J China. (2019 ) 99 :154 –7\n. 10.3760/cma.j.issn.0376-2491.2019.02.016 \n12. Tamiya M Shiroyama T Nishihara T Nishida T Hayama M Tanaka A \nAfatinib successfully treated leptomeningeal metastasis during erlotinib treatment in a patient with EGFR-mutant (Exon18:G719S) lung adenocarcinoma as a second-line chemotherapy\n. Asia Pac J Clin Oncol . (2017 ) 13 :e531 –3\n. 10.1111/ajco.12643 28004883 \n13. Banno E Togashi Y Nakamura Y Chiba M Kobayashi Y Hayashi H . Sensitivities to various epidermal growth factor receptor-tyrosine kinase inhibitors of uncommon epidermal growth factor receptor mutations L861Q and S768I: what is the optimal epidermal growth factor receptor-tyrosine kinase inhibitor?\n\nCancer Sci. (2016 ) 107 :1134 –40\n. 10.1111/cas.12980 27240419 \n14. Bai H Wang Z Chen K Zhao J Lee JJ Wang S . Influence of chemotherapy on EGFR mutation status among patients with non-small-cell lung cancer\n. J Clin Oncol. (2012 ) 30 :3077 –83\n. 10.1200/jco.2011.39.3744 22826274 \n15. Huang R Xu X Li D Chen K Zhan Q Ge M . Digital PCR-based detection of EGFR mutations in paired plasma and CSF samples of lung adenocarcinoma patients with central nervous system metastases\n. Target Oncol. (2019 ) 14 :343 –50\n. 10.1007/s11523-019-00645-5 31161597 \n16. Ma C Zhang J Tang D Ye X Li J Mu N . Tyrosine kinase inhibitors could be effective against non-small cell lung cancer brain metastases harboring uncommon EGFR mutations\n. Front Oncol. (2020 ) 10 :224 . 10.3389/fonc.2020.00224 32195178 \n17. Burel-Vandenbos F Ambrosetti D Coutts M Pedeutour F . EGFR mutation status in brain metastases of non-small cell lung carcinoma\n. J Neurooncol. (2013 ) 111 :1 –10\n. 10.1007/s11060-012-0990-5 23086434 \n18. Hata A Katakami N Yoshioka H Takeshita J Tanaka K Nanjo S . Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: comparison between T790M mutation-positive and mutation-negative populations\n. Cancer. (2013 ) 119 :4325 –32\n. 10.1002/cncr.28364 24105277 \n19. Kelly WJ Shah NJ Subramaniam DS . Management of brain metastases in epidermal growth factor receptor mutant non-small-cell lung cancer\n. Front Oncol. (2018 ) 8 :208 . 10.3389/fonc.2018.00208 30018881 \n20. McGranahan N Swanton C . Clonal heterogeneity and tumor evolution: past, present, and the future\n. Cell. (2017 ) 168 :613 –28\n. 10.1016/j.cell.2017.01.018 28187284 \n21. Jia Q Wu W Wang Y Alexander PB Sun C Gong Z . Local mutational diversity drives intratumoral immune heterogeneity in non-small cell lung cancer\n. Nat Commun. (2018 ) 9 :5361 . 10.1038/s41467-018-07767-w 30560866 \n22. Winkler F . Hostile takeover: how tumours hijack pre-existing vascular environments to thrive\n. J Pathol. (2017 ) 242 :267 –72\n. 10.1002/path.4904 28390068 \n23. Preusser M Winkler F Valiente M Manegold C Moyal E Widhalm G . Recent advances in the biology and treatment of brain metastases of non-small cell lung cancer: summary of a multidisciplinary roundtable discussion\n. ESMO Open. (2018 ) 3 :e000262 . 10.1136/esmoopen-2017-000262 29387475 \n24. Hoffknecht P Tufman A Wehler T Pelzer T Wiewrodt R Schutz M \nEfficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease\n. J Thorac Oncol. (2015 ) 10 :156 –63\n. 10.1097/JTO.0000000000000380 25247337 \n25. Schuler M Wu YL Hirsh V O'Byrne K Yamamoto N Mok T . First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases\n. J Thorac Oncol. (2016 ) 11 :380 –90\n. 10.1016/j.jtho.2015.11.014 26823294\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "G719A mutation; cerebrospinal fluid; leptomeningeal metastasis; lung neoplasms; non-classical mutations of EGFR",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "1635",
"pmc": null,
"pmid": "33014823",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "21274592;28187284;30560866;23804027;25248713;31161597;29387475;19059670;25247337;22826274;32195178;28004883;23086434;26051236;28390068;26483335;29030356;29346604;23328548;24105277;27240419;30018881;28606923;26823294",
"title": "Effective Treatment With Afatinib of Lung Adenocarcinoma With Leptomeningeal Metastasis Harboring the Exon 18 p.G719A Mutation in the EGFR Gene Was Detected in Cerebrospinal Fluid: A Case Report.",
"title_normalized": "effective treatment with afatinib of lung adenocarcinoma with leptomeningeal metastasis harboring the exon 18 p g719a mutation in the egfr gene was detected in cerebrospinal fluid a case report"
} | [
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"abstract": "OBJECTIVE\nTo report a case of arterial thrombosis in a 63-year-old female undergoing treatment with multiagent chemotherapy for breast cancer. An overview of the prevalence and pathogenesis of the disorder, clinical diagnosis, and treatment are discussed.\n\n\nMETHODS\nCase report, diagnostic evidence, and scientific literature.\n\n\nCONCLUSIONS\nArterial thrombosis is an extremely rare complication of multichemotherapy treatment of breast cancer. Although the risk of arterial thromboembolism appears to be low, it can have devastating complications that result in significant morbidities and, sometimes, death.\n\n\nCONCLUSIONS\nAs the risk of arterial thrombosis is low, many healthcare providers may not be aware of this potentially serious complication. Thrombosis prophylaxis should be considered for patients with risk factors. In cases where arterial thrombosis occurs, immediate thrombolitic therapy or operative intervention should be considered.",
"affiliations": "Department of Medical Oncology, City of Hope, National Medical Center and Beckman Research Institute, Duarte, California 91010, USA. lbourdeanu@apu.edu",
"authors": "Bourdeanu|Laura|L|;Luu|Thehang|T|",
"chemical_list": "D000925:Anticoagulants; D000970:Antineoplastic Agents; D010975:Platelet Aggregation Inhibitors; D006493:Heparin; D001241:Aspirin",
"country": "United States",
"delete": false,
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"issue": "22(3)",
"journal": "Journal of the American Academy of Nurse Practitioners",
"keywords": null,
"medline_ta": "J Am Acad Nurse Pract",
"mesh_terms": "D000925:Anticoagulants; D000970:Antineoplastic Agents; D001241:Aspirin; D001943:Breast Neoplasms; D018275:Carcinoma, Lobular; D017024:Chemotherapy, Adjuvant; D017128:Embolectomy; D005260:Female; D006493:Heparin; D006801:Humans; D008875:Middle Aged; D009722:Nurse Practitioners; D010975:Platelet Aggregation Inhibitors; D012307:Risk Factors; D013923:Thromboembolism",
"nlm_unique_id": "8916634",
"other_id": null,
"pages": "140-3",
"pmc": null,
"pmid": "20236397",
"pubdate": "2010-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Arterial thrombosis associated with adjuvant chemotherapy for breast cancer: a case report.",
"title_normalized": "arterial thrombosis associated with adjuvant chemotherapy for breast cancer a case report"
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"abstract": "Coronavirus disease 2019 (COVID-19) is associated with high morbidity and mortality worldwide in both the general population and kidney transplant recipients. Acute kidney injury is a known complication of COVID-19 and appears to most commonly manifest as acute tubular injury on renal biopsy. Coagulopathy associated with COVID-19 is a known but poorly understood complication that has been reported to cause thrombotic microangiopathy on rare occasions in native kidneys of patients with COVID-19. Here, we report the first case of biopsy-proven thrombotic microangiopathy in a kidney transplant recipient with COVID-19 who developed acute pancreatitis and clinical features of microangiopathic hemolytic anemia. The patient recovered with supportive care alone.",
"affiliations": "Division of Nephrology, University of California, Davis School of Medicine, Sacramento, California.;Division of Nephrology, University of California, Davis School of Medicine, Sacramento, California.;Division of Nephrology, University of California, Davis School of Medicine, Sacramento, California.;Department of Pathology and Laboratory Medicine, University of California, Davis School of Medicine, Sacramento, California.;Division of Nephrology, University of California, Davis School of Medicine, Sacramento, California.;Department of Pathology and Laboratory Medicine, University of California, Davis School of Medicine, Sacramento, California. Electronic address: kyjen@ucdavis.edu.",
"authors": "Jespersen Nizamic|Tiana|T|;Huang|Yihung|Y|;Alnimri|Muna|M|;Cheng|Mingyu|M|;Chen|Ling-Xin|LX|;Jen|Kuang-Yu|KY|",
"chemical_list": "D003404:Creatinine; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.10.048",
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"issn_linking": "0041-1345",
"issue": "53(4)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000086382:COVID-19; D003404:Creatinine; D005260:Female; D006801:Humans; D007668:Kidney; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008875:Middle Aged; D010195:Pancreatitis; D010976:Platelet Count; D000086402:SARS-CoV-2; D016559:Tacrolimus; D057049:Thrombotic Microangiopathies; D014184:Transplantation, Homologous",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1211-1214",
"pmc": null,
"pmid": "33436168",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "COVID-19 Manifesting as Renal Allograft Dysfunction, Acute Pancreatitis, and Thrombotic Microangiopathy: A Case Report.",
"title_normalized": "covid 19 manifesting as renal allograft dysfunction acute pancreatitis and thrombotic microangiopathy a case report"
} | [
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"companynumb": "US-PBT-000625",
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"abstract": "Primary retroperitoneal melanoma is a very rare extracutaneous presentation of melanoma. In this case report, we present a 65-year-old female with unilateral lower extremity edema secondary to occlusion of iliac vessels by a primary retroperitoneal melanoma tumor. We also review the findings in other cases previously described in the literature.",
"affiliations": "University of California Riverside School of Medicine, Riverside, CA, USA.;Kaiser Permanente Riverside Medical Center, Riverside, CA, USA.;Department of Dermatology, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA.",
"authors": "Oulee|Aislyn|A|https://orcid.org/0000-0003-1300-9840;Xu|Ling|L|;Worswick|Scott|S|https://orcid.org/0000-0002-2700-1041",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/3526071",
"fulltext": "\n==== Front\nCase Rep Med\nCase Rep Med\nCRIM\nCase Reports in Medicine\n1687-9627\n1687-9635\nHindawi\n\n10.1155/2021/3526071\nCase Report\nPrimary Retroperitoneal Malignant Melanoma with Involvement of Iliac Artery and Vein\nhttps://orcid.org/0000-0003-1300-9840\nOulee Aislyn aoule001@medsch.ucr.edu\n1\nXu Ling 2\nhttps://orcid.org/0000-0002-2700-1041\nWorswick Scott 3\n1University of California Riverside School of Medicine, Riverside, CA, USA\n2Kaiser Permanente Riverside Medical Center, Riverside, CA, USA\n3Department of Dermatology, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA\nAcademic Editor: Gerald S. Supinski\n\n2021\n4 9 2021\n2021 352607110 4 2021\n28 8 2021\nCopyright © 2021 Aislyn Oulee et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This 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.\nPrimary retroperitoneal melanoma is a very rare extracutaneous presentation of melanoma. In this case report, we present a 65-year-old female with unilateral lower extremity edema secondary to occlusion of iliac vessels by a primary retroperitoneal melanoma tumor. We also review the findings in other cases previously described in the literature.\n==== Body\npmc1. Introduction\n\nPrimary retroperitoneal melanoma (PRM) is an extremely rare form of malignant extracutaneous melanoma with a poor prognosis. Although malignant melanomas arise from the skin in vast majority of cases, they can also appear in other organs where melanocytes are present including the eye, meninges and mucosa, and much less commonly in the retroperitoneal space. Diagnosis of a retroperitoneal melanoma requires a thorough cutaneous, mucosal, and ocular exam to ensure there are no primary lesions in these areas that may have metastasized to the retroperitoneal space. In this case report, we present a rare case of primary retroperitoneal melanoma with involvement of the left iliac artery and vein.\n\n2. Case Report\n\nA 65-year-old Caucasian female presented with a two-week history of left lower extremity swelling and pain. The patient stated that the swelling slightly improved with elevation of her legs and that the pain was partially alleviated with NSAIDs. The patient denied any shortness of breath, recent trauma, fever, chest pain, or unexplained weight loss. She had a past medical history significant for inflammatory polyarthritis (on methotrexate and Humira), hyperlipidemia, hypertension, asthma-COPD overlap syndrome, osteopenia, and paroxysmal atrial fibrillation. She had been taking warfarin for atrial fibrillation with international normalized ratio (INR) levels within the therapeutic range. The patient had a history of three-pack years of smoking but stated she quit approximately 40 years ago.\n\nOn physical examination, the presence of pitting edema of her left lower extremity was noted (Figure 1). There were strong peripheral pulses, and her abdomen was soft and nondistended. Blood work was significant for severe hypokalemia (2.8 mEq/L), which was repleted in clinic. Both erythrocyte sedimentation rates and C-reactive protein levels were checked and found to be elevated at 35.0 mm/hr and 30.1 mg/L, respectively. An ultrasound examination of the left lower extremity was negative for deep venous thrombosis (DVT). A computed tomography (CT) angiography of the abdomen/pelvis was then performed and revealed a large heterogeneous left pelvic retroperitoneal mass centered at the left iliac chain region spanning 8.7 × 6.9 × 8.5 cm with probable compression/occlusion of the adjacent iliac vein (Figure 2). Based on the imaging study, the differential diagnosis included sarcoma, lymphoma, ovarian neoplasm, or germ cell tumor.\n\nA CT-guided abdominal mass needle core biopsy was performed, and the sample was sent for H&E staining (Figure 3(a)) as well as immunohistochemical (IHC) staining. Immunostaining showed that the tumor cells were diffusely and strongly positive for SOX10 (Figure 3(b)) but were negative for CK7, CK20, GATA3, and PAX8. These immunohistochemical stain findings support a diagnosis of melanoma. The tumor cells were also positive for S100 immunostaining (Figure 3(c)) and BRAF V600E mutation, thereby further confirming the diagnosis. Upon review of the case and the CT scan, surgical oncology determined that the mass was surgically unresectable due to invasion of the adjacent iliac vessels. A comprehensive workup was performed to search for primary and secondary involvement of other sites, including an MRI brain and brainstem with no contrast and a full body PET scan, both of which were unremarkable.\n\nThe patient was referred to a dermatologist for a detailed skin examination, and no primary lesion was found. Therefore, a diagnosis of primary retroperitoneal melanoma was rendered. The patient was also referred to an oncologist who offered the patient clinical trial for EA6134 (a randomized phase III trial of dabrafenib and trametinib followed by ipilimumab and nivolumab) since the tumor contained the mutation BRAF V600. Five months after being started on the clinical trial, the patient was admitted to the hospital with shortness of breath and encephalopathy. She was evaluated by an oncologist who determined that her encephalopathy was the result of her chemotherapy, and her participation in the trial was therefore withdrawn. The patient was discharged to a hospice facility and succumbed to the disease one month later, six months after her initial diagnosis.\n\n3. Discussion\n\nMelanoma, a malignancy arising from melanocytes, is the deadliest form of cutaneous malignancy. Most malignant melanomas arise from the skin, and only 5% of all primary melanomas arise from extracutaneous tissues [1]. Extracutaneous malignant melanomas are extremely rare and aggressive lesions, and therefore the rarity and aggressive nature of this disease make its diagnosis and treatment a challenging task. To date, only 7 cases of PRM have been reported in the English-language literature (Table 1) [2–8]. The initial symptoms of primary retroperitoneal melanoma can be nonspecific and include fatigue, weight loss, anorexia, and leg swelling; however, of these 7 previously reported cases and our own 8th case, some specific presenting signs can be identified. In 4 of the 8 cases (50%), patients presented with abdominal pain, in three cases (38%) with abdominal distension/fullness, and in one case with postmenopausal vaginal bleeding [3–5, 8]. CT plays an important role in the diagnosis of primary retroperitoneal melanoma as it can localize the tumor [9]. However, immunohistochemical stains are required for the definitive diagnosis of PRM. Both cutaneous and noncutaneous melanomas exhibit the same immunohistochemical and structural features [2]. Despite the variety of immunohistochemical markers for melanoma, S100 remains the most sensitive [10]. In addition, SOX10 is a transcription factor that has also been shown to be a sensitive marker of melanoma [11]. Both S100 and SOX10 immunostains were positive in our case. The patient's melanoma also contained a mutation in the BRAF gene, which is present in approximately 50% of cases of advanced melanoma [12]. Negative immunostaining for CK7, CK20, GATA3, and PAX8 also played a vital role in ruling out other probable malignancies and arriving at the diagnosis of melanoma. For instance, PAX8 is a specific and sensitive marker for renal and ovarian carcinomas [13] and protein GATA3 has been previously reported to be expressed in epithelial proliferations of the female genital tract [14].\n\nClear guidelines for the treatment of primary retroperitoneal malignant melanoma have not yet been defined due to the rarity of this disease, and therefore, therapy is based on evidence derived from the treatment of cutaneous melanoma. The mainstay of therapy for melanoma remains surgical resection, but if the tumor is surgically unresectable or in the case of more advanced disease, then systemic therapy is recommended. Vemurafenib and dabrafenib are small molecule inhibitors of BRAF kinase and are first-line treatment for BRAF mutation-positive melanoma [15]. Vemurafenib and dabrafenib are similar in efficacy, but dabrafenib is associated with less toxicity [16]. Another treatment regimen option includes programmed cell death protein 1 (PD-1) and programmed death-ligand 1(PD-L1) inhibitors, such as pembrolizumab and nivolumab, which are emerging as successful therapy for metastatic melanoma [15]. In conclusion, we report a case of primary retroperitoneal melanoma with involvement of the iliac artery and vein causing lower extremity edema. It is reasonable for physicians to take into consideration malignant melanoma when evaluating retroperitoneal masses.\n\nData Availability\n\nNo datasets were generated or analyzed during the current study.\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Patient's initial presentation of left lower extremity edema.\n\nFigure 2 Computed tomography of the abdomen reveals 8.7 × 6.9 × 8.5 cm mass (red arrow) in the retroperitoneal space.\n\nFigure 3 (a) Nest of tumor cells showing areas of necrosis (H&E, original magnification ×100). (b) Immunohistochemical stain positive for SOX10 (H&E, original magnification ×100). (c) Immunohistochemical stain positive for S100 (H&E, original magnification ×100).\n\nTable 1 Literature review of other reported cases of PRM.\n\nCase report\tInitial presentation\tImaging results\tImmunohistochemistry results\t\nPrimary retroperitoneal malignant melanoma: a case report [2]\t18-y/o F with 6-month h/o a progressively enlarging mass in the right upper abdomen with no other symptoms\tCT scan of the abdomen showed an irregular heterogeneous soft-tissue density mass located in the anterior pararenal space\tImmunohistochemical (IHC) staining was positive for S100, human melanoma black-45 (HMB45), and melanin-A and mildly positive for tyrosinase\t\nRetroperitoneal malignant melanoma—a curiosity [3]\t76-y/o M with 2-week h/o pain and distension of the abdomen, followed by fever and vomiting for 4 days\tCT scan of the abdomen revealed a well-defined, 8.6 × 5.1 cm, heterogeneously enhancing mass in the retroperitoneum\tNot reported in case report\t\nPrimary retroperitoneal malignant melanoma [4]\t34-y/o F with 3-month h/o recurrent abdominal pain and distension, asthenia, anorexia, vomiting, and fever\tCT scan of the abdomen confirmed the presence of a large retroperitoneal tumor measuring 8, 22 × 8, 15 cm\tIHC staining was positive for S100, HMB45, and melanin-A\t\nA rare presentation of melanoma as a retroperitoneal mass: a case report and a brief review of the literature [5]\t77-y/o M with 3-month h/o fatigue, abdominal pain, decreased appetite, and 40-lb weight loss\tPET/CT scan showed a large heterogeneous, lobulated subhepatic mass\tIHC staining was positive for vimentin, HMB45, melanin-A, and S100\t\nIleus secondary to a retroperitoneal malignant melanoma [6]\t77-h/o F with progressive abdominal distension and decreased appetite for 4 months\tCT scan of the abdomen showed a retroperitoneal tumor with irregular margin and heterogeneous density, measuring approximately 18.2 × 21.5 cm in the largest section\tIHC staining was positive for S100 protein, HMB45, and vimentin and negative for cytokeratin AE1/AE3, cytokeratin 7, epithelial membrane antigen, and CD34\t\nPrimary retroperitoneal melanoma presented in a rare extracutaneous site for malignant melanoma [7]\t53-y/o F with postmenopausal vaginal bleeding\tTransvaginal ultrasound revealed left-side complex pelvic mass measuring 4.3 × 3.4 × 3 cm\tIHC staining was positive for HMB45, melanin-A, and S100\t\nA rare presentation of melanoma as a retroperitoneal mass seen on FDG PET [8]\t55-y/o F with 4-week h/o fatigue and abdominal pain\tUltrasound and CT scan showed a large heterogeneous mass in the retroperitoneum, and PET/CT images showed a hypermetabolic retroperitoneal mass\tIHC staining was positive for HMB45, S100, and melanin-A but negative for CK and CgA; negative BRAF or C-kit mutation\t\nF, female; M, male; y/o, year-old; h/o, history of; HMB45, human melanoma black-45; CK, cytokeratin.\n==== Refs\n1 Hussein M. R. Extracutaneous malignant melanomas Cancer Investigation 2008 26 5 516 534 10.1080/07357900701781762 2-s2.0-45949094798 18568775\n2 Liu G.-B. Wu G.-Y. Ghimire P. Zhang Z.-P. Primary retroperitoneal malignant melanoma: a case report Oncology Letters 2011 2 6 1107 1111 10.3892/ol.2011.397 2-s2.0-80052752679 22848275\n3 Pawale J. Javalgi A. P. Hiremath R. Dombale V. D. Kansagara M. H. Retroperitoneal malignant melonoma—a curiosity Journal of Clinical and Diagnostic Research 2011 5 372 373\n4 Zentar A. Makhmari R. Elkaoui H. Primary retroperitoneal malignant melanoma The Pan African Medical Journal 2012 12 p. 20\n5 Randhawa A. Sonpal N. Machnicki S. Spaccavento C. Novoselac A. A rare presentation of melanoma as a retroperitoneal mass: a case report and a brief review of the literature Journal of Solid Tumors 2013 3 2 10.5430/jst.v3n2p10\n6 Chen C.-F. Chuang C.-H. Hu C. Wang J.-Y. Ileus secondary to a retroperitoneal malignant melanoma Biomarkers and Genomic Medicine 2013 5 3 113 116 10.1016/j.bgm.2013.08.001 2-s2.0-84885223047\n7 Alsharedi M. Zgheib N. B. Khelfa Y. Raufi A. Elmsherghi N. Lebowicz Y. Primary retroperitoneal melanoma presented in a rare extracutaneous site for malignant melanoma Rare Tumors 2016 8 3 p. 6308 10.4081/rt.2016.6308 2-s2.0-85015886184\n8 Yao Y. Liu W. Zuo Z. Cheng Z. A rare presentation of melanoma as a retroperitoneal mass seen on FDG PET Clinical Nuclear Medicine 2020 45 4 324 325 10.1097/rlu.0000000000002920 31977477\n9 Patnana M. Bronstein Y. Szklaruk J. Multimethod imaging, staging, and spectrum of manifestations of metastatic melanoma Clinical Radiology 2011 66 3 224 236 10.1016/j.crad.2010.10.014 2-s2.0-79551591503 21295201\n10 Ohsie S. J. Sarantopoulos G. P. Cochran A. J. Binder S. W. Immunohistochemical characteristics of melanoma Journal of Cutaneous Pathology 2008 35 5 433 444 10.1111/j.1600-0560.2007.00891.x 2-s2.0-42049113246 18399807\n11 Palla B. Su A. Binder S. Dry S. SOX10 expression distinguishes desmoplastic melanoma from its histologic mimics The American Journal of Dermatopathology 2013 35 5 576 581 10.1097/dad.0b013e31827a0b98 2-s2.0-84880572520 23291581\n12 Cheng L. Lopez-Beltran A. Massari F. MacLennan G. T. Montironi R. Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine Modern Pathology 2018 31 1 24 38 10.1038/modpathol.2017.104 2-s2.0-85040184723 29148538\n13 Tacha D. Zhou D. Cheng L. Expression of PAX8 in normal and neoplastic tissues Applied Immunohistochemistry & Molecular Morphology 2011 19 4 293 299 10.1097/pai.0b013e3182025f66 2-s2.0-79959310044 21285870\n14 Esheba G. E. Longacre T. A. Atkins K. A. Higgins J. P. Expression of the urothelial differentiation markers GATA3 and placental S100 (S100P) in female genital tract transitional cell proliferations The American Journal of Surgical Pathology 2009 33 3 347 353 10.1097/pas.0b013e3181908e24 2-s2.0-62849083671 19092634\n15 Talag M. M. Alsharedi M. Bou Zgheib N. Lebowicz Y. Immunotherapy in a rare case of primary pelvic retroperitoneal melanoma BMJ Case Reports 2016 2016 216450 10.1136/bcr-2016-216450 2-s2.0-84988037049\n16 Menzies A. M. Long G. V. Murali R. Dabrafenib and its potential for the treatment of metastatic melanoma Drug Design, Development and Therapy 2012 6 391 405 10.2147/DDDT.S38998 2-s2.0-84872361487\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2021()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "3526071",
"pmc": null,
"pmid": "34527055",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "27746882;19092634;22848275;23291581;22826744;29148538;21285870;21295201;18399807;23251089;18568775;31977477;27624447",
"title": "Primary Retroperitoneal Malignant Melanoma with Involvement of Iliac Artery and Vein.",
"title_normalized": "primary retroperitoneal malignant melanoma with involvement of iliac artery and vein"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-117818",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "Venlafaxine is a widely prescribed antidepressant drug acting as a reuptake inhibitor of serotonin and noradrenaline. An overdose of venlafaxine can cause cardiovascular toxicity and cardiogenic shock can occur. A 32-year-old man ingested 12g of sustained-release venlafaxine in a suicidal attempt and developed within 24h acute heart failure with refractory cardiogenic shock requiring support by ECMO. The blood toxicology showed persistence of high levels of venlafaxine at day 10. The patient fully recovered and showed normal cardiac function at 3-months follow-up.",
"affiliations": ") Service de Cardiologie, CHU Liège, Belgique.;Service de Cardiologie, CHR Citadelle, Liège, Belgique.;Service des Soins intensifs, CHR Citadelle, Liège, Belgique.;Service des Soins intensifs, CHR Citadelle, Liège, Belgique.;Service de Biologie Clinique, CHR Citadelle, Liège, Belgique.;Service de Biologie Clinique, CHR Citadelle, Liège, Belgique.",
"authors": "Born|B|B|;Hoffer|E|E|;Fraipont|V|V|;Joachim|S|S|;Gougnard|T|T|;Minon|J M|JM|",
"chemical_list": "D000069470:Venlafaxine Hydrochloride",
"country": "Belgium",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0370-629X",
"issue": "75(11)",
"journal": "Revue medicale de Liege",
"keywords": " Extracorporeal membrane oxygenation ; Intoxication ; Pharmacokinetics ; Venlafaxine ; Cardiogenic shock ",
"medline_ta": "Rev Med Liege",
"mesh_terms": "D000328:Adult; D062787:Drug Overdose; D015199:Extracorporeal Membrane Oxygenation; D006333:Heart Failure; D006801:Humans; D008297:Male; D012770:Shock, Cardiogenic; D000069470:Venlafaxine Hydrochloride",
"nlm_unique_id": "0404317",
"other_id": null,
"pages": "699-702",
"pmc": null,
"pmid": "33155441",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Case of refractory cardiogenic shock due to venlafaxine overdose : illustration of the support with veno-arterial extracorporeal membrane oxygenation.",
"title_normalized": "case of refractory cardiogenic shock due to venlafaxine overdose illustration of the support with veno arterial extracorporeal membrane oxygenation"
} | [
{
"companynumb": "BE-PFIZER INC-2020449174",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "We report a case of a stress fracture of the ulna secondary to long-term bisphosphonate therapy and walking cane. Physicians need to have a high index of suspicion of stress fractures occurring in patients complaining of chronic upper limb pain if they are on bisphosphonate therapy and are using walking aids. Stress fractures of the upper extremities are rare and are usually associated with athletes; however, a few recent case reports have shown an association between stress fractures of the upper extremities and the use of walking aids. The association between increased incidence of upper extremity stress fractures and the use of both bisphosphonates and walking aids in patients has not been well studied, with only one previously reported case. Here, we report a case of a complete stress fracture of the ulna in a 77-year-old female, premorbidly ambulant with walking cane, on long-term bisphosphonates without any pre-existing medical conditions which could result in secondary causes of bone loss. Investigations did not reveal any causes of pathological fracture. This fracture is attributed to the use of long-term bisphosphonate therapy in conjunction with the use of a walking cane. This case highlights the importance of entertaining the possibility of such fractures occurring in any patient who is on bisphosphonate therapy presenting with stress fractures of the upper extremity.",
"affiliations": "National University Health System, 1E, Kent Ridge Road, Singapore, 119228, Singapore, grace_sh_chiang@nuhs.edu.sg.",
"authors": "Chiang|G S H|GS|;Grace|C S H|CS|;Koh|K W B|KW|;Kelvin|K W B|KW|;Chong|T W|TW|;Wei|C T|CT|;Tan|B Y|BY|;Yeow|T B|TB|",
"chemical_list": "D050071:Bone Density Conservation Agents; D019386:Alendronate",
"country": "England",
"delete": false,
"doi": "10.1007/s00198-014-2739-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-941X",
"issue": "25(8)",
"journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA",
"keywords": null,
"medline_ta": "Osteoporos Int",
"mesh_terms": "D000368:Aged; D019386:Alendronate; D050071:Bone Density Conservation Agents; D005260:Female; D015775:Fractures, Stress; D006801:Humans; D008279:Magnetic Resonance Imaging; D015663:Osteoporosis, Postmenopausal; D011859:Radiography; D012656:Self-Help Devices; D014457:Ulna; D016138:Walking",
"nlm_unique_id": "9100105",
"other_id": null,
"pages": "2151-4",
"pmc": null,
"pmid": "24833031",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16983459;9885097;12768465;1509542;12202465;20335574;23712442;20493982;19707843;18522980;17190893;21195812;22407939;20463351;9875874",
"title": "Stress fracture of the ulna associated with bisphosphonate therapy and use of walking aid.",
"title_normalized": "stress fracture of the ulna associated with bisphosphonate therapy and use of walking aid"
} | [
{
"companynumb": "SG-WATSON-2015-10525",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALENDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "The TNF-α antagonist golimumab is approved for the treatment of ulcerative colitis but not for Crohn's disease (CD). We herein report a case series of 8 difficult-to-treat patients with severe and refractory CD receiving golimumab as an off-label rescue medication and fourth-line anti-TNF agent in our tertiary referral inflammatory bowel disease center.\nWe performed a retrospective analysis of clinical, biochemical, and radiological as well as endoscopic parameters. The patients all suffered from severe refractory CD with ongoing symptoms. Moreover, all 8 patients had previously been treated with all 3 other TNF-α antagonists approved for CD in Switzerland (infliximab, adalimumab, and certolizumab pegol) without durable clinical response.\nThree out of 8 patients showed a primary nonresponse. Among the 5 patients responding after induction, 1 patient showed a loss of response, and in 1 patient, treatment was terminated due to side effects. Three patients have a continuous clinical response under golimumab. We did not observe any severe adverse events during golimumab administration.\nA considerable fraction of this highly selected subgroup of difficult-to-treat CD patients responded to golimumab, indicating a promising potential for refractory CD patients, including those with multiple previous anti-TNF exposures.",
"affiliations": "Department of Gastroenterology and Hepatology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.;Department of Gastroenterology and Hepatology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.;Department of Gastroenterology and Hepatology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.;Department of Gastroenterology and Hepatology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.",
"authors": "Russi|Linda|L|;Scharl|Michael|M|;Rogler|Gerhard|G|;Biedermann|Luc|L|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000481400",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2296-9365",
"issue": "2(2)",
"journal": "Inflammatory intestinal diseases",
"keywords": "Anti-TNF agent-exposed patients; Crohn's disease; Difficult-to-treat Crohn's disease; Golimumab; TNF-α antagonist",
"medline_ta": "Inflamm Intest Dis",
"mesh_terms": null,
"nlm_unique_id": "101677990",
"other_id": null,
"pages": "131-138",
"pmc": null,
"pmid": "30018964",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article",
"references": "19709098;21272808;20131276;19644849;26963940;23735746;24084775;20519961;22378566;23678153;26188351;26284562;18383539;27489526;19560810;22128083;23770005",
"title": "The Efficacy and Safety of Golimumab as Third- or Fourth-Line Anti-TNF Therapy in Patients with Refractory Crohn's Disease: A Case Series.",
"title_normalized": "the efficacy and safety of golimumab as third or fourth line anti tnf therapy in patients with refractory crohn s disease a case series"
} | [
{
"companynumb": "CH-JNJFOC-20171212558",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Rat bite fever is rare in Western countries. It can be very difficult to diagnose as blood cultures are typically negative and a history of rodent exposure is often missed. Unless a high index of suspicion is maintained, the associated polyarthritis can be mistaken for rheumatoid arthritis. We report a case of culture-positive rat bite fever in a 46-year-old female presenting with fever and polyarthritis. The clinical presentation mimicked rheumatoid arthritis. Infection was complicated by discitis, a rare manifestation. We discuss the diagnosis and management of this rare zoonotic infection. We also review nine reported cases of rat bite fever, all of which had an initial presumptive diagnosis of a rheumatological disorder. Rat bite fever is a potentially curable infection but can have a lethal course if left untreated.",
"affiliations": "Department of Internal Medicine, Memorial University, St. John's, NL, Canada A1B 3V6.;Department of Internal Medicine, Memorial University, St. John's, NL, Canada A1B 3V6.;Disciplines of Medicine and Laboratory Medicine, Memorial University, St. John's, NL, Canada A1B 3V6.;Department of Medicine, Memorial University, St. John's, NL, Canada A1B 3V6.;Eastern Health, St. John's, NL, Canada A1C 5B8.",
"authors": "Akter|Ripa|R|;Boland|Paul|P|;Daley|Peter|P|;Rahman|Proton|P|;Al Ghanim|Nayef|N|",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2016/7270413",
"fulltext": "\n==== Front\nCan J Infect Dis Med MicrobiolCan J Infect Dis Med MicrobiolCJIDMMThe Canadian Journal of Infectious Diseases & Medical Microbiology = Journal Canadien des Maladies Infectieuses et de la Microbiologie Médicale1712-95321918-1493Hindawi Publishing Corporation 10.1155/2016/7270413Case ReportRat Bite Fever Resembling Rheumatoid Arthritis Akter Ripa \n1\nBoland Paul \n1\nDaley Peter \n2\nRahman Proton \n3\n\n*\nAl Ghanim Nayef \n4\n1Department of Internal Medicine, Memorial University, St. John's, NL, Canada A1B 3V62Disciplines of Medicine and Laboratory Medicine, Memorial University, St. John's, NL, Canada A1B 3V63Department of Medicine, Memorial University, St. John's, NL, Canada A1B 3V64Eastern Health, St. John's, NL, Canada A1C 5B8*Proton Rahman: prahman@mun.caAcademic Editor: Alice Tseng\n\n2016 12 4 2016 2016 727041312 9 2015 30 3 2016 Copyright © 2016 Ripa Akter et al.2016This 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.Rat bite fever is rare in Western countries. It can be very difficult to diagnose as blood cultures are typically negative and a history of rodent exposure is often missed. Unless a high index of suspicion is maintained, the associated polyarthritis can be mistaken for rheumatoid arthritis. We report a case of culture-positive rat bite fever in a 46-year-old female presenting with fever and polyarthritis. The clinical presentation mimicked rheumatoid arthritis. Infection was complicated by discitis, a rare manifestation. We discuss the diagnosis and management of this rare zoonotic infection. We also review nine reported cases of rat bite fever, all of which had an initial presumptive diagnosis of a rheumatological disorder. Rat bite fever is a potentially curable infection but can have a lethal course if left untreated.\n==== Body\n1. Introduction\nRat bite fever (RBF) is a systemic febrile illness caused by either Streptobacillus moniliformis, common in Western countries, or Spirillum minus, which is the most prevalent pathogen in Asia [1, 2]. It is transmitted to humans by bites or scratches from infected rats. Classic clinical features include fever, rash, and polyarthritis [1]. When RBF presents with symmetrical polyarticular synovitis, rheumatoid arthritis may initially be diagnosed incorrectly, leading to delay in appropriate therapy [3–7]. Complications of RBF include septic arthritis, endocarditis, and rarely discitis, as in our patient. The mortality rate of untreated cases ranges from 7% to 13% and for cases complicated by endocarditis it can be up to 53% [1, 2].\n\n2. Case Report\nA 46-year-old female was admitted with a one-week history of fever and symmetric polyarthritis of the distal upper and lower extremities, with thirty minutes of morning stiffness. A few days prior to her admission, she had a one-day history of nausea, vomiting, and diarrhea. She denied recent travel or illicit drug use. Her previous medical history was significant for a seizure disorder, irritable bowel syndrome, chronic mechanical back pain, and iron deficiency anemia. Her family history was unremarkable for any rheumatological illness.\n\nOn examination, she was febrile (38°C), tachycardic (130 beats per minute), and hypotensive (96/64 mmHg). The most prominent physical finding was effusions in her wrists, ankles, and selected metatarsophalangeal joints. Her cardiopulmonary, abdominal, and dermatological examinations were otherwise unremarkable. Erythrocyte sedimentation rate was 76 mm/hr (normal: 0–12 mm/hr) and C-reactive protein was 149 mg/L (normal: 0–8 mg/L). There was a mild leukocytosis of 11.1 × 109/L (normal: 4.8–10.8 × 109/L). Initial blood culture and serological tests including hepatitis B and hepatitis C, parvovirus B19, HIV, Lyme disease, Chlamydia trachomatis, and Neisseria gonorrhea were negative. Rheumatological workup including rheumatoid factor, anti-nuclear antibody, anti-cyclic citrullinated peptide antibody, anti-neutrophil cytoplasmic antibodies, anti-dsDNA antibody, and complement levels was all within normal limits. Chikungunya virus serology was not ordered as this diagnosis was unlikely given she had not travelled. A presumptive diagnosis of seronegative rheumatoid arthritis was made, based on the clinical presentation of symmetrical inflammatory polyarthritis and negative infectious workup. She was started on a trial of oral prednisone. She experienced mild improvement in her synovitis. She was discharged home on triple therapy for rheumatoid arthritis which included methotrexate, sulfasalazine, and hydroxychloroquine.\n\nThe patient returned to the hospital next day with worsening synovitis, fever (39°C), and new onset of back pain localized to the lumbar spine. Sulfasalazine and methotrexate were discontinued because of a new transaminitis (aspartate aminotransferase 105 U/L (normal: 0–37 U/L); alanine aminotransferase 114 U/L (normal: 0–55 U/L)). The ESR was elevated at 124 MM/HR and C-reactive protein at 170 mg/L. Right ankle aspiration was performed followed by methylprednisolone injection due to ongoing severe pain. The synovial fluid sample was inadequate for gram stain; however, the culture was negative. She then received intravenous methylprednisolone, 250 mg every 24 hours for 2 days without improvement. Repeated blood culture grew Streptobacillus moniliformis in the anaerobic flask. MRI revealed L5-S1 discitis (Figure 1) and transthoracic echocardiogram showed no evidence of endocarditis. On further questioning, the patient admitted to having a pet rat and a pet cat, both of which had died of an unknown illness in the week prior to the initial presentation to hospital. The patient was told by a local veterinarian that the rat was “in kidney failure” though further details are unavailable. The patient spent the night prior to the death of the rat comforting the ailing animal in her arms. During this time, she received a scratch to her chest.\n\nA diagnosis of RBF was made. The patient then was treated with intravenous ceftriaxone with discontinuation of steroids and hydroxychloroquine with symptomatic improvement. She was discharged home with a 3-month course of intravenous ceftriaxone on the advice of infectious disease and neurosurgery specialists to ensure resolution of her discitis. Three months after discharge, the patient was well with complete resolution of her arthritis, marked improvement in the lower back pain, and normal inflammatory markers. A repeat MRI showed resolution of the discitis.\n\n3. Discussion\n\nStreptobacillus moniliformis is not routinely reported to public health authorities in most jurisdictions, and hence the true incidence rate is unknown. We report a challenging case of RBF with discitis involving L5-S1, which was initially presumed to be rheumatoid arthritis. RBF with discitis is extremely rare. To our knowledge, this is the third reported case of discitis associated with rat bite fever. Dubois et al. reported a case of RBF with spondylodiscitis involving T5-T6 and L2-L3 [12]. Nei et al. described another case of discitis involving L3-L4 [13].\n\nApart from direct rat bite or scratch, infection can also spread to humans by bites or scratches from animals that prey on rodents, such as cats, dogs, and pigs [8]. Streptobacillus moniliformis is part of the normal nasopharyngeal flora of rats. Other rodents such as mice, guinea pigs, ferrets, squirrels, and gerbils also colonize this bacteria [7]. Ingesting contaminated food products can also cause RBF, as described in Haverhill, Massachusetts, in 1926 [8]. RBF in farmers due to ingestion of unpasteurized milk has been reported [8]. Pet owners, children, and those working in pet shops and animal research laboratories are at an elevated risk of contracting this infection [14]. Ninety percent of patients develop fever within 3–10 days of exposure, which can follow a relapsing pattern [2]. Typically a maculopapular, petechial, or purpuric rash is seen in the extremities and biopsy is consistent with a leukocytoclastic vasculitis [2, 15, 16]. Other symptoms include vomiting and headache [14]. A migratory polyarthritis is seen commonly affecting the hands, wrists, elbows, knees, and, rarely, the sternoclavicular and sacroiliac joints [2, 3, 17, 18]. Streptobacillus moniliformis septic monoarthritis is described, in some cases requiring surgical debridement [19, 20]. Additional complications include osteomyelitis, pericardial effusion, endocarditis, pneumonia, meningitis, and multiorgan failure [1, 2, 14, 20].\n\nThe pathogenesis of arthritis in RBF is multifactorial. Systemic symptoms, such as fever and rash, may occur with a sterile synovial fluid culture, suggesting a reactive phenomenon due to an immune mediated process. In other cases, synovial fluid cultures are positive with or without bacteremia suggesting a direct infectious process [4, 21, 22]. Features that suggest an immune mediated phenomenon may include vasculitic rash, hypocomplementemia, and cryoglobulinemia [23]. Wang and Wong suggest that septic arthritis caused by Streptobacillus moniliformis detected in synovial fluid without bacteremia is a separate entity with distinct clinical features in which fever and rash are uncommon [21].\n\nThe diagnosis of RBF can be challenging as blood cultures are usually negative [14]. Streptobacillus moniliformis is a facultatively anaerobic, highly pleomorphic gram negative bacillus [21]. Bacteria can vary in length from two to fifteen μm. Its growth can be inhibited by sodium polyanethol sulfonate, an anticoagulant found on most aerobic culture bottles [21]. Therefore, this organism is more likely to grow in anaerobic cultures [3]. Positive blood, synovial fluid, or rarely skin lesion culture followed by identification using gas chromatography or sequencing of 16 s rRNA genes can confirm the diagnosis [3–6, 16]. Up to 25% of affected patients may have a false positive serology test for syphilis [23].\n\nAlthough this infection is difficult to diagnose, its prognosis is favorable. The standard treatment of RBF is penicillin or, in the case of penicillin allergy, tetracycline [21]. Streptobacillus moniliformis is also susceptible to cephalosporins, carbapenems, erythromycin, and clindamycin [21].\n\n\nTable 1 summarizes nine cases of RBF mimicking a rheumatological disorder. Six out of the nine cases received steroid therapy (Table 1). In a case described by Tattersall and Bourne, a patient received cyclophosphamide when inflammatory vasculitis was suspected (Table 1). These cases highlight the importance of maintaining a broad differential that includes RBF when assessing potential cases of rheumatoid arthritis. The positive blood culture was the main clue to the diagnosis in our case. This case report also highlights the potential hazard of misdiagnosis and treatment with immunosuppressive agents. Infectious etiology is always on the differential, such that a zoonotic exposure history and blood cultures should be obtained when assessing a patient with fever and arthritis. Also occupational, travel, and recreational history should be sought for potential rodent exposure in suspected cases.\n\nAcknowledgments\nThe authors would like to thank the Department of Radiology for providing MRI images.\n\nAdditional Points\n\nRat bite fever is uncommon and very difficult to diagnose.\n\nA history of zoonotic exposure is key to diagnosis.\n\nClinicians should include rat bite fever in the differential diagnosis of symmetrical inflammatory polyarthritis.\n\nPrognosis is good when treated appropriately but potentially lethal if left untreated.\n\nRepeating joint aspiration and blood cultures could increase the likelihood of a positive identification of pathogens associated with RBF.\n\n\n\n\nEthical Approval\nNo ethical approval was required for this case report.\n\nConsent\nPatient consent was obtained.\n\nCompeting Interests\nAll authors have no competing interests to declare.\n\nFigure 1 Sagittal MRI pulse sequences of lumbosacral spine at presentation. (a) (T1-weighted) shows markedly reduced signal at the L5-S1 level while (b) (T2-weighted) shows increased T2 signal both in keeping with edema. (c) shows enhancement of the vertebral end plates. All findings are in keeping with discitis.\n\nTable 1 Reported Cases of Rat bite fever with initial presumed diagnosis of rheumatological disorders. \n\nStudy/year/ \n[reference]\tAge/sex\tRat bite/scratch\tOccupation\tFamily history of rheumatological disorders\tClinical features\tAffected joints\tJoint aspirate analysis\tJoint aspirate culture\tIdentification method of Streptobacillus moniliformis\n\tBlood culture\tRheumatological workup\tJoint erosion\tInitial presumed diagnosis\tTreatment\tOutcome\t\nLegout et al./2005 \n[3]\t60/female\tRat bite\tPet shop employee\tFather- seropositive rheumatoid arthritis\tFever and polyarthritis\tSymmetrical affecting small joints of both hands and ankles and right knee\tRight knee synovial fluid: leukocytosis (40 × 109/L) with 90% neutrophils\tGNB\tPCR amplification of part of 16S RNA gene \tNegative\tRF, ANA, ANCAs, specific anti-filaggrin antibody, and cryoglobulin were negative\tNo erosion\tRheumatoid arthritis\t\nInitial: NSAIDs and IV methylprednisolone 500 mg/day for 3 days, no improvement \n\nPostculture: arthrotomy of right knee and 4 weeks of antibiotics which included IV penicillin followed by oral rifampin and clindamycin\tSuccessfully treated \t\n\n\n\t\nDendle et al./2006 \n[4]\t49/female\tRat bite\tNot reported\tNot reported \tPolyarthritis, fever, rash, pneumonia, and hepatitis\tMCP, wrists, knees, right elbow, and right ankle\tRight elbow: numerous PMN \nNo formal analysis-sample clotted\tPleomorphic GNB\t16S rRNA gene sequencing\tNegative\tANA and RF compliment levels were normal\tNo erosion\tRheumatoid arthritis or Still's disease\t\nInitial: oral prednisone 25 mg daily with worsening synovitis \n\nPostculture: doxycycline 100 mg twice daily for 6 weeks\tSuccessfully treated\t\n\n\n\t\nStehle et al./2003 \n[5]\t72/male\tRat bite\tNot reported\tNot reported\tPolyarthritis\tBoth knees, elbows, and left 3rd MCP\tRight Knee: leukocytosis \n(around 50 × 109/L) with 83% neutrophils \nRearthrocentesis of both knees, right elbow, and left 3rd MCP: analysis not reported\t\nStreptobacillus moniliformis grew on repeat synovial fluid culture\t16S rRNA gene sequencing\tNegative\tNot reported\tNo erosion\tAtypical rheumatoid arthritis\t\nOutpatient: NSAID and deflazacort for almost 1 month, no improvement \n\nPostadmission: bolus of IV steroids, minimal improvement \n\nPostculture: broad spectrum antibiotics\tSuccessfully treated\t\n\n\n\t\nHolroyd et al./1988 \n[6]\t59/male\tNo\tNot reported\tNot reported\tFever and polyarthritis\tPIP, MCP, wrist and knees, ankles, elbows, and shoulders bilaterally\tLeft knee: leukocyte 3,700/mm3 with 80% PMN \nLeft wrist: 57,000/mm3 and 90% PMN\tLeft wrist: \npleomorphic GNB with bullous swelling\tGas chromatography of the cellular fatty acid of organism\t\nStreptobacillus moniliformis\n\tNegative RF and weakly positive ANA 1 : 40\tNot reported\tRheumatoid arthritis \t\nOutpatient: patient took NSAIDs for 1 day prior to admission \n\nPostculture: ticarcillin and gentamicin; penicillin G for total 10 days\tSuccessfully treated\t\n\n\n\t\n\nKanechorn and Niumpradit/\n2005 [7]\t61/female\tRodent bite\tRetired nurse\tNot reported\tFever, petechial rash, myalgia, and symmetrical polyarthritis\tFingers, wrists, knees, and ankles\tSite of joint aspiration not reported. \nAnalysis: leukocyte counts of over 64,000 cells/mm3 and all neutrophils\tNegative \tNot reported \tNegative\tANA and RF negative\tNot reported \tSeptic arthritis and rheumatoid arthritis\t\nInitial: erythromycin, Ibuprofen as well as rabies vaccination and tetanus toxoid prior to admission \n\nPostadmission: dexamethasone 4 mg every 6 hours, amoxicillin/clavulanic acid plus doxycycline, no improvement \n\nAfter joint analysis: ceftriaxone and penicillin G for 4 weeks, arthrotomy and debridement of joints, unreported sites of joints\tSuccessfully treated\t\n\n\n\t\nAbdulaziz et al./2006 \n[8]\t68/male\tRat exposure, no bite\tDairy farmer\tNot reported\tSymmetrical polyarthritis, rash, fever, myalgias, and headache\tPIP's, MCP's, wrists, ankles, and knees\tLeft knee: white blood cell count of 19,250/mm3, 84% PMN leukocytes, and CPPD crystals\tNegative\tNot reported\tPleomorphic gram negative bacilli\tNot reported\tNo erosion\tAcute polyarticular pseudo gout\t\nInitial: ibuprofen and NSAIDs \n\nPostculture: penicillin G for 14 days successfully treated\tSuccessfully treated\t\n\n\n\t\n\nTattersall and Bourne/2003 \n[9]\t56/male\tRat bite\tNot reported\tNot reported\tFever, rash, asymmetric polyarthritis, hand ischemia, sore throat, and loose stools\tRight elbow, wrist, shoulder, left thumb MCP joint, both midtarsal joints, and right ankle\tLeft thumb MCP: analysis not reported \nLeft ankle: urate crystals\tGram negative pleomorphic coccobacillus Streptobacillus moniliformis\n\tDNA sequencing\tNegative\tAutoantibodies and ANCAs were negative\tNot reported\tVasculitis \n or reactive arthritis\t\nInitial: IV methylprednisolone and cyclophosphamide for few days with minimal improvement \n\nPostculture: oral doxycycline for 6 weeks\tSuccessfully treated\t\n\n\n\t\nDworkin et al./2010 \n[10]\t59/male\tRat exposure, no bite\tNot reported\tNot reported\tPolyarthritis, diarrhea, malaise, and presumed endocarditis\tknees, ankles, wrists, right elbow\tLeft knee: analysis not reported\tPleomorphic GNB\t16S rRNA gene sequencing\tNegative\tANA elevated 1 : 160 and normal compliment, RF and, ANCA levels\tNot reported\tPolyarthritis of infectious or collagen vascular disease etiology\t\nInitial: NSAIDs and steroids \n\nPostculture: penicillin, doxycycline, and gentamycin for 6 weeks\tSuccessfully treated\t\n\n\n\t\nBudair et al./2014 \n[11]\t29/male\tRat exposure\tManual laborer in a warehouse\tNot reported\tMalaise, fever, sore throat, rash, and polyarthralgia \tRight second MCP, right elbow, right knee and both ankles\tRight ankle aspiration: yellow cloudy fluid \nAnalysis not reported\tCulture negative\t16S rRNA PCR identified organism\tNegative\tANA, double stranded DNA antibody, glomerular basement membrane antibody, myeloperoxidase antibody and proteinase-3 antibodies, RF, and immunoglobulins were all normal\tNot reported \tVasculitis\t\nPostorganism identification: intravenous benzylpenicillin and 3 weeks of oral amoxicillin\tSuccessfully treated\t\nGNB: gram negative bacilli; PIP: Proximal Interphalangeal; MCP: metacarpophalangeal; RF: rheumatoid factor, ANA: anti-nuclear antibody, ANCA: anti-neutrophil cytoplasmic antibody; NSAID: nonsteroidal anti-inflammatory drug; IV: Intravenous; PCR: polymerase chain reaction; PMN: Polymorphonuclear; CPPD: calcium pyrophosphate dihydrate. \n==== Refs\n1 McKee G. Pewarchuk J. Rat-bite fever Canadian Medical Association Journal 2013 185 15, article 1346 10.1503/cmaj.121704 2-s2.0-84886429672 \n2 Crews J. D. Palazzi D. L. Starke J. R. A teenager with fever, rash, and arthralgia JAMA Pediatrics 2014 168 12 1165 1166 10.1001/jamapediatrics.2014.1604 2-s2.0-84925226188 25436846 \n3 Legout L. Senneville E. Mulleman D. Solau-Gervais E. Flipo R. M. Mouton Y. Rat bite fever mimicking rheumatoid arthritis Scandinavian Journal of Infectious Diseases 2005 37 6-7 532 533 10.1080/00365540510032114 2-s2.0-22844452181 16012023 \n4 Dendle C. Woolley I. J. Korman T. M. Rat-bite fever septic arthritis: illustrative case and literature review European Journal of Clinical Microbiology and Infectious Diseases 2006 25 12 791 797 10.1007/s10096-006-0224-x 2-s2.0-33751249359 17096137 \n5 Stehle P. Dubuis O. So A. Dudler J. Rat bite fever without fever Annals of the Rheumatic Diseases 2003 62 9 894 896 10.1136/ard.62.9.894 2-s2.0-0041885048 12922966 \n6 Holroyd K. J. Reiner A. P. Dick J. D. \nStreptobacillus moniliformis polyarthritis mimicking rheumatoid arthritis: an urban cae of rat bite fever The American Journal of Medicine 1988 85 5 711 714 10.1016/s0002-9343(88)80247-x 2-s2.0-0024226723 3189374 \n7 Kanechorn N. A. Niumpradit N. Rat-bite fever presenting with rash and septic arthritis Journal of the Medical Association of Thailand 2005 88 supplement 3 S247 S251 16858964 \n8 Abdulaziz H. Touchie C. Toye B. Karsh J. Haverhill fever with spine involvement The Journal of Rheumatology 2006 33 7 1409 1410 2-s2.0-33745785633 16821275 \n9 Tattersall R. S. Bourne J. T. Systemic vasculitis following an unreported rat bite Annals of the Rheumatic Diseases 2003 62 7 605 606 10.1136/ard.62.7.605 2-s2.0-0037532940 12810419 \n10 Dworkin J. Bankowski M. J. Wenceslao S. M. Young R. A case of septic arthritis from rat-bite fever in Hawai'i Hawaii Medical Journal 2010 69 3 65 67 2-s2.0-77952475713 20397505 \n11 Budair B. Goswami K. Dhukaram V. Septic arthritis secondary to rat bite fever: a challenging diagnostic course BMJ Case Reports 2014 10.1136/bcr-2014-204086 \n12 Dubois D. Robin F. Bouvier D. \nStreptobacillus moniliformis as the causative agent in spondylodiscitis and psoas abscess after rooster scratches Journal of Clinical Microbiology 2008 46 8 2820 2821 10.1128/jcm.00744-08 2-s2.0-53149125369 18562588 \n13 Nei T. Sato A. Sonobe K. Miura Y. Takahashi K. Saito R. \nStreptobacillus moniliformis bacteremia in a rheumatoid arthritis patient without a rat bite: a case report BMC Research Notes 2015 8 1, article 694 10.1186/s13104-015-1642-6 \n14 Madhubashini M. George S. Chandrasekaran S. Streptobacillus moniliformis endocarditis: case report and review of literature Indian Heart Journal 2013 65 4 442 446 10.1016/j.ihj.2013.06.019 2-s2.0-84888641111 23993005 \n15 Rosser A. Wiselka M. Pareek M. Rat bite fever: an unusual cause of a maculopapular rash Postgraduate Medical Journal 2014 90 1062 236 237 10.1136/postgradmedj-2013-132420 2-s2.0-84896491593 24453224 \n16 Albedwawi S. LeBlanc C. Show A. Slinger R. W. A teenager with fever, rash and arthritis Canadian Medical Association Journal 2006 175 4 p. 354 10.1503/cmaj.060309 2-s2.0-33747502508 \n17 Rupp M. E. \nStreptobacillus moniliformis endocarditis: case report and review Clinical Infectious Diseases 1992 14 3 769 772 10.1093/clinids/14.3.769 2-s2.0-0026599629 1562665 \n18 Brown C. Tsai G. Sanchez-Flores X. Oh rats! Fever, rash and arthritis in a young woman BMJ Case Reports 2015 10.1136/bcr-2015-212240 \n19 Hockman D. E. Pence C. D. Whittler R. R. Smith L. E. Septic arthritis of the hip secondary to rat bite fever Clinical Orthopaedics and Related Research 2000 380 173 176 2-s2.0-0033744006 11064988 \n20 Flannery D. D. Akinboyo I. Ty J. M. Averill L. W. Freedman A. Septic arthritis and concern for osteomyelitis in a child with rat bite fever Journal of Clinical Microbiology 2013 51 6 1987 1989 10.1128/JCM.03139-12 2-s2.0-84878478982 23554193 \n21 Wang T. K. F. Wong S. S. Y. Streptobacillus moniliformis septic arthritis: a clinical entity distinct from rat-bite fever? BMC Infectious Diseases 2007 7, article 56 10.1186/1471-2334-7-56 2-s2.0-34447129409 \n22 Rumley R. L. Patrone N. A. White L. Rat-bite fever as a cause of septic arthritis: a diagnostic dilemma Annals of the Rheumatic Diseases 1987 46 10 793 795 10.1136/ard.46.10.793 2-s2.0-0023226556 3689005 \n23 Mandel D. R. Streptobacillary fever. An unusual cause of infectious arthritis Cleveland Clinic Journal of Medicine 1985 52 2 203 205 10.3949/ccjm.52.2.203 2-s2.0-0022263462\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1712-9532",
"issue": "2016()",
"journal": "The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale",
"keywords": null,
"medline_ta": "Can J Infect Dis Med Microbiol",
"mesh_terms": null,
"nlm_unique_id": "101226876",
"other_id": null,
"pages": "7270413",
"pmc": null,
"pmid": "27366177",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "16908894;26584844;16821275;3189374;18562588;23529964;16858964;11064988;20397505;23993005;16012023;12810419;1562665;17096137;23554193;17561996;4028420;25436846;24695665;24453224;26701936;12922966;3689005",
"title": "Rat Bite Fever Resembling Rheumatoid Arthritis.",
"title_normalized": "rat bite fever resembling rheumatoid arthritis"
} | [
{
"companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-130639",
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"drug": [
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"activesubstance": {
"activesubstancename": "METHOTREXATE"
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"abstract": "A 78-year-old woman had a semicircular ulcerative lesion of AV 7 cm, as detected using colonoscopy, and pathologic examination based on a biopsy showed well-differentiated adenocarcinoma. On contrast-enhanced CT of the liver, a number of nodular lesions that seemed to be liver metastases were observed. It was decided to administer chemotherapy containing mFOLFOX6 plus panitumumab. Bilateral hemorrhage of the ocular conjunctiva and eyelid edema were observed from the 4th day of chemotherapy. Edema of the lips, epidermolysis, and erythema appeared in addition to vision impairment. We diagnosed her with SJS based on these symptoms. We also administered steroid pulse therapy. Eyelid edema improved, and vision impairment improved 24 hours after the initiation of treatment. For severe cases with visual impairment, systemic administration of corticosteroids is recommended. In this case, administering steroid pulse therapy from an early stage resulted in improvement without sequelae.",
"affiliations": "Dept. of Surgery, Saiseikai Senri Hospital.",
"authors": "Fukata|Tadafumi|T|;Ito|Yoshiro|Y|;Miyagaki|Hiromichi|H|;Nishida|Hisashi|H|;Toyoda|Yasuhiro|Y|;Shingai|Tatsushi|T|;Takayama|Osamu|O|;Yoshioka|Setsuko|S|;Hojo|Shigeyuki|S|;Fukuzaki|Takayuki|T|;Ohigashi|Hiroaki|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0385-0684",
"issue": "46(4)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003110:Colonic Neoplasms; D005260:Female; D006801:Humans; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "748-750",
"pmc": null,
"pmid": "31164523",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Stevens-Johnson Syndrome Induced by Chemotherapy for Metastatic Colon Cancer.",
"title_normalized": "a case of stevens johnson syndrome induced by chemotherapy for metastatic colon cancer"
} | [
{
"companynumb": "JP-TEVA-2019-JP-1093569",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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"activesubstancename": "LEUCOVORIN"
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"abstract": "BACKGROUND\nThe formation of neutralizing antifactor VIII (fVIII) antibodies, called inhibitors, is the most common complication in modern haemophilia A care. Novel non-factor replacement therapies, such as emicizumab, have sought to address the limitations of bypassing agents for bleeding management in patients with inhibitors. However, immune tolerance induction (ITI) remains the primary method for eradicating inhibitors and restoring the hemostatic response to fVIII.\n\n\nOBJECTIVE\nThe aim of this study was to review a case series of paediatric patients with haemophilia A and inhibitors who have received ITI for inhibitor eradication concomitantly with emicizumab prophylaxis for bleeding prevention.\n\n\nMETHODS\nSingle institution retrospective chart review of paediatric patients with severe haemophilia A receiving ITI and emicizumab.\n\n\nRESULTS\nSeven patients were included in this cohort. Six patients used three different recombinant fVIII products at 100 IU/kg three times per week, and one patient used a plasma-derived fVIII product at an initial dose of 50 IU/kg three times per week. Three patients achieved a negative inhibitor titre <0.6 Chromogenic Bethesda Units per mL (CBU/mL), and two patients achieved a normal fVIII recovery ≥66%. There were nine bleeding events in four patients, but no thrombotic events. All patients remained on ITI and emicizumab.\n\n\nCONCLUSIONS\nImmune tolerance induction while on emicizumab prophylaxis is a feasible approach in paediatric haemophilia A patients with inhibitors. This is the first report of the concomitant use of ITI in patients receiving emicizumab prophylaxis described as the 'Atlanta Protocol'.",
"affiliations": "Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, Georgia.;Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, Georgia.;Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Atlanta, Georgia.;Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, Georgia.;Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, Georgia.",
"authors": "Batsuli|Glaivy|G|https://orcid.org/0000-0002-0122-9320;Zimowski|Karen L|KL|;Tickle|Kelly|K|;Meeks|Shannon L|SL|;Sidonio|Robert F|RF|",
"chemical_list": "D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; C000608208:emicizumab",
"country": "England",
"delete": false,
"doi": "10.1111/hae.13819",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1351-8216",
"issue": "25(5)",
"journal": "Haemophilia : the official journal of the World Federation of Hemophilia",
"keywords": "bypassing agents; emicizumab; haemophilia A; immune tolerance; inhibitors; paediatrics",
"medline_ta": "Haemophilia",
"mesh_terms": "D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D002675:Child, Preschool; D005260:Female; D006467:Hemophilia A; D006801:Humans; D007108:Immune Tolerance; D008297:Male; D012189:Retrospective Studies",
"nlm_unique_id": "9442916",
"other_id": null,
"pages": "789-796",
"pmc": null,
"pmid": "31373431",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Immune tolerance induction in paediatric patients with haemophilia A and inhibitors receiving emicizumab prophylaxis.",
"title_normalized": "immune tolerance induction in paediatric patients with haemophilia a and inhibitors receiving emicizumab prophylaxis"
} | [
{
"companynumb": "US-SHIRE-US201926501",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT"
},
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{
"abstract": "We present a 20-year-old man who suffered anaphylactic shock during posterior spinal fusion for neuromuscular scoliosis with the offending agent later identified via intradermal testing to be tranexamic acid (TXA).\n\n\n\nTXA, although an increasingly common drug, can be the cause of sudden anaphylactic shock intraoperatively. This now represents the fifth reported case in the literature of patients ranging from 15 years to 80 years old with no previous exposure to the drug.",
"affiliations": "1Department of Orthopaedics and Rehabilitation, The University of New Mexico Health Sciences Center, Albuquerque, New Mexico.",
"authors": "Plaster|Scott|S|;Holy|Filip|F|;Antony|Antony Kallur|AK|",
"chemical_list": "D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid",
"country": "United States",
"delete": false,
"doi": "10.2106/JBJS.CC.20.00130",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2160-3251",
"issue": "10(3)",
"journal": "JBJS case connector",
"keywords": null,
"medline_ta": "JBJS Case Connect",
"mesh_terms": "D000328:Adult; D000707:Anaphylaxis; D000933:Antifibrinolytic Agents; D006801:Humans; D007431:Intraoperative Complications; D008297:Male; D020371:Pelizaeus-Merzbacher Disease; D012600:Scoliosis; D013123:Spinal Fusion; D014148:Tranexamic Acid",
"nlm_unique_id": "101596828",
"other_id": null,
"pages": "e2000130",
"pmc": null,
"pmid": "32910610",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anaphylactic Reaction to Tranexamic Acid During Posterior Spinal Fusion: A Case Report.",
"title_normalized": "anaphylactic reaction to tranexamic acid during posterior spinal fusion a case report"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK202103095",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": "1",
... |
{
"abstract": "After 6 weeks of a risperidone rechallenge therapy (2-4 mg/day), no hematological abnormalities were observed in a 26-year-old schizophrenic woman. Two years previously after 9 days of risperidone therapy (2-6 mg/day), the same patient had developed a reversible neutropenia during a cold.",
"affiliations": "Département Universitaire de Psychiatrie Adulte (DUPA), Service Hospitalo-ambulatoire A, Prilly-Lausanne, Switzerland.",
"authors": "Bondolfi|G|G|;Morena|P|P|;Dascal|D R|DR|;Bertschy|G|G|",
"chemical_list": "D018967:Risperidone",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/0924-977x(96)00024-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0924-977X",
"issue": "6(3)",
"journal": "European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology",
"keywords": null,
"medline_ta": "Eur Neuropsychopharmacol",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D009503:Neutropenia; D018967:Risperidone; D012559:Schizophrenia",
"nlm_unique_id": "9111390",
"other_id": null,
"pages": "257",
"pmc": null,
"pmid": "8880087",
"pubdate": "1996-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Risperidone and reversible neutropenia: a negative rechallenge.",
"title_normalized": "risperidone and reversible neutropenia a negative rechallenge"
} | [
{
"companynumb": "CH-RANBAXY-2012R1-55528",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "Non-tuberculous mycobacterial pulmonary disease (NTM-PD) may simulate Pulmonary Tuberculosis (PTB) in its clinical and radiological expression posing a diagnostic dilemma and challenge to the treating physician, especially in high TB prevalent countries. Though recent emerging data indicates inter-human transmission, infection with non-tuberculous mycobacteria (NTM) is commonly acquired from the environmental sources [1]. NTM can produce disease not only in immunocompromised populations but also in healthy individuals leading to significant morbidity and mortality [2]. Unlike PTB, NTM-PD is usually difficult to confirm and speciate in resource limited clinical settings and high TB endemic countries due to non-availability, poor accessibility and affordability to a specific culture facility. Apart from diagnostic challenges, adverse drug effects with treatment leading to non-adherence are another vexing problem. We present here case descriptions of four patients of NTM-PD, confirmed by culture isolates, one was a rapid grower and the other three were slow growers. All four patients were treated with available guideline-based treatment protocols and followed up.",
"affiliations": "Department of Respiratory Medicine, Prathima Institute of Medical Sciences, Karimnagar, Telangana, India.;Department of Respiratory Medicine, Prathima Institute of Medical Sciences, Karimnagar, Telangana, India.;Department of Respiratory Medicine, Prathima Institute of Medical Sciences, Karimnagar, Telangana, India.;Department of Respiratory Medicine, Prathima Institute of Medical Sciences, Karimnagar, Telangana, India.;Department of Respiratory Medicine, Prathima Institute of Medical Sciences, Karimnagar, Telangana, India.;Department of Respiratory Medicine, Prathima Institute of Medical Sciences, Karimnagar, Telangana, India.;Department of Respiratory Medicine, Prathima Institute of Medical Sciences, Karimnagar, Telangana, India.;Department of Microbiology and Serology, SRL Diagnostics, Mumbai, Maharashtra, India.",
"authors": "Chindam|Aditya|A|;Vengaldas|Samanvitha|S|;Srigiri|Vijetha Reddy|VR|;Syed|Umair|U|;Kilaru|Hemanth|H|;Chenimilla|Nagender Prasad|NP|;Kilaru|Satish Chandra|SC|;Patil|Ekta|E|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jctube.2021.100271",
"fulltext": "\n==== Front\nJ Clin Tuberc Other Mycobact Dis\nJ Clin Tuberc Other Mycobact Dis\nJournal of Clinical Tuberculosis and Other Mycobacterial Diseases\n2405-5794\nElsevier\n\nS2405-5794(21)00060-7\n10.1016/j.jctube.2021.100271\n100271\nCase Report\nChallenges of diagnosing and treating non-tuberculous mycobacterial pulmonary disease [NTM-PD]: A case series\nChindam Aditya a\nVengaldas Samanvitha a\nSrigiri Vijetha Reddy a\nSyed Umair a\nKilaru Hemanth a\nChenimilla Nagender Prasad a\nKilaru Satish Chandra drsatish284@hotmail.com\nab⁎\nPatil Ekta c\na Department of Respiratory Medicine, Prathima Institute of Medical Sciences, Karimnagar, Telangana, India\nb JAYA Hospital, Warangal, Telangana, India\nc Department of Microbiology and Serology, SRL Diagnostics, Mumbai, Maharashtra, India\n⁎ Corresponding author at: Department of Respiratory Medicine, Prathima Institute of Medical Sciences, Karimnagar, India; JAYA Hospital, Warangal, Telangana, India. drsatish284@hotmail.com\n30 8 2021\n12 2021\n30 8 2021\n25 100271© 2021 The Authors. Published by Elsevier Ltd.\n2021\n\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/).\nHighlights\n\n• NTM-PD clinico-radiologically may simulate Pulmonary TB posing diagnostic challenges.\n\n• Smear positive AFB with Xpert MTB/RIF assay negativity provides clue for suspecting NTM.\n\n• Provision for Culture and speciation of NTM in National TB Programs recommended.\n\nNon-tuberculous mycobacterial pulmonary disease (NTM-PD) may simulate Pulmonary Tuberculosis (PTB) in its clinical and radiological expression posing a diagnostic dilemma and challenge to the treating physician, especially in high TB prevalent countries. Though recent emerging data indicates inter-human transmission, infection with non-tuberculous mycobacteria (NTM) is commonly acquired from the environmental sources [1]. NTM can produce disease not only in immunocompromised populations but also in healthy individuals leading to significant morbidity and mortality [2]. Unlike PTB, NTM-PD is usually difficult to confirm and speciate in resource limited clinical settings and high TB endemic countries due to non-availability, poor accessibility and affordability to a specific culture facility. Apart from diagnostic challenges, adverse drug effects with treatment leading to non-adherence are another vexing problem. We present here case descriptions of four patients of NTM-PD, confirmed by culture isolates, one was a rapid grower and the other three were slow growers. All four patients were treated with available guideline-based treatment protocols and followed up.\n\nKeywords\n\nNon-tuberculous Mycobacteria\nPulmonary Disease\nDiagnosis\nTreatment\n==== Body\npmc1 Introduction\n\nNTM are environmental opportunistic organisms found in the soil, dust and water including its natural resources. Yet, NTM-PD is caused by relatively few species of NTM [3]. NTM represent about 190 species and subspecies and can produce disease in humans of all ages [4]. Worldwide, various population-based data and studies indicate a high and increasing prevalence of NTM-PD. Improved diagnostics and laboratory methodologies along with increased awareness among physicians might be contributory for the higher prevalence reported. Pulmonary disease (PD) is the most common clinical presentation of NTM infection accounting for 80 to 90% of all NTM-associated diseases [5]. The annual prevalence rate of NTM-PD varies in different regions ranging from 0.2 to 9.8/100,000 population. This may not reflect the true prevalence due to lack of consistent reporting and NTM infection not being notifiable in many countries. Period prevalence in studies including all ages was between 9 and 41/100,000. In all studies, Mycobacterium avium complex (MAC) was the most common (64%–85% of cases) cause of NTM-PD [6], [7].Table 1 Clinical Profile of The Study Subjects.\n\nCase Characteristics\tCASE 1\tCASE 2\tCASE 3\tCASE 4\t\nSex/age in years\tF/70\tF/38\tF/30\tF/68\t\nFever\tPresent\tPresent\tPresent\tPresent\t\nCough\tProductive cough (on and off) since 2 years\tProductive cough with three episodes of minimal hemoptysis for 3 months\tProductive cough with mucoid expectoration since 2 months\tIncreasing cough with purulent expectoration since 5 months\t\nShortness of breath\tmMRC Grade II for 2 years [19].\tEpisodic, seasonal increasing since 3 months\t–\tmMRC Grade II for 5 months [19].\t\nLoss of appetite\tPresent\tPresent\tPresent\tPresent\t\nLoss of weight\tPresent\tPresent\tPresent\tPresent\t\nHistory of TB\tPTB 2 years ago\tPTB 17 years and 4 years ago\tPTB 2 years ago\tPTB 10 years ago\t\nHistory of Anti-tuberculous treatment (ATT) use\tFor 6 months, 2 years ago\tFor 6 months and 9 months, 17 years and 4 years ago respectively\tFor 6 months, 2 years ago\tFor 6 months 10 years ago, ATT use on and off from 2 years (irregularly)\t\nCo-morbidities (if any)\tAsthma\tAllergic Rhinitis, Asthma\tPatient has no co-morbidities\tCOPD\t\nDrugs used for Co-morbidities\tSalmeterol-Fluticasone Inhalation (twice daily)\tFluticasone Nasal spray (once daily); Budesonide-Formoterol inhalation (twice daily)\t–\tFormoterol-Budesonide Inhalation (twice daily) on as needed basis\t\n\nVarious factors including pre-existing lung diseases, immunosuppressive therapies and interaction with environmental conditions may predispose to NTM-PD. Amongst medical host factors, structural lung diseases like COPD, bronchiectasis, prior infections, e.g. PTB and recently identified risk factors including thoracic skeletal abnormalities, viz., scoliosis, kyphosis, and pectus excavatum and low body mass index are some of the predisposing factors associated with NTM-PD. Recent biologics in the treatment of autoimmune disorders like rheumatoid arthritis along with systemic glucocorticoids might also predispose to NTM-PD [8], [9], [10]. Environmental factors like warm, humid climatic conditions (saturated vapor pressure) in various geographical regions may add a four-fold increased risk of infection of any NTM species [11].\n\nThe overall isolation rate of NTM reported in India ranges from 0.5% to 8.6% with a higher prevalence reported from south India [12]. In a single institutional study from Mumbai, India, 67 of 103 (65.0%) patients had pulmonary NTM isolates [13]. NTM isolation rate of 3.5% has been reported among HIV- negative (immunocompetent) patients in India [12].\n\nThus, it is a harbinger that healthcare providers will be encountering NTM-PD more frequently in the coming years, as noted in the recent clinical practice guidelines [4]. In patients with previous history of treatment for PTB, recent persistent symptoms with smear AFB (acid-fast bacilli) positivity may suggest relapse, reactivation or drug resistance to the treating physician, especially in high TB burden countries [14]. Improved awareness regarding NTM and a wider availability of nucleic acid amplification tests (NAAT)/ Xpert MTB/RIF assay (Cepheid GeneXpert System, Sunnyvale, US) resulted in differentiating NTM from MTB infections early on [15]. Mycobacterium avium complex (MAC) among slow growers and Mycobacterium abscessus complex amongst rapid growers are the most frequently encountered pathogens associated with NTM-PD, accounting for up to 95% of total cases reported [16]. Prior to molecular tests, standard way of diagnosing NTM was culture followed by biochemical testing. Newer molecular identification methods, viz., 16sRNA sequencing, line probe assay, and Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) are the preferred methods for speciation now [17], [18]. Molecular testing enabled an early diagnosis of NTM-PD and differentiation from Mycobacterium Tuberculosis Complex (MTBC). Specific treatment for NTM-PD can be instituted after species identification since newer rapid tests can decrease the delay in initiation of treatment thus lessening morbidity and mortality.\n\n2 Design\n\nPresent study consisting of four patients of NTM-PD carried on in our single centre-Prathima Institute of Medical Sciences, Karimnagar, India between February 2017 and March 2021 is being reported. Prior IRB permission to conduct this study was obtained before registering the patients in the present case series [IRB approval Number: IEC/PIMS/2017/004]. A written informed consent was obtained from the patients for publication of this article.\n\n3 Case reports\n\nHerein we present four patients of NTM-PD having respiratory symptoms with constitutional disturbances like loss of appetite and loss of weight and a history of previously treated Pulmonary Tuberculosis (PTB). Demographic, diagnostic and treatment descriptions of these patients are shown in Table 1, Table 2, Table 3 respectively.Table 2 Investigation Profile of Study Subject.\n\nCase Characteristics\tCASE 1\tCASE 2\tCASE 3\tCASE 4\t\nRadiological features\tRight Fibro-cavitary lung disease was evident on Chest X-ray & HRCT-Chest (Fig. 1,Fig. 2.)\tChest-X-ray and HRCT-Chest were suggestive of Left Fibro-cavitary lung disease (Fig. 3,Fig. 4, Fig. 5, Fig. 6)\tChest-X-ray was suggestive of Right Fibro-cavitary lung disease (Fig. 7,Fig. 8)\tRight upper lobe cavitation with bilateral fibrosis was seen on Chest X-ray and HRCT chest (Fig. 9,Fig. 10)\t\nESR (in 1sthr)\t60 mm\t84 mm\t90 mm\t74 mm\t\nMicroscopy on 3 consecutive sputum samples\tTested positive for AFB\tTested positive for AFB\tTested positive for AFB\tTested positive for AFB\t\nSputum sample for XpertMTB/RIF assay\tMycobacterium tuberculosis not detected\tMycobacterium tuberculosis not detected\tMycobacterium tuberculosis not detected\tMycobacterium tuberculosis not detected\t\nSputum sample for Fluorometric BACTEC MGIT liquid culture\tGrowth of Mycobacteria within 7 days\tGrowth of Mycobacteria after 3 weeks\tGrowth of Mycobacteria after 3 weeks\tGrowth of Mycobacteria after 3 weeks\t\nIdentification of Mycobacteria by MPT64 antigen and growth characteristics on solid media.\tRapid grower Mycobacteria (RGM)\tSlow grower Mycobacteria (SGM)\tSlow grower Mycobacteria (SGM)\tSlow grower Mycobacteria (SGM)\t\nNTM Species identification\tNot done\tNot done\tNot done\tNot done\t\nSubsequent AFB culture for NTM confirmation[5]\tRGM confirmed in BAL fluid\tSGM confirmed in two sputum samples\tSGM confirmed in two sputum samples\tSGM confirmed in BAL fluid\t\n\nFig. 1 Case-1: Chest X-ray PA view shows loss of lung volume in right hemi-thorax with elevated right hemi-diaphragm, rib crowding and ipsilateral mediastinal shift. Multiple fibro-cavitary lesions are seen in the entire right lung associated with upper lobe collapse and right basal pleural thickening.\n\nFig. 2 Case-1: Axial HRCT at the level of mid-thorax reveals collapsed upper lobe, cavities and small nodules in the right lower lobe and ipsilateral mediastinal shift.\n\nFig. 3 Case-2: Coronal HRCT of the chest reveal fibro-cavitary lesions in the right upper lobe with partial loss of volume. A large cavity is seen in left upper lobe with severe fibrotic lesions in the left lower lobe associated with loss of volume in left hemithorax.\n\nFig. 4 Case-2: Axial HRCT of the chest reveal fibro-cavitary lesions in the right upper lobe with partial loss of volume. A large cavity is seen in left upper lobe with severe fibrotic lesions in the left lower lobe associated with loss of volume in left hemithorax.\n\nFig. 5 Case-2: Chest radiograph PA view reveals consolidation in the right upper and mid lung zones, large cavity in the left upper lung zone, collapse consolidation in the left mid and lower zone and volume loss in the left hemithorax.\n\nFig. 6 Case-2: Chest radiograph PA view after completion of treatment reveals significant resolution of the right upper and mid zone consolidations.\n\nFig. 7 Case-3: Chest radiograph PA view before commencement of treatment reveals fibro-cavitary lesions in the right lung, multiple nodules in the right mid and lower zones and loss of volume in right hemi-thorax.\n\nFig. 8 Case-3: Chest radiograph PA view after completion of treatment reveals significant resolution of right lung nodular lesions.\n\nFig. 9 Case-4: Chest radiograph PA view shows right upper zone cavities and extensive bilateral fibrotic bands.\n\nFig. 10 Case-4: HRCT Chest coronal section shows right upper lobe consolidation, cavities in the superior segment of the right lower lobe and bronchiectasis with fibrotic lesions in the left lower lobe.\n\nAs per Revised National TB control program (RNTCP) guidelines of India, these four patients can be considered as presumptive Drug resistant TB (DR-TB) cases for which Nucleic acid amplification test (NAAT) / Xpert MTB/RIF assay must be performed to rule out Drug resistant PTB (DR-TB) [20].\n\nOur patients had sputum smear positive for acid fast bacilli (AFB) persistently but Mycobacterium tuberculosis was not detected on Xpert MTB/RIF assay. This raised a diagnostic dilemma that was resolved by growth of NTM on AFB culture. All our patients were symptomatic. Based on the clinico-radiological profiles of the patients with a positive mycobacteriological data, treatment regimen was framed. The NTM treatment regimens were guideline based [21]. The following is the description of treatment regimens assigned to each of our patients and the clinical outcomes (Table 3).Table 3 Treatment Profile of Study Subjects.\n\nCase Characteristics\tCASE 1\tCASE 2\tCASE 3\tCASE 4\t\nNTM growth assumed to be:\tRGM: Mycobacterium abscessus complex (MABC)\tSGM: Mycobacterium avium complex(MAC)\tSGM: Mycobacterium avium complex (MAC)\tSGM: Mycobacterium avium complex (MAC)\t\nEmpirical treatment regimen started\tClarithromycin + Moxifloxacin (tablets) + Injection Amikacin (discontinued after 3 months)\tAzithromycin + Rifampicin + Ethambutol (tablets) + Injection Amikacin (for 4 months)\tAzithromycin + Rifampicin + Ethambutol (tablets) + Injection Amikacin (for 6 months)\tAzithromycin + Rifampicin + Ethambutol (tablets) + Injection Amikacin (for 4 months)\t\nInitial treatment response\tSymptomatic improvement after 3 months of therapy\tClinico-radiological resolution seen during treatment course\tSymptomatic improvement after 6 months of therapy\tSymptomatic improvement after 2 months of therapy\t\nAFB cultures during treatment course showed\tCulture conversion noted at 6 months of treatment and culture was positive again at 9thmonth during treatment.\tCulture conversion noted at 6 months, subsequent culture after 12 months of treatment was negative.\tCulture conversion noted at 6 months, subsequent culture after 12 months of treatment was negative.\tCulture conversion noted at 6 months, subsequent culture after 12 months of treatment was negative.\t\nSubsequent culture conversion during therapy was not seen due to\tRefractory NTM-PD considered. Moxifloxacin resistance seen on subsequent antimicrobial susceptibility testing (AST).\t–\t–\t–\t\nRedesigned therapeutic regimen\tAmikacin + Tigecycline + Imipenem (Injections) + Clarithromycin (tablets) for 4 weeks [Initiation phase]\t–\t–\t–\t\nFinal treatment response\tPatient discontinued treatment due to severe nausea, vomiting and thrombo-phlebitis as a result of repeated injections, within first 2 weeks. Refused further continuation of treatment and left against medical advice\tTreatment was continued for 12 months after culture conversion and the patient is currently in remission\tTreatment was continued for 12 months after culture conversion and the patient is currently in remission\tTreatment just concluded at the end of 12 months after culture conversion\t\n\n4 Discussion\n\nFor decades, diagnosis, relapse and resistance of PTB with Mycobacterium tuberculosis was and is a vexing problem for the clinicians in high TB-endemic countries like India. Hitherto, this aspect of management approach was based on smear AFB from sputum and other respiratory specimens. Even today, culture AFB facility to be available uniformly in the National program is a far cry. Advent of Xpert MTB/RIF assay fulfilled this deficiency of culture facility to a greater extent in treating Tuberculosis (TB).\n\nFor confirmation of PTB or otherwise in high TB endemic countries, clinicians rely on sputum microscopy and chest radiograph which cannot differentiate PTB from NTM-PD. Although culture remains the gold standard for diagnosis, identification using nucleic acid amplification testing (NAAT), viz., Xpert MTB/RIF assay, which has a sensitivity of 95.7% and specificity of 99.3% for MTB, aids to detect Mycobacterium Tuberculosis and drug resistant TB and a negative result in suspecting NTM-PD. Thus, patients of presumed DR-TB who are smear positive, NAAT (Xpert MTB/RIF assay) negative, Line probe assay-Tuberculosis Band (LPA-TUB) absent with or without R resistance need to be evaluated for NTM-PD. This enables specific and prompt initiation of therapy for NTM-PD [22], [20].\n\nThe two most important risk factors for NTM-PD are presence of structural lung disease (Cystic Fibrosis, COPD, history of PTB, etc.) and Immunosuppression (HIV, Transplantation, Primary Immunodeficiency, etc.) [23], [3]. In patients with Mycobacterium avium complex pulmonary disease (MAC-PD) serum adiponectin levels were found to be inappropriately increased especially in individuals with lower BMI values. A similar correlation was not found with serum leptin levels in MAC-PD and control subjects. Increased levels of adiponectin in slender individuals might have a pro-inflammatory effect and play a role in its pathogenesis [24]. All our patients were immunocompetent, had a low BMI with a past history of treated pulmonary tuberculosis and were at some point of time involved with agriculture, suggesting that environmental exposure in these individuals might have predisposed them to NTM-PD, since contaminated soil and water supplies are considered an important source for NTM causing human infections [17].\n\nDiagnosis of NTM-PD is usually delayed, in view of its indolent nature with nonspecific clinical features. Frequent coexistence of NTM-PD with underlying and predisposing conditions like COPD or Bronchiectasis and the latter presenting with similar clinical expressions, may further add to the diagnostic dilemma [25]. Minimum evaluation needed to diagnose NTM-PD, when suspected, requires: appropriate exclusion of other disorders in a patient with pulmonary symptoms, chest radiograph or HRCT chest suggestive of characteristic radiological findings (cavitary or multifocal nodulo-bronchiectatic lesions) and three consecutive, early morning sputum samples for AFB analysis [20], [5].\n\nMicrobiologic criteria for the diagnosis of NTM-PD needs: Two positive cultures of the sputum specimens or one positive culture of broncho alveolar lavage fluid (BAL) / washings; compatible histopathology (granulomatous inflammation) of transbronchial or any other lung biopsy with culture positive for NTM [21], [20]. NTM-PD is manifested by two main radiographic patterns: (i) an upper lobe fibro-cavitary pattern that occurs predominantly in men with an underlying lung disease and (ii) a nodular-bronchiectasis pattern involving right middle lobe and lingula that is more common in women having no clear risk factors [26]. All the patients in the present study had fibro-cavitary disease with one of them having both fibro-cavitary and nodular lesions.\n\nInstitution of therapy for NTM-PD is a decision based on potential risks and benefits of therapy in symptomatic patients. Making a diagnosis of NTM-PD does not per se necessitate institution of therapy [25]. Identification of NTM species is ideal and allows for assessment of clinical significance, prognosis, and expected antimicrobial resistance necessary for guiding an empirical therapeutic strategy [2]. The aim of diagnosis should be to formulate an appropriate treatment regimen preferably based on the susceptibility testing. But in view of discrepancies between in vitro and in vivo drug susceptibility results and absence of definitive consensus for guidelines regarding drug sensitivity test correlations, one may have to cautiously choose an empirical treatment approach initially, when accessibility and affordability to such facility is not possible. However, susceptibility-based treatment regimens are to be preferred over empiric therapies whenever such facility for AST is available.\n\nThe management of NTM is usually guided by the ATS/IDSA or the BTS guidelines and is challenging because of antibiotic resistance of NTM species attributed to their biofilm production, requirement of multi-drug regimens for an extended period, frequent intolerance of the prescribed regimens and relatively high frequency of relapse and/or reinfection [5], [21], [27]. In the present case series, three of the four patients reported positive for NTM-slow-growers. During evaluation of these patients there was no accessibility to the nearby facility for speciation. The attendant cost constraints also prevented us from performing speciation routinely. Global epidemiological data noted, in most of the studies, MAC was the most common species complex (up to 85% of cases) followed by M. abscessus/chelonae (3–13%). Based on these observations we treated our patients of ‘slow growers’ for MAC and ‘Rapid growing mycobacteria’ (RGM) for M.abscessus complex [7]. Predisposition to and progression of NTM disease is reported to be associated with poor nutritional status. Hence, dietary consultation can be recommended in NTM-PD because poor nutritional status is associated with increased adverse effects and drug intolerance, thereby resulting in a poor therapeutic response. Likewise, vitamin deficiencies, especially Vitamin A, are suggested to have been associated with NTM-PD [28], [29], [30]. These nutritional aspects were taken care of during the treatment of our patients.\n\nFailure to achieve culture conversion after 6–12 months of therapy is defined as treatment failure [28]. Retreatment strategy would depend on Macrolide sensitivity of the isolate and if these patients are found to be intolerant to treatment or drug resistant, lung resection can be effective in controlling infection, provided the disease is localized [21]. In the present study, the three SGM patients achieved culture conversion and did not relapse during the follow up period. Patient with RGM discharged herself at request due to adverse drug effects.\n\n5 Conclusion\n\nIn summary, PTB patients who are non-responders to standard ATT regimen should be evaluated for NTM-PD. As NTM are ubiquitous organisms, neither their mere isolation from pulmonary samples is sufficient evidence for the presence of NTM-PD nor is an indication for treatment. NTM-PD diagnosis requires integration of clinical, radiographic and microbiological criteria for prompt therapy. The patient’s wish, affordability and ability to receive treatment as well as the goals of therapy should be discussed with patients prior to initiating treatment. These patient-centric aspects along with species identification and antimicrobial sensitivity testing (whenever available) needs to be considered an integral part of NTM-PD management. In some instances, viz., patients with mild signs and symptoms and those with potential for drug intolerance and those with RGM isolates less responsive to treatment (eg.M. abscessus), “watchful waiting” may be the preferred course of action [4].\n\nTo conclude, there is a need for increased awareness and clinical suspicion on the part of the treating physician and provision of improved mycobacteriology services to be incorporated into the National Programs. This facilitates institution of prompt evidence-based treatment options for NTM-PD which is extremely challenging in resource limited clinical practice.\n\nDeclaration of Competing Interest\n\nThe authors: No reported conflicts of interest. All authors have submitted the ICMJE form for Disclosure of Potential Conflicts of Interest.\n\nAcknowledgements\n\nNil.\n\nAuthor contributions\n\nAuthor Aditya Chindam helped in acquisition of data and provided the needed inputs on writing the manuscript and made multiple edits and suggestions in the preparation of this report. Authors Samanvitha Vengaldas and Vijetha Reddy Srigiri reviewed background information, and literature. Authors Umair Syed and Hemanth Kilaru provided inputs for the manuscript writing, its analysis and interpretation. Author Nagender Prasad Chenimilla’s contribution was - drafting and revising it critically for important intellectual content, final approval of the version to be submitted. Author Satish Chandra Kilaru is involved in the conception and design of the study and drafting the main content of the article and is the corresponding author. Author Ekta Patil provided the Microbiological investigations and the necessary laboratory support for the study.\n\nFunding source\n\nThis did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n==== Refs\nReferences\n\n1 Bryant J.M. Grogono D.M. Rodriguez-Rincon D. Everall I. Brown K.P. Moreno P. Emergence and spread of a human-transmissible multidrug-resistant nontuberculous mycobacterium Science 354 6313 2016 Nov 11 751 757 27846606\n2 Pennington K.M. Vu A. Challener D. Rivera C.G. Shweta F.N.U. Zeuli J.D. Approach to the diagnosis and treatment of non-tuberculous mycobacterial disease J Clin Tuberc Other Mycobact Dis. 24 2021 100244 10.1016/j.jctube.2021.100244 34036184\n3 Honda J.R. Knight V. Chan E.D. 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Rapid identification of mycobacteria from positive MGIT broths of primary cultures by MALDI-TOF mass spectrometry.PLoS One. 2018 Feb 2;13(2):e0192291. doi: 10.1371/journal.pone.0192291.\n19 Mahler D.A. Rosiello R.A. Harver A. Lentine T. McGovern J.F. Daubenspeck J.A. Comparison of clinical dyspnea ratings and psychophysical measurements of respiratory sensation in obstructive airway disease American Review of Respiratory Disease. 135 6 1987 Jun 1229 1233\n20 Central TB Division. Guidelines on Programmatic Management of Drug Resistant TB (PMDT) in India.2017.\n21 Haworth CS, Banks J, Capstick T, et al. BritishThoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD).Thorax.2017 Nov 1;72(Suppl 2):ii1-64 https://doi.org/10.1136/2017/000242.\n22 Sharma S.K. Kohli M. Yadav R.N. Chaubey J. Bhasin D. Sreenivas V. Evaluating the diagnostic accuracy of Xpert MTB/RIF assay in pulmonary tuberculosis PLoS One 10 10 2015 e0141011 10.1371/journal.pone.014101110.1371/journal.pone.0141011.g00110.1371/journal.pone.0141011.t00110.1371/journal.pone.0141011.t00210.1371/journal.pone.0141011.t00310.1371/journal.pone.0141011.t004 26496123\n23 Gupta N. Mittal A. Muhammed Niyas V.K. Banerjee S. Ray Y. Kodan P. Nontuberculous mycobacteria: A report of eighteen cases from a tertiary care center in India Lung India. 37 6 2020 495 10.4103/lungindia.lungindia_365_19 33154211\n24 Tasaka S. Hasegawa N. Nishimura T. Yamasawa W. Kamata H. Shinoda H. Elevated serum adiponectin level in patients with Mycobacterium avium-intracellulare complex pulmonary disease Respiration. 79 5 2010 383 387 19641295\n25 Marathe N, Canavan B. Rare Case of Non-Tuberculous Mycobacterial: A Diagnostic dilemma. Irish Medical Journal 2017 Feb 10;110(2).\n26 Chung M.J. Lee K.S. Koh W.-J. Lee J.H. Kim T.S. Kwon O.J. Thin-section CT findings of nontuberculous mycobacterial pulmonary diseases: comparison between Mycobacterium avium-intracellulare complex and Mycobacterium abscessus infection J Korean Med Sci 20 5 2005 777 10.3346/jkms.2005.20.5.777 16224151\n27 Falkinham J.O. III Challenges of NTM drug development Front Microbiol 18 9 2018 1613\n28 Kim S.J. Park J. Lee H. Lee Y.J. Park J.S. Cho Y.-J. Risk factors for deterioration of nodular bronchiectatic Mycobacterium avium complex lung disease Int J Tuberc Lung Dis 18 6 2014 730 736 24903946\n29 Sharma S. Dhar R. Nontuberculous mycobacterial diseases: current diagnosis and treatment Astrocyte. 4 1 2017 67 10.4103/astrocyte.astrocyte_54_17\n30 Oh J. Park H.D. Kim S.Y. Koh W.J. Lee S.Y. Assessment of vitamin status in patients with nontuberculous mycobacterial pulmonary disease: Potential role of vitamin a as a risk factor Nutrients. 11 2 2019 343\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2405-5794",
"issue": "25()",
"journal": "Journal of clinical tuberculosis and other mycobacterial diseases",
"keywords": "Diagnosis; Non-tuberculous Mycobacteria; Pulmonary Disease; Treatment",
"medline_ta": "J Clin Tuberc Other Mycobact Dis",
"mesh_terms": null,
"nlm_unique_id": "101682877",
"other_id": null,
"pages": "100271",
"pmc": null,
"pmid": "34541338",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports",
"references": "21572618;20626945;34036184;29635026;28657261;25676516;33154211;19845700;27846606;29394275;30072975;30764587;25676515;22859521;17277290;3592398;32628747;22312016;32814943;25068291;16224151;19641295;24903946;25826589;29054853;26496123",
"title": "Challenges of diagnosing and treating non-tuberculous mycobacterial pulmonary disease [NTM-PD]: A case series.",
"title_normalized": "challenges of diagnosing and treating non tuberculous mycobacterial pulmonary disease ntm pd a case series"
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"abstract": "OBJECTIVE\nInvasive, medically refractory, and multiply recurrent pituitary adenomas pose a rare, but nevertheless significant, challenge for conventional management modalities. Temozolomide (TMZ) has been reported to be useful as an adjunctive treatment for some patients. We describe the efficacy of TMZ when used early in the management of invasive prolactinoma.\n\n\nMETHODS\nA 56-year-old man presented with an invasive, refractory macroprolactinoma for which long-term dopamine agonists, stereotactic radiosurgery, and multiple transsphenoidal surgical resections had failed. He had experienced persistent hyperprolactinemia and tumor progression. Thus, TMZ was started. During the 11 cycles of TMZ therapy, the patient's prolactin level decreased from 696 ng/mL to 15.2 ng/mL, with a >90% decrease in tumor size. Nearly 6 years after discontinuing chemotherapy, the patient remained in sustained remission (prolactin level, 3.1 ng/mL) requiring only 1.5 mg of cabergoline weekly, without radiographic or clinical evidence of tumor recurrence.\n\n\nCONCLUSIONS\nWe conclude that TMZ can be efficacious in the management of medically and surgically refractory, invasive atypical prolactinomas, resulting in normalization of the prolactin levels and control of the tumor size. We encourage the inclusion of TMZ in the management of refractory, recurrent, and invasive prolactinomas, as a fourth-line treatment strategy, after dopamine agonist treatment, transsphenoidal resection, and radiation therapy. We especially advocate the early use of TMZ for aggressive and otherwise refractory prolactinomas.",
"affiliations": "Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, California, USA. Electronic address: BarkhoudarianG@JWCI.org.;Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, California, USA.;Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, California, USA.;Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, California, USA.;Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, California, USA.;Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, California, USA.",
"authors": "Barkhoudarian|Garni|G|;Palejwala|Sheri K|SK|;Ogunbameru|Ronke|R|;Wei|Hua|H|;Eisenberg|Amalia|A|;Kelly|Daniel F|DF|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2018.07.082",
"fulltext": null,
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"issn_linking": "1878-8750",
"issue": "118()",
"journal": "World neurosurgery",
"keywords": "Atypical prolactinoma; Chemotherapy; Dopamine agonist; Invasive adenoma; Pituitary adenoma; Refractory prolactinoma; Temozolomide",
"medline_ta": "World Neurosurg",
"mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010911:Pituitary Neoplasms; D015175:Prolactinoma; D000077204:Temozolomide; D013995:Time",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "118-124",
"pmc": null,
"pmid": "30031177",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Early Recognition and Initiation of Temozolomide Chemotherapy for Refractory, Invasive Pituitary Macroprolactinoma with Long-Term Sustained Remission.",
"title_normalized": "early recognition and initiation of temozolomide chemotherapy for refractory invasive pituitary macroprolactinoma with long term sustained remission"
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"abstract": "Post-transplant immunosuppression is necessary to prevent organ rejection. Immunosuppression itself can introduce complications arising from opportunistic infections. We present a case of disseminated blastomycosis manifested only as a skin lesion in an asymptomatic patient post-orthotopic heart transplantation. A 64-year-old female who had recently undergone orthotopic heart transplant for end-stage ischemic cardiomyopathy presented for a scheduled routine cardiac biopsy. The patient had no current complaints other than a crusted plaque noticed at her nasal tip. It initially manifested 6 months after surgery as a pimple that she repeatedly tried to manipulate resulting in redness and crust formation. Her immunosuppressive and prophylactic medications included: mycophenolate, tacrolimus, prednisone, bactrim, acyclovir, valganciclovir, pyrimethamine/sulfadiazine, and fluconazole. On physical examination, she was flushed, with a large and exquisitely tender crusted necrotic lesion involving almost the entire half of the nose anteriorly, the left forehead and right side of the neck. She had decreased air entry over the right lung field as well. A computed tomography (CT) image of the chest was ordered to investigate this concerning physical exam finding in the post-transplant state of this patient on immunosuppressive therapy. Chest CT revealed bilateral nodular pulmonary infiltrates with confluence in the posterior right upper lobe. Blood cultures for aerobic and anerobic organisms were negative. Both excisional biopsy of the nasal cutaneous ulcer and bronchial biopsy demonstrated numerous fungal yeast forms morphologically consistent with Blastomyces. Cultures of both specimens grew Blastomyces dermatitidis, with methicillin-resistant Staphylococcus aureus (MRSA) superinfection of the nose. She received 14 days of intravenous (IV) amphotericin B for disseminated blastomycosis and 7 days of IV vancomycin for MRSA. Her symptoms and cutaneous lesions improved and she received maintenance itraconazole treatment for 1 year. This case illustrates a delicate balance that must be struck between suppressing the immune response to prevent graft rejection and avoiding over-immunosuppression that can lead to susceptibility to infection. Thus, in any post-transplant patient, a vigorous history and physical must be performed given that infections may present without symptoms and cause grave consequences.",
"affiliations": "Department of Internal Medicine, Advocate Christ Medical Center, 105 Covington Ct Oak Brook, IL 60523, USA.;Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.;Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.;Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.;Department of Internal Medicine, Advocate Christ Medical Center, 105 Covington Ct Oak Brook, IL 60523, USA.;Department of Internal Medicine, Advocate Christ Medical Center, 105 Covington Ct Oak Brook, IL 60523, USA.;Department of Internal Medicine, Advocate Christ Medical Center, 105 Covington Ct Oak Brook, IL 60523, USA.;Department of Cardiology, Advocate Christ Medical Center, 105 Covington Ct Oak Brook, IL 60523, USA.",
"authors": "Yousuf|Tariq|T|;Kramer|Jason|J|;Kopiec|Adam|A|;Jones|Brody|B|;Iskandar|Joy|J|;Ahmad|Khansa|K|;Keshmiri|Hesam|H|;Dia|Muhyaldeen|M|",
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"fulltext": "\n==== Front\nJ Clin Med ResJ Clin Med ResElmer PressJournal of Clinical Medicine Research1918-30031918-3011Elmer Press 10.14740/jocmr2439wCase ReportIn Search for Equilibrium: Immunosuppression Versus Opportunistic Infection Immunosuppression and InfectionYousuf Tariq adKramer Jason bKopiec Adam bJones Brody bIskandar Joy aAhmad Khansa aKeshmiri Hesam aDia Muhyaldeen ca Department of Internal Medicine, Advocate Christ Medical Center, 105 Covington Ct Oak Brook, IL 60523, USAb Rosalind Franklin University of Medicine and Science, North Chicago, IL, USAc Department of Cardiology, Advocate Christ Medical Center, 105 Covington Ct Oak Brook, IL 60523, USAd Corresponding Author: Tariq Yousuf, Department of Internal Medicine, Advocate Christ Medical Center, 105 Covington Ct Oak Brook, IL 60523, USA. Email: tmyousuf614@gmail.com2 2016 28 12 2015 8 2 175 177 14 12 2015 Copyright 2016, Yousuf et al.2016This 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 work is properly cited.Post-transplant immunosuppression is necessary to prevent organ rejection. Immunosuppression itself can introduce complications arising from opportunistic infections. We present a case of disseminated blastomycosis manifested only as a skin lesion in an asymptomatic patient post-orthotopic heart transplantation. A 64-year-old female who had recently undergone orthotopic heart transplant for end-stage ischemic cardiomyopathy presented for a scheduled routine cardiac biopsy. The patient had no current complaints other than a crusted plaque noticed at her nasal tip. It initially manifested 6 months after surgery as a pimple that she repeatedly tried to manipulate resulting in redness and crust formation. Her immunosuppressive and prophylactic medications included: mycophenolate, tacrolimus, prednisone, bactrim, acyclovir, valganciclovir, pyrimethamine/sulfadiazine, and fluconazole. On physical examination, she was flushed, with a large and exquisitely tender crusted necrotic lesion involving almost the entire half of the nose anteriorly, the left forehead and right side of the neck. She had decreased air entry over the right lung field as well. A computed tomography (CT) image of the chest was ordered to investigate this concerning physical exam finding in the post-transplant state of this patient on immunosuppressive therapy. Chest CT revealed bilateral nodular pulmonary infiltrates with confluence in the posterior right upper lobe. Blood cultures for aerobic and anerobic organisms were negative. Both excisional biopsy of the nasal cutaneous ulcer and bronchial biopsy demonstrated numerous fungal yeast forms morphologically consistent with Blastomyces. Cultures of both specimens grew Blastomyces dermatitidis, with methicillin-resistant Staphylococcus aureus (MRSA) superinfection of the nose. She received 14 days of intravenous (IV) amphotericin B for disseminated blastomycosis and 7 days of IV vancomycin for MRSA. Her symptoms and cutaneous lesions improved and she received maintenance itraconazole treatment for 1 year. This case illustrates a delicate balance that must be struck between suppressing the immune response to prevent graft rejection and avoiding over-immunosuppression that can lead to susceptibility to infection. Thus, in any post-transplant patient, a vigorous history and physical must be performed given that infections may present without symptoms and cause grave consequences.\n\nBlastomyces dermatitidisImmunosuppressionOrthotopic heart transplantOpportunistic infection\n==== Body\nIntroduction\nSince 1954 with the advent of solid organ transplant, there has been a way to definitively treat end-organ damage. However, the surgery is just the first step. What follows is a long-term commitment on the part of both patient and physician to manage the new organ. One of the major challenges is to prevent the host body from rejecting the donor organ and in order to do so, the patient must strictly adhere to a group of medications that deliberately suppress the host’s immune system. Unfortunately, with this immunosuppressive therapy, the host is subject to constant bombardment from pathogens both common and opportunistic. Therefore, both physician and patient must remain vigilant in order to catch infections early before damage occurs.\n\nFungal organisms specifically cause a big threat to our patient population. Infections tend to be more severe than bacterial or viral and can sometimes be fatal. Recipients of solid organ and bone marrow transplants are predisposed to invasive fungal infections with Candida species, Aspergillus, and Cryptococcus neoformans [1]. Infections caused by Blastomyces dermatitidis are quite rare in transplant recipients [1]. What follows is a case of disseminated blastomycosis manifested only as a skin lesion in an asymptomatic patient post-orthotopic heart transplantation.\n\nIt is important for the clinician to be aware of the potentially serious consequences of opportunistic infections in patients that are over-immunosuppressed status post-transplant surgery despite being completely asymptomatic. We describe a rare case of a patient who developed systemic blastomycosis infection after an orthotopic heart transplantation.\n\nCase Report\nA 64-year-old female who had recently undergone orthotopic heart transplant for end-stage ischemic cardiomyopathy presented for a scheduled routine cardiac biopsy 6 months after her transplant. She had a long-standing history of coronary artery disease, bioprosthetic mitral valve replacement and cardiac arrest. In the postoperative cardiac recovery room, following the cardiac biopsy, the patient complained of a painful lesion on her nose. A crusted plaque was observed at the nasal tip (Fig. 1). She then reported squeezing the pimple 2 weeks prior to the myocardial biopsy and the following day, it became more swollen and involved. From here, the patient became more aggressive in squeezing this lesion on her nose which resulted in a dramatic increase in the amount of redness, swelling, and crusting at the tip of her nose. She tried multiple creams and ointments that provided no relief, then it was time for her myocardial biopsy, so she presented to the hospital.\n\nFigure 1 Photograph of the patient’s face showing the nose lesion on presentation to the hospital. \n\nHer immunosuppressive and prophylactic medications after the orthotopic heart transplant included: mycophenolate, tacrolimus, prednisone, bactrim, acyclovir, valganciclovir, pyrimethamine/sulfadiazine, and fluconazole. On physical exam, she was flushed, with a large and exquisitely tender crusted necrotic lesion involving almost the entire half of the nose anteriorly, the left forehead and right side of the neck. She had decreased air entry over the right lung field despite denying any respiratory symptoms.\n\nChest computed tomography (CT) displayed extensive bilateral nodular pulmonary infiltrates with confluence in the posterior right upper lobe (Fig. 2). Blood cultures for aerobic and anerobic organisms were negative. Both excisional biopsy of the nasal cutaneous ulcer and bronchial biopsy demonstrated numerous fungal yeast forms morphologically consistent with Blastomyces. Cultures of both specimens grew Blastomyces dermatitidis, with MRSA superinfection of the nose. She received 14 days of IV amphotericin B for disseminated blastomycosis and 7 days of IV vancomycin for MRSA. Her symptoms and cutaneous lesions improved and she received maintenance itraconazole treatment for 1 year.\n\nFigure 2 Initial chest CT of patient with bilateral nodular pulmonary infiltrates with predominance in the posterior right upper lobe. \n\nDiscussion\nBlastomycosis is a systemic disease caused by the dimorphic fungus B. dermatitidis that is seen mostly in the Ohio-Mississippi and St. Lawrence River areas of North America [2]. B. dermatitidis is usually benign in immunocompetent hosts presenting with mild respiratory symptoms. However, in those with weakened or compromised immune systems, B. dermatitidis can behave opportunistically creating a severe infection and increasing mortality rates as compared to infected immunocompetent hosts. The infection primarily presents with pulmonary symptoms such as cough, fever, sputum production, chest pain, hemoptysis, night sweats, weight loss and shortness of breath [3]. Chest radiographs will primarily show alveolar infiltrates or a mass lesion.\n\nThe second most commonly affected organ that is infected is the skin. The characteristic verrucous lesion has irregular borders and may range in color from gray to purple. Furthermore, these lesions can appear anywhere on the skin. Microscopic examination will show broad based budding yeasts characteristic of B. dermatitidis [4]. Other sites of infection for blastomycosis include the skeletal system, the genitourinary system, and the central nervous system. However manifestations in these systems are rare and occur in 4%, 2%, and 1% respectively in patients infected with blastomycosis.\n\nAfter a literature review of post-transplant blastomycosis infections, our research has found that blastomycosis infection is quite rare in this patient population. A 2007 retrospective review by Gauthier et al found that between 1986 and 2004 there were only 11 documented cases of post-transplant blastomycosis out of 8,104 transplant surgeries, an incidence of 0.14%. Another retrospective review published in 2011 by Grim et al found that between 1996 and 2008 only eight cases of post-transplant blastomycosis were identified out of a possible 5,989 transplant operations, a similar incidence of 0.13%. However, the incidence of blastomycosis infection is not the only aspect that makes this case so rare. Of the 19 cases found in the two reviews mentioned previously, none of the patients who became infected with B. dermatitidis had undergone a heart transplant. In the review performed by Grim et al, all eight patients had received renal transplants and in the review by Gauthier et al, seven patients underwent renal transplants, three patients had liver transplants, and one case was a lung transplant. Furthermore, our patient presented with signs of infection 6 months after surgery, Gauthier et al found the median time to first infection to be 26 months. Our patient’s initial complaint of skin lesion was also unusual. Blastomycosis infection most commonly presents with infections involving the lungs as documented by the review performed by Gauthier et al which revealed that in 82% (9/11) of the cases, pneumonia was the presenting diagnosis. Cutaneous lesions, however, is often not an initial symptom of disease but rather that of disease dissemination. Gauthier et al found disease dissemination in 36% of cases (4/11), but of these four cases, three of them had various cutaneous lesions. Grim et al found that 50% (4/8) of their blastomycosis cases had skin involvement. So while cutaneous lesions are often seen with advancing infection, it is rarely the chief complaint.\n\nThe primary means of treatment for blastomycosis infection in immunocompromised patients is amphotericin B therapy for a maximum of 2 weeks at which point therapy is transitioned to itraconazole. Patients for whom immunosuppression is irreversible, itraconazole therapy should be a chronic treatment because relapse is a common problem in this patient population.\n\nTreatment for our patient’s disseminated blastomycosis infection required delicacy as to not damage the transplanted heart but at the same time to adequately treat the infection. Deciding whether to favor immunosuppression or increased patient humoral immunity must be taken on a case-by-case basis. In our patient, we ultimately decided to tip the balance towards less immunosuppression. We accomplished this by decreasing the tacrolimus and mycophenolate dosages while maintaining the prednisone dose. Voriconazole was stopped and amphotericin B was started in its place. Additionally, azithromycin and imipenem were discontinued.\n\nThis case illustrates the delicate balance that must be struck between suppressing the immune response to prevent graft rejection and avoiding over-immunosuppression that can lead to susceptibility to infection. Thus, in any post-transplant patient, clinicians should be diligent in their assessment for infections because the patient may not present with any symptoms. Quick diagnosis and aggressive treatments are keys to fighting infection, but immunosuppressed patients present many more challenges to diagnosis and therefore treatment. Immunosuppressed patients will often have dampened initial responses to infection, with unreliable physical signs and laboratory findings, causing the diagnosis to be quite challenging. Consequently, immunocompromised patients usually present with atypical symptoms and with more disseminated infections at presentation. To further complicate the situation, a weakened immune system increases the number of possible sources due to the inclusion of opportunistic infections. All of these factors together create a challenge to the physician specifically in diagnosis and treatment of infection in immunocompromised patients [4].\n\nConclusion\nTransplant patients must be treated with anti-rejection medications in order to ensure the survival of their new organ. As such, it is the job of both patient and provider to examine any signs or symptoms that could be a manifestation of infection no matter how small or how benign they seem to be.\n==== Refs\nReferences\n1 Serody JS Mill MR Detterbeck FC Harris DT Cohen MS Blastomycosis in transplant recipients: report of a case and review Clin Infect Dis 1993 16 1 54 58 10.1093/clinids/16.1.54 8448319 \n2 Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients Transpl Infect Dis 2007 9 4 310 317 10.1111/j.1399-3062.2007.00227.x 17428278 \n3 Grim SA Proia L Miller R Alhyraba M Costas-Chavarri A Oberholzer J Clark NM A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation Transpl Infect Dis 2012 14 1 17 23 10.1111/j.1399-3062.2011.00658.x 21749587 \n4 Fishman JA Infection in solid-organ transplant recipients N Engl J Med 2007 357 25 2601 2614 10.1056/NEJMra064928 18094380\n\n",
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"issn_linking": "1918-3003",
"issue": "8(2)",
"journal": "Journal of clinical medicine research",
"keywords": "Blastomyces dermatitidis; Immunosuppression; Opportunistic infection; Orthotopic heart transplant",
"medline_ta": "J Clin Med Res",
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"nlm_unique_id": "101538301",
"other_id": null,
"pages": "175-7",
"pmc": null,
"pmid": "26767088",
"pubdate": "2016-02",
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"references": "17428278;18094380;21749587;8448319",
"title": "In Search for Equilibrium: Immunosuppression Versus Opportunistic Infection.",
"title_normalized": "in search for equilibrium immunosuppression versus opportunistic infection"
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"abstract": "We report on the natural history of a cohort of patients presenting with transient ischemic attack or stroke and nonbacterial thrombotic endocarditis treated with warfarin.Patients with valvular vegetations on echocardiography, stroke, or transient ischemic attack presenting to a single neurologist were included. All patients were treated with warfarin until the vegetation resolved or for two years, then were switched to aspirin and had at least one clinical and echocardiographic follow-up.Twenty-nine patients were included and followed for a median of 27 months. Average age was 42 years and 72% were female. Two patients had vegetations on two valves. Five patients (17%) had recurrent strokes, three had systemic lupus erythematosus and antiphospholipid antibodies, one had antiphospholipid antibodies alone and one had neither condition. Three of the five patients did not have resolution of the vegetation at the time of the event. The valvular vegetations resolved in 23 of the 31 affected valves (74%) after a median of 11 months (range 4.5-157.5). Eleven patients had at least one follow-up echocardiogram after resolution of the vegetation and none had recurrent vegetations after warfarin was stopped.This study should serve to provide general recommendations regarding treatment of patients with TIA/stroke with nonbacterial thrombotic endocarditis. Valvular vegetations resolve in most patients and the risk of recurrent stroke is low. Warfarin can safely be switched to aspirin in most patients when the vegetation resolves or after two years if it does not resolve. Prolonged warfarin may be warranted in patients with systemic lupus erythematosus, positive antiphospholipid antibodies, and a persistent vegetation.",
"affiliations": "Department of Neurology, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.;Department of Neurology, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.;Department of Internal Medicine, Division of Cardiovascular Medicine, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.",
"authors": "Slivka|Andrew P|AP|0000-0001-7620-9036;Agriesti|Julie E|JE|;Orsinelli|David A|DA|0000-0002-6420-856X",
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"issue": "16(5)",
"journal": "International journal of stroke : official journal of the International Stroke Society",
"keywords": "Nonbacterial thrombotic endocarditis; stroke; transient ischemic attack; warfarin",
"medline_ta": "Int J Stroke",
"mesh_terms": "D000328:Adult; D004452:Echocardiography; D004696:Endocarditis; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D020521:Stroke; D014859:Warfarin",
"nlm_unique_id": "101274068",
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"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
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"title": "Natural history of nonbacterial thrombotic endocarditis treated with warfarin.",
"title_normalized": "natural history of nonbacterial thrombotic endocarditis treated with warfarin"
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"abstract": "Increased number of left ventricular assist device placement in patients with end stage heart failure as well as years of survival increases the likelihood of need for non-cardiac procedures. Prostate artery embolization is a safe, minimally invasive procedure performed in the setting of lower urinary tract symptoms or refractory gross hematuria of prostatic origin. These patients require a multidisciplinary approach to weigh the benefits and risks of the procedure and provide optimal periprocedural care. We report a case of technically successful prostate artery embolization performed in a patient with HeartWare HVAD presenting with refractory hematuria of prostatic origin (RHPO).",
"affiliations": "Department of Diagnostic Radiology, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216, USA.;Department of Interventional Radiology, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216, USA.;Department of Surgery Division of Urology, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216, USA.;Department of Surgery Division of Urology, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216, USA.;Department of Interventional Radiology, University of Miami/ Jackson Memorial Hospital, 1400 NW 12th Ave, Miami, FL, 33136, USA.",
"authors": "Vasani|Jay|J|;Kim|Sanghun|S|;Hynes|Kieran|K|;Pound|Charles|C|;Kably|Issam|I|",
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"delete": false,
"doi": "10.1016/j.eucr.2021.101588",
"fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420 Elsevier \n\nS2214-4420(21)00028-0\n10.1016/j.eucr.2021.101588\n101588\nFunctional Medicine\nProstate artery embolization in a patient with left ventricular assist device\nVasani Jay jvasani@umc.edua∗ Kim Sanghun b Hynes Kieran c Pound Charles c Kably Issam d a Department of Interventional Radiology, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216, USA\nb Department of Diagnostic Radiology, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216, USA\nc Department of Surgery Division of Urology, University of Mississippi Medical Center, 2500 N State St. Jackson, Mississippi, 39216, USA\nd Department of Interventional Radiology, University of Miami/ Jackson Memorial Hospital, 1400 NW 12th Ave, Miami, FL, 33136, USA\n∗ Corresponding author. jvasani@umc.edu\n29 1 2021 \n5 2021 \n29 1 2021 \n36 10158830 12 2020 26 1 2021 © 2021 The Authors. Published by Elsevier Inc.2021This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Increased number of left ventricular assist device placement in patients with end stage heart failure as well as years of survival increases the likelihood of need for non-cardiac procedures. Prostate artery embolization is a safe, minimally invasive procedure performed in the setting of lower urinary tract symptoms or refractory gross hematuria of prostatic origin. These patients require a multidisciplinary approach to weigh the benefits and risks of the procedure and provide optimal periprocedural care. We report a case of technically successful prostate artery embolization performed in a patient with HeartWare HVAD presenting with refractory hematuria of prostatic origin (RHPO).\n\nKeywords\nBenign prostatic hyperplasiaLower urinary tract symptomProstate artery embolizationLeft ventricular assist deviceInterventional radiology\n==== Body\nIntroduction\nIncreased survival in end stage heart failure patients with left ventricular assist devices (LVAD) has led to an increased need for non-cardiac procedures. Gross hematuria in the setting of benign prostatic hyperplasia (BPH) can be treated with prostate artery embolization. Patients with LVAD must be carefully evaluated for perioperative complications related to anticoagulation. Compared to traditional surgery, minimally invasive catheter directed therapy offer increased safety especially in patients with chronic anticoagulation, and therefore should be considered as first line treatment option when indicated.\n\nCase presentation\nA 73-year-old male with a history of paroxysmal atrial fibrillation on warfarin status post dual chamber implantable cardioverter defibrillator placement and nonischemic cardiomyopathy with HeartWare HVAD system (LVAD) as destination therapy implanted in an outside hospital 2 years prior to presentation.\n\nThe patient was seen at an outside hospital for gross hematuria and dysuria for one week which was conservatively managed with Foley catheter and antibiotics. The patient returned to the outside hospital after the completion of an antibiotic regimen with persistent hematuria. Continuous bladder irrigation was started during which the patient received 2 units of packed red blood cells for acute blood loss anemia. The patient was eventually transferred to our medical center for cystoscopy given the patient's complex medical history and the probable requirement for cardiac anesthesia during the procedure.\n\nCT urogram obtained prior to cystoscopy showed marked prostatomegaly measuring approximately 175 cc with median lobe projecting into bladder neck and significant clot burden within the bladder lumen. Warfarin was held and therapeutic heparin was started. Cystoscopy performed under anesthesia showed severe trilobar hypertrophy of the prostate with friable enlarged median lobe consistent with BPH. The formed clot was evacuated, and the following re-examination of the bladder showed normal-appearing mucosa without evidence of urothelial cancer. Interventional radiology was consulted for prostate artery embolization (PAE). Prior to having hematuria, the patient's international prostate symptom score (IPSS) was 18 and the quality of life score (QOL) was 3 which were managed with alpha-blockers. On the day of the procedure, transfemoral approach prostate artery embolization was performed under general anesthesia using 300–500 μm embospheres (Fig. 1). The procedure was technically successful without acute complications and an estimated blood loss of less than 5 ml. Hematuria completely resolved and CBI was stopped on postoperative day (POD) 2. The patient was able to spontaneously void on POD 3 with postvoid residual (PVR) of approximately 300ml and was then discharged home on POD 5 after resuming warfarin. At the post discharge follow up at the cardiology clinic, the patient reported good activity tolerance without issues with LVAD, ICD, or hematuria. At 2 weeks follow up with urology, hematuria remained completely resolved while on anticoagulation, along with significant improvement of urinary stream with PVR of 90ml (previously 300ml). At 3 month follow up with IR, he remained asymptomatic and reported significant improvement of IPSS 1 (mild LUTs) previously 18 (moderate LUTs), and QOL 0 (delighted), previously 3 (mixed) and PVR of 9ml (previously 90 at 2 weeks follow up) (Fig. 2).Fig. 1 A: Right internal iliac angiogram showing right prostate artery (Red arrow) arising from right obturator artery. B: Right prostate artery angiogram opacifying branches supplying median and lateral lobes of the right side of prostate gland. C: Intra-procedure CT scan showing enhancement of right hemi-prostate gland with no enhancement of adjacent organs. D: Left internal iliac angiogram showing left prostate artery (red arrow) arising as a common origin with inferior vesicle artery. E: Left prostate artery angiogram showing branches supplying the left hemi-prostate. F: Cone beam CT showing enhancement of the left side of the prostate gland without enhancement of adjacent structures. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 1Fig. 2 A & B: 3-month Pre-void Ultrasound (US) of urinary bladder in longitudinal and transverse planes (respectively) measuring 7.9 × 9.47 x 7.17 (Pre-void volume 280ml). C & D: 3 month Post Void US of the urinary bladder in longitudinal and transverse planes (respectively) measuring 3.2 × 2.7 × 2.1 cm (Post void volume 9 ml).\n\nFig. 2\n\nDiscussion\nLeft ventricular assist device (LVAD) is an implantable device that has been introduced in 1990s to bridge patients with end stage heart failure refractory to maximal medical therapy to heart transplant. Continued development and resulting improvement of hemodynamics, end organ function, and quality of life in patients with LVAD has led to its usage as long term mechanical circulatory support in non-transplant patients as a destination therapy. LVAD also shows clinically significant improvement of survival benefit over optimal medical therapy at 1 or 2 years after device implantation.1 Prior studies have shown that 20–50% of patients with LVAD undergo non-cardiac surgical procedures.2\n\nHematuria is the presence of red blood cells in the urine accounting for 4–20% of inpatient urology consultations and hospitalizations.3 Common causes of hematuria include malignancy, benign prostatic hyperplasia, urinary tract infection, and urolithiasis. Prostatic hyperplasia can be considered a cause of hematuria after the patient has been evaluated for urologic malignancy. Gross hematuria, defined as blood visible in urine, especially in adults is highly suspicious for urologic malignancy thus appropriate imaging and cystoscopic evaluations are necessary in establishing the diagnosis. Hematuria in the setting of prostatic hyperplasia can result from the increased expression of vascular endothelial growth factor, anticoagulation, Foley catheterization, and infection. The management of hematuria encompasses continuous bladder irrigation, fulguration, and embolization.\n\nProstate artery embolization (PAE) is a minimally invasive procedure in which bilateral prostate arteries are embolized in the setting of moderate or severe lower urinary tract syndrome (LUTS) refractory to medications. PAE along with catheter directed arterial embolization of other pelvic vessels can also be performed to treat severe hematuria in high risk population whose conventional therapies have failed. Technical success, defined as bilateral prostate artery embolization, can be achieved at 100% with very low recurrence rate at one year when cone beam computed tomography is used during the procedure.4 CBCT can help visualize the prostatic arteries and detect accessory or collateral supplying vessels and in turn decrease the risks of non-target embolization. In addition to recurrence of hematuria, questionnaires such as international prostate symptoms score (IPSS) and quality of life score (QOL) are used to assess the outcome of the procedure.\n\nContinuous flow LVADs are at increased risk of nonsurgical bleeding from arteriovenous malformations in gastrointestinal tract and acquired von Willebrand disease secondary to nonphysiological sheer stress on blood components and reduced pulse pressure.5 This, coupled with thrombotic risk from the mechanical circulatory device, poses a clinical dilemma in physicians performing endovascular procedures.\n\nConclusion\nProstate artery embolization can be performed safely with favorable outcome for patients with left ventricular assist device presenting with hematuria refractory to conventional therapy. PAE should also be considered as an alternative treatment option in patients with moderate LUTs secondary to BPH, especially in those patients who are on chronic anticoagulation.\n\nConsent\nInformed consent was obtained from the patient and patient information was de-identified prior to submission of the case report.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nDeclaration of competing interest\nNone.\n==== Refs\nReferences\n1 Rose E.A. Gelijns A.C. Moskowitz A.J. Long-term use of a left ventricular assist device for end-stage heart failure N Engl J Med. 345 20 Nov 2001 1435 1443 10.1056/NEJMoa012175 11794191 \n2 Hwang K.Y. Hwang N.C. Facilitating noncardiac surgery for the patient with left ventricular assist device: a guide for the anesthesiologist Ann Card Anaesth 21 4 2018 351 362 10.4103/aca.ACA_239_17 Oct-Dec 2018 30333327 \n3 Bj L, SA B. Management of Emergency Bleeding, Recalcitrant Clots and Hemorrhagic Cystitis. AUA Update Series 342015.\n4 Tapping C.R. Macdonald A. Hadi M. Prostatic artery embolization (PAE) for benign prostatic hyperplasia (BPH) with haematuria in the absence of an upper urinary tract pathology Cardiovasc Intervent Radiol 41 8 Aug 2018 1160 1164 10.1007/s00270-018-1941-0 29582127 \n5 Suarez J. Patel C.B. Felker G.M. Becker R. Hernandez A.F. Rogers J.G. Mechanisms of bleeding and approach to patients with axial-flow left ventricular assist devices Circ Heart Fail 4 6 Nov 2011 779 784 10.1161/CIRCHEARTFAILURE.111.962613 22086831\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "36()",
"journal": "Urology case reports",
"keywords": "Benign prostatic hyperplasia; Interventional radiology; Left ventricular assist device; Lower urinary tract symptom; Prostate artery embolization",
"medline_ta": "Urol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101626357",
"other_id": null,
"pages": "101588",
"pmc": null,
"pmid": "33552921",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports",
"references": "11794191;22086831;29582127;30333327",
"title": "Prostate artery embolization in a patient with left ventricular assist device.",
"title_normalized": "prostate artery embolization in a patient with left ventricular assist device"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-022717",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
},
"dr... |
{
"abstract": "Tyrosine kinase inhibitors (TKIs) are oral chemotherapy drugs used primarily to treat leukemias, renal cell carcinomas, gastrointestinal stromal tumors, and neuroendocrine tumors. Within this group, a number of drugs have already been implicated in jaw necrosis. Axitinib (Inlyta) is a novel TKI currently licensed for the treatment of renal cell carcinoma. We report the first case, to our knowledge, of jaw necrosis solely related to this medication and review the literature surrounding TKIs and their implication in osteonecrosis of the jaw.",
"affiliations": "Department of Oral Surgery, Guys Dental Hospital, London, UK. Electronic address: vinod.patel@hotmail.co.uk.;Department of Oral Surgery, Guys Dental Hospital, London, UK.;Department of Oral Surgery, Guys Dental Hospital, London, UK.;Department of Oral Surgery, Eastman Dental Hospital, London, UK.",
"authors": "Patel|Vinod|V|;Sproat|Chris|C|;Kwok|Jerry|J|;Tanna|Nikki|N|",
"chemical_list": "D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D000077784:Axitinib",
"country": "United States",
"delete": false,
"doi": "10.1016/j.oooo.2017.08.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "124(5)",
"journal": "Oral surgery, oral medicine, oral pathology and oral radiology",
"keywords": null,
"medline_ta": "Oral Surg Oral Med Oral Pathol Oral Radiol",
"mesh_terms": "D000368:Aged; D000077784:Axitinib; D002292:Carcinoma, Renal Cell; D000072700:Conservative Treatment; D006801:Humans; D007093:Imidazoles; D007191:Indazoles; D007680:Kidney Neoplasms; D008297:Male; D008439:Maxillary Diseases; D010020:Osteonecrosis; D047428:Protein Kinase Inhibitors; D011862:Radiography, Panoramic",
"nlm_unique_id": "101576782",
"other_id": null,
"pages": "e257-e260",
"pmc": null,
"pmid": "28918879",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Axitinib-related osteonecrosis of the jaw.",
"title_normalized": "axitinib related osteonecrosis of the jaw"
} | [
{
"companynumb": "GB-PFIZER INC-2018170586",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nImmunosuppressive treatment of patients with idiopathic membranous nephropathy (IMN) is debated due to its possible side effects. The 2012 KDIGO guidelines suggest alkylating agents as first choice therapy. The aim of the study is to retrospectively evaluate the induction and maintenance of clinical remission in patients with histological diagnosis of IMN undergoing steroid and/or cyclosporine therapy at the Nephrology Unit of the Sant'Andrea Hospital in Rome.\n\n\nMETHODS\nTherapy A (conservative) was reserved to low-risk patients. 8 medium and high risk patients were induced by Therapy B (Prednisone 1 mg / kg ≤12-16 weeks plus 8 weeks withdrawal); 6 patients by Therapy C (Prednisone 1 mg /kg ≥20-24 weeks plus 8 week withdrawal) and, finally, 6 steroid-resistent patients by Therapy D (steroid withdrawal + cyclosporine 3-5 mg / kg for 2 years).\n\n\nRESULTS\nComplete remission was observed in 37.5% of patients in Therapy B, in 83.3% of patients in Therapy C and in 66.6% of patients in Therapy D. Patients in group B relapsed more frequently than patients in the other groups. Side effects were irrelevant.\n\n\nCONCLUSIONS\nIn view of the potential cytotoxicity of alkylating agents, steroids are a valid alternative in inducing and maintaining clinical remission over time, when administered with a more aggressive induction scheme. In cases of steroid resistance or rapid relapse, cyclosporine is a valid alternative to alkylating agents.",
"affiliations": "UOC Nefrologia e Dialisi Sant'Andrea, Roma. Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma.;Istituto di Biochimica e Biochimica Clinica, Università Cattolica del Sacro Cuore, Roma, Italia and Fondazione Policlinico Universitario A Gemelli IRCCS, Roma, Italia.;UOC Nefrologia e Dialisi Sant'Andrea, Roma. Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma.;UOC Nefrologia e Dialisi Sant'Andrea, Roma. Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma.;UOC Nefrologia e Dialisi Sant'Andrea, Roma. Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma.;UOC Nefrologia e Dialisi Sant'Andrea, Roma. Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma.",
"authors": "Zotta|Federica|F|;Di Stasio|Enrico|E|;Manzione|Andrea|A|;Pirozzi|Nicola|N|;Stoppacciaro|Antonella|A|;Menè|Paolo|P|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011241:Prednisone",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0393-5590",
"issue": "36(3)",
"journal": "Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia",
"keywords": "cyclosporine; idiopathic membranous nephropathy; nephrotic syndrome; steroid therapy",
"medline_ta": "G Ital Nefrol",
"mesh_terms": "D000328:Adult; D000368:Aged; D016572:Cyclosporine; D005260:Female; D015433:Glomerulonephritis, Membranous; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D012074:Remission Induction; D012189:Retrospective Studies",
"nlm_unique_id": "9426434",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31251003",
"pubdate": "2019-06-11",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Steroid and cyclosporine therapy in idiopathic membranous nephropathy: monocentric experience and literature review.",
"title_normalized": "steroid and cyclosporine therapy in idiopathic membranous nephropathy monocentric experience and literature review"
} | [
{
"companynumb": "NVSC2020IT089167",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Trichodysplasia spinulosa (TS) is a rare skin condition caused by trichodysplasia spinulosa-associated polyomavirus (TSPyV). It affects immunosuppressed patients, and <50 cases have been reported. The majority of these cases are seen in solid organ transplant recipients. TS often poses a diagnostic and therapeutic challenge because of its rarity and resemblance with other skin conditions. Several forms of treatment are usually tried prior to establishing a definitive diagnosis. Oral valganciclovir and topical cidofovir have been found to give the best results and hence are the most commonly used agents once the diagnosis is established. Here, we present two cases with a review of literature of TS in solid organ transplant recipients, focusing on time to develop the condition post-transplant, immunosuppression regimen used, and treatment initiated both before and after a definitive diagnosis.",
"affiliations": "Division of Nephrology, Tufts Medical Center, Boston, Massachusetts, USA.;Division of Nephrology, Tufts Medical Center, Boston, Massachusetts, USA.;Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, Massachusetts, USA.;Pathology and Laboratory Medicine, Tufts Medical Center, Boston, Massachusetts, USA.;Department of Dermatology, Tufts Medical Center, Boston, Massachusetts, USA.;Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, Massachusetts, USA.;Division of Nephrology, Tufts Medical Center, Boston, Massachusetts, USA.;Division of Nephrology, Tufts Medical Center, Boston, Massachusetts, USA.;Division of Nephrology, Tufts Medical Center, Boston, Massachusetts, USA.",
"authors": "Jose|Aju|A|;Dad|Taimur|T|;Strand|Andrew|A|;Tse|Julie Y|JY|;Plotnikova|Natalia|N|;Boucher|Helen W|HW|;Sarnak|Mark J|MJ|;Gilbert|Scott J|SJ|;Goyal|Nitender|N|https://orcid.org/0000-0001-9539-9111",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13342",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "22(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "polyoma; transplant; trichodysplasia spinulosa",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D006201:Hair Diseases; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D011120:Polyomavirus; D027601:Polyomavirus Infections",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13342",
"pmc": null,
"pmid": "32475005",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Trichodysplasia spinulosa: Case reports and review of literature.",
"title_normalized": "trichodysplasia spinulosa case reports and review of literature"
} | [
{
"companynumb": "US-VELOXIS PHARMACEUTICALS-2021VELUS-000246",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditio... |
{
"abstract": "Small-colony variants (SCVs) are a morphologic subtype of Staphylococcus aureus that may occur through several mechanisms including auxotrophism for thymidine, hemin, or menadione. Auxotrophic SCV for thymidine fail to synthesize DNA specifically because of mutations in the thymidylate synthase gene. We isolated S. aureus thymidine-dependent SCVs (TD-SCV) from blood and respiratory samples of a pediatric patient with cystic fibrosis and pulmonary exacerbation.\n\n\n\nNutritional dependence of SCVs on hemin, menadione, and thymidine was evaluated. Antimicrobial susceptibility testing was performed through broth microdilution. Polymerase chain reaction was carried out for mecA, ermA, ermB, ermC, msrA, and msrB resistance genes. DNA sequencing was used to determine mutations in thyA and the multilocus sequence typing to identify genetic relatedness.\n\n\n\nMethicillin-sensitive S. aureus with normal and TD-SCV phenotypes were isolated from respiratory samples and a TD-SCV phenotype was isolated from blood culture. Macrolides resistance was attributed to ermC and msrB genes. All isolates belonged to ST398. The thyA gene in S. aureus is 957 nucleotides in length and encodes a protein of 318 amino acids. The TD-SCV isolates carried a -2 nt frameshift mutation (delta 667GC668) in thyA, creating a stop codon at residue 222 close to the predicted binding site for deoxyuridine monophosphate.\n\n\n\nThe pathogenesis of SCVs is complex and not fully elucidated. Factors inherent to the patient such as physiological conditions, recurrent infections, or coinfection should be considered. Although SCVs are considered less virulent, they showed the ability to invade and cause bacteremia in the patient.",
"affiliations": "Laboratório de Bacteriologia, Complexo Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, Brazil.;Laboratório de Bacteriologia, Complexo Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, Brazil.;Programa de Pós-graduação em Biotecnologia e saúde da Criança e do Adolescente, Faculdades e Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil.;Programa de Pós-graduação em Biotecnologia e saúde da Criança e do Adolescente, Faculdades e Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil.;Laboratório de Bacteriologia, Complexo Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, Brazil.;Departamento de Pediatria, Complexo Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, Brazil.;Departamento de Pediatria, Complexo Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, Brazil.",
"authors": "de Souza|Dilair C|DC|0000-0003-3095-5273;Cogo|Laura L|LL|;Palmeiro|Jussara K|JK|;Dalla-Costa|Libera M|LM|;de Oliveira Tomaz|Ana P|AP|;Riedi|Carlos A|CA|;Rosario Filho|Nelson A|NA|0000-0002-8550-8051",
"chemical_list": "D000900:Anti-Bacterial Agents; D024483:Vitamin K 3; D006427:Hemin; D013936:Thymidine",
"country": "United States",
"delete": false,
"doi": "10.1002/ppul.24730",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1099-0496",
"issue": "55(6)",
"journal": "Pediatric pulmonology",
"keywords": "SCVs; auxotrophism; thyA; thymidine-dependent",
"medline_ta": "Pediatr Pulmonol",
"mesh_terms": "D000900:Anti-Bacterial Agents; D016470:Bacteremia; D003550:Cystic Fibrosis; D024881:Drug Resistance, Bacterial; D005798:Genes, Bacterial; D014644:Genetic Variation; D006427:Hemin; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010641:Phenotype; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus; D013936:Thymidine; D024483:Vitamin K 3",
"nlm_unique_id": "8510590",
"other_id": null,
"pages": "1388-1393",
"pmc": null,
"pmid": "32176841",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Thymidine-auxotrophic Staphylococcus aureus small-colony variant bacteremia in a patient with cystic fibrosis.",
"title_normalized": "thymidine auxotrophic staphylococcus aureus small colony variant bacteremia in a patient with cystic fibrosis"
} | [
{
"companynumb": "NVSC2020BR127601",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Genetic diseases are a major cause of neonatal morbidity and mortality. The clinical differential diagnosis in severely ill neonates, especially in premature infants, is challenging. Next generation sequencing (NGS) diagnostics is a valuable tool, but the turnaround time is often too long to provide a diagnosis in the time needed for clinical guidance in newborn intensive care units (NICU). To minimize turnaround time, we developed an ultra-rapid whole genome sequencing pipeline and tested it in clinical practice. Our pilot case, was a preterm infant presenting with several crises of dehydration, hypoglycaemia and hyponatremia together with nephrocalcinosis and hypertrophic cardiomyopathy. Whole genome sequencing was performed using a paired-end 2x75bp protocol. Sequencing data were exported after 50 sequencing cycles for a first analysis. After run completion, the rapid-sequencing protocol, a second analysis of the 2 x 75 paired-end run was performed. Both analyses comprised read-mapping and SNP-/indel calling on an on-site Edico Genome DRAGEN server, followed by functional annotation and pathogenicity prediction using in-house scripts. After the first analysis within 17 h, the emergency ultra-rapid protocol identified two novel compound heterozygous variants in the insulin receptor gene (INSR), pathogenic variants in which cause Donohue Syndrome. The genetic diagnosis could be confirmed by detection of hyperinsulinism and patient care adjusted. Nonetheless, we decided to pursue RNA studies, proving the functional effect of the novel splice variant and reduced expression levels of INSR in patients skin fibroblasts.",
"affiliations": "Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.;Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.;Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.;Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.;Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.;Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.;Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.;Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.;Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.;Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.",
"authors": "Bamborschke|Daniel|D|0000-0002-9868-0184;Özdemir|Özkan|Ö|;Kreutzer|Mona|M|;Motameny|Susanne|S|;Thiele|Holger|H|;Kribs|Angela|A|;Dötsch|Jörg|J|;Altmüller|Janine|J|;Nürnberg|Peter|P|;Cirak|Sebahattin|S|",
"chemical_list": "D015703:Antigens, CD; D020033:Protein Isoforms; C435941:INSR protein, human; D011972:Receptor, Insulin",
"country": "United States",
"delete": false,
"doi": "10.1002/ajmg.a.61917",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1552-4825",
"issue": "185(1)",
"journal": "American journal of medical genetics. Part A",
"keywords": "Donohue syndrome; INSR; emergency genomics; hyperinsulinism; ultra-rapid genome sequencing",
"medline_ta": "Am J Med Genet A",
"mesh_terms": "D015703:Antigens, CD; D003681:Dehydration; D005260:Female; D030342:Genetic Diseases, Inborn; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007003:Hypoglycemia; D007223:Infant; D007226:Infant Mortality; D007231:Infant, Newborn; D007234:Infant, Premature; D007363:Intensive Care Units, Neonatal; D008297:Male; D058977:Molecular Sequence Annotation; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms; D011972:Receptor, Insulin; D000073336:Whole Genome Sequencing",
"nlm_unique_id": "101235741",
"other_id": null,
"pages": "90-96",
"pmc": null,
"pmid": "33048476",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Ultra-rapid emergency genomic diagnosis of Donahue syndrome in a preterm infant within 17 hours.",
"title_normalized": "ultra rapid emergency genomic diagnosis of donahue syndrome in a preterm infant within 17 hours"
} | [
{
"companynumb": "DE-TEVA-2021-DE-1872532",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "BACKGROUND\nEctopic Cushing syndrome due to ACTH secretion from metastatic medullary thyroid cancer (MTC) is associated with significant morbidity and mortality.\n\n\nOBJECTIVE\nThe aim of the study was to describe the first case of Cushing syndrome associated with MTC in a pediatric patient and the successful reversal of Cushing syndrome with tyrosine kinase inhibitor (vandetanib) therapy.\n\n\nMETHODS\nA 17-year-old Brazilian adolescent presented with metastatic MTC and associated ACTH-dependent ectopic Cushing syndrome in the context of multiple endocrine neoplasia type 2B. When the patient was treated with the tyrosine kinase inhibitor vandetanib, rapid decrease in serum cortisol and improvement of clinical symptoms were observed.\n\n\nCONCLUSIONS\nWe describe the first pediatric case of clinical and biochemical improvement of paraneoplastic MTC-related Cushing syndrome after treatment with vandetanib. Vandetanib and possibly other tyrosine kinase inhibitors may be a novel beneficial option in patients with neuroendocrine tumor-related ectopic Cushing syndrome.",
"affiliations": "Section on Endocrinology and Genetics (A.A.N., M.B.L., C.A.S.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Pharmacology and Experimental Therapeutics Section, Pediatric Oncology Branch (E.F., F.M.B., P.O.W., J.D., B.C.W.), General Surgical Pathology Section (M.M.Q.), and Endocrine Oncology Branch (E.K.), Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892; and Division of Oncology and Center for Childhood Cancer Research (E.F., F.M.B.), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.",
"authors": "Nella|A A|AA|;Lodish|M B|MB|;Fox|E|E|;Balis|F M|FM|;Quezado|M M|MM|;Whitcomb|P O|PO|;Derdak|J|J|;Kebebew|E|E|;Widemann|B C|BC|;Stratakis|C A|CA|",
"chemical_list": "D010880:Piperidines; D011799:Quinazolines; D000324:Adrenocorticotropic Hormone; D011505:Protein-Tyrosine Kinases; C452423:N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2013-4340",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-972X",
"issue": "99(9)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000293:Adolescent; D000324:Adrenocorticotropic Hormone; D018278:Carcinoma, Neuroendocrine; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003480:Cushing Syndrome; D006801:Humans; D008297:Male; D018814:Multiple Endocrine Neoplasia Type 2b; D016609:Neoplasms, Second Primary; D010880:Piperidines; D011505:Protein-Tyrosine Kinases; D011799:Quinazolines; D013964:Thyroid Neoplasms",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "3055-9",
"pmc": null,
"pmid": "24617713",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052060:Research Support, N.I.H., Intramural",
"references": "17123344;24002501;23564596;21346064;22105169;22965939;3963984;2544919;23705946;9874472;1763905;15184865;21306237;24012098;23407483;20847059;22042784;23766359;18402529;16029131;23924025;12183421;23450053;10655437",
"title": "Vandetanib successfully controls medullary thyroid cancer-related Cushing syndrome in an adolescent patient.",
"title_normalized": "vandetanib successfully controls medullary thyroid cancer related cushing syndrome in an adolescent patient"
} | [
{
"companynumb": "US-BAYER-2015-378432",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": null,
"d... |
{
"abstract": "We report a 35-year-old woman who suddenly developed left hemiparesis and dysarthria at 13days after treatment with intrathecal and intravenous methotrexate for intravascular large B cell lymphoma with possible central nervous system infiltration. Seven hours after onset, she developed further right hemiparesis and aphasia. However, the majority of neurologic symptoms disappeared spontaneously and completely by 34hours. We also recorded the dynamic progression and regression of abnormal signals in the bilateral corona radiata on diffusion-weighted imaging, in parallel with neurologic symptoms. The rapid reversal of MR abnormalities and neurologic symptoms allowed us to diagnose methotrexate encephalopathy, and exclude intravascular large B cell lymphoma recurrence and regular brain infarction. The case provides new data on the dynamic changes of abnormal signals on magnetic resonance imaging in methotrexate encephalopathy over a short recovery time.",
"affiliations": "Department of Neurology, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan; Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: kei-y@intmed2.med.kyushu-u.ac.jp.;Department of Neurology, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan.;Department of Neurology, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan.;Department of Hematology and Oncology, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan.;Department of Hematology and Oncology, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Neurology, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan.",
"authors": "Yamanaka|Kei|K|;Okata|Takuya|T|;Sambongi|Yoshiki|Y|;Yamanaka|Ikumi|I|;Tanimoto|Kazuki|K|;Ago|Tetsuro|T|;Kitazono|Takanari|T|;Kitayama|Jiro|J|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2018.06.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "27(11)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Demyelination; diffusion-weighted image; encephalopathy; intravascular lymphoma; methotrexate; stroke-mimic",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000328:Adult; D000964:Antimetabolites, Antineoplastic; D002545:Brain Ischemia; D003937:Diagnosis, Differential; D038524:Diffusion Magnetic Resonance Imaging; D004401:Dysarthria; D042241:Early Diagnosis; D004660:Encephalitis; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell; D008727:Methotrexate; D010291:Paresis; D011237:Predictive Value of Tests; D020521:Stroke",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "e233-e235",
"pmc": null,
"pmid": "30049517",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Subacute Methotrexate Encephalopathy Mimicking Ischemic Stroke With Dynamic Changes on Magnetic Resonance Imaging.",
"title_normalized": "subacute methotrexate encephalopathy mimicking ischemic stroke with dynamic changes on magnetic resonance imaging"
} | [
{
"companynumb": "JP-MYLANLABS-2018M1088329",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Purpose: Genomic profiling of tumor biopsies from advanced gastrointestinal and anal cancers is increasingly used to inform treatment. In some cases, tissue biopsy can be prohibitive, and we sought to investigate whether analysis of blood-derived circulating tumor DNA (ctDNA) may provide a minimally invasive alternative.Experimental Design: Hybrid capture-based genomic profiling of 62 genes was performed on blood-based ctDNA from 417 patients with gastrointestinal carcinomas to assess the presence of genomic alterations (GA) and compare with matched tissue samples.Results: Evidence of ctDNA was detected in 344 of 417 samples (82%), and of these, ≥1 reportable GA was detected in 89% (306/344) of samples. Frequently altered genes were TP53 (72%), KRAS (35%), PIK3CA (14%), BRAF (8%), and EGFR (7%). In temporally matched ctDNA and tissue samples available from 25 patients, 86% of alterations detected in tissue were also detected in ctDNA, including 95% of short variants, but only 50% of amplifications. Conversely, 63% of alterations detected in ctDNA were also detected in matched tissue. Examples demonstrating clinical utility are presented.Conclusions: Genomic profiling of ctDNA detected potentially clinically relevant GAs in a significant subset of patients with gastrointestinal carcinomas. In these tumor types, most alterations detected in matched tissue were also detected in ctDNA, and with the exception of amplifications, ctDNA sequencing routinely detected additional alterations not found in matched tissue, consistent with tumor heterogeneity. These results suggest feasibility and utility of ctDNA testing in advanced gastrointestinal cancers as a complementary approach to tissue testing, and further investigation is warranted. Clin Cancer Res; 24(8); 1881-90. ©2018 AACR.",
"affiliations": "Foundation Medicine, Inc. Cambridge, Massachusetts. aschrock@foundationmedicine.com.;Foundation Medicine, Inc. Cambridge, Massachusetts.;The Angeles Clinic and Research Institute, Los Angeles, California.;Foundation Medicine, Inc. Cambridge, Massachusetts.;Foundation Medicine, Inc. Cambridge, Massachusetts.;Foundation Medicine, Inc. Cambridge, Massachusetts.;Foundation Medicine, Inc. Cambridge, Massachusetts.;Avera Cancer Institute, Sioux Falls, South Dakota.;Georgia Cancer Specialists, Marietta, Georgia.;Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.;Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, California.;Moores Cancer Center, University of California San Diego, La Jolla, California.;Moores Cancer Center, University of California San Diego, La Jolla, California.;Foundation Medicine, Inc. Cambridge, Massachusetts.;Foundation Medicine, Inc. Cambridge, Massachusetts.;Northwell Health, Lake Success, New York.;Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada.;Foundation Medicine, Inc. Cambridge, Massachusetts.;Foundation Medicine, Inc. Cambridge, Massachusetts.",
"authors": "Schrock|Alexa B|AB|;Pavlick|Dean|D|;Klempner|Samuel J|SJ|;Chung|Jon H|JH|;Forcier|Brady|B|;Welsh|Allison|A|;Young|Lauren|L|;Leyland-Jones|Bryan|B|;Bordoni|Rodolfo|R|;Carvajal|Richard D|RD|;Chao|Joseph|J|;Kurzrock|Razelle|R|;Sicklick|Jason K|JK|;Ross|Jeffrey S|JS|;Stephens|Philip J|PJ|;Devoe|Craig|C|;Braiteh|Fadi|F|;Ali|Siraj M|SM|;Miller|Vincent A|VA|",
"chemical_list": "D014408:Biomarkers, Tumor; D000074141:Circulating Tumor DNA",
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-17-3103",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
"issue": "24(8)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001005:Anus Neoplasms; D014408:Biomarkers, Tumor; D000074141:Circulating Tumor DNA; D005260:Female; D005500:Follow-Up Studies; D005770:Gastrointestinal Neoplasms; D023281:Genomics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009693:Nucleic Acid Hybridization; D009928:Organ Specificity",
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "1881-1890",
"pmc": null,
"pmid": "29363525",
"pubdate": "2018-04-15",
"publication_types": "D016428:Journal Article",
"references": "25623215;24676216;28537764;27108243;22042947;27780856;28850629;22810696;26774880;28617917;26644315;19001320;28507204;27760322;26474073;24142049;24024839;24141978;23729478;28911069;26980473;22588877;28945887;25293556;28235761;21135276;17936563;20728210;26933125;26030179;24553385;29370427;27384348;29196463;27682134",
"title": "Hybrid Capture-Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Cancers of the Gastrointestinal Tract or Anus.",
"title_normalized": "hybrid capture based genomic profiling of circulating tumor dna from patients with advanced cancers of the gastrointestinal tract or anus"
} | [
{
"companynumb": "PHHY2018US026833",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CERITINIB"
},
"drugadditional": null,
"druga... |
{
"abstract": "Bone marrow necrosis (BMN) describes necrosis of the myeloid tissues without cortical bone involvement. Imatinib, a tyrosine kinase inhibitor, can trigger BMN during the treatment of malignant disease. In such cases, it is necessary to reduce imatinib dose or discontinue its administration, which could influence treatment outcomes. Here, we report a 6-year-old boy with Philadelphia chromosome-positive acute lymphoblastic leukemia, who developed BMN in response to imatinib. We replaced imatinib with dasatinib, and necrotic lesions gradually disappeared and were never exacerbated. In Philadelphia chromosome-positive acute lymphoblastic leukemia with BMN, tyrosine kinase inhibitor replacement may allow continued chemotherapy without intensity reduction.",
"affiliations": "Departments of Pediatrics Orthopaedic Surgery Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.",
"authors": "Mikami|Takashi|T|;Kato|Itaru|I|;Oiki|Nanami|N|;Okamoto|Seiji|S|;Kamitori|Tatsuya|T|;Tasaka|Keiji|K|;Ogata|Hideto|H|;Tanaka|Kuniaki|K|;Umeda|Katsutsugu|K|;Hiramatsu|Hidefumi|H|;Okamoto|Takeshi|T|;Adachi|Souichi|S|;Takita|Junko|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000002157",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": null,
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "9505928",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33843813",
"pubdate": "2021-04-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Improvement of Bone Marrow Necrosis by Tyrosine Kinase Inhibitor Substitution in a Pediatric Patient With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia.",
"title_normalized": "improvement of bone marrow necrosis by tyrosine kinase inhibitor substitution in a pediatric patient with philadelphia chromosome positive acute lymphoblastic leukemia"
} | [
{
"companynumb": "JP-TEVA-2022-JP-2045575",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugadditional": "1",
"... |
{
"abstract": "A male lifelong nonsmoker aged 58 years with no prior asbestos exposure complained of gradual worsening breathlessness over 3 months. This was associated with abdominal and leg swelling and a 2-kg weight loss. He had no fever, night sweats, hemoptysis, joint pain, rash, abdominal pain, chest pain, or orthopnea. The patient had no recent travel or contact with pulmonary TB. He had stage I left-side testicular seminoma treated with left-sided radical orchidectomy 10 years previous and recently received a diagnosis of Child's B alcoholic liver cirrhosis. His hepatitis B and C screen result was normal.",
"affiliations": "Division of Respiratory and Critical Care Medicine, National University Hospital, Singapore. Electronic address: andrew_yunkai_li@nuhs.edu.sg.;Department of Haematology-Oncology, National University Cancer Institute of Singapore, Singapore.;Division of Respiratory and Critical Care Medicine, National University Hospital, Singapore.;Department of Pathology, National University Hospital, Singapore.;Department of Diagnostic-Imaging, National University Hospital, Singapore.;Division of Respiratory and Critical Care Medicine, National University Hospital, Singapore.",
"authors": "Li|Andrew|A|;Poon|Limei|L|;Khoo|Kay-Leong|KL|;Seet|Ju-Ee|JE|;Sinha|Arvind Kumar|AK|;Lee|Pyng|P|",
"chemical_list": "D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D011092:Polyethylene Glycols; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; C423652:pegylated granulocyte colony-stimulating factor",
"country": "United States",
"delete": false,
"doi": "10.1378/chest.14-2237",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "147(6)",
"journal": "Chest",
"keywords": null,
"medline_ta": "Chest",
"mesh_terms": "D000970:Antineoplastic Agents; D001201:Ascites; D001402:B-Lymphocytes; D003520:Cyclophosphamide; D004317:Doxorubicin; D004359:Drug Therapy, Combination; D017809:Fatal Outcome; D016179:Granulocyte Colony-Stimulating Factor; D019288:Herpesvirus 8, Human; D006801:Humans; D054685:Lymphoma, Primary Effusion; D008297:Male; D008875:Middle Aged; D010996:Pleural Effusion; D011092:Polyethylene Glycols; D049268:Positron-Emission Tomography; D011994:Recombinant Proteins; D014057:Tomography, X-Ray Computed; D014750:Vincristine",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "e208-e214",
"pmc": null,
"pmid": "26033134",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A man with pleural effusion and ascites.",
"title_normalized": "a man with pleural effusion and ascites"
} | [
{
"companynumb": "SG-JNJFOC-20150822122",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo investigate drug-resistant mutations in and genotypes of hepatitis B virus (HBV) in chronic HBV carriers using PCR sequencing technology.\n\n\nMETHODS\nChronic HBV carriers were recruited from Tianjin Second People's Hospital between June 2013 and May 2014 and 317 were enrolled in the study according to receipt of nucleos(t)ide analogues (NAs) for at least three months prior. Drug-resistant mutations were detected by PCR followed by sequencing. SPSS21.0 was used for statistical analysis.\n\n\nRESULTS\nDrug-resistant mutations were detected in 119 of the 317 patients, including 20 of 46 patients who received lamivudine (LAM), 16 of 34 patients who received adefovir (ADV), 13 of 80 patients who received entecavir (ETV), 5 of 23 patients who received telbivudine (LdT), and 65 of 124 patients who received various sequential/combined NA therapies. Each of the NAs had dominant drug-resistant mutational profiles, with rtM204I+rtL180M±rtL80I (30.9%) for LAM, rtA181T/N (21.3%), rtS213T/N (21.3%) and rtV214A (21.3%) for ADV, rtl180M (48%) for ETV, rtM204I for LdT, and rtA194T for tenofovir disoproxil fumarate (TDF). A total of 308 HBV genotypes were detected, including type B in 27 cases (8.8%), type C in 279 cases (90.6%), and type D in 2 cases (0.6%). The different HBV genotypes had no statistically significant difference in drug-resistance mutations, though (χ(2) = 1.11, P > 0.05). Two TDF drug-resistant mutations rtA194T were detected.\n\n\nCONCLUSIONS\nThe results provide new information on NA drug-resistant mutations and HBV genotype profiles in chronic HBV carriers and may have important clinical implication for HBV drug resistance management. In addition, the data confirmed the preexisting TDF mutation rtA194T.",
"affiliations": "Tianjin Institute of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China.",
"authors": "Jiang|B|B|;Dai|C Y|CY|;Li|X M|XM|;Su|R|R|;Xu|J|J|;Cao|Y|Y|;Hou|W|W|;Lu|W|W|",
"chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; D000077712:Telbivudine; D019259:Lamivudine; C413685:entecavir; D006147:Guanine; C053001:adefovir; D000068698:Tenofovir; D000225:Adenine; D013936:Thymidine",
"country": "China",
"delete": false,
"doi": "10.3760/cma.j.issn.1007-3418.2016.01.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-3418",
"issue": "24(1)",
"journal": "Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology",
"keywords": null,
"medline_ta": "Zhonghua Gan Zang Bing Za Zhi",
"mesh_terms": "D000225:Adenine; D000998:Antiviral Agents; D004279:DNA, Viral; D024882:Drug Resistance, Viral; D005838:Genotype; D006147:Guanine; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D019259:Lamivudine; D009154:Mutation; D063065:Organophosphonates; D016133:Polymerase Chain Reaction; D000077712:Telbivudine; D000068698:Tenofovir; D013936:Thymidine",
"nlm_unique_id": "9710009",
"other_id": null,
"pages": "36-9",
"pmc": null,
"pmid": "26983387",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Drug-resistant mutations in hepatitis B virus found in chronic HBV carriers using PCR sequencing technology.",
"title_normalized": "drug resistant mutations in hepatitis b virus found in chronic hbv carriers using pcr sequencing technology"
} | [
{
"companynumb": "CN-GLAXOSMITHKLINE-CN2016GSK059065",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": nul... |
{
"abstract": "OBJECTIVE\nTo evaluate the feasibility of chemotherapy including fluoropyrimidine, platinum and taxane with modified dosages for unresectable gastric cancer in Japanese patients.\n\n\nMETHODS\nWe performed a feasibility study of a modified docetaxel, cisplatin and capecitabine (DCX) regimen for stage IV gastric cancer. In particular, 30 or 40 mg/m2 of docetaxel on day 1, 60 mg/m2 of cisplatin on day 1, and 2000 mg/m2 of capecitabine for 2 wk were administered every three weeks.\n\n\nRESULTS\nThree patients were treated with modified DCX (mDCX) with 30 mg/m2 docetaxel, and five patients were treated with this regimen with 40 mg/m2 docetaxel. Grade 3 or 4 neutropenia was observed in six of the eight patients; no patients exhibited febrile neutropenia. Partial response was achieved in four of the eight patients. Three patients underwent gastrectomy, which achieved R0 resection without residual tumors in dissected lymph nodes. In one of these three patients, resected specimens revealed pathological complete response in the primary lesion and in lymph nodes.\n\n\nCONCLUSIONS\nmDCX was well tolerated by Japanese patients with stage IV gastric cancer. This regimen might be useful for allowing gastric cancer patients with distant lymph node metastasis to undergo conversion surgery.",
"affiliations": "Osamu Maeda, Ayumu Matsuoka, Yuichi Ando, Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya 466-8560, Japan.;Osamu Maeda, Ayumu Matsuoka, Yuichi Ando, Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya 466-8560, Japan.;Osamu Maeda, Ayumu Matsuoka, Yuichi Ando, Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya 466-8560, Japan.;Osamu Maeda, Ayumu Matsuoka, Yuichi Ando, Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya 466-8560, Japan.;Osamu Maeda, Ayumu Matsuoka, Yuichi Ando, Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya 466-8560, Japan.;Osamu Maeda, Ayumu Matsuoka, Yuichi Ando, Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya 466-8560, Japan.;Osamu Maeda, Ayumu Matsuoka, Yuichi Ando, Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya 466-8560, Japan.;Osamu Maeda, Ayumu Matsuoka, Yuichi Ando, Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya 466-8560, Japan.;Osamu Maeda, Ayumu Matsuoka, Yuichi Ando, Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya 466-8560, Japan.;Osamu Maeda, Ayumu Matsuoka, Yuichi Ando, Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya 466-8560, Japan.",
"authors": "Maeda|Osamu|O|;Matsuoka|Ayumu|A|;Miyahara|Ryoji|R|;Funasaka|Kohei|K|;Hirooka|Yoshiki|Y|;Fukaya|Masahide|M|;Nagino|Masato|M|;Kodera|Yasuhiro|Y|;Goto|Hidemi|H|;Ando|Yuichi|Y|",
"chemical_list": "D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D000069287:Capecitabine; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v23.i6.1090",
"fulltext": "\n==== Front\nWorld J GastroenterolWorld J. GastroenterolWJGWorld Journal of Gastroenterology1007-93272219-2840Baishideng Publishing Group Inc jWJG.v23.i6.pg109010.3748/wjg.v23.i6.1090Prospective StudyModified docetaxel, cisplatin and capecitabine for stage IV gastric cancer in Japanese patients: A feasibility study Maeda Osamu Matsuoka Ayumu Miyahara Ryoji Funasaka Kohei Hirooka Yoshiki Fukaya Masahide Nagino Masato Kodera Yasuhiro Goto Hidemi Ando Yuichi Osamu Maeda, Ayumu Matsuoka, Yuichi Ando, Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya 466-8560, JapanRyoji Miyahara, Kohei Funasaka, Hidemi Goto, Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, JapanYoshiki Hirooka, Department of Endoscopy, Nagoya University Hospital, Nagoya 466-8560, JapanMasahide Fukaya, Masato Nagino, Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 466-8550 Nagoya, JapanYasuhiro Kodera, Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 466-8550 Nagoya, JapanAuthor contributions: Maeda O and Ando Y designed the research, performed the protocol treatment and wrote the manuscript; Matsuoka A, Miyahra R, Funasaka K and Fukaya M contributed to performing the protocol treatment; Hirooka Y, Nagino M, Kodera Y and Goto H were involved in patient recruitment and data analysis.\n\nCorrespondence to: Osamu Maeda, MD, PhD, Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Aichi, Japan. maeda-o@med.nagoya-u.ac.jp\n\nTelephone: +81-52-7441903 Fax: +81-52-7441903\n\n14 2 2017 14 2 2017 23 6 1090 1097 20 10 2016 19 12 2016 17 1 2017 ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.2017This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is 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 and the use is non-commercial.AIM\nTo evaluate the feasibility of chemotherapy including fluoropyrimidine, platinum and taxane with modified dosages for unresectable gastric cancer in Japanese patients.\n\nMETHODS\nWe performed a feasibility study of a modified docetaxel, cisplatin and capecitabine (DCX) regimen for stage IV gastric cancer. In particular, 30 or 40 mg/m2 of docetaxel on day 1, 60 mg/m2 of cisplatin on day 1, and 2000 mg/m2 of capecitabine for 2 wk were administered every three weeks.\n\nRESULTS\nThree patients were treated with modified DCX (mDCX) with 30 mg/m2 docetaxel, and five patients were treated with this regimen with 40 mg/m2 docetaxel. Grade 3 or 4 neutropenia was observed in six of the eight patients; no patients exhibited febrile neutropenia. Partial response was achieved in four of the eight patients. Three patients underwent gastrectomy, which achieved R0 resection without residual tumors in dissected lymph nodes. In one of these three patients, resected specimens revealed pathological complete response in the primary lesion and in lymph nodes.\n\nCONCLUSION\nmDCX was well tolerated by Japanese patients with stage IV gastric cancer. This regimen might be useful for allowing gastric cancer patients with distant lymph node metastasis to undergo conversion surgery.\n\nDocetaxelCisplatinCapecitabineGastric cancer\n==== Body\nCore tip: A combination of fluoropyrimidine and platinum is a standard treatment for unresectable gastric cancer. Although the addition of a taxane to this doublet is expected to improve effectiveness, research has demonstrated that such triplet regimens often cause adverse effects, including neutropenia. To reduce adverse events but maintain therapeutic effectiveness, we devised a triplet regimen with modified dosages. Modified docetaxel, cisplatin and capecitabine treatment was safe and effective for stage IV gastric cancer. Three of the eight treated patients underwent conversion surgery and achieved long-term survival without recurrence.\n\nINTRODUCTION\nThe prognosis of stage IV gastric cancer is poor, and the median overall survival time is approximately one year. The standard treatment for Stage IV gastric cancer is chemotherapy with agents such as fluoropyrimidines and platinum compounds. In Japan, the oral fluoropyrimidine S-1 plus cisplatin (SP) is the standard regimen for HER2-negative advanced gastric cancer because SP was proven to be superior to S-1 alone in a phase III randomized trial[1]. Because capecitabine, similarly to S-1, is an effective oral fluoropyrimidine, capecitabine plus cisplatin (XP) is also a possible regimen[2].\n\nThe addition of docetaxel to fluoropyrimidine and cisplatin was expected to improve therapeutic efficacy. A combination of docetaxel, cisplatin and 5-fluorouracil (DCF) produced longer overall survival than cisplatin plus 5-fluorouracil; however, the use of DCF is limited due to severe side effects, including hematologic toxicity[3]. Various modified DCF regimens have been tested in attempts to improve tolerability without losing efficacy[4-8]. Research has also examined regimens that replace the infusion of 5-fluorouracil with an oral fluoropyrimidine, such as docetaxel, cisplatin and S-1 (DCS)[9] and docetaxel, cisplatin and capecitabine (DCX)[10]. Although DCX has been reported to be effective for unresectable gastric cancer, this regimen often causes adverse events, including hematologic toxicities[10-12]. We believed that a modification of the doses used for DCX might reduce toxicity but maintain effectiveness. In previous reports, doses of docetaxel used for DCX ranged from 60 mg/m2 to 75 mg/m2[10-12]. In certain studies of DCS, the dose of docetaxel was set to 30-40 mg/m2, and good effectiveness and adequate safety were achieved[13-15]. In the present study, we set the dose of docetaxel to 30 or 40 mg/m2, which was a lower dose than that used in previous reports on DCX, and evaluated the safety and efficacy of our modified DCX (mDCX) regimen in Japanese patients.\n\nMATERIALS AND METHODS\nPatient eligibility\nThe eligibility criteria included stage IV unresectable HER2-negative gastric cancer, an age of 20-75 years, Eastern Cooperative Oncology Group performance status 0-1, conserved organ functions, and no prior chemotherapy.\n\nTreatment\nThe treatment regimen, which consisted of 1000 mg/m2 capecitabine twice per day on days 1-14, 60 mg/m2 cisplatin on day 1 and 30 or 40 mg/m2 docetaxel on day 1, was administered every three weeks. The dosage of docetaxel was 30 mg/m2 for the first three patients and was planned to increase to 40 mg/m2 for subsequent patients if no dose-limiting toxicities (DLTs) were observed after the first three patients' first treatment cycle. The treatment was continued until the disease progressed, patients experienced intolerable side effects, or curative resection was expected.\n\nTreatment was interrupted if a patient developed grade ≥ 3 hematologic toxicity. If a patient experienced grade 4 neutropenia for more than 5 d or grade 3 febrile neutropenia, the dosage of all agents was decreased to 75% for the next course. If a patient exhibited grade 4 thrombocytopenia, dosages of all agents were decreased to 50%. If a patient had grade ≥ 2 diarrhea and/or grade ≥ 2 hand-foot syndrome, the treatment course was interrupted. If creatinine clearance (Ccr) was < 60 mL/min and ≥ 50 mL/min, cisplatin was decreased to 75%. If Ccr was < 50 mL/min and ≥ 40 mL/min, cisplatin was decreased to 50%. If Ccr was < 40 mL/min, the treatment protocol was terminated. Supportive treatment, including G-CSF and anti-emetics, was permitted.\n\nSafety and anti-tumor activity assessments\nAdverse events were assessed using the National Cancer Institute's CTCAE v4.0. DLTs were defined as adverse events that occurred after the beginning of the first cycle and before the beginning of the second cycle that satisfied any of the following criteria: (1) non-hematologic toxicities ≥ grade 3 that did not resolve to grade 0 or grade 1 within two consecutive days, except for nausea, vomiting, anorexia and asymptomatic electrolyte imbalance; (2) neutropenia ≥ grade 3 for > 5 consecutive days; (3) febrile neutropenia (absolute neutrophil count < 1.0 × 109/L and fever ≥ 38 °C); (4) grade 4 thrombocytopenia or platelet transfusion; or (5) delay of the treatment cycle for > 2 wk.\n\nRadiological tumor assessments were conducted using computed tomography every eight weeks in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.\n\nRESULTS\nThree patients received mDCX with 30 mg/m2 of docetaxel. Because no DLTs were observed in the first three patients, treatment with 40 mg/m2 docetaxel was administered to five subsequent patients.\n\nThe patients' characteristics and clinical courses are summarized in Table 1, and adverse events are summarized in Table 2. No DLTs were observed after the first treatment cycles in any patient. The relative dose intensities of DCX were 90.6%, 90.0% and 76.2%, respectively. Four of the eight patients exhibited a partial response (PR). Three patients (cases 2, 5 and 8) underwent gastrectomy with lymph node dissection; for all of these patients, R0 resection was achieved, and no viable tumors were detected in resected lymph nodes (ypN0). Case 2 achieved pathological complete response in both the primary lesion and lymph node metastasis. Regarding case 5, the observed therapeutic effect was grade 2, and she received capecitabine for ten weeks as adjuvant chemotherapy. The clinical courses of three representative cases are presented below.\n\nTable 1 Patient characteristics and prognoses\n\n\tAge\tSex\tMacroscopic type\tHistopathology\tMetastasis\tNumber of courses\tObjective tumor response\tPrognosis (mo)\tConversion surgery\t\n1\t64\tM\t3\ttub2/por\tLiver, LNs\t7\tPR\t21.9\tDead\t\t\n2\t59\tM\t3\ttub2/por\tLNs\t5\tPR\t50.9\tAlive\tYes\t\n3\t62\tM\t2\tpor\tLiver, LNs\t6\tSD\t7.4\tDead\t\t\n4\t65\tM\t3\tpor\tLNs\t5\tPR\t7.7\tDead\t\t\n5\t67\tF\t3\ttub2/por\tLNs\t3\tnon-CR/non-PD\t31.3\tAlive\tYes\t\n6\t66\tM\t3\tpor\tLNs\t4\tnon-CR/non-PD\t12.0\tDead\t\t\n7\t62\tM\t2\tpor\tLiver, LNs\t3\tSD\t5.4\tDead\t\t\n8\t63\tF\t2\ttub2/por\tLNs\t4\tPR\t24.4\tAlive\tYes\t\ntub2: Moderately differentiated tubular adenocarcinoma; por: Differentiated adenocarcinoma; LNs: Lymph nodes; PR: Partial response; SD: Stable disease; CR: Complete response.\n\nTable 2 Hematologic and non-hematologic adverse events n (%)\n\n\tAny grade\tGrade 3\tGrade 4\t\nLeukopenia\t7 (87.5)\t2 (25)\t0\t\nNeutropenia\t7 (87.5)\t4 (50)\t2 (25)\t\nAnemia\t6 (75)\t1 (12.5)\t0\t\nThrombocytopenia\t7 (87.5)\t0\t0\t\nHyperbilirubinemia\t3 (37.5)\t0\t0\t\nElevated serum aspartate aminotransferase\t6 (75)\t0\t0\t\nElevated serum alanine aminotransferase\t8 (100)\t0\t0\t\nElevated serum creatinine\t3 (37.5)\t0\t0\t\nFever\t4 (50)\t0\t0\t\nFatigue\t2 (25)\t0\t0\t\nAlopecia\t1 (12.5)\t0\t0\t\nSkin rash\t1 (12.5)\t0\t0\t\nAnorexia\t7 (87.5)\t4 (50)\t0\t\nDiarrhea\t4 (50)\t2 (25)\t0\t\nNausea\t3 (37.5)\t0\t0\t\nVomiting\t3 (37.5)\t0\t0\t\nConstipation\t1 (12.5)\t0\t0\t\nPeripheral neuropathy\t1 (12.5)\t0\t0\t\nInfection\t1 (12.5)\t1 (12.5)\t0\t\nCase 1\nA 64-year-old man had type III advanced cancer in the fornix of the stomach and multiple liver metastases (Figure 1). Biopsy specimens were pathologically diagnosed as moderately and poorly differentiated adenocarcinoma. The patient received three courses of mDCX, and the liver metastases shrank, a phenomenon judged to be PR. After five courses, PR was confirmed. After seven courses, shrinkage of the liver metastases was sustained. The treatment protocol was discontinued due to grade 2 sensory peripheral neuropathy. Other adverse events were grade 2 anemia, grade 1 aspartate aminotransferase elevation, grade 1 alanine aminotransferase elevation, and grade 1 anorexia. The patient received post-protocol treatment that included irinotecan and weekly paclitaxel. He died 22 mo after enrollment in the study.\n\nFigure 1 Case 1. Endoscopic findings (A, B) and computed tomography images (C, D) before (A, C) and after (B, D) seven courses of modified docetaxel, cisplatin and capecitabine (DCX) (mDCX).\n\nCase 2\nA 59-year-old man had type III advanced cancer at the small curvature of the angulus with lymph node metastasis along the superior mesenteric artery (#14a; Figure 2). Biopsy specimens were pathologically diagnosed as moderately and poorly differentiated adenocarcinoma. After three courses of mDCX, the lymph node metastasis shrank; after five courses, PR was confirmed. Adverse events included grade 2 leukopenia, grade 3 neutropenia, and grade 2 anemia. The patient underwent subtotal gastrectomy with lymph node dissection. Pathological findings revealed no residual carcinoma, and the observed therapeutic effect was grade 3. He received S-1 for one year as adjuvant chemotherapy. He remains alive without any findings indicative of recurrence four years after enrollment.\n\nFigure 2 Case 2. Endoscopic findings (A, B) and computed tomography images (C, D, E, F) before treatment (A, C, E) and after (B, D, F) five courses of modified docetaxel, cisplatin and capecitabine (DCX) (mDCX). The primary lesion (A, B), swollen lymph nodes along the common hepatic artery (#8) (C, D) and lymph nodes along the superior mesenteric artery (#14a) (E, F) markedly shrank. Microscopic findings for the resected specimens of the primary lesion (E, magnification × 100) and lymph nodes (F, magnification × 400) revealed no residual tumor.\n\nCase 8\nA 63-year-old woman had type III advanced cancer at the gastric antrum with lymph node metastasis that included left supraclavicular lymph nodes and para-aortic lymph nodes (Figure 3). Biopsy specimens were pathologically diagnosed as moderately and poorly differentiated adenocarcinoma. After two courses of mDCX, the lymph nodes shrank; after four courses, PR was confirmed. Adverse events included grade 2 leukopenia, grade 4 neutropenia, grade 3 anorexia, and grade 3 diarrhea. Because the patient's lymph node metastasis became undetectable by computed tomography, she underwent subtotal gastrectomy with D2 dissection; the para-aortic lymph nodes were not dissected. Pathological findings revealed no residual tumors in the lymph nodes, and the observed therapeutic effect was grade 1b. As adjuvant chemotherapy, she underwent two courses of capecitabine plus oxaliplatin which were discontinued due to grade 2 nausea and fatigue. She subsequently received S-1 for one year. The patient remains alive without any findings indicative of recurrence two years after enrollment.\n\nFigure 3 Case 8. Computed tomography images before (A, C) and after (B, D) four courses of modified docetaxel, cisplatin and capecitabine (DCX) (mDCX). Left supraclavicular nodes (A, B) and para-aortic nodes (C, D) became undetectable.\n\nDISCUSSION\nReports have described the effectiveness of DCX for unresectable gastric cancer[10,16], as preoperative chemotherapy[17], as adjuvant chemotherapy[18] and as perioperative chemotherapy[12]. These reports indicate that DCX is highly effective but also rather toxic, particularly in hematologic respects. To our knowledge, no prior reports have described a DCX trial in Japan.\n\nIn the present study, six of the eight patients (75%) experienced grade 3 or grade 4 neutropenia, although no patients experienced febrile neutropenia. Although the modifications to the DCX regimen decreased the dose of docetaxel to 30 or 40 mg/m2, the frequency of hematologic toxicity in this study was similar to those reported in prior studies of DCX (neutropenia ≥ grade 3, 40%-76.5%; Table 3). However, we regarded the observed side effects as tolerable because no DLT was observed after the first cycle, and all patients were able to receive three or more courses of treatment with appropriate supportive care. In addition, the median admission period was five days (data not shown), indicating that for the most part, admission was primarily necessary for hydration due to the administration of cisplatin.\n\nTable 3 Previous reports regarding docetaxel, cisplatin and capecitabine\n\nRef.\tSetting\tCapecitabine\tCisplatin\tDocetaxel\tInterval (d)\tNumber of patients\t\tGrade 3-4 neutropenia\tFebrile neutropenia\tRR (95%CI)\tPFS (95%CI)\tOS (95%CI)\tR0 resection\tpCR\t\n(mo)\t(mo)\t\nKang et al[10], 2010\tMetastatic or recurrent\t1875 mg, days 1-14\t60 mg, day 1\t60 mg, day 1\t21\t40\t\t62.5%\t10%\t68% (53%-83%)\t7.6 (6.9-8.4)\t14.4 (7.3-21.5)\t\t10.0%\t\nSym et al[17], 2010\tNeoadjuvant\t1875 mg, days 1-14\t60 mg, day 1\t60 mg, day 1\t21\t49 (36 resected cases)\t\t69%\t4%\t\tR0: 54.3 (0-112.9)\tR0: not reached\t63.0%\t\t\n\tNon-R0: 5.1 (3.6-6.6)\tNon-R0: 11.5 (7.3-15.7)\t\t\t\nThuss-Patience et al[12], 2012\tPerioperative\t1875 mg, days 1-14\t60 mg, day 1\t75 mg, day1\t21\t51\tPreoperative\t76.5%\t21.5%\t\t\t\t90.2%\t13.7%\t\nPostoperative\t62.9%\t11.1%\t\t\t\t\nPolyzos et al[16], 2012\tMetastatic\t2000 mg, days 2-15\t60 mg, day 1\t60 mg, day 1\t21\t36\t\t50%\t16%\t44.4% (28%-60%)\t5 (3-6)1\t12 (5-24)\t\t\t\nYoon et al[18], 2015\tAdjuvant for stage IIIB-IV\t1875 mg, days 1-14\t60 mg, day 1\t60 mg, day 1\t21\t46\t\t40%\t15%\t\t26.9 (7.5-46.4)2\t43.9 (29.2-58.7)\t\t\t\n1 Time to progression; \n\n2 Relapse-free survival. RR: Response rate; PFS: Progression-free survival; OS: Overall survival; pCR: Pathological complete response.\n\nThree of the five patients with only distant lymph node metastasis underwent conversion surgery, and all three patients have remained alive for more than two years without recurrence. Therefore, we believe that intensive treatment with a triplet regimen could be a useful preoperative treatment that enables conversion surgery for patients with distant lymph node metastasis. However, in certain cases, survival time was shorter than one year; in particular, one case died 7.7 mo after the start of treatment, although PR was achieved. It is necessary to identify certain biomarkers to select patients suitable for a triplet regimen. Furthermore, a randomized control study is needed to evaluate whether the proposed triplet regimen is superior to a standard platinum and oral fluoropyrimidine doublet.\n\nIn conclusion, mDCX is safe and effective for Stage IV gastric cancer in Japanese patients.\n\nCOMMENTS\nBackground\nFor stage IV gastric cancer, doublet regimens including fluoropyrimidine and platinum agents are standard chemotherapy. The addition of taxanes to the doublet regimen may improve effectiveness but may also increase toxicity.\n\nResearch frontiers\nThe addition of a smaller amount of docetaxel than previously reported to capecitabine and cisplatin was evaluated.\n\nInnovations and breakthroughs\nThe authors set the dose of docetaxel to 30 or 40 mg/m2, which was a lower dose than used in previous reports on docetaxel, cisplatin and capecitabine (DCX).\n\nApplications\nIntensive treatment with a triplet regimen could be a useful preoperative treatment that allows for conversion surgery in patients with distant lymph node metastasis.\n\nTerminology\nDCX: A combination chemotherapy regimen including docetaxel, cisplatin and capecitabine. Conversion surgery: Surgical operation for patients with cancer that was unresectable before chemotherapy and became to be resectable after chemotherapy.\n\nPeer-review\nThe authors designed the dose of docetaxel to 30 or 40 mg/m2, which was a lower dose than used in previous reports on DCX, and evaluated the safety and efficacy.\n\nManuscript source: Invited manuscript\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry of origin: Japan\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): 0\n\nGrade C (Good): C, C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nInstitutional review board statement: This study was approved by the review boards of Nagoya University Hospital.\n\nClinical trial registration statement: This study was registered at http://www.umin.ac.jp/ctr/index.htm, registration identification number is UMIN000006009.\n\nInformed consent statement: All patients provided written informed consent.\n\nConflict-of-interest statement: Kodera Y has received research funding from Chugai Pharmaceutical Co., Ltd., Sanofi, Yakult Honsha Co., Ltd., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., and Bristol-Myers Squib. Goto H has received research funding from Bristol-Myers Squibb, and Takeda Pharmaceutical Co., Ltd. Ando Y has received research funding from Sanofi, Chugai Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Yakult Honsya Co., Ltd., and Mochida Pharmaceutical Co., Ltd.\n\nData sharing statement: No additional data are available.\n\nOpen-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is 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 and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/\n\nPeer-review started: October 24, 2016\n\nFirst decision: October 28, 2016\n\nArticle in press: January 17, 2017\n\nP- Reviewer: Arigami T, Chuang SM S- Editor: Yu J L- Editor: A E- Editor: Liu WX\n==== Refs\n1 Koizumi W Narahara H Hara T Takagane A Akiya T Takagi M Miyashita K Nishizaki T Kobayashi O Takiyama W S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial Lancet Oncol 2008 9 215 221 18282805 \n2 Tsuburaya A Morita S Kodera Y Kobayashi M Shitara K Yamaguchi K Yoshikawa T Yoshida K Yoshino S Sakamoto J A randomized phase II trial to elucidate the efficacy of capecitabine plus cisplatin (XP) and S-1 plus cisplatin (SP) as a first-line treatment for advanced gastric cancer: XP ascertainment vs. SP randomized PII trial (XParTS II) BMC Cancer 2012 12 307 22824079 \n3 Van Cutsem E Moiseyenko VM Tjulandin S Majlis A Constenla M Boni C Rodrigues A Fodor M Chao Y 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B Randomized Multicenter Phase II Study of Modified Docetaxel, Cisplatin, and Fluorouracil (DCF) Versus DCF Plus Growth Factor Support in Patients With Metastatic Gastric Adenocarcinoma: A Study of the US Gastric Cancer Consortium J Clin Oncol 2015 33 3874 3879 26438119 \n8 Wang J Xu R Li J Bai Y Liu T Jiao S Dai G Xu J Liu Y Fan N Randomized multicenter phase III study of a modified docetaxel and cisplatin plus fluorouracil regimen compared with cisplatin and fluorouracil as first-line therapy for advanced or locally recurrent gastric cancer Gastric Cancer 2016 19 234 244 25604851 \n9 Sato Y Takayama T Sagawa T Takahashi Y Ohnuma H Okubo S Shintani N Tanaka S Kida M Sato Y Phase II study of S-1, docetaxel and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer Cancer Chemother Pharmacol 2010 66 721 728 20041328 \n10 Kang YK Ryu MH Yoo C Chang HM Yook JH Oh ST Kim BS Kim TW Phase I/II study of a combination of docetaxel, capecitabine, and cisplatin (DXP) as first-line chemotherapy in patients with advanced gastric cancer Cancer Chemother Pharmacol 2011 67 1435 1443 20811894 \n11 Sym SJ Ryu MH Kang HJ Lee SS Chang HM Lee JL Kim TW Yook JH Oh ST Kim BS Phase I study of 3-weekly docetaxel, capecitabine and oxaliplatin combination chemotherapy in patients with previously untreated advanced gastric cancer Cancer Chemother Pharmacol 2010 66 373 380 19936751 \n12 Thuss-Patience PC Hofheinz RD Arnold D Florschütz A Daum S Kretzschmar A Mantovani-Löffler L Bichev D Breithaupt K Kneba M Perioperative chemotherapy with docetaxel, cisplatin and capecitabine (DCX) in gastro-oesophageal adenocarcinoma: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO){dagger} Ann Oncol 2012 23 2827 2834 22734012 \n13 Fushida S Fujimura T Oyama K Yagi Y Kinoshita J Ohta T Feasibility and efficacy of preoperative chemotherapy with docetaxel, cisplatin and S-1 in gastric cancer patients with para-aortic lymph node metastases Anticancer Drugs 2009 20 752 756 19543076 \n14 Nakayama N Koizumi W Sasaki T Higuchi K Tanabe S Nishimura K Katada C Nakatani K Takagi S Saigenji K A multicenter, phase I dose-escalating study of docetaxel, cisplatin and S-1 for advanced gastric cancer (KDOG0601) Oncology 2008 75 1 7 \n15 Koizumi W Nakayama N Tanabe S Sasaki T Higuchi K Nishimura K Takagi S Azuma M Ae T Ishido K A multicenter phase II study of combined chemotherapy with docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer (KDOG 0601) Cancer Chemother Pharmacol 2012 69 407 413 21796483 \n16 Polyzos A Felekouras E Karatzas T Griniatsos J Dimitroulis D Polyzos K Kontzoglou K Mantas D Karavokyros J Nikiteas N Modified docetaxel-cisplatin in combination with capecitabine as first-line treatment in metastatic gastric cancer. a phase II study Anticancer Res 2012 32 4151 4156 22993377 \n17 Sym SJ Chang HM Ryu MH Lee JL Kim TW Yook JH Oh ST Kim BS Kang YK Neoadjuvant docetaxel, capecitabine and cisplatin (DXP) in patients with unresectable locally advanced or metastatic gastric cancer Ann Surg Oncol 2010 17 1024 1032 19941081 \n18 Yoon S Yoo C Ryu MH Kang MJ Ryoo BY Park SR Yook JH Oh ST Yoo MW Kim BS Phase 2 study of adjuvant chemotherapy with docetaxel, capecitabine, and cisplatin in patients with curatively resected stage IIIB-IV gastric cancer Gastric Cancer 2017 20 182 189 26661592\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1007-9327",
"issue": "23(6)",
"journal": "World journal of gastroenterology",
"keywords": "Capecitabine; Cisplatin; Docetaxel; Gastric cancer",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D002945:Cisplatin; D000077143:Docetaxel; D005240:Feasibility Studies; D005260:Female; D005743:Gastrectomy; D006801:Humans; D007564:Japan; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009503:Neutropenia; D011446:Prospective Studies; D013274:Stomach Neoplasms; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "1090-1097",
"pmc": null,
"pmid": "28246483",
"pubdate": "2017-02-14",
"publication_types": "D016428:Journal Article",
"references": "23818349;17075117;19936751;20041328;19633962;23054756;22824079;18282805;19543076;22993377;18719348;26661592;20811894;22734012;19941081;25604851;21796483;26438119",
"title": "Modified docetaxel, cisplatin and capecitabine for stage IV gastric cancer in Japanese patients: A feasibility study.",
"title_normalized": "modified docetaxel cisplatin and capecitabine for stage iv gastric cancer in japanese patients a feasibility study"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2017RR-141959",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
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{
"abstract": "BACKGROUND\nMetronidazole is a widely known and used antibiotic. In exceptional cases, an encephalopathy with characteristic lesions on magnetic resonance imaging (MRI), usually located in the cerebellum and splenium of the corpus callosum, may be an adverse effect. The incidence and pathogenesis are unknown. The suspension of the treatment usually resolves the symptoms and normalizes the MRI in a few weeks. Due to the usual good prognosis, the anatomopathological findings are exceptional. We present a clinical case with the radiological findings suggestive of metronidazole-induced encephalopathy and, exceptionally, we provide the anatomopathological findings.\n\n\nMETHODS\nA 72 years-old woman with severe Crohn's disease who, months after starting treatment with metronidazole, presented a slowly progressing bradypsychia and difficulty walking until she came to coma. In MRI it showed hyperintense images in T2 in the corpus callosum, red and dentate nuclei. He improved by stopping metronidazole but later developed sepsis and died. At autopsy, softening of the red nucleus was observed and, microscopically, cell necrosis and demyelination.\n\n\nCONCLUSIONS\nWith the publication of the clinical, radiological and anatomopathological information of our case we intend to promote the knowledge of this infrequent treatable cause of subacute encephalopathy and provide data that help to clarify its pathogenesis.",
"affiliations": "Hospital Universitario Rio Hortega, Valladolid, Espana.;Hospital Universitario Rio Hortega, 47010 Valladolid, Espana.;Hospital Universitario Rio Hortega, 47010 Valladolid, Espana.;Hospital Universitario Rio Hortega, 47010 Valladolid, Espana.;Hospital Universitario Rio Hortega, 47010 Valladolid, Espana.;Hospital Universitario Rio Hortega, 47010 Valladolid, Espana.;Hospital Universitario Rio Hortega, 47010 Valladolid, Espana.",
"authors": "Gonzalez-Nafria|N|N|;Rojo-Lopez|A|A|;Martinez-Velasco|E|E|;Gonzalez-Gonzalez|D|D|;de la Fuente-Bobillo|M A|MA|;Tola-Arribas|M A|MA|;Ortega-Valin|F|F|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008795:Metronidazole",
"country": "Spain",
"delete": false,
"doi": "10.33588/rn.6901.2018501",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0210-0010",
"issue": "69(1)",
"journal": "Revista de neurologia",
"keywords": null,
"medline_ta": "Rev Neurol",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D001927:Brain Diseases; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008795:Metronidazole",
"nlm_unique_id": "7706841",
"other_id": null,
"pages": "27-31",
"pmc": null,
"pmid": "31236908",
"pubdate": "2019-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metronidazole-induced encephalopathy: description of a case with radiological and anatomopathological findings.",
"title_normalized": "metronidazole induced encephalopathy description of a case with radiological and anatomopathological findings"
} | [
{
"companynumb": "ES-BAUSCH-BL-2019-019940",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "If anaplastic lymphoma kinase (ALK) gene rearrangement in lung cancer is identified, ALK-tyrosine kinase inhibitors (ALK-TKIs) can be an effective treatment. However, the details of drug-induced lung injury (DILI) caused by ALK-TKI, which can be a serious side effect of ALK-TKIs, remains unclear. This study aimed to investigate the clinical features and the onset risk factors of DILI by ALK-TKIs in clinical practice.\n\n\n\nThe clinical features of 56 consecutive patients who received crizotinib, alectinib, and/or ceritinib at our hospital from 2012 to 2018 were retrospectively examined. Among these, patients diagnosed with DILI due to ALK-TKIs were evaluated in terms of clinical features and parameters. Each clinical parameter before the administration of ALK-TKIs was compared between the DILI onset group and the non-onset group.\n\n\n\nA total of seven cases were diagnosed with DILI due to ALK-TKIs; no DILI-related deaths were observed. Chest computed tomography (CT) scan findings identified six patients with the organizing pneumonia (OP) pattern and one with the hypersensitivity pneumonia pattern. The onset of DILI was significantly different in patients age ≥ 64 years and with a creatinine clearance <80 mL/minute.\n\n\n\nExtra caution for DILI due to ALK-TKIs may be needed when recommending ALK-TKIs for patients over 64 years of age, or with decreased renal function. CT images of the majority of patients with DILI by ALK-TKIs show an OP pattern.\n\n\n\nSignificant findings of the study: Extra caution is needed when recommending ALK-TKIs for patients over 64 years of age or those with decreased renal function. Computed tomography images of the majority of patients with DILI by ALK-TKIs show an OP pattern.\n\n\n\nThe same or a different ALK-TKI may be considered as a treatment option after the onset of DILI, based on careful judgment.",
"affiliations": "Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.;Biostatistics Section, Clinical Research Center, Chiba University Hospital, Chiba, Japan.;Department of Pulmonary Medicine, International University of Health and Welfare, School of Medicine, Narita city, Chiba, Japan.;Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.",
"authors": "Koshikawa|Ken|K|;Terada|Jiro|J|0000-0001-9019-4053;Abe|Mitsuhiro|M|;Iwasawa|Shunichiro|S|;Sakayori|Masashi|M|;Yoshioka|Keiichiro|K|;Hirasawa|Yasutaka|Y|;Kasai|Hajime|H|;Kawasaki|Yohei|Y|;Tsushima|Kenji|K|;Tatsumi|Koichiro|K|",
"chemical_list": "D002227:Carbazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013450:Sulfones; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C586847:ceritinib; C582670:alectinib",
"country": "Singapore",
"delete": false,
"doi": "10.1111/1759-7714.13416",
"fulltext": "\n==== Front\nThorac Cancer\nThorac Cancer\n10.1111/(ISSN)1759-7714\nTCA\nThoracic Cancer\n1759-7706 1759-7714 John Wiley & Sons Australia, Ltd Melbourne \n\n10.1111/1759-7714.13416\nTCA13416\nOriginal Article\nOriginal Articles\nClinical characteristics and risk factors of drug‐induced lung injury by ALK tyrosine kinase inhibitors: A single center retrospective analysis\nDILI by ALK‐TKIsK. Koshikawa et al.Koshikawa Ken \n1\n Terada Jiro https://orcid.org/0000-0001-9019-4053\n1\njirotera@chiba-u.jp Abe Mitsuhiro \n1\n Iwasawa Shunichiro \n1\n Sakayori Masashi \n1\n Yoshioka Keiichiro \n1\n Hirasawa Yasutaka \n1\n Kasai Hajime \n1\n Kawasaki Yohei \n2\n Tsushima Kenji \n3\n Tatsumi Koichiro \n1\n \n1 \nDepartment of Respirology, Graduate School of Medicine\nChiba University\nChiba\nJapan\n\n\n2 \nBiostatistics Section\nClinical Research Center, Chiba University Hospital\nChiba\nJapan\n\n\n3 \nDepartment of Pulmonary Medicine\nInternational University of Health and Welfare, School of Medicine, Narita city\nChiba\nJapan\n\n* Correspondence\n\nJiro Terada, Department of Respirology, Graduate School of Medicine, Chiba University, Chuo‐ku, Chiba city, Chiba 260‐8670, Japan.\n\nTel: +81 43 222 7171\n\nFax: +81 43 226 2176\n\nEmail: jirotera@chiba-u.jp\n\n01 4 2020 \n6 2020 \n11 6 10.1111/tca.v11.61495 1502\n23 12 2019 15 3 2020 16 3 2020 © 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract\nBackground\nIf anaplastic lymphoma kinase (ALK) gene rearrangement in lung cancer is identified, ALK‐tyrosine kinase inhibitors (ALK‐TKIs) can be an effective treatment. However, the details of drug‐induced lung injury (DILI) caused by ALK‐TKI, which can be a serious side effect of ALK‐TKIs, remains unclear. This study aimed to investigate the clinical features and the onset risk factors of DILI by ALK‐TKIs in clinical practice.\n\nMethods\nThe clinical features of 56 consecutive patients who received crizotinib, alectinib, and/or ceritinib at our hospital from 2012 to 2018 were retrospectively examined. Among these, patients diagnosed with DILI due to ALK‐TKIs were evaluated in terms of clinical features and parameters. Each clinical parameter before the administration of ALK‐TKIs was compared between the DILI onset group and the non‐onset group.\n\nResults\nA total of seven cases were diagnosed with DILI due to ALK‐TKIs; no DILI‐related deaths were observed. Chest computed tomography (CT) scan findings identified six patients with the organizing pneumonia (OP) pattern and one with the hypersensitivity pneumonia pattern. The onset of DILI was significantly different in patients age ≥ 64 years and with a creatinine clearance <80 mL/minute.\n\nConclusions\nExtra caution for DILI due to ALK‐TKIs may be needed when recommending ALK‐TKIs for patients over 64 years of age, or with decreased renal function. CT images of the majority of patients with DILI by ALK‐TKIs show an OP pattern.\n\nKey points\n\nSignificant findings of the study: Extra caution is needed when recommending ALK‐TKIs for patients over 64 years of age or those with decreased renal function. Computed tomography images of the majority of patients with DILI by ALK‐TKIs show an OP pattern.\n\nWhat this study adds: The same or a different ALK‐TKI may be considered as a treatment option after the onset of DILI, based on careful judgment.\n\n\n\n\nAlectinibanaplastic lymphoma kinaseceritinibcrizotinibdrug‐related side effects and adverse reactionsThe Intractable Respiratory Diseases and Pulmonary Hypertension Research Group, the Ministry of Health, Labor and WelfareThe Japan Agency for Medical Research and Development source-schema-version-number2.0cover-dateJune, 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.3 mode:remove_FC converted:01.06.2020\n==== Body\nIntroduction\nAnaplastic lymphoma kinase (ALK) gene rearrangements are found in approximately 2.4%–5.6% of patients with non‐small cell lung cancer (NSCLC) who show a distinct clinical course with substantial antitumor response to oral tyrosine kinase inhibitors targeting ALK.1, 2 Since tyrosine kinase activity is present in the ALK protein, the effect is obtained by inhibiting this activity.3 To date, four different ALK‐tyrosine kinase inhibitors (ALK‐TKIs), crizotinib, alectinib, ceritinib and lorlatinib have been used in clinical practice for the treatment of advanced ALK positive lung cancer in Japan. However, ALK‐TKIs are known to potentially cause serious adverse events (SAEs), including lung injury.\n\nALK‐TKI‐induced lung injury was first reported in Japanese patients treated with crizotinib for metastatic NSCLC.4 Subsequently, sporadic cases were reported5, 6 indicating that ALK inhibitor‐induced pneumonitis can be clinically problematic in some patients. Although re‐administration of another ALK‐TKI after ALK‐TKI‐induced interstitial lung disease seems possible and has been reported in previous studies,7, 8 there have been few reports regarding the detailed clinical course after drug‐induced lung injury (DILI), or readministration of ALK‐TKIs. According to the results of all case surveys by pharmaceutical companies, the incidence rate of lung injury was 2.6%–5.9%, and the mortality rate was 0%–19% for the three ALK‐TKIs.9, 10 On the other hand, a recent systematic review and meta‐analysis of the incidence of ALK inhibitor‐related pneumonitis in patients with advanced NSCLC indicated a slightly lower global incident rate (2.1%). This report also suggested a higher incidence of ALK inhibitor‐induced pneumonitis in cohorts from Japan (6.3%) when compared to cohorts from other countries (1.1%).11 However, the information of ALK‐TKI‐induced lung injury in the clinical practice remains limited.\n\nThe purpose of this study was to investigate the clinical features, risk factors, and the safety of readministration of ALK‐TKIs after ALK‐TKI‐induced lung injury.\n\nMethods\nIn accordance with the amended Declaration of Helsinki, we conducted a single‐center, retrospective study for ALK‐TKI‐induced lung injury. All procedures involving human participants were approved by the Human Ethics Committee of the Graduate School of Medicine of Chiba University (approval number 2265). Approval for the opt‐out consent method was given by the Chiba University Hospital.\n\nPatients\nThe records of 56 consecutive patients with ALK positive lung cancer who were treated with crizotinib, alectinib, and/or ceritinib from August 2012 to August 2018 at our hospital were retrospectively examined. Crizotinib, alectinib, and ceritinib were administered to 23, 25, and eight patients, respectively. Patients treated with lorlatinib were not included as lorlatinib was not available at the time of the present study in Japan. Among the 56 patients, cases diagnosed with DILI due to ALK‐TKIs were evaluated with regard to their clinical features, risk factors, and recurrence after treatment of DILI with ALK‐TKIs. Each clinical parameter before administration of an ALK‐TKI was also compared between the DILI onset group and the non‐onset group (Figure S1). Patients for whom multiple ALK‐TKIs had been used were included as different cases according to the type of ALK‐TKI they received. A total of 11 patients who switched to alectinib from crizotinib, seven patients who switched to ceritinib from alectinib, two patients who switched to crizotinib from alectinib, and one patient who switched to ceritinib from crizotinib due to the disease progression or side effects were included in the total of 56 patients. There were no patients who had a prior history of having received radiotherapy.\n\nDiagnosis of ALK‐TKI‐induced lung injury\nDrug‐induced lung injury was diagnosed using the following diagnostic criteria:12 (i) patients with a treatment history of ALK‐TKI; (ii) clinical manifestations reported to be induced by the corresponding drug; (iii) exclusion of other causes of clinical manifestations; (iv) improvement after drug discontinuation; and (v) exacerbation by re‐administration. Two physicians individually confirmed the final diagnosis of DILI.\n\nEvaluation of parameters and clinical progression\nData regarding clinical progression, blood test findings, and chest computed tomography (CT) scan findings for the 56 patients were retrieved from their medical records. We analyzed the presence of pulmonary metastasis, history and comorbidity of interstitial pneumonia, histologic lung cancer type, and smoking history. We evaluated laboratory data included the estimated creatinine clearance (Ccr), lactate dehydrogenase (LDH) levels, white blood cell (WBC) and eosinophil counts, Krebs von den Lungen‐6 (KL‐6; normal range, <500 U/mL) protein levels, brain natriuretic peptide (BNP; normal range, <18.4 pg./mL) levels, percentage of predicted vital capacity, and forced expired volume in one second/forced vital capacity. Clinical course after the onset of DILI (eg, response to cessation of drug or steroid, status of improved, stable, etc) was also evaluated.\n\nChest CT data analysis\nBased on the official American Thoracic Society/European Respiratory Society statement and The Japanese Respiratory Society Guidelines for the Management of Drug‐induced Lung Disease 2018,13, 14 the CT pattern‐organizing pneumonia (OP), diffuse alveolar damage (DAD), nonspecific interstitial pneumonia (NSIP), or hypersensitivity pneumonia (HP) for each patient was determined. Additionally, patients' course (ie, improved, unchanged, worsened) were also evaluated. In periodical follow‐up CT scan for lung cancer, conventional 5 mm slice CT was basically performed for all patients. A 0.5 or 1 mm slice chest high‐resolution computed tomography (HRCT) scan was reperformed on three patients at the onset of DILI.\n\nStatistical analysis\nClinical data are expressed as means ± standard deviation (SD). All statistical analyses were conducted using the JMP Pro 13.2.0 (Japanese version, SAS Institute Inc). We considered a P‐value of <0.05 to be statistically significant. Odds ratios and 95% confidence intervals (CI) for DILI onset were evaluated using univariate analyses. We defined the different patient categories according to the number of risk factors observed to be related to DILI onset. We used the Cochran‐Armitage trend test to evaluate the relation between the number of risk factors and DILI onset and the Kaplan‐Meier method to estimate the time to DILI onset for each subgroup stratified by the number of risk factors.\n\nResults\nBaseline characteristics of total cases, DILI‐ and non‐DILI groups\nA total of seven (two men and five women) of the 56 (12.5%) patients were diagnosed with DILI (crizotinib, n = 1; alectinib, n = 5; ceritinib, n = 1). The baseline characteristics in all cases are shown in Table 1. There were no significant differences between the DILI and non‐DILI groups with regard to sex, smoking history, LDH, KL‐6, BNP levels, whereas significant differences were noted with regard to age ≥ 64 years and Ccr < 80 mL/min at baseline obtained by ROC analysis. The two groups showed no significant differences in baseline chest CT findings, including the presence of pulmonary metastasis and interstitial changes (Table 2).\n\nTable 1 Baseline characteristics of total patients\n\n\tTotal (n = 56)\tDILI group (n = 7)\tNon‐DILI group (n = 49)\t\nAge (years)\t59.5 ± 12.9\t71.2 ± 5.8\t57.8 ± 12.8\t\nMale/female\t26/30\t2/5\t24/25\t\nSmoking history, n (%)\t23 (41.0%)\t2 (28.5%)\t21 (42.8%)\t\n\nHistologic type\n\t\nAdenocarcinoma, n (%)\t54 (96.4%)\t7 (100%)\t46 (95.9%)\t\nSquamous cell carcinoma, n (%)\t1 (1.7%)\t0 (0%)\t1 (2.0%)\t\nOther, n (%)\t1 (1.7%)\t0 (0%)\t1 (2.0%)\t\nLung metastasis, n (%)\t43 (76.7%)\t6 (85.7%)\t37 (75.5%)\t\nPre‐existing ILD, n (%)\t10 (17.8%)\t1 (1.4%)\t9 (18.3%)\t\n\nLaboratory findings\n\t\nLDH (IU/L)\t265.9 ± 150.9\t336.1 ± 292.0\t255.8 ± 120.9\t\nCcr (mL/min)\t82.9 ± 31.5\t60.4 ± 21.5\t86.1 ± 31.6\t\nKL‐6 (U/mL)\t\n979 ± 1004\n\n\n(n = 23)\n\n\n\t\n1038 ± 1215\n\n\n(n = 4)\n\n\n\t\n966 ± 993\n\n\n(n = 19)\n\n\n\t\nBNP (pg/mL)\t\n25.5 ± 21.3\n\n\n(n = 21)\n\n\n\t\n26.5 ± 8.5\n\n\n(n = 4)\n\n\n\t\n25.2 ± 23.5\n\n\n(n = 17)\n\n\n\t\nWBC (/μL)\t7141 ± 3336\t9228 ± 6349\t6842 ± 2644\t\nEosinophils/WBC (%)\t2.4 ± 1.8\t2.1 ± 2.3\t2.4 ± 1.8\t\n\nSpirometry\n\t\n%VC\t\n81.7 ± 17.7\n\n\n(n = 23)\n\n\n\t\n89.9 ± 23.7\n\n\n(n = 4)\n\n\n\t\n80.0 ± 16.5\n\n\n(n = 19)\n\n\n\t\nFEV1/FVC\t\n76.7 ± 7.5\n\n\n(n = 23)\n\n\n\t\n73.1 ± 7.7\n\n\n(n = 4)\n\n\n\t\n77.4 ± 7.1\n\n\n(n = 19)\n\n\n\t\nData are expressed as mean ± standard deviation.\n\n%VC, percent vital capacity; BNP, brain natriuretic peptide; Ccr, creatinine clearance; DILI, drug‐induced lung injury; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; ILD, interstitial lung disease; KL‐6, Krebs von den Lungen‐6; LDH, lactate dehydrogenase; WBC, white blood cells.\n\nTable 2 Risk factors associated with DILI onset due to ALK‐TKIs\n\n\t\nn\n\tDILI onset\tUnivariate analysis\t\nFactors\t(n = 56)\t(n = 7)\tOR (95% CI)\t\nP‐value\t\n\nSex\n\t\nM\t30\t2\t1\t\t\nF\t26\t5\t2.40 (0.47–17.89)\t0.30\t\n\nAge\n\t\nContinuous value\t\t\t1.11 (1.03–1.22)\t0.01\t\n<64\t34\t1\t1\t\t\n≥64\t22\t6\t12.38 (1.90–244.18)\t0.01\t\n\nSmoking history\n\t\nCurrent + Ex\t23\t2\t1\t\t\nNon‐smoker\t33\t5\t1.88 (0.36–13.99)\t0.46\t\nLung metastasis\t\nNonexistent\t13\t1\t1\t\t\nExistent\t43\t6\t1.95 (0.29–38.66)\t0.53\t\nPre‐existing ILD\t\nExistent\t10\t1\t1\t\t\nNonexistent\t46\t6\t1.35 (0.20–27.13)\t0.79\t\nLDH (IU/L)\t\nContinuous value\t\t\t1.00 (1.00–1.01)\t0.25\t\n<230\t31\t3\t1\t\t\n≥230\t25\t4\t1.78(0.36–9.84)\t0.48\t\nCcr (mL/min)\t\nContinuous value\t\t\t0.96 (0.92–1.00)\t0.02\t\n≥80\t29\t1\t1\t\t\n<80\t27\t6\t8.00 (1.24–157.11)\t0.03\t\nKL‐6 (U/mL)\t\nContinuous value\t\t\t1.00 (1.00–1.00)\t0.90\t\n<500\t12\t2\t1\t\t\n≥500\t11\t2\t1.11 (0.11–10.91)\t0.92\t\nBNP (pg/mL)\t\nContinuous value\t\t\t1.00 (0.94–1.05)\t0.92\t\n<18.4\t10\t1\t1\t\t\n≥18.4\t11\t3\t3.38 (0.35–76.18)\t0.30\t\nALK‐TKI, anaplastic lymphoma kinase‐tyrosine kinase inhibitor; BNP, brain natriuretic peptide; Ccr, creatinine clearance; DILI, drug‐induced lung injury; ILD, interstitial lung disease; KL‐6, Krebs von den Lungen‐6; LDH, lactate dehydrogenase.\n\nFrom these results, two patient‐related risk factors, age ≥ 64 years and Ccr < 80 mL/min, were identified as significantly related to DILI onset. The number of risk factors and their relation to the frequency of DILI onset are summarized in Figure 1. The number of risk factors was significantly associated with DILI onset; DILI onset was not seen in patients with no patient‐related risk factors, while 26.3% of patients who had both risk factors experienced DILI onset. The progress to DILI onset according to the number of risk factors is significantly different between patients with no risk factors and patients with one or two risk factors (Fig 1).\n\nFigure 1 Kaplan‐Meier plot of time to DILI onset classified according to the number of risk factors. Solid, dotted, and dashed lines correspond to zero (in 26 patients), one (in 11 patients), and two (in 19 patients) risk factors. *Categorical data analysis conducted using the Cochran‐Armitage trend test.\n\nCharacteristics of cases at DILI onset\nThe characteristics of patients at DILI onset are shown in Table 3. Five cases were diagnosed with DILI at the time of routine follow‐up chest CT, and two cases were diagnosed with DILI using CT to evaluate the appearance of shadows on chest radiographs after dyspnea and/or slight fever. The CT images of each patient were separately evaluated by two physicians. Bronchoscopy was performed in three patients and the results were all consistent with DILI: the finding of interstitial pneumonia in pathological diagnosis (Case A); the finding of epithelioid granulomas in pathological diagnosis (Case C); the finding of organizing pneumonia in pathological diagnosis; and a high percentage of lymphocytes in bronchoalveolar lavage (Case D). The median time from the start of ALK‐TKI administration to the onset of DILI was 97 days (range: 9–531 days). We observed one case of grade 2 pneumonitis due to DILI with crizotinib. For alectinib, we observed one case of grade 1, three cases of grade 2, and one case of grade 4 pneumonitis due to DILI. Only one case of grade 2 pneumonitis was observed due to DILI with ceritinib. Each ALK‐TKI type usually resulted in a grade 2 pneumonitis.\n\nTable 3 The characteristics of patients at DILI onset\n\nCase\tALK‐TKI\tOnset (day)\tPrevious treatment\tHistory of DILI by ALK‐TKI\tImage pattern\tGrade\tTreatment for DILI\tOutcome\t\nA\tAlectinib\t531\tCrizotinib\t−\tOP\t2\tAlectinib discontinuation and PSL\tImprovement\t\nB\tCeritinib\t97\tAlectinib\t+\tOP\t2\tCeritinib discontinuation and PSL\tImprovement\t\nC\tAlectinib\t97\tCrizotinib\t−\tHP\t2\tPSL\tImprovement\t\nD\tAlectinib\t246\tCrizotinib\t−\tOP + NSIP\t2\tAlectinib discontinuation and PSL\tImprovement\t\nE\tAlectinib\t254\tCrizotinib\t−\tOP\t1\tAlectinib continuation\tImprovement\t\nF\tAlectinib\t9\tNo\t−\tOP\t4\tAlectinib discontinuation and PSL\t\nNo improvement\n\n\n(death from lung cancer)\n\n\n\t\nG\tCrizotinib\t63\tNo\t−\tOP\t2\tCrizotinib discontinuation and PSL\tImprovement\t\nDILI, drug‐induced lung injury; ALK‐TKI, anaplastic lymphoma kinase‐tyrosine kinase inhibitor; OP, organizing pneumonia; PSL, prednisolone; HP, hypersensitivity pneumonia; NSIP, nonspecific interstitial pneumonia.\n\n\nCT pattern of cases at DILI onset\nThe CT patterns of patients at DILI onset are shown in Table 3. Six (85.7%) patients exhibited the OP pattern, one (14.3%) exhibited the HP pattern, and one (14.3%) exhibited the NSIP pattern. Figures 2 and 3 show the plain CT images of the seven patients.\n\nFigure 2 Clinical course of two re‐administration cases. A 70‐year‐old woman with advanced ALK‐positive non‐small cell lung cancer (NSCLC) was treated with crizotinib as second‐line chemotherapy. DILI was not observed during crizotinib administration, but progress of cancer was recognized. Therefore, alectinib was administered to the patient as third‐line chemotherapy (Case A). DILI was observed during alectinib administration (day 531), and improved with steroid therapy and discontinuation of alectinib. Re‐administration of ALK‐TKI was with ceritinib (Case B). There was onset of DILI upon administration of ceritinib (day 97). DILI improved with discontinuation of ceritinib and with steroid therapy.\n\nFigure 3 Computed tomography (CT) findings at the onset of DILI. Computed tomography findings in five cases with ALK‐TKI‐induced drug injury. Case C, hypersensitivity pneumonia pattern; Case D, organizing pneumonia (OP) + nonspecific interstitial pneumonia pattern; Case E, OP pattern; Case F, OP pattern; Case G, OP pattern.\n\nOutcome after DILI onset\nOf the seven patients with DILI, one exhibited an improvement on follow‐up with no intervention and without discontinuation of an ALK‐TKI of alectinib (Case E), one exhibited an improvement with systemic corticosteroid therapy, and four exhibited improvement with systemic corticosteroid therapy and ALK‐TKI discontinuation (Table 3). One patient (Case F) did not recover. The primary cause of death in Case F was considered to be progression of lung cancer. An ALK‐TKI was re‐administered in the five patients after improvement of DILI, of which three had no relapse of DILI. Cases A and B were the cases where different ALK‐TKIs had been used in the same patient. The patient continued treatment with ALK‐TKI after the onset of the DILI. With regard to the clinical course of the patient who had a DILI relapse (the first DILI was due to alectinib, the second DILI was due to ceritinib; Fig 2), the treatment of the patient with the first DILI due to alectinib was changed to treatment with ceritinib. Then, the second DILI was observed in chest CT scan 110 days after using ceritinib, but subsequently improved with corticosteroid therapy. The DILI resulted in discontinuation of ceritinib. Ceritinib was changed to a cytotoxic agent and no further DILI was observed. The two cases of DILI recurrence showed improvement with systemic corticosteroid treatment (Table S1).\n\nDiscussion\nIn the present study, we investigated the clinical characteristics of ALK‐TKI‐induced lung injury and found that age ≥ 64 years and Ccr < 80 mL/min at baseline may be risk factors. In most cases with ALK‐TKI‐induced lung injury, an OP pattern on chest CT scan was observed at DILI onset; the therapeutic response to corticosteroid therapy was then relatively good.\n\nPatients age ≥ 64 years was a significantly different factor between the DILI group and non‐DILI group; in addition, Ccr < 80 mL/min before ALK‐TKI administration was also significantly different. The post‐marketing survey of crizotinib has suggested that the risk factors for DILI include old age, performance status of Eastern Cooperative Oncology Group ≥2, existing interstitial pneumonia, or history of interstitial pneumonia, existing pleural effusion, and a history of smoking.9 In a previous retrospective review of interstitial lung disease (ILD) associated with crizotinib therapy, a greater percentage of ex‐smokers were shown in the patients with crizotinib‐related ILD.15 One of the ways in which this study was different from the previous literature might be that the present study targeted multiple ALK‐TKI drugs and not just a single one (eg, crizotinib).\n\nA total of 12.5% patients (7 of 56 patients) in the present study were diagnosed with DILI, and the median time from ALK‐TKI administration to DILI onset was 97 days (range: 9–531 days). Suh et al. conducted a systematic review and meta‐analysis which reported that the global incident rate of ALK inhibitor‐related pneumonitis in patients with advanced NSCLC was 2.1%.11 We considered that the higher incidence rate in this study (n = 7/56, 12.5%) was attributed to the population difference (Japanese) and our study design (ie, a retrospective study for a small number of cases with various comorbidities and therapeutic course, and the readministration of ALK‐TKI after the onset of DILI due to another ALK‐TKI). In particular, the incidence of ILD by alectinib which was mainly administered in our study was differently reported in two phase III studies with a similar design comparing alectinib with crizotinib.16, 17 The incidence of alectinib‐induced ILD was 8% (n = 8/103) in J‐ALEX conducted exclusively in Japan16 and 1% (n = 2/152) in ALEX study not including Japan.17 In the subanalysis in the systematic review and meta‐analysis by Suh et al.11 also suggested the incidence of ALK inhibitor‐induced pneumonitis in cohorts from Japan were higher (6.3%) when compared to cohorts from other countries (1.1%).11\n\n\nIn general clinical practice, drugs suspected to cause DILI should not be re‐administered. However, resuming ALK‐TKIs after resolution of a lung injury might be a clinical option because ALK‐TKIs have a potent antitumor effect. In fact, some studies have reported successful readministration of a different ALK‐TKI after the occurrence of DILI.7, 8 In the present study, ALK‐TKIs were again successfully administered to three patients after the resolution of DILI. In addition, the relapse of ALK‐TKI DILI after the initial resolution of DILI was improved in two patients with treatment (Cases A and G). In Case A, the first DILI due to alectinib was improved when corticosteroids and alectinib were discontinued. After the resolution of the first DILI due to alectinib, Case A was switched to ceritinib to treat their lung cancer. A DILI recurrence was subsequently recognized, but it was also improved by corticosteroid and ceritinib discontinuation. In Case G, the first DILI due to crizotinib was improved by corticosteroid and crizotinib discontinuation. After the resolution of the first DILI due to crizotinib, Case G again received crizotinib with a dose reduction, and under treatment with corticosteroid. The DILI recurrence was recognized, but it was improved after crizotinib discontinuation. With regard to the response to corticosteroid therapy in the present study, among the six patients with improved DILI, five improved with corticosteroid therapy and one was relieved only after the cessation of ALK‐TKI.\n\nIn this study, the CT patterns of patients at the onset of DILI were mainly OP patterns. On the other hand, in a previous retrospective review of CT images in patients with EGFR‐TKI‐induced interstitial lung disease, the DAD pattern was most commonly observed.18 Approximately one third of cases of DILI as a result of EGFR‐TKIs are fatal with DAD appearance on chest CT scan.19, 20 For DILI‐induced by ALK‐TKIs in the present study, improvements were observed in almost all cases. When the same or a different ALK‐TKI was administered after the improvement of the first DILI following administration of ALK‐TKI, some patients did not show a recurrence of DILI, and some patients who showed a recurrence of DILI subsequently improved with corticosteroid therapy (Table S1). From these results, even if DILI is diagnosed, the prognosis of DILI after administration of ALK‐TKIs may be better than that by EGFR‐TKIs. One of the possible reasons might be that the DAD pattern in DILI by ALK‐TKI is uncommon. Therefore, we considered that treatment continuation may be one of our options under careful observation or in future issues to be considered.\n\nThis study had several limitations. First, it was designed as a retrospective, single‐center study. Second, the sample size was small, which was also why univariate and not multivariate logistic regression analysis was chosen. Third, DILI was primarily diagnosed based on conventional CT findings. DILI in asymptomatic patients could have been overlooked because the timing of CT was at the discretion of the physician, and we included not only HRCT but also conventional CT data in the study. Since ALK‐TKI‐induced lung injury is reportedly a relatively rare condition (2.1%–6.3%) and the number of ALK‐TKI administered cases in this study were quite small, it is difficult to accurately describe the clinical implications. However, we believe that it is important to elucidate the underlying condition in order to accurately reflect a clinical outcome, even with a small number of cases, and assist in assembly of the total number of reported cases.\n\nIn conclusion, our results suggest that patients age ≥ 64 years and with Ccr < 80 mL/min at baseline may be at an increased risk of DILI by ALK‐TKIs. Extra caution may be needed when recommending ALK‐TKIs for patients who meet these criteria, although the treatment response appears to be good. The same or a different ALK‐TKI may be considered as a treatment option after DILI onset, based on careful judgment because DILI might not recur, or the treatment response might be relatively good, even if it does recur. Readministration of ALK‐TKI is one of the issues that requires resolution as it is currently not definitive and there are only a few reported cases in the literature.\n\nDisclosure\nS.I. reports receipt of lecture fees from Chugai Pharmaceutical Co., Ltd．The other authors report no conflicts of interest in this work.\n\nSupporting information\n\nAPPENDIX S1. Supporting information\n\nClick here for additional data file.\n\n Acknowledgments\nThis study was supported in‐part by a grant to The Intractable Respiratory Diseases and Pulmonary Hypertension Research Group, the Ministry of Health, Labor and Welfare, Japan (http://www.mhlw.go.jp/english/index.html); the Japan Agency for Medical Research and Development (AMED; https://www.amed.go.jp).\n==== Refs\nReferences\n1 \n\nSolomon \nB \n, \nVarella‐Garcia \nM \n, \nCamidge \nDR \n. ALK gene rearrangements: A new therapeutic target in a molecularly defined subset of non‐small cell lung cancer\n. J Thorac Oncol \n2009 ; 4 (12 ): 1450 –4\n.20009909 \n2 \n\nScagliotti \nG \n, \nStahel \nRA \n, \nRosell \nR \n, \nThatcher \nN \n, \nSoria \nJC \n. ALK translocation and crizotinib in non‐small cell lung cancer: An evolving paradigm in oncology drug development\n. Eur J Cancer \n2012 ; 48 (7 ): 961 –73\n.22397764 \n3 \n\nGarber \nK \n. ALK, lung cancer, and personalized therapy: Portent of the future?\n\nJ Natl Cancer Inst \n2010 ; 102 (10 ): 672 –5\n.20460631 \n4 \n\nTamiya \nA \n, \nOkamoto \nI \n, \nMiyazaki \nM \n, \nShimizu \nS \n, \nKitaichi \nM \n, \nNakagawa \nK \n. Severe acute interstitial lung disease after crizotinib therapy in a patient with EML4‐ALK‐positive non‐small‐cell lung cancer\n. J Clin Oncol \n2013 ; 31 (1 ): e15 –7\n.23169500 \n5 \n\nMaka \nVV \n, \nKrishnaswamy \nUM \n, \nAnil Kumar \nN \n, \nChitrapur \nR \n, \nKilara \nN \n. Acute interstitial lung disease in a patient with anaplastic lymphoma kinase‐positive non‐small‐cell lung cancer after crizotinib therapy\n. Oxf Med Case Reports \n2014 ; 2014 (1 ): 11 –2\n.25988009 \n6 \n\nWatanabe \nN \n, \nNakahara \nY \n, \nTaniguchi \nH e a \n. Crizotinib‐induced acute interstitial lung disease in a patient with EML4‐ALK positive non‐small cell lung cancer and chronic interstitial pneumonia\n. Acta Oncol \n2014 ; 53 (1 ): 158 –60\n.23750540 \n7 \n\nHwang \nA \n, \nIskandar \nA \n, \nDasanu \nCA \n. Successful re‐introduction of alectinib after inducing interstitial lung disease in a patient with lung cancer\n. J Oncol Pharm Pract \n2019 ; 25 (6 ): 1531 –3\n.30572795 \n8 \n\nBender \nL \n, \nMeyer \nG \n, \nQuoix \nE \n, \nMennecier \nB \n. Ceritinib‐related interstitial lung disease improving after treatment cessation without recurrence under either crizotinib or brigatinib: A case report\n. Ann Transl Med \n2019 ; 7 (5 ): 106 .31019956 \n9 Xalkori® (crizotinib): Proper usage information Vol. 5, Interim report of specific use result investigation. Pfizer Japan Inc.: 2017. Available from URL: https://www.pfizerpro.jp/documents/info/xlk02info.pdf. 2018 .\n10 Zykadia® (ceritinib): pharmaceutical risk management plan. 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"fulltext_license": "CC BY-NC",
"issn_linking": "1759-7706",
"issue": "11(6)",
"journal": "Thoracic cancer",
"keywords": "Alectinib; anaplastic lymphoma kinase; ceritinib; crizotinib; drug-related side effects and adverse reactions",
"medline_ta": "Thorac Cancer",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D000971:Antineoplastic Combined Chemotherapy Protocols; D002227:Carbazoles; D002294:Carcinoma, Squamous Cell; D000077547:Crizotinib; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D055370:Lung Injury; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D011379:Prognosis; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012189:Retrospective Studies; D012307:Risk Factors; D013450:Sulfones; D015996:Survival Rate",
"nlm_unique_id": "101531441",
"other_id": null,
"pages": "1495-1502",
"pmc": null,
"pmid": "32237210",
"pubdate": "2020-06",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "28373069;17239288;23169500;20460631;31097098;22397764;25988009;28586279;31019956;21913033;15316202;17545850;24032382;23750540;20009909;28501140;30572795",
"title": "Clinical characteristics and risk factors of drug-induced lung injury by ALK tyrosine kinase inhibitors: A single center retrospective analysis.",
"title_normalized": "clinical characteristics and risk factors of drug induced lung injury by alk tyrosine kinase inhibitors a single center retrospective analysis"
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"companynumb": "JP-PFIZER INC-2020153658",
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"activesubstancename": "CRIZOTINIB"
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... |
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"abstract": "Recurrent hepatitis C after orthotopic liver transplantation (OLT) is universal and can lead to graft failure and, consequently, reduced survival. Hepatitis C treatment can be used to prevent these detrimental outcomes. The aim of this study was to describe rates of hepatitis C recurrence and sustained virological response (SVR) to interferon-based treatment after OLT and its relationship to survival and progression of liver disease through retrospective analysis of medical records of 127 patients who underwent OLT due to cirrhosis or hepatocellular carcinoma secondary to chronic hepatitis C between January 2002 and December 2013. Fifty-six patients were diagnosed with recurrent disease, 42 started interferon-based therapy and 37 completed treatment. Demographic, treatment- and outcome-related variables were compared between SVR and non-responders (non-SVR). There was an overall 54.1% SVR rate with interferon-based therapies. SVR was associated with longer follow-up after treatment (median 66.5 vs 37 months for non-SVR, P=0.03) and after OLT (median 105 vs 72 months, P=0.074), and lower rates of disease progression (15 vs 64.7%, P=0.0028) and death (5 vs 35.3%, P=0.033). Regardless of the result of therapy (SVR or non-SVR), there was a significant difference between treated and untreated patients regarding the occurrence of death (P<0.001) and months of survival (P<0.001). Even with suboptimal interferon-based therapies (compared to the new direct-acting antivirals) there is a 54.1% SVR rate to treatment. SVR is associated with improved survival and reduced risks of clinical decompensation, loss of the liver graft and death.",
"affiliations": "Disciplina de Infectologia, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.;Disciplina de Infectologia, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.;Disciplina de Infectologia, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.;Disciplina de Infectologia, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.;Departamento de Anatomia Patológica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.;Unidade de Transplante de Fígado, Departamento de Cirurgia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.;Unidade de Transplante de Fígado, Departamento de Cirurgia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.;Disciplina de Infectologia, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.",
"authors": "Zanaga|L P|LP|;Vigani|A G|AG|;Angerami|R N|RN|;Giorgetti|A|A|;Escanhoela|C A F|CA|;Ataíde|E C|EC|;Boin|I F S F|IF|;Stucchi|R S B|RS|",
"chemical_list": "D000998:Antiviral Agents; D007372:Interferons",
"country": "Brazil",
"delete": false,
"doi": "10.1590/1414-431X20165540",
"fulltext": "\n==== Front\nBraz J Med Biol ResBraz. J. Med. Biol. ResbjmbrBrazilian Journal of Medical and Biological Research0100-879X1414-431XAssociação Brasileira de Divulgação Científica 280764510070110.1590/1414-431X20165540Clinical InvestigationSurvival benefits of interferon-based therapy in patients with recurrent\nhepatitis C after orthotopic liver transplantation Zanaga L.P. 1Vigani A.G. 1Angerami R.N. 1Giorgetti A. 1Escanhoela C.A.F. 2Ataíde E.C. 3Boin I.F.S.F. 3Stucchi R.S.B. 11 Disciplina de Infectologia, Departamento de Clínica Médica, Faculdade\nde Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil2 Departamento de Anatomia Patológica, Faculdade de Ciências Médicas,\nUniversidade Estadual de Campinas, Campinas, SP, Brasil3 Unidade de Transplante de Fígado, Departamento de Cirurgia, Faculdade\nde Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, BrasilCorrespondence: L.P. Zanaga: leticia.zanaga@gmail.com09 1 2017 2017 50 1 e554025 5 2016 1 11 2016 This is an Open Access article distributed under the terms of the Creative\nCommons Attribution Non-Commercial License, which permits unrestricted\nnon-commercial use, distribution, and reproduction in any medium, provided the\noriginal work is properly cited.Recurrent hepatitis C after orthotopic liver transplantation (OLT) is universal and\ncan lead to graft failure and, consequently, reduced survival. Hepatitis C treatment\ncan be used to prevent these detrimental outcomes. The aim of this study was to\ndescribe rates of hepatitis C recurrence and sustained virological response (SVR) to\ninterferon-based treatment after OLT and its relationship to survival and progression\nof liver disease through retrospective analysis of medical records of 127 patients\nwho underwent OLT due to cirrhosis or hepatocellular carcinoma secondary to chronic\nhepatitis C between January 2002 and December 2013. Fifty-six patients were diagnosed\nwith recurrent disease, 42 started interferon-based therapy and 37 completed\ntreatment. Demographic, treatment- and outcome-related variables were compared\nbetween SVR and non-responders (non-SVR). There was an overall 54.1% SVR rate with\ninterferon-based therapies. SVR was associated with longer follow-up after treatment\n(median 66.5 vs 37 months for non-SVR, P=0.03) and after OLT (median\n105 vs 72 months, P=0.074), and lower rates of disease progression\n(15 vs 64.7%, P=0.0028) and death (5 vs 35.3%,\nP=0.033). Regardless of the result of therapy (SVR or non-SVR), there was a\nsignificant difference between treated and untreated patients regarding the\noccurrence of death (P<0.001) and months of survival (P<0.001). Even with\nsuboptimal interferon-based therapies (compared to the new direct-acting antivirals)\nthere is a 54.1% SVR rate to treatment. SVR is associated with improved survival and\nreduced risks of clinical decompensation, loss of the liver graft and death.\n\nHepatitis CLiver transplantationSustained virological responseRecurrent hepatitis CTransplantation outcomes\n==== Body\nIntroduction\nChronic hepatitis C virus (HCV) infection leading to decompensated liver cirrhosis or\nhepatocellular carcinoma is the main cause of orthotopic liver transplantation (OLT)\nworldwide. It is expected that the number of patients with HCV infection referred for\nOLT will continue to increase in the next years, in spite of advances in antiviral\ntherapy (1).\n\nNonetheless, if HCV viremia is present during the transplantation procedure, the result\nis universal reinfection of liver allografts, happening as early as the reperfusion\nphase of the surgical procedure, with viral replication within hours after OLT (2,3).\nRecurrent liver disease due to HCV usually develops after 3 months and is present in up\nto 70–90% of patients 1 year after OLT. Furthermore, the progression of recurrent\ndisease is faster than in the immunocompetent population (4\n–7). Recurrent\nliver disease associated with HCV infection leads to consequent graft loss in about one\nthird of patients within 5 years of OLT (6,8) and graft failure due to recurrent HCV is the\nmain cause of patient death and retransplantation by the 5th postoperative year (9). Therefore, survival of patients with chronic HCV\ninfection is significantly reduced when compared to other causes of OLT (4–8,10).\n\nThe virological efficacy of HCV therapeutic options has improved drastically over recent\nyears, from 30% success rate with interferon-based therapies to around 90% with\ninterferon-free direct acting antiviral agents (DAAs) (11). However, regardless of the medication used, the objectives of HCV\ntreatment have not changed: to prevent progression to cirrhosis and loss of the graft\n(12\n\n\n\n–20). In\nHCV-infected patients, the achievement of sustained virological response (SVR) after\ntreatment reduces the risk of progression to clinical decompensation or development of\nhepatocellular carcinoma in cirrhotic patients and can even result in histological\nimprovement in those with less advanced fibrosis. Some studies have evaluated this\nbenefit in post-OLT patients as well as the impact on survival, but studies of long-term\noutcomes are lacking (10,12–16,21–25).\n\nThe aim of this study is to describe rates of hepatitis C recurrence and SVR to\ninterferon-based treatment after OLT and its relationship to survival and progression of\nliver disease in a group of patients transplanted due to end-stage chronic HCV infection\nin a single center in Brazil.\n\nMaterial and Methods\nPatient selection\nThis study included adult patients (age ≥18 years) who underwent OLT due to cirrhosis\nor hepatocellular carcinoma secondary to chronic HCV infection from January 2002 to\nDecember 2013 at the Hospital de Clínicas of the Universidade Estadual de Campinas,\nBrazil, with positive anti-HCV serology and HCV-RNA. A retrospective analysis of the\npatients’ medical records was performed. The follow-up period ended at the time of\nthe patient's death or at the end of the observation period (July 2014) and was the\nbasis for the evaluation of survival. The exclusion criteria were coinfection with\nhepatitis B virus (detectable hepatitis B surface antigen), negative HCV-RNA before\nOLT, use of alcohol or illicit drugs after OLT, follow up at another transplant unit,\nincomplete medical records and survival after OLT shorter than 1 month (to rule out\ncases of early mortality related to the surgical procedure).\n\nRecurrent hepatitis C after liver transplantation was defined as the presence of\ndetectable serum HCV-RNA assessed by polymerase chain reaction (PCR; qualitative or\nquantitative) and compatible histology (for differential diagnosis with other\ncomplications, such as rejection, biliary disease or vascular complications).\n\nHistological examination\nLiver biopsies were not routinely scheduled, but performed after the detection of\nelevated liver transaminases during follow-up. Biopsies were considered compatible\nwith recurrent hepatitis C based on findings of portal or lobular infiltration by\nmononuclear cells with piecemeal necrosis and were graded according to the Metavir\nscore. If histology presented mixed portal infiltrate, venous endothelitis and bile\nduct injury, acute rejection was diagnosed. Chronic rejection was considered when\nthere was bile duct atrophy, paucity or foam cell obliterative arteriopathy. If the\nbiopsy was compatible with rejection and diagnosed during or immediately after\nstopping treatment, the case was analyzed by the assistant physician to define if its\noccurrence was associated to HCV therapy.\n\nAntiviral treatment regimen\nAntiviral treatment regimen consisted of ribavirin (RBV, 15 mg/kg daily) associated\nwith pegylated interferon (PegIFN, α2a 180 µg or α2b 1.5 µg/kg weekly) or\nconventional interferon alpha (IFN, 3 million IU three times a week). Local protocols\nestablished that patients should be treated for 12 months after achieving HCV-RNA\nnegativity. For patients who have been retreated, the information collected was that\nof the most recent regimen. SVR was defined as negative HCV-RNA 24 weeks after the\ncompletion of therapy.\n\nAdjunctive medication could be used for the management of side effects, such as\nerythropoietin (doses up to 40.000 UI weekly) if hemoglobin ≤10 g/dL, and filgrastim\n(300 µg weekly) if neutrophils ≤750/mm3. The dosage of IFN, PegIFN, and\nRBV could also be decreased. Absolute contraindications for HCV treatment were the\npresence of rejection at the beginning of treatment, decompensated cirrhosis\n(Child-Pugh B or C), severely low platelets (<30,000/mm3) and\npsychiatric comorbidities.\n\nImmunosuppression\nImmunosuppression was managed according to the internal guidelines, consisting of\ncorticosteroids (generally withdrawn within 6 months after OLT) and a calcineurin\ninhibitor as the main immunosuppressive agent (cyclosporine or tacrolimus), at times\nassociated to mycophenolate mofetil. Acute rejection episodes were managed with high\ndoses of intravenous corticosteroids (methylprednisolone 1 g daily for 3 days).\nChronic rejection was managed with steroids and alteration of the main\nimmunosuppressive agent. When rejection was diagnosed before the start of\ninterferon-based therapy, the antiviral treatment was postponed until rejection\nepisodes were controlled.\n\nData collection\nData regarding patient characteristics (age, gender, body mass index, comorbidities),\nsurgical procedures, laboratory and biopsy results, use of medication\n(immunosuppression and HCV therapy) and clinical follow-up were collected using a\nstandardized form.\n\nEndpoints\nFour endpoints were analyzed: 1) HCV recurrence after OLT, 2) virological response to\ntherapy, 3) occurrence of progression of liver disease, and 4) survival after\ntreatment.\n\nProgression of disease post-treatment was defined by the presence of worsening of\nfibrosis on graft biopsy or the development of clinical decompensation, such as\nhepatic encephalopathy, jaundice, ascites, spontaneous peritonitis, esophageal\nhemorrhage or hepatocellular carcinoma (HCC).\n\nStatistical analysis\nStatistical analysis was performed using EpiInfo Software version 7.1.5.2 (CDC, USA).\nCategorical data are reported as percentages and continuous variables are reported as\nmedians with ranges. The chi-square or Fisher's exact test was used to compare\ncategorical data, when appropriate. The Kruskal-Wallis method was used to analyze\ncontinuous data. Overall survival was calculated by Kaplan-Meier survival curves with\nlog-rank survival comparisons and 95% confidence intervals. Variables for which an\nassociation was suspected (P<0.2) in the univariate analysis were included in a\nstepwise logistic regression model. P≤0.05 was considered to be significant.\n\nEthical considerations\nThe study was approved by the Ethics Committee of the Faculty of Medical Sciences of\nthe Universidade Estadual de Campinas.\n\nResults\nFrom January 2002 to December 2013, 193 patients underwent OLT at the Universidade\nEstadual de Campinas due to cirrhosis or hepatocellular carcinoma secondary to chronic\nHCV infection and 127 (65.8%) met the inclusion criteria for the study. One patient was\nexcluded because of incomplete medical records, 2 patients were excluded because they\nwere referred to another hospital for follow-up, 3 patients as a result of narcotics use\nafter OLT, 4 due to coinfection with hepatitis B virus, 11 because of negative HCV-PCR\nbefore OLT, and 45 due to survival of less than 1 month after OLT.\n\nDemographics and pretreatment patient characteristics\nThe patients were mostly male (76.4%) and at OLT the median age was 52 years (range:\n24–70 years), median body mass index of 26 (range: 18–42), median model for end-stage\nliver disease (MELD) (without adjustment) of 17 (range: 7–42) and 65 (51.2%) were\nChild-Pugh C. HCC was present in 69 cases (54.3%), with 11 incidental tumors (15.7%).\nNine patients required retransplantation (7.1% of the total), 6 (66.7%) due to\narterial thrombosis, and 3 (33.3%) due to chronic rejection. The patients were\nfollowed for a median period of 33 months post-transplantation (range: 1–144).\n\nEighty-five patients (66.9%) were submitted to liver biopsies after the detection of\nelevated liver tests (aspartate aminotransferase, alanine aminotransferase,\nbillirrubin) on routine follow-up. Fifty-six patients (44.1%) were diagnosed with\nrecurrent hepatitis C, at a median of 12.5 months after OLT (range: 1–100\nmonths).\n\nForty-two patients (33.1%) received at least one dose of treatment with either IFN or\nPegIFN and RBV: 37 (29.1%) completed treatment and 5 were still on treatment during\ndata collection. Eighty-five (66.9%) patients never started treatment, 14 (11%) due\nto contraindications to interferon-based therapy (psychiatric disease, Child-Pugh B\nor C cirrhosis and uncontrolled comorbidities, such as coronary heart disease and\ndiabetes). Seventy-one patients (55.9%) were not treated due to lack of diagnosis of\nrecurrent HCV disease, since 29 patients’ biopsies had diagnoses other than recurrent\nHCV, and 42 were not submitted to biopsy, because of absence of alteration of liver\ntransaminases or lack of clinical conditions for biopsy. The complete patient\nselection algorithm is shown in Figure 1. The\npatients’ characteristics, stratified into treated and untreated, are described in\nTable 1.\n\nFigure 1 Algorithm of patient selection and treatment outcome. HCV: hepatitis C\nvirus; OLT: orthotopic liver transplantation; SVR: sustained virological\nresponse.\n\n\n\n\nIn the univariate analysis, factors associated with HCV treatment were younger age at\nOLT, absence of HCC before OLT, higher MELD score and Child-Pugh C (Table 1). In multivariate analysis, male gender\n[odds ratio (OR)= 0.29; 95% confidence interval (CI): 0.09–0.92], younger age at OLT\n(OR=0.94; 95%CI=0.88-0.99) and absence of HCC before OLT (OR=0.27; 95%CI=0.11–0.68)\nwere independently and significantly associated with HCV treatment. Regardless of\ntreatment response, death outcome was significantly more frequent among untreated\n(58.8%, 50 of 85 patients) than treated patients (16.7%, 7 of 42), P<0.001. There\nwas a noteworthy difference in survival between treated and untreated patients\n(P<0.001, Figure 2).\n\nFigure 2 Cumulative survival (Kaplan-Meier) of interferon-treated versus untreated\npatients who had recurrent hepatitis C viral (HCV) infection after orthotopic\nliver transplantation. Survival was significantly better in those who received\nrecurrent HCV treatment (P<0.001).\nTreatment characteristics and virological response\nThirty-seven patients (66.1% of those with HCV recurrence) completed treatment.\nTherapy was initiated at median 18 months after OLT (range: 4–49) and the median\nduration was 68 weeks (range: 2–172). Sixteen patients had been treated before OLT,\nwithout achieving SVR.\n\nFive (13.5%) patients were treated with IFN and RBV and 32 (86.5%) with PegIFN and\nRBV. The overall SVR rate was 54.1% (20 of 37 patients treated) and 50% of those who\nreached SVR had already been treated unsuccessfully before OLT. The SVR rate of\npatients treated with PegIFN and RBV was 46.9% (15 of 32), and was higher for\ngenotype 3 infection (46.1%, 6 of 13 patients, versus 37.5%, 9 of 24 patients with\nHCV genotype 1). The characteristics of the treated patients are described in Table 2.\n\n\n\n\n\nEight patients (21.6%) were retreated. Among the patients treated with IFN and RBV, 3\nwere retreated with PegIFN due to previous non-response, but only 1 achieved SVR. On\nthe other hand, 5 patients of the PegIFN group were retreated, with change in the\ntype of medication (PegIFN α 2a or 2b), with 2 (40%) additional SVR cases. The\ntreatment characteristics are described in Table\n3.\n\n\n\n\n\nUnivariate analysis revealed genotype 3, type of interferon and longer treatment\nduration as being significantly associated with SVR (Tables 2 and 3). In multivariate\nanalysis, no variable was significantly associated with SVR.\n\nClinical outcomes after treatment - chronic liver disease progression and\nsurvival\nAmong the 37 patients who completed treatment, the median duration of follow-up after\ntreatment was 51 months (range: 1–111). Three (15%) patients with SVR had signs of\nprogression of liver disease (one with jaundice and ascites, one with fibrosis\nevolution on biopsy and another with worsening of fibrosis and encephalopathy). On\nthe other hand, among 17 non-SVR patients, 11 (64.7%) had disease progression\n(P=0.002; Table 4). Nine non-SVR patients had\nworsening of fibrosis on biopsy specimens. Three of these patients have been\nretreated due to previous treatment failure and had progression of fibrosis when\ncomparing biopsies before and after the first treatment. There were no cases of\nesophageal variceal bleeding or HCC post OLT among the treated patients. In\nmultivariate analysis, prevention of liver disease progression after treatment\n(OR=0.09; 95%CI=0.014–0.66) was independently and significantly associated with\nSVR.\n\n\n\n\n\nOverall, 7 patients died, 1 (5%) in the SVR group and 6 (35.3%) non-SVR, P=0.03. The\nonly death among SVR patients was related to metastatic colonic adenocarcinoma and\namong non-SVR patients 4 died due to sepsis, 1 due to hepatic insufficiency, and 1\ndue to multiorgan failure. Median post-transplant survival was 105 months (range:\n45–144) for SVR patients and 72 months (range: 16–144) for non-SVR, P=0.003 (Table 4).\n\nThe Kaplan-Meier survival analysis demonstrated that patients who achieved SVR had\nsignificantly longer survival than non-SVR (P<0.001, Figure 3).\n\nFigure 3 Cumulative survival (Kaplan-Meier) of patients who had recurrent hepatitis\nC viral (HCV) infection after orthotopic liver transplantation with sustained\nvirological response (SVR) versus non-SVR. Survival was significantly better in\nthose who achieve SVR after recurrent HCV therapy (P<0.001).\nDiscussion\nRecurrent hepatitis C following OLT is a challenge to physicians worldwide and is a\nsignificant threat to the survival of both the patient and his or her graft, since OLT\nrecipients with recurrent hepatitis C have faster disease progression when compared to\nnon-immunosuppressed individuals (4–7). However, antivirals have been used in an attempt\nto modify the course of HCV recurrent disease. Our study showed a significant rate of\nrecurrent hepatitis C after OLT and the majority of patients had mild to moderate\nfibrosis (F1–F2) severity on liver biopsy. The factors associated with antiviral\ntreatment were younger age at OLT, male gender and absence of HCC at OLT. Treated\npatients who did not achieve SVR had longer survival, and those who reached SVR had\nlonger survival and lower rates of clinical decompensation, loss of the graft and\ndeath.\n\nEven though there is universal recurrence of HCV after OLT, HCV was only diagnosed in\n44.1% of the patients included in the study and in 65.9% if considering those who were\nsubmitted to liver biopsies after the elevation of transaminases. The use of protocol\nliver biopsies may result in higher rates of recurrence, as in the study by Shuhart et\nal. (4), who described a 66% rate. The population\nstudied had recurrent disease diagnosed 9 months after OLT (range: 4–36), in contrast to\nprevious studies which detected delayed-onset recurrence, ranging from 13.4 to 34 months\npost-OLT (4,8).\n\nIn the present study, only 21.8% of patients transplanted due to HCV cirrhosis started\ninterferon-based therapies, which is lower than treatment rates described in previous\nstudies, ranging from 38.6 to 68% (7,12,14,21,22,25). This difference could be explained by the lack\nof protocol biopsies and the presence of contraindications to treatment. The rates of\ncontraindications are about 17.3% in the general population (26) and reached 25% of patients with recurrent HCV in our study.\n\nAntiviral therapy with PegIFN and RBV for 48 weeks results in a SVR rate of around 30.2%\n(23\n). The present study found a significantly higher\noverall SVR rate of 54.1% and this difference could be justified by the prolonged\nduration of treatment (median of 68 weeks) when compared to other studies in which\npatients were treated for 48 weeks on average (10,12,14,16,18–25,27,28). Besides, in the population\nstudied there was a considerable difference in length of treatment among SVR and non-SVR\npatients.\n\nEven though over the last decades many patients have been treated and reached SVR with\ninterferon-based therapies, nowadays studies focus on DAAs (protease, NS5A and\npolymerase inhibitors) for the treatment of HCV, due to higher SVR rates, and fewer\ncontraindications and side-effects. Data from clinical trials and real-life settings\nwill provide information to assess the impact of therapy in the DAA era and the role of\nribavirin nowadays (11). Especially for OLT\nrecipients, these new drugs bring renewed hope, since the use of interferon and\nribavirin in the post-transplantation population is associated with lower SVR rates and\nhigh rates of adverse events, such as anemia and neutropenia. This population requires\nmodifications on the dosage of interferon or ribavirin, adjunctive therapies, like\nfilgrastim or erythropoietin, or even treatment interruption. Patients treated were\nevaluated frequently (weekly if necessary), to assess for adverse events of treatment\nand prompt management, allowing for treatment continuation. The rates of medication dose\nreduction found in our population are compatible with previous studies. Another major\nconcern regarding OLT recipients under interferon therapy is the occurrence of rejection\ndue to immune-mediated graft dysfunction. In the population studied, 38.9% of cases of\nrejection were related to HCV interferon-based therapy, which was higher than rates of 0\nto 25% previously described in other studies (23). Moreover, two non-SVR patients developed chronic rejection related to HCV\ntherapy, leading to graft failure and consequent retransplantation. The ideal therapy\nfor recurrent HCV should have high efficacy, good tolerability, lack of interaction with\nimmunosuppressants and should not induce graft rejection.\n\nPrevious studies have shown benefits in treating this special patient population, since\nthe achievement of SVR can lead to histological improvement (16,18–21,23,25). Therefore, the achievement of SVR is expected to reduce the\noccurrence of progression to chronic liver disease, manifested by progression of\nfibrosis on subsequent liver biopsies, diagnosis of hepatocellular carcinoma or other\ncomplications associated to cirrhosis, such as ascites, spontaneous bacterial\nperitonitis, esophageal variceal bleeding, hepatic encephalopathy, jaundice and loss of\nthe graft. The present study encountered a significant difference among SVR patients and\nnon-SVR regarding liver disease progression.\n\nFurthermore, patient survival was overall significantly better in patients who achieved\nSVR, which is compatible with results from other cohort studies (10,12–16,21–25). The only death among the patients who achieved SVR was\nunrelated to transplantation complications or recurrent hepatitis C. It must be noted\nthat, regardless of the result of therapy (SVR or non-SVR), there was a significant\ndifference between treated and untreated patients regarding the occurrence of death and\nlength of survival.\n\nLimitations of this study include its small sample size, the retrospective design and\nchanges in clinical management protocols (regarding immunosuppression and hepatitis\ntreatment), which could introduce confounding factors. Another concern is the fact that\nliver biopsies were not performed by protocol, potentially reducing the diagnoses of\nrecurrent hepatitis C and, consequently, the indication for treatment. A selection bias\ncould also be involved, since interferon-based therapies have contraindications that\ncould exclude the sickest patients from treatment. Furthermore, during the study period,\naccess to HCV-RNA assays was limited and it was not possible to perform viral kinetics\nanalysis. Since treatment protocol established that therapy should last for 12 months\nafter a negative PCR was obtained, difficulty of access to the exam could have led to\nthe prolonged treatment periods observed.\n\nThe main conclusion of this study is that the achievement of SVR is associated with\nimproved survival and reduced risks of clinical decompensation, loss of the liver graft\nand death.\n\nAcknowledgments\nThe authors would like to thank Noelle Miotto, Leandro César Mendes, Maria Sílvia Kroll\nLazarini, Elisabete Yoko Udo and Maria de Fátima Trovato Mei for the support in\nperforming this study.\n==== Refs\nReferences\n1 Razavi H Waked I Sarrazin C Myers RP Idilman R Calinas F The present and future disease burden of hepatitis C virus (HCV)\ninfection with today's treatment paradigm J Viral Hepat 2014 21 (Suppl 1) 34 59 10.1111/jvh.12248 24713005 \n2 Garcia-Retortillo M Forns X Feliu A Moitinho E Costa J Navasa M Hepatitis C virus kinetics during and immediately after 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Transpl 2009 15 1063 1071 10.1002/lt.21784 19718647 \n8 Ghobrial RM Steadman R Gornbein J Lassman C Holt CD Chen P A 10-year experience of liver transplantation for hepatitis C:\nanalysis of factors determining outcome in over 500 patients Ann Surg 2001 234 384 393 10.1097/00000658-200109000-00012 11524591 \n9 Charlton M Natural history of hepatitis C and outcomes following liver\ntransplantation Clin Liver Dis 2003 7 585 602 10.1016/S1089-3261(03)00046-1 14509528 \n10 Wawrzynowicz-Syczewska M Zeair S Andruszkiewicz A Bartoszewicz K Slawinski J Laurans L Impact of antiviral treatment on survival in HCV-positive liver\nrecipients Ann Transplant 2014 19 367 372 10.12659/AOT.890612 25073736 \n11 Berenguer M Management of HCV in the liver transplant setting Clin Res Hepatol Gastroenterol 2015 39 (Suppl 1) S115 S119 10.1016/j.clinre.2015.05.004 26206579 \n12 Bizollon T Pradat P Mabrut JY Chevallier M Adham M Radenne S Benefit of sustained virological response to combination therapy on\ngraft survival of liver transplanted patients with recurrent chronic hepatitis\nC Am J Transplant 2005 5 1909 1913 10.1111/j.1600-6143.2005.00976.x 15996238 \n13 Kornberg A Kupper B Tannapfel A Thrum K Barthel E Habrecht O Sustained clearance of serum hepatitis C virus-RNA independently\npredicts long-term survival in liver transplant patients with recurrent hepatitis\nC Transplantation 2008 86 469 473 10.1097/TP.0b013e31817c0e20 18698252 \n14 Picciotto FP Tritto G Lanza AG Addario L De Luca M Di Costanzo GG Sustained virological response to antiviral therapy reduces mortality\nin HCV reinfection after liver transplantation J Hepatol 2007 46 459 465 10.1016/j.jhep.2006.10.017 17196700 \n15 Faisal N Bilodeau M Aljudaibi B Hirsch G Yoshida EM Hussaini T Sofosbuvir-antiviral therapy is highly effective in recurrent\nhepatitis C in liver transplant recipients: Canadian multicenter \"Real-Life\"\nexperience Transplantation 2016 100 1059 1065 10.1097/TP.0000000000001126 26950722 \n16 Berenguer M Schuppan D Progression of liver fibrosis in post-transplant hepatitis C:\nmechanisms, assessment and treatment J Hepatol 2013 58 1028 1041 10.1016/j.jhep.2012.12.014 23262248 \n17 Berenguer M Palau A Aguilera V Rayon JM Juan FS Prieto M Clinical benefits of antiviral therapy in patients with recurrent\nhepatitis C following liver transplantation Am J Transplant 2008 8 679 687 10.1111/j.1600-6143.2007.02126.x 18294165 \n18 Berenguer M Aguilera V Rubin A Ortiz C Jimenez M Prieto M Comparison of two non-contemporaneous HCV-liver transplant cohorts:\nstrategies to improve the efficacy of antiviral therapy J Hepatol 2012 56 1310 1316 10.1016/j.jhep.2011.12.031 22314429 \n19 Berenguer M Palau A Fernandez A Benlloch S Aguilera V Prieto M Efficacy, predictors of response, and potential risks associated with\nantiviral therapy in liver transplant recipients with recurrent hepatitis\nC Liver Transpl 2006 12 1067 1076 10.1002/lt.20737 16622844 \n20 Berenguer M Roche B Aguilera V Duclos-Vallee JC Navarro L Rubin A Efficacy of the retreatment of hepatitis C virus infections after\nliver transplantation: role of an aggressive approach Liver Transpl 2013 19 69 77 10.1002/lt.23555 23008144 \n21 Kawaoka T Takahashi S Kawakami Y Tsuge M Hiramatsu A Imamura M Sustained virological response to antiviral therapy improves survival\nrate in patients with recurrent hepatitis C virus infection after liver\ntransplantation Hepatol Res 2015 45 1047 1054 10.1111/hepr.12447 25376902 \n22 Tanaka T Selzner N Therapondos G Renner EL Lilly LB Virological response for recurrent hepatitis C improves long-term\nsurvival in liver transplant recipients Transpl Int 2013 26 42 49 10.1111/j.1432-2277.2012.01571.x 23137287 \n23 Berenguer M Systematic review of the treatment of established recurrent hepatitis\nC with pegylated interferon in combination with ribavirin J Hepatol 2008 49 274 287 10.1016/j.jhep.2008.05.002 18571272 \n24 Gurusamy KS Tsochatzis E Toon CD Xirouchakis E Burroughs AK Davidson BR Antiviral interventions for liver transplant patients with recurrent\ngraft infection due to hepatitis C virus Cochrane Database Syst Rev 2013 CD006803 24307460 \n25 Selzner N Renner EL Selzner M Adeyi O Kashfi A Therapondos G Antiviral treatment of recurrent hepatitis C after liver\ntransplantation: predictors of response and long-term outcome Transplantation 2009 88 1214 1221 10.1097/TP.0b013e3181bd783c 19935376 \n26 Talal AH LaFleur J Hoop R Pandya P Martin P Jacobson I Absolute and relative contraindications to pegylated-interferon or\nribavirin in the US general patient population with chronic hepatitis C: results\nfrom a US database of over 45 000 HCV-infected, evaluated patients Aliment Pharmacol Ther 2013 37 473 481 10.1111/apt.12200 23289640 \n27 Ponziani FR Milani A Gasbarrini A Zaccaria R Vigano R Iemmolo RM Treatment of genotype-1 hepatitis C recurrence after liver transplant\nimproves survival in both sustained responders and relapsers Transpl Int 2013 26 281 289 10.1111/tri.12027 23230956 \n28 Garcia-Reyne A Lumbreras C Fernandez I Colina F Abradelo M Magan P Influence of antiviral therapy in the long-term outcome of recurrent\nhepatitis C virus infection following liver transplantation Transpl Infect Dis 2013 15 405 415 10.1111/tid.12097 23725370\n\n",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D006528:Carcinoma, Hepatocellular; D018450:Disease Progression; D019698:Hepatitis C, Chronic; D006801:Humans; D007372:Interferons; D008103:Liver Cirrhosis; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D012008:Recurrence; D012189:Retrospective Studies; D012307:Risk Factors; D016019:Survival Analysis; D000072230:Sustained Virologic Response; D016896:Treatment Outcome",
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"title": "Survival benefits of interferon-based therapy in patients with recurrent hepatitis C after orthotopic liver transplantation.",
"title_normalized": "survival benefits of interferon based therapy in patients with recurrent hepatitis c after orthotopic liver transplantation"
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"abstract": "BACKGROUND\nAdjuvant chemotherapy with new cytotoxic agents for breast cancer must be properly assessed for toxicity.\n\n\nOBJECTIVE\nTo describe adverse events associated with adjuvant chemotherapy for breast cancer, which led to premature termination of a clinical trial.\n\n\nMETHODS\nWe conducted a prospective randomized multicenter study (Reposant sur des Arguments Pronostiques et Predictifs [RAPP]-01) to compare the effectiveness of 2 chemotherapy regimens. Patients (women aged 18-70 years) had primary unilateral breast cancer and either a moderate number of positive axillary lymph nodes (< or =3) or no positive axillary lymph nodes (N0), but were at a high risk of relapse. Patients were treated at 11 French cancer referral centers from June 1999 through January 2003. Primary prophylaxis for febrile neutropenia was not recommended in the study protocol.\n\n\nMETHODS\nDoxorubicin, 50 mg/m2, plus docetaxel, 75 mg/m2, or doxorubicin, 60 mg/m2, plus cyclophosphamide, 600 mg/m2, given postoperatively for 4 courses.\n\n\nMETHODS\nThe main end point was the disease-free survival rate at 5 years, as estimated using the Kaplan-Meier product limit method. Secondary end points included safety, which is the focus of this article, and overall survival.\n\n\nRESULTS\nA total of 627 women were enrolled. Median follow-up is currently too short (24 months) to analyze the primary end point. The trial was terminated prematurely when 2 deaths related to drug toxicity and 1 case of perforative peritonitis occurred among patients with febrile neutropenia, all in the doxorubicin-docetaxel group. The incidence of febrile neutropenia was significantly higher with the doxorubicin-docetaxel regimen (40.8%) than with the doxorubicin-cyclophosphamide regimen (7.1%) (P<.001).\n\n\nCONCLUSIONS\nA high risk of life-threatening complications associated with the doxorubicin-docetaxel regimen was found in this open-label controlled trial. The doxorubicin-docetaxel combination should not be considered as an alternative to the doxorubicin-cyclophosphamide regimen outside carefully designed studies that include primary prophylaxis for febrile neutropenia.",
"affiliations": "Department of Medical Oncology, René Huguenin Cancer Centre, Saint-Cloud, France. e.brain@stcloud-huguenin.org",
"authors": "Brain|Etienne G C|EG|;Bachelot|Thomas|T|;Serin|Daniel|D|;Kirscher|Sylvie|S|;Graic|Yvon|Y|;Eymard|Jean-Christophe|JC|;Extra|Jean-Marc|JM|;Combe|Martin|M|;Fourme|Emmanuelle|E|;Noguès|Catherine|C|;Rouëssé|Jacques|J|;|||",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D000077143:Docetaxel; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008875:Middle Aged; D018805:Sepsis; D043823:Taxoids",
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"references": null,
"title": "Life-threatening sepsis associated with adjuvant doxorubicin plus docetaxel for intermediate-risk breast cancer.",
"title_normalized": "life threatening sepsis associated with adjuvant doxorubicin plus docetaxel for intermediate risk breast cancer"
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"abstract": "BACKGROUND\nThe prognosis of stage IV gastric cancer and human epidermal growth factor 2 (HER2)-positive gastric cancer is poor, although new drugs and regimens have been developed. We report a case of a patient with stage IV HER2-positive gastric cancer treated successfully by conversion therapy and trastuzumab.\n\n\nMETHODS\nThe patient was a 73-year-old Japanese man diagnosed as L, type 3, circ, T4aNxCy1P1M1, stage IV (the Japanese classification of gastric carcinoma). The patient was treated with docetaxel, cisplatin, and TS-1 (DCS regimen). After two courses of the regimen, peritoneal dissemination disappeared, and peritoneal lavage cytology revealed no tumor cells in the abdominal cavity. Subsequently, he underwent laparoscopic distal gastrectomy with D1+. Pathological findings were ypT2(MP), ypN2(3/15), ypP0, ypCY0, M0, ypstage II. He received TS-1 as an adjuvant chemotherapy, but he had peritoneal recurrence. The original gastric cancer was HER2-positive. We therefore treated him with TS-1 with trastuzumab. This regimen was quite effective and achieved a complete response. After complete response, we switched the patient to trastuzumab monotherapy. He had no evidence of recurrence for 6 years, 3 months after surgery.\n\n\nCONCLUSIONS\nDCS regimen, R0 resection, and adjuvant chemotherapy with trastuzumab can be a powerful strategy for stage IV HER2-positive gastric cancer.",
"affiliations": "Department of Surgery, Osaka Red Cross Hospital, 5-30 Fudegasakicho, Tennoji Ward, Osaka, 543-8555, Japan. maskgch@kuhp.kyoto-u.ac.jp.;Department of Surgery, Osaka Red Cross Hospital, 5-30 Fudegasakicho, Tennoji Ward, Osaka, 543-8555, Japan.;Department of Surgery, Osaka Red Cross Hospital, 5-30 Fudegasakicho, Tennoji Ward, Osaka, 543-8555, Japan.;Department of Surgery, Osaka Red Cross Hospital, 5-30 Fudegasakicho, Tennoji Ward, Osaka, 543-8555, Japan.",
"authors": "Sakaguchi|Masazumi|M|http://orcid.org/0000-0002-3885-2503;Shimoike|Norihiro|N|;Akagawa|Shin|S|;Kanaya|Seiichiro|S|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"country": "England",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 200110.1186/s13256-019-2001-3Case ReportStrategy for treatment of stage IV human epidermal growth factor 2-positive gastric cancer: a case report http://orcid.org/0000-0002-3885-2503Sakaguchi Masazumi maskgch@kuhp.kyoto-u.ac.jp Shimoike Norihiro n.shimoike@osaka-med.jrc.or.jp Akagawa Shin akagawa@osaka-med.jrc.or.jp Kanaya Seiichiro skanaya@osaka-med.jrc.or.jp 0000 0004 1764 7409grid.417000.2Department of Surgery, Osaka Red Cross Hospital, 5-30 Fudegasakicho, Tennoji Ward, Osaka, 543-8555 Japan 22 2 2019 22 2 2019 2019 13 4223 10 2018 28 1 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\nThe prognosis of stage IV gastric cancer and human epidermal growth factor 2 (HER2)-positive gastric cancer is poor, although new drugs and regimens have been developed. We report a case of a patient with stage IV HER2-positive gastric cancer treated successfully by conversion therapy and trastuzumab.\n\nCase presentation\nThe patient was a 73-year-old Japanese man diagnosed as L, type 3, circ, T4aNxCy1P1M1, stage IV (the Japanese classification of gastric carcinoma). The patient was treated with docetaxel, cisplatin, and TS-1 (DCS regimen). After two courses of the regimen, peritoneal dissemination disappeared, and peritoneal lavage cytology revealed no tumor cells in the abdominal cavity. Subsequently, he underwent laparoscopic distal gastrectomy with D1+. Pathological findings were ypT2(MP), ypN2(3/15), ypP0, ypCY0, M0, ypstage II. He received TS-1 as an adjuvant chemotherapy, but he had peritoneal recurrence. The original gastric cancer was HER2-positive. We therefore treated him with TS-1 with trastuzumab. This regimen was quite effective and achieved a complete response. After complete response, we switched the patient to trastuzumab monotherapy. He had no evidence of recurrence for 6 years, 3 months after surgery.\n\nConclusion\nDCS regimen, R0 resection, and adjuvant chemotherapy with trastuzumab can be a powerful strategy for stage IV HER2-positive gastric cancer.\n\nKeywords\nStage IV gastric cancerHuman epidermal growth factor 2-positive gastric cancerConversion therapyTrastuzumabissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nThe prognosis of stage IV gastric cancer (GC) is poor. However, as new drugs and regimens have been developed, sometimes tumors have shown good response and they are converted from unresectable to resectable. Conversion therapy is defined as a surgical treatment aiming at R0 resection after chemotherapy for unresectable tumors. Conversion therapy can be one of the treatments for stage IV GC, but there are many problems, to be clear: proper preoperative and postoperative regimens, duration, timing of the operation, and so forth [1].\n\nHuman epidermal growth factor 2 (HER2) is a proto-oncogene encoded by ERBB2 and associated with tumor cell proliferation and apoptosis [2, 3]. Some studies showed that HER2-positive GC is associated with poor outcomes [4–6]. It is treated with trastuzumab with chemotherapy based on the result of the ToGA trial [7]. According to the results of that trial, median overall survival was 13.8 months (95% confidence interval, 12–16) in patients with HER2-positive GC treated with trastuzumab with chemotherapy.\n\nFew studies of conversion therapy against stage IV HER2-positive GC have been reported, owing to its low incidence. Patients with stage IV HER2-positive GC are usually treated with trastuzumab with chemotherapy; however, we treated our patient with another chemotherapy regimen without trastuzumab and performed conversion therapy. After peritoneal recurrence, trastuzumab was initiated, and a complete response (CR) was achieved; our strategy was successful. There were no reports about long-term survivors with stage IV HER2-positive GC, to our knowledge; therefore, we decided to report this suggestive case.\n\nCase presentation\nA 73-year-old Japanese man with a 2-month history of dysphasia and heartburn first presented to his local doctor and was later admitted to our hospital. He had difficulties in swallowing and eating; did not have melena, epigastralgia, or hematemesis; and had a history of hypertension and no known allergies. At the time of admission, he was taking at lansoprazole 15 mg/day and olmesartan medoxomil 10 mg/day. He did not drink alcohol but used to smoke 30 cigarettes per day for 45 years. His environmental and employment histories were unremarkable. His family history was remarkable for colon cancer in his father and lung cancer in his brother. On admission, his height was 161 cm, body weight was 56.5 kg, blood pressure was 126/62 mm Hg, pulse was 70 beats per minute, temperature was 36.9 °C, and oxygen saturation was 98% while he was breathing ambient air. His conjunctiva was not icteric but slightly anemic. On chest examination, his heart rhythm was regular with no murmur, and his lungs were clear to auscultation. His abdomen was soft, not distended, and not tender. A soft and movable mass was palpable around the epigastrium. The legs and feet showed no edema. Laboratory tests showed a creatinine level of 0.89 mg/dl, blood urea nitrogen level of 12.6 mg/dl, total bilirubin level of 0.3 mg/dl, aspartate transaminase level of 17 IU/L, and alanine transaminase level of 19 IU/L. The patient’s white blood cell count was 8930 per cubic milliliter, hemoglobin was 9.2 g/dl, and platelet count was 438,000 per cubic milliliter. An esophagogastric fiber (EGF) showed type 3 gastric carcinoma in the antrum. The tumor caused pyloric stenosis and invasion to the duodenum, so the patient was admitted to the hospital (Fig. 1a–c). Staging laparoscopy was performed to assess the extent of tumor spread, and laparoscopic bypass was performed. Staging laparoscopy revealed peritoneal dissemination, and peritoneal lavage cytology revealed tumor cells in the abdominal cavity. We diagnosed L, type 3, circ, cT4a(SE), cNx, pP1, pCY1, M0, stage IV (the Japanese classification of gastric carcinoma). The patient was initially treated with docetaxel 40 mg/m2 on day 1, cisplatin (CDDP) 60 mg/m2 on day 1, and TS-1 120 mg/day on days 1–14, followed by a 2-week recovery period (DCS regimen). Dexamethasone 9.9 mg and palonosetron 0.75 mg were administered on day 1, and dexamethasone 6.6 mg was administered on days 2 and 3 as premedication. The patient had grade 3 diarrhea (according to Common Terminology Criteria for Adverse Events criteria) after one course (Fig. 2a, b). Then TS-1 was reduced (100 mg). After two courses of the DCS regimen, EGF and computed tomography (CT) showed that the tumor had shrunk (Fig. 1c–e), and then staging laparoscopy was performed to evaluate a response. Peritoneal dissemination disappeared, and peritoneal lavage cytology revealed no tumor cells in the abdominal cavity. Then salvage operation, laparoscopic distal gastrectomy with D1+ dissection, was performed. Pathological findings were ypT2(MP), ypN2(3/15), ypP0, ypCY0, M0, ystage II (Fig. 3). TS-1100 mg/day on days 1–14, every 3 weeks was started as adjuvant chemotherapy. After 15 months, CT revealed multiple peritoneal nodules (Fig. 4a). They were highly suspected as a recurrence. Paclitaxel 80 mg/m2 on days 1, 8, and 15 was started as a second regimen. Dexamethasone 6.6 mg, famotidine 20 mg, and granisetron 3 mg were administered on days 1, 8, and 15 as premedication. This regimen achieved partial response (Fig. 4b), but its efficacy did not last. After 3 months, CT revealed progressive disease (Fig. 4c). The original gastric carcinoma was HER2-positive (Fig. 5). The patient’s Eastern Cooperative Oncology Group performance status was 2; his body weight was 50.7 kg; and he complained of appetite loss. We concluded that the patient could not tolerate doublet therapy. Therefore, TS-1100 mg on days 1–14 with Herceptin 6 mg/kg (Roche/Genentech, South San Francisco, CA, USA) on day 1 every 3 weeks was introduced. This regimen was substantially effective and achieved CR after 9 months based on CT findings (Fig. 4d, e). The patient had no adverse effects while receiving this regimen (Fig. 2a, b). Since then, the patient has been treated with only Herceptin 6 mg/kg every 3 weeks without any side effects, and no radiological findings of recurrence had yet occurred for 6 years, 7 months after surgery (Fig. 4f).Fig. 1 Computed tomography (CT) and esophagogastric fiber (EGF) findings at diagnosis and after two courses of docetaxel, cisplatin, and TS-1 chemotherapy. a, b Abdominal CT showed thickened wall of the antrum and a bulky lymph node (arrows). c EGF showed type 3 tumor in the antrum. d, e Thickened antrum wall was significantly improved, and the bulky lymph node was significantly shrunk (arrows). f Type 3 tumor was remarkably shrunk. Side bar = 1 cm\n\nFig. 2 a Changes in tumor markers (CEA, CA19-9 and CA125), CBC, and CRP. b Changes in liver function, serum albumin, renal fanction and electrolytes. CEA Carcinoembryonic antigen (U/ml), CA19-9 Cancer antigen 19-9 (U/ml), CA125 Cancer antigen 125 (U/ml), WBC White blood cell count (× 100 per cubic milliliter), Neut Neutrophil (× 100 per cubic milliliter), Hg Hemoglobin (g/dl), PLT Platelet count (× 10,000 per cubic milliliter), CRP C-reactive protein (mg/L), T-Bil Total bilirubin (mg/dl), AST Aspartate transaminase (IU/L), ALT Alanine transaminase (IU/L), ALP Alkaline phosphatase (IU/L), Alb Albumin (g/dl), BUN Blood urea nitrogen (mg/dl), CRE Creatinine (mg/dl), Na Sodium (mEq/L), Cl Chloride (mEq/L), P Potassium (mEq/L)\n\nFig. 3 Pathological findings. a Microscopic view of the cancer (H&E stain, × 12.5). b Microscopic view showed fibrosis in subserosa in which the cancer cells seemed to have disappeared (H&E stain, × 12.5). c H&E stain showed massive number of cancer cells were present in subserosa (× 40). d Cancer cells were present in muscularis propria (H&E stain, × 100)\n\nFig. 4 Trastuzumab is effective against HER2-positive gastric cancer. a Abdominal computed tomography (CT) showed a peritoneal nodule (arrow). b Paclitaxel was effective against peritoneal dissemination (arrow). c CT showed a new peritoneal nodule appeared (arrow). d, e Peritoneal dissemination disappeared (arrows). f CT showed peritoneal dissemination was disappeared for 6 years and 3 months after surgery (arrow)\n\nFig. 5 Immunostaining of the cancer. Immunostaining with HER2 showed the cancer cells were HER2-positive (× 200)\n\n\n\nDiscussion\nOur patient with stage IV HER2-positive GC was initially administered docetaxel, CDDP, and TS-1 (DCS regimen) to convert unresectable GC to resectable GC, despite trastuzumab with chemotherapy. The conversion therapy was successful. After peritoneal recurrence, trastuzumab with chemotherapy was introduced, which achieved a CR. Trastuzumab monotherapy was then started, and CR was maintained. This patient has remained alive without disease progression for 6 years, 7 months after surgery.\n\nThe number of conversion therapies for stage IV GC is increasing as the result of development of new drugs and regimens [8–12]. However, regimens as induction chemotherapy, timing of the operation, and regimens after surgery remain unclear. In this case, we selected DCS regimens as an induction chemotherapy and did not check HER2 status, because we planned conversion surgery and DCS showed a better response rate (RR, 81%) than that of chemotherapy with Herceptin (RR, 47%) [7, 13]. In addition to the difference in RR, Janjigian et al. reported loss of HER2 expression in patients with HER2-positive esophagogastric tumors treated with trastuzumab, resulting in resistance to trastuzumab [14]. Given these reports, trastuzumab with chemotherapy is not proper as an induction therapy. After two courses of chemotherapy, we performed staging laparoscopy to assess peritoneal dissemination and lavage cytology and confirmed no dissemination and no tumors in the abdominal cavity. Some studies showed that patients with stage IV GC who underwent R0 resection after chemotherapy had a better prognosis [8, 9, 12]. We therefore performed distal gastrectomy with D1+ resection aiming at R0 resection.\n\nWe started TS-1 as adjuvant chemotherapy. After 3 months, peritoneal recurrence was suspected, and we changed the regimen. Paclitaxel is known for good transition to the peritoneum, so we administered it to the patient. However, it was not effective. We started therapy with Herceptin because the patient’s original GC showed HercepTest 3+ (Dako, Carpinteria, CA, USA). The ToGA trial showed that six cycles of chemotherapy with trastuzumab and then trastuzumab monotherapy until disease progression was effective for HER2-positive GC. In this case, we selected only TS-1 for chemotherapy because some studies showed TS-1 was effective for peritoneal recurrence [15, 16]. We judged that the patient could not tolerate doublet therapy. TS-1 with trastuzumab was significantly effective, and the patient was able to tolerate this regimen, so we continued it until CR. After that, we continued trastuzumab monotherapy as maintenance therapy. To date, we have found no evidence of recurrence. To the best of our knowledge, there are no other reports of long-term survivors of stage IV HER2-positive GC who underwent conversion surgery.\n\nTrastuzumab inhibits the HER2 signaling pathway in tumor cells expressing HER2 and induces antibody-dependent cell-mediated cytotoxicity through binding HER2-positive cancer cells [17]. The HER2 signal pathway is related to cancer cell proliferation and inhibition of apoptosis [18]. Trastuzumab monotherapy therefore has antitumor activity. However, more than half of patients with HER2-positive GC in the ToGA trial did not respond to trastuzumab [3]. Kataoka et al. reported that HER2 expression in gastroesophageal adenocarcinoma (GEA) is often heterogeneous [19]. Therefore, a predictive biomarker is needed to select patients who exhibit a good objective response to trastuzumab. Deguchi et al. showed that loss of phosphatase and tensin homolog (PTEN) contributed to trastuzumab resistance in a GEA cell line, and they concluded that PTEN loss can be a clinically valuable biomarker of resistance to trastuzumab [20]. In our patient, trastuzumab monotherapy could suppress peritoneal recurrence after surgery. Therefore, it is possible that PTEN was intact in our patient, although we did not assess it.\n\nConclusion\nIn summary, for patients with stage IV HER2-posisitve GC, the strategy should be to include a DCS regimen as induction therapy and to perform conversion therapy. The adjuvant chemotherapy is TS-1 for 1 year. If there is a recurrence, trastuzumab with chemotherapy is introduced and is switched to trastuzumab monotherapy after six cycles. Trastuzumab monotherapy is continued until disease progression. Owing to its low incidence, there is no established regimen for conversion therapy against stage IV HER2-positive GC. On the basis of this experience, our strategy can be a powerful treatment for stage IV HER2-positive GC.\n\nAbbreviations\nCRComplete response\n\nCTComputed tomography\n\nEGFEsophagogastric fiber\n\nGCGastric cancer\n\nGEAGastroesophageal adenocarcinoma\n\nHER2Human epidermal growth factor 2\n\nPTENPhosphatase and tensin homolog\n\nRRResponse rate\n\nAcknowledgements\nAll authors thank the patient and his family.\n\nFunding\nThis paper is not supported by any grants.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nAuthors’ contributions\nMS collected and analyzed data and wrote the manuscript. SK, SA, and NS revised the manuscript critically. 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 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\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Yoshida K Yamaguchi K Okumura N Tanahashi T Kodera Y Is conversion therapy possible in stage IV gastric cancer: the proposal of new biological categories of classification Gastric Cancer 2015 19 329 338 10.1007/s10120-015-0575-z 26643880 \n2. Ménard S, Pupa SM, Campiglio M, Tagliabue E. Biologic and therapeutic role of HER2 in cancer. Oncogene. Nature Publishing Group; 2003;22:6570–8.\n3. Rubin I, Yarden Y. The Basic Biology of HER2. Annals of Oncology. Oxford University Press; 2001;12:S3–S8.\n4. Dang H-Z, Yu Y, Jiao S-C. Prognosis of HER2 over-expressing gastric cancer patients with liver metastasis. WJG. 2012;18:2402–7.\n5. Jørgensen JT, Hersom M. HER2 as a Prognostic Marker in Gastric Cancer - A Systematic Analysis of Data from the Literature. J Cancer. 2012;3:137–44.\n6. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19:1523–9.\n7. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–97. A published erratum appears in Lancet. 2010;376(9749):1302.\n8. Han D-S, Suh Y-S, Kong S-H, Lee H-J, Im S-A, Bang Y-J, et al. Outcomes of surgery aiming at curative resection in good responder to induction chemotherapy for gastric cancer with distant metastases. J Surg Oncol. Wiley-Blackwell; 2013;107:511–6.\n9. Satoh S, Okabe H, Teramukai S, Hasegawa S, Ozaki N, Ueda S, et al. Phase II trial of combined treatment consisting of preoperative S-1 plus cisplatin followed by gastrectomy and postoperative S-1 for stage IV gastric cancer. Gastric Cancer. 2011;15:61–9.\n10. Yoshida K, Yamaguchi K, Okumura N, Osada S, Takahashi T, Tanaka Y, et al. The Roles of Surgical Oncologists in the New Era – Minimally Invasive Surgery for Early Gastric Cancer and Adjuvant Surgery for Metastatic Gastric Cancer. PAT. Karger Publishers; 2011;78:343–52.\n11. Suzuki T, Tanabe K, Taomoto J, Yamamoto H, Tokumoto N, Yoshida K, et al. Preliminary trial of adjuvant surgery for advanced gastric cancer. Oncol Lett. Spandidos Publications; 2010;1:743–7.\n12. Okabe H, Ueda S, Obama K, Hosogi H, Sakai Y. Induction chemotherapy with S-1 plus cisplatin followed by surgery for treatment of gastric cancer with peritoneal dissemination. Ann Surg Oncol. Springer-Verlag; 2009;16:3227–36.\n13. Koizumi W, Nakayama N, Tanabe S, Sasaki T, Higuchi K, Nishimura K, et al. A multicenter phase II study of combined chemotherapy with docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer (KDOG 0601). Cancer Chemother Pharmacol. Springer-Verlag; 2011;69:407–13.\n14. Janjigian YY, Riches JC, Ku GY, Imtiaz T, Capanu M, Chou JF, et al. Loss of human epidermal growth factor receptor 2 (HER2) expression in HER2-overexpressing esophagogastric (EG) tumors treated with trastuzumab [abstract]. J Clin Oncol. 2015;33(3 Suppl):63.\n15. Yonemura Y, Endo Y, Obata T, Sasaki T. Recent advances in the treatment of peritoneal dissemination of gastrointestinal cancers by nucleoside antimetabolites. Cancer Science. Wiley/Blackwell (10.1111); 2007;98:11–8.\n16. Osugi H, Takada N, Takemura M, Kaseno S, Lee S, Ueno M, Tanaka Y, Fukuhara K, Fujiwara Y, Kinoshita H (2002) Oral fluoropyrimidine anticancer drug TS-1 for gastric cancer patients with peritoneal dissemination. Oncology Reports\n17. Fujimoto-Ouchi K, Sekiguchi F, Yasuno H, Moriya Y, Mori K, Tanaka Y. Antitumor activity of trastuzumab in combination with chemotherapy in human gastric cancer xenograft models. Cancer Chemother Pharmacol. 2006;59:795–805.\n18. Roukos DH. Targeting gastric cancer with trastuzumab: new clinical practice and innovative developments to overcome resistance. Ann Surg Oncol. 2009;17:14–7.\n19. Kataoka Y, Okabe H, Yoshizawa A, Minamiguchi S, Yoshimura K, Haga H, et al. HER2 expression and its clinicopathological features in resectable gastric cancer. Gastric Cancer. 2012;16:84–93.\n20. Deguchi Y, Okabe H, Oshima N, Hisamori S, Minamiguchi S, Muto M, et al. PTEN loss is associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma. Gastric Cancer. 2017;20:416–27.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "13(1)",
"journal": "Journal of medical case reports",
"keywords": "Conversion therapy; Human epidermal growth factor 2-positive gastric cancer; Stage IV gastric cancer; Trastuzumab",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D017024:Chemotherapy, Adjuvant; D006801:Humans; D008297:Male; D018719:Receptor, ErbB-2; D013270:Stomach; D013274:Stomach Neoplasms; D000068878:Trastuzumab; D016896:Treatment Outcome",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "42",
"pmc": null,
"pmid": "30791934",
"pubdate": "2019-02-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12066214;14528282;17031648;17052255;18441328;19777180;19841980;20728210;21667134;21796483;22104206;22410801;22481979;22654433;23090791;26643880;27517839",
"title": "Strategy for treatment of stage IV human epidermal growth factor 2-positive gastric cancer: a case report.",
"title_normalized": "strategy for treatment of stage iv human epidermal growth factor 2 positive gastric cancer a case report"
} | [
{
"companynumb": "JP-SA-2019SA067100",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "LANSOPRAZOLE"
},
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{
"abstract": "SEE SCABER AND TALBOT DOI101093/AWW264 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: A GGGGCC repeat expansion in C9orf72 leads to frontotemporal dementia and/or amyotrophic lateral sclerosis. Diverse pathological features have been identified, and their disease relevance remains much debated. Here, we describe two illuminating patients with frontotemporal dementia due to the C9orf72 repeat expansion. Case 1 was a 65-year-old female with behavioural variant frontotemporal dementia accompanied by focal degeneration in subgenual anterior cingulate cortex, amygdala, and medial pulvinar thalamus. At autopsy, widespread RNA foci and dipeptide repeat protein inclusions were observed, but TDP-43 pathology was nearly absent, even in degenerating brain regions. Case 2 was a 74-year-old female with atypical frontotemporal dementia-motor neuron disease who underwent temporal lobe resection for epilepsy 5 years prior to her first frontotemporal dementia symptoms. Archival surgical resection tissue contained RNA foci, dipeptide repeat protein inclusions, and loss of nuclear TDP-43 but no TDP-43 inclusions despite florid TDP-43 inclusions at autopsy 8 years after first symptoms. These findings suggest that C9orf72-specific phenomena may impact brain structure and function and emerge before first symptoms and TDP-43 aggregation.",
"affiliations": "1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, USA.;2 Department of Neurology, Eulji University Hospital, Eulji University School of Medicine, Daejeon 35233, South Korea.;1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, USA.;3 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.;1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, USA.;1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, USA.;4 Department of Neurology and Department of Psychiatry, Semel Institute for Neuroscience and Human Behaviour, University of California, Los Angeles, CA 90095, USA.;5 Department of Pathology and Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.;1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, USA.;6 Epilepsy Center, Department of Neurology, University of California San Francisco, CA 94143, USA.;6 Epilepsy Center, Department of Neurology, University of California San Francisco, CA 94143, USA.;1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, USA.;4 Department of Neurology and Department of Psychiatry, Semel Institute for Neuroscience and Human Behaviour, University of California, Los Angeles, CA 90095, USA.;4 Department of Neurology and Department of Psychiatry, Semel Institute for Neuroscience and Human Behaviour, University of California, Los Angeles, CA 90095, USA.;3 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.;1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, USA.;1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, USA wseeley@memory.ucsf.edu.",
"authors": "Vatsavayai|Sarat C|SC|;Yoon|Soo Jin|SJ|;Gardner|Raquel C|RC|;Gendron|Tania F|TF|;Vargas|Jose Norberto S|JN|;Trujillo|Andrew|A|;Pribadi|Mochtar|M|;Phillips|Joanna J|JJ|;Gaus|Stephanie E|SE|;Hixson|John D|JD|;Garcia|Paul A|PA|;Rabinovici|Gil D|GD|;Coppola|Giovanni|G|;Geschwind|Daniel H|DH|;Petrucelli|Leonard|L|;Miller|Bruce L|BL|;Seeley|William W|WW|",
"chemical_list": "D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins; C000598624:TARDBP protein, human",
"country": "England",
"delete": false,
"doi": "10.1093/brain/aww250",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-8950",
"issue": "139(Pt 12)",
"journal": "Brain : a journal of neurology",
"keywords": "TDP-43; frontotemporal dementia; protein aggregation",
"medline_ta": "Brain",
"mesh_terms": "D000368:Aged; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion; D004268:DNA-Binding Proteins; D005260:Female; D057180:Frontotemporal Dementia; D006801:Humans; D011506:Proteins",
"nlm_unique_id": "0372537",
"other_id": null,
"pages": "3202-3216",
"pmc": null,
"pmid": "27797809",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22366793;24129584;25081482;3957627;24290757;24139042;26085200;23393093;24598541;24096617;24963678;21944778;25173361;23415312;22305768;24445903;26735706;24444359;25103406;25185840;24417314;26374446;23381195;24154603;22399793;24170096;21944779;24252525;25273996;24248382;12417364;22154785;25662776;26308983;26308899;22366791;25521377;25943887;22875087;21173221;26308891",
"title": "Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia.",
"title_normalized": "timing and significance of pathological features in c9orf72 expansion associated frontotemporal dementia"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/17/0090280",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nTo evaluate the effectiveness of interventional therapy in acute, non-malignant, non-cirrhotic portal vein thrombosis.\n\n\nMETHODS\nWe present a retrospective study of eight consecutive patients who presented with an acute non-malignant, non-cirrhotic portal vein thrombosis and were treated by mechanical recanalization using an escalating scheme including local aspiration, thrombolysis, rheolysis and the implantation of transjugular intrahepatic portosystemic shunt or other visceral stents.\n\n\nRESULTS\nRecanalization rates applying the escalating scheme were good, with a success rate of 75%. However, major complications occurred in 50% of patients, mostly due to bleeding at the percutaneous access site, and minor complications in 12.5% of patients.\n\n\nCONCLUSIONS\nInterventional therapy is effective in acute portal vein thrombosis, but should only be performed at specialized centers and based on an individual treatment decision.",
"affiliations": "Institute of Clinical Radiology, University Hospital Münster, Münster, Germany.;Department of Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany.;Department of Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany.;Institute of Clinical Radiology, University Hospital Münster, Münster, Germany.;Institute of Clinical Radiology, University Hospital Münster, Münster, Germany.;Department of Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany.;Institute of Clinical Radiology, University Hospital Münster, Münster, Germany.;Institute of Clinical Radiology, University Hospital Münster, Münster, Germany.",
"authors": "Gerwing|Mirjam|M|;Wilms|Christian|C|;Heinzow|Hauke|H|;Sporns|Peter B|PB|;Heindel|Walter|W|;Schmidt|Hartmut|H|;Wildgruber|Moritz|M|;Köhler|Michael|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1097/MEG.0000000000001559",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-691X",
"issue": "31(12)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011169:Portal Vein; D019168:Portasystemic Shunt, Transjugular Intrahepatic; D012189:Retrospective Studies; D015912:Thrombolytic Therapy; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D018608:Ultrasonography, Doppler; D020246:Venous Thrombosis; D055815:Young Adult",
"nlm_unique_id": "9000874",
"other_id": null,
"pages": "1584-1591",
"pmc": null,
"pmid": "31584464",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Escalating interventional recanalization therapy in non-cirrhotic, non-malignant acute portal vein thrombosis.",
"title_normalized": "escalating interventional recanalization therapy in non cirrhotic non malignant acute portal vein thrombosis"
} | [
{
"companynumb": "DE-ROCHE-2593740",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Immune checkpoint inhibitor therapy has become a cornerstone in the management of many oncologic diseases. Although it is well tolerated in most patients, a wide spectrum of adverse events has been described as a result of immune system alteration. We present a case of a woman with metastatic bronchogenic adenocarcinoma who was initially thought to have immune-mediated hepatitis, but eventually discovered to have a rarely described immune-mediated cholangiopathy. Her cholangiopathy appeared to stabilize following ursodeoxycholic acid and tocilizumab after several lines of guideline-directed therapy. Awareness of this unique toxicity following immune checkpoint inhibitor, and potential treatment options may help clinicians manage this rare but serious complication.",
"affiliations": "Division of Gastroenterology & Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.;Division of Hematology & Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.;Division of Hematology & Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.;Division of Gastroenterology & Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.",
"authors": "Reddy|Chanakyaram A|CA|0000-0001-7741-1973;Schneider|Bryan J|BJ|;Brackett|Lindsay M|LM|;Tai|Andrew W|AW|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D002756:Cholagogues and Choleretics; D000077594:Nivolumab; D014580:Ursodeoxycholic Acid; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.2217/imt-2019-0121",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1750-743X",
"issue": "11(18)",
"journal": "Immunotherapy",
"keywords": "cholangiopathy; immune-related adverse event; nivolumab; tocilizumab; ursodeoxycholic acid",
"medline_ta": "Immunotherapy",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D001649:Bile Duct Diseases; D002756:Cholagogues and Choleretics; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms; D008875:Middle Aged; D000077594:Nivolumab; D016896:Treatment Outcome; D014580:Ursodeoxycholic Acid",
"nlm_unique_id": "101485158",
"other_id": null,
"pages": "1527-1531",
"pmc": null,
"pmid": "31789069",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nivolumab-induced large-duct cholangiopathy treated with ursodeoxycholic acid and tocilizumab.",
"title_normalized": "nivolumab induced large duct cholangiopathy treated with ursodeoxycholic acid and tocilizumab"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-123002",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "We examined the combination of the mammalian target of rapamycin inhibitor everolimus with bortezomib and rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM) in a phase I/II study. All patients received six cycles of the combination of everolimus/rituximab or everolimus/bortezomib/rituximab followed by maintenance with everolimus until progression. Forty-six patients were treated; 98% received prior rituximab and 57% received prior bortezomib. No dose-limiting toxicities were observed in the phase I. The most common treatment-related toxicities of all grades were fatigue (63%), anemia (54%), leucopenia (52%), neutropenia (48%) and diarrhea (43%). Thirty-six (78%) of the 46 patients received full dose therapy (FDT) of the three drugs. Of these 36, 2 (6%) had complete response (90% confidence interval (CI): 1-16). In all, 32/36 (89%) of patients experienced at least a minimal response (90% CI: 76-96%). The observed partial response or better response rate was 19/36 (53, 90 CI: 38-67%). For the 36 FDT patients, the median progression-free survival was 21 months (95% CI: 12-not estimable). In summary, this study demonstrates that the combination of everolimus, bortezomib and rituximab is well tolerated and achieved 89% response rate even in patients previously treated, making it a possible model of non-chemotherapeutic-based combination therapy in WM.",
"affiliations": "Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.;Department of Biostatistics, Dana-Farber Cancer Institute, Boston, MA, USA.;Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.;Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.;Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.;Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.;Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.;Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.;Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.;Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.;Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.;Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.;Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.;Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.;Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.;Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.;Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.;Colorado Blood Cancer Institute, Denver, CO, USA.;Department of Biostatistics, Dana-Farber Cancer Institute, Boston, MA, USA.;Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.",
"authors": "Ghobrial|I M|IM|;Redd|R|R|;Armand|P|P|;Banwait|R|R|;Boswell|E|E|;Chuma|S|S|;Huynh|D|D|;Sacco|A|A|;Roccaro|A M|AM|;Perilla-Glen|A|A|;Noonan|K|K|;MacNabb|M|M|;Leblebjian|H|H|;Warren|D|D|;Henrick|P|P|;Castillo|J J|JJ|;Richardson|P G|PG|;Matous|J|J|;Weller|E|E|;Treon|S P|SP|",
"chemical_list": "C527276:CXCR4 protein, human; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D019718:Receptors, CXCR4; D000069283:Rituximab; D000069286:Bortezomib; D000068338:Everolimus",
"country": "England",
"delete": false,
"doi": "10.1038/leu.2015.164",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "29(12)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000069286:Bortezomib; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053594:Myeloid Differentiation Factor 88; D019718:Receptors, CXCR4; D012008:Recurrence; D000069283:Rituximab; D008258:Waldenstrom Macroglobulinemia",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "2338-46",
"pmc": null,
"pmid": "26139427",
"pubdate": "2015-12",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "19150980;23321251;25212891;20142598;16473275;19196866;25371371;24553177;23782158;19289601;15365568;10623712;25027391;22187460;12242656;20652865;24405328;22931316;15115652;12720118;23054875;15634685;24711662;19074725;18653228;19506160;20371443;24716234;15735132;15270672;23048077;23233721;24366360;23150997;19617573;22797699;20142586",
"title": "Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia.",
"title_normalized": "phase i ii trial of everolimus in combination with bortezomib and rituximab rvr in relapsed refractory waldenstrom macroglobulinemia"
} | [
{
"companynumb": "US-TAKEDA-2018MPI003796",
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"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": null,
... |
{
"abstract": "Sinusoidal obstruction syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), is a serious complication after hematopoietic stem cell transplantation (HSCT). SOS/VOD usually occurs within 3 weeks of HSCT, but the 2016 European Society for Blood and Marrow Transplantation diagnosis criteria have been revised to include late forms. Prophylactic use of defibrotide is recommended in the pediatric setting, but its value remains uncertain in the adult population. We report here a single-center series of 63 adult patients considered at high risk for SOS/VOD who received defibrotide prophylaxis in combination with ursodeoxycholic acid between May 2012 and August 2016. The median duration of defibrotide therapy was 23 days. Bleeding occurred in 14 patients (21.5%). Defibrotide prophylaxis was discontinued in 7 patients (10.8%): 4 cases (6.3%) due to bleeding and 3 cases (4.6%) because of the need for antithrombotic therapy. Overall, SOS/VOD occurred in 4 cases (6.3%) within 21 days after HSCT (days 13 and 14) in 2 cases and late-onset SOS/VOD (days 57 and 58) in the other 2 cases. SOS/VOD was moderate in 1 case, very severe in 3 cases, with 2 deaths related to SOS/VOD. Cumulative incidence of grades II to IV acute graft-versus-host disease and transplant-associated thrombotic microangiopathy were 22.2% and 3.2%, respectively. With a median follow-up of 31 months (range, 10.7 to 60.3), the rates of 2-year overall survival, progression-free survival, incidence of relapse, and nonrelapse mortality were 56.5%, 49%, 28.7%, and 22.3%, respectively. In our experience defibrotide prophylaxis is associated with a low incidence of SOS/VOD after allogeneic HSCT in a high-risk adult population with an acceptable safety profile.",
"affiliations": "Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France; Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France; Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France; INSERM, UMRs 938, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France; Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France; INSERM, UMRs 938, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France; Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France; Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France.;UPAC & C (Unité de préparation des anticancéreux et contrôle), Saint Antoine Hospital, AP-HP, Paris, France.;UPAC & C (Unité de préparation des anticancéreux et contrôle), Saint Antoine Hospital, AP-HP, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France; Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France; Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France; INSERM, UMRs 938, Paris, France.;Hematology and Cellular Therapy Service, Saint Antoine Hospital, AP-HP, Paris, France; Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France; INSERM, UMRs 938, Paris, France. Electronic address: mohamad.mohty@inserm.fr.",
"authors": "Picod|Adrien|A|;Bonnin|Agnès|A|;Battipaglia|Giorgia|G|;Giannotti|Federica|F|;Ruggeri|Annalisa|A|;Brissot|Eolia|E|;Malard|Florent|F|;Médiavilla|Clémence|C|;Belhocine|Ramdane|R|;Vekhoff|Anne|A|;Gueye|Mor Sény|MS|;Lapusan|Simona|S|;Adaeva|Rosa|R|;Isnard|Françoise|F|;Legrand|Ollivier|O|;Baylatry|Minh-Tam|MT|;Joly|Anne-Christine|AC|;Labopin|Myriam|M|;Duléry|Rémy|R|;Mohty|Mohamad|M|",
"chemical_list": "D011089:Polydeoxyribonucleotides; C036901:defibrotide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2018.02.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "24(7)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Defibrotide; Endothelial cell activation syndrome; Hematopoietic stem cell transplantation; Hepatic veno-occlusive disease; Sinusoidal obstruction syndrome",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D011089:Polydeoxyribonucleotides; D055815:Young Adult",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1471-1475",
"pmc": null,
"pmid": "29477779",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Defibrotide for Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease Prophylaxis in High-Risk Adult Patients: A Single-Center Experience Study.",
"title_normalized": "defibrotide for sinusoidal obstruction syndrome veno occlusive disease prophylaxis in high risk adult patients a single center experience study"
} | [
{
"companynumb": "FR-JAZZ-2018-FR-019354",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEFIBROTIDE SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "A young man with cystic fibrosis in his early 30s presented to accident and emergency with acute onset unilateral lower motor neuron facial palsy, hearing loss and impaired balance following Mycobacterium abscessus eradication induction therapy. The hearing loss and impaired balance developed over a 3-day period prior to the onset of facial palsy. Further investigation with a CT scan and MRI scan led to a diagnosis of vestibular schwannoma. The facial palsy resolved with steroid treatment; however, the hearing loss is irreversible, which has had a profound impact on his life and career. This case is intriguing as the cause and association of events are unclear. A working diagnosis of incidental Bell's palsy and unilateral hearing loss caused by the vestibular schwannoma was applied. However, the onset of these symptoms in relation to M. abscessus eradication induction therapy promotes discussion.",
"affiliations": "Medical Postgraduate Education and Training, Cardiff University, Cardiff, UK.;All Wales Adult CF Centre, University Hospital Llandough, Llandough, UK.;Audio-vestibular medicine, University Hospital of Wales, Cardiff, UK.",
"authors": "Wilson|Chloe|C|;Duckers|Jamie|J|;Rajenderkumar|Deepak|D|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-225572",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "Tb and other respiratory infections; cystic fibrosis; ear, nose and throat; ear, nose and throat/otolaryngology; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D003550:Cystic Fibrosis; D003937:Diagnosis, Differential; D005158:Facial Paralysis; D034381:Hearing Loss; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009165:Mycobacterium Infections, Nontuberculous; D000073358:Mycobacterium abscessus; D009464:Neuroma, Acoustic; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30158267",
"pubdate": "2018-08-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17653135;26666259;26564118;10993464;19034733;17429875;938024;29199098;27747231;26690506;21796866;1583319;24455994;7148998;5446818;3485932;24995898;22754805;26248372;22451804;22554194",
"title": "Unusual discovery of a vestibular schwannoma following eradication therapy for Mycobacterium abscessus.",
"title_normalized": "unusual discovery of a vestibular schwannoma following eradication therapy for mycobacterium abscessus"
} | [
{
"companynumb": "GB-TEVA-2018-GB-961351",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
"drugadditional": "1"... |
{
"abstract": "In this open-label study, we evaluated the effect of upfront macitentan and riociguat combination in newly diagnosed pulmonary arterial hypertension (PAH) patients. In 15 consecutive PAH patients, we collected clinical and hemodynamic data at baseline, visit 1 (median 4 months) and visit 2 (median 12 months). Survival and transplantation status were analyzed over 36 months. Statistical analysis included student t-test and 95% confidence interval (CI) ( t-statistic or Clopper-Pearson). Kaplan-Meier was used to estimate survival rate. There were 11/15 women (mean age 56 years), in World Health Organization (WHO) functional class (FC) III ( n = 14) or IV ( n = 1). The 6 min walk distance increased from 281.6 m (baseline) to 315.7 m (visit 1) and visit 2 (313.9 m), representing a 34- and 32-m change ( P < 0.05), respectively, associated with Borg score improvements. Brain natriuretic peptide decreased: 318.2 pg/mL (baseline) to 122.0 pg/mL (visit 1) and 98.6 pg/mL (visit 2) ( P < 0.05). WHO FC improved in eight patients (53%, 95% CI 27%-79%). Pulmonary vascular resistance (9.2 to 5.7 Wood Units) and mean pulmonary artery pressure (47.3 to 38.9 mmHg) decreased; cardiac index increased (2.3 to 3.0 L/min/m2) (baseline to visit 2, all P < 0.05). All patients had intermediate and high risk score (baseline); at 1-year follow-up, dual therapy led to reduction to low risk score in 7/15 (47%) patients. There were no unexpected or serious side effects. Three patients died due to unrelated causes; one patient received a lung transplant. Transplant-free survival rate (36 months) was 85%. Preliminary evidence is provided for effectiveness of initial macitentan and riociguat combination therapy in PAH.",
"affiliations": "1 NYU Langone Pulmonary Hypertension Program, New York University School of Medicine, USA.;2 Pulmonary and Critical Care Department, Mayo Clinic, Rochester, USA.;3 Pulmonary, Critical Care and Sleep Medicine, Mount Sinai Beth Israel Hospital, New York, USA.;3 Pulmonary, Critical Care and Sleep Medicine, Mount Sinai Beth Israel Hospital, New York, USA.",
"authors": "Sulica|Roxana|R|;Sangli|Swathi|S|;Chakravarti|Aloke|A|;Steiger|David|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2045894019826944",
"fulltext": "\n==== Front\nPulm CircPulm CircPULsppulPulmonary Circulation2045-89322045-8940SAGE Publications Sage UK: London, England 3063843210.1177/204589401982694410.1177_2045894019826944Research ArticleClinical and hemodynamic benefit of macitentan and riociguat upfront combination in patients with pulmonary arterial hypertension Sulica Roxana 1Sangli Swathi 2Chakravarti Aloke 3Steiger David 341 NYU Langone Pulmonary Hypertension Program, New York University School of Medicine, USA2 Pulmonary and Critical Care Department, Mayo Clinic, Rochester, USA3 Pulmonary, Critical Care and Sleep Medicine, Mount Sinai Beth Israel Hospital, New York, USA4 Icahn School of Medicine at Mount Sinai, New York, USARoxana Sulica, NYU Langone Pulmonary Hypertension Program, NYU School of Medicine, New York, NY 10003, USA. Email: Roxana.Sulica@nyulangone.org07 2 2019 Jan-Mar 2019 9 1 204589401982694420 7 2018 3 1 2019 © The Author(s) 20192019SAGE Publications Ltd, or Pulmonary Vascular Research Institute, unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.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 pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).In this open-label study, we evaluated the effect of upfront macitentan and riociguat combination in newly diagnosed pulmonary arterial hypertension (PAH) patients. In 15 consecutive PAH patients, we collected clinical and hemodynamic data at baseline, visit 1 (median 4 months) and visit 2 (median 12 months). Survival and transplantation status were analyzed over 36 months. Statistical analysis included student t-test and 95% confidence interval (CI) (t-statistic or Clopper-Pearson). Kaplan-Meier was used to estimate survival rate. There were 11/15 women (mean age 56 years), in World Health Organization (WHO) functional class (FC) III (n = 14) or IV (n = 1). The 6 min walk distance increased from 281.6 m (baseline) to 315.7 m (visit 1) and visit 2 (313.9 m), representing a 34- and 32-m change (P < 0.05), respectively, associated with Borg score improvements. Brain natriuretic peptide decreased: 318.2 pg/mL (baseline) to 122.0 pg/mL (visit 1) and 98.6 pg/mL (visit 2) (P < 0.05). WHO FC improved in eight patients (53%, 95% CI 27%–79%). Pulmonary vascular resistance (9.2 to 5.7 Wood Units) and mean pulmonary artery pressure (47.3 to 38.9 mmHg) decreased; cardiac index increased (2.3 to 3.0 L/min/m2) (baseline to visit 2, all P < 0.05). All patients had intermediate and high risk score (baseline); at 1-year follow-up, dual therapy led to reduction to low risk score in 7/15 (47%) patients. There were no unexpected or serious side effects. Three patients died due to unrelated causes; one patient received a lung transplant. Transplant-free survival rate (36 months) was 85%. Preliminary evidence is provided for effectiveness of initial macitentan and riociguat combination therapy in PAH.\n\npulmonary arterial hypertensionmacitentanriociguatupfront combinationActelion Pharmaceuticalshttps://doi.org/10.13039/100005646cover-dateJanuary-March 2019\n==== Body\nIntroduction\nPulmonary arterial hypertension (PAH) is a rare and progressive disease characterized by vascular proliferation and vasoconstriction of the pulmonary arterial bed, associated with increased pulmonary vascular resistance, which, over time, may lead to progressive clinical deterioration resulting in right ventricular failure and death.1,2 PAH is diagnosed by right heart catheterization (RHC) and, at the time of study enrollment, was defined as a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg at rest, pulmonary artery occlusion pressure (PAOP) ≤ 15 mmHg, and pulmonary vascular resistance (PVR) > 3 Wood Units.3–5 The broader term “pulmonary hypertension” is categorized into five World Health Organization (WHO) groups according to clinical presentation, pathological findings and hemodynamic characteristics.5 WHO Group 1 includes patients with PAH.\n\nDysfunction in three pathways (endothelin, nitric oxide (NO), and prostacyclin) involved in PAH pathophysiology has now been targeted with five classes of medication (endothelin receptor antagonists (ERAs), phosphodiesterase type 5 (PDE-5) inhibitors, soluble guanylate cyclase (sGC) stimulators, prostacyclin analogues, and prostacyclin receptor agonists).6 Fourteen formulations of medications from these pathways are approved by the Food and Drug Administration (FDA) for treatment of PAH. Despite treatment, mortality remains high in patients with PAH, with the lack of curative therapy.7 Treatment goals in PAH include improvement in symptoms and functional capacity, slowing of disease progression, and increased survival.8\n\nGiven the complex pathogenesis of PAH, there is a strong rationale to use combinations of drugs that target multiple pathways simultaneously. Historically, combination therapy in PAH has been used in a sequential manner in patients with inadequate response to monotherapy. There is a growing body of evidence that dual, or even triple, upfront combination therapy in PAH leads to improved clinical outcomes.9,10 The Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial is the first randomized controlled trial of initial dual combination therapy, and showed a highly significant reduction in the risk of clinical failure for patients on upfront dual therapy as compared with the pooled monotherapy arm.11 This clinical trial did not, however, include hemodynamic data, and it is currently unknown if this is a class effect, and if similar results might be obtained by substituting the respective agents with other compounds from the respective class.\n\nIn this analysis, we sought to evaluate the effect of initial combination of macitentan and riociguat in patients newly diagnosed with PAH. In our practice, we have successfully employed macitentan and riociguat combination either as de novo therapy, or as transition from other NO-pathway-ERA combinations.12 Macitentan is an ERA that was developed by modifying the structure of bosentan to increase efficacy and safety.13 Macitentan has been shown to reduce morbidity and mortality among patients with PAH.14 Riociguat—a sGC stimulator—has a dual mode of action: synergy with endogenous NO and stimulation of sGC independent of NO availability.15,16 Riociguat has shown improved hemodynamic variables, symptoms, and exercise capacity in patients with PAH, and recent data showed potential benefit in patients who do not reach treatment goals with PDE-5 inhibitors.12,15,17–19\n\nMethods\nObjectives\nOur goal was to evaluate the clinical and hemodynamic effect of the combination of macitentan and riociguat as the first-line treatment in PAH patients from our practice. We defined as initial or upfront combination the use of the two medications in the following manner: the decision to start both medications in combination was made upon the diagnostic RHC without a waiting period to assess the effect of the medication started first, and if logistical considerations (insurance approval) allowed medication initiation within less than 3 months from each other.\n\nPatients\nBetween 2014 and 2016, we evaluated 15 consecutive newly diagnosed PAH patients (incident cases) from the Mount Sinai Beth Israel Pulmonary Hypertension Program who received upfront dual macitentan and riociguat combination therapy. The diagnosis of PAH was established at RHC and defined by mPAP ≥ 25 mmHg at rest, mean PAOP ≤ 15 mmHg, and PVR > 3 Wood units.4 We included only patients diagnosed with idiopathic PAH (IPAH) or associated PAH (APAH) as determined by the recommended diagnostic algorithm. We excluded patients with high risk PAH in need of parenteral PAH therapy.\n\nData collection and study design\nThe study was a retrospective chart review of consecutive PAH patients in our program who received upfront macitentan-riociguat combination in an open-label fashion. The choice of this particular combination was made at the discretion of the treating physician. At baseline, we collected demographic, clinical (WHO functional class (WHO FC), 6-min walk distance [6MWD], Borg score, and brain natriuretic peptide (BNP)), and hemodynamic data. We collected follow-up data at two time points. The first follow-up, visit 1, was planned in accordance to current guidelines at 3–4 months after medication combination initiation. It was practically performed at a median time interval of 4 months (range 3–10 months), and mean of 4.9 months (SD 3.8 months). Visit 1 included evaluation of WHO FC, 6MWD, Borg score, and BNP levels. The second follow-up, visit 2, was performed at a median of 12.0 months (range 6–12 months), mean 13.7 months (SD 3.6 months), as dictated by the time of the first follow-up RHC on combination therapy. Throughout the study, patients could receive prostacyclin therapy in case of clinical or hemodynamic deterioration, or in clinical scenarios that required additional PAH treatment (for example, one patient had parenteral prostacyclin started after 6 months of dual macitentan-riociguat therapy for hemodynamic optimization for planned abdominal surgery). In these cases, both clinical and hemodynamic data presented as the second follow-up was collected prior to starting the third PAH medication. Clinical outcome data (survival and transplantation status) was collected by 12 September 2018, with a median time of 41.3 months (mean 41.5 months, SD = 10.4 months), with a total follow-up time from the moment of the last patient’s enrollment of 56.8 months. Throughout the study, we collected information on adverse events, including medication side effects and clinical deterioration events (death, transplantation, hospital admission for right heart failure, and the need to escalate PAH therapy due to clinical and/or hemodynamic deterioration or lack of improvement). The local institutional review board approved the protocol and data collection.\n\nStatistical analysis\nStatistical analysis, mainly descriptive, also included student t-test, 95% CI from t statistic and Clopper-Pearson method as appropriate. Survival time was calculated from the initiation of the first PAH therapy. Patients who were alive as of 12 September 2018 were censored on that date. Survival rate was estimated by Kaplan-Meier method. Patients were classified as low, intermediate, and high risk at baseline and follow-up visit 2, where RHC were measured. Average risk from variables WHO FC, 6MWD, BNP, right atrial pressure, cardiac index, and mixed venous oxygen saturation were calculated per European Society of Cardiology (ESC)/ European Respiratory Society (ERS) 2015 guidelines to determine patient’s risk group.\n\nResults\nBaseline characteristics were as follows; our patients had a female predominance, with 11/15 (73.3%) women, and a mean age of 55.8 years (range from 27 to 82 years). At the time of treatment initiation (baseline), all patients belonged to WHO FC III, with the exception of one patient with systemic lupus erythematosus (SLE)-PAH who was classified as WHO FC IV based on the history of exertional syncope. She had been hospitalized and briefly received subcutaneous treprostinil, but the medication had been discontinued at patient’s request when she achieved a dose of 16 ng/kg/min. We have included her in the analysis since she was switched to dual macitentan-riociguat combination, started upon discharge, subsequent to discontinuation of treprostinil. Six patients (40.0%) had IPAH, and nine patients had APAH (including six patients with connective tissue disease and five patients associated with other risk factors) (Table 1).\nTable 1. Demographics and baseline characteristics.\n\nVariable\tAll patients\t\nAge (year) at Baseline, 15 patients, mean (SD)\t55.8 (17.1)\t\n Median\t55.0\t\nGender, n (percent)\t\t\n Female\t11 (73.3%)\t\n Male\t4 (26.7%)\t\nBaseline WHO Functional Class, n (percent)\t\t\n III\t14 (93.3%)\t\n IV\t1 (6.7%)\t\nTime to RHC (months), 14 patients, mean (SD)\t14.2 (4.7)\t\n Median\t14.0\t\nPulmonary Hypertension Risk Factors, n (percent)\t\t\n ASD, Cirrhosis, HIV\t1 (6.7%)\t\n ASD, VSD\t1 (6.7%)\t\n CTD-Scleroderma\t5 (33.3%)\t\n CTD-RA\t1 (6.7%)\t\n HIV\t1 (6.7%)\t\n IPAH\t6 (40.0%)\t\nASD: atrial septal defect; CTD: connective tissue disease; HIV: human immunodeficiency virus; IPAH: idiopathic pulmonary arterial hypertension; RA: rheumatoid arthritis; RHC: right heart catherization; VSD: ventricular septal defect; WHO: World Health Organization.\n\n\n\nPatients were included in the study with follow-up for survival and transplantation status by 12 September 2018, with a median time of 41.3 months (mean 41.5 months, SD = 10.4 months). The mean (SD) time of first follow-up was at 4.9 (3.8) months and 13.7 (3.6) months at time of second follow-up. At the end of study, 12 patients were alive, including 1 patient who had received lung transplantation, and 3 patients had died.\n\nData on 6MWD was available in 14 out of 15 patients, since 1 patient with multifactorial PAH (atrial septal defect (ASD), portal hypertension and HIV infection) was wheelchair-bound due to a prior stroke and was unable to walk. For the group, the 6MWD increased from a mean of 281.6 m at baseline to 315.7 m at the first follow-up and was maintained at 313.9 m at the second follow-up, representing a 6MWD increase of 34 m (P < 0.05) and 32 m (P < 0.05), respectively. For this patient population, the mean 6MWD at baseline of 281.6 m ranged from 91.4 to 457.2 m. Four patients that had exercise limitation due to musculoskeletal reasons with reduced 6MWD at 91.44, 179.82, 198.12, and 213.36 m. We therefore analyzed the change by using percent change from baseline. The mean percent change was 12.3% (P < 0.05) and 13.5% (P < 0.05) at follow-up visits 1 and 2, respectively (Table 2).\nTable 2. Summary of 6-minute walk distance (6MWD) and Borg at baseline, first follow-up and second follow-up (n = 14).\n\nParameter\tBaseline mean (SD)\tFirst follow-up mean (SD)\tChange from baseline mean (SD)\tP-value* for change\t%Change from baseline mean (SD)\tP-value* for %change\tSecond follow-up mean (SD)\tChange from baseline mean (SD)\tP-value* for change\t%Change from baseline mean (SD)\tP-value* for %change\t\n6MWD (m)\t281.6 (93.4)\t315.7 (108.4)\t34.1 (56.6)\t0.0421\t12.3 (20.2)\t0.0397\t313.9 (108.4)\t32.2 (58.8)\t0.0610\t13.5 (19.9)\t0.0244\t\nBorg\t3.0 (2.0)\t1.7 (1.9)\t–1.3 (2.0)\t0.0295\tNA\tNA\t2.0 (2.7)\t–1.0 (2.7)\t0.2087\tNA\tNA\t\n*6 Note: P-value is calculated from paired t-test to test whether or not the change is equal to zero. MWD: 6-minute walk distance; NA: not applicable; SD: standard deviation.\n\n\n\nMean Borg score was 3.0 at baseline, and decreased to 1.7 at the first follow-up and 2.0 at the second follow-up (Table 2). Mean BNP decreased from 318.2 pg/mL at baseline to 122.0 pg/mL at first follow-up and 98.6 pg/mL at second follow-up (P < 0.05 for the second follow-up compared with Baseline (Table 3). There was an improvement in FC in 8 (53%, 95% CI 27%–79%) patients, and no patient had FC deterioration (Fig. 1).\nFig. 1. Functional class status at baseline, first follow-up, and second follow-up. First follow-up: median time of 4 months (range 3–10 months) and a mean of 4.9 months (SD 3.8 months). Second follow-up was performed at a median of 12 months (range 6–20 months), and a mean of 13.7 months (SD 3.6 months). From baseline to second follow-up survival was 100% (long-term survival data is presented separately, see Fig. 2). CI: confidence interval; FC: functional class; WHO: World Health Organization.\n\n\nTable 3. Biomarker (brain natriuretic peptide (BNP), pg/mL) at baseline, first follow-up, and second follow-up (n = 15).\n\nBaseline mean (SD)\tFirst follow-up mean (SD)\tChange from baseline mean (SD)\tP-value* for change\tSecond follow-up mean (SD)\tChange from baseline mean (SD)\tP-value* for change\t\n318.2 (369.7)\t122.0 (156.2)\t–196.2 (365.7)\t0.0566\t98.6 (62.6)\t–219.7 (325.4)\t0.0204\t\n* Note: P-value is calculated from paired t-test to test whether or not the change is equal to zero.\n\n\n\nOne patient refused repeat RHC, and complete hemodynamic assessment was available in only 14 patients. Significant improvements in mean hemodynamic measurements included PVR decrease from 9.2 to 5.7 Wood Units, mPAP reduction from 47.3 to 38.9 mmHg, CI increase from 2.3 to 3.0 L/min/m2, and cardiac output (CO) increase from 4.1 to 5.2 L/min from baseline (Table 4).\nTable 4. Summary of right heart catherization data at baseline and follow-up.\n\nParameters\tBaseline (n = 15); mean (SD)\tFollow-up (n = 14); mean (SD)\tChange from baseline mean (SD)\tP-value* for change\t\nMean blood pressure (mmHg)\t100.4 (11.7)\t87.1 (12.0)\t–13.3 (12.8)\t0.0019\t\nHeart rate (bpm)\t85.1 (15.1)\t79.1 (11.3)\t–7.9 (18.9)\t0.1412\t\nO2 saturation (%)\t93.9 (2.8)\t93.2 (3.5)\t–0.9 (3.2)\t0.3038\t\nRAP (mmHg)\t11.2 (4.4)\t8.0 (3.4)\t–2.8 (5.1)\t0.0632\t\nSPAP (mmHg)\t77.8 (17.9)\t65.2 (12.3)\t–11.1 (15.0)\t0.0158\t\nDPAP (mmHg)\t33.1 (8.5)\t28.4 (6.3)\t–4.9 (6.6)\t0.0157\t\nmPAP (mmHg)\t47.3 (10.0)\t38.9 (6.9)\t–8.1 (8.6)\t0.0039\t\nPA saturation (%)\t59.3 (7.5)\t68.5 (3.4)\t9.7 (7.6)\t0.0004\t\nCO (L/min)\t4.1 (0.8)\t5.2 (1.0)\t1.2 (0.6)\t<.0001\t\nCI (L/min/m2)\t2.3 (0.4)\t3.0 (0.5)\t0.7 (0.4)\t<.0001\t\nPVR (Wood units)\t9.2 (3.0)\t5.7 (1.8)\t–3.6 (2.5)\t0.0001\t\nPVRI (Wood units/m2)\t16.9 (5.6)\t10.0 (3.5)\t–6.9 (4.6)\t<.0001\t\n* Note: p-value is calculated from paired t-test to test whether or not the change is equal to zero. CI: cardiac index; CO: cardiac output; DPAP: diastolic pulmonary arterial pressure; mPAP: mean pulmonary arterial pressure; O2: oxygen; PAS: pulmonary artery systolic pressure; PVR: pulmonary vascular resistance; PVRI: pulmonary vascular resistance index; RAP: right arterial pressure; SPAP: Systolic pulmonary artery pressure.\n\n\n\nKaplan Meier analysis showed a survival of 100% at 1 year, 92.9% at 2 years, and 85.1% at 3 years (Fig. 2). When the risk of progression and adverse outcomes defined by the 2015 European guidelines at baseline and follow-up were examined for the group, treatment effect led to achievement of a low status in approximately 50% of the patients at the first follow-up, which had been maintained at the second follow-up. In Fig. 3 we present data at baseline and at follow-up visit 2, the two time points where the largest number of parameters to calculate the risk score were available.\nFig. 2. Kaplan-Meier curve.\n\n\nFig. 3. Risk score at baseline and second follow-up. Risk Score was calculated average score from individual assessments collected in the study including WHO FC, 6MWD, BNP, and RHC. Second follow-up was performed at a median of 12 months (range 6–20 months), and a mean of 13.7 months (SD 3.6 months).\n\n\n\nAt Baseline, 14 patients (93%) were at intermediate risk and 1 patient (7%) was at high risk (Fig. 3). At follow-up visit 2, seven patients (47%) had a risk reduction; six patients (40% had a decrease in their risk from intermediate to low, and one patient (7%) from high to low); eight patients (53%) had no change and maintained intermediate risk status (Fig. 3).\n\nMild medication-related side effects were recorded in five patients: two patients had increased nasal congestion, two patients had headaches, and one patient had increased lower extremity edema, all resolved with supportive therapy. Riociguat up-titration was stopped in three patients due to hypotension, and in one patient due to headache, but the medication had been continued at a lower dose, with 73% of the patients achieving and maintaining maximum FDA-approved dose of 2.5 mg po tid.\n\nBy the end of the second follow-up visit, one patient required hospital admission for right heart failure/fluid overload, which resolved with intravenous diuretics. By the end of the observation period, this patient was still receiving treatment with dual therapy only, with stable 6MWD, and improved RV function by echocardiogram.\n\nFour patients required addition of a third medication. One patient has been started on continuous prostacyclin at 6 months for hemodynamic optimization due to impending cholecystectomy, while three other patients required a third class of drugs, as a measure of insufficient therapeutic response, two patients due to lack of improvement, and one patient due to clinical and hemodynamic deterioration.\n\nThe two patients who received additional prostacyclin therapy due to lack of clinical and/or hemodynamic improvement at the second follow-up, were both started on inhaled treprostinil, but one of them switched subsequently to selexipag, for reasons of convenience. By the end of the observation period, one more patient had been started on additional selexipag due to clinical deterioration (increased exertional symptoms and decreasing 6MWD). One patient with scleroderma received bilateral lung transplant, and there were three deaths at 19, 32, and 51 months since initiation of the dual therapy, all from causes unrelated to pulmonary hypertension: one intra-abdominal sepsis in a patient with cirrhosis, one hypoxic respiratory failure due to aspiration pneumonia in a patient with scleroderma, and one with Acute Respiratory Distress Syndrome (ARDS) from bacterial pneumonia in an 84-year-old patient with rheumatoid arthritis. At month 36, overall survival rate was 85.1% (Fig. 2). Of the 11 non-transplanted patients alive at 36 months, 7 were still on dual macitentan-riociguat therapy.\n\nDiscussion\nCurrently, there is ample evidence that supports the use of dual upfront combination therapy as the standard of care in most patients with low and intermediate risk PAH.11 Most of the available data demonstrates that the initial combination of an ERA with a PDE-5 inhibitor leads to significant clinical, hemodynamic, and functional improvement in PAH patients.20–25\n\nIn this retrospective analysis of real-world data, we provide the first evidence in the literature of the use of upfront combination of macitentan and riociguat in incident patients with PAH. Results of this study demonstrate improvement in the exercise capacity and functional class, degree of dyspnea on exertion, right ventricular function biomarkers, and hemodynamic variables, which represent guideline-recommended treatment targets, known to be associated with outcome and survival benefit.\n\nThe 6MWD in our study showed a significant increase at first follow-up and it was maintained at the second follow-up, and was comparable with the minimally important difference in PAH trials of 33 m.26 It did not, however, reach the target distance on therapy of 380 m or 440 m associated with improved outcomes.27,28,29 One explanation for this observation is the fact that a large number of patients in our cohort had a low initial 6MWD, not because of the PAH and right ventricular impairment, but due to musculoskeletal limitation, associated with co-morbidities, arthritis in rheumatologic disorders, fatigue in cirrhosis, or HIV neuropathy. This explanation is substantiated by the low 6MWD at baseline of 281.6 m, which is substantially shorter than the 324 m or 353 m reported in comparable retrospective case series of upfront dual ERA-PDE-5 inhibitor combination, such as the one from France or Italy.20,23 This lower baseline distance is encountered in PAH patients with co-morbidities, as it has been described in the scleroderma PAH series in the French registry or in contemporary PAH registries that include older patients.30 In the COMPERA registry, the average age was 64 years, and the baseline 6MWD 298 m. The improvement in exercise capacity had been associated with a significant decrease in the Borg index of dyspnea on exertion, which was significantly lower by 1.3 and 1 units at first and second follow-up, and was of a similar magnitude to that described in the French and Italian case series.\n\nThere was a significant improvement in FC; from a majority of FC III and IV on presentation, more than half of the patients achieved the goal of FC I and II at the second follow-up, again with similar findings to the Sitbon and D’Alto cohorts.20,23\n\nBNP, a marker of right ventricular function, had normalized at the first follow-up and decreased even further by the time of the second follow-up. Hemodynamic follow-up demonstrated a mean mPAP decrease by 8.1 mmHg and below 40 mmHg, while PVR had decreased by 40%, which is the expected change in studies of dual upfront combination therapy (Table 4).20 Mean hemodynamic parameters of right ventricular function all showed significant improvement; RAP was 8 mmHg, CI 3 L/min/m2, and PA saturation 68.5%—all consistent with the prognostic status of low risk (Table 4).29\n\nCompared with individual results from both PATENT and SERAPHIN trials, improved hemodynamic parameters in our study showed a more substantial change as effect of therapy, with a mean decrease in the mPAP of 8.1 mmHg and a mean increase in the CI of 0.7 L/min/m2. For the treatment naïve riociguat-treated patients in PATENT mean reduction in mPAP was 4.4 mmHg.31 Similarly, for patients treated with 10 mg of macitentan without PAH background therapy in the SERAPHIN trial, the mean decrease at 6 months in mPAP was 7 mmHg.32 The mean increase of 0.7 L/min/m2 in CI in our series also compares favorably with the mean increase in CI of 0.6 L/min/m2 in PATENT and 0.32 L/min/m2 in SERAPHIN.\n\nSurvival data shows results comparable with other studies of upfront combination therapy;20 in our study, three recorded deaths were unrelated to pulmonary hypertension, but were secondary to intraabdominal sepsis, aspiration pneumonia with acute respiratory failure, and bacterial pneumonia with ARDS. This is the first study of upfront dual combination therapy to evaluate the effect of treatment on the risk score, and we have shown that, in a cohort of patients at intermediate and high risk, a status of low risk can be achieved in approximately half of these patients as early as 4 months, and can be maintained at 12 months, without the addition of a third drug. It was also noted that we have observed only one episode of worsening of right ventricular function throughout the duration of the study.\n\nSide effect profile of the combination was favorable, with no unexpected adverse events that were treated with supportive measures. Even though for the group the mean blood pressure had decreased (Table 4), the change was mostly not clinically significant. In four patients, riociguat uptitration had to be stopped due to blood pressure decrease, with 73% of patients achieving the maximal dose of 2.5 mg tid. This compares favorably with data from PATENT study, in which 75% of patients received the maximal dose, but 50% of the patients had been on riociguat monotherapy.\n\nThe main limitations to our study include the single center and retrospective design, and the relatively small number of patients with heterogeneous etiologies for PAH. The concept of upfront combination therapy in PAH is gaining momentum, and our study offers preliminary evidence for the use of this novel dual combination in patients with advanced PAH.\n\nConclusion\nCurrent clinical guidelines recommend upfront dual therapy in most patients with PAH and functional class II–III symptoms. This small retrospective cohort of patients with group I PAH is the first report to show that other dual combinations besides ambrisentan and tadalafil may be used. Further investigations, with a more definitive design are required to delineate the role of this upfront combination in PAH.\n\nContributorship\nRoxana Sulica contributed to the research design and writing of the manuscript. All authors revised critically for important intellectual content, approved and agree to be accountable for all aspects of the manuscript.\n\nDeclaration of Conflicting Interests\nRoxana Sulica: Ad board Actelion, Arena, Bayer, United Therapeutics; research Reata, Bellerophon, United Therapeutics Swathi Sangli: The author has no conflict of interest. Aloke Chakravarti: The author has no conflict of interest. David Steiger: The author has no conflict of interest.\n\nEthical approval\nThe local institutional review board approved the protocol and data collection.\n\nFunding/Acknowledgments\nActelion Pharmaceuticals US, Inc provided funding for this manuscript produced by Donna Simcoe of Simcoe Consultants, Inc., and did not contribute to the content nor provide any review or editorial support. The manuscript was written independently by the authors with writing support provided by Donna Simcoe, MS, MS, MBA, CMPP, of Simcoe Consultants, Inc and statistical support provided by Carol Zhao, Actelion Pharmaceuticals US, Inc. All statements and opinions expressed in the manuscript are those of the authors and do not reflect those of Actelion Pharmaceuticals US, Inc or its representatives.\n\nGuarantor\nRoxana Sulica accepts full responsibility for the work and the conduct of the study, had access to the data, and controlled the decision to publish the work.\n==== Refs\nReferences\n1 Galiè N Palazzini M Manes A \nPulmonary arterial hypertension: From the kingdom of the near-dead to multiple clinical trial meta-analyses . Eur Heart J \n2010 ; 31 : 2080 –2086 .20504865 \n2 McLaughlin VV Archer SL Badesch DB et al. \nACCF/AHA 2009 expert consensus document on pulmonary hypertension: A report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: Developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association . Circulation \n2009 ; 119 : 2250 –2294 .19332472 \n3 Galiè N Humbert M Vachiery JL et al. \n2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The joint 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: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT) . Eur Heart J \n2016 ; 37 (1 ): 67 –119 .26320113 \n4 Hoeper MM Bogaard HJ Condliffe R et al. \nDefinitions and diagnosis of pulmonary hypertension . J Am Coll Cardiol \n2013 ; 62 : D42 –D50 .24355641 \n5 Simonneau G Gatzoulis MA Adatia I et al. \nUpdated clinical classification of pulmonary hypertension . J Am Coll Cardiol \n2013 ; 62 : D34 –D41 .24355639 \n6 Humbert M Lau EMT Montani D et al. \nAdvances in therapeutic interventions for patients with pulmonary arterial hypertension . Circulation \n2014 ; 130 : 2189 –2208 .25602947 \n7 Benza RL Miller DP Barst RJ et al. \nAn evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL registry . Chest \n2012 ; 142 : 448 –456 .22281797 \n8 McLaughlin VV Gaine SP Howard LS et al. \nTreatment goals of pulmonary hypertension . J Am Coll Cardiol \n2013 ; 62 (25 Suppl ): D73 –D81 .24355644 \n9 Sitbon O Jaïs X Savale L et al. \nUpfront triple combination therapy in pulmonary arterial hypertension: a pilot study . Eur Respir J \n2014 ; 43 (6 ): 1691 –1697 .24627535 \n10 Sitbon O, Canuet M, Picard F, et al. Initial combination therapy with macitentan and tadalafil in newly diagnosed patients with pulmonary arterial hypertension: Results from the OPTIMA Trial. InA68. WOW: PHARMACOLOGICAL TREATMENT OF PULMONARY HYPERTENSION 2017 May, pp. A2297–A2297. New York: American Thoracic Society .\n11 Galiè N Barberà JA Frost AE et al. \nInitial use of ambrisentan plus tadalafil in pulmonary arterial hypertension . N Engl J Med \n2015 ; 373 (9 ): 834 –844 .26308684 \n12 Sulica R Fenton R Cefali F \nEarly observations on the use of riociguat in a large, metropolitan pulmonary arterial hypertension/chronic thromboembolic pulmonary hypertension treatment center . Cardiol Ther \n2015 ; 4 (2 ): 209 –218 .26411969 \n13 Bolli MH Boss C Binkert C et al. \nThe discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl) oxy] ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (macitentan), an orally active, potent dual endothelin receptor antagonist . J Med Chem \n2012 ; 55 (17 ): 7849 –7861 .22862294 \n14 Pulido T Adzerikho I Channick RN et al. \nMacitentan and morbidity and mortality in pulmonary arterial hypertension . N Engl J Med \n2013 ; 369 (9 ): 809 –818 .23984728 \n15 Grimminger F Weimann G Frey R et al. \nFirst acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension . Eur Respir J \n2009 ; 33 (4 ): 785 –792 .19129292 \n16 Stasch JP Pacher P Evgenov OV \nSoluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease . Circulation \n2011 ; 123 (20 ): 2263 –2273 .21606405 \n17 Ghofrani HA Hoeper MM Halank M et al. \nRiociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study . Eur Respir J \n2010 ; 36 (4 ): 792 –799 .20530034 \n18 Ghofrani HA Galiè N Grimminger F et al. \nRiociguat for the treatment of pulmonary arterial hypertension . N Engl J Med \n2013 ; 369 (4 ): 330 –340 .23883378 \n19 Hoeper MM Simonneau G Corris PA et al. \nRESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors . Eur Respir J \n2017 ; 50 (3 ): 1602425 .28889107 \n20 Sitbon O Sattler C Bertoletti L et al. \nInitial dual oral combination therapy in pulmonary arterial hypertension . Eur Respir J \n2016 ; 47 (6 ): 1727 –1736 .26989105 \n21 Hassoun PM Zamanian RT Damico R et al. \nAmbrisentan and tadalafil up-front combination therapy in scleroderma-associated pulmonary arterial hypertension . Am J Respir Crit Care Med \n2015 ; 192 (9 ): 1102 –1110 .26360334 \n22 van de Veerdonk MC Marcus JT Westerhof N et al. \nUpfront combination therapy reduces right ventricular volumes in pulmonary arterial hypertension . Eur Respir J \n2017 ; 49 (6 ): 1700007 .28663315 \n23 D’Alto M Romeo E Argiento P et al. \nInitial tadalafil and ambrisentan combination therapy in pulmonary arterial hypertension: cLinical and haemodYnamic long-term efficacy (ITALY study) . J Cardiovasc Med (Hagerstown) \n2018 ; 19 (1 ): 12 –17 .29215546 \n24 Badagliacca R Raina A Ghio S et al. \nInfluence of various therapeutic strategies on right ventricular morphology, function and hemodynamics in pulmonary arterial hypertension . J Heart Lung Transplant \n2018 ; 37 (3 ): 365 –375 .28912026 \n25 Sato T Ambale-Venkatesh B Lima JA et al. \nThe impact of ambrisentan and tadalafil upfront combination therapy on cardiac function in scleroderma associated pulmonary arterial hypertension patients: cardiac magnetic resonance feature tracking study . Pulm Circ \n2018 ; 8 (1 ): 2045893217748307 .29251556 \n26 Mathai SC Puhan MA Lam D et al. \nThe minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension . Am J Respir Critical Care Med \n2012 ; 186 (5 ): 428 –433 .22723290 \n27 Sitbon O Humbert M Nunes H et al. \nLong-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival . J Am Coll Cardiol \n2002 ; 40 (4 ): 780 –788 .12204511 \n28 Provencher S Chemla D Herve P et al. \nHeart rate responses during the 6-minute walk test in pulmonary arterial hypertension . Eur Respir J \n2006 ; 27 (1 ): 114 –120 .16387943 \n29 Benza RL Miller DP Gomberg-Maitland M et al. \nPredicting survival in pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL) . Circulation \n2010 ; 122 (2 ): 164 –172 .20585012 \n30 Weatherald JC, Boucly A, Taniguchi Y, et al. Hemodynamics and prognosis in scleroderma-associated PAH. InA27. You got another thing coming: diagnosis and prognostication in pulmonary hypertension. May 2018, pp. A1179–A1179). New York: American Thoracic Society .\n31 Galiè N Grimminger F Grünig E et al. \nComparison of hemodynamic parameters in treatment-naïve and pre-treated patients with pulmonary arterial hypertension in the randomized phase III PATENT-1 study . J Heart Lung Transplant \n2017 ; 36 (5 ): 509 –519 .28190787 \n32 Galiè N Jansa P Pulido T et al. \nSERAPHIN haemodynamic substudy: the effect of the dual endothelin receptor antagonist macitentan on haemodynamic parameters and NT-proBNP levels and their association with disease progression in patients with pulmonary arterial hypertension . Eur Heart J \n2017 ; 38 (15 ): 1147 –1155 .28329315\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2045-8932",
"issue": "9(1)",
"journal": "Pulmonary circulation",
"keywords": "macitentan; pulmonary arterial hypertension; riociguat; upfront combination",
"medline_ta": "Pulm Circ",
"mesh_terms": null,
"nlm_unique_id": "101557243",
"other_id": null,
"pages": "2045894019826944",
"pmc": null,
"pmid": "30638432",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "12204511;16387943;19129292;19332472;20504865;20530034;20585012;21606405;22281797;22723290;22862294;23883378;23984728;24355639;24355641;24355644;24627535;25602947;26308684;26320113;26360334;26411969;26989105;28190787;28329315;28663315;28889107;28912026;29215546;29251556",
"title": "Clinical and hemodynamic benefit of macitentan and riociguat upfront combination in patients with pulmonary arterial hypertension.",
"title_normalized": "clinical and hemodynamic benefit of macitentan and riociguat upfront combination in patients with pulmonary arterial hypertension"
} | [
{
"companynumb": "US-ACTELION-A-CH2019-187334",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "MACITENTAN"
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{
"abstract": "During treatment for malignant lymphoma, cytopenia can develop for several reasons. In the treatment of cytopenia, various possibilities should be considered because inadequate treatment causes exacerbation of cytopenia and can lead to fatal conditions, such as infection and bleeding. Herein, we describe immune pancytopenia 3 months after the last exposure to chemotherapy in a patient with diffuse large B-cell lymphoma (DLBCL). She suffered from severe pancytopenia after two courses of rituximab and bendamustine therapy for a second relapse of DLBCL. Immune pancytopenia was diagnosed with bone marrow tests and the presence of autoantibodies; it promptly resolved after initiation of prednisolone therapy. Clinicians should be aware of immune cytopenia and monitor for it carefully, even if patients have already finished chemotherapy treatment.",
"affiliations": "Department of Internal Medicine, Asahi General Hospital, Asahi, Chiba, Japan.;Department of Hematology, Asahi General Hospital, Asahi, Chiba, Japan.;Department of Hematology, Asahi General Hospital, Asahi, Chiba, Japan.;Department of Hematology, Asahi General Hospital, Asahi, Chiba, Japan.",
"authors": "Nagashima|Kazuyo|K|;Tanaka|Hiroaki|H|;Nagai|Yurie|Y|;Sugita|Yasumasa|Y|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D000069283:Rituximab; D000069461:Bendamustine Hydrochloride; D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D044466:Asians; D000069461:Bendamustine Hydrochloride; D001853:Bone Marrow; D005260:Female; D006801:Humans; D007564:Japan; D016403:Lymphoma, Large B-Cell, Diffuse; D009364:Neoplasm Recurrence, Local; D010198:Pancytopenia; D011239:Prednisolone; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27651408",
"pubdate": "2016-09-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19809007;7059268;8535198;18287133;16207350;20964811;17577777;19357394;12426661;20141438;12111776;25337296;19293004;4574456;15908650;7985481;23907444;22077526;3499930;7615056;19260124;24785506;23650408;12826650",
"title": "Immune pancytopenia after chemotherapy in a patient with diffuse large B-cell lymphoma.",
"title_normalized": "immune pancytopenia after chemotherapy in a patient with diffuse large b cell lymphoma"
} | [
{
"companynumb": "JP-ROCHE-1849568",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "COVID-19-associated mold infections have been increasingly reported, and the main entity is COVID-19-associated aspergillosis (CAPA). Similarly, COVID-19-associated mucormycosis has been reported in hematology, and its prevalence is high and has been increasing in the diabetic population in India during the third COVID-19 pandemic wave. Simultaneous infection with Mucorales and Aspergillus is rare and even rarer during COVID-19. Here, we report the case of a previously immunocompetent patient with severe SARS-CoV-2 infection complicated with probable CAPA and mucormycosis co-infection. Specific diagnostic tools for mucormycosis are lacking, and this case highlights the advantages of analyzing blood and respiratory samples using the quantitative polymerase chain reaction to detect these fungi. We further reviewed the literature on mixed Aspergillus/Mucorales invasive fungal diseases to provide an overview of patients presenting with both fungi and to identify characteristics of this rare infection.",
"affiliations": "Université de Paris, Laboratoire de Parasitologie-Mycologie, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.;Université de Paris, Laboratoire de Parasitologie-Mycologie, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.;Université de Paris, FHU Promice, Département d'anesthésie-réanimation, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; INI-CRCT Network, Nancy, France; INSERM U942, Paris, France.;Université de Paris, FHU Promice, Département d'anesthésie-réanimation, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; INI-CRCT Network, Nancy, France; INSERM U942, Paris, France.;Université de Paris, Laboratoire de Parasitologie-Mycologie, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Institut Pasteur, Université de Paris, CNRS UMR2000, unité de Mycologie Moléculaire, Centre national de Référence Mycoses Invasives et Antifongiques, F-75015 Paris, France.;Université de Paris, FHU Promice, Département d'anesthésie-réanimation, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; INI-CRCT Network, Nancy, France; INSERM U942, Paris, France.;Université de Paris, Laboratoire de Parasitologie-Mycologie, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Institut Pasteur, Université de Paris, CNRS UMR2000, unité de Mycologie Moléculaire, Centre national de Référence Mycoses Invasives et Antifongiques, F-75015 Paris, France.;Université de Paris, Laboratoire de Parasitologie-Mycologie, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Institut Pasteur, Université de Paris, CNRS UMR2000, unité de Mycologie Moléculaire, Centre national de Référence Mycoses Invasives et Antifongiques, F-75015 Paris, France. Electronic address: sarah.delliere@aphp.fr.",
"authors": "Benhadid-Brahmi|Yasmine|Y|;Hamane|Samia|S|;Soyer|Benjamin|B|;Mebazaa|Alexandre|A|;Alanio|Alexandre|A|;Chousterman|Benjamin|B|;Bretagne|Stéphane|S|;Dellière|Sarah|S|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1016/j.mycmed.2021.101231",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1156-5233",
"issue": "32(1)",
"journal": "Journal de mycologie medicale",
"keywords": "Aspergillosis; COVID-19; Corticosteroids; Invasive fungal disease; Mucormycosis; SARS-CoV-2",
"medline_ta": "J Mycol Med",
"mesh_terms": null,
"nlm_unique_id": "9425651",
"other_id": null,
"pages": "101231",
"pmc": null,
"pmid": "34864498",
"pubdate": "2021-11-26",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "33333012;29188178;33716414;31613818;20946236;31802125;34022772;32860682;26706615;15480762;23964036;27350324;34454093;33388572;18753183;31713052;32599813;29611227;22517788;14654323;32445626;24782933;34218427;19568978;32719848;15755275;7907626;34575746;32835257;33364168;34668768;22247443;19180726;22004440;33920755;33527098;33316401;27535951;33842203;34522421;32572532;15078435;30076119;31699664;31114213;18589192;29163378;34114540;25086667;30975967;30703527;33619451;23381986;26969258;34563471",
"title": "COVID-19-associated mixed mold infection: A case report of aspergillosis and mucormycosis and a literature review.",
"title_normalized": "covid 19 associated mixed mold infection a case report of aspergillosis and mucormycosis and a literature review"
} | [
{
"companynumb": "FR-MYLANLABS-2022M1023451",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nTolerability, long-term toxicities and selection of resistant variants limit the use and efficacy of antiretroviral drugs in HIV-positive patients. Novel combinations are needed for mantaining long-term control of HIV replication; nevertheless scarse data are available on protease inhibitor-free dual antiretroviral therapies.\n\n\nMETHODS\nA multi-centric retrospective study was conducted including HIV-1-positive patients on raltegravir/nevirapine dual regimens. Plasma concentrations were measured as therapeutic drug monitoring while a subset of patients underwent intensive 12-hour pharmacokinetic evaluation.\n\n\nRESULTS\nA total of 77 patients switching from successful regimens (76.6% male, median age 52 years) was included; 10 patients on raltegravir plus nevirapine once-daily while 67 subjects on twice-daily schedule. After a median follow-up of 32 months 69 patients (89.6%) were still successfully on treatment. Three patients discontinued for side effects (skin rash or hepatoxicity). Virological failure was observed in five patients (6.5%, 3 on once-daily schedule): in 4 patients (80%) resistance-associated mutations were observed (4 reverse transcriptase, 2 integrase). Triglycerides decreased in patients switching with lipid abnormalities (n=52) and estimated creatinine clearance increased in those with less than 60 ml/min (n=13). Median trough raltegravir and nevirapine concentrations were 83 ng/ml (32-227) and 5460 ng/ml (4037-7221); intensive 12-hours pharmacokinetic parameters (n=7) were similar to published data.\n\n\nCONCLUSIONS\nDual therapy with raltegravir/nevirapine in selected patients was highly effective over a 32-month follow up: virological failure was infrequent (6.5%), most common with once-daily schedule (60%) and often associated with the selection of resistance-associated mutations (80%). Twice-daily raltegravir plus nevirapine deserves further clinical evaluation as an NRTI- and PI-sparing strategy in selected patients.",
"affiliations": "Clinica Univesitaria di Malattie Infettive, Ospedale Amedeo di Savoia, C.so Svizzera 164, 10159, Torino, Italy. andrea.calcagno@unito.it.",
"authors": "Calcagno|Andrea|A|;Montrucchio|Chiara|C|;Capetti|Amedeo|A|;Guaraldi|G|G|;Cenderello|G|G|;Calza|Leonardo|L|;Lanzafame|M|M|;Marinaro|Letizia|L|;Tettoni|M C|MC|;Trentini|Laura|L|;D'Avolio|Aantonio|A|;Di Perri|Giovanni|G|;Bonora|Stefano|S|",
"chemical_list": "D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D000068898:Raltegravir Potassium; D019829:Nevirapine",
"country": "Netherlands",
"delete": false,
"doi": "10.2174/1570162x13666150929112135",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1570-162X",
"issue": "14(1)",
"journal": "Current HIV research",
"keywords": null,
"medline_ta": "Curr HIV Res",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D004334:Drug Administration Schedule; D024921:Drug Resistance, Multiple, Viral; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D019428:HIV Integrase Inhibitors; D006801:Humans; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D019829:Nevirapine; D000068898:Raltegravir Potassium; D012189:Retrospective Studies; D019562:Viral Load",
"nlm_unique_id": "101156990",
"other_id": null,
"pages": "54-60",
"pmc": null,
"pmid": "26415700",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Raltegravir Plus Nevirapine as Maintenance Antiretroviral Therapy in HIV-Positive Patients: Safety, Efficacy and Pharmacokinetics.",
"title_normalized": "raltegravir plus nevirapine as maintenance antiretroviral therapy in hiv positive patients safety efficacy and pharmacokinetics"
} | [
{
"companynumb": "IT-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-04245IT",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
... |
{
"abstract": "Drug-induced hypertension was described with several pharmacological classes, especially with serotonin reuptake inhibitors (SRIs). However, this link has remained controversial: the French summary of product characteristics specify a risk of hypertension only with paroxetine and sertraline. To identify a possible class effect common to all SRIs, our study investigated the reports of hypertension associated with SRIs in two pharmacovigilance databases. Two different types of investigations were performed: (i) a comparative study in VigiBase® , which is the World Health Organization (WHO) pharmacovigilance database (PVDB), from where notifications of hypertension with six SRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) were extracted. The relationship between the suspected SRIs and the occurrence of hypertension was assessed by calculating reporting odds ratio (ROR) in a case/non-case design; (ii) a descriptive study of hypertension reports associated with SRIs in the French pharmacovigilance database (FPVDB). In VigiBase® , 14 824 notifications of SRI-induced hypertension (2.5%) were identified (mean age 54.3 years, mainly women 69.1%). Among them, 3 879 (26.2%) were associated to sertraline; 3 118 (21.0%) to fluoxetine; 2 725 (18.4%) to paroxetine; 2 570 (17.3%) to citalopram; 2 295 (15.5%) to escitalopram; and 237 (1.6%) to fluvoxamine. A significant ROR value was found with all six SRIs (ROR range from 1.16 to 1.92). In the FPVDB, 24 reports of hypertension were found with all six SRIs used at standard doses, mainly in women (66.7%) with a mean age of 57.8 years and a median time of onset of 6 days. In 10 cases (42%), patients had a history of hypertension. This study, performed in real conditions of life, shows a significant pharmacovigilance safety signal between the use of SRIs and the development or worsening of hypertension.",
"affiliations": "Département de médecine générale, UNICAEN, EA4650, Normandie Université, Caen, 14000, France.;Service de pharmacologie, UNICAEN, EA4650, CHU Caen Normandie, Normandie Université, Caen, 14000, France.;Service de pharmacologie, UNICAEN, CHU Caen Normandie, Normandie Université, Caen, 14000, France.;Service de pharmacologie, UNICAEN, CHU Caen Normandie, Normandie Université, Caen, 14000, France.;CHU Toulouse, Centre régional de pharmacovigilance, Toulouse, 31000, France.;CHU Dijon, Centre régional de pharmacovigilance, Dijon, 21000, France.;CHU Nice, Centre régional de pharmacovigilance, Nice, 06000, France.;Département de médecine générale, UNICAEN, EA4650, Normandie Université, Caen, 14000, France.;UNICAEN, EA4650, Normandie Université, Caen, 14000, France.;Service de pharmacologie, UNICAEN, EA4650, CHU Caen Normandie, Normandie Université, Caen, 14000, France.",
"authors": "Humbert|Xavier|X|https://orcid.org/0000-0003-2747-9229;Fedrizzi|Sophie|S|;Chrétien|Basile|B|;Sassier|Marion|M|;Bagheri|Haleh|H|;Combret|Sandrine|S|;Drici|Milou-Daniel|MD|;Le Bas|François|F|;Puddu|Paolo E|PE|;Alexandre|Joachim|J|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1111/fcp.12440",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0767-3981",
"issue": "33(3)",
"journal": "Fundamental & clinical pharmacology",
"keywords": "antidepressants; hypertension; serotonin reuptake inhibitors",
"medline_ta": "Fundam Clin Pharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D016208:Databases, Factual; D005260:Female; D005602:France; D006801:Humans; D006973:Hypertension; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D060735:Pharmacovigilance; D017367:Serotonin Uptake Inhibitors; D013997:Time Factors; D055815:Young Adult",
"nlm_unique_id": "8710411",
"other_id": null,
"pages": "296-302",
"pmc": null,
"pmid": "30489655",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hypertension induced by serotonin reuptake inhibitors: analysis of two pharmacovigilance databases.",
"title_normalized": "hypertension induced by serotonin reuptake inhibitors analysis of two pharmacovigilance databases"
} | [
{
"companynumb": "FR-TEVA-2019-FR-1061180",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "Benign intracranial hypertension (BIH) is a condition which is strongly associated with weight gain. A well-known potential adverse effect of anti-psychotic treatment, especially the atypical group, is weight gain. Our case describes the use of risperidone in a young obese lady who gained significant weight after commencing the antipsychotic and later developed headache and blurred vision. Withdrawing the offending drug (causing reduction in her weight) in addition to acetazolamide drastically improved her symptoms within a month. Our case highlights that, obese patients started on antipsychotic medication, who develop headache, should be considered for investigation of BIH.",
"affiliations": "Epsom General Hospital, Epsom and St Helier University NHS Trust, Epsom, Surrey, UK.",
"authors": "Ahmed|Hira|H|;Ali|Hala|H|",
"chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2011()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D005260:Female; D006801:Humans; D009767:Obesity, Morbid; D011559:Pseudotumor Cerebri; D018967:Risperidone; D015430:Weight Gain; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "22689727",
"pubdate": "2011-07-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15169706;16633140;9566400;10553730;11642473;20586697;15232335;11944227;17386271;9534686",
"title": "Risperidone induced weight gain leading to benign intracranial hypertension.",
"title_normalized": "risperidone induced weight gain leading to benign intracranial hypertension"
} | [
{
"companynumb": "GB-JNJFOC-20110902721",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadditional": nu... |
{
"abstract": "A 63-year-old Caucasian woman developed severe Plasmodium falciparum malaria when travelling back from Cameroun. No antimalarial chemoprophylaxis had been observed. The patient was immediately admitted to the intensive care unit after evidence of multiple organ failure (coma, shock, acute respiratory distress syndrome, acute renal failure, etc.). However, initial parasitemia was less than 1%. The patient was managed by intravenous quinine and norepinephrine infusion due to refractory shock. The patient developed as an early complication ischemic lesions of both arms and feet. In addition to laboratory changes consistent with disseminated intravascular coagulation, there was also evidence for a low activity of the von Willebrand factor (VWF) cleaving protease ADAMTS13. Later complications included repeated candidemia and bacteraemia despite appropriate therapy; the origin appeared to be diffuse ischemic injury of the gastrointestinal tract. The patient ultimately recovered, but quadriamputation was necessary to treat symmetrical peripheral gangrene (SPG). In severe Plasmodium falciparum malaria, ischemic changes may be due to microvascular obstruction, but, in patients with low parasitemia, other endothelial factors may also be involved as observed in other groups of thrombotic microangiopathies.",
"affiliations": "Département des Soins Intensifs, Université Catholique de Louvain, Cliniques Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium.;Département des Soins Intensifs, Université Catholique de Louvain, Cliniques Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium ; Louvain Centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Cliniques Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium ; Department of Intensive Care, Cliniques Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium.",
"authors": "Masse|Emeline|E|;Hantson|Philippe|P|0000-0003-4409-3352",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2014/696725",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2014/696725Case Report\nPlasmodium falciparum Malaria Complicated by Symmetrical Peripheral Gangrene, Bowel Ischemia, Repeated Candidemia, and Bacteraemia Masse Emeline \n1\nhttp://orcid.org/0000-0003-4409-3352Hantson Philippe \n1\n\n2\n\n3\n*1Département des Soins Intensifs, Université Catholique de Louvain, Cliniques Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium2Louvain Centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Cliniques Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium3Department of Intensive Care, Cliniques Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium*Philippe Hantson: philippe.hantson@uclouvain.beAcademic Editor: Jeannette Guarner\n\n2014 9 4 2014 2014 6967253 2 2014 18 3 2014 18 3 2014 Copyright © 2014 E. Masse and P. Hantson.2014This 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.A 63-year-old Caucasian woman developed severe Plasmodium falciparum malaria when travelling back from Cameroun. No antimalarial chemoprophylaxis had been observed. The patient was immediately admitted to the intensive care unit after evidence of multiple organ failure (coma, shock, acute respiratory distress syndrome, acute renal failure, etc.). However, initial parasitemia was less than 1%. The patient was managed by intravenous quinine and norepinephrine infusion due to refractory shock. The patient developed as an early complication ischemic lesions of both arms and feet. In addition to laboratory changes consistent with disseminated intravascular coagulation, there was also evidence for a low activity of the von Willebrand factor (VWF) cleaving protease ADAMTS13. Later complications included repeated candidemia and bacteraemia despite appropriate therapy; the origin appeared to be diffuse ischemic injury of the gastrointestinal tract. The patient ultimately recovered, but quadriamputation was necessary to treat symmetrical peripheral gangrene (SPG). In severe Plasmodium falciparum malaria, ischemic changes may be due to microvascular obstruction, but, in patients with low parasitemia, other endothelial factors may also be involved as observed in other groups of thrombotic microangiopathies.\n==== Body\n1. Introduction\n\nSymmetrical peripheral gangrene (SPG) is a possible but still infrequent complication of Plasmodium falciparum malaria [1–13]. The mechanism is usually ascribed to the activation of the coagulation pathway and to microvascular obstruction [5]. More recently, the role of ADAMTS13 (a von Willebrand factor (VWF) cleaving protease) activity has also been discussed to explain malaria-related microangiopathy [14]. Early coinfection with bacteria or even fungi may be the consequence of a relative immunosuppression and increased intestinal permeability [15]. We describe herein a severe case illustrating these acute pathophysiological changes.\n\n2. Case Report\nA 63-year-old Caucasian woman without medical history stayed for several weeks in Cameroun, without taking any antimalarial chemoprophylaxis. She developed severe gastrointestinal symptoms and, after three days, due to her suspicion of a malaria attack, she took at once four pills of Coartem (each containing 20 mg artemether and 120 mg lumefantrine). After that, the patient became unable to ingest any food or drug and a transfer to Europe was rapidly decided. She became seriously ill during the flight back. On arrival at the airport, she was found stuporous and hypotensive and was rapidly transferred to the intensive care unit (ICU) of the nearest hospital. The diagnosis of Plasmodium falciparum malaria was rapidly made on the blood smear and treatment was started with intravenous quinine and doxycycline (as artesunate was not available). Parasitemia was estimated less than 1%. Admission coagulation tests revealed activated partial thromboplastin time 37 sec, international normalized ratio 1.2, fibrinogen 299 mg/dL, D-dimers >8000 ng/mL (normal, <500), ADAMTS13 activity undetectable (reference range, 50–150%), von Willebrand factor (VWF) antigen 340% (reference range, 50–150%), and platelet count 21,000/mm³. Early complications included refractory hypotension and hypoxemia and neurological worsening. Intubation was required for mechanical ventilation; norepinephrine infusion was progressively increased to the maximal infusion rate of 46 μg/min. An acute left ventricular dysfunction could be demonstrated at echocardiography. Continuous venovenous hemofiltration was initiated for acute renal failure. Due to the evidence of multiple organ failure and despite relatively low parasitemia, exchange transfusion therapy was performed. Only one session of 87 minutes was performed. The patient's theoretical total blood volume was 4407 mL; on the whole, 1409 mL of red blood cells was removed and replaced by 1277 mL of packed red blood cells. Blood coagulation tests remained disturbed, with epistaxis and rectal bleeding. The nadir of platelet count (5,000/mm³) and plasma fibrinogen (66 mg/dL) was noted on day 4, but there was only a mild increase in activated partial thromboplastin time and prothrombin time. The activity of ADAMTS13 slightly increased to 32%; no inhibitor or ADAMTS13 autoantibodies were found. From day 2, blackish discoloration of both hands and feet was noted and by the following days a definite line of demarcation was observed between gangrenous and normal skin (Figure 1). Ultrasound-Doppler examination confirmed the absence of distal perfusion. Plastic surgeon suggested postponing the extensive surgery. Further clinical course was characterized by repeated candidemia (days 4, 7, 9, 10, and 11) and bacteraemia (Pseudomonas aeruginosa on day 7 and Enterococcus faecalis on days 12, 13, and 18), despite appropriate antifungal and antimicrobial therapy. The abdomen computed tomography (CT) failed to reveal bowel ischemia, but diffuse thickening of the jejunal wall was found. Endoscopy on day 11 disclosed multiple duodenal ulcerations from ischemic origin (Figure 2); colonoscopy performed on day 28 was also consistent with ischemic injury disseminated in the sigmoid colon (Figure 3). Norepinephrine infusion had been definitely stopped on day 14. The patient regained consciousness progressively from day 22 and extubation was possible on day 32.\n\nThe decision to perform quadriamputation was discussed after recovery from the critical period, when she became able to give her consent. Surgery was performed two months after the first signs of peripheral gangrene. Renal function recovered and the patient was further transferred for rehabilitation.\n\n3. Discussion\nSymmetrical peripheral gangrene (SPG) may be encountered after Plasmodium falciparum malaria but remains rare in travelers returning from endemic areas [1–13]. It is usually associated with the most severe forms complicated by multiple organ failure and is regarded as a consequence of distal vessel obstruction by fragments of parasites and erythrocytes and disseminated intravascular coagulation (DIC). Mortality rate may be as high as 35%, with a rate of amputation ranging from 70% to 90% [12]. In most of the published cases reporting on SPG, parasitemia is either not mentioned or not exceptionally elevated [13]. The effect of the treatment may not be underestimated and, in the present observation, the patient had already received a single loading dose of artemether-lumefantrine before the first determination of parasitemia. SPG appears usually within the first 3 days of effective antimalarial therapy, at which time parasitemia is often very significantly reduced [3]. As in our observation, SPG may develop before any bacterial infection. It appears therefore that the blood coagulation cascade is initially activated by changes in the erythrocyte membrane following Plasmodium falciparum infection and by the release of inflammatory cytokines leading to thrombin formation [5]. There is also a recent interest for the determination of ADAMTS13 activity in severe malaria. A deficiency in ADAMTS13 (a von Willebrand factor (VWF) cleaving protease) is associated with accumulation of prothrombogenic unusually large VWF multimers in plasma. It has been reported that symptomatic Plasmodium falciparum infection was associated with a significant increase in VWF and active VWF levels and a decrease in ADAMTS13 activity, resulting in the presence of circulating ultra-large VWF multimers [14]. The presence of reduced ADAMTS13 activity may contribute to the pathophysiological changes observed in severe malaria and particularly to microvascular disorders as observed in other groups of thrombotic microangiopathy. Till now, there is no direct link between ADAMTS13 activity and the occurrence of SPG.\n\nThe role of concomitant therapy in the pathogenesis of SPG has also to be discussed. In a review of 23 cases of Plasmodium falciparum malaria associated with DIC and SPG, 17 had received quinine as antimalarial therapy [3]. Patients treated with high doses of norepinephrine are also particularly at risk of developing SPG [7].\n\nThere is no evidence that blood exchange transfusions or fresh frozen plasma administration could be effective treatment options for patients with DIC and SPG. Heparin or streptokinase is not indicated. Surgery is often performed after some delay, when the delimitation of dry necrotic areas is evident.\n\nSeverely ill patients with complicated Plasmodium falciparum malaria are also profoundly immunosuppressed and susceptible to opportunistic fungal infections [15, 16]. Invasive candidiasis was reported in a single case of a nonimmune previously healthy 47-year-old man with Plasmodium falciparum malaria with a high parasite count (24%), shock, and multiple organ failure [15]. Blood cultures were positive for Candida albicans from admission. The patient had a favourable outcome after amphotericin B plus flucytosine therapy. Several factors may be involved in this acquired immunosuppression: free iron overload as a result of massive hemolysis, immunosuppressive effects of some antimalarial drugs, interference of the organism with innate cellular and specific cell-mediated immunity… [16]. Repeated candidemia and bacteraemia in the present observation may also be related to a breakdown in intestinal mucosal barrier caused by disturbances in the microcirculation [17, 18].\n\nIn conclusion, by some aspects, the clinical course of severe Plasmodium falciparum malaria may mimic the evolution of other thrombotic microangiopathies. The limitation of this observation is that some specific coagulation tests (VWF multimers, prothrombin fragment 1 + 2, and thrombin antithrombin complexes) could not be obtained.\n\nCytoadherence of parasitized erythrocytes causes not only mechanical obstruction but also endothelial activation. Further investigations of the coagulation cascade could be helpful to better investigate microcirculatory disorders and subsequent ischemic injuries.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Aspect of the symmetrical peripheral gangrene affecting both arms and legs after 1 month in the ICU.\n\nFigure 2 Gastroscopy performed on day 11 and showing diffuse hemorrhagic lesions in the stomach and duodenum, with an ischemic pattern of the mucosa.\n\nFigure 3 Colonoscopy performed on day 28 and showing diffuse ischemic lesions mainly in the sigmoid colon.\n==== Refs\n1 Gupta A Dwivedi Y Saxena AK Joshi K Symmetrical peripheral gangrene with Plasmodium falciparum malaria Journal of Natural Science, Biology and Medicine 2013 4 262 264 \n2 Kotokey RK Kaushik K Symmetrical peripheral gangrene and neurological manifestations in Plasmodium falciparum malaria Journal of Association of Physicians of India 2011 59 7 449 450 2-s2.0-79960374612 22315752 \n3 Alkizim FO Matheka D Mwanda OW Malaria complicated by gangrene: a case presentation and review The Pan African Medical Journal 2011 10, article 46 \n4 Ghafoor SZ MacRae EA Harding KG Patel GK Symmetrical peripheral digital gangrene following severe Plasmodium falciparum malaria-induced disseminated intravascular coagulopathy International Wound Journal 2010 7 5 418 422 2-s2.0-77956964218 20586820 \n5 Tessier-Marteau A Le Cruguel S Grand F Zandecki M Asfar P Macchi L DIC and peripheral gangrene in a severe Plasmodium falciparum malaria: the coagulation-inflammation cycle with Plasmodium falciparum as a model Annales de Biologie Clinique 2009 67 5 569 572 2-s2.0-73949118705 19789130 \n6 Bhattacharyya PC Agarwal JP Sharma M Symmetric peripheral gangrene of the lower limbs in a case of complicated falciparum malaria Southeast Asian Journal of Tropical Medicine and Public Health 2008 39 4 589 592 2-s2.0-49749129591 19058594 \n7 Helbok R Lackner P Schmutzhard E Severe Plasmodium falciparum malaria with peripheral gangrene The Lancet Infectious Diseases 2008 8 6 p. 400 2-s2.0-43849101399 \n8 Thanachartwet V Krudsood S Wilairatana P Phumratanaprapin W Silachamroon U Looareesuwan S Peripheral gangrene in patients with severe falciparum malaria: report of 3 cases The Korean Journal of Parasitology 2006 44 2 139 143 2-s2.0-39049182901 16809962 \n9 Anuradha S Prabhash K Shome DK Symmetric peripheral gangrene and falciparum Malaria—an interesting association Journal of Association of Physicians of India 1999 47 7 733 735 2-s2.0-0033156764 10778599 \n10 Kakati S Doley B Barman B Devi A Symmetric peripheral gangrene and falciparum malaria Journal of Association of Physicians of India 2004 52 498 499 2-s2.0-13844321950 15645963 \n11 Sharma BD Gupta B Peripheral gangrene in a case of complicated falciparum malaria Journal, Indian Academy of Clinical Medicine 2002 3 297 299 \n12 Ghosh S Bandyopadhyay D Ghosh A Symmetrical peripheral gangrene: a prospective study of 14 consecutive cases in a tertiary-care hospital in eastern India Journal of the European Academy of Dermatology and Venereology 2010 24 2 214 218 2-s2.0-74549124861 19522719 \n13 Liechti ME Zumsteg V Hatz CFR Herren T \nPlasmodium falciparum cerebral malaria complicated by disseminated intravascular coagulation and symmetrical peripheral gangrene: case report and review European Journal of Clinical Microbiology and Infectious Diseases 2003 22 9 551 554 2-s2.0-0141751681 12938006 \n14 Löwenberg EC Charunwatthana P Cohen S Severe malaria is associated with a deficiency of von Willebrand factor cleaving protease, ADAMTS13 Thrombosis and Haemostasis 2010 103 1 181 187 2-s2.0-74249118600 20062916 \n15 Soesan M Kager PA Leverstein-van Hall MA Van Lieshout JJ Coincidental severe Plasmodium falciparum infection and disseminated candidiasis Transactions of the Royal Society of Tropical Medicine and Hygiene 1993 87 3 288 289 2-s2.0-0027291166 8236394 \n16 Däbritz J Schneider M Just-Nuebling G Groll AH Minireview: invasive fungal infection complicating acute Plasmodium falciparum malaria Mycoses 2011 54 4 311 317 2-s2.0-79955050021 20028459 \n17 Bruneel F Tubach F Corne P Severe imported falciparum malaria: a cohort study in 400 critically Ill adults PLoS ONE 2010 5 10 2-s2.0-78149443165 e13236 \n18 Wilairatana P Meddings JB Ho M Vannaphan S Looareesuwan S Increased gastrointestinal permeability in patients with Plasmodium falciparum malaria Clinical Infectious Diseases 1997 24 3 430 435 2-s2.0-0031019945 9114195\n\n",
"fulltext_license": "CC BY",
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"other_id": null,
"pages": "696725",
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"pmid": "24812562",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "15645963;22315752;19789130;22384292;10778599;20586820;19058594;18501856;23633880;8236394;9114195;12938006;20949045;20028459;20062916;16809962;19522719",
"title": "Plasmodium falciparum Malaria Complicated by Symmetrical Peripheral Gangrene, Bowel Ischemia, Repeated Candidemia, and Bacteraemia.",
"title_normalized": "plasmodium falciparum malaria complicated by symmetrical peripheral gangrene bowel ischemia repeated candidemia and bacteraemia"
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"abstract": "A 69 year old woman developed chronic diarrhoea while being treated with ranitidine. Sigmoidoscopy was performed after six weeks and showed typical histological features of lymphocytic colitis. Ranitidine was withdrawn and the diarrhoea resolved. Eight months later, a 72 hour oral rechallenge period of ranitidine, was performed immediately preceded (period 1) and followed (period 2) by sigmoidoscopy and biopsy. Diarrhoea recurred during the rechallenge period and resolved again within one day after drug withdrawal. The mean (SEM) intraepithelial lymphocyte count was not significantly different between periods 1 and 2 (11.9 (0.6) and 13.1 (0.4) per 100, respectively). An immunopathological study of 30 serial sections of biopsy specimens was performed for both periods 1 and 2. The expression of HLA-DR by the rectal epithelium was mild or absent in all sections from period 1, and was considerable in 25 of 30 sections from period 2 (p < 10(-9)). It is suggested that the oral intake of ranitidine was responsible for the diarrhoea and induced the immunopathological signs of activation of the rectal mucosal immune system during the rechallenge period.",
"affiliations": "Department of Gastroenterology, Hôpital Rothschild, Paris, France.",
"authors": "Beaugerie|L|L|;Patey|N|N|;Brousse|N|N|",
"chemical_list": "D000897:Anti-Ulcer Agents; D011899:Ranitidine",
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"issue": "37(5)",
"journal": "Gut",
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"medline_ta": "Gut",
"mesh_terms": "D000368:Aged; D000897:Anti-Ulcer Agents; D002908:Chronic Disease; D003092:Colitis; D003106:Colon; D003967:Diarrhea; D005260:Female; D006801:Humans; D008218:Lymphocytosis; D011899:Ranitidine; D012007:Rectum",
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"title": "Ranitidine, diarrhoea, and lymphocytic colitis.",
"title_normalized": "ranitidine diarrhoea and lymphocytic colitis"
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"abstract": "We describe a case of primary hypertensive iridocyclitis with biopsy-proven Cytomegaloviral retinitis. It is an observational case report of a 69-year-old diabetic gentleman on azathioprine for Crohn's disease who presented with recurrent episodes of hypertensive iridocyclitis. On the 4 th attendance in 5 months, a granular white lesion was noted in the temporal periphery of the mid-peripheral fundus and a chorioretinal and vitreous biopsy performed. Vitreous PCR was positive for Cytomegalovirus (CMV). Hematoxylin and eosin staining revealed cytomegalic-like inclusions within necrotic neural retina. Transmission electron microscopy revealed herpes family virus particles and immunohistochemistry demonstrated CMV protein. This case provides further evidence implicating CMV infection in the etiology of hypertensive iridocyclitis. With hindsight, the cumulative effect of diabetes and azathioprine on the immune surveillance system proved sufficient to render the patient susceptible to CMV retinitis.",
"affiliations": "Department of Ophthalmology, Royal Hallamshire Hospital, Sheffield, United Kingdom.",
"authors": "Squirrell|David M|DM|;Bhatta|Sudipto|S|;Mudhar|Hardeep S|HS|;Rennie|Ian G|IG|",
"chemical_list": "D004279:DNA, Viral",
"country": "India",
"delete": false,
"doi": "10.4103/0301-4738.97086",
"fulltext": "\n==== Front\nIndian J OphthalmolIndian J OphthalmolIJOIndian Journal of Ophthalmology0301-47381998-3689Medknow Publications & Media Pvt Ltd India 23548320IJO-62-65610.4103/0301-4738.97086Brief CommunicationsHypertensive iridocyclitis associated with delayed onset biopsy proven Cytomegalovirus retinitis Squirrell David M Bhatta Sudipto 1Mudhar Hardeep S 2Rennie Ian G 1Department of Ophthalmology, Greenlane Clinical Centre, Auckland, New Zealand1 Department of Ophthalmology, Royal Hallamshire Hospital, Sheffield, United Kingdom2 Department of Pathology, Royal Hallamshire Hospital, Sheffield, United KingdomCorrespondence to: Mr. Sudipto Bhatta, Department of Ophthalmology, Royal Hallamshire Hospital, Sheffield, S10 2JF, United Kingdom. E-mail: sudiptobhatta@rediffmail.com5 2014 62 5 656 658 24 7 2011 10 4 2012 Copyright: © Indian Journal of Ophthalmology2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We describe a case of primary hypertensive iridocyclitis with biopsy-proven Cytomegaloviral retinitis. It is an observational case report of a 69-year-old diabetic gentleman on azathioprine for Crohn's disease who presented with recurrent episodes of hypertensive iridocyclitis. On the 4th attendance in 5 months, a granular white lesion was noted in the temporal periphery of the mid-peripheral fundus and a chorioretinal and vitreous biopsy performed. Vitreous PCR was positive for Cytomegalovirus (CMV). Hematoxylin and eosin staining revealed cytomegalic-like inclusions within necrotic neural retina. Transmission electron microscopy revealed herpes family virus particles and immunohistochemistry demonstrated CMV protein. This case provides further evidence implicating CMV infection in the etiology of hypertensive iridocyclitis. With hindsight, the cumulative effect of diabetes and azathioprine on the immune surveillance system proved sufficient to render the patient susceptible to CMV retinitis.\n\nCytomegalovirus retinitishypertensive iridocyclitisvitreous polymerace chain reaction\n==== Body\nPosner-Schlossman syndrome (PSS) is recognized as a distinct clinical entity, comprising unilateral recurrent attacks of glaucoma where the intraocular pressure rise is out of proportion to the associated cyclitis.[1] Although it was initially hypothesized that PSS may have an allergic etiology,[1] more recently positive polymerace chain reaction (PCR) for Cytomegalovirus (CMV) has been described in anterior chamber isolates from immunocompetent individuals presenting with PSS.[234] These data suggest that at least in a subgroup of patients with presumed PSS, hypertensive iridocyclitis may actually be caused by a primary herpetic, particularly CMV infection of the eye, which individuals with a competent immune system limit to the anterior chamber. We describe the case of a 69-year-old diabetic gentleman who presented with recurrent episodes of hypertensive iridocyclitis mimicking PSS. On the fourth attendance in 5 months, a granular white lesion was noted in the temporal periphery of the mid peripheral fundus and a chorioretinal and vitreous biopsy performed. This revealed an unexpected diagnosis of CMV retinitis. We suggest that this case provides further evidence to implicate CMV infection of the eye as a causative trigger for hypertensive iridocyclitis, which in our case, went on to cause posterior segment disease. It also serves to emphasize the need to maintain a high index of suspicion for unusual infections when managing patients with compromised immune systems, from whatever cause.\n\nCase Report\nA 69-year-old gentleman presented with a history of episodic blurred vision in his right eye. On examination, visual acuity was 6/12, the intraocular pressure was 48 mmHg, but aside a mild anterior chamber cellular reaction and fine stellate KPs, ocular examination was unremarkable. The patient's medical history included type 2 diabetes and terminal ileal Crohn's disease, for which he was prescribed Rosiglitazone and Azathioprine 150 mg od. There was no significant past ocular history.\n\nA diagnosis of Posner-Schlossman Syndrome was made, and topical corticosteroids and timolol were prescribed. Following treatment, the ocular condition rapidly resolved with complete resolution of anterior chamber inflammation and normalization of IOP, but over the ensuing 3 months, the patient presented with 2 further episodes of presumed PSS. On each occasion, the condition was controlled with topical corticosteroids and timolol. On a further attendance 6 weeks later, the visual acuity was noticeably more reduced than previously (6/36), and in addition to a mild anterior chamber reaction and high intraocular pressure (42 mmHg), there was also a moderate vitritis. An examination of the posterior pole at this attendance revealed a small discrete area (2 disc diameters) of granular retinal pallor in the temporal periphery. There was no associated hemorrhage, and this was diagnosed as peripheral drusen. The patient was treated with topical and systemic prednisolone with resolution of the ocular inflammation and improved visual acuity. Over the ensuing 12 weeks, the systemic and topical steroids were tapered, but the ocular inflammation recurred as the dose was reduced. It was also noted that the previously noted white patch had enlarged [Fig. 1] and a chorioretinal and vitreous biopsy organized. Vitreous PCR [LightCycler® FRET technology (Roche)] was positive for Cytomegalovirus (CMV) and negative for HZV, HSV 1 and 2. Hematoxylin and eosin staining revealed cytomegalic-like inclusions within necrotic neural retina. Transmission electron microscopy revealed herpes family virus particles, and immunohistochemistry demonstrated CMV protein [Fig. 2]. The patient was investigated for other causes of immunocompromise without a positive result. In particular, 3rd generation HIV test (ELISA) was negative, his CD4 counts were consistently above 350, and his full blood count was normal. Despite treatment with intravenous ganciclovir and long-term oral valcyclovir (as per local guidelines), the retinitis progressed rapidly to involve the central macula. The patient's final visual acuity was “hand movements”.\n\nFigure 1 Color fundus photograph. There is an area of granular retinal pallor in the temporal periphery, which had enlarged over 4 months. There is a possible satellite lesion at the fovea, an associated vitritis and new vessels at the disc\n\nFigure 2 Chorioretinal biopsy (a) Hematoxylin and eosin stained chorioretinal biopsy. The black arrows point to cytomegalic-like inclusions within the eosionophilic, necrotic neural retina (Magnification, ×400), (b) Immunohistochemistry: chorioretinal tissue stained with monoclonal antibodies to cytomegalovirus protein shows positive brown signal within the necrotic neural retina (Magnification, ×400), (c) Transmission electron microscopy shows herpes family viruses particles within the necrotic neural retina (Magnification, ×20000)\n\nDiscussion\nOcular CMV infection is most commonly known for the typical retinitis that is seen in those patients who are severely immunocompromised or receiving combination immunosuppressive therapy.[5] It is however recognized that CMV infection may also be implicated in PSS/ ‘hypertensive iridocyclitis’.[34] Currently, the pathophysiology of CMV associated hypertensive iridocyclitis remains obscure.[6] Anterior chamber involvement in patients with CMV retinitis secondary to AIDS is occasionally seen, but when present, is not typically a Posner-Schlossman like syndrome. The anterior chamber inflammation, observed in patients with AIDS, could be due to either primary anterior segment infection or it may also simply be an inflammatory response, secondary to posterior segment pathology.\n\nThe discovery of positive PCR for CMV in anterior chamber isolates from immunocompetent patients presenting with isolated PSS suggests that, at least in some patients, hypertensive iridocyclitis may actually be caused by primary herpetic infection of the anterior chamber and thus mimics PSS.[34] With the benefit of hindsight, it is likely that in the case we describe the CMV infection was unrecognized for some months. The fact that the patient had a moderate vitritis also caused confusion as CMV retinitis is typically associated with a quiet vitreous. Only one can assume that the vitritis represented an inadequate immunological response to the virus, a response that is often not generated in patients with low CD4 counts associated with HIV CMV retinitis. Therefore, although the presentation of PSS in our patient predated the definitive diagnosis of CMV retinitis by 6 months, it is tempting to speculate that the initial presentation of PSS in our case also coincided with the primary presentation of CMV in the eye. Whilst not conclusive, we suggest that our case provides further evidence that CMV infection of the eye can present with a clinical syndrome of hypertensive iridocyclitis, which without further diagnostic testing, is indistinguishable from PSS. The evolving clinical scenario presented a number of diagnostic difficulties. With hindsight, the cumulative effect of diabetes and azathioprine on the immune surveillance system proved sufficient to render the patient susceptible to CMV retinitis. In patients without HIV, it is regrettably not unusual for the diagnosis of CMV retinitis to be delayed.[7] This case therefore also emphasizes the need to maintain a high index of suspicion for unusual infections when managing patients with compromised immune systems, from whatever cause.\n\nSource of Support: Nil.\n\nConflict of Interest: None declared.\n==== Refs\n1 Theodore FH Observations on glaucomatocyclitic crises (Posner Schlossman syndrome) Br J Ophthalmol 1952 36 207 10 14916093 \n2 Teoh SB Thean L Koay E Cytomegalovirus in aetiology of Posner-Schlossman syndrome: Evidence from quantitative polymerase chain reaction Eye (Lond) 2005 19 1338 40 15543169 \n3 de Schryver I Rozenberg F Cassoux N Michelson S Kestelyn P Lehoang P Diagnosis and treatment of cytomegalovirus iridocyclitis without retinal necrosis Br J Ophthalmol 2006 90 852 5 16597667 \n4 Chee SP Bacsal K Jap A Se-Thoe SY Cheng CL Tan BH Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients Am J Ophthalmol 2008 145 834 40 18255045 \n5 Yoser SL Forster DJ Rao NA Systemic viral infections and their retinal and choroidal manifestations Surv Ophthalmol 1993 37 312 52 \n6 Kim EC Moargolis TP Hypertensive iridocyclitis Br J Ophthalmol 2006 90 812 3 16782945 \n7 Eid AJ Bakri SJ Kijpittayarit S Razonable RR Clinical features and outcomes of cytomegalovirus retinitis after transplantation Transpl Infect Dis 2008 10 13 8 17511815\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0301-4738",
"issue": "62(5)",
"journal": "Indian journal of ophthalmology",
"keywords": null,
"medline_ta": "Indian J Ophthalmol",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D017726:Cytomegalovirus Retinitis; D004279:DNA, Viral; D003937:Diagnosis, Differential; D015828:Eye Infections, Viral; D006801:Humans; D015863:Iridocyclitis; D008297:Male; D016133:Polymerase Chain Reaction",
"nlm_unique_id": "0405376",
"other_id": null,
"pages": "656-8",
"pmc": null,
"pmid": "23548320",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18255045;15543169;8387231;16782945;14916093;17511815;16597667",
"title": "Hypertensive iridocyclitis associated with delayed onset biopsy proven Cytomegalovirus retinitis.",
"title_normalized": "hypertensive iridocyclitis associated with delayed onset biopsy proven cytomegalovirus retinitis"
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"abstract": "Von Willebrand disease is the most common inherited blood disorder, occurring in about 1% of the population. It results from a deficiency in the quality or quantity of von Willebrand factor, which is necessary for adequate hemostasis. An evidenced-based approach is prudent when this derangement is coupled with a potentially fatal obstetric complication. This article examines the anesthetic management of a parturient with a known diagnosis of von Willebrand disease who presented to the labor and delivery unit in active labor and with a suspected uterine placental abruption.",
"affiliations": "is a staff nurse anesthetist at Mississippi Baptist Medical Center in Jackson, Mississippi.;is a staff nurse at Mississippi Baptist Medical Center.;is a professor of nurse anesthesia in the Doctor of Nurse Anesthesia Practice program at Texas Wesleyan University, Fort Worth, Texas.",
"authors": "Roberson|Michael C|MC|;Wigley|Morgan D|MD|;Austin|Paul N|PN|",
"chemical_list": "D003894:Deamino Arginine Vasopressin",
"country": "United States",
"delete": false,
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"fulltext": null,
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"issn_linking": "0094-6354",
"issue": "86(3)",
"journal": "AANA journal",
"keywords": "Abruption; Von Willebrand; anesthesia; placenta; uterus",
"medline_ta": "AANA J",
"mesh_terms": "D000037:Abruptio Placentae; D000328:Adult; D000773:Anesthesia, Obstetrical; D002585:Cesarean Section; D003894:Deamino Arginine Vasopressin; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D009719:Nurse Anesthetists; D018743:Perinatal Care; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic; D011256:Pregnancy Outcome; D056725:von Willebrand Disease, Type 1",
"nlm_unique_id": "0431420",
"other_id": null,
"pages": "209-212",
"pmc": null,
"pmid": "31580809",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anesthetic Management of a Patient With Type 1 von Willebrand Disease and Uterine Placental Abruption: A Case Report.",
"title_normalized": "anesthetic management of a patient with type 1 von willebrand disease and uterine placental abruption a case report"
} | [
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"abstract": "OBJECTIVE\nMany guidelines for septic olecranon bursitis recommend aspiration of the bursa prior to initiation of antimicrobial therapy despite the absence of robust clinical data to support this practice and known risk of aspiration complications. Our objective was to describe outcomes associated with empiric antibiotic therapy without bursal aspiration among emergency department (ED) patients with suspected septic olecranon bursitis.\n\n\nMETHODS\nWe conducted a retrospective observational cohort study of patients presenting to an academic ED from January 1, 2011, to December 31, 2018, with olecranon bursitis. The health record was reviewed to assess patient characteristics and outcomes within 6 months of the ED visit. Olecranon bursitis was considered \"suspected septic\" if the patient was treated with antibiotics. The primary outcome of interest was complicated versus uncomplicated bursitis resolution. Uncomplicated resolution was defined as bursitis resolution without subsequent bursal aspiration, surgery, or hospitalization.\n\n\nRESULTS\nDuring the study period, 264 ED patients were evaluated for 266 cases of olecranon bursitis. The median age was 57 years and 85% were men. Four (1.5%) patients had bursal aspiration during their ED visit, 39 (14.7%) were admitted to the hospital, 76 (28.6%) were dismissed without antibiotic therapy, and 147 (55.3%) were dismissed with empiric antibiotic therapy for suspected septic olecranon bursitis. Among these 147 patients, 134 had follow-up available including 118 (88.1%, 95% confidence interval [CI] = 81.1%-92.8%) with an uncomplicated resolution, eight (6.0%, 95% CI = 2.8%-11.8%) who underwent subsequent bursal aspiration, and nine (6.7%, 95% CI = 3.3%-12.7%) who were subsequently admitted for inpatient antibiotics.\n\n\nCONCLUSIONS\nEighty-eight percent of ED patients with suspected septic olecranon bursitis treated with empiric antibiotics without aspiration had resolution without need for subsequent bursal aspiration, hospitalization, or surgery. Our findings suggest that empiric antibiotics without bursal aspiration may be a reasonable initial approach to ED management of select patients with suspected septic olecranon bursitis.",
"affiliations": "Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Department of Emergency Medicine and Sports Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Department of Emergency Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Department of Emergency Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA.;Department of Orthopedics, Mayo Clinic, Rochester, Minnesota, USA.;Department of Emergency Medicine, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Beyde|Adrian|A|https://orcid.org/0000-0002-1304-1755;Thomas|Alexa L|AL|;Colbenson|Kristina M|KM|;Sandefur|Benjamin J|BJ|;Kisirwan|Imtithal|I|;Mullan|Aidan F|AF|;O'Driscoll|Shawn W|SW|;Campbell|Ronna L|RL|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1111/acem.14406",
"fulltext": "\n==== Front\nAcad Emerg Med\nAcad Emerg Med\n10.1111/(ISSN)1553-2712\nACEM\nAcademic Emergency Medicine\n1069-6563\n1553-2712\nJohn Wiley and Sons Inc. Hoboken\n\n34698411\n10.1111/acem.14406\nACEM14406\nOriginal Contribution\nEditor's Pick\nEfficacy of empiric antibiotic management of septic olecranon bursitis without bursal aspiration in emergency department patients\nBeyde Adrian https://orcid.org/0000-0002-1304-1755\n1\nThomas Alexa L. MD 1 2\nColbenson Kristina M. MD 3\nSandefur Benjamin J. MD 4\nKisirwan Imtithal DNP 4\nMullan Aidan F. MA 5\nO’Driscoll Shawn W. MD, PhD 6\nCampbell Ronna L. MD, PhD 4 campbell.ronna@mayo.edu\n\n1 Mayo Clinic Alix School of Medicine Mayo Clinic Rochester Minnesota USA\n2 Department of Emergency Medicine Vanderbilt University Medical Center Nashville Tennessee USA\n3 Department of Emergency Medicine and Sports Medicine Mayo Clinic Rochester Minnesota USA\n4 Department of Emergency Medicine Mayo Clinic Rochester Minnesota USA\n5 Department of Quantitative Health Sciences Mayo Clinic Rochester Minnesota USA\n6 Department of Orthopedics Mayo Clinic Rochester Minnesota USA\n* Correspondence\nRonna L. Campbell, Department of Emergency Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.\nEmail: campbell.ronna@mayo.edu\n\n09 11 2021\n1 2022\n29 1 10.1111/acem.v29.1 614\n17 10 2021\n11 7 2021\n18 10 2021\n© 2021 The Authors. Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine\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\nObjectives\n\nMany guidelines for septic olecranon bursitis recommend aspiration of the bursa prior to initiation of antimicrobial therapy despite the absence of robust clinical data to support this practice and known risk of aspiration complications. Our objective was to describe outcomes associated with empiric antibiotic therapy without bursal aspiration among emergency department (ED) patients with suspected septic olecranon bursitis.\n\nMethods\n\nWe conducted a retrospective observational cohort study of patients presenting to an academic ED from January 1, 2011, to December 31, 2018, with olecranon bursitis. The health record was reviewed to assess patient characteristics and outcomes within 6 months of the ED visit. Olecranon bursitis was considered “suspected septic” if the patient was treated with antibiotics. The primary outcome of interest was complicated versus uncomplicated bursitis resolution. Uncomplicated resolution was defined as bursitis resolution without subsequent bursal aspiration, surgery, or hospitalization.\n\nResults\n\nDuring the study period, 264 ED patients were evaluated for 266 cases of olecranon bursitis. The median age was 57 years and 85% were men. Four (1.5%) patients had bursal aspiration during their ED visit, 39 (14.7%) were admitted to the hospital, 76 (28.6%) were dismissed without antibiotic therapy, and 147 (55.3%) were dismissed with empiric antibiotic therapy for suspected septic olecranon bursitis. Among these 147 patients, 134 had follow‐up available including 118 (88.1%, 95% confidence interval [CI] = 81.1%–92.8%) with an uncomplicated resolution, eight (6.0%, 95% CI = 2.8%–11.8%) who underwent subsequent bursal aspiration, and nine (6.7%, 95% CI = 3.3%–12.7%) who were subsequently admitted for inpatient antibiotics.\n\nConclusions\n\nEighty‐eight percent of ED patients with suspected septic olecranon bursitis treated with empiric antibiotics without aspiration had resolution without need for subsequent bursal aspiration, hospitalization, or surgery. Our findings suggest that empiric antibiotics without bursal aspiration may be a reasonable initial approach to ED management of select patients with suspected septic olecranon bursitis.\n\naspiration\nemergency department\nmanagement\nolecranon bursitis\nseptic bursitis\nNational Center for Advancing Translational Sciences 10.13039/100006108 UL1TR002377 source-schema-version-number2.0\ncover-dateJanuary 2022\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.2.0 mode:remove_FC converted:07.10.2022\nBeyde A , Thomas AL , Colbenson KM , et al. Efficacy of empiric antibiotic management of septic olecranon bursitis without bursal aspiration in emergency department patients. Acad Emerg Med. 2022;29 :6–14. doi:10.1111/acem.14406 34698411\n\nPresented at the Society for Academic Emergency Medicine Virtual Meeting, May 2020.\n\nSupervising Editor: Michael S. Runyon, MD, MPH.\n\nFunding information\n\nThis publication was made possible in part by the Mayo Clinic CTSA through grant number UL1TR002377 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH).\n==== Body\npmcINTRODUCTION\n\nPatients with symptomatic olecranon bursitis commonly present to the emergency department (ED) for evaluation. 1 Up to 50% of all olecranon bursitis cases in the ED are septic in nature. 2 It is important to recognize and appropriately treat these cases to prevent complications including septic arthritis and sepsis. 3\n\nThe ED evaluation and diagnosis of septic bursitis is widely variable and often based on anecdotal evidence. 4 Diagnostic aspiration of the olecranon bursa to assess for septic bursitis is commonly recommended and performed 1 , 2 , 3 , 5 , 6 despite the paucity of evidence to support this practice. 3 Aspiration may increase the risk for complications including chronic fistula formation, infection, and need for a future bursectomy. 2 , 3 , 7\n\nThere are only limited studies focused on ED evaluation and management of septic bursitis. Additionally, the efficacy of conservative management of suspected septic olecranon bursitis with empiric antibiotic therapy is unknown. The objective of our study was to describe outcomes associated with empiric antibiotic therapy without bursal aspiration among ED patients with suspected septic olecranon bursitis.\n\nMETHODS\n\nStudy design\n\nWe conducted a retrospective observational cohort study. The study was deemed exempt by the Mayo Clinic institutional review board. The STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for reporting observational studies were followed. 8\n\nStudy setting and population\n\nThis study was conducted at the ED of Mayo Clinic Hospital–Saint Mary's Campus, Rochester, Minnesota, a quaternary care academic ED that has a volume of approximately 77,000 annual patient visits. Most patients come from Olmsted County and six adjacent counties in southeastern Minnesota. All adult ED patients (age ≥ 18 years) with olecranon bursitis between January 1, 2011, and December 31, 2018, were eligible for inclusion. Patients with an ED diagnosis containing “olecranon bursitis” or “bursitis,” but not “prepatellar bursitis,” were identified and the electronic health record (EHR) was manually reviewed to determine whether the patient had olecranon bursitis. All diagnoses associated with the ED visit were assessed for potential inclusion in the study. We considered the olecranon bursitis to be “suspected septic” if the patient was treated with antibiotics. Patients who declined research authorization, had an underlying fracture, or had surgery on the joint within 3 months prior to their presentation were excluded. Follow up was considered to be bursitis related if the provider specifically addressed the bursitis in the visit note. If the patient continued to have documented care in the EMR but the bursitis was not addressed, the visits were reviewed as part of the follow‐up period for 6 months but not considered bursitis‐related follow‐up. Patients were considered lost to follow‐up if they had less than 14 days of follow‐up available in the EHR.\n\nStudy protocol\n\nAll data were abstracted from the EHR using a standardized extraction process. Study data were collected and managed using REDCap (Research Electronic Data Capture, Nashville, TN) electronic data capture tools hosted at Mayo Clinic. 9 ED visits were independently extracted by two medical students (A.B. and A.T.) and an emergency nurse practitioner (I.K.). Extractors were trained on 10 random charts, and coding rules were developed. Abstractors were not blinded to study objectives. Random chart numbers were generated by www.random.org. Coding rules included using the first recorded value for vital signs with more than one measurement; a history of acute trauma was defined as trauma within the past 1 month; fever was defined as a temperature of 38° C or higher; steroid use was defined as present if the patient was taking steroids at the time of the index ED visit; patient‐reported fever was defined as present if a patient reported a fever at any point in the illness. Investigators met on numerous occasions with the principal investigator (R.C.) to discuss the abstraction process, ambiguities, and inconsistencies. Inter‐rater agreement was assessed for the key variables including aspiration of the bursa in the ED, subsequent hospitalization, need for subsequent aspiration of the bursa, development of complications from initial bursal aspiration, complications from antibiotic use, and need for surgical procedure. New extraction guidelines were developed as needed to ensure consistency and accuracy. Repeated rounds of extraction and assessment were performed until there was near perfect agreement for all key variables. Approximately 20% of charts were extracted in triplicate during the training and assessment process. All charts with a bursal aspiration in the ED or following the ED visit were also reviewed by the principal investigator to ensure accuracy.\n\nMeasures\n\nDemographic data, presenting symptoms, comorbidities (history of diabetes, rheumatoid arthritis, gout, human immunodeficiency virus, immunocompromised, steroid use, or other immunocompromised states at the time of the ED visit), ED evaluation and management, outpatient management, and complications within 6 months of the initial ED visit were collected. Complications from antibiotic management including anaphylaxis, allergic reaction, Clostridioides difficile colitis, any clinically significant diarrhea, or other clinically significant complications that were recorded. An uncomplicated resolution was defined as resolution of bursitis without need for subsequent aspiration of the bursa, surgery, or hospitalization.\n\nData analysis\n\nContinuous features were summarized with medians, interquartile ranges (IQRs), and ranges; categorical features were summarized with frequency counts and percentages. Patient characteristics, ED management, and outcomes were compared using Kruskal‐Wallis, chi‐square, and Fisher’s exact tests based on the type and distribution of the feature under study. Confidence intervals (CIs) for key frequency counts were computed using an asymptotic binomial approximation. Statistical analyses were performed using R version 3.6.2 (R Foundation for Statistical Computing, Vienna, Austria). All tests were two‐sided and p‐values < 0.05 were considered statistically significant. p‐values were not adjusted based on multiple comparisons.\n\nRESULTS\n\nParticipant identification\n\nA total of 458 ED patient visits between January 1, 2011, and December 31, 2018, had a diagnosis of olecranon or nonprepatellar bursitis. After exclusion criteria were applied, a total of 266 ED visits from 264 distinct patients with olecranon bursitis were included. A detailed flowchart of patient enrollment and outcomes is shown in Figure 1. Among the 266 patient visits, medical doctors were the providers for 227 (85.3%) of the visits, and the remaining visits were covered by advanced practice providers. There were 67 total providers included in our study.\n\nFIGURE 1 Patient enrollment and outcomes.1One patient had both a subsequent bursal aspiration and subsequent hospitalization for parenteral antibiotics. MRSA, methicillin‐resistant Staphylococcus aureus; MSSA, methicillin‐sensitive Staphylococcus aureus\n\nDescriptive data\n\nThe median (IQR) patient age of the cohort was 57 (42–69) years and 85% were male (Table 1). Swelling (94%), erythema (77%), and pain (85%) were the most common presenting symptoms. A total of 39 (15%) patients were taking steroids at the time of their ED visit and 37 (14%) had diabetes. Twenty‐four (9.0%) patients were lost to follow‐up, of which 20 (83%) were males with a median (IQR) age of 51.5 (40–65) years. A total of 229 (86%) had at least 3 months of follow‐up in the EMR and 220 (83%) had at least 6 months of follow‐up.\n\nTABLE 1 Olecranon bursitis patient and ED management based on ED bursal aspiration and ED disposition\n\nCharacteristic\tPatients, No. (%) a\t\nED bursal aspiration (n = 4)\tAdmitted (n = 39)\tDismissed with antibiotics (n = 147)\tDismissed without antibiotics (n = 76)\tAll patients (N = 266)\tp value e\t\nAge (years), median (IQR)\t45 (39–52)\t54 (42–61)\t58 (45–70)\t59 (47–69)\t57 (42–69)\t0.583\t\nSex\t\t\t\t\t\t0.041\t\nFemale\t0 (0)\t11 (28)\t21 (14)\t7 (9)\t39 (14.6)\t\t\nMale\t4 (100)\t28 (72)\t126 (86)\t69 (91)\t227 (85.3)\t\t\nRace\t\t\t\t\t\t0.503\t\nWhite\t4 (100)\t35 (90)\t138 (94)\t69 (91)\t246 (92.8)\t\t\nBlack\t0 (0)\t3 (8)\t3 (2)\t1 (1)\t7 (2.6)\t\t\nAsian\t0 (0)\t0 (0)\t1 (1)\t1 (1)\t2 (0.7)\t\t\nOther\t0 (0)\t1 (3)\t5 (3)\t5 (7)\t11 (4.1)\t\t\nED presentation\t\t\t\t\t\t\t\nReported fever\t2 (50)\t9 (23)\t17 (12)\t0 (0)\t28 (10.4)\t<0.001\t\nFever in ED\t0 (0)\t2 (5)\t2 (1)\t0 (0)\t4 (1.5)\t0.144\t\nErythema\t4 (100)\t39 (100)\t133 (91)\t28 (37)\t204 (77.0)\t<0.001\t\nCellulitis\t0 (0)\t17 (44)\t36 (24)\t4 (5)\t57 (21.4)\t<0.001\t\nWarmth\t3 (75)\t30 (77)\t97 (66)\t19 (25)\t149 (56.0)\t<0.001\t\nSwelling\t4 (100)\t37 (95)\t142 (97)\t67 (88)\t250 (94.0)\t0.070\t\nAbrasion/wound\t1 (25)\t9 (23)\t49 (33)\t7 (9)\t66 (24.8)\t<0.001\t\nTenderness\t3 (75)\t28 (72)\t100 (68)\t32 (42)\t163 (61.3)\t0.002\t\nPain\t4 (100)\t36 (92)\t126 (86)\t59 (78)\t225 (84.6)\t0.159\t\nComorbid conditions\t\t\t\t\t\t\t\nSteroids\t1 (25)\t5 (13)\t22 (15)\t11 (14)\t39 (14.6)\t0.677\t\nHIV\t0 (0)\t0 (0)\t1 (1)\t0 (0)\t1 (0.4)\t>0.99\t\nGout\t0 (0)\t4 (10)\t9 (6)\t9 (12)\t22 (8.2)\t0.420\t\nArthritis\t0 (0)\t2 (5)\t2 (1)\t0 (0)\t4 (1.5)\t0.136\t\nHistory of MRSA\t0 (0)\t2 (5)\t4 (3)\t1 (1)\t7 (2.6)\t0.474\t\nDiabetes\t0 (0)\t7 (18)\t17 (12)\t13 (17)\t37 (13.8)\t0.502\t\nOther immunocompromised\t0 (0)\t3 (8)\t2 (1)\t1 (1)\t6 (2.2)\t0.172\t\nImaging/laboratory values\t\t\t\t\t\t\t\nRadiograph\t2 (50)\t31 (80)\t88 (60)\t40 (53)\t161 (60.5)\t0.030\t\nUltrasound\t2 (50)\t2 (5)\t10 (7)\t1 (1)\t15 (5.6)\t0.007\t\nWBCs b (cells/mm3)\t10 (9–11)\n\n[N = 2]\n\n\t10 (7–12)\n\n[N = 38]\n\n\t10 (8–12)\n\n[N = 70]\n\n\t9 (8–10)\n\n[N = 13]\n\n\t10 (8–12)\n\n[N = 123]\n\n\t0.739\t\nCRP b (µg/dL)\t—\n\n[N = 0]\n\n\t50 (22–89)\n\n[N = 36]\n\n\t32 (14–50)\n\n[N = 53]\n\n\t11 (5–61)\n\n[N = 8]\n\n\t36 (14–62)\n\n[N = 97]\n\n\t0.006\t\nESR b (mm/h)\t—\n\n[N = 0]\n\n\t19 (10–41)\n\n[N = 32]\n\n\t11 (6–24)\n\n[N = 52]\n\n\t12 (7–41)\n\n[N = 7]\n\n\t14 (7–31)\n\n[N = 91]\n\n\t0.112\t\nED orthopedic consult\t0 (0)\t29 (74)\t36 (25)\t4 (5)\t69 (25.9)\t<0.001\t\nAntibiotics prescribed at dismissal\t4 (100)\t32 (82)\t147 (100)\t0 (0)\t183 (68.8)\t—\t\nCephalosporin (first/second generation)\t0 (0)\t10 (26)\t75 (51)\t0 (0)\t85 (32.0)\t—\t\nCephalosporin (third generation)\t0 (0)\t4 (10)\t1 (1)\t0 (0)\t5 (1.9)\t—\t\nPenicillin\t2 (50)\t1 (3)\t21 (14)\t0 (0)\t23 (8.6)\t—\t\nClindamycin\t1 (25)\t0 (0)\t11 (7)\t0 (0)\t12 (4.5)\t—\t\nTrimethoprim/sulfamethoxazole\t1 (25)\t5 (13)\t11 (7)\t0 (0)\t17 (6.4)\t—\t\nIV vancomycin\t0 (0)\t3 (8)\t2 (1)\t0 (0)\t5 (1.9)\t—\t\nDoxycycline\t0 (0)\t3 (8)\t6 (4)\t0 (0)\t9 (3.3)\t—\t\nOther\t0 (0)\t2 (5) c\t4 (3) d\t0 (0)\t7 (2.6)\t—\t\nCephalosporin + trimethoprim/sulfamethoxazole\t0 (0)\t2 (5)\t10 (7)\t0 (0)\t12 (4.5)\t—\t\nCephalosporin + doxycycline\t0 (0)\t1 (3)\t2 (1)\t0 (0)\t3 (1.1)\t—\t\nPenicillin + trimethoprim/sulfamethoxazole\t0 (0)\t1 (3)\t3 (2)\t0 (0)\t4 (1.5)\t—\t\nPenicillin + doxycycline\t0 (0)\t0 (0)\t1 (1)\t0 (0)\t1 (0.4)\t—\t\nInpatient antibiotics\t\t\t\t\t\t\t\nCephalosporin (first/second generation)\t0 (0)\t1 (3)\t0 (0)\t0 (0)\t1 (0.4)\t—\t\nTrimethoprim/sulfamethoxazole\t0 (0)\t1 (3)\t0 (0)\t0 (0)\t1 (0.4)\t—\t\nDoxycycline\t0 (0)\t1 (3)\t0 (0)\t0 (0)\t1 (0.4)\t—\t\nIV cefazolin\t0 (0)\t6 (15)\t0 (0)\t0 (0)\t6 (2.3)\t—\t\nIV trimethoprim/sulfamethoxazole\t0 (0)\t1 (3)\t0 (0)\t0 (0)\t1 (0.4)\t—\t\nIV vancomycin\t0 (0)\t15 (38)\t0 (0)\t0 (0)\t15 (5.6)\t—\t\nCephazolin + vancomycin\t0 (0)\t4 (10)\t0 (0)\t0 (0)\t4 (1.5)\t—\t\nCeftriaxone + vancomycin\t0 (0)\t3 (8)\t0 (0)\t0 (0)\t3 (1.1)\t—\t\nVancomycin + other\t0 (0)\t5 (13)\t0 (0)\t0 (0)\t5 (1.9)\t—\t\nLost to follow‐up\t1 (25)\t1 (3)\t13 (9)\t9 (12)\t24 (9.0)\t0.174\t\nAt least 6 months of follow‐up\t3 (75)\t34 (87)\t122 (83)\t61 (80)\t220 (82.7)\t0.792\t\nAt least 3 months of follow‐up\t3 (75)\t34 (87)\t128 (87)\t64 (84)\t229 (86.1)\t0.851\t\nNote\n\nData are reported as n (%) unless otherwise specified. SI conversion factors: To convert WBC to 109/L multiply by 1. To convert CRP to mg/L multiply by 10.\n\nAbbreviations: CRP, C‐reactive protein; ESR, erythrocyte sedimentation rate; HIV, human immunodeficiency virus; IQR, interquartile range; MRSA, methicillin‐resistant Staphylococcus aureus; WBC, white blood cell count.\n\na Unless otherwise noted.\n\nb Medians and IQRs are given only for patients with available data, indicated for each entry.\n\nc Both patients were dismissed on IV daptomycin.\n\nd Two of the four patients were dismissed with MRSA coverage (one IV daptomycin, one minocycline).\n\ne p‐values are from comparisons between the four disposition groups given in the table using Kruskal‐Wallis tests for continuous features and chi‐square or Fisher's exact tests for categorical features.\n\nJohn Wiley & Sons, Ltd\n\nED diagnostic evaluation and disposition\n\nDiagnostic evaluation included a white blood cell count in 123 (46%) patients, a sedimentation rate in 91 (34%), a C‐reactive protein (CRP) in 97 (36%), and an X‐ray in 161 (61%; Table 1). The orthopedic service was consulted in 69 (26%) of cases.\n\nOverall, among the 266 patients with olecranon bursitis, four (1.5%) patients underwent aspiration of the olecranon bursa during their ED visit. Of the 262 patients who were not aspirated in the ED, 39 (15%) were admitted to the hospital from the ED, 76 (29%) were dismissed from the ED without antibiotic therapy, and 147 (56%) were dismissed from the ED with antibiotic therapy for suspected septic olecranon bursitis (Figure 1). Two patients underwent arthrocentesis to assess for septic arthritis in the ED. Both were negative.\n\nComparison of patient characteristics based on ED disposition\n\nWhen patients were compared based on ED disposition, we found that the median (IQR) CRP was highest in patients admitted to the hospital (50 [22–89] µg/dL) and the lowest in patients dismissed without antibiotics (11 [5–61] mg/dL; Table 1). However, there was no significant difference between the median sedimentation rate or median white blood cell count based on disposition. Patients who were initially admitted to the hospital at the time of the index ED visit were the most likely to have reported a fever (23%), have associated cellulitis (44%), and have an orthopedics consult in the ED (74%). Among patients who were dismissed to home without antibiotics, none reported a fever or had a documented fever in the ED. In addition, patients dismissed without antibiotics had the lowest rates of erythema (37%), warmth (25%), and tenderness (42%).\n\nPost‐ED bursitis management and outcomes\n\nAmong the four (1.5%) patients who underwent bursal aspiration in the ED, one patient was lost to follow‐up (Table 2). This patient's aspiration culture grew methicillin‐sensitive Staphylococcus aureus. Of the remaining three patients, one aspiration culture grew methicillin‐resistant S. aureus, one grew group C Streptococcus, and one did not show microbial growth or crystals. There were no known complications from the bursal aspirations including future bursectomy or chronic fistula formation.\n\nTABLE 2 Patient outcomes based on ED bursal aspiration and ED disposition among patients with olecranon bursitis for whom follow‐up was available\n\nCharacteristic\tPatients a\t\nED bursal aspiration (n = 3)\tAdmitted (n = 38)\tDismissed with antibiotics (n = 134)\tDismissed without antibiotics (n = 67)\tAll patients (N = 242)\tp‐value d\t\nUncomplicated resolution\t2 (66)\t34 (89)\t118 (88)\t61 (91)\t215 (88.8)\t0.496\t\nSubsequent interventions\t\t\t\t\t\t\t\nSubsequent hospitalization\t1 (25)\t0 (0)\t9 (7)\t2 (3)\t12 (5.0)\t0.053\t\nBursal surgery\t0 (0)\t0 (0)\t0 (0)\t1 (1)\t1 (0.4)\t—\t\nSubsequent bursal aspiration\t0 (0)\t4 (10)\t8 (6)\t2 (3)\t14 (5.8)\t0.411\t\nIncision and drainage\t0 (0)\t0 (0)\t0 (0)\t1 (1)\t1 (0.4)\t0.446\t\nNon‐ED aspiration provider b\t\t\t\t\t\t—\t\nPrimary care\t0 (0)\t0 (0)\t3 (38)\t2 (100)\t5 (36)\t\t\nRheumatology\t0 (0)\t0 (0)\t3 (38)\t0 (0)\t3 (21)\t\t\nOrthopedics\t0 (0)\t3 (75)\t0 (0)\t0 (0)\t3 (21)\t\t\nOther\t0 (0)\t1 (25)\t2 (25)\t0 (0)\t3 (21)\t\t\nBursitis‐related subsequent visits\t2 (67)\t31 (82)\t79 (59)\t26 (39)\t139 (57.8)\t0.002\t\nSubsequent visits c\t\t\t\t\t\t\t\nPrimary care\t1 (50)\t21 (66)\t49 (61)\t19 (73)\t90 (64.3)\t\t\nRheumatology\t0 (0)\t0 (0)\t0 (0)\t1 (4)\t1 (0.7)\t\t\nOrthopedics\t0 (0)\t1 (3)\t3 (4)\t2 (8)\t6 (4.3)\t\t\nInfectious disease\t0 (0)\t6 (19)\t1 (1)\t0 (0)\t7 (5.0)\t\t\nED\t1 (50)\t1 (3)\t23 (29)\t3 (12)\t28 (20)\t\t\nOther or multiple\t0 (0)\t2 (6)\t3 (4)\t1 (4)\t6 (4.3)\t\t\nAntibiotic complications\t\t\t\t\t\t—\t\nAllergic reaction\t0 (0)\t0 (0)\t1 (1)\t0 (0)\t1 (0.4)\t\t\nAnaphylaxis\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t\t\nC. difficile colitis\n\n\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t\t\nClinically significant diarrhea\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t\t\nOther\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t\t\nNote\n\nData are reported as n (%).\n\na Unless otherwise noted.\n\nb Includes both outpatient and inpatient aspirations. Percentages are given relative to the number of follow‐up aspirations.\n\nc Percentages are given relative to the number of patients with bursitis‐related subsequent visits.\n\nd p‐values are from comparisons between the four disposition groups given in the table using Fisher's exact tests for categorical features.\n\nJohn Wiley & Sons, Ltd\n\nA total of 147 (55%) patients were dismissed home from the ED on empiric antibiotic therapy, including 48 (33%) with coverage for methicillin‐resistant S. aureus (Table 1). Among the 147 patients, 13 (8.8%) were lost to follow‐up. Among the 134 patients with follow‐up available, 118 (88.1%, 95% CI = 81.1%–92.8%) had an uncomplicated resolution and none required subsequent bursa surgery (Figure 1, Table 2). Eight (6.0%, 95% CI = 2.8%–11.8%) patients underwent a bursal aspiration after their ED visit. Of these eight patients, two had confirmed septic bursitis, one had inadequate fluid volume for analysis thought to be due to improvement on the antibiotics, and five had findings consistent with nonseptic bursitis. Nine (6.7%, 95% CI = 3.3%–12.7%) of the 134 patients had a subsequent hospital stay related to their septic bursitis. Among these patients, three (33%) had initially been dismissed from the ED with coverage for methicillin‐resistant S. aureus (MRSA). The median (IQR) time between the index ED visit and subsequent hospitalization was 2 (1–2) days. All of the patients with subsequent hospital stays received inpatient parenteral antibiotics with subsequent full resolution of the bursitis and none underwent bursal aspiration. Twenty‐three (17.2%, 95% CI = 11.4%–25.9%) patients who were dismissed from the ED on antibiotics had a subsequent bursitis‐related ED visit. Among these patients, five (21%) had initially been dismissed from the ED with coverage for MRSA. The median (IQR) time between the initial and subsequent ED visits was 2 (1–3) days. Known antibiotic complications were limited to a single patient who reported an allergic rash. If all patients who were lost to follow‐up were assumed to have had a complicated resolution, 118/147 (80.3%, 95% CI = 72.7%–86.2%) would have had an uncomplicated resolution.\n\nAmong the 76 (29%) patients who were dismissed from the ED without antibiotics, nine (12%) were lost to follow‐up. Among the 67 patients with follow‐up available, 65 (97%, 95% CI = 89%–99%) had resolution without any antibiotics, and 61 (91%, 95% CI = 81%–96%) had an uncomplicated resolution (i.e., did not require subsequent aspiration, hospitalization, or surgery; Figure 1, Table 2). One (1%, 95% CI = 0%–9%) patient underwent a subsequent therapeutic aspiration and one (1%, 95% CI = 0%–9%) patient underwent a subsequent diagnostic aspiration that yielded an inadequate sample for analysis and was believed to be nonseptic. One (1%, 95% CI = 0%–9%) patient underwent an olecranon bursectomy and partial ostectomy of the olecranon due to recurrent bursitis thought to be secondary to sports‐related overuse. One patient had a subsequent arthrocentesis to assess for septic arthritis, which was negative. Two (3%, 95% CI = 1%–11%) patients had a subsequent hospital stay and received inpatient antibiotics before obtaining a full resolution. Of the patients with a hospital stay, none underwent a bursal aspiration.\n\nAmong the 39 (15%) patients who were admitted to the hospital at the time of the index ED visit for inpatient antibiotic therapy, 30 (77%) were treated with antibiotics covering MRSA (Table 1). One patient was lost to follow‐up (Figure 1). Among the 38 patients for which follow‐up was available, 34 (89%, 95% CI = 74%–97%) had an uncomplicated resolution with only empiric antibiotics. Three (8%) of the 38 patients with follow‐up had resolution after aspiration during their admission. Two of the aspiration cultures grew methicillin‐sensitive S. aureus and one grew Prototheca wickerhamii. One (3%) patient among the 38 with follow‐up had a subsequent outpatient aspiration which was non‐septic. No patients underwent subsequent surgeries or hospital stays related to their olecranon bursitis (Table 2). Thirty‐one (82%) had a subsequent bursitis‐related outpatient follow‐up, including one (3%, 95% CI = 0%–15%) who had a subsequent bursitis‐related ED visit.\n\nDISCUSSION\n\nWe studied the management of ED patients presenting with acute olecranon bursitis and found that among 266 patients included in our study only four (1.5%) underwent bursal aspiration at the time of their initial ED visit. To our knowledge, this represents the largest study of ED patients with olecranon bursitis. Among patients who did not undergo bursal aspiration in the ED and were dismissed home on oral antibiotics for suspected septic olecranon bursitis, 88% had an uncomplicated resolution, 7% were subsequently hospitalized, and 6% subsequently underwent bursal aspiration, including two patients with confirmation of septic bursitis and five patients with septic bursitis ruled out. In addition, among patients admitted for suspected septic bursitis, 89% did not undergo bursal aspiration at any point and all of these patients had an uncomplicated resolution on antibiotics. Among patients dismissed without antibiotics, only two patients (3%) required subsequent hospitalization for parenteral antibiotics for a possible, although unconfirmed, septic bursitis. None of the patients in our cohort with confirmed or suspected septic bursitis went on to develop a chronic wound or require operative management. Taken together, these findings suggest that empiric antibiotic administration for suspected septic bursitis without bursal aspiration may be an appropriate first‐line management strategy among select ED patients with suspected septic olecranon bursitis who are reliable, understand return precautions, and are at low risk of antibiotic complications and treatment failure.\n\nWhile it is known that physical examination is not reliable for establishing the diagnosis of septic versus nonseptic bursitis, 5 it has not been established if bursal aspiration is necessary for definitive diagnosis or if empiric antibiotic administration is a reasonable initial approach for management of suspected septic olecranon bursitis at the time of ED evaluation. 5 Many guidelines advocate for bursal aspiration if there is suspicion of septic bursitis. 1 , 2 , 3 , 5 , 6 However, aspiration of the bursa has been shown to lead to potential complications including fistula formation, infection, and future bursectomies. 3 , 7 Fifty‐five percent of patients in our cohort were dismissed on empiric antibiotics, which is consistent with a prior ED study that found that approximately 50% of olecranon bursitis cases were septic. 2 A recent study of 30 patients referred to an orthopedic surgical department demonstrated that, among patients who had undergone an olecranon bursal aspiration for septic bursitis, 55% developed a chronic draining wound at the aspiration site and 73% went on to eventual bursectomy. 3 In comparison, none of the patients in that study who had been treated with empiric antibiotics went on to develop a chronic wound or require bursectomy. In another study of 31 patients admitted to the hospital for septic olecranon bursitis after undergoing bursal aspiration, 10% required an operative intervention. 10 Similarly, in a study of 22 ED patients with septic olecranon bursitis based on bursal aspirates, three (14%) patients developed a chronic fistula tract and one (4.5%) required incision and drainage. 2\n\nInitial management of suspected septic olecranon bursitis with empiric antibiotic management among ED patients has not been well described. Two findings in our study suggest that empiric antibiotics may be a reasonable initial management strategy, including: (1) 89% of the patients admitted to the hospital for empiric antibiotic management for whom follow‐up was available did not undergo bursal aspiration in the ED or after admission and 100% of these patients had an uncomplicated resolution, and (2) among patients dismissed on empiric antibiotics with follow‐up available, 88% of had an uncomplicated resolution. Additionally, if all of the 14 patients initially treated with empiric antibiotics without bursal aspiration who were lost to follow‐up were assumed to have experienced a complication, 82% would have had an uncomplicated resolution. Although findings among patients referred to an orthopedic surgical department, as discussed above, also favor empiric antibiotic management without bursal aspiration, they are not definitive given that the patient population was likely biased toward those with recalcitrant or complicated courses. 3\n\nContemporary studies of olecranon bursitis management among ED patients not undergoing bursal aspiration are lacking. A study conducted among patients with septic olecranon bursitis who had been referred to a home parenteral therapy program reported that 49% of patients with suspected septic bursitis were not aspirated and were only treated with antibiotics. They reported no difference in outcome among patients who were aspirated and those who were not, although 38% of those who underwent a drainage procedure required more than one drainage procedure. 11 Studies conducted several decades ago reported that among patients with septic bursitis treated with outpatient antibiotics, 38%–75% went on to require inpatient parenteral antibiotics. 12 , 13 In contrast, only 6% of patients treated with empiric outpatient antibiotics in our study went on to require hospitalization for inpatient antibiotics, although they were more likely to have a subsequent bursitis‐related ED visit.\n\nEmpiric antibiotic management has been criticized as possibly leading to lowered diagnostic accuracy and poor antibiotic stewardship. 11 Eight patients who were initially dismissed from the ED on empiric antibiotics in our study for suspected septic bursitis did not have resolution with empiric antibiotic therapy and underwent a subsequent aspiration. Five of these patients were found to have nonseptic bursitis. These patients as well as some patients who did have resolution after empiric antibiotics may have received antibiotics unnecessarily, placing them at unnecessary risk for antibiotic complications. With increasing antibiotic resistance and complications such as C. difficile colitis, these risks are important to consider when assessing the benefits of empiric antibiotic management. 14\n\nAmong patients who were dismissed home on empiric antibiotic coverage, 33% received MRSA coverage, in contrast to 77% of patients who were admitted to the hospital. This is likely because admitted patients were more systemically ill as demonstrated by higher rates of associated fever, cellulitis, and elevated CRP.\n\nOnly three patients in our cohort underwent arthrocentesis to assess for possible concomitant septic arthritis and none had septic arthritis. Rates of concomitant presentations of septic bursitis with septic arthritis have not been described, to our knowledge, likely because the presence of septic arthritis is often an exclusion criterion for studies of bursitis. 3 , 10 Furthermore, to our knowledge, there have been no studies evaluating the reliability of physical examination for distinguishing septic bursitis from septic arthritis. However, anecdotally, septic arthritis is typically suspected in the presence of substantial pain throughout range of motion while allowing for discomfort due to tension on the bursa with maximal flexion. 3\n\nLIMITATIONS\n\nOur study has several limitations. All patients were included retrospectively and the data quality is dependent on the accuracy of the medical records. To mitigate these limitations, we adhered to standardized guidelines for observational studies and used a data abstraction form that was designed to optimize precision and accuracy of collected variables and minimize random and systematic errors. Abstractors were not blinded to the study objectives. We conducted our study in a single quaternary care ED and most of our visits were covered by medical doctors. Practice patterns and provider distribution may vary at other institutions. Our ED has a robust follow‐up system and a high percentage of patients who have a primary care provider. This is not the case for all EDs. Because most patients did not undergo an aspiration of the bursa, some nonseptic cases could have been included in the cohort of suspected septic bursitis. An additional limitation was the lack of diversity in our patient population, which was predominantly white, limiting generalizability; however, 85% were males with a median age of 57 years, which is similar to prior studies. 3 , 15 Finally, 24 patients were lost to follow‐up and therefore outcomes for these patients are unknown.\n\nCONCLUSIONS\n\nEighty‐eight percent of ED patients with suspected septic olecranon bursitis treated with empiric outpatient antibiotics without aspiration had resolution without need for subsequent bursal aspiration, hospitalization, or surgery. Eighty‐nine percent of patients admitted to the hospital for empiric antibiotic management for whom follow‐up was available did not undergo bursal aspiration in the ED or after admission and 100% of these patients had an uncomplicated resolution. Our findings suggest that empiric antibiotics without bursal aspiration is a reasonable initial approach to ED management of select patients with suspected septic olecranon bursitis who have adequate access to follow‐up care, are immunocompetent, are able to tolerate oral antibiotics, and are at low risk for antibiotic complications.\n\nCONFLICT OF INTEREST\n\nThe authors have no potential conflicts to disclose.\n\nAUTHOR CONTRIBUTIONS\n\nStudy concept and design: Ronna L. Campbell, Kristina M. Colbenson, Benjamin J. Sandefur, Alexa L. Thomas, Adrian Beyde. Acquisition of data: Alexa L. Thomas, Adrian Beyde, Imtithal Kisirwan, Benjamin J. Sandefur, Ronna L. Campbell. Analysis and interpretation of the data: Ronna L. Campbell, Alexa L. Thomas, Aidan F. Mullan, Shawn W. O’Driscoll. Drafting of the manuscript: Ronna L. Campbell, Alexa L. Thomas, Aidan F. Mullan, Adrian Beyde. Critical revision of the manuscript: all authors. Statistical expertise: Aidan F. Mullan.\n\nACKNOWLEDGMENT\n\nThe authors thank Jennifer L. Condon for her assistance with data acquisition.\n==== Refs\nREFERENCES\n\n1 Lormeau C , Cormier G , Sigaux J , Arvieux C , Semerano L . Management of septic bursitis. Joint Bone Spine. 2019;86 :583‐588.31615686\n2 Stell IM . Management of acute bursitis: outcome study of a structured approach. J R Soc Med. 1999;92 :516‐521.10692903\n3 Deal JB Jr , Vaslow AS , Bickley RJ , Verwiebe EG , Ryan PM . Empirical treatment of uncomplicated septic olecranon bursitis without aspiration. J Hand Surg Am. 2020;45 :20‐25.31421940\n4 Sayegh ET , Strauch RJ . Treatment of olecranon bursitis: a systematic review. Arch Orthop Trauma Surg. 2014;134 :1517‐1536.25234151\n5 Baumbach SF , Lobo CM , Badyine I , Mutschler W , Kanz KG . Prepatellar and olecranon bursitis: literature review and development of a treatment algorithm. Arch Orthop Trauma Surg. 2014;134 :359‐370.24305696\n6 McFarland EG , Mamanee P , Queale WS , Cosgarea AJ . Olecranon and prepatellar bursitis: treating acute, chronic, and inflamed. Phys Sportsmed. 2000;28 :40‐52.\n7 Degreef I , De Smet L . Complications following resection of the olecranon bursa. Acta Orthop Belg. 2006;72 :400‐403.17009818\n8 Elm EV , Altman DG , Egger M , et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ. 2007;335 :806‐808.17947786\n9 Harris PA , Taylor R , Thielke R , Payne J , Gonzalez N , Conde JG . Research electronic data capture (REDCap)–a metadata‐driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42 :377‐381.18929686\n10 Lieber SB , Fowler ML , Zhu C , Moore A , Shmerling RH , Paz Z . Clinical characteristics and outcomes of septic bursitis. Infection. 2017;45 :781‐786.28555416\n11 Laupland KB , Davies HD ; Calgary Home Parenteral Therapy Program Study Group . Olecranon septic bursitis managed in an ambulatory setting. The Calgary Home Parenteral Therapy Program Study Group. Clin Invest Med. 2001;24 :171‐178.11558851\n12 Ho G Jr , Tice AD , Kaplan SR . Septic bursitis in the prepatellar and olecranon bursae: an analysis of 25 cases. Ann Intern Med. 1978;89 :21‐27.666181\n13 Raddatz DA , Hoffman GS , Franck WA . Septic bursitis: presentation, treatment and prognosis. J Rheumatol. 1987;14 :1160‐1163.3437425\n14 Frieri M , Kumar K , Boutin A . Antibiotic resistance. J Infect Public Health. 2017;10 :369‐378.27616769\n15 Garcia‐Porrua C , Gonzalez‐Gay MA , Ibanez D , Garcia‐Pais MJ . The clinical spectrum of severe septic bursitis in northwestern Spain: a 10 year study. J Rheumatol. 1999;26 :663‐667.10090179\n\n",
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"keywords": "aspiration; emergency department; management; olecranon bursitis; septic bursitis",
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"title": "Efficacy of empiric antibiotic management of septic olecranon bursitis without bursal aspiration in emergency department patients.",
"title_normalized": "efficacy of empiric antibiotic management of septic olecranon bursitis without bursal aspiration in emergency department patients"
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"abstract": "As immune checkpoint inhibitor drugs are being used in the treatment of some cancers, unusual adverse events are being reported, labeled as immune-related adverse events. Various endocrinopathies related to immune-related adverse events have been described, among which hypoparathyroidism is exceedingly rare. We report a case of hypoparathyroidism induced by immune checkpoint drugs, highlighting the need for awareness of this emerging complication.",
"affiliations": "Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester, MN.;Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester, MN.;Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester, MN.;Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester, MN.",
"authors": "El Kawkgi|Omar M|OM|;Li|Dingfeng|D|;Kotwal|Anupam|A|;Wermers|Robert A|RA|",
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"doi": "10.1016/j.mayocpiqo.2020.07.006",
"fulltext": "\n==== Front\nMayo Clin Proc Innov Qual Outcomes\nMayo Clin Proc Innov Qual Outcomes\nMayo Clinic Proceedings: Innovations, Quality & Outcomes\n2542-4548\nElsevier\n\nS2542-4548(20)30132-6\n10.1016/j.mayocpiqo.2020.07.006\nCase Report\nHypoparathyroidism: An Uncommon Complication Associated With Immune Checkpoint Inhibitor Therapy\nEl Kawkgi Omar M. MB, BCh, BAO Elkawkgi.Omar@mayo.edu\n∗\nLi Dingfeng MD, MSc\nKotwal Anupam MBBS\nWermers Robert A. MD\nDivision of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester, MN\n∗ Correspondence: Address to Omar M. El Kawkgi, MB, BCh, BAO, Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic, 200 First St SW, Rochester, MN 55905 Elkawkgi.Omar@mayo.edu\n03 11 2020\n12 2020\n03 11 2020\n4 6 821825\n© 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.\n2020\nMayo Foundation for Medical Education and Research\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nAs immune checkpoint inhibitor drugs are being used in the treatment of some cancers, unusual adverse events are being reported, labeled as immune-related adverse events. Various endocrinopathies related to immune-related adverse events have been described, among which hypoparathyroidism is exceedingly rare. We report a case of hypoparathyroidism induced by immune checkpoint drugs, highlighting the need for awareness of this emerging complication.\n\nAbbreviations and Acronyms\n\nCaSR, calcium-sensing receptor\nICI, immune checkpoint inhibitor\nirAE, immune-related adverse event\nPD-1, programmed cell death protein 1\nPTH, parathyroid hormone\n==== Body\nImmune checkpoint molecules such as cytotoxic T-lymphocyte–associated protein 4 and programmed cell death protein 1 (PD-1) have been identified as critical factors in cancer pathogenesis, leading to a revolution in cancer therapy with the use of immune checkpoint inhibitor (ICI) drugs.1 Immune checkpoint inhibitor drugs are currently being used to target these molecules to modulate T-cell function and employ the immune response in the treatment of several solid and hematological malignancies.2 However, as immune checkpoints are closely involved in the maintenance of immunological tolerance to self-antigens, ICIs have been associated with autoimmune-like manifestations, referred to as immune-related adverse events (irAEs).3 Endocrinopathies including hypothyroidism, hyperthyroidism, hypophysitis, primary adrenal insufficiency, and autoimmune diabetes mellitus are among the more commonly reported events.4 As the use of ICIs increases, the incidence of such events is expected to rise and the spectrum of described irAEs may broaden to include other rarely reported conditions.5 Hypoparathyroidism with ICI use is an exceedingly rare endocrine complication with only 3 previous cases reported.6, 7, 8 We report a case of hypoparathyroidism along with hypophysitis in the setting of ipilimumab (anti–cytotoxic T-lymphocyte–associated protein 4 therapy) and nivolumab (anti–PD-1 therapy) use, illustrating the need for clinicians to consider this complication vigilantly and call for further research to focus on its management, including identification of those patients at highest risk.\n\nCase Report\n\nA 76-year-old man presented to the emergency department with symptoms of weakness, anorexia, and confusion of 1 week in duration. His history was remarkable for widespread metastatic melanoma to the pericardium, lung, liver, and lymph nodes for which he had been receiving combination immunotherapy with ipilimumab plus nivolumab 7 months earlier. Within 2 months of the initiation of this therapy, he developed irAEs of colitis and pneumonitis for which immunotherapy had been held. Approximately 4 months later, he was switched to nivolumab monotherapy. He received 2 infusion cycles, with the last dose given 28 days before our evaluation (Figure).Figure Serum levels of calcium, phosphate, and parathyroid hormone (PTH) over the course of immune checkpoint inhibitor therapy. Time expressed as days relative to presentation. irAE = immune-related adverse event.\n\nOn presentation, his vital signs were significant for a blood pressure of 93/48 mm Hg. Physical examination was unremarkable with negative Chovstek and Trousseau signs.\n\nLaboratory evaluation found severe hypocalcemia with a total serum calcium level of 5.7 mg/dL (reference range, 8.8-10.2 mg/dL), a serum albumin level of 3.0 g/dL (reference range, 3.5-5.0 g/dL), an albumin-corrected calcium level of 6.5 mg/dL, hyperphosphatemia with a serum phosphorus level of 5.1 mg/dL (reference range, 2.5-4.5 mg/dL), and a normal serum magnesium level of 1.7 mg/dL (reference range, 1.7-2.3 mg/dL). The serum creatinine level was 1.18 mg/dL (reference range, 0.74- 1.35 mg/dL). The serum ionized calcium level was 3.01 mg/dL (reference range, 4.57-5.43 mg/dL), further confirming hypocalcemia. In addition, he was found to have hyponatremia with a serum sodium level of 118 mmol/L (reference range, 135-145 mmol/L).\n\nElectrocardiogram was remarkable for a prolonged QT-corrected interval (corrected using the Bazett formula) of 492 ms. He was immediately treated with a total of 3 g of intravenous calcium gluconate and normal saline infusion.\n\nFurther workup found an undetectable serum parathyroid hormone (PTH) level of less than 6.0 pg/mL (reference range, 15-65 pg/mL) and a normal serum total 25-hydroxyvitamin D level of 31 ng/mL. A 1,25-dihydroxyvitamin D level was not measured. He was diagnosed with primary hypoparathyroidism. He denied any history of neck surgery or head and neck radiation. Anti-parathyroid antibody, a clinically available test performed by radiobinding assay (Quest Diagnostics), previously recognized in some cases of autoimmune hyopoparathyroidism, was undetectable in this case. Anti–calcium-sensing receptor (CaSR)–activating antibodies were not measured. Notably, his calcium level had been within the normal range until this presentation (Figure). The median serum calcium and creatinine levels over a time period of 5 years before any ICI therapy was 9.3±0.23 and 1.29±0.27 mg/dL, respectively. The parathyroid hormone level 6 years before presentation was normal at 49 pg/mL.\n\nGiven concerns for other endocrinopathies, particularly adrenal insufficiency due to noted hyponatremia, the morning cortisol level was checked, which was low at 2.0 μg/dL (reference range, 7-25 μg/dL). Additionally, the serum corticotropin level was inappropriately normal at 8.3 pg/mL (reference range, 7.2-63 pg/mL). Magnetic resonance imaging of the brain did not reveal any pituitary or hypothalamic abnormalities. Both thyroid-stimulating hormone and free T4 levels were normal at 2.9 mIU/L (reference range, 0.3-4.2 mIU/L) and 1.1 ng/dL (reference range, 0.9-1.7 ng/dL), respectively. Other hypothalamic-pituitary hormones were not assessed.\n\nThe patient began treatment with 500 mg of calcium carbonate (elemental calcium) 3 times daily and 1000 IU of cholecalciferol daily, with improvement in his serum calcium level over the course of 3 days (Figure). Given the absence of PTH and the resultant impairment of 1-alpha-hydroxylation of 25 hydroxyvitamin D, 0.25 μg of calcitriol twice daily was also initiated concurrently. Hydrocortisone replacement was initiated with good clinical response in blood pressure, sodium levels, and symptoms. After 22 days of initiating this regimen, the serum calcium level was 8.1 mg/dL with a serum albumin level of 4.0 g/dL and a 24-hour urine calcium level of 198 mg/24 h.\n\nDiscussion\n\nAcute hypocalcemia is a potentially life-threatening metabolic disturbance that requires prompt recognition and treatment. Because calcium in serum is 40% protein bound, with albumin accounting for 90% of protein binding, measurement of the albumin level is essential in the assessment of hypocalcemia. In cases in which the albumin level is abnormal, as in this case, the serum calcium level can be corrected for the albumin level by using a standard formula whereby each 1 g/dL reduction in the serum albumin concentration will lower the total calcium concentration by approximately 0.8 mg/dL. In practice, however, some observational evidence suggests that the diagnostic accuracy of uncorrected calcium is superior to corrected calcium in reflecting true calcium status.9 Measurement of the ionized calcium level can also be used as a more direct evaluation of calcium status, although limitations include difficulties in accurate analysis, lack of standardization, and need for special handling of specimens. Despite correction and measurement of the ionized calcium level, the serum calcium level remained low by both measures in this patient, confirming true hypocalcemia. Once hypocalcemia is confirmed, PTH levels should be measured. In the absence of PTH or in circumstances of low to normal PTH levels despite hypocalcemia, hypoparathyroidism must be considered.10 Hypoparathyroidism should be distinguished from pseudohypoparathyroidism or hypocalcemia secondary to hypomagnesemia, both of which can also be characterized by a low serum calcium level. However, these can be distinguished by PTH levels. In pseudohyoparathyroidism, PTH levels may be elevated because of PTH resistance, whereas hypomagnesaemia may impair PTH secretion, leading to low PTH levels.11,12 Hypoparathyroidism is a rare disorder with an estimated incidence of 23 to 37 cases per 100,000 person-years. The condition is most commonly seen as a complication of anterior neck surgery (75% of cases), but increasingly other etiologies including genetic and autoimmune causes are being reported.11,12 Conventionally, autoimmune hypoparathyroidism can occur as an isolated endocrinopathy or as a component of autoimmune polyendocrine syndrome type 1.12 With use of ICI in the treatment of cancer, the condition is being seen in association with ICI blockade but has been described only 3 times previously.6, 7, 8\n\nGiven the lack of other associated causes of hypoparathyroidism, late age of onset, and absence of other autoimmune polyendocrine syndrome features, combined with the temporal relationship between ICI therapy and other associated irAEs including hypophysitis with secondary adrenal insufficiency, we believe this case illustrates hypoparathyroidism as a rare complication associated with ipilimumab and nivolumab therapy. Although his pituitary on magnetic resonance imaging was unremarkable, pituitary enlargement can be seen in ICI drug–associated hypophysitis combined with headache and hypopituitarism.13 Although this combination of drugs has been found to improve progression-free survival in melanoma, it may be associated with an increase in irAEs, specifically in 1 meta-analysis at an incidence of 55%, compared with 27% or 16% for nivolumab or ipilimumab monotherapy, respectively.14 With regard to hypophysitis, which our patient also developed, there is a 2.2-fold increased risk of developing this complication when receiving combination therapy compared with monotherapy.5 Moreover, endocrine complications present earlier with combination therapy (30 days) in comparison to 76 days in those treated with a single agent (ipilimumab).15 Other PD-1 inhibitors have been associated with hypocalcemia in a meta-analysis as a rare complication affecting 11 of 604 patients.16 Our patient also had previously reported irAEs (colitis and pneumonitis), which may be of importance as a predictor of developing additional irAEs.17 Whether this patient’s course of combination therapy followed by nivolumab monotherapy created a cumulative toxicity effect is difficult to ascertain on the basis of the current literature.\n\nThe mechanism of irAE-related hypoparathyroidism remains unclear, but it is postulated that autoantibodies may play a role. Anti-parathyroid and CaSR-activating autoantibodies have been implicated in autoimmune hypoparathyroidism.18 Indeed, CaSR-activating autoantibodies were detected in a patient with primary hypoparathyroidism receiving nivolumab.6 Anti-parathyroid antibodies have been described in patients with autoimmune endocrine conditions such as Addison disease and Hashimoto thyroiditis as well as in cases of idiopathic hyoparathyroidism19 and animal models of autoimmune hypoparathyroidism.20 However, in the previously reported case, when common autoantibody targets of autoimmune polyendocrine syndrome type 1 were assessed in the same individual with anti–CaSR-stimulating autoantibodies, they were undetectable. Notably, anti-parathyroid antibodies were also negative in our patient but anti-CaSR antibodies were not measured. Further research is needed to elucidate the role of these various antibodies and whether ICI-associated hypoparathyroidism may be due to a destructive immune process as may occur in other endocrinopathies.\n\nUnlike other irAEs, endocrinopathies often require lifelong treatment with permanent hormone replacement for unclear reasons. In 1 study of patients who received ipilimumab, 85% required long-term treatment, primarily with thyroid and corticosteroid hormone replacement.21 In our case, 77 days after ICI use, PTH remained undetectable and the patient continues to require 500 mg of elemental calcium 3 times daily and 0.25 μg of calcitriol twice daily to maintain his serum calcium within a satisfactory range. Persistence of hypoparathyroidism despite discontinuation of ICI drugs has been previously recognized.8\n\nSummary\n\n• Immune checkpoint inhibitor drugs are currently being used to employ the immune response in the treatment of several solid and hematological malignant neoplasms and are associated with improved survival. However, they are associated with autoimmune-like manifestations, referred to as immune-related adverse events (irAEs).\n\n• Hypoparathyroidism is a rare but emerging irAE of immune checkpoint inhibitor drugs, which clinicians need to recognize in patients with acute hypocalcemia.\n\n• Multiple irAEs can occur simultaneously, and diagnosis of 1 irAE should heighten the surveillance for other irAEs.\n\nPatient’s Perspective\n\n“My battle with cancer started 7 years ago and as it got worse I am happy these drugs [ICI] kept me alive for the last year. I remember when they wanted me to start them they gave me 10 pages on the side effects. You just say yes because you are desperate. Now I am alive but unhappy with what these drugs left me with. I wish my case can show others what can happen and teach them to look out for this.”\n\nConclusion\n\nIn an era of novel immuno-oncology treatments, one needs to consider ICI blockade–mediated hypoparathyroidism in those presenting with hypocalcemia. Particular attention may be needed for patients who received combination ICI and have had previous irAEs. Future studies should focus on understanding the mechanism of ICI-associated hypoparathyroidism, predicting factors, and long-term outcome with such events.\n\nORCID\n\nOmar M. El Kawkgi: https://orcid.org/0000-0003-2923-6829\n\nDingfeng Li: https://orcid.org/0000-0001-5795-0419\n\nAnupam Kotwal: https://orcid.org/0000-0002-4500-8546\n\nAcknowledgments\n\nWe thank our patient for kindly offering his perspective and allowing us to share this case for the purpose of our education.\n\nPotential Competing Interests: The authors report no competing interests.\n==== Refs\nReferences\n\n1 Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy Nat Rev Cancer 12 4 2012 252 264 22437870\n2 Kumar V. Chaudhary N. Garg M. Floudas C.S. Soni P. Chandra A.B. Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy [published correction appears in Front Pharmacol. 2017;8:311] Front Pharmacol 8 2017 49 28228726\n3 Postow M.A. Sidlow R. Hellmann M.D. Immune-related adverse events associated with immune checkpoint blockade N Engl J Med 378 2 2018 158 168 29320654\n4 Byun D.J. Wolchok J.D. Rosenberg L.M. Girotra M. Cancer immunotherapy—immune checkpoint blockade and associated endocrinopathies Nat Rev Endocrinol 13 4 2017 195 207 28106152\n5 Barroso-Sousa R. Barry W.T. Garrido-Castro A.C. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis JAMA Oncol 4 2 2018 173 182 28973656\n6 Piranavan P. Li Y. Brown E. Kemp E.H. Trivedi N. Immune checkpoint inhibitor-induced hypoparathyroidism associated with calcium-sensing receptor-activating autoantibodies J Clin Endocrinol Metab 104 2 2019 550 556 30252069\n7 Win M.A. Thein K.Z. Qdaisat A. Yeung S.C.J. Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism Am J Emerg Med 35 7 2017 1039.e5 1039.e7\n8 Trinh B. Sanchez G.O. Herzig P. Läubli H. Inflammation-induced hypoparathyroidism triggered by combination immune checkpoint blockade for melanoma J Immunother Cancer 7 1 2019 52 30791949\n9 Lian I.A. Åsberg A. Should total calcium be adjusted for albumin? A retrospective observational study of laboratory data from central Norway BMJ Open 8 4 2018 e017703\n10 Cooper M.S. Gittoes N.J. Diagnosis and management of hypocalcaemia [published correction appears in BMJ. 2008;336(7659)] BMJ 336 7656 2008 1298 1302 18535072\n11 Gafni R.I. Collins M.T. Hypoparathyroidism N Engl J Med 380 18 2019 1738 1747 31042826\n12 Shoback D.M. Bilezikian J.P. Costa A.G. Presentation of hypoparathyroidism: etiologies and clinical features J Clin Endocrinol Metab 101 6 2016 2300 2312 26943721\n13 Faje A. Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights Pituitary 19 1 2016 82 92 26186958\n14 De Velasco G. Je Y. Bosse D. Comprehensive meta-analysis of key immune-related adverse events from CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients [published correction appears in Cancer Immunol Res. 2018;6(4):498-499] Cancer Immunol Res 5 4 2017 312 318 28246107\n15 Scott E.S. Long G.V. Guminski A. Clifton-Bligh R.J. Menzies A.M. Tsang V.H. The spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors for metastatic melanoma Eur J Endocrinol 178 2 2018 173 180 29187509\n16 Manohar S. Kompotiatis P. Thongprayoon C. Cheungpasitporn W. Herrmann J. Herrmann S.M. Programmed cell death protein 1 inhibitor treatment is associated with acute kidney injury and hypocalcemia: meta-analysis Nephrol Dial Transplant 34 1 2019 108 117 29762725\n17 Gowen M.F. Giles K.M. Simpson D. Baseline antibody profiles predict toxicity in melanoma patients treated with immune checkpoint inhibitors J Transl Med 16 1 2018 82 29606147\n18 Brown E.M. Anti-parathyroid and anti-calcium sensing receptor antibodies in autoimmune hypoparathyroidism Endocrinol Metab Clin North Am 38 2 2009 437 445 19328421\n19 Blizzard R.M. Chee D. Davis W. The incidence of parathyroid and other antibodies in the sera of patients with idiopathic hypoparathyroidism Clin Exp Immunol 1 2 1966 119 128 5330781\n20 Brandi M.L. Aurbach G.D. Fattorossi A. Quarto R. Marx S.J. Fitzpatrick L.A. Antibodies cytotoxic to bovine parathyroid cells in autoimmune hypoparathyroidism Proc Natl Acad Sci U S A 83 21 1986 8366 8369 3534888\n21 Weber J.S. Dummer R. de Pril V. Lebbé C. Hodi F.S. MDX010-20 Investigators. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma Cancer 119 9 2013 1675 1682 23400564\n\n",
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"issn_linking": "2542-4548",
"issue": "4(6)",
"journal": "Mayo Clinic proceedings. Innovations, quality & outcomes",
"keywords": "CaSR, calcium-sensing receptor; ICI, immune checkpoint inhibitor; PD-1, programmed cell death protein 1; PTH, parathyroid hormone; irAE, immune-related adverse event",
"medline_ta": "Mayo Clin Proc Innov Qual Outcomes",
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"pages": "821-825",
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"pmid": "33367219",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "26943721;30791949;23400564;28228726;31042826;29320654;28106152;30252069;19328421;28973656;18535072;29762725;26186958;28363614;28246107;29187509;22437870;29627804;5330781;3534888;29606147",
"title": "Hypoparathyroidism: An Uncommon Complication Associated With Immune Checkpoint Inhibitor Therapy.",
"title_normalized": "hypoparathyroidism an uncommon complication associated with immune checkpoint inhibitor therapy"
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"abstract": "OBJECTIVE\nTo report the clinical features and prognosis of drug-associatedacute respiratory distress syndrome (ARDS).\n\n\nMETHODS\nA retrospective analysis of data collected during a prospective cohort study.\n\n\nMETHODS\nIntensive care unit in a teaching hospital.\n\n\nMETHODS\nA total of 197 Japanese patients with ARDS diagnosed by the Berlin definition who were admitted to the Division of Respiratory Medicine from October 2004 to December 2015 were enrolled in the study and were classified as two groups according to their causes: a drug-associated ARDS group (n=27) and a non-drug-associated ARDS group (n=170). Primary outcome measure is 28-day mortality, and the secondaryoutcome measure is ventilator-free days.\n\n\nRESULTS\nThe Acute Physiology and Chronic Health Evaluation II scores were significantly lower in the drug-associated ARDS group than in the non-drug-associated ARDS group (median (IQR): 18.0 (16.5-21.0) vs 23.0 (18.0-26.0), p<0.001), and the arterial oxygen tension/fractional inspired oxygen ratio was higher (148.0 (114.1-177.5) vs 101.0 (71.5-134.0), p=0.003). In the drug-associated ARDS group, although high-resolution CT scores indicative of the extent of fibroproliferation (301.6 (244.1-339.8) vs 208.3 (183.4-271.6), p<0.001), serum lactate dehydrogenase levels (477 (365-585) vs 322 (246-434), p=0.003) and the McCabe scores (score 1/2/3, n (%): 20 (74)/4 (15)/3 (11)vs154 (91)/7 (4)/9 (5), p=0.04) were significantly higher, ventilator weaning was earlier (p<0.001) and 28-day mortality was better (p=0.043). After adjusting for potentially confounding covariates, drug-associated ARDS group was associated with lower 28-day mortality (adjusted HR (HR) 0.275; 95% CI 0.106 to 0.711; p=0.008).\n\n\nCONCLUSIONS\nAlthough more severe lung damage with fibroproliferation was observed in patients with drug-associated ARDS, ventilator weaning was earlier, and their prognosis was better than the others. Further well-designed prospective studies are needed.",
"affiliations": "Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan.;Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan.;Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan.;Department of Radiology, Kiniki Central Hospital of Mutual Aid Association of Public School Teachers, Itami, Hyogo, Japan.;Department of Radiology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.;Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan.",
"authors": "Anan|Keisuke|K|;Ichikado|Kazuya|K|;Kawamura|Kodai|K|;Johkoh|Takeshi|T|;Fujimoto|Kiminori|K|;Suga|Moritaka|M|",
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"fulltext": "\n==== Front\nBMJ OpenBMJ OpenbmjopenbmjopenBMJ Open2044-6055BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bmjopen-2016-01533010.1136/bmjopen-2016-015330Respiratory MedicineResearch15061731Clinical characteristics and prognosis of drug-associated acute respiratory distress syndrome compared with non-drug-associated acute respiratory distress syndrome: a single-centre retrospective study in Japan Anan Keisuke 1Ichikado Kazuya 1Kawamura Kodai 1Johkoh Takeshi 2Fujimoto Kiminori 34Suga Moritaka 11 Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan2 Department of Radiology, Kiniki Central Hospital of Mutual Aid Association of Public School Teachers, Itami, Hyogo, Japan3 Department of Radiology, Kurume University School of Medicine, Kurume, Fukuoka, Japan4 Center for Diagnostic Imaging, Kurume University Hospital, Kurume, Fukuoka, JapanCorrespondence to Dr Keisuke Anan; keisuke-anan@saiseikaikumamoto.jp2017 8 11 2017 7 11 e01533002 1 2017 30 8 2017 20 9 2017 © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.2017This 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 and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Objectives\nTo report the clinical features and prognosis of drug-associatedacute respiratory distress syndrome (ARDS).\n\nDesign\nA retrospective analysis of data collected during a prospective cohort study.\n\nSetting\nIntensive care unit in a teaching hospital.\n\nParticipants\nA total of 197 Japanese patients with ARDS diagnosed by the Berlin definition who were admitted to the Division of Respiratory Medicine from October 2004 to December 2015 were enrolled in the study and were classified as two groups according to their causes: a drug-associated ARDS group (n=27) and a non-drug-associated ARDS group (n=170). Primary outcome measure is 28-day mortality, and the secondaryoutcome measure is ventilator-free days.\n\nResults\nThe Acute Physiology and Chronic Health Evaluation II scores were significantly lower in the drug-associated ARDS group than in the non-drug-associated ARDS group (median (IQR): 18.0 (16.5–21.0) vs 23.0 (18.0–26.0), p<0.001), and the arterial oxygen tension/fractional inspired oxygen ratio was higher (148.0 (114.1–177.5) vs 101.0 (71.5–134.0), p=0.003). In the drug-associated ARDS group, although high-resolution CT scores indicative of the extent of fibroproliferation (301.6 (244.1–339.8) vs 208.3 (183.4–271.6), p<0.001), serum lactate dehydrogenase levels (477 (365–585) vs 322 (246–434), p=0.003) and the McCabe scores (score 1/2/3, n (%): 20 (74)/4 (15)/3 (11)vs154 (91)/7 (4)/9 (5), p=0.04) were significantly higher, ventilator weaning was earlier (p<0.001) and 28-day mortality was better (p=0.043). After adjusting for potentially confounding covariates, drug-associated ARDS group was associated with lower 28-day mortality (adjusted HR (HR) 0.275; 95% CI 0.106 to 0.711; p=0.008).\n\nConclusions\nAlthough more severe lung damage with fibroproliferation was observed in patients with drug-associated ARDS, ventilator weaning was earlier, and their prognosis was better than the others. Further well-designed prospective studies are needed.\n\nAcute Respiratory Distress SyndromeDrug Associated Lung DiseaseAdultspecial-featureunlocked\n==== Body\nStrengths and limitations of this study\nAll data were collected prospectively as part of an ongoing high-resolution CT study in acute respiratory distress syndrome (ARDS).\n\nThe first report on the prognostic factors associated with drug-associated ARDS (DARDS) performed for the purpose of elucidating differences in the clinical characteristics of DARDS and non-DARDS.\n\nThis is a single-centre, retrospective cohort study, and the number of patients in the DARDS group was relatively small.\n\nThere are some difficulties in judging whether a certain drug is causative in drug-associated ARDS group and whether underlying illness is actually ARDS.\n\nApproximately half of the cases underwent bronchoalveolar lavage, and no histopathological investigations were performed.\n\nIntroduction\nAcute respiratory distress syndrome (ARDS) is a condition that presents with acute respiratory failure and has a poor prognosis. Most cases are evidently due to infectious diseases such as pneumonia or sepsis.\n\nCertain drugs are also reportedly capable of causing ARDS. For example, it has been reported that some new molecular target drugs such as gefitinib, amiodarone and dipeptidyl peptidase 4 inhibitor can induce severe interstitial lung disease.1–3 There are also reports of severe respiratory failure or ARDS resulting from the use of drugs such as methotrexate4 and certain herbal medicines.5 Most of these reports were case studies, and there are very few reports on the incidence or prognosis of drug-associated ARDS (DARDS). It has been reported that the hospital mortality rate of patients with drug-induced ‘diffuse alveolar damage (DAD)’, which has been the strongest prognostic factor in ARDS, diagnosed by surgical lung biopsy was only 17%.6 We hypothesised that clinical characteristics would differ between DARDS and non-drug-associated ARDS (non-DARDS), and patients with DARDS would have better outcomes. However, since the Berlin definition of ARDS was published in 2012,7 there have been no reports of definitively confirmed DARDS. In the current study, we compared the clinical characteristics of DARDS with those of non-DARDS.\n\nMaterials and methods\nPatients\nThis was a retrospective analysis of data collected during an ongoing prospective cohort study of ARDS with high-resolution CT (HRCT), some of which have been published previously.8 9 A total of 197 Japanese patients with ARDS diagnosed by the Berlin definition7 were admitted to the Division of Respiratory Medicine at our hospital from October 2004 to December 2015. Our hospital is an acute medicine teaching hospital in an urban area, with 400 beds. We reviewed the patients with ARDS using the prior ARDS definition10 before 2012 and included those patients that met the criteria. Written informed consent was obtained from all patients or their families. Details of excluded cases are shown in the CONSORT diagram (figure 1). We did not include patients with chronic interstitial lung disease including idiopathic pulmonary fibrosis, those with vasculitis or alveolar haemorrhage or those diagnosed with acute organising pneumonia, hypersensitivity pneumonitis or acute eosinophilic pneumonia.\n\nFigure 1 Flow chart of the study design.\n\nDefinition of DARDS\nWe classified the patients with ARDS into DARDS group and non-DARDS groups according to ARDS aetiology. We used the definition of drug-associated acute lung injury (DALI) described by Dhokarh et al11 using traditional risk factors for acute lung injury (ALI): sepsis, septic shock, pneumonia, pancreatitis, trauma, massive blood transfusion and gastric aspiration. Probable DALI was considered in patients with no established ALI risk factors except specific drug exposure within 1 year. Patients with possible DALI had at least one risk factor for ALI and a history of specific drug exposure within 1 year. Those with conditional DALI had received drugs not previously reported to cause ALI but with similarity to known causative agents. Non-DALI patients who were not exposed to drugs reported or assumed to cause ALI. Drug exposure data in the year prior to ARDS onset was obtained from ‘medicine notebooks’ that list all drugs prescribed to the patients. This is a unique system in Japan.\n\nTreatment\nVentilator management and ventilator weaning were conducted in accordance with evidence-based guidelines12 with reference to the lower tidal volume (VT) strategy and predicted body weight (PBW) (6 mL/kg PBW < VT < 8 mL/kg PBW) in the ARDS Clinical Trial13 and to the guidelines for weaning and discontinuing ventilatory support from the American College of Chest Physicians.14 Plateau pressure was limited to less than 30 cmH2O, with a positive end-expiratory pressure (PEEP) of 8–12 cmH2O. At the first day, PEEP, peak inspiratory pressure and VT were daily recorded. High-dose corticosteroids therapy was defined that the patient was administered more than 2 mg/kg/day. There were no patients treated with extracorporeal membrane oxygenation therapy in this study cohort.\n\nComparison of prognostic factors and outcome\nWe performed a comparative investigation using patient age, gender, 28-day mortality, duration of mechanical ventilation, Acute Physiology and Chronic Health Evaluation (APACHE) II score, sequential organ failure assessment (SOFA) score, HRCT score indicative of the extent of fibroproliferation,8 McCabe score, arterial oxygen tension (PaO2)/fractional inspired oxygen (FiO2) ratio and blood test results. As previously published,15 HRCT score was graded on a scale of 1–6: score of 1: normal attenuation; score of 2: ground-glass attenuation; score of 3: consolidation; score of 4: ground-grass attenuation with traction bronchiolectasis or bronchiectasis; score of 5: consolidation with traction bronchiolectasis or bronchiectasis and score of 6: honeycombing. The presence of each of these six abnormalities was assessed independently in upper, middle and lower zones of each lung. The extent of each abnormality was determined by visually estimating the percentage of the affected lung parenchyma in each zone. Each abnormality score was calculated by multiplying the percentage area by each grading score. The six zone scores were averaged to determine the total score for each abnormality in each patient. The overall CT score was obtained by adding the six averaged scores. The McCabe score was recorded as one of three possible values: non-fatal: score 1; near-fatal: score 2; fatal: score 3.16 The primary outcome was 28-day mortality, and the secondary outcome was the duration of mechanical ventilation.\n\nStatistical analysis\nContinuous variables were expressed as the median values and IQR. In the univariate analysis of the two groups, categorical variables were compared using the χ2 test or Fisher’s exact test, and continuous variables were compared using the Mann-Whitney test. Clinically significant variables with a p Value <0.05 at univariate analysis were included in the multivariate analysis. We excluded the variables that had an r value of >0.4 in the factor analysis from multivariate analysis. The multivariate analysis was performed using a Cox proportional hazard model with a backward-selection procedure. Unadjusted and adjusted survival curves were plotted using the Kaplan-Meier method. Log-rank tests were used to compare differences in survival. The time to successful discontinuation of mechanical ventilation was also evaluated. We also estimated adjusted relationships between diagnosing DARDS and outcome using the Cox proportional hazards regression model via inverse probability of treatment weighting (IPTW) using a propensity score. The propensity score model for DARDS versus non-DARDS was constructed using a logistic regression including main term for age, sex, white cell count, C reactive protein, lactate dehydrogenase, albumin, platelet count, APACHE II score, SOFA score, McCabe score, HRCT score and PaO2/FiO2. Propensity score model discrimination was assessed by the area under the curve. The weights were based on the probability of diagnosing DARDS. Potential factors of 28-day mortality in the DARDS group were analysed by univariate Cox regression analysis. We used the SPSS software (V.22.0) for the statistical analyses, and generated survival plots with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R VV.3.2.2 (The R Foundation for Statistical Computing, Vienna, Austria). A p value of less than 0.05 was considered significant.\n\nResults\nThere were 27 patients in the DARDS group and 170 in the non-DARDS group. The causes of the non-DARDS group were sepsis (n=75; 44%), pneumonia (n=56; 33%), aspiration (n=35; 21%) and others (n=3; 2%).\n\nClinical characteristics\nThe background information of the patients in the DARDS and non-DARDS groups is shown in table 1.\n\nTable 1 Clinical characteristics of the patients\n\nRisk factor of acute lung injury\tDARDS group \n(n=27)\tNon-DARDS group \n(n=170)\tp Value\t\nSepsis: 1 (4), \npneumonia: 2 (7), \naspiration: 2 (7), \nothers: 0 (0)\tSepsis: 75 (44), \npneumonia: 57 (33), \naspiration: 35 (21), \nothers: 4 (3)\t\nAge (years)\t76.0 (70.5–78.5)\t76.5 (67.0–83.0)\t0.742\t\nSex (male/female)\t10 (37)/17 (63)\t113 (66)/57 (34)\t0.004\t\nWhite cell count (per mm3)\t12 000 (9150–15 250)\t9900 (5100–14 800)\t0.658\t\nC reactive protein (mg/dL)\t15.3 (13.4–21.5)\t15.4 (8.8–25.0)\t0.977\t\nLactate dehydrogenase (IU/L)\t477 (365–585)\t322 (246–434)\t0.003\t\nAlbumin (g/dL)\t2.9 (2.7–3.1)\t2.9 (2.4–3.2)\t0.536\t\nPlatelet count (per mm3)\t22.5 (12.4–29.9)\t18.0 (10.8–24.7)\t0.391\t\nPEEP (cmH2O)\t9.0 (8.0–10.0)\t8.0 (8.0–10.0)\t0.796\t\nPIP (cmH2O)*\t19.5 (11.0–24.0)\t22.0 (18.0–25.0)\t0.231\t\nTidal volume (mL)†\t410 (350–500)\t425 (350–486)\t0.583\t\nAPACHE II score\t18.0 (16.5–21.0)\t23.0 (18.0–26.0)\t<0.001\t\nSOFA score\t6.0 (3.0–7.5)\t7.0 (5.0–11.0)\t0.057\t\nHRCT score\t301.6 (244.1–339.8)\t208.3 (183.4–271.6)\t<0.001\t\nMcCabe score (1/2/3)\t20 (74)/4 (15)/3 (11)\t154 (91)/7 (4)/9 (5)\t0.04\t\nPaO2/FiO2\t148.0 (114.1–177.5)\t101.0 (71.5–134.0)\t0.003\t\nSeverity (mild/moderate/severe)\t3 (11)/18 (67)/6 (22)\t10 (6)/76 (45)/84 (49)\t0.029\t\nVentilator-free days\t19.0 (10.0–21.5)\t0 (0–18.0)\t<0.001‡\t\n28-day mortality\t5 (19)\t64 (38)\t0.043‡\t\nContinuous variables are reported as median and IQR and compared with the use of the Mann-Whitney U test. Categorical variables are reported as number (percentage) and compared with the χ2 test or Fisher’s exact test.\n\n*DARDS group (n=22), non-DARDS group (n=131).\n\n†DARDS group (n=22), non-DARDS group (n=116).\n\n‡Calculated using the log-rank tests.\n\nAPACHE II, Acute Physiology and Chronic Health Evaluation II; DARDS, drug-associated acute respiratory distress syndrome; FiO2, fractional inspired oxygen; HRCT, high-resolution CT; PaO2, arterial oxygen tension; PEEP, positive end-expiratory pressure; PIP, peak inspiratory pressure; SOFA, sequential organ failure assessment.\n\nThe aetiological agents in the DARDS group are shown in table 2. In our study, causative agents were anticancer drugs in seven cases (26%), the Chinese herbal medicine ‘kampo’ in 5 (19%), antibiotics in 4 (15%), the antiarrythmic drug amiodarone in 4 (15%), antirheumatic drugs in 3 (11%) and the others in 4 (15%).\n\nTable 2 Aetiological agents of drug-associated ARDS\n\nDARDS (n=27)\t\t\nProbable DARDS (n=22, 81%)\t\t\nPossible DARDS (n=5, 19%)\t\t\nDrug\tNumber\t\nAntineoplastic drug\t7\t\n CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)\t2\t\n Gefitinib\t1\t\n Irinotecan\t1\t\n Bicalutamide\t1\t\n Docetaxel\t1\t\n Epirubicin\t1\t\nChinese herbal medicine\t5\t\nAntibiotics\t4\t\n Cephalosporin\t2\t\n Penicillin\t1\t\n Daptomycin\t1\t\nAntiarrhythmic drug\t\t\n Amiodarone\t4\t\nAntirheumatic drug\t3\t\nNon-steroidal anti-inflammatory drugs\t2\t\nNovel oral anticoagulant\t1\t\nAntiviral agents\t\t\n Daclatasvir and asunaprevir\t1\t\nARDS, acute respiratory distress syndrome; DARDS, drug-associated ARDS.\n\nPrognostic implications\nFive of the 27 patients (19%) in the DARDS group and 64 of the 170 (38%) in the non-DARDS group died within 28 days. The Kaplan-Meier survival curves for each group at 28 days are shown in figure 2. The 28-day mortality was significantly better in the DARDS group than in the non-DARDS group (19% vs 38%, p=0.043). The duration of mechanical ventilation was significantly shorter in the DARDS group than in the non-DARDS group: the median ventilator time was 10 days (95% CI 7 to 18) in the DARDS group and not reached (95% CI 18 to not reached) in the non-DARDS group (p<0.001, figure 3). After adjustment for confounding covariates including PaO2/FiO2, DARDS was independently associated with lower mortality (adjusted HR 0.275; 95% CI 0.106 to 0.711; p=0.008) (figure 4) and shorter duration of mechanical ventilation (adjusted HR 3.791; 95% CI 2.197 to 6.539; p<0.001). In the adjusted analysis, APACHE II score (adjusted HR 1.058; 95% CI 1.007 to 1.113; p=0.026) and HRCT score (adjusted HR 1.220; 95% CI 1.105 to 1.315; p<0.001) were also independently associated with a poor prognosis in the regression model (table 3).\n\nTable 3 Cox proportional hazards model results for 28-day mortality\n\nFactor\tHR (95% CI)\tp Value\t\nAPACHE II score\t1.058 (1.007 to 1.113)\t0.026\t\nHRCT score\t1.220* (1.105 to 1.315)\t<0.001\t\nDrug-associated ARDS\t0.274 (0.106 to 0.711)\t0.008\t\n*Expressed as mortality change per 10% increase in area of attenuation with traction bronchiectasis on HRCT.\n\nARDS, acute respiratory distress syndrome; APACHE II, Acute Physiology and Chronic Health Evaluation II; HRCT, high-resolution CT.\n\nFigure 2 Kaplan-Meier curves show the distribution of 28-day mortality. Patients in the drug-associated acute respiratory distress syndrome (DARDS) group (n=27, solid line) had a significantly better mortality rate than did those in the non-DARDS group (n=170, dotted line) (log-rank test, p=0.043).\n\nFigure 3 Kaplan-Meier curves show the distribution of ventilator-free days. In the drug-associated acute respiratory distress syndrome (DARDS) group (n=27, solid line), the duration of ventilator weaning was significantly shorter than in the non-DARDS group (p=170, dotted line) (log-lank test, p<0.001).\n\nFigure 4 Survival curve for the association between DARDS and 28-day mortality from the Cox proportional hazards model, adjusted for Acute Physiology and Chronic Health Evaluation (APACHE) II and high-resolution CT (HRCT) score. DARDS, drug-associated acute respiratory distress syndrome.\n\nIPTW estimators with propensity adjustment also showed that diagnosis and treatment for ARDS caused by drug was associated with lower mortality (HR 0.139; 95% CI 0.044 to 0.440; p=0.001) and shorter duration of mechanical ventilation (HR 3.602; 95% CI 2.045 to 6.344; p<0.001). The area under the curve for the calculated propensity score was 0.903 (95% CI 0.850 to 0.955). Figure 5 shows an examples of HRCT scans of a survivor.\n\nFigure 5 The patient was an 80-year-old woman with acute respiratory distress syndrome due to herbal medicine. High-resolution CT (HRCT) shows extensive ground-glass attenuation with bronchiectasis (A). We determined a diffuse alveolar damage pattern. After starting corticosteroid therapy, hypoxaemia was markedly improved, and she was discharged from the hospital on day 22 with room air. HRCT on day 20 shows improvement of the diffuse ground-glass attenuation with bronchiectasis (B).\n\nComparison of prognostic factors\nWe compared the clinical parameters in both groups. In the DARDS group, the APACHE II scores were significantly lower, the PaO2/FiO2 ratios were significantly higher, and the SOFA scores tended to be lower than in the non-DARDS group, suggesting that the general severity of the condition and the extent of multiorgan failure were lower in the DARDS group. In addition, the McCabe scores, HRCT scores and lactate dehydrogenase values were significantly higher in the DARDS group, suggesting that the prognosis of the underlying disease was poor, and the degree of lung injury was severe. We analysed clinical factors of 28-day mortality in the DARDS group with univariate analysis and found that albumin, platelet count, PaO2/FiO2 and McCabe score were significant predictors for 28-day mortality (table 4).\n\nTable 4 Univariate analysis of predictors of 28-day mortality in drug-associated ARDS\n\nCharacteristic\tHR\t95% CI\tp Value\t\nAge (years)\t1.149\t0.948 to 1.394\t0.158\t\nSex (male)\t7.984\t0.891 to 71.56\t0.063\t\nWhite cell count (per mm3)\t0.999\t0.999 to 1.000\t0.095\t\nC reactive protein (mg/dL)\t1.065\t0.964 to 1.177\t0.214\t\nLactate dehydrogenase (IU/L)\t1.001\t1.000 to 1.002\t0.147\t\nAlbumin (g/dL)\t0.088\t0.018 to 0.428\t0.003\t\nPlatelet count (per mm3)\t0.848\t0.742 to 0.969\t0.015\t\nAPACHE II score\t0.951\t0.730 to 1.237\t0.706\t\nSOFA score\t0.970\t0.714 to 1.317\t0.844\t\nHRCT score\t1.133\t0.798 to 1.601\t0.510\t\nMcCabe score\t5.343\t1.763 to 16.19\t0.003\t\nPaO2/FiO2\t1.018\t1.005 to 1.032\t0.009\t\nAPACHE II, Acute Physiology and Chronic Health Evaluation II; ARDS, acute respiratory distress syndrome; FiO2, fractional inspired oxygen; HRCT, high-resolution CT; PaO2, arterial oxygen tension; SOFA, sequential organ failure assessment.\n\nCorticosteroid treatment\nThere were 17/27 (63.0%) patients in the DARDS group and 32/170 (18.8%) in the non-DARDS group who initially received high-dose corticosteroids, and significantly higher doses were administered in the DARDS group (p<0.001).\n\nBronchoalveolar lavage (BAL) findings\nOf the 27 patients in the DARDS group, BAL was performed in 13 and the median (IQR) for each cellular fraction was 16.0% (13.5–44.0) for neutrophils, 29.1% (19.0–66.0) for lymphocytes and 1.0% (0.0–3.5) for eosinophils. Neutrophils were predominant in five patients, lymphocytes were predominant in seven and eosinophils were predominant in one.\n\nDiscussion\nUnlike the result of the previous studies, the current study showed that patients with DARDS did not necessarily show poorer prognosis than those with the other causes of ARDS. These differences might depend on whether the causative agents are anticancer drugs, and whether the prognosis of the underlying disease is poor.\n\nDhokarh et al11 reported that a DALI group had a poorer prognosis than a non-drug-associated group. Similarly, Gibelin et al17 recently reported that there was a trend towards a higher intensive care unit mortality rate in ARDS patients without common risk factors, including drug-induced ARDS, as compared with ARDS patients with common risk factors. In these reports, the most common suspected drugs were anticancer drugs. The rate of anticancer drugs reported in their studies by Dhokarh et al11 was 48% and that by Gibelin et al17 was 69%, respectively. In contrast to these studies, only 26% of the patients with DARDS in our study received anticancer drug, which accounted for less than those in the previous studies, and there is a possibility that the difference in the population of patients with DARDS reflect difference of prognosis. One of the factors that predicted mortality within 28 days in the DARDS group was the McCabe score in this study. Four of the seven patients (57%) with DARDS who received antineoplastic drug therapy died within 28 days. Although the 28-day mortality was better in the DARDS group, the 28-day mortality rate in patients who received antineoplastic drug therapy was as high as those in the results of previous investigations.11 It is expected that the patients with poor prognosis of underlying disease might be more susceptible to lung injury when anticancer drug being administered and that dysregulated immune system in those patients could affect increased risk for mortality compared with patients without cancer. We believe that the fact that the McCabe score was higher in tumour-bearing patients may reflect the poor prognoses of the underlying diseases reported in studies by Dhokarh et al11 and Gibelin et al.17\n\nThere are two reported types of drug-associated lung injury: those caused by a cytotoxic mechanism that is sensitive to the total dosage and those caused by an immunostimulatory mechanism.18 It is widely held that anticancer drugs act via a cytotoxic mechanism, and the results of corticosteroid therapy are considered to be limited.1 Conversely, corticosteroids are expected to be effective when treating cases caused by immunostimulatory agents.17 These differences may reflect differences in the mechanisms of lung injury and differences in responsiveness to treatment, even where a similar extent of fibroproliferation occurred in the lungs. It was reported that histopathological findings of DAD were present in only 45% of ARDS cases diagnosed based on the Berlin definition at autopsy.19 This implies that cases that fulfil the criteria for ARDS do not necessarily exhibit the histopathological features of DAD. In our previous study, the HRCT findings reflected the pathological staging of DAD, and ARDS cases with high HRCT scores—indicating extensive fibroproliferative lesions—needed prolonged ventilation and ultimately suffered from multiorgan failure caused by ventilator-associated lung injury.8 Although the HRCT score indicating fibroproliferative lesions was higher in the DARDS group, which suggested DAD, the prognoses as well as the extent of multiorgan failure were significantly better than non-DARDS group. We believe there may be two potential reasons for this. The first is that there might be the differences in the pathological profiles in DARDS cases that develop fibroproliferative lesions, and the corticosteroid therapy could be more effective to DARDS. In the current study, there were varied cellular fractions in the 13 patients who underwent BAL. Furthermore, only 5/13 patients (39%) showed a predominance of neutrophils, while 8/13 patients (62%) showed a predominance of lymphocytes or eosinophils. Neutrophilic BAL in patients with ARDS suggests a DAD pattern reportedly associated with the poorest prognosis.20 21 In addition, the ARDS patients with a predominantly haemorrhagic or lymphocytic BAL fluid cytology, as opposed to those with predominantly macrophagic or neutrophilic one, had more often chance of corticosteroid therapy and showed a better prognosis.17 Although BAL was performed only 13/27 patients in our DARDS group, BAL lymphocytosis in these patients might have reflected good response to corticosteroid therapy. If the cause of ARDS is suspected to be a certain drug and the BAL lymphocytosis is observed, corticosteroid therapy may be supposed to be more beneficial. The results of our study are concordant with this previous report,17 in terms of better responses to corticosteroid therapy and subsequent improvement in survival in patients with DARDS.\n\nVarious questions remain unresolved with regard to the use of corticosteroid therapy for the treatment of ARDS.22–26 However, initial high-dose corticosteroid administration followed by a tapering regimen has been reported to be effective in some immune disorders.27 28 In Japan, in cases of acute respiratory failure due to DALI or interstitial pneumonias, initial high-dose corticosteroids followed by a gradually tapering regimen is recommended by the Practical Guidelines of the Japanese Respiratory Society.29 Significantly lower mortality in the patients with DARDS in the current study treated with initial high-dose steroid therapy may reflect the immunomodulatory effect of corticosteroids in the context of lung injury caused by drugs.\n\nA second potential explanation is even where patients with DARDS exhibit histological DAD, the prognosis may be better than those with non-DARDS. It has been reported that the hospital mortality rate of patients with drug-induced DAD diagnosed by surgical lung biopsy was only 17%.6Compared with the hospital mortality with 40% of DAD due to major cause of ARDS such as infection, that of drug-induced DAD was the lowest among the causes in the report. It is suggested that the cause of ARDS should be taken into account in the therapeutic reactivity even if DAD is pathologically proven.\n\nGiven the above considerations, we propose the following hypotheses: (1) there may have been a few patients with histological DAD in the DARDS group in our study, and corticosteroid therapy may have been effective in these patients and (2) even where patients with DARDS exhibit histological DAD, the prognosis may be good in cases of non-fatal underlying disease.\n\nNotably, drug-associated lung injury has frequently been reported to exhibit differences based on ethnicity.30–35 These ethnicity-based differences suggest that there may be differences in the genes related to lung fragility in Japanese and other East Asian patients.\n\nThere were some limitations to the present study. First, it was a retrospective analysis by use of prospective collected cohort study data, and it is possible that this may have biased the results or that multiple unmeasured variables may have affected the outcomes. However, compared with a typical retrospective design, these problems might be minimised. Second, it was a single-centre study, and the number of patients in the DARDS group was relatively small. Therefore, we used statistical analysis such as IPTW to compensate for the small number of patients. Third, it only included Japanese patients, and ethnic differences need to be considered. Fourth, there is some difficulties in judging whether a certain drug is causative in DARDS group. For example, whether cephalosporin really caused the ARDS or the infection for which the patient was receiving the cephalosporin caused it was uncertain in the strict sense. However, this is unavoidable problem on this topic because specific markers, histological findings and diagnostic clinical features are generally unremarkable, and there are no criterion standard diagnostic tests for drug-associated lung disease. Fifth, there is some possibility of underlying illness that is not actually ARDS. For example, some patients may actually have hypersensitivity pneumonitis, underlying diffuse alveolar haemorrhage or another disease with a favourable outcome. That may create an unequal comparison between DARDS and non-DARDS group. Finally, approximately half of the cases underwent BAL, and no histopathological investigations were performed. Notably however, the cases of ARDS were severe, and to date, the clinical relevance of BAL and biopsy have not yet been established. Further investigation of DARDS including assessments of the potential influences of ethnic differences is required, as are further studies investigating the individual aetiologies of ARDS itself.\n\nIn conclusion, patients with DARDS may not necessarily show poor prognosis than those with the other causes of ARDS, depending on the causative agents or prognosis of underlying disease. Another well-designed prospective study is needed to determine whether the prognosis is better in patients with DARDS than in patients without DARDS.\n\nSupplementary Material\nReviewer comments\n Author's manuscript\n We would like to thank Hiroyuki Muranaka (Department of Total Quality Management, Saiseikai Kumamoto Hospital, Kumamoto, Japan), Yasuhiro Gushima and Makoto Takaki (Department of Emergency and Critical Care Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan), Norihiro Iwamoto, Mitsuko Honda, Naoko Arakawa, Aoi Teruya, Yuko Yasuda, Yoshitomo Eguchi, Yoshihiko Sakata, Naoki Shingu, Jumpei Hisanaga and Tatsuya Nitawaki (Division of Respiratory Medicine, Saiseikai Kumamoto Hospital, Kumamoto, Japan) for their clinical assistance.\n\nContributors: KA had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. KA and KI contributed to study design and conduct and manuscript writing. KK contributed to conduct of the study. TJ and KF contributed to revision of the manuscript. MS contributed to the integrity of the data.\n\nCompeting interests: None declared.\n\nEthics approval: The study was approved by our institutional review board (permission number 238).\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData sharing statement: Extra data can be accessed via the Dryad data repository at http://datadryad.org/ with the doi:10.5061/dryad.7d8k0.\n==== Refs\nReferences\n1. Kudoh S , Kato H , Nishiwaki Y , et al \nInterstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study . Am J Respir Crit Care Med \n2008 ;177 :1348 –57 . 10.1164/rccm.200710-1501OC 18337594 \n2. Wolkove N , Baltzan M \nAmiodarone pulmonary toxicity . Can Respir J \n2009 ;16 :43 –8 . 10.1155/2009/282540 19399307 \n3. Hanaka T , Imanaga T , Kawakami S , et al \nA case of drug-induced lung injury caused by sitagliptin . Nihon Kokyuki Gakkai Zasshi \n2014 ;3 :594 –8 (in Japanese) .\n4. Imokawa S , Colby TV , Leslie KO , et al \nMethotrexate pneumonitis: review of the literature and histopathological findings in nine patients . Eur Respir J \n2000 ;15 :373 –81 . 10.1034/j.1399-3003.2000.15b25.x 10706507 \n5. Enomoto Y , Nakamura Y , Enomoto N , et al \nJapanese herbal medicine-induced pneumonitis: a review of 73 patients . Respir Investig \n2017 ;55 :138 –44 . 10.1016/j.resinv.2016.11.007 \n6. Parambil JG , Myers JL , Aubry MC , et al \nCauses and prognosis of diffuse alveolar damage diagnosed on surgical lung biopsy . Chest \n2007 ;132 :50 –7 . 10.1378/chest.07-0104 17475632 \n7. Ranieri VM , Rubenfeld GD , Thompson BT , et al \nAcute respiratory distress syndrome: the Berlin Definition . JAMA \n2012 ;307 :2526 –33 . 10.1001/jama.2012.5669 22797452 \n8. Ichikado K , Muranaka H , Gushima Y , et al \nFibroproliferative changes on high-resolution CT in the acute respiratory distress syndrome predict mortality and ventilator dependency: a prospective observational cohort study . BMJ Open \n2012 ;2 :e000545\n10.1136/bmjopen-2011-000545 \n9. Kawamura K , Ichikado K , Takaki M , et al \nEfficacy of azithromycin in sepsis-associated acute respiratory distress syndrome: a retrospective study and propensity score analysis . Springerplus \n2016 ;5 :1193 \n10.1186/s40064-016-2866-1 27516931 \n10. Bernard GR , Artigas A , Brigham KL , et al \nThe American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination . Am J Respir Crit Care Med \n1994 ;149 :818 –24 . 10.1164/ajrccm.149.3.7509706 7509706 \n11. Dhokarh R , Li G , Schmickl CN , et al \nDrug-associated acute lung injury: a population-based cohort study . Chest \n2012 ;142 :845 –50 . 10.1378/chest.11-2103 22539646 \n12. Japanese society of respiratory society for ARDS . [Clinical practice guideline for acute lung injury and acute respiratory distress syndrome] . Nihon Kokyuki Gakkai Zasshi . In Press \n2010 ;Suppl :1 –101 . (in Japanese) .21520668 \n13. Brower RG , Matthay MA , Morris A , et al \nVentilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome . N Engl J Med \n2000 ;342 :1301 –8 . 10.1056/NEJM200005043421801 10793162 \n14. MacIntyre NR , Cook DJ , Ely EW , et al \nEvidence-based guidelines for weaning and discontinuing ventilatory support: a collective task force facilitated by the American College of Chest Physicians; the American Association for Respiratory Care; and the American College of Critical Care Medicine . Chest \n2001 ;120 :375S –95 .11742959 \n15. Ichikado K , Suga M , Muranaka H , et al \nPrediction of prognosis for acute respiratory distress syndrome with thin-section CT: validation in 44 cases . Radiology \n2006 ;238 :321 –9 . 10.1148/radiol.2373041515 16293804 \n16. McCABE WR \nGram-Negative Bacteremia Ⅰ. Etiology and ecology . Arch Intern Med \n1962 ;110 :847 –55 .\n17. Gibelin A , Parrot A , Maitre B , et al \nAcute respiratory distress syndrome mimickers lacking common risk factors of the Berlin definition . Intensive Care Med \n2016 ;42 :164 –72 . 10.1007/s00134-015-4064-y 26408150 \n18. Delaunois LM \nMechanisms in pulmonary toxicology . Clin Chest Med \n2004 ;25 :1 –14 . 10.1016/S0272-5231(03)00122-9 15062592 \n19. Thille AW , Esteban A , Fernández-Segoviano P , et al \nComparison of the Berlin definition for acute respiratory distress syndrome with autopsy . Am J Respir Crit Care Med \n2013 ;187 :761 –7 . 10.1164/rccm.201211-1981OC 23370917 \n20. Meyer KC , Raghu G , Baughman RP , et al \nAn official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease . Am J Respir Crit Care Med \n2012 ;185 :1004 –14 . 10.1164/rccm.201202-0320ST 22550210 \n21. Maldonado F , Parambil JG , Yi ES , et al \nHaemosiderin-laden macrophages in the bronchoalveolar lavage fluid of patients with diffuse alveolar damage . Eur Respir J \n2009 ;33 :1361 –6 . 10.1183/09031936.00119108 19129275 \n22. Weigelt JA , Norcross JF , Borman KR , et al \nEarly steroid therapy for respiratory failure . Arch Surg \n1985 ;120 :536 –40 . 10.1001/archsurg.1985.01390290018003 3885915 \n23. Bone RC , Fisher CJ , Clemmer TP , et al \nEarly methylprednisolone treatment for septic syndrome and the adult respiratory distress syndrome . Chest \n1987 ;92 :1032 –6 . 10.1378/chest.92.6.1032 3315478 \n24. Luce JM , Montgomery AB , Marks JD , et al \nIneffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock . Am Rev Respir Dis \n1988 ;138 :62 –8 . 10.1164/ajrccm/138.1.62 3202402 \n25. Bernard GR , Luce JM , Sprung CL , et al \nHigh-dose corticosteroids in patients with the adult respiratory distress syndrome . N Engl J Med \n1987 ;317 :1565 –70 . 10.1056/NEJM198712173172504 3317054 \n26. Meduri GU , Golden E , Freire AX , et al \nMethylprednisolone infusion in early severe ARDS: results of a randomized controlled trial . Chest \n2007 ;131 :954 –63 . 10.1378/chest.06-2100 17426195 \n27. Wanchu A , Suryanaryana BS , Sharma S , et al \nHigh-dose prednisolone and bolus cyclophosphamide in interstitial lung disease associated with systemic sclerosis: a prospective open study . Int J Rheum Dis \n2009 ;12 :239 –42 . 10.1111/j.1756-185X.2009.01417.x 20374353 \n28. Mazlumzadeh M , Hunder GG , Easley KA , et al \nTreatment of giant cell arteritis using induction therapy with high-dose glucocorticoids: a double-blind, placebo-controlled, randomized prospective clinical trial . Arthritis Rheum \n2006 ;54 :3310 –8 . 10.1002/art.22163 17009270 \n29. Kubo K , Azuma A , Kanazawa M , et al \nConsensus statement for the diagnosis and treatment of drug-induced lung injuries . Respir Investig \n2013 ;51 :260 –77 . 10.1016/j.resinv.2013.09.001 \n30. Azuma A , Kudoh S \nHigh prevalence of drug-induced pneumonia in Japan . Japan Med Assoc J \n2007 ;50 :405 –11 .\n31. Kudoh S , Kato H , Nishiwaki Y , et al \nInterstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study . Am J Respir Crit Care Med \n2008 ;177 :1348 –57 . 10.1164/rccm.200710-1501OC 18337594 \n32. Natsuizaka M , Chiba H , Kuronuma K , et al \nEpidemiologic survey of Japanese patients with idiopathic pulmonary fibrosis and investigation of ethnic differences . Am J Respir Crit Care Med \n2014 ;190 :773 –9 . 10.1164/rccm.201403-0566OC 25162152 \n33. Jeon K , Chung MP , Lee KS , et al \nPrognostic factors and causes of death in Korean patients with idiopathic pulmonary fibrosis . Respir Med \n2006 ;100 :451 –7 . 10.1016/j.rmed.2005.06.013 16084076 \n34. Fernández Pérez ER , Daniels CE , St. Sauver J , et al \nIncidence, prevalence, and clinical course of idiopathic pulmonary Fibrosis . Chest \n2010 ;137 :129 –37 . 10.1378/chest.09-1002 19749005 \n35. Won Huh J , Soon Kim D , Keun Lee C , et al \nTwo distinct clinical types of interstitial lung disease associated with polymyositis-dermatomyositis . Respir Med \n2007 ;101 :1761 –9 . 10.1016/j.rmed.2007.02.017 17428649\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2044-6055",
"issue": "7(11)",
"journal": "BMJ open",
"keywords": "Acute Respiratory Distress Syndrome; Adult; Drug Associated Lung Disease",
"medline_ta": "BMJ Open",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001784:Blood Gas Analysis; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D007362:Intensive Care Units; D007564:Japan; D007770:L-Lactate Dehydrogenase; D008168:Lung; D008297:Male; D011379:Prognosis; D012128:Respiratory Distress Syndrome; D012189:Retrospective Studies; D012720:Severity of Illness Index; D016019:Survival Analysis; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D015300:Ventilator Weaning",
"nlm_unique_id": "101552874",
"other_id": null,
"pages": "e015330",
"pmc": null,
"pmid": "29122783",
"pubdate": "2017-11-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "17475632;19129275;20374353;26408150;21520668;7509706;27516931;22797452;22550210;3885915;22539646;17428649;19749005;3315478;10793162;3202402;17426195;11742959;3317054;23370917;16084076;16293804;25162152;10706507;28274529;19399307;22382117;17009270;18337594;24238235;15062592",
"title": "Clinical characteristics and prognosis of drug-associated acute respiratory distress syndrome compared with non-drug-associated acute respiratory distress syndrome: a single-centre retrospective study in Japan.",
"title_normalized": "clinical characteristics and prognosis of drug associated acute respiratory distress syndrome compared with non drug associated acute respiratory distress syndrome a single centre retrospective study in japan"
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"abstract": "A middle-aged man presented with fever and shortness of breath. He had significant history of congestive heart disease and received deceased donor renal transplant 2 years prior to presentation. He was febrile and found to have sepsis. His initial blood cultures grew Streptococcus canis. Streptococcus canis causes rare infection in humans, and this is most likely the first case in the renal transplant population.",
"affiliations": "1 State University of New York Upstate Medical University, Syracuse, NY, USA.;1 State University of New York Upstate Medical University, Syracuse, NY, USA.",
"authors": "Zaidi|Syed M H|SMH|;Eranki|Ambika|A|",
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"doi": "10.1177/2324709619834592",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961983459210.1177_2324709619834592Case ReportStreptococcus canis Bacteremia in a Renal Transplant\nRecipient Zaidi Syed M. H. MBBS1Eranki Ambika MD, MPH11 State University of New York Upstate\nMedical University, Syracuse, NY, USASyed M. H. Zaidi, State University of New\nYork Upstate Medical University, Physicians’ Office Building, Suite 311, 725\nIrving Avenue, Syracuse, NY 13210, USA. Emails:\nzaidi.hammad201@gmail.com,\nzaidisy@upstate.edu01 4 2019 Jan-Dec 2019 7 23247096198345921 11 2019 18 1 2019 © 2019 American Federation for Medical\nResearch2019American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which\npermits any use, reproduction and distribution of the work without further\npermission provided the original work is attributed as specified on the SAGE\nand Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).A middle-aged man presented with fever and shortness of breath. He had\nsignificant history of congestive heart disease and received deceased donor\nrenal transplant 2 years prior to presentation. He was febrile and found to have\nsepsis. His initial blood cultures grew Streptococcus canis.\nStreptococcus canis causes rare infection in humans, and this is\nmost likely the first case in the renal transplant population.\n\nStreptococcus canisrenal transplantbacteremiacover-dateJanuary-December 2019\n==== Body\nBrief History of the Present Illness\nA 62-year-old man presented with complaints of fever, chills, nausea, and vomiting\nfrom 3 days and progressive dyspnea from the past 2 days. In the emergency room, he\nwas found to be febrile at 39.4°C, hypotensive blood pressure 90/60 mm Hg, and\nhypoxic (oxygen saturation 88%). He was started on piperacillin/tazobactam as a\nbroad-spectrum empiric antibiotic.\n\nThe patient received a deceased donor renal transplant 2 year prior to presentation.\nHis posttransplant course was complicated with CMV (cytomegalovirus) viremia, and he\nwas on the following posttransplant regimen: belatacept 675 mg q 28 days, prednisone\n5 mg daily, and prophylactic valganciclovir. His past medical history is also\nsignificant for congestive heart failure, atrial fibrillation, pituitary adenoma,\nhypertension, hypothyroidism, diabetes mellitus, and obstructive sleep apnea.\n\nHe used to get lower limb superficial skin ulcers and relates it to multiple factors\nincluding diabetes mellitus, chronic pedal edema, and use of prednisolone. He lives\nat home with his wife. His wife runs a dog obedience school from home, and they\ncurrently have 6 dogs. The dogs are very close to him and they often lick his\nskin.\n\nOn our examination, blood pressure was 130/90 mm Hg, pulse rate was 90 beats per\nminute, temperature was 38.3°C, and respiratory rate was 22 breaths per minute. The\npatient was noted to have pedal edema and multiple ecchymoses at venipuncture sites.\nChest examination was positive for bilateral fine crepitations at bases, and abdomen\nwas mildly distended. On cardiac examination, he was found to have irregularly\nirregular rhythm; no murmurs were appreciable. Neurologic examination was grossly\nintact. Skin examination showed a healed ulcer on the medial aspect of left leg.\n\nOn admission, patient’s white blood cell count was 3.5 × 109/L, hemoglobin\n10.2 mg/dL, platelet 81 × 109/L, creatinine 2.5 mg/dL, blood urea\nnitrogen 35 mg/dL, and lactate 3.2 mmol. The chest X-ray showed bilateral congestion\nsuggestive of pulmonary edema. His blood cultures from admission grew\nStreptococcus canis in aerobic and anaerobic broths; isolate\nwas penicillin susceptible with minimum inhibitory concentration of 0.023.\n\nHis hypotension and fever improved after initial treatment. Shortness of breath\ngradually improved over 3 days with aggressive diuresis. On day 2 when the blood\ncultures result came his antibiotics were switched to ceftriaxone. Transthoracic\nechocardiogram did not show any vegetations, and transesophageal echocardiogram was\nnot done because of the transient nature of bacteremia. The patient responded well\nto appropriate antibiotic therapy, and repeat blood cultures after 48 hours were\nnegative. His creatinine levels improved and came back to his baseline of 1.3 mg/dL\non day 3.\n\nHe was discharged home with intravenous ceftriaxone 2 g once daily for a total\nduration of 14 days. He was doing well on follow-up visit after 2 weeks, and the\ntreatment was discontinued.\n\nDiscussion\nBloodstream infections are a major reason of mortality and morbidity after transplantation.1 In solid organ transplant recipients, blood stream inflection–related\nmortality can be up to 50% when bacteremia is associated with septic shock.2\n\nSeveral case reports have shown the transmission of zoonoses to humans during and\nafter solid-organ and hematopoietic stem cell transplantations.3 Most zoonoses occur as a primary infection after transplantation, and\nimmunocompromised patients are more likely to experience significant morbidity and\nmortality from these infections.4\n\nStreptococcus canis is part of the pyogenic Lancefield group G\nfamily and has a long known history in veterinary medicine. It can cause\nrespiratory, cutaneous, genital, and urinary infections in several animal species\nand reportedly causes bacteremia and mastitis.5,6\n\nThe group G β-hemolytic streptococci consist of Streptococcus\ndysgalactiae subspecies equisimilis, S milleri, S\ncanis, and S intestinalis. Humans are the reservoirs\nof S dysgalactiae subspecies equisimilis and\nS milleri, whereas dogs and pigs are the reservoirs of\nS canis and S intestinalis, respectively.\n\nIn humans, S canis has been reported to cause mild noninvasive\ninfections to severe sepsis.7\nStreptococcus canis infections are rare and constitute only 1% of\nall streptococcal infections. Most patients have animal contact, especially\ndogs.8,9 It is difficult\nto distinguish β-hemolytic Lancefield group G S dysgalactiae and\nS canis when only Lancefield typing is performed. To accurately\nidentify S canis, phenotypic testing and 16S rRNA gene sequencing\nis required. Therefore, there may be an underestimation of the true number of infections.10\n\nMost of the reported cases were associated with history of dog contact and found to\nhave skin wounds. In those cases, blood or wound cultures were positive with\nS canis.10 In our case, the patient had chronic pedal edema and history of recurrent\nsuperficial skin ulcers on the legs and close contact with dogs. At the time of\npresentation, he did not have open wound or infected ulcer, which makes the case\nunique.\n\nBert and Lambert-Zechovsky described a similar case of S canis\nbacteremia in a patient with exposure to a dog, and the apparent focus of infection\nwas healed ulcers due to varicose veins on the legs. However, that patient was\nimmunocompetent unlike our patient who was severely immunocompromised.11\n\nBased on our review of the available literature, there have been no reported cases of\nS canis bacteremia in transplant recipients.\n\nThis case elucidates a rarely reported cause of bacteremia in a profoundly\nimmunocompromised patient population and highlights the importance of obtaining a\nthorough history from every patient, as this can provide important epidemiologic\nclues about the underlying diagnosis.\n\nWe acknowledge help and guidance of Dr Scott Riddell (Head of Microbiology) for the\ndiagnosis of the pathogen.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual\ncases.\n\nInformed Consent: Verbal informed consent was obtained from the patient for the anonymized\ninformation to be published in this article.\n==== Refs\nReferences\n1 \nSingh N Paterson DL Gayowski T Wagener MM Marino IR. \nPredicting bacteremia and bacteremic mortality in liver\ntransplant recipients . Liver Transpl .\n2000 ;6 :54 -61 .10648578 \n2 \nMoreno A Cervera C Gavaldá J et al \nBloodstream infections among transplant\nrecipients: results of a nationwide surveillance in Spain .\nAm J Transplant .\n2007 ;7 :2579 -2586 .17868067 \n3 \nWoolhouse ME Gowtage-Sequeria S. \nHost range and emerging and reemerging pathogens .\nEmerg Infect Dis .\n2005 ;11 :1842 -1847 .16485468 \n4 \nKotton CN. \nZoonoses in solid-organ and hematopoietic stem cell transplant\nrecipients . Clin Infect Dis .\n2007 ;44 :857 -866 .17304461 \n5 \nFacklam R. \nWhat happened to the streptococci: overview of taxonomic and\nnomenclature changes . Clin Microbiol Rev .\n2002 ;15 :613 -630 .12364372 \n6 \nDevriese LA Hommez J Klipper-Balz R Schleifer KH. \nStreptococcus canis \nsp. nov. : a species of group G\nstreptococci from animals \nInt J Syst\nBacteriol .\n1986 ;36 :422 -425 .\n7 \nSkogberg K Simonen H Renkonen OV Valtonen VV. \nBeta-haemolytic group A, B, C and G streptococcal septicemia: a\nclinical study . Scand J Infect Dis .\n1988 ;20 :119 -125 .3041561 \n8 \nWoo PC Fung AM Lau SK Wong SS Yuen KY. \nGroup G beta-hemolytic streptococcal bacteremia characterized by\n16S ribosomal RNA gene sequencing . J Clin\nMicrobiol .\n2001 ;39 :3147 -3155 .11526143 \n9 \nLewthwaite P Parsons HK Bates CJ McKendrick MW Dockrell DH. \nGroup G streptococcal bacteremia: an opportunistic infection\nassociated with immune senescence . Scand J Infect\nDis .\n2002 ;34 :83 -87 .11928858 \n10 \nLam MM Clarridge JE 3rdYoung EJ Mizuki S. \nThe other group G Streptococcus: increased\ndetection of Streptococcus canis ulcer infections in dog\nowners . J Clin Microbiol .\n2007 ;45 :2327 -2329 .17475761 \n11 \nBert F Lambert-Zechovsky N. \nSepticemia caused by Streptococcus canis in a\nhuman . J Clin Microbiol .\n1997 ;35 :777 -779 .9041434\n\n",
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"keywords": "bacteremia; renal transplant",
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"mesh_terms": "D016470:Bacteremia; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D013290:Streptococcal Infections; D013291:Streptococcus; D066027:Transplant Recipients",
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"title": "Streptococcus canis Bacteremia in a Renal Transplant Recipient.",
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"abstract": "Cerebral venous sinus thrombosis (CVST) related to intracranial tumors has most commonly been recognized as an operative complication related to local operative factors such as retraction or direct venous injury. CVST may also be caused by tumor-related factors such as local mass effect but rarely occurs geographically remote from the site of the tumor. We report 6 cases treated at our institution of intracranial supratentorial tumors associated with CVST. In each case, the CVST was remote from the surgical site. In 3 cases CVST was noted at the time of resection, and 3 cases occurred in a delayed fashion. Each case is discussed in detail, and the utility of intraoperative magnetic resonance imaging in the early diagnosis of this complication is highlighted.",
"affiliations": "Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, USA.;Department of Neurology, Division of Neuro-Oncology, University of Virginia, Charlottesville, Virginia, USA.;Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, USA; Department of Neurology, Division of Neuro-Oncology, University of Virginia, Charlottesville, Virginia, USA.;Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, USA. Electronic address: ara5x@hscmail.mcc.virginia.edu.",
"authors": "Raper|Daniel M S|DM|;Zukas|Alicia M|AM|;Schiff|David|D|;Asthagiri|Ashok R|AR|",
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"keywords": "Cerebral venous sinus thrombosis; Glioblastoma; Intraoperative MRI; Neuro-oncology; Surgery",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000328:Adult; D000368:Aged; D001932:Brain Neoplasms; D003399:Craniotomy; D005260:Female; D005909:Glioblastoma; D006801:Humans; D018810:Magnetic Resonance Angiography; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012851:Sinus Thrombosis, Intracranial; D015173:Supratentorial Neoplasms; D016896:Treatment Outcome; D055815:Young Adult",
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"title": "Geographically Remote Cerebral Venous Sinus Thrombosis in Patients with Intracranial Tumors.",
"title_normalized": "geographically remote cerebral venous sinus thrombosis in patients with intracranial tumors"
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"abstract": "Background: The outbreak of coronavirus disease 2019 (COVID-19) had become a global public health event. Lymphoma patients need to be distinguished from the general population because of their deficient immune status and intensive anti-tumor treatment. The impacts of cancer subtypes and treatment on COVID-19 infection are unclear. Case Presentation: We here report the case of a primary mediastinal large B-cell lymphoma patient who was infected with COVID-19 after intensive immunochemotherapy (DA-EPOCH-R). The patient developed a neutropenic fever during chemotherapy, and fever was persistent, although antibiotics were used. Initial chest CT was negative, and the patient received a throat swab test since the second CT showed evidence of pneumonia. With treatment with Arbidol Hydrochloride and LianHuaQingWen capsule, his COVID-19 was cured. Conclusions: To the best of our knowledge, this is the first report focusing on COVID-19 infection in a lymphoma patient undergoing intensive immunochemotherapy. For those patients being treated with immunochemotherapy in epidemic areas, a reduced dose intensity of intensive chemotherapy should be considered, and the effect of immunotherapies such as rituximab on COVID-19 infection should be considered. The impacts of anti-cancer treatment on COVID-19 infection need to be explored further.",
"affiliations": "Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.",
"authors": "Li|Qiuhui|Q|;Zhu|Fang|F|;Xiao|Yin|Y|;Liu|Tao|T|;Liu|Xinxiu|X|;Wu|Gang|G|;Zhang|Liling|L|",
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"doi": "10.3389/fonc.2020.00924",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.00924\nOncology\nCase Report\nA Primary Mediastinal Large B-Cell Lymphoma Patient With COVID-19 Infection After Intensive Immunochemotherapy: A Case Report\nLi Qiuhui Zhu Fang Xiao Yin Liu Tao Liu Xinxiu Wu Gang Zhang Liling * Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China\nEdited by: Antonio Russo, Paolo Giaccone University Hospital in Palermo, Italy\n\nReviewed by: Luca Falzone, University of Catania, Italy; Zohreh Sanaat, Tabriz University of Medical Sciences, Iran\n\n*Correspondence: Liling Zhang lily-1228@hotmail.comThis article was submitted to Cancer Epidemiology and Prevention, a section of the journal Frontiers in Oncology\n\n\n22 5 2020 \n2020 \n22 5 2020 \n10 92407 4 2020 11 5 2020 Copyright © 2020 Li, Zhu, Xiao, Liu, Liu, Wu and Zhang.2020Li, Zhu, Xiao, Liu, Liu, Wu and ZhangThis 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.Background: The outbreak of coronavirus disease 2019 (COVID-19) had become a global public health event. Lymphoma patients need to be distinguished from the general population because of their deficient immune status and intensive anti-tumor treatment. The impacts of cancer subtypes and treatment on COVID-19 infection are unclear.\n\nCase Presentation: We here report the case of a primary mediastinal large B-cell lymphoma patient who was infected with COVID-19 after intensive immunochemotherapy (DA-EPOCH-R). The patient developed a neutropenic fever during chemotherapy, and fever was persistent, although antibiotics were used. Initial chest CT was negative, and the patient received a throat swab test since the second CT showed evidence of pneumonia. With treatment with Arbidol Hydrochloride and LianHuaQingWen capsule, his COVID-19 was cured.\n\nConclusions: To the best of our knowledge, this is the first report focusing on COVID-19 infection in a lymphoma patient undergoing intensive immunochemotherapy. For those patients being treated with immunochemotherapy in epidemic areas, a reduced dose intensity of intensive chemotherapy should be considered, and the effect of immunotherapies such as rituximab on COVID-19 infection should be considered. The impacts of anti-cancer treatment on COVID-19 infection need to be explored further.\n\nCOVID-19lymphomamyelosuppressionchemotherapyimmunotherapy\n==== Body\nIntroduction\nPrimary mediastinal large B-cell lymphoma is a distinct subtype of non-Hodgkin lymphoma and has features that overlap with classic nodular sclerosing Hodgkin lymphoma (1). There is no standard treatment of primary mediastinal large B-cell lymphoma because of its rarity. DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) is a promising and effective regimen with an event-free survival rate of 93% and an overall survival rate of 97% during a median of 5 years of follow-up. However, grate 4 neutropenia occurred during 50% of cycles, and hospitalization for febrile neutropenia occurred during 13% of cycles (2).\n\nSince December 2019, an epidemic of coronavirus disease 2019 (COVID-19) has broken out in Wuhan and spread across China and beyond. Patients with cancer might have an increased risk of COVID-19 and a poor outcome, as reported by Liang et al. (3). In Liang's report, only two (lung cancer patients) of 18 patients had received chemotherapy within the previous month. However, the effects of chemotherapy and immunotherapy on the risk of COVID-19 were not described. Here, we report a case of a patient who was infected with COVID-19 during the course of intensive immunochemotherapy.\n\nCase Description\nA 26-year-old Chinese male patient presenting with a large mediastinal mass was diagnosed as having primary mediastinal large B-cell lymphoma (IPI 1 score). He denied a history of smoking or other diseases. He had finished two cycles of DA-EPOCH-R regimens and suffered febrile neutropenia each time. He was admitted for the third cycle of chemotherapy on January 9, 2020. Physical examination revealed that the swelling in the face, neck, and upper limbs was reduced, but distention of the jugular vein was still visible. Also, enlarged lymph nodes in the cervical and supraclavicular areas returned to normal size and were not palpated after two cycles of therapy. He was evaluated as being in partial remission on the basis of contrast CT.\n\nWith no obvious abnormalities in CT images and laboratory examinations, the patient was administrated the third cycle of DA-EPOCH-R as planned from January 12 to January 17. On January 19, the patient developed a fever (38.8°C) without cough, dyspnea, myalgia, or fatigue. His neutrocyte count was 0.89 × 109 cells/L, his lymphocyte count was 0.68 × 109 cells/L, and chest CT showed no evidence of infection. We treated the patient for febrile neutropenia using antibiotics (Meropenem and Linezolid) and granulocyte colony-stimulating factor (G-CSF). However, fever was persistent, and grade 3/4 neutropenia remained from January 21 to January 25, 2020 (Figure 1). Further examination revealed that antibodies of Mycoplasma pneumoniae IgM, coxsackie B5 virus IgM, and enterovirus RNA were positive, and procalcitonin was normal. Thus, Azithromycin and Ganciclovir were applied, and Oseltamivir and Posaconazole were also applied to prevent the influenza virus and fungal infections. On January 27, the neutrophils returned to normal, but the patient complained of sore throat and nausea and had a fever of 38.4°C. A repeated chest CT revealed bilateral scattered opacities and consolidation; bilateral pleural effusion and segmental atelectasis were also seen (Figure 2). Consultation with the infectious disease expert group suggested that a mixed infection could be in existence, and SARS-CoV-2 infection should be suspected. Therefore, an RT-PCR test for SARS-CoV-2 was performed, and the patient was confirmed to have COVID-19 infection. He was transferred to a designated hospital on January 30. With the treatment of oral Arbidol Hydrochloride (0.2 g per time, three times a day for 1 week) and LianHuaQingWen capsule (1.4 g per time, three times a day for 10 days), his RT-PCR tests became negative, and CT images improved. He was considered cured and was discharged on February 17. He did not develop severe pneumonia during treatment and did not need a ventilator to help him breathe.\n\nFigure 1 Changes in maximum body temperature and blood cell count after the onset of fever.\n\nFigure 2 Representative images of the chest CT comparing between January 19, 2020 (A1, A2), and January 27, 2020 (B1, B2). The later CT images show multifocal opacities and consolidations in different lobes of the lungs.\n\nDiscussion\nLymphopenia is a common laboratory finding in confirmed COVID-19 cases; it was present in 83.2% of the patients on admission (4). It is also a key item recommended for clinical suspicion of a case according to the Diagnosis and Treatment Program of COVID-19 (trial Seventh version) issued by China's National Health Commission in March 2020. However, intensive chemotherapy can cause severe neutropenia and lymphopenia. Therefore, the lymphocyte count cannot be regarded as a key point upon which SARS-CoV-2 infection can be suspected in cancer patients who are undergoing intensive chemotherapy and suffering grade 3/4 hematologic toxicity.\n\nIn the early stage of the COVID-19 epidemic, chest CT scan plays a vital role in early diagnosis. As radiologists have described, COVID-19 pneumonia typically manifests with rapid evolution from focal unilateral to diffuse bilateral ground-glass opacities that progress to or co-exist with consolidations in chest CT imaging. “White lung” may be seen in critically ill patients, and, rarely, patients may develop pleural effusion (5, 6). However, the initial CT scan of this patient since the onset of fever did not show any typical manifestations of COVID-19, suggesting that some COVID-19 cases take a few days to show significant CT changes. Indeed, several studies have revealed that 3.5–19% of laboratory-confirmed COVID-19 cases had a negative initial CT before progressing to pneumonia 3–5 days later (4, 6, 7).\n\nSevere myelosuppression from intensive chemotherapy may increase risk of infection by bacteria, viruses, and fungi (8). For this patient, biomarkers reflecting infections by other pathogens, such as M. pneumoniae, coxsackie B5 virus, and enterovirus, were positive. Therefore, even when there was evidence of other viral infections and CT findings were atypical, a co-infection with SARS-CoV-2 should be considered and tested for. We should consider that the cases of cancer patients undergoing intensive chemotherapy and with confirmed SARS-CoV-2 infection could be complicated by other pathogen infections.\n\nThe first report focusing on COVID-19 and cancer indicated that patients with cancer may have worse outcomes (3). This patient's COVID-19 infection occurred when he was experiencing grade 3/4 hematologic toxicity after intensive immunochemotherapy. Thus, it was suspected that he might develop severe pneumonia because of the immunosuppression induced by immunochemotherapy. However, the course of this patient's illness seems to contradict this conclusion. Actually, other researchers have raised questions about Liang's conclusions (9, 10). They pointed out that the current evidence to support the conclusion that cancer patients have a higher susceptibility to SARS-CoV-2 and poorer prognosis remains insufficient. They also suggested that older age and smoking might be the true factors associated with worse COVID-19 outcomes (9–11). Whether the blunted immune status of cancer promotes or inhibits the development of COVID-19 infection is not clear. Therefore, larger samples and well-designed studies are needed to elucidate the relationship between cancer and COVID-19.\n\nRituximab is a chimeric monoclonal antibody directed against CD20-positive surface antigens on B lymphocytes. Rituximab induces a rapid and prolonged depletion of CD20-positive B lymphocytes and thus targets the cells that are key to successful immunization (12). Recently, although there is not enough evidence to stop using rituximab in lymphoma patients, some suggestions have been proposed by the American Society of Hematology (ASH) and the European Society for Medical Oncology (ESMO). The ASH website suggests trying to avoid or skip treatment with monoclonal antibodies (rituximab, obinutuzumab), especially when given in combination with targeted agents for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (13). On the other hand, rituximab maintenance may be delayed for mantle cell lymphoma and follicular lymphoma patients, as suggested by the ASH and ESMO (14, 15). However, rituximab is still recommended for diffuse large B-cell lymphoma patients (16). Decisions to use rituximab should thus be made on a case-by-case basis.\n\nSo far, both RNA vaccine in the United States and recombinant vaccine (adenovirus vector) in China targeting SARS-CoV-2 have entered phase I clinical trial (17, 18). It can be predicted that SARS-CoV-2 vaccines will be available in the near future. Previous studies have shown that patients undergoing rituximab-containing treatment regimens within the past 6 months do not respond to influenza A vaccination (19, 20). Whether the application of rituximab will affect the production of antibodies to SARS-CoV-2 or the effect of the SARS-CoV-2 vaccination is worth exploring further.\n\nOur case illustrates the first reported case of COVID-19 infection in a lymphoma patient who underwent intensive immunochemotherapy and exhibited grade 4 myelosuppression. Since COVID-19 was declared a pandemic on March 11, 2020, lymphoma patients worldwide face risk of infection. For those patients being treated with immunochemotherapy in epidemic areas, reduced dose intensity of intensive chemotherapy should be considered, and the effect of immunotherapy, such as rituximab, on COVID-19 infection should be considered. The impacts of anti-cancer treatment on COVID-19 infection need to be explored further.\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\nWritten informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nQL and LZ wrote and edited the final manuscript. GW, LZ, and QL designed the study and managed the patient's care at the cancer center. FZ, YX, TL, and XL assisted in data collection, data analysis, interpretation, and construction of figures. All authors read and approved the final manuscript.\n\nConflict of Interest\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\nThe authors would like to thank all healthcare workers who are helping us fight against COVID-19 in Wuhan. The authors would also like to thank the patient and his family.\n==== Refs\nReferences\n1. Giulino-Roth L . How I treat primary mediastinal B-cell lymphoma\n. Blood . (2018 ) 132 :782 –90\n. 10.1182/blood-2018-04-791566 29976557 \n2. Dunleavy K Pittaluga S Maeda LS Advani R Chen CC Hessler J . Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma\n. N Engl J Med. (2013 ) 368 :1408 –16\n. 10.1056/NEJMoa1214561 23574119 \n3. Liang W Guan W Chen R Wang W Li J Xu K . Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China\n. Lancet Oncol . (2020 ) 21 :335 –7\n. 10.1016/S1470-2045(20)30096-6 32066541 \n4. Guan WJ Ni ZY Hu Y Liang WH Ou CQ He JX . Clinical characteristics of coronavirus disease 2019 in China\n. N Engl J Med. (2020 ) 382 :1708 –20\n. 10.1056/NEJMoa2002032 32109013 \n5. Shi H Han X Jiang N Cao Y Alwalid O Gu J . Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study\n. Lancet Infect Dis. (2020 ) 20 :425 –34\n. 10.1016/S1473-3099(20)30086-4 32105637 \n6. Pan F Ye T Sun P Gui S Liang B Li L . Time course of lung changes on chest CT during recovery from 2019 novel coronavirus (COVID-19) pneumonia\n. Radiology. (2020 ) 10.1148/radiol.2020200370 . [Epub ahead of print].32053470 \n7. Ai T Yang Z Hou H Zhan C Chen C Lv W . Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases\n. Radiology . (2020 ) 10.1148/radiol.2020200642 . [Epub ahead of print].32101510 \n8. Lyman GH Michels SL Reynolds MW Barron R Tomic KS Yu J . Risk of mortality in patients with cancer who experience febrile neutropenia\n. Cancer . (2010 ) 116 :5555 –63\n. 10.1002/cncr.25332 20715160 \n9. Wang H Zhang L . Risk of COVID-19 for patients with cancer\n. Lancet Oncol . (2020 ) 21 :e181 . 10.1016/S1470-2045(20)30149-2 32142621 \n10. Xia Y Jin R Zhao J Li W Shen H . Risk of COVID-19 for cancer patients\n. Lancet Oncol . (2020 ) 21 :e180 . 10.1016/S1470-2045(20)30150-9 32142622 \n11. Wang D Hu B Hu C Zhu F Liu X Zhang J . Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China\n. JAMA . (2020 ) 323 :1061 -9\n. 10.1001/jama.2020.1585 32031570 \n12. Edwards JCW Szczepanski L Szechinski J Filipowicz-Sosnowska A Emery P Close DR . Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis\n. N Engl J Med. (2004 ) 350 :2572 –81\n. 10.1056/NEJMoa032534 15201414 \n13. COVID-19, and CLL: Frequently Asked Questions,. Available online at: https://www.hematology.org/covid-19/covid-19-and-cll (accessed May 04, 2020).\n14. COVID-19, and Indolent Lymphomas: Frequently Asked Questions,. Available online at: https://www.hematology.org/covid-19/covid-19-and-indolent-lymphomas (accessed May 04, 2020).\n15. ESMO Management and Treatment Adapted Recommendations in the COVID-19 Era: Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma and Aggressive T-Cell Lymphomas . Available online at: https://www.esmo.org/guidelines/cancer-patient-management-during-the-covid-19-pandemic/haematological-malignancies-dlbcl-mcl-and-aggressive-t-cell-lymphoma-in-the-covid-19-era (accessed May 04, 2020).\n16. COVID-19 and Aggressive Lymphoma: Frequently Asked Questions . Available online at: https://www.hematology.org/covid-19/covid-19-and-aggressive-lymphoma (accessed May 04, 2020).\n17. A phase I Clinical Trial for Recombinant Novel Coronavirus (2019-COV) Vaccine (Adenoviral Vector) . Available online at: http://www.chictr.org.cn/showproj.aspx?proj=51154 (accessed April 02, 2020).\n18. Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) to Prevent SARS-CoV-2 Infection . Available online at: https://clinicaltrials.gov/ct2/show/NCT04283461 (accessed April 02, 2020).\n19. Berglund A Willen L Grodeberg L Skattum L Hagberg H Pauksens K . The response to vaccination against influenza A(H1N1) 2009, seasonal influenza and Streptococcus pneumoniae in adult outpatients with ongoing treatment for cancer with and without rituximab\n. Acta Oncol. (2014 ) 53 :1212 –20\n. 10.3109/0284186X.2014.914243 24865118 \n20. Yri OE Torfoss D Hungnes O Tierens A Waalen K Nordøy T . Rituximab blocks protective serologic response to influenza A (H1N1) 2009 vaccination in lymphoma patients during or within 6 months after treatment\n. Blood . (2011 ) 118 :6769 –71\n. 10.1182/blood-2011-08-372649 22058114\n\n",
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"journal": "Frontiers in oncology",
"keywords": "COVID-19; chemotherapy; immunotherapy; lymphoma; myelosuppression",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "924",
"pmc": null,
"pmid": "32574278",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "32101510;32109013;32142621;20715160;32031570;29976557;32142622;32053470;23574119;32105637;32066541;15201414;24865118;22058114",
"title": "A Primary Mediastinal Large B-Cell Lymphoma Patient With COVID-19 Infection After Intensive Immunochemotherapy: A Case Report.",
"title_normalized": "a primary mediastinal large b cell lymphoma patient with covid 19 infection after intensive immunochemotherapy a case report"
} | [
{
"companynumb": "CN-ACCORD-188652",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
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"drugadditional": "3",
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{
"abstract": "BACKGROUND\nThe aim was to evaluate the feasibility and the effectiveness of neoadjuvant systemic chemotherapy followed by cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC) in patients with peritoneal carcinomatosis (PC) from gastric cancer.\n\n\nMETHODS\nEighteen patients (median age 57 years, range 38-74) were scheduled for three months' neoadjuvant systemic chemotherapy followed by CRS + HIPEC + EPIC.\n\n\nRESULTS\nAt the time of surgery, the peritoneal tumor burden was extensive with tumor growth on the entire peritoneal cavity. Only eight patients received the entire treatment and OS was 14.3 months (range 6.1-34.3, 95% CI 6.6-20.3). Six patients had macroscopically radical (CC0) surgery and for this subgroup OS was 19.1 months (range 6.1-34.3, 95% CI 6.9-27.1). Postoperative 90-day mortality was 10% (one patient) and the perioperative grades II-IV adverse events (AE) rate was 62.5%.\n\n\nCONCLUSIONS\nNeoadjuvant chemotherapy followed by CRS + HIPEC + EPIC does not seem to be associated with prolonged OS in patients with extensive PC growth from gastric cancer unless macroscopically radical surgery is achieved. However, morbidity from this treatment is considerable and it cannot be recommended for routine care until a prospective randomized trial has been performed.",
"affiliations": "Department of Surgical Sciences, Section of Surgery, Uppsala University, Uppsala, Sweden. bo.hultman@surgsci.uu.se",
"authors": "Hultman|Bo|B|;Lind|Pehr|P|;Glimelius|Bengt|B|;Sundbom|Magnus|M|;Nygren|Peter|P|;Haglund|Ulf|U|;Mahteme|Haile|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3109/0284186X.2012.702925",
"fulltext": null,
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"issn_linking": "0284-186X",
"issue": "52(4)",
"journal": "Acta oncologica (Stockholm, Sweden)",
"keywords": null,
"medline_ta": "Acta Oncol",
"mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002277:Carcinoma; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D008875:Middle Aged; D010534:Peritoneal Neoplasms; D010537:Peritoneum; D013274:Stomach Neoplasms",
"nlm_unique_id": "8709065",
"other_id": null,
"pages": "824-30",
"pmc": null,
"pmid": "22974074",
"pubdate": "2013-05",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase II study of patients with peritoneal carcinomatosis from gastric cancer treated with preoperative systemic chemotherapy followed by peritonectomy and intraperitoneal chemotherapy.",
"title_normalized": "phase ii study of patients with peritoneal carcinomatosis from gastric cancer treated with preoperative systemic chemotherapy followed by peritonectomy and intraperitoneal chemotherapy"
} | [
{
"companynumb": "SE-ROCHE-1685924",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
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"abstract": "A 33-year-old healthy woman at 6 weeks of gestation without any underlying disease developed erythema multiforme (EM) after misoprostol. She had no history of herpes simplex virus infection and drug allergy to nonsteroidal anti-inflammatory drugs and antibiotic agents. Medical abortion was performed at 6 weeks' gestation. Later day, the patient developed oral lesions as several white bullae lesions in her buccal mucosa and hyperkeratotic lip plaques with mild pain. Then, lesions resolved within approximately 3 weeks. Microscopic finding of oral biopsy from beneath the tongue and lesions was performed. The result was consistent with erosive mucosa with granulation tissue formation and acute inflammation in favor of EM. This is the case report of probable misoprostol-induced EM. Because EM may produce in skin as a Stevens-Johnson syndrome in subsequent attack, monitoring of this adverse drug reaction should be considered for proper management and follow-up.",
"affiliations": "1Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 2School of Traditional Medicine, Tehran University of Medical Science, Tehran, Iran; and 3Department of Clinical Pharmacy, Faculty of Pharmacy-International Campus, Iran University of Medical Sciences, Tehran, Iran.",
"authors": "Sahraei|Zahra|Z|;Mirabzadeh|Mehran|M|;Eshraghi|Azadeh|A|",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D016595:Misoprostol",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000193",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "23(5)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D000028:Abortion, Induced; D000328:Adult; D003875:Drug Eruptions; D004892:Erythema Multiforme; D005260:Female; D006801:Humans; D016595:Misoprostol; D009061:Mouth Mucosa",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e1230-3",
"pmc": null,
"pmid": "26196523",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Erythema Multiforme Associated With Misoprostol: A Case Report.",
"title_normalized": "erythema multiforme associated with misoprostol a case report"
} | [
{
"companynumb": "IR-NOVEL LABORATORIES, INC-2016-04684",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MISOPROSTOL"
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"drugadditional":... |
{
"abstract": "The critical role of arterial infusion chemotherapy in the multimodal treatment of extremity bone cancer has been investigated extensively, but few studies have focused on pelvic osteosarcoma. Therefore, we attempted to evaluate the clinical significance of arterial infusion chemotherapy in the treatment of pelvic osteosarcoma.\nWe combined a cisplatin arterial infusion regimen with multidrug systematic chemotherapy as a neoadjuvant protocol for the treatment of pelvic osteosarcoma. The course number and dosage of cisplatin arterial infusion were adjusted to achieve a maximal tumor response evaluated by contrast-enhanced MRI per RECIST 1.1. Good responders received the same systematic combination for postoperative chemotherapy, and poor responders received second-line therapy. Twelve patients with nonmetastatic high-grade pelvic osteosarcoma were included. Survival, chemotherapy response and adverse events data were analyzed.\nThe mean follow-up period was 56.1 months. Four patients died of refractory tumor progression, and 1 patient with local recurrence had no evidence of disease for 27 months after receiving secondary amputation and resection. Kaplan-Meier survival analysis demonstrated a 57.8% overall survival and 52.5% event-free survival rate at 5 years. Eight of 12 patients had a >90% tumor necrosis rate according to histopathologic examinations. The rates of local adverse events were lower than those reported for extremity osteosarcoma.\nOur study initially indicated that the cisplatin arterial infusion regimen was a potential therapy with good tolerance in the treatment of pelvic osteosarcoma.",
"affiliations": "Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People's Republic of China.;Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People's Republic of China.;Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People's Republic of China.;Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People's Republic of China.;Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People's Republic of China.;Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People's Republic of China.",
"authors": "Hu|Xuantao|X|0000-0003-1889-3081;Chen|Xia|X|;Li|Tao|T|0000-0002-5074-0184;Liu|Zicheng|Z|;Guo|Xiaoning|X|;Ouyang|Zhengxiao|Z|0000-0002-8997-0446",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/CMAR.S294677",
"fulltext": "\n==== Front\nCancer Manag Res\nCancer Manag Res\ncmar\ncancmanres\nCancer Management and Research\n1179-1322 Dove \n\n294677\n10.2147/CMAR.S294677\nOriginal Research\nEffect of Cisplatin Arterial Infusion (CAI) on Primary Nonmetastatic Pelvic Osteosarcoma: A Preliminary Study\nHu et alHu et alhttp://orcid.org/0000-0003-1889-3081Hu Xuantao 1 Chen Xia 1 http://orcid.org/0000-0002-5074-0184Li Tao 1 Liu Zicheng 1 Guo Xiaoning 1 http://orcid.org/0000-0002-8997-0446Ouyang Zhengxiao 1 1 Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People’s Republic of China\nCorrespondence: Xiaoning Guo; Zhengxiao Ouyang Department of Orthopedics, The Second Xiangya Hospital of Central South University, 139 Renmin Road, Changsha, 410011, Hunan, People’s Republic of ChinaTel +86-0731-85295127 Email guoxiaoning@csu.edu.cn; ouyangzhengxiao@csu.edu.cn\n15 2 2021 \n2021 \n13 1491 1503\n29 11 2020 28 1 2021 © 2021 Hu et al.2021Hu et al.This work is published and licensed by Dove Medical Press Limited. The 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. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Purpose\nThe critical role of arterial infusion chemotherapy in the multimodal treatment of extremity bone cancer has been investigated extensively, but few studies have focused on pelvic osteosarcoma. Therefore, we attempted to evaluate the clinical significance of arterial infusion chemotherapy in the treatment of pelvic osteosarcoma.\n\nPatients and Methods\nWe combined a cisplatin arterial infusion regimen with multidrug systematic chemotherapy as a neoadjuvant protocol for the treatment of pelvic osteosarcoma. The course number and dosage of cisplatin arterial infusion were adjusted to achieve a maximal tumor response evaluated by contrast-enhanced MRI per RECIST 1.1. Good responders received the same systematic combination for postoperative chemotherapy, and poor responders received second-line therapy. Twelve patients with nonmetastatic high-grade pelvic osteosarcoma were included. Survival, chemotherapy response and adverse events data were analyzed.\n\nResults\nThe mean follow-up period was 56.1 months. Four patients died of refractory tumor progression, and 1 patient with local recurrence had no evidence of disease for 27 months after receiving secondary amputation and resection. Kaplan-Meier survival analysis demonstrated a 57.8% overall survival and 52.5% event-free survival rate at 5 years. Eight of 12 patients had a >90% tumor necrosis rate according to histopathologic examinations. The rates of local adverse events were lower than those reported for extremity osteosarcoma.\n\nConclusion\nOur study initially indicated that the cisplatin arterial infusion regimen was a potential therapy with good tolerance in the treatment of pelvic osteosarcoma.\n\nKeywords\nosteosarcomapelviscisplatinarterial infusionchemotherapy toxicityatural Science Foundation of Hunan Province for YouthsThis study was supported by the Natural Science Foundation of Hunan Province for Youths (Grant number 2020JJ5799).\n==== Body\nIntroduction\nOsteosarcoma is the most common solid malignant tumor of bone with a highly aggressive behavior.1 The most susceptible age of osteosarcoma is bimodal, which is characterized by one peak at 10-to-20 years and another at over 60 years.2,3 Although this disease endangers the health of both adolescent and aged populations, limited progress has been made to improve survival and functional prognosis, especially in patients with pelvic osteosarcoma.4–6 Osteosarcoma patients treated with mere immediate surgical resection register a recurrence rate up to 60–90%.7 (Since 1980s, traditional adjuvant intravenous (IV) systematic chemotherapy produces an improved five-year event-free survival (EFS) rate of 61%.8 In the early 2000s, the propagation of a multidrug neoadjuvant chemotherapy regimen elevated this rate to 60% and above.9,10) Henceforth, numerous explorations have been conducted to optimize the category, dosage, combination and duration of chemotherapy drug administration. The most recent studies of EURAMOS revealed a 5-year EFS of 65–70% for localized osteosarcoma treated by multidrug neoadjuvant chemotherapy. However, there are few studies focusing on arterial infusion as an improved method and its clinical outcome in the treatment of pelvic osteosarcoma.\n\nOsteosarcoma in pelvic bone is more notorious than that in extremities. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate than those with extremity lesions, which may be associated with a poor chemotherapy response and an inability to achieve adequate surgical resection.11 Therefore, more challenges are faced in the management of pelvic osteosarcoma.\n\nPlatinum complexes, such as cis-diamine-dichloro platinum (cisplatin, CDDP), have been proven to be cell cycle-nonspecific agents and to have multiple broad-spectrum antitumor effects.12 Several clinical trials reported that employing an arterial infusion technique to deliver CDDP, in combination with an IV systematic chemotherapy regimen or not, can elevate the local drug concentration to fivefold that of IV administration and can produce better survival in the treatment of extremity osteosarcoma.13–15 Therefore, the arterial infusion of CDDP might have potential in the treatment of pelvic osteosarcoma.\n\nThe histopathologic response of surgically removed tumors has been shown to be one of most critical indicators of chemotherapeutic effectiveness and survival prognosis.16,17 However, preoperative examination is more valuable to predict tumor response and allow individualized neoadjuvant chemotherapy. Response evaluation criteria in solid tumors version 1.1 (RECIST 1.1), which was commonly adopted for the tumor-response evaluation of a variety of cancers, affirmed the value of sectional radiological imaging measurement.18–20 Therefore, preoperative contrast-enhanced MRI (CE-MRI) evaluation based on RECIST 1.1 is expected to guide the adjustment of treatment for optimal surgical timing in pelvic osteosarcoma.\n\nGiven all these findings, we combined CDDP arterial infusion (CAI) with individualized multidrug systematic chemotherapy (MSC) and surgery (S) to treat nonmetastatic pelvic osteosarcoma and attempted to investigate (1) the chemotherapy response and survival yielded from this protocol, (2) the individualized adjustment of the neoadjuvant MSC regimen necessary to achieve the maximal tumor response according to RECIST-1.1-based CE-MRI reassessment, and (3) the potential adverse effects caused by the arterial infusion technique and the multidrug systematic chemotherapy regimen.\n\nPatients and Methods\nStudy Design and Consent\nThis is a retrospective cohort study (Level III evidence) in which subjects received a protocol comprising multidrug systematic chemotherapy, cisplatin arterial infusion and resection surgery (CAI + MSC + S). The study design conformed with the Declaration of Helsinki, and the treatment protocol was approved by the hospital institutional review board. All patients provided written informed consent for receiving this treatment protocol. All data used in the present study were obtained from the electronic medical records of our hospital and treated with strict confidentiality; therefore, the requirement of obtaining specific informed consent for this retrospective study was waived.\n\nPatients\nInclusion criteria for subjects included (1) histopathologically defined primary osteosarcoma of pelvic bone; (2) no metastatic foci; (3) no past history of cancer treatment; and (4) normal cardiac, hepatic and renal function. All patients were confirmed to have high-grade osteosarcoma morbidity via biopsy. Pretreatment baseline safety indexes were determined with routine blood tests, hepatic and renal function tests, and Doppler echocardiography. A peripherally inserted central catheter was placed in each patient for the IV administration of neoadjuvant chemotherapy agents.\n\nFrom January 2010 to June 2015, 21 patients were consecutively diagnosed with osteosarcoma of the pelvic bones in our work unit. A total of 4 patients were excluded for the following reasons: 2 patients had evidence of distant metastasis, and 2 tumors involved the femur or lumbar vertebra. Among the eligible people, 2 refused to take CAI + MSC + S treatment: 1 had hemophilia with severely impaired coagulation function; 1 intended to transfer to another hospital after being definitively diagnosed via biopsy. Subsequently, 15 patients took the CAI + MSC + S treatment, but 1 of them stopped midway (because of intolerance to vomiting as the adverse effect in the first two rounds of IV multidrug therapy) and turned to other treatment. Two patients were lost to follow-up after surgical resection. Eventually, 12 patients finished the treatment protocol and yielded analyzable data for survival, chemotherapy response and toxicity assessment.\n\nThe data of these 12 patients are listed in Table 1. The study population consisted of 7 (58.3%) males and 5 (41.7%) females with an average age of 28.8 years (11 to 69 years). The morbid sites included the pubis (n = 2), ilium (n = 4), ischium (n = 1), sacrum (n = 1) and unclear sites (n = 4).Table 1 Patient Data\n\nCase No.\tAge (y)\tSex\tTumor Size (cm)\tMorbid Site\tMRI Tumor Response Before Surgery\tSurgical Margins\tHistopathologic Response\tDiagnosis Date\tSurgery Type\tFollow-Up (Month)\tFirst Relapse\tStatus\t\n1\t62\tF\t<8\tUnclear\t+27.4%, PD\tR0\t<90%\t5/19/2010\t1\t42\t\tCDF\t\n2\t19\tM\t<8\tIlium\t−35.1%, PR\tR0\t>90%\t10/4/2010\t2\t46\tJan. 2014\tDOD\t\n3\t14\tM\t<8\tUnclear\t+14.6%, SD\tR0\t95%\t7/23/2011\t2\t52\t\tCDF\t\n4\t53\tF\t>8\tSacrum\t−7.3%, SD\tR1\t<90%\t6/30/2012\t4\t57\tFeb. 2015\tNED\t\n5\t15\tM\t<8\tIlium\t−32.7%, PR\tR0\t>90%\t10/28/2012\t2\t93\t\tCDF\t\n6\t21\tF\t7\tIlium\t+25.9%, PD\tR0\t>90%\t4/24/2013\t2\t87\t\tCDF\t\n7\t16\tM\t>8\tUnclear\t+8.6%, SD\tR1\t<90%\t9/22/2013\t2\t37\tAug. 2015\tDOD\t\n8\t36\tF\t9\tPubis\t−24.1%, SD\tR0\t>90%\t4/14/2014\t2\t76\t\tCDF\t\n9\t69\tM\t12\tIschium\t+43.7% PD\tR1\t<90%\t5/17/2014\t3\t15\tJan. 2015\tDOD\t\n10\t12\tF\t<8\tUnclear\t−37.4%, PR\tR0\t99%\t8/21/2014\t2\t72\t\tCDF\t\n11\t41\tM\t<8\tPubis\t+33.5%, PR\tR0\t>90%\t3/6/2015\t2\t34\t\tCDF\t\n12\t47\tM\t<8\tIlium\t+16.6%, SD\tR0\t95%\t6/30/2015\t2\t62\tDec. 2019\tDOD\t\nNotes: Surgical type = 1) primary lower limb amputation; 2) lower limb salvage surgery; 3) secondary amputation and reresection due to local recurrence; 4) revision surgery due to periprosthetic infection.\n\nAbbreviations: CAI, cisplatin arterial infusion; PR, partial response; PD, progressive disease; SD, stable disease; CAP, cisplatin arterial perfusion; CDF, continuously disease free; NED, no evidence of disease; DOD, died of disease.\n\n\n\n\nDescription of the Study Treatments and Outcome Measures\nThe adopted CAI + MSC + S treatment protocol is depicted in Figure 1. In general, MSCs usually consist of high-dose methotrexate (MTX), vincristine (VCR), adriamycin (ADM), CDDP and ifosfamide (IFO). Specifically, the routine CAI + MSC regimen was initiated with 24-hour continuous IV dripping of high-dose MTX at 10 g/m2 followed by 2 mg IV VCR the next day for the first group at Week 0; in Week 2, 120 mg/m2 CDDP AI over 3 to 6 hours and following 30 mg/m2/d IV ADM for 2 days were given to the second group; these 2 groups were repeated in Weeks 3 and 4; then, the resection surgery was performed 2 weeks after the neoadjuvant chemotherapy was finished. Notably, 160 mg/m2 was determined as the enhanced dosage of CDDP for tumors with the longest diameter over 8 cm in CE-MRI slices. In addition, IV IFO at 2 g/m2/d for 5 days was given in Week 5 for tumors over 8 cm after the 4-week routine regimen was completed. Central venous catheterization for MSC administration was performed under inhalation anesthesia if necessary. Before each CAI regimen, percutaneous punctuation of the femoral artery was performed using the Seldinger technique, and the catheter was inserted from the femoral artery of the contralateral side to the beginning of the artery trunk supplying the tumor with the assistance of CT-guided positioning.21 Then, CT arterial angiography was conducted. Each course of MSC and CAI was accompanied by IV hydration, diuretics, rescue and protecting drugs. The CDDP was perfused via the catheter with chemotherapy pumps (LimLess Infusion Pump; PFM Medical Inc, Cologne, Germany) in a pulsed manner (Bolus dose administrator; PFM Medical Inc, Cologne, Germany). The patients were asked to have strict bed rest under multiparameter monitoring. Routine blood tests for electrolytes and hepatic and renal function were performed on the first day after drug administration and every 3 days thereafter.Figure 1 The individualized pelvic osteosarcoma treatment protocol combined cisplatin arterial infusion, multidrug systematic chemotherapy and resection surgery (CAI + MSC + S).\n\n\n\nTo evaluate the therapeutic response, primary plain X-ray (Figure 2A) and physical examination parameters of the tumor, including pre- and postchemotherapy size, tenderness, pain and inflammation, were collected. More importantly, CE-MRI was performed to monitor the tumor chemotherapy response before and after routine neoadjuvant CAI + MSC administration. (Figure 2B–E) According to the RECIST 1.1 guidelines, tumor size was calculated in gadolinium-enhancing T1-weighted fat‐saturated coronal images using the following criteria: complete response (CR), complete elimination of target lesion; partial response (PR), ≥30% decrease in the diameter of target lesion compared to baseline); progressive disease (PD), ≥20% increase in the diameter of target lesion compared to baseline or new metastatic lesion); and stable disease (SD) or observed changes in the diameter of the target lesion between 30% decrease and 20% increase compared to baseline. Each tumor lesion was assessed by orthopedic oncologists and interventional radiologists who were blinded to the treatment allocation and clinical outcome data. For patients who achieved PD after the routine neoadjuvant regimen was finished, surgery was performed immediately. For patients who demonstrated CR or PR, surgery was performed 2 weeks after the neoadjuvant regimen as usual. For patients who presented SD, the same IFO course as that mentioned in the adjustment for large tumors was added to maximize the tumor response of the neoadjuvant regimen. Then, a multidisciplinary consultation was conducted to identify the achievement of maximal tumor response. If any uncertainty of maximal response achievement was left, one more course of IFO could be given, and patients received resection surgery no later than 9 weeks after the first diagnosis.Figure 2 (A) Pelvis X-ray of a 36-year-old female with an osteosarcoma in the pubis. (B) and (C) Fat-saturated T1- and T2-weighted coronal slices of contrast-enhanced MRI showing the maximum diameter of the tumor at the first diagnosis, which showed heterogeneous enhancement, thick septa and obscure boundaries of the tumor. (D) and (E) MRI reevaluation after completion of the neoadjuvant CAI + MSC regimen, showing thin septa, clear boundaries and stable disease according to RECIST 1.1 with a decrease in the tumor diameter. (F) Pelvis plain X-ray of this patient. (The identifiable captions in these images are occluded.).\n\n\n\nA chest CT scan, a full-body bone scan and a pelvic CE-MRI scan (Figure 2D and E) were repeated before surgery. The tumor response per RECIST 1.1 measured in the last CE-MRI examination was compared with the baseline level. Surgical excision extension was determined by the involved scope of the tumor and the tumor response category according to the CE-MRI assessment per RECIST 1.1. The pelvic reconstruction project depended on the morbidity site, excision extension, bone mineral density and functional requirements.\n\nIn case of uncontrollable hemorrhage during the resection surgery, a temporary balloon blocking technique for the abdominal aorta was performed under the guidance of CTA 4 hours before resection surgery. A balloon compatible in size to the abdominal aortic diameter was placed intraarterially at the level of 2 to 3 cm above the bifurcation of the common iliac arteries. The injection of saline with 0.1% heparin inflated the balloon, consequently blocking blood perfusion of the surgical site. Angiography was performed to confirm the satisfactory blockage of the iliac arteries and unobstruction of the renal arteries. Then, the balloon was deflated until the surgery began. Each deflation was performed with an interval of 60 min during the resection surgery before satisfactory hemostasis was achieved.\n\nHistopathologic examination was conducted using the method reported by Huvos et al to quantify the necrosis ratio of the tumor after removal.22 Patients with a ≥90% tumor necrosis rate (TNR) (Grade III and IV) were classified as good responders. The other (Grade Ⅰ and Ⅱ) were deemed poor responders.\n\nThe postoperative IV chemotherapy cycle was repeated every 3 weeks. The recovery of hematopoietic function in patients was required before each course, which was defined as a white blood cell count over 1×104/mm3 and a platelet count over 5×106/mm3 for 3 successive days without hematopoietic stimulants. For good responders, the duration of postoperative MSC was usually 3 courses, which could be extended to the maximum of 6 courses accompanied by the existence of high-risk factors, including SD or PD in the CE-MRI per RECIST 1.1 before surgery or histology-proven tumor involvement in the surgical margin (R1 resection). For poor responders, IFO at 2 g/m2/d for 5 days and etoposide (ETOP) at 100 mg/m2/d for 5 days were given sequentially as one cycle repeated every 3 weeks for 6 cycles.23\n\nAfter the planned treatment was finished, the discontinuation of chemotherapy was allowed by the orthopedic oncologist if X-ray (Figure 2F) and CE-MRI of the primary morbidity site along with chest X-ray every 2 months, chest CT scanning every 6 months in the first year off the treatment prove no local recurrence or lung metastasis. Routine blood tests and hepatic and renal function tests were deployed every week until the recovery of hematopoietic function.\n\nStatistical Analysis\nWe used the Kaplan-Meier method to analyze the overall survival (OS) and EFS, which were calculated from the day the preoperative MSC + CAI regimen began. The events were defined as local recurrence, distant metastasis or death from the disease. Additionally, the OS and EFS in groups with different histopathologic chemotherapy responses or tumor sizes were calculated. All statistical analyses were conducted with SPSS software packages (SPSS Inc., Chicago, IL, USA).\n\nResults\nChemotherapy Response\nSignificant improvement in physical examination parameters was observed in 10 of 12 patients after the neoadjuvant regimen, including alleviation of pain. In terms of tumor response measurement per RECIST 1.1, 4 patients had PR and 5 had SD after routine neoadjuvant CAI + MSC administration. Three patients had to undergo resection surgery ahead of schedule because of PD, as shown by CE-MRI after neoadjuvant CAI + MSC administration. No patient demonstrated CR.\n\nAccording to the histopathologic assessment, 66.7% (8 of 12) of patients demonstrated TNR over 90%. One of the 3 patients with PD according to the CE-MRI assessment turned out to be good responders with Grade III histopathologic results.\n\nSurgery\nThree patients underwent local radical excision and lower limb amputation because of neurovascular bundle involvement. The remaining 9 patients received limb salvage surgery followed by pelvic reconstruction using a modular prosthesis (Lidakang Inc., Beijing, China), tumor bone devitalization and replantation, or just bone fusion. As a result, 1 patient who underwent primary limb salvage surgery developed local recurrence and underwent secondary amputation and local reresection. Two patients had surgical site infections but were cured 2 months after surgery. One patient who developed a periprosthetic infection underwent a secondary amputation.\n\nSurvival\nA total of 58.3% of patients (7 of 12) remained continuously disease free in an average follow-up period of 65.1 months (range, 34–93 months). One patient who developed local recurrence was proven alive with no evidence of disease for 31 months after receiving a secondary amputation and resection. Four patients (3 lung metastases and 1 local recurrence) died of refractory disease progression. Kaplan-Meier survival analysis suggested an OS rate of 57.8% and an EFS of 52.5% at 5 years (Figure 3). For patients with a good chemotherapy response, the 5-year OS and EFS rates were 68.6%, both of which showed significant differences (P = 0.04 for OS and 0.01 for EFS) compared with the corresponding measures for poor responders (Table 2). The comparison of patients with tumor sizes greater (n = 4) or less (n = 8) than 8 cm did not yield statistical significance (P = 0.32 and 0.13, respectively). As shown in the pathological report, 75% (9 of 12) patients received R0 resection and 25% (3 of 12) had R1 resection. There was no significant difference in the OS but in the EFS between patient group with R0 or R1 surgical resection (P = 0.15 and 0.05, respectively). The confidence interval of all OS and EFS are 95%.Table 2 Overall Survival (OS) and Event-Free Survival (EFS) Rate\n\nVariables\t1 y\t5 y\t\nAll patients – OS\t91.7%\t57.8%\t\nAll patients – EFS\t91.7%\t52.5%\t\nGood responders – OS\t100.0%\t68.6%\t\nGood responders – EFS\t100.0%\t68.6%\t\nPoor responders – OS\t75.0%\t50.0%\t\nPoor responders – EFS\t75.0%\t25.0%\t\nPatients with tumor size ≥8 cm – OS\t75.0%\t50.0%\t\nPatients with tumor size ≥8 cm – EFS\t75.0%\t25.0%\t\nPatients with tumor size<8 cm – OS\t100.0%\t62.5%\t\nPatients with tumor size<8 cm – EFS\t100.0%\t64.3%\t\nR0 resection – OS\t85.7%\t70.0%\t\nR0 resection – EFS\t88.9%\t71.1%\t\nR1 resection – OS\t66.7%\t33.3%\t\nR1 resection – EFS\t66.7%\t33.3%\t\nNote: Confidence Interval = 95%\n\n\nFigure 3 The Kaplan-Meier survival curve for overall survival (OS) and event-free survival (EFS) rates of 12 pelvic osteosarcoma patients treated with the CAI + MSC + S protocol.\n\n\n\nChemotherapy Toxicity\nWe recorded the adverse effects referred to in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.24 The statistics of CAI-related adverse events are summarized in Table 3. Three of 12 patients had local adverse events, including grade 1 to 2 skin pelvic soft tissue necrosis in muscle and hyperpigmentation, which exhibited no effect on the surgical method choice or wound healing. Nausea and vomiting were the most common systematic adverse events, with 41.7% of patients developing grade 3 events. A 36-year-old female received a reduced dosage of MTX (7 g/m2) due to intolerable vomiting after the first MTX course. Four of 12 patients developed grade 1 infusion-related reactions.Table 3 Statistics of CAI-Related Adverse Events\n\nAdverse Events\tNo. of Courses\tPercentage of Patients with Grade 3–4 Adverse Events\t\nSkin hyperpigmentation\t12.5% (3/24)\t0% (0/12)\t\nPelvic soft tissue necrosis (muscle)\t4.2% (1/24)\t0% (0/12)\t\nPelvic pain\t16.7% (4/24)\t8.3% (1/12)\t\nNausea and vomiting\t75.0% (18/24)\t41.7% (5/12)\t\nAnemia\t8.3% (2/24)\t8.3% (1/12)\t\nIncrease in creatinine level\t8.3% (2/24)\t0% (0/12)\t\nIncrease in aminotransferase level\t4.2% (1/24)\t0% (0/12)\t\nInfusion related reaction\t29.2% (7/24)\t0% (0/12)\t\n\n\n\nDuring the postoperative MSC period, one 12-year-old child complained of grade 1 palpitations and chest pain. Therefore, we replaced ADM with ETOP, and the complaint disappeared with no evidence reported in Doppler echocardiography. Three patients out of 12 developed grade 1 to 2 increases in alanine/aspartate aminotransferase levels.\n\nThree children developed oral mucositis at grade 2 to 3, 2 of whom were under IV nutrition, and one used a mouth rinse with metronidazole to treat thrush. All patients eventually resumed normal oral food intake.\n\nBlood system disorders were commonly noted in patients after the second cycle of postoperative MSC administration. Three patients developed febrile neutropenia and were treated by injection of recombinant human granulocyte stimulating factor.\n\nDiscussion\nConventional IV adjuvant chemotherapy and neoadjuvant chemotherapy have been applied extensively in multimodal osteosarcoma treatment for over 45 years.25 Though changes in drug combination, dosage, and administration duration were made to optimize the regimen, no significant improvement was achieved based on the approximately 50% to 70% 5-year OS and EFS rates in the past decade.26–28 As a modified approach to augment the potential of chemotherapy drugs, the AI technique combined with MSCs has been studied for years.13,29,30 In the present study, we attempted to investigate the therapeutic effect of the CAI + MSC + S protocol in osteosarcoma treatment. The 5-year OS and EFS rates were 57.8% and 52.5%, respectively.\n\nThe CAI regimen and its outcome measurements were first documented by Jaffe et al in 1983.31 Then, a series of studies concerning CAI-facilitated multidrug chemotherapy followed.13,30,32–37 Information on all 9 studies, including the present study, is listed in Table 4.Table 4 Synopsis of IA CDDP Information Reported in the Literature\n\nAuthors\tType of Study\tNo. of Patients\tAges (y)\tSites\tMetastases\tPreoperative CDDP Courses No.\t>90% TN\tOS\tEFS\t\nWinkler et al and Fuchs et al30,34\tNonrandomized, 2 arms\t50\t<40\tAll\tIncluded\t2\t68%\t67% at 10 y\t63% at 10 y\t\nFerrari et al33\tSingle arm\t164\t<40\tExtremity\tExcluded\t2\tNA\t72% at 8 y\t63% at 8 y\t\nFerrari et al33\tRandomized, 2 arms\t59\t<40\tExtremity\tExcluded\t2\t64%\t61% at 8 y\t54% at 8 y\t\nRha et al35\tSingle arm\t37\t8~41\tExtremity\t?\t3\t75%\t78% at 3 y\t55% at 3 y\t\nBacci et al32\tRandomized, 2 arms\t40\t<40\tExtremity\tIncluded\t2\t77%\tNA\t26% at 5 y\t\nBacci et al32\tRandomized, 2 arms\t72\t<40\tExtremity\tIncluded\t2\t80%\tNA\t61% at 5 y\t\nWilkins et al37\tSingle arm\t47\t<21\tExtremity\tExcluded\t3–5 (response dependent)\t87%\t92% at 10 y\t84% at 10 y\t\nWilkins et al36\tSingle arm\t62\t<22\tExtremity\tExcluded\t3–5 (response dependent)\t87%\t93% at 10 y\t86% at 10 y\t\nXie et al13\tNonrandomized, 2 arms\t48\tNA\tExtremity\tIncluded\t3\t63%\t64% at 5 y\t60% at 5 y\t\nHu et al (Current study)\tSingle arm\t12\t11~69\tPelvis\tExcluded\t2\t66.7%\t57.8% at 5 y\t52.5% at 5 y\t\nAbbreviations: IA, intraarterial; CDDP, cisplatin; TN, tumor necrosis; OS, overall survival; EFS, event-free survival.\n\n\n\n\nAmong these 9 studies, 8 used CAI and systematic chemotherapy sequentially before surgery, and 5 studies scheduled a 2-course preoperative regimen. Six of 9 studies suggested a higher chemotherapy response rate and/or survival rate in the CAI group compared with the IV CDDP group; 2 of these investigations were 2-arm randomized cohort studies and reported a statistically significant improvement in the good-response ratio (21% and 31%, respectively). In the third randomized cohort study reported by Rha et al, the improvement was not statistically significant, probably because the limited sample size was insufficient to test the 9% difference between the two groups.35 In the multicenter study reported by Winkler et al and Fuchs et al in the 1990s, no difference in chemotherapy response was observed between the intraarterial and IV CDDP groups.30,34 Similarly, Xie et al also proved a superior histological response rate but equivalent survival in the CAI group versus the IV group in 2019.13 However, the reliability of the conclusions in the 2 studies may be impaired by the nonrandomized grouping design conducted at the researchers’ discretion, which could be affected by the severity of disease. Although CAI may bring benefits to chemotherapy response augmentation and survival rates in limb osteosarcoma patients, how pelvic osteosarcoma reacts to CAI-facilitated multidrug chemotherapy remains elusive.\n\nPelvic tumor resection surgeries such as hemipelvectomy are notoriously known as one of the most destructive operations in modern orthopedic surgery.38 Due to the adjacency of the vascular network, nerves and viscera in the pelvis, surgeons have to weigh tumor eradication against functional preservation in the determination of the extent of surgical excision. This dilemma makes the treatment more challenging. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate compared with the extremity-morbidity population, which could be explained by the higher rate of not only failure of surgical remission but also advanced age, large tumor size, primary metastasis, prolonged latency periods and poor chemotherapy responses.11,39 Thus, it is critical to maximize the chemotherapy response and achieve better survival outcomes in pelvic osteosarcoma patients.\n\nThe combination of agents in our MSC protocol was determined by reference to NCCN guidelines for bone cancer and the study reported by Xie et al.13 Although the agent numbers and categories differed, all of the above-reviewed studies and the present study deployed a multidrug protocol to treat tumor cells in different phases of the cell cycle. Unfortunately, insufficient data are available to appropriately compare the therapeutic effect of CAI alone or in various combinations with MTX, VCR, ADM and IFO because of great heterogeneity. In the present study, we used high-dose MTX at 10 g/m2 and CAI at 120 mg/m2 in 2 doses as routine preoperative treatment. For patients with tumors over 8 cm, we employed an enhanced dose of CAI at 160 mg/m2. Additionally, additional IFO courses were given to slow responders. This individualized regimen directly yielded a 66.7% prevalence of good histopathologic responders and contributed to the 5-year survival rate of 57.8% in pelvic osteosarcoma. Both of the two figures were seemingly improved when compared to those from conventional systematic chemotherapy.11\n\nThe cumulative dosage of CDDP was 780 mg/m2 for a good responder with a tumor size ≤ 8 cm in the present study. Wilkins et al reported the highest accumulated dose of CDDP at 960 mg/m2 and a single dose at 160 mg/m2 over 24 h as an enhanced regimen for patients with tumors over 10 cm versus 120 mg/m2 over 6 h as routine, which consequently yielded the highest 10-year OS and EFS rates (93% and 86%, respectively) among all reviewed studies. Notably, Ferrari et al and Xie et al investigated CDDP administration at equivalent doses to those in the present study but yielded poorer survival outcomes seemingly.13,33 This may be because 120 mg/m2 CDDP was given intraarterially in 72 h in the first study, which is too long to achieve a high enough blood concentration; patients with tumor metastases at the initial diagnosis were included in the second study so that the survival rate would be reduced. We used relatively high-dose CDDP administered over 3 to 6 h combined with 4 other drugs, including ETOP, and made individualized adjustments to the protocol for patients with high-risk factors. This may have contributed to the 57.8% OS and 52.5% EFS rate at 5 years, which is favorable for pelvic osteosarcoma. Moreover, we discovered that the OS and EFS rates in the population with tumors ≤ or >8 cm showed insignificant differences. Patients who received R0 resection also shared equivalent OS but higher EFS with R1 patients. These finding suggest that this protocol with risk-dependent adjustment in the drug dosage and combination could be beneficial to bridge the gap in survival rate between patients with large or small tumors, and those who received R0 or R1 resection.\n\nWe noticed that 3 of 5 cases developing SD turned out to demonstrate TNR >90%, which probably means that good response of osteosarcoma is not necessarily accompanied with tumor size decrease. This may be attributed to the formation of tumor bone generated by subtypes like osteoblastic osteosarcoma, which could prevent tumors from shrinkage.40\n\nOnly 4 poor responders were observed, 3 of whom developed tumor relapses. Two of the 3 patients died of metastasis during postoperative MSC; another showed no evidence of disease after receiving secondary amputation and resection for local recurrence. This protocol seemed to provide limited benefit to the poor responders. However, the present data are so limited that few tenable conclusions can be drawn from it to guide salvage treatment for poor responders.\n\nAlthough the AI technique and additional courses were given in this protocol, no patients received an overdose of chemotherapy drugs compared with previous studies using similar drug combinations. No AI-relative grade 4 or 5 adverse events were observed. Although systematic adverse events, including nausea, vomiting, anemia and an increase in creatinine/aminotransferase levels, shared equivalent incidence rates and severities with the study reported by Xie et al, local skin hyperpigmentation and pelvic soft tissue necrosis in muscle occurred after only 3 and 1 of 24 CAI events (12.5% and 4.2%, respectively), which is more favorable than the situation reported in the most reviewed studies concerning extremity osteosarcoma.13,30,33 This finding could be explained by the shorter local drug-retention time since the pelvis has a more sufficient blood supply and drainage.\n\nIn terms of the postoperative MSC regimen for poor responders, we determined the IFO + ETOP regimen by reference to the second-line chemotherapy recommended in NCCN guidelines for bone cancer, which is supported by the study reported by Goorin et al and Miser et al.23,41 These two studies were conducted in patients with initial metastasis or recurrence of osteosarcoma, and the former one used IFO + ETOP as an induction regimen accompanied by surgical resection and continuation MSC of MTX + ADM + ETOP + IFO. Therefore, we adopted the regimen similar as the one reported by Miser et al However, the study of EURAMOS reported by Marina et al suggested that treatment with MTX + ADM + CDDP + IFO + ETOP resulted in similar EFS to MTX + ADM + CDDP and increased toxicity. In the present study, we found it hard for patients to accept 12 cycles of second-line therapy in 3 years in view of the high expenditure and physical discomfort. Therefore, the number of cycles was reduced to 6 for poor responders, which is equivalent to a half of the regimen of Miser et al in accumulative dosage and duration time. During the postoperative MSC period, there was no early death. The reported cardiac irritation, increase in creatinine/aminotransferase, oral mucosa inflammation and hematologic system abnormality were acceptable. In summary, our chemotherapy regimen seems to be well tolerated.\n\nTo monitor the chemotherapy response, several methods have been reported in previous studies. In the studies reported by Winkler et al and Fuch et al, plain X-ray, local CT and emission CT of bone were used to monitor the TNR before the surgery.30,34 Bacci et al, Wilkins et al and Xie et al deployed CT arterial angiography, which yielded sensitivity and specificity over 90% and 50%, respectively.13,32,36,37 Nevertheless, a repeated CT arterial angiography assessment is difficult to be accepted by patients because it requires multiple invasive operations and high expenditure. RECIST-1.1-based MRI remains one of the most commonly used approaches in tumor response evaluation.42,43 In the present study, we used CE-MRI to detect the tumor response and guide the adjustment of treatment for each patient. Although the results did not seem to suggest that this method is highly predictive of the histopathologic chemotherapy response, the equivalent survival rate between patients with large and small tumors may reflect the effectiveness of the individualized treatment.\n\nThere were several limitations in our investigation. First, the design was restricted to a small-sample-size single-arm clinical study due to the rarity of pelvis osteosarcoma morbidity, therefore reducing the reliability of the conclusions. Second, several previous studies reported that pathological subtypes of osteosarcoma, such as chondroblastic and telangiectatic osteosarcoma, respond differently to chemotherapy.39,44 However, the pathological subtype of each patient was not analyzed as an independent prognostic factor in our study. Heterogeneity of the osteosarcoma subtype constitution could distort chemotherapy response and survival outcomes. Third, we used CE-MRI per RECIST 1.1 to monitor the tumor response before surgery and guide the individualized adjustment of the treatment protocol. However, CE-MRI evaluation was not the gold standard for TNR prediction. Multiple innovative approaches for TNR prediction in osteosarcoma have been researched in the past 30 years, such as dynamic CE-MRI with sensitivity and specificity over 70% and 80%, respectively, according to previous studies.45–47 We would attempt to deploy approaches with higher accuracy to evaluate viable tumors in hope of providing more precise guidance for individualized pelvic osteosarcoma treatment in further studies.\n\nConclusions\nIn the present study, we employed CAI in the multimodal treatment of pelvic osteosarcoma patients. Our findings suggest that the CAI-facilitated chemotherapy regimen demonstrated great potential for improving the survival of patients with pelvic osteosarcoma. This treatment protocol yielded high tolerance with acceptable adverse effects. However, further randomized controlled trials with large sample sizes are required to elucidate the findings of this preliminary study.\n\nAcknowledgments\nWe would like to thank all patients for their devotion to taking unidentified risks in this clinical trial. We are also grateful to the participating orthopedic oncologists and interventional radiologists for their prudence and patience in the therapeutic effect evaluation and the multidisciplinary consultation.\n\nAbbreviations\nADM, adriamycin; CAI, effect of cisplatin arterial infusion; CDDP, cis-diamine-dichloro platinum; CE-MRI, contrast-enhanced MRI; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; EFS, event-free survival; ETOP, etoposide; IFO, ifosfamide; IV, intravenous; MSC, multidrug systematic chemotherapy; MTX, methotrexate; OS, overall survival; PD, progressive disease; PR, partial response; RECIST, response evaluation criteria in solid tumors version; S, surgery; SD, stable disease; TNR, tumor necrosis rate; VCR, vincristine.\n\nData Sharing Statement\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthics Approval and Informed Consent\nThis study was approved by the ethics committees and the institutional review board of the Second Xiangya Hospital. All patients provided written informed consent for receiving this treatment protocol. The requirement of obtaining specific informed consent for this retrospective study was waived for the reason mentioned before.\n\nConsent for Publication\nThis study conforms to Declaration of Helsinki. The requirement of obtaining specific informed consent from the patients for the publication of the case presentation and any accompanying images.\n\nAuthor Contributions\nAll authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.\n\nDisclosure\nNo commercial sponsorship was involved in any part of this study. 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Fuchs \nN , Bielack \nSS , Epler \nD , et al. Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group’s protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs\n. Ann Oncol . 1998 ;9 (8 ):893 –899\n. doi:10.1023/a:1008391103132 9789613 \n35. Rha \nSY , Chung \nHC , Gong \nSJ , et al. Combined pre-operative chemotherapy with intra-arterial cisplatin and continuous intravenous adriamycin for high grade osteosarcoma\n. Oncol Rep . 1999 ;6 (3 ):631 –637\n. doi:10.3892/or.6.3.631 10203605 \n36. Wilkins \nRM , Cullen \nJW , Camozzi \nAB , Jamroz \nBA , Odom \nL . Improved survival in primary nonmetastatic pediatric osteosarcoma of the extremity\n. Clin Orthop Relat Res . 2005 ;&NA; (438 ):128 –136\n. doi:10.1097/01.blo.0000179736.10871.76 \n37. Wilkins \nRM , Cullen \nJW , Odom \nL , et al. Superior survival in treatment of primary nonmetastatic pediatric osteosarcoma of the extremity\n. Ann Surg Oncol . 2003 ;10 (5 ):498 –507\n. doi:10.1245/aso.2003.03.061 12794015 \n38. van Houdt \nWJ , Griffin \nAM , Wunder \nJS , Ferguson \nPC . Oncologic outcome and quality of life after hindquarter amputation for sarcoma: is it worth it?\n\nAnn Surg Oncol . 2018 ;25 (2 ):378 –386\n. doi:10.1245/s10434-017-5806-6 28321692 \n39. Song \nWS , Cho \nWH , Jeon \nDG , et al. Pelvis and extremity osteosarcoma with similar tumor volume have an equivalent survival\n. J Surg Oncol . 2010 ;101 (7 ):611 –617\n. doi:10.1002/jso.21540 20461769 \n40. Liu \nC , Xi \nY , Li \nM , et al. Monitoring response to neoadjuvant chemotherapy of primary osteosarcoma using diffusion kurtosis magnetic resonance imaging: initial findings\n. Korean J Radiol . 2019 ;20 (5 ):801 –811\n. doi:10.3348/kjr.2018.0453 30993931 \n41. Goorin \nAM , Harris \nMB , Bernstein \nM , et al. Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial\n. J Clin Oncol . 2002 ;20 (2 ):426 –433\n. doi:10.1200/jco.2002.20.2.426 11786570 \n42. Eisenhauer \nEA , Therasse \nP , Bogaerts \nJ , et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)\n. Eur J Cancer . 2009 ;45 (2 ):228 –247\n. doi:10.1016/j.ejca.2008.10.026 19097774 \n43. Tawbi \nHA , Burgess \nM , Bolejack \nV , et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial\n. Lancet Oncol . 2017 ;18 (11 ):1493 –1501\n. doi:10.1016/s1470-2045(17)30624-1 28988646 \n44. Fahey \nM , Spanier \nSS , Vander Griend \nRA . Osteosarcoma of the pelvis. A clinical and histopathological study of twenty-five patients\n. J Bone Joint Surg Am . 1992 ;74 (3 ):321 –330\n. doi:10.2106/00004623-199274030-00002 1548258 \n45. Erlemann \nR , Sciuk \nJ , Bosse \nA , et al. Response of osteosarcoma and Ewing sarcoma to preoperative chemotherapy: assessment with dynamic and static MR imaging and skeletal scintigraphy\n. Radiology . 1990 ;175 (3 ):791 –796\n. doi:10.1148/radiology.175.3.2188300 2188300 \n46. Torricelli \nP , Montanari \nN , Spina \nV , et al. Dynamic contrast enhanced magnetic resonance imaging subtraction in evaluating osteosarcoma response to chemotherapy\n. Radiol Med . 2001 ;101 (3 ):145 –151\n.11402952 \n47. Kubo \nT , Furuta \nT , Johan \nMP , Adachi \nN , Ochi \nM . Percent slope analysis of dynamic magnetic resonance imaging for assessment of chemotherapy response of osteosarcoma or Ewing sarcoma: systematic review and meta-analysis\n. Skeletal Radiol . 2016 ;45 (9 ):1235 –1242\n. doi:10.1007/s00256-016-2410-y 27229874\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-1322",
"issue": "13()",
"journal": "Cancer management and research",
"keywords": "arterial infusion; chemotherapy toxicity; cisplatin; osteosarcoma; pelvis",
"medline_ta": "Cancer Manag Res",
"mesh_terms": null,
"nlm_unique_id": "101512700",
"other_id": null,
"pages": "1491-1503",
"pmc": null,
"pmid": "33623429",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "20461769;30405759;28988646;3114435;30993931;29912746;4203933;31447583;6932827;32845986;1884563;11402952;19097774;10203605;1548258;24797726;7645476;11821461;29210294;2208024;16298125;19197972;11669597;32452026;29445029;12357307;9789613;11237499;27400942;32742918;16105923;16131881;30685685;28321692;25688494;2188300;29915436;299812;6571796;27569442;10774566;31739675;32243077;162853;27229874;11786570;12794015",
"title": "Effect of Cisplatin Arterial Infusion (CAI) on Primary Nonmetastatic Pelvic Osteosarcoma: A Preliminary Study.",
"title_normalized": "effect of cisplatin arterial infusion cai on primary nonmetastatic pelvic osteosarcoma a preliminary study"
} | [
{
"companynumb": "CN-PFIZER INC-202101169692",
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"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
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{
"abstract": "Psoriasis is a chronic inflammatory skin disease that is characterized by well-demarcated erythematous plaques with a silver scale. Although many new and emerging therapeutic agents are often sufficient to control the disease, there is still a need for alternative treatment options in challenging cases. Extracorporeal photopheresis (ECP) has been applied to many T-cell-mediated diseases to restore immune homeostasis and treat psoriasis effectively. In this paper, we present a psoriasis patient who did not respond to methotrexate, narrowband ultraviolet B, or acitretin. Because of a diagnosis of non-Hodgkin lymphoma, the patient had contraindications for cyclosporine, fumaric acid esters, and biologics but achieved remission with a total of 12 sessions of ECP in two and a half months. Although exacerbation was recorded after polymerase chain reaction (PCR) confirmed coronavirus 2019 (COVID-19) disease infection at the end of the first month, scores from the psoriasis area severity index (PASI) and dermatological life quality index (DLQI) were regressed significantly within two and a half months. ECP seems to provide an effective and rapid response for psoriasis and should be considered for psoriasis patients who fail to respond or have contraindications to existing treatments.",
"affiliations": "Departments of Dermatology and Venereology, University of Health Sciences, Gulhane Training and Research Hospital, Ankara, Turkey. Electronic address: pelinnesme@gmail.com.;Departments of Dermatology and Venereology, University of Health Sciences, Gulhane Training and Research Hospital, Ankara, Turkey. Electronic address: semanurcobnn@gmail.com.;Departments of Hematology, University of Health Sciences, Gulhane Training and Research Hospital, Ankara, Turkey. Electronic address: uurbilge@yahoo.com.;Departments of Hematology, University of Health Sciences, Gulhane Training and Research Hospital, Ankara, Turkey. Electronic address: ayli.meltem@gmail.com.;Departments of Dermatology and Venereology, University of Health Sciences, Gulhane Training and Research Hospital, Ankara, Turkey. Electronic address: drecaliskan@yandex.com.",
"authors": "Esme|Pelin|P|;Coban|Sema Nur|SN|;Ugur|Bilge|B|;Aylı|Meltem|M|;Caliskan|Ercan|E|",
"chemical_list": "D016572:Cyclosporine; D017255:Acitretin; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1016/j.transci.2021.103200",
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"issn_linking": "1473-0502",
"issue": "60(5)",
"journal": "Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis",
"keywords": "Comorbidity; Extracorporeal photopheresis; Management; Psoriasis; Treatment",
"medline_ta": "Transfus Apher Sci",
"mesh_terms": "D017255:Acitretin; D000086382:COVID-19; D056486:Chemical and Drug Induced Liver Injury; D003131:Combined Modality Therapy; D000075203:Contraindications, Drug; D016572:Cyclosporine; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009262:Nails; D058873:Pandemics; D017893:Photopheresis; D011565:Psoriasis; D011788:Quality of Life; D000086402:SARS-CoV-2; D012720:Severity of Illness Index; D014467:Ultraviolet Therapy",
"nlm_unique_id": "101095653",
"other_id": null,
"pages": "103200",
"pmc": null,
"pmid": "34215520",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of psoriasis successfully treated by extracorporeal photopheresis during COVID-19 pandemic.",
"title_normalized": "a case of psoriasis successfully treated by extracorporeal photopheresis during covid 19 pandemic"
} | [
{
"companynumb": "TR-ACCORD-231777",
"fulfillexpeditecriteria": "2",
"occurcountry": "TR",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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"dr... |
{
"abstract": "There are no reports of adjuvant treatments for early breast cancer causing hearing loss. Yet in this exploratory study 14/16 women who had received Fluorouracil, Epirubicin and Cyclophosphamide (FEC) chemotherapy regimen, 11 of whom also received endocrine treatment, had reduced hearing sensitivity, with 9/16 being atypical. It is not clear whether this finding is related to oestrogen reduction and/or ototoxicity but a more detailed investigation in this area is warranted given the large number of women with breast cancer who receive adjuvant treatments.",
"affiliations": "Cancer Research UK Psychosocial Oncology Group, Brighton and Sussex Medical School, University of Sussex, Falmer, East Sussex, and Department of Audiology, Royal Sussex County Hospital, Brighton, UK. val@sussex.ac.uk",
"authors": "Jenkins|V|V|;Beveridge|H|H|;Low|R|R|;Mitra|S|S|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.breast.2005.06.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-9776",
"issue": "15(3)",
"journal": "Breast (Edinburgh, Scotland)",
"keywords": null,
"medline_ta": "Breast",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001301:Audiometry, Pure-Tone; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D005260:Female; D034381:Hearing Loss; D006801:Humans; D008875:Middle Aged; D010865:Pilot Projects",
"nlm_unique_id": "9213011",
"other_id": null,
"pages": "448-51",
"pmc": null,
"pmid": "16135407",
"pubdate": "2006-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Atypical hearing loss in women with breast cancer receiving adjuvant treatment.",
"title_normalized": "atypical hearing loss in women with breast cancer receiving adjuvant treatment"
} | [
{
"companynumb": "GB-MYLANLABS-2019M1087479",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
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... |
{
"abstract": "To investigate a clinical outcome after more than 4 years for polypoidal choroidal vasculopathy (PCV) treated with anti-vascular endothelial growth factor (VEGF) therapy and to investigate the factors predictive of long-term visual outcomes.\n\n\n\nThis retrospective study included 31 eyes, with PCV treated with anti-VEGF therapy (either ranibizumab or bevacizumab, or both), and were followed up for 4 years or longer. The best-corrected visual acuity (BCVA) at baseline was compared with that measured at 3 months and at the final follow-up. Factors associated with final visual acuity were also analyzed.\n\n\n\nThe mean follow-up period was 53.0 ± 4.3 months. During the follow-up period, the patients were treated with an average of 8.8 ± 3.0 intravitreal anti-VEGF injections. BCVA at diagnosis at 12, 24, and 36 months, and at final follow-up was 0.52 ± 0.35, 0.46 ± 0.36, 0.57 ± 0.45, 0.76 ± 0.56, and 0.83 ± 0.60, respectively. When compared to the baseline value, the BCVA was significantly improved at 3 months (P = 0.006), whereas the BCVA at final follow-up was significantly decreased compared to the baseline value (P = 0.018). Among the included eyes, 48.4% experienced deterioration of visual acuity and 51.6% showed stable vision. BCVA at 12 months was most strongly associated with visual acuity at final follow-up.\n\n\n\nAlthough the long-term treatment outcome of PCV is generally unfavorable, stable vision can be achieved in approximately half of the patients. Visual acuity at 12 months after the initial treatment is predictive of long-term visual outcomes.",
"affiliations": "1 Department of Ophthalmology, Konyang University College of Medicine , Daejeon, South Korea .;2 Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine , Seoul, South Korea .;2 Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine , Seoul, South Korea .;2 Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine , Seoul, South Korea .;2 Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine , Seoul, South Korea .;2 Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine , Seoul, South Korea .;2 Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine , Seoul, South Korea .",
"authors": "Chang|Young Suk|YS|;Kim|Jae Hui|JH|;Kim|Kyung Min|KM|;Kim|Jong Woo|JW|;Lee|Tae Gon|TG|;Kim|Chul Gu|CG|;Cho|Sung Won|SW|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D042442:Vascular Endothelial Growth Factors; D000068258:Bevacizumab; D000069579:Ranibizumab",
"country": "United States",
"delete": false,
"doi": "10.1089/jop.2015.0073",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1080-7683",
"issue": "32(4)",
"journal": "Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics",
"keywords": null,
"medline_ta": "J Ocul Pharmacol Ther",
"mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D020256:Choroidal Neovascularization; D005260:Female; D006801:Humans; D008297:Male; D000069579:Ranibizumab; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D042442:Vascular Endothelial Growth Factors",
"nlm_unique_id": "9511091",
"other_id": null,
"pages": "219-24",
"pmc": null,
"pmid": "26991591",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Long-Term Outcomes of Anti-Vascular Endothelial Growth Factor Therapy for Polypoidal Choroidal Vasculopathy.",
"title_normalized": "long term outcomes of anti vascular endothelial growth factor therapy for polypoidal choroidal vasculopathy"
} | [
{
"companynumb": "KR-ROCHE-1731493",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "High out-of-pocket drug costs can cause patients to skip treatment and worsen outcomes, and high insurer drug payments could increase premiums. Drug wholesale list prices have doubled in recent years. However, because of manufacturer discounts and rebates, the extent to which increases in wholesale list prices are associated with amounts paid by patients and insurers is poorly characterized.\n\n\n\nTo determine whether increases in wholesale list prices are associated with increases in amounts paid by patients and insurers for branded medications.\n\n\n\nCross-sectional retrospective study analyzing pharmacy claims for patients younger than 65 years in the IBM MarketScan Commercial Database and pricing data from SSR Health, LLC, between January 1, 2010, and December 31, 2016. Pharmacy claims analyzed represent claims of employees and dependents participating in employer health benefit programs belonging to large employers. Rebate data were estimated from sales data from publicly traded companies. Analysis focused on the top 5 patent-protected specialty and 9 traditional brand-name medications with the highest total drug expenditures by commercial insurers nationwide in 2014. Data were analyzed from July 2017 to July 2020.\n\n\n\nCalendar year.\n\n\n\nChanges in inflation-adjusted amounts paid by patients and insurers for branded medications.\n\n\n\nIn this analysis of 14.4 million pharmacy claims made by 1.8 million patients from 2010-2016, median drug wholesale list price increased by 129% (interquartile range [IQR], 78%-133%), while median insurance payments increased by 64% (IQR, 28%-120%) and out-of-pocket costs increased by 53% (IQR, 42%-82%). The mean percentage of wholesale list price accounted for by discounts increased from 17% in 2010 to 21% in 2016, and the mean percentage of wholesale list price accounted for by rebates increased from 22% in 2010 to 24% in 2016. For specialty medications, median patient out-of-pocket costs increased by 85% (IQR, 73%-88%) from 2010 to 2016 after adjustment for inflation and 42% (IQR, 25%-53%) for nonspecialty medications. During that same period, insurer payments increased by 116% for specialty medications (IQR, 100%-127%) and 28% for nonspecialty medications (IQR, 5%-34%).\n\n\n\nThis study's findings suggest that drug list prices more than doubled over a 7-year study period. Despite rising manufacturer discounts and rebates, these price increases were associated with large increases in patient out-of-pocket costs and insurer payments.",
"affiliations": "Department of Dermatology, Warren Alpert Medical School, Brown University, Providence, Rhode Island.;Center for Healthcare Value, Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco.;Center for Healthcare Value, Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco.;Center for Healthcare Value, Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco.;Center for Healthcare Value, Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco.;Department of Family Medicine and Community Health, University of Hawaii John A. Burns School of Medicine, Honolulu.;Department of Dermatology, University of California, San Francisco.;Center for Health Policy and Outcomes, Memorial Sloan Kettering Cancer Center, New York, New York.;School of Medicine, School of Public Health, Institute for Health Informatics, University of Minnesota, Minneapolis.",
"authors": "Yang|Eric J|EJ|;Galan|Emilio|E|;Thombley|Robert|R|;Lin|Andrew|A|;Seo|Jaeyun|J|;Tseng|Chien-Wen|CW|;Resneck|Jack S|JS|;Bach|Peter B|PB|;Dudley|R Adams|RA|",
"chemical_list": "D018954:Drugs, Essential; D016568:Drugs, Generic; D055553:Prescription Drugs",
"country": "United States",
"delete": false,
"doi": "10.1001/jamanetworkopen.2020.28510",
"fulltext": "\n==== Front\nJAMA Netw Open\nJAMA Netw Open\nJAMA Netw Open\nJAMA Network Open\n2574-3805 American Medical Association \n\n33295971\n10.1001/jamanetworkopen.2020.28510\nzoi200912\nResearch\nOriginal Investigation\nOnline Only\nHealth Policy\nChanges in Drug List Prices and Amounts Paid by Patients and Insurers\nChanges in Drug List Prices and Amounts Paid by Patients and InsurersChanges in Drug List Prices and Amounts Paid by Patients and InsurersYang Eric J. MD1 Galan Emilio MSc2 Thombley Robert BS2 Lin Andrew BS2 Seo Jaeyun BS2 Tseng Chien-Wen MDMPHMS3 Resneck Jack S. MD4 Bach Peter B. MDMAPP5 Dudley R. Adams MDMBA67 1 Department of Dermatology, Warren Alpert Medical School, Brown University, Providence, Rhode Island\n2 Center for Healthcare Value, Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco\n3 Department of Family Medicine and Community Health, University of Hawaii John A. Burns School of Medicine, Honolulu\n4 Department of Dermatology, University of California, San Francisco\n5 Center for Health Policy and Outcomes, Memorial Sloan Kettering Cancer Center, New York, New York\n6 School of Medicine, School of Public Health, Institute for Health Informatics, University of Minnesota, Minneapolis\n7 Minneapolis VA Medical Center, Minneapolis, Minnesota\nArticle Information\nAccepted for Publication: October 4, 2020.\n\nPublished: December 9, 2020. doi:10.1001/jamanetworkopen.2020.28510\n\nOpen Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Yang EJ et al. JAMA Network Open.\n\nCorresponding Author: Eric J. Yang, MD, Department of Dermatology, Warren Alpert Medical School, Brown University, 593 Eddy St, Providence, RI 02903 (ericjyang@outlook.com).Author Contributions: Drs Yang and Dudley 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.\n\nConcept and design: Yang, Galan, Bach, Dudley.\n\nAcquisition, analysis, or interpretation of data: Yang, Galan, Thombley, Lin, Seo, Tseng, Resneck, Dudley.\n\nDrafting of the manuscript: Yang, Galan, Bach, Dudley.\n\nCritical revision of the manuscript for important intellectual content: All authors.\n\nStatistical analysis: Yang, Bach.\n\nObtained funding: Galan, Dudley.\n\nAdministrative, technical, or material support: Galan, Thombley, Lin, Seo, Bach.\n\nSupervision: Galan, Bach, Dudley.\n\nConflict of Interest Disclosures: Dr Resneck reported serving as an American Medical Association (AMA) trustee and as a paid expert witness for the US Department of Justice on cases related to fraudulent prescribing of compounded medications outside the submitted work. Dr Bach reported receiving speaking fees and travel reimbursement from the American Society for Health-System Pharmacists, America's Health Insurance Plans, Geisinger, Gilead Pharmaceuticals, Hematology Oncology Pharmacy Association, Kaiser Permanente Institute for Health Policy, Oncology Analytics, Oppenheimer & Co, United Rheumatology, and the US Congressional Budget Office; speaking fees from Anthem, Cello Health, Defined Health, JMP Securities, Magellan Health, Mercer, Morgan Stanley, the NYS Rheumatology Society, and WebMD; consulting fees from Foundation Medicine and Grail; stock from Arnold Ventures, EQRx, Grail, and Kaiser Permanente; and advisory fees from EQRx, all outside the submitted work. No other disclosures were reported.\n\nFunding/Support: This research was supported by grant 5R25MD006832, which was received jointly from the PROF-PATH program of the University of California, San Francisco, and the National Institutes of Health (NIH) National Institute on Minority Health and Health Disparities. Dr Tseng is supported by the Hawaii Medical Service Association Endowed Chair in Health Services and Quality Research.\n\nRole of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.\n\nDisclaimer: The opinions expressed in this article are those of the authors and do not necessarily represent the views of the AMA.\n\n\n9 12 2020 \n12 2020 \n9 12 2020 \n3 12 e202851023 7 2020 4 10 2020 Copyright 2020 Yang EJ et al. JAMA Network Open.This is an open access article distributed under the terms of the CC-BY License.jamanetwopen-e2028510.pdfThis cross-sectional study uses data from the IBM MarketScan Commercial Database to examine the association between increases in wholesale list prices of branded medications and amounts paid by patients and insurers for the same drugs.\n\nKey Points\nQuestion\nHow are increases in wholesale list prices for medications distributed among increases in patient out-of-pocket costs, insurer payments, and changes in rebates and discounts?\n\nFindings\nIn this cross-sectional analysis of 14.4 million pharmacy claims made by 1.8 million patients for the top 5 patent-protected specialty and 9 traditional brand-name medications with the highest total drug expenditures by commercial insurers in 2014, the median drug wholesale list price (as defined by Average Wholesale Price) increased by 129% from 2010-2016, while median patient out-of-pocket costs increased by 53% and median insurance payments after rebates and discounts increased by 64%.\n\nMeaning\nThis study’s findings suggest that, after adjusting for inflation, increases in drug list prices are associated with increased patient out-of-pocket costs, which may have implications for cost-related nonadherence, and insurer payments.\n\nImportance\nHigh out-of-pocket drug costs can cause patients to skip treatment and worsen outcomes, and high insurer drug payments could increase premiums. Drug wholesale list prices have doubled in recent years. However, because of manufacturer discounts and rebates, the extent to which increases in wholesale list prices are associated with amounts paid by patients and insurers is poorly characterized.\n\nObjective\nTo determine whether increases in wholesale list prices are associated with increases in amounts paid by patients and insurers for branded medications.\n\nDesign, Setting, and Participants\nCross-sectional retrospective study analyzing pharmacy claims for patients younger than 65 years in the IBM MarketScan Commercial Database and pricing data from SSR Health, LLC, between January 1, 2010, and December 31, 2016. Pharmacy claims analyzed represent claims of employees and dependents participating in employer health benefit programs belonging to large employers. Rebate data were estimated from sales data from publicly traded companies. Analysis focused on the top 5 patent-protected specialty and 9 traditional brand-name medications with the highest total drug expenditures by commercial insurers nationwide in 2014. Data were analyzed from July 2017 to July 2020.\n\nExposures\nCalendar year.\n\nMain Outcomes and Measures\nChanges in inflation-adjusted amounts paid by patients and insurers for branded medications.\n\nResults\nIn this analysis of 14.4 million pharmacy claims made by 1.8 million patients from 2010-2016, median drug wholesale list price increased by 129% (interquartile range [IQR], 78%-133%), while median insurance payments increased by 64% (IQR, 28%-120%) and out-of-pocket costs increased by 53% (IQR, 42%-82%). The mean percentage of wholesale list price accounted for by discounts increased from 17% in 2010 to 21% in 2016, and the mean percentage of wholesale list price accounted for by rebates increased from 22% in 2010 to 24% in 2016. For specialty medications, median patient out-of-pocket costs increased by 85% (IQR, 73%-88%) from 2010 to 2016 after adjustment for inflation and 42% (IQR, 25%-53%) for nonspecialty medications. During that same period, insurer payments increased by 116% for specialty medications (IQR, 100%-127%) and 28% for nonspecialty medications (IQR, 5%-34%).\n\nConclusions and Relevance\nThis study’s findings suggest that drug list prices more than doubled over a 7-year study period. Despite rising manufacturer discounts and rebates, these price increases were associated with large increases in patient out-of-pocket costs and insurer payments.\n==== Body\nIntroduction\nLarge increases in drug prices outpacing increases in income or general inflation in recent years have put the pharmaceutical industry under scrutiny.1,2,3,4,5 As cost-related drug nonadherence is already widespread, rising drug prices raise concerns that patients will be unable to afford their prescriptions, leading to negative health outcomes.6\n\nNewly developed medications are often expected to be expensive because of high research and development costs, although there is debate about how to estimate these costs.7 Recent reports of substantial increases in list prices of drugs already on the market cannot be explained by development costs and have received considerable media attention3,4,8,9 and criticism from lawmakers, insurers, and consumers alike.1,10,11,12 However, pharmaceutical industry leaders argue that changes in wholesale list prices do not necessarily lead to large changes in amounts patients or insurers pay for drugs.13,14,15 Drug manufacturers have argued that increases in list prices are due to increases in discounts or rebates, not increases in actual amounts paid by patients and payers.16\n\nHernandez et al17 recently demonstrated that discounts and rebates have increased, as manufacturers report. However, after accounting for these price reductions, total payments manufacturers received rose faster than general inflation. What remains unknown, however, is how this mix of increases in list prices with rising discounts and rebates affects patients’ out-of-pocket costs. If discounts and rebates are large enough and targeted to patients, patient out-of-pocket costs may not rise as list prices increase. However, this hypothesis cannot be evaluated without evaluating discounts, rebates, and amounts paid by payers and by patients out of pocket in a single analysis. This issue is particularly relevant to clinical practice in which news about list price changes must be translated into discussions about drug costs with patients.\n\nTo address these issues, we studied a national sample of employer and commercial insurer pharmaceutical claims and sales data from 2010 to 2016 for drugs previously identified as contributing the most to total drug expenditures for commercial insurers.18 We analyzed changes over time in wholesale list prices and amounts paid by patients and insurers after accounting for discounts and rebates to understand how rising list prices are associated with patients’ out-of-pocket costs and the net cost of these drugs to insurers.\n\nMethods\nDrugs Studied\nWe focused our analyses on the top 5 patent-protected specialty and 9 traditional brand-name medications with the highest total drug expenditures by commercial insurers nationwide in 2014.18,19 The most widely used specialty drugs include treatments for rheumatoid arthritis, Crohn disease, psoriasis, cancer, and HIV, among other conditions.20 Specialty medications commonly have high prices and have been implicated in driving rising national drug expenditures.18,21\n\nDatabase and Study Population\nWe used Health Insurance Portability and Accountability Act–compliant, deidentified, patient-level outpatient pharmacy claims data from the IBM MarketScan Commercial Database. This database represents the claims of 67.4 million employees and dependents participating in employer health benefit programs belonging to large employers between January 1, 2010, and December 31, 2016. The plans represented include a variety of fee-for-service, preferred provider organization, and capitated health plans. For clarity, we refer to these collectively as insurers. Claims for patients aged 65 years and older were excluded because of likely confounding differences in benefit design secondary to dual coverage with Medicare. We excluded claims in which reported prescribed dose exceeded the maximum clinical dose. This study was determined to be exempt from review by the institutional review board at the University of California, San Francisco because the patient claims data were deidentified. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies.\n\nAverage Wholesale Price (List Price), Discounts, and Out-of-Pocket Costs\nEach pharmacy claim reports the Average Wholesale Price (AWP) for the drug prescribed, actual payment to the pharmacy (ie, the discounted price paid by the insurer but not accounting for rebates), and the patient’s out-of-pocket cost for the medication. Because drug manufacturers report substantial discounts and rebates, for this analysis we use the AWP, equivalent to the manufacturer’s suggested retail price, as the starting wholesale list price. Another price available on claims is the Wholesale Acquisition Cost, but manufacturers would argue that this price already includes a discount they offer, so we start with the higher AWP as the wholesale list price. We calculated the manufacturer’s discount for each claim as AWP minus actual payment to the pharmacy.\n\nWe converted all costs for each claim into unit price (ie, the cost of each claim was divided by the number of doses listed in that claim), to ensure that variation in prices was not due to differences in dosing. Mean AWP, patient out-of-pocket costs, and discounted price were calculated by totaling all claims for a drug and dividing by the number of claims. Discounts were calculated as the difference between AWP and the discounted price. Mean AWP per unit and discounts were calculated for each drug per quarter, whereas mean patient costs were calculated annually to account for patient deductibles.\n\nEstimated Rebates\nLike Hernandez et al,17 we obtained rebate data from SSR Health, LLC, a health care–focused investment research firm, and Symphony Health. SSR Health compiles data from pharmaceutical company investor reports to determine total revenue after all price reductions (including discounts and rebates) have been factored in. This is divided by the total number of prescriptions, estimated by Symphony Health, to calculate the net payment for drugs, accounting for discounts and rebates.\n\nSSR Health estimated discounts to Medicaid payers by using the sum of the Medicaid statutory rebate (23.1% of average manufacturer price) and the pricing penalty for price increases exceeding the Consumer Price Index increase. These are discounts offered to state Medicaid programs as part of “best price” regulations to make drug spending more affordable for Medicaid. The number of units of each medication sold to Medicaid was obtained by SSR Health from the Centers for Medicare & Medicaid Services’ drug utilization files. SSR Health then estimated total revenue from Medicaid by multiplying the discounted Medicaid price by the number of units sold to Medicaid. SSR Health calculated revenue from non-Medicaid sales for each drug by subtracting Medicaid revenue from total revenue. Similarly, the number of non-Medicaid units sold for each medication was estimated by subtracting Medicaid units sold from total units sold. SSR Health then divided non-Medicaid revenue by the number of non-Medicaid units sold to estimate the net price for non-Medicaid insurers. To allow for comparison with the pharmacy claims data (which does not include Medicaid payers), we used only the non-Medicaid sales data from this data set.\n\nWe then calculated the mean rebate for non-Medicaid payers as the difference between the mean discounted price paid on claims and the non-Medicaid net price from SSR Health. With these figures, we could assess how the AWP for each drug could be broken down into discounts shown on the claim, rebates passed on to insurers, patient out-of-pocket costs, and insurer payments net of discounts and rebates such that\n\n AWP = (Discount + Rebate) + Insurer payments + Patient Out-of-Pocket Costs. Independent and Dependent Variables Assessed\nOur primary independent variable was percentage of change in AWP from 2010 to 2016 for medications maintaining patent protection during this period. Our secondary independent variables were percentage of change in AWP from 2010 to 2014 and from 2010 to 2015 for medications maintaining patent protection during these respective periods. Our primary dependent variables were the percentage of change in patient out-of-pocket costs and insurer payments after rebates. Secondary dependent variables included the mean percentage of change in discounts and rebates over the study period. In addition, differences in the changes in AWP, net payments (sum of insurer payments and patient out-of-pocket costs), insurer payments, and patient out-of-pocket costs between specialty medications and nonspecialty medications were evaluated. The proportion of change in AWP accounted for by changes in discounts, rebates passed on to insurers, insurer payments, and patient out-of-pocket costs was computed for all medications.\n\nStatistical Analysis\nWe assessed differences in price trends between specialty and nonspecialty medications by comparing the proportion of increase in AWP from 2010 to 2016 accounted for by changes in rebates, discounts, insurer payments, and patient out-of-pocket costs between these 2 groups of drugs. Median values were used as a measure of central tendency to reduce the impact of outlier claims or benefits designs. All prices and payments shown were adjusted to 2016 dollars using the Consumer Price Index for All Urban Consumers. Analyses were performed with Excel 2013, version 15.0.4535.1507 (Microsoft Corp). Data were analyzed from July 2017 to July 2020.\n\nSensitivity Analysis\nSome information about Medicaid discounts and rebates, such as best price discounts or rebates required by individual states, was not available to SSR Health. However, we could calculate a range of possible Medicaid prices. Because total discount and rebate amounts given by drug manufacturers are split between Medicaid and non-Medicaid purchasers, assuming higher Medicaid discounts and rebates would result in an estimation of lower non-Medicaid discounts and rebates.\n\nFor our main analysis, the estimates made by SSR Health about Medicaid statutory rebates and pricing penalties led to the highest possible estimates of discounts and rebates to the commercial insurers being studied to maximally reflect manufacturer claims about high discount and rebate rates. As a sensitivity analysis and to estimate a range of patient out-of-pocket costs and insurer payments, we also calculated those outcomes with the assumption of every Medicaid unit in the SSR Health data set being rebated at 100% of average manufacturer price. Because this would be the maximum possible discount paid to Medicaid, it would consequently result in the lowest possible discounts and rebates to commercial insurers.\n\nResults\nFor 2010-2016, the MarketScan database included data for 67.4 million enrollees who filled at least 1 prescription, with 1.8 million enrollees having 14.4 million pharmacy claims for the drugs of interest (eTable 1 in the Supplement). Taken together, claims for the 14 drugs accounted for $13 billion in spending, or 6.6% of total drug spending during this study period. The drugs included in our analysis consisted of 5 specialty drugs and 9 nonspecialty drugs.\n\nNot all drugs in our study retained patent protection through 2016. Figure 1 shows increases in AWP and net payments (the sum of patient and insurer payments after discounts and rebates) from 2010-2016. For the 14 drugs retaining patent protection through 2014, the median increase in AWP was 59% (interquartile range [IQR], 47%-71%), whereas median net payments increased by 78% (IQR, 27%-111%) above the rate of increase in the Consumer Price Index (eFigure 1 in the Supplement). For the 9 drugs retaining patent protection through 2016, the median increase in AWP was 129% (IQR, 78%-133%) from 2010 to 2016, whereas median net payments increased by 74% (IQR, 27%-158%; eFigure 1 in the Supplement).\n\nFigure 1. Average Cumulative Percentage of Change in Average Wholesale Price (AWP) and Total Payments per Quarter for Drugs Keeping Patent Protection From 2010 to 2016\nAll results were adjusted to 2016 dollars using the Consumer Price Index. The AWP represents the total payment, that is, the amount paid by insurance payers and patients after discounts and rebates.\n\naFourteen drugs kept patent protection through 2014 and were included in analysis from 2010 to 2014.\n\nbEleven drugs kept patent protection through 2015 and were included in analysis from 2014 to 2015.\n\ncNine drugs kept patent protection through 2016 and were included in analysis from 2015 to 2016.\n\nFrom 2010 to 2016, the median out-of-pocket patient payments and insurance payments increased by 53% (IQR, 42%-82%) and 64% (IQR, 28%-120%), respectively. During this time, manufacturer discounts and rebates passed on to insurers rose by a median of 163% (IQR, 130%-212%) and 103% (IQR, −18% to 293%). As a result, the mean percentage of wholesale list price accounted for by discounts increased from 17% in 2010 to 21% in 2016, and the mean percentage of wholesale list price accounted for by rebates increased from 22% in 2010 to 24% in 2016 (eFigure 2 in the Supplement).\n\nThe amounts paid by patients out of pocket and by insurers increased for most drugs included in our analysis from 2010 to 2016 (Table 1). For Humalog and Nexium, insurer expenditures decreased slightly.\n\nTable 1. Annual Change in Average Wholesale Price (AWP) and Cost by Patients and Insurers After Rebates per Unit of Medication, Ordered by Increase in Patient Out-of-Pocket Cost\nMedication\tAnnual cost increase above rate of inflation, %a\t\nAWP\tInsurer\tPatient\t\nSpecialty\t\t\t\t\n Stelara\t8.6\t14.1\t6.3\t\n Gleevec\t15.4\t17.8\t7.6\t\n Atripla\t6.2\t8.5\t10.5\t\n Enbrel\t13.6\t16.2\t11.0\t\n Humira\t14.3\t13.3\t11.3\t\nNonspecialty\t\t\t\t\n Crestor\t10.5\t4.4\t3.2\t\n Januvia\t10.3\t0.8\t3.5\t\n Lantus\t15.9\t5.0\t3.8\t\n Abilify\t12.7\t13.4\t4.5\t\n Androgel\t10.1\t23.4\t4.6\t\n Nexium\t7.6\t−4.9\t4.6\t\n Lyrica\t14.5\t17.0\t6.0\t\n Humalog\t13.8\t−1.9\t7.3\t\n Vyvanse\t9.6\t4.3\t8.6\t\na The reported change per year is net of the rate of general inflation reported from 2010 to end of patent protection or 2016, whichever came first. All results have been adjusted to 2016 dollars using the Consumer Price Index.\n\nAmong all study drugs that retained patent protection from 2010 to 2014, every $1 increase in AWP was associated with a median increase in patient out-of-pocket costs of $0.04 (range, $0.01-$0.19) (Table 2). Patient out-of-pocket costs increased $0.04 (range, $0.03-$0.19) for nonspecialty drugs and $0.03 (range, $0.01-$0.04) for specialty drugs. Insurer payments for this period increased $0.63 (range, −$0.07 to $1.61) for all eligible study drugs during this period. Insurer payments increased $0.13 (range, −$0.07 to $1.61) for nonspecialty medications and $0.81 (range, $0.67-$1.15) for specialty drugs for every $1 increase in AWP during this period.\n\nTable 2. Median Absolute Increase in Insurer and Patient Payments per $1 Increase in Average Wholesale Price for Medications Maintaining Patent Protection During Each of the Studied Periodsa\nType of payment\tMedian (range), $\t\n2010-2014 (14 drugs)\t2010-2015 (11 drugs)\t2010-2016 (9 drugs)\t\nInsurer payments\t\t\t\t\n Overall\t0.63 (−0.07 to 1.61)\t0.56 (0.05 to 0.93)\t0.57 (−0.04 to 1.02)\t\n Specialty\t0.81 (0.67 to 1.15)\t0.75 (0.66 to 0.93)\t0.74 (0.57 to 1.02)\t\n Nonspecialty\t0.13 (−0.07 to 1.61)\t0.12 (0.05 to 0.56)\t0.13 (−0.04 to 0.62)\t\nPatient payments\t\t\t\t\n Overall\t0.04 (0.01 to 0.19)\t0.04 (0.01 to 0.20)\t0.04 (0.01 to 0.20)\t\n Specialty\t0.03 (0.01 to 0.04)\t0.02 (0.01 to 0.05)\t0.03 (0.01 to 0.06)\t\n Nonspecialty\t0.04 (0.03 to 0.19)\t0.05 (0.02 to 0.20)\t0.05 (0.02 to 0.20)\t\na All results have been adjusted to 2016 dollars using the Consumer Price Index.\n\nAmong all study drugs retaining patent protection from 2010 to 2016, every $1 increase in AWP was associated with a median increase in patient out-of-pocket costs of $0.04 (range, $0.01-$0.20). Patient out-of-pocket costs increased $0.05 (range, $0.02-$0.20) for nonspecialty drugs and $0.03 (range, $0.01-$0.06) for specialty drugs. Insurer payments for this period increased $0.57 (range, −$0.04 to $1.02) for all eligible study drugs during this period. Insurer payments increased $0.13 (range, −$0.04 to $0.62) for nonspecialty drugs and $0.74 (range, $0.57-$1.02) for specialty drugs for every $1 increase in AWP during this period.\n\nIn total, median patient out-of-pocket costs for specialty medications increased by 85% (IQR, 73%-88%) after adjustment for inflation as compared with 42% (IQR, 25%-53%) for nonspecialty medications from 2010 to 2016, while insurer payments for specialty medications increased by 116% (IQR, 100%-127%) compared with 28% (IQR, 5%-34%) for nonspecialty medications (Figure 2).\n\nFigure 2. Changes in Median Annual Average Wholesale Price (AWP) and Patient and Payer Expenditures per Medication Relative to 2010 for Specialty and Nonspecialty Medications \nA, All results were adjusted to 2016 dollars using the Consumer Price Index. B, All results were adjusted to 2016 dollars using the Consumer Price Index. The AWP represents total payment, that is, the amount paid by insurance payers and patients after discounts and rebates.\n\naFive specialty drugs kept patent protection through 2015 and were included in analysis from 2010 to 2015.\n\nbFour specialty drugs kept patent protection through 2016 and were included in analysis from 2015 to 2016.\n\ncNine nonspecialty drugs kept patent protection through 2014 and were included in analysis from 2010 to 2014.\n\ndSix nonspecialty drugs kept patent protection through 2015 and were included in analysis from 2014 to 2015.\n\neFive nonspecialty drugs kept patent protection through 2016 and were included in analysis from 2015 to 2016.\n\nIn our sensitivity analysis in which we assessed the range of possible discounts and rebates to commercial insurers, patient out-of-pocket costs were unchanged. Median insurer payment increases were slightly lower than those in our primary analysis, although still far above the rate of increase in the Consumer Price Index. With these assumptions, median insurer payments for drugs retaining patent protection through 2016 increased by 61% (IQR, 34%-122%) after adjustment for inflation.\n\nDiscussion\nIn a large, national sample of patients with commercial insurance, we found that increases in drug wholesale list prices were accompanied by increases in out-of-pocket payments by patients and by insurers. Increases in payments for specialty medications from 2010 to 2016 were greater than those for nonspecialty medications in our analysis over the study period.\n\nPharmaceutical manufacturers have argued that increases in drug wholesale list prices are accompanied by corresponding large increases in discounts and rebates, reducing the impact of list price changes on patients and insurers.13,14,15 Our analysis corroborates that rebates and discounts are large, and the proportion of AWP attributed to discounts and rebates did increase from 2010 to 2016 (eFigure 3 in the Supplement). However, after accounting for these changes, we show that increases in wholesale list prices were associated with increases in patient out-of-pocket costs and insurer payments for the drugs studied. This varies by drug, but wholesale list prices, insurer payments, and patient out-of-pocket costs all increased from 2010 to 2016 at rates above the rate of increase in the Consumer Price Index (eTable 2 in the Supplement).\n\nAlthough patient out-of-pocket costs for drugs vary greatly, patients paid a median of 53% more for these drugs in 2016 than they did in 2010, after adjusting for general inflation. During the same period, median household income rose 8.6%,22 so these out-of-pockets costs have increased relative to income. Because we used claims to determine out-of-pocket costs, this finding persists despite coupons and patient assistance programs aimed at lowering patient spending. This observed rise in patient out-of-pocket costs with increasing drug list prices is of particular concern to clinicians because high drug costs can lead to poor drug regimen adherence, increased use of utilization management systems such as prior authorizations and step therapy, and adverse health outcomes.6,20 Although patients paid a smaller percentage of the wholesale list price over time, the absolute amount that they paid for the drugs we studied continued to increase at rates higher than general inflation or the growth of income, which may have important implications for the ever larger population of patients with chronic diseases.23,24 This study highlights that increases in prices for drugs that have been on the market for several years increase the cost of treatment for patients.\n\nSpending for specialty drugs has increased significantly over the past decade and is projected to contribute to rapidly increasing health care costs.20,25,26 Our results indicate that discounts and rebates for these drugs are lower relative to list prices than discounts and rebates for nonspecialty medications. Insurer payments for Nexium and Humalog did not outpace inflation in our analysis, presumably because they face more competition from similar drugs in their classes. Manufacturers of single-source specialty medications may offer fewer price concessions because most face little market competition.27 Consequently, insurer payments for specialty drugs are also rising at a much higher rate than payments for nonspecialty medications, also increasing coinsurance costs. Although patient out-of-pocket costs are a smaller proportion of the total price of specialty medications than nonspecialty medications, specialty drugs are still more costly to patients. As use of these drugs increases, the high costs may affect patients through higher out-of-pocket spending per prescription and rising premiums, as well as both government programs and commercial insurers.18,28\n\nLimitations\nOur study has several limitations. Given differences in pricing of generic medications with regard to discounts and rebates, we opted not to include medications that did not have patent protection during our study period. The findings of our study reflect the pricing breakdown of the 14 medications accounting for the greatest portion of insurer medication expenditures and may not be generalizable to other medications. In addition, several of the analyzed medications lost patent protection shortly after the study period. Further study is needed to characterize how impending patent protection expiration affects list prices, discounts, rebates, and amounts paid for medications.\n\nWe were also unable to control for changes in cost sharing during this period, which may also contribute to changes in amounts paid for medications. Furthermore, contracting and pricing are different for Medicare, Medicaid, the 340B program, and the Department of Veterans Affairs, so it is not clear how generalizable our findings are to those markets.\n\nIn addition, we could not obtain precise estimates of all Medicaid discounts and rebates, resulting in some uncertainty about the total discounts and rebates offered to the commercial insurers we studied. Therefore, our sensitivity analyses provide only a range of possible insurer payments rather than exact figures. However, under any set of assumptions, we found that increases in list prices resulted in increases in insurer payments. This limitation has no effect on our estimates of patient out-of-pocket costs, since these were identified directly from claims data.\n\nOur study also does not characterize who receives manufacturers’ rebates in detail. Rather, we report what can be directly measured: the amount that is passed on to insurers. Insurers may then pass some of these savings on to employers, but rebates are also frequently paid—at least in part—to pharmaceutical benefits managers.29 We are not aware of data that allow description of how rebates are shared among these relevant parties, but they are not shared with patients.\n\nFinally, we were not able to measure other mechanisms by which rising drug prices may increase patient out-of-pocket costs, such as increasing insurance premiums. Additional study of the association between rising insurer payments and these other patient out-of-pocket costs is needed to further clarify the total effect of these pricing changes on patients.\n\nConclusions\nIn this cross-sectional study, we found that increases in drug wholesale list prices are associated with increases in net patient out-of-pocket costs and insurer payments. This finding suggests that, although discounts and rebates significantly reduce the amount paid for drugs and have increased over the past several years, they have not prevented an inflation-adjusted rise in patients’ and insurers’ costs. This could have both important clinical implications for patient outcomes and an impact on total health care expenditures.\n\nSupplement. eTable 1. Characteristics of the Patient Population in the Sample\n\neFigure 1. Average Cumulative Percent Change in Average Wholesale Price (AWP) and Net Payments per Quarter\n\neFigure 2. Mean Percent of Average Wholesale Price (AWP) Attributed to Discounts and Rebates by Quarter from 2010 to 2016\n\neFigure 3. Proportions of Average Wholesale Price (AWP) Accounted for by Discounts, Net Rebates Passed Onto Insurers, Insurer Expenditures, and Patient Out-of-Pocket Payments in 2010 and 2016 for Non-specialty Medications and Specialty Medications\n\neTable 2. Median Annual Percent Increase in List Prices, Price Reductions, and Payments for Medications Maintaining Patent Protection During Each of the Studied Time Periods\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Humer C Makers took big price increases on widely used U.S. drugs. Reuters. Updated April 5, 2016. Accessed May 26, 2018. https://www.reuters.com/article/us-usa-healthcare-drugpricing/exclusive-makers-took-big-price-increases-on-widely-used-u-s-drugs-idUSKCN0X10TH\n2 Pollack A Big price increase for tuberculosis drug is rescinded. New York Times Updated September 21, 2015. Accessed May 27, 2018. https://www.nytimes.com/2015/09/22/business/big-price-increase-for-tb-drug-is-rescinded.html\n3 Pollack A Drug goes from $13.50 a tablet to $750, overnight. New York Times Updated September 20, 2015. 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Janssen Pharmaceutical Companies of Johnson & Johnson. Updated 2018-03-02. Accessed May 26, 2018. http://jnj-janssen.brightspotcms.com/us/us-pharmaceutical-transparency-report/pricing-and-patient-access\n14 Testimony of Mylan CEO Heather Bresch before the United States House of Representatives Committee on Oversight and Government Reform. Accessed November 4, 2020. https://www.mylan.com/-/media/mylancom/files/news/oral-testimony-of-mylan-ceo-heather-bresch-before-the-united-states-house-of-representatives-committee-on-oversight-and-government-reform.pdf?la=en\n15 Tirell M Johnson & Johnson lifts lid on drug pricing data, shows 3.5% net hike in 2016 \nCNBC Published February 27, 2017. Updated February 27, 2017. Accessed May 26, 2018. https://www.cnbc.com/2017/02/27/johnson-johnson-lifts-lid-on-drug-pricing-data-shows-35-net-hike-in-2016.html\n16 Pharmaceutical Research and Manufacturers of America. Let's talk about cost. Published 2018. Accessed March 4, 2020. https://www.letstalkaboutcost.org/\n17 Hernandez I , San-Juan-Rodriguez A , Good CB , Gellad WF \nChanges in list prices, net prices, and discounts for branded drugs in the US, 2007-2018\n. JAMA . 2020 ;323 (9 ):854 -862\n. doi:10.1001/jama.2020.1012 \n32125403 \n18 Dusetzina SB \nShare of specialty drugs in commercial plans nearly quadrupled, 2003-14\n. Health Aff (Millwood) . 2016 ;35 (7 ):1241 -1246\n. doi:10.1377/hlthaff.2015.1657 \n27385240 \n19 Comprehensive Specialty Pharmacy Drug List. CVS Specialty. Published October 2019. Accessed September 20, 2020. https://www.caremark.com/portal/asset/IBM_Specialty_Drug_List.pdf\n20 Lotvin AM , Shrank WH , Singh SC , Falit BP , Brennan TA \nSpecialty medications: traditional and novel tools can address rising spending on these costly drugs\n. Health Aff (Millwood) . 2014 ;33 (10 ):1736 -1744\n. doi:10.1377/hlthaff.2014.0511 \n25288417 \n21 Cuckler GA , Sisko AM , Poisal JA , \nNational health expenditure projections, 2017-26: despite uncertainty, fundamentals primarily drive spending growth\n. Health Aff (Millwood) . 2018 ;37 (3 ):482 -492\n. doi:10.1377/hlthaff.2017.1655 \n29443634 \n22 US Census Bureau. Real median household income in the United States [MEHOINUSA672N], retrieved from FRED, Federal Reserve Bank of St Louis. Updated September 16, 2020. Accessed September 20, 2020 \nhttps://fred.stlouisfed.org/series/MEHOINUSA672N\n23 Ward BW , Schiller JS , Goodman RA \nMultiple chronic conditions among US adults: a 2012 update\n. Prev Chronic Dis . 2014 ;11 :E62. doi:10.5888/pcd11.130389 \n24742395 \n24 Piette JD , Heisler M , Wagner TH \nCost-related medication underuse among chronically ill adults: the treatments people forgo, how often, and who is at risk\n. Am J Public Health . 2004 ;94 (10 ):1782 -1787\n. doi:10.2105/AJPH.94.10.1782 \n15451750 \n25 Martin AB , Hartman M , Washington B , Catlin A ; National Health Expenditure Accounts Team \nNational health spending: faster growth in 2015 as coverage expands and utilization increases\n. Health Aff (Millwood) . 2017 ;36 (1 ):166 -176\n. doi:10.1377/hlthaff.2016.1330 \n27913569 \n26 Kesselheim AS , Avorn J , Sarpatwari A \nThe high cost of prescription drugs in the United States: origins and prospects for reform\n. JAMA . 2016 ;316 (8 ):858 -871\n. doi:10.1001/jama.2016.11237 \n27552619 \n27 Dusetzina SB , Bach PB \nPrescription drugs-list price, net price, and the rebate caught in the middle\n. JAMA . 2019 ;321 (16 ):1563 -1564\n. doi:10.1001/jama.2019.2445 \n30840047 \n28 Schumock GT , Li EC , Wiest MD , \nNational trends in prescription drug expenditures and projections for 2017\n. Am J Health Syst Pharm . 2017 ;74 (15 ):1158 -1173\n. doi:10.2146/ajhp170164 \n28533252 \n29 Dusetzina SB , Conti RM , Yu NL , Bach PB \nAssociation of prescription drug price rebates in Medicare Part D with patient out-of-pocket and federal spending\n. JAMA Intern Med . 2017 ;177 (8 ):1185 -1188\n. doi:10.1001/jamainternmed.2017.1885 \n28558108\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2574-3805",
"issue": "3(12)",
"journal": "JAMA network open",
"keywords": null,
"medline_ta": "JAMA Netw Open",
"mesh_terms": "D003365:Costs and Cost Analysis; D016527:Drug Costs; D018954:Drugs, Essential; D016568:Drugs, Generic; D005102:Health Expenditures; D006801:Humans; D007343:Insurance Carriers; D007345:Insurance Claim Review; D055553:Prescription Drugs; D014481:United States",
"nlm_unique_id": "101729235",
"other_id": null,
"pages": "e2028510",
"pmc": null,
"pmid": "33295971",
"pubdate": "2020-12-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "27385240;30840047;30615532;25288417;27141308;27673458;16476874;27913569;29443634;25970049;32125403;28533252;26553078;28558108;15451750;27552619;24742395",
"title": "Changes in Drug List Prices and Amounts Paid by Patients and Insurers.",
"title_normalized": "changes in drug list prices and amounts paid by patients and insurers"
} | [
{
"companynumb": "US-OTSUKA-2021_001465",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Central venous catheter is commonly utilized as a hemodialysis access in the pediatric population. Long-standing central venous catheters can be complicated by superior vena cava (SVC) stenosis and thrombosis that can rarely present as pleural effusions. We report a case of a 5-year-old boy on chronic hemodialysis who presented with combined pleural and pericardial effusions, which was secondary to catheter induced SVC stenosis. Both the pleural effusion and the pericardial effusion in this patient subsequently improved with the relief of SVC stenosis. This case report highlights the serious complications of SVC stenosis associated with long-standing central venous catheters which is an under-recognized problem in the pediatric population.",
"affiliations": "Children's National Medical Center, Washington, DC, USA.;Children's National Medical Center, Washington, DC, USA.;Children's National Medical Center, Washington, DC, USA.",
"authors": "Siddiqui|Sahar|S|;Mistry|Kirtida|K|;Moudgil|Asha|A|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.1111/hdi.12353",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1492-7535",
"issue": "19 Suppl 3()",
"journal": "Hemodialysis international. International Symposium on Home Hemodialysis",
"keywords": "SVC stenosis; pericardial effusion; pleural effusion",
"medline_ta": "Hemodial Int",
"mesh_terms": "D002648:Child; D002908:Chronic Disease; D006801:Humans; D008297:Male; D010490:Pericardial Effusion; D010996:Pleural Effusion; D006435:Renal Dialysis; D013479:Superior Vena Cava Syndrome",
"nlm_unique_id": "101093910",
"other_id": null,
"pages": "S51-3",
"pmc": null,
"pmid": "26448389",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pleural and pericardial effusion: A manifestation of SVC syndrome in a child on chronic hemodialysis.",
"title_normalized": "pleural and pericardial effusion a manifestation of svc syndrome in a child on chronic hemodialysis"
} | [
{
"companynumb": "US-ASTELLAS-2015US043787",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Fluoroquinolones are a key component of multidrug-resistant tuberculosis treatment. We describe the first reported case of probable levofloxacin-associated intracranial hypertension in a 6-year-old girl with pulmonary multidrug-resistant tuberculosis. The case highlights the potential risk of secondary intracranial hypertension in multidrug-resistant tuberculosis patients who require prolonged fluoroquinolone therapy and the need for ophthalmologic screening in children with suggestive signs and symptoms.",
"affiliations": "From the *Desmond Tutu TB Centre, Department of Pediatrics and Child Health, ‡Department of Pediatrics and Child Health, and §Department of Ophthalmology, Faculty of Medicine and Health Sciences, Stellenbosch University; and †Brooklyn Hospital for Chest Diseases, Cape Town, South Africa.",
"authors": "van der Laan|Louvina E|LE|;Schaaf|H Simon|HS|;Solomons|Regan|R|;Willemse|Marianne|M|;Mohamed|Nabil|N|;Baboolal|Sandika O|SO|;Hesseling|Anneke C|AC|;van Toorn|Ronald|R|;Garcia-Prats|Anthony J|AJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D064704:Levofloxacin",
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0000000000001137",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0891-3668",
"issue": "35(6)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002648:Child; D005260:Female; D006801:Humans; D019586:Intracranial Hypertension; D064704:Levofloxacin; D018088:Tuberculosis, Multidrug-Resistant; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "706-8",
"pmc": null,
"pmid": "26974890",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Probable Levofloxacin-associated Secondary Intracranial Hypertension in a Child With Multidrug-resistant Tuberculosis.",
"title_normalized": "probable levofloxacin associated secondary intracranial hypertension in a child with multidrug resistant tuberculosis"
} | [
{
"companynumb": "ZA-GLENMARK PHARMACEUTICALS INC, USA.-2016GMK023500",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMIKACIN"
},
"drug... |
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