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{ "abstract": "Combination immune checkpoint blockade with concurrent administration of the anti-ctla4 antibody ipilimumab and the anti-PD-1 antibody nivolumab has demonstrated impressive responses in patients with advanced melanoma and other diseases. That combination has also been associated with increased toxicity, including rare immune-related adverse events. Here we describe a case of fatal steroid-refractory myocarditis and panmyositis associated with the use of this combination in a patient with metastatic melanoma. Correlative studies indicated increased levels of serum interleukin 6 in this patient at the onset of toxicity, suggesting a possible role for anti-interleukin 6 receptor antibodies in the treatment of subsequent cases of this rare, but fatal, toxicity.", "affiliations": "Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON.;Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON.;Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON.;Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON.;Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON.;Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON.;Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON.;Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON.", "authors": "Saibil|S D|SD|;Bonilla|L|L|;Majeed|H|H|;Sotov|V|V|;Hogg|D|D|;Chappell|M A|MA|;Cybulsky|M|M|;Butler|M O|MO|", "chemical_list": "D000074322:Antineoplastic Agents, Immunological; C508600:IL6 protein, human; D015850:Interleukin-6; D000074324:Ipilimumab; D000077594:Nivolumab", "country": "Switzerland", "delete": false, "doi": "10.3747/co.26.4381", "fulltext": null, "fulltext_license": null, "issn_linking": "1198-0052", "issue": "26(3)", "journal": "Current oncology (Toronto, Ont.)", "keywords": "Melanoma; checkpoint blockade; myocarditis", "medline_ta": "Curr Oncol", "mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D017809:Fatal Outcome; D006801:Humans; D015850:Interleukin-6; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma; D009205:Myocarditis; D009220:Myositis; D000077594:Nivolumab; D012878:Skin Neoplasms", "nlm_unique_id": "9502503", "other_id": null, "pages": "e418-e421", "pmc": null, "pmid": "31285688", "pubdate": "2019-06", "publication_types": "D002363:Case Reports", "references": "28123888;28915085;28069323;27595932;27141381;25539810;27340279;22848232;29077601;27207799;27806233;28102662", "title": "Fatal myocarditis and rhabdomyositis in a patient with stage IV melanoma treated with combined ipilimumab and nivolumab.", "title_normalized": "fatal myocarditis and rhabdomyositis in a patient with stage iv melanoma treated with combined ipilimumab and nivolumab" }
[ { "companynumb": "CA-SAMSUNG BIOEPIS-SB-2019-27739", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditi...
{ "abstract": "Linezolid is an efficacious and well tolerated antimicrobial but can have serious adverse effects including myelo-suppression, serotonin syndrome, neuropathy, hypoglycemia, liver dysfunction, and lactic acidosis. The side effects are generally duration dependent; linezolid use is not recommended for more than 28 days. Case. A 59-year-old female presented with malaise, loss of appetite, and altered mentation. She had multiple medical comorbidities and required long-term anticoagulation with warfarin for venous thromboembolism. She had multiple medication allergies. Prior to admission, she was on linezolid for cellulitis of foot due to Methicillin-resistant Staphylococcus aureus (MRSA). On physical exam, she was drowsy and required endotracheal intubation for airway protection. Initial laboratory parameters showed lactic acidosis, thrombocytopenia, supra-therapeutic coagulation profile, low blood glucose, and transaminitis. Her altered mentation was due to hypoglycemia. The interaction with warfarin led to altered coagulation profile. She developed shock and vasopressors were initiated. Given her presentation, she was managed as severe sepsis. There were no active infectious foci attributing to decline of her clinical status. Linezolid was discontinued and she was managed with intravenous polymyxin B, aztreonam, and vancomycin. Her hemodynamic status improved within one day. She was extubated on Day 5 of her presentation. Her laboratory parameters showed gradual improvement over 12 days after discontinuation of linezolid. Retrospective evaluation revealed linezolid toxicity as possible cause of presentation. Linezolid toxicity can present as sepsis mimic and should be considered as a differential diagnosis while managing sepsis with other antimicrobial agents.", "affiliations": "Department of Medicine, Penn Highlands Healthcare, PA, USA.;Division of the Gastroenterology, BronxCare Health System, NY, USA.;Mercy Medical Center, IA, USA.;Department of Medicine, BronxCare Health System, NY, USA.", "authors": "Mishra|Rashmi|R|https://orcid.org/0000-0001-6747-6490;Patel|Harish|H|https://orcid.org/0000-0002-8232-9672;Goel|Bindu|B|;Vakde|Trupti|T|https://orcid.org/0000-0002-5154-3051", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2019/2157674", "fulltext": "\n==== Front\nCase Rep Crit CareCase Rep Crit CareCRICCCase Reports in Critical Care2090-64202090-6439Hindawi 10.1155/2019/2157674Case ReportA Case of Linezolid Toxicity Presenting as a Sepsis Mimic https://orcid.org/0000-0001-6747-6490Mishra Rashmi \n1\nhttps://orcid.org/0000-0002-8232-9672Patel Harish hpatel@bronxleb.org\n2\n\n3\nGoel Bindu \n4\nhttps://orcid.org/0000-0002-5154-3051Vakde Trupti \n3\n\n5\n\n1Department of Medicine, Penn Highlands Healthcare, PA, USA\n2Division of the Gastroenterology, BronxCare Health System, NY, USA\n3Department of Medicine, BronxCare Health System, NY, USA\n4Mercy Medical Center, IA, USA\n5Division of the Pulmonary and Critical care Medicine, BronxCare Health System, NY, USAAcademic Editor: Kenneth S. Waxman\n\n2019 17 12 2019 2019 21576744 7 2019 22 8 2019 31 8 2019 Copyright © 2019 Rashmi Mishra et al.2019This 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.Linezolid is an efficacious and well tolerated antimicrobial but can have serious adverse effects including myelo-suppression, serotonin syndrome, neuropathy, hypoglycemia, liver dysfunction, and lactic acidosis. The side effects are generally duration dependent; linezolid use is not recommended for more than 28 days. Case. A 59-year-old female presented with malaise, loss of appetite, and altered mentation. She had multiple medical comorbidities and required long-term anticoagulation with warfarin for venous thromboembolism. She had multiple medication allergies. Prior to admission, she was on linezolid for cellulitis of foot due to Methicillin-resistant Staphylococcus aureus (MRSA). On physical exam, she was drowsy and required endotracheal intubation for airway protection. Initial laboratory parameters showed lactic acidosis, thrombocytopenia, supra-therapeutic coagulation profile, low blood glucose, and transaminitis. Her altered mentation was due to hypoglycemia. The interaction with warfarin led to altered coagulation profile. She developed shock and vasopressors were initiated. Given her presentation, she was managed as severe sepsis. There were no active infectious foci attributing to decline of her clinical status. Linezolid was discontinued and she was managed with intravenous polymyxin B, aztreonam, and vancomycin. Her hemodynamic status improved within one day. She was extubated on Day 5 of her presentation. Her laboratory parameters showed gradual improvement over 12 days after discontinuation of linezolid. Retrospective evaluation revealed linezolid toxicity as possible cause of presentation. Linezolid toxicity can present as sepsis mimic and should be considered as a differential diagnosis while managing sepsis with other antimicrobial agents.\n==== Body\n1. Introduction\nLinezolid is an oxazolidinedione antibiotic approved for use against serious Gram-positive infections, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus faecium [1]. It is generally well tolerated, but can have serious adverse effects including myelosuppression [2], thrombocytopenia [3], serotonin syndrome [4], neuropathy [5], liver dysfunction [6], hypoglycemia, and lactic acidosis. However, rare but potential warfarin interaction leading to hypercoaguable state has been reported [7].\n\nAntibiotics are used for the management of the bacterial infection. The antimicrobial induced adverse events, like lactic acidosis, can be confused with presentation of severe sepsis. It is imperative to recognize the cluster of adverse events to guide optimal treatment. A rare triad of toxicity of the hypoglycemia, lactic acidosis, and acute pancreatitis from linezolid has been reported [8]. We present a novel case of the linezolid toxicity presenting with a rare constellation of adverse events in the form of thrombocytopenia, lactic acidosis, hypoglycemia, and warfarin toxicity. It is imperative to include linezolid toxicity in differential diagnosis of sepsis and use alternative antibiotics for the management of possible bacterial infection.\n\n2. Case\nA 59-year-old female presented with malaise and low appetite for one day. Her family brought her to emergency room (ER) in view of altered mentation. Her medical comorbid conditions included coronary artery disease, hypertension, diabetes mellitus, and multiple venous thromboembolism requiring long-term anticoagulation with warfarin, chronic renal insufficiency, and steroid dependent asthma.\n\nFew weeks prior to her index presentation, she was hospitalized for foot infection. Her evaluation did not reveal osteomyelitis. She developed cellulitis near the ulcer and wound culture revealed growth of Methicillin resistant Staphylococcus aureus (MRSA). The antibiotics susceptibility revealed sensitivities to vancomycin and moxifloxacin. Infectious disease consultation was obtained and in view of the allergy to moxifloxacin and renal insufficiency, 3 weeks of the linezolid was recommended. She was initiated on intravenous linezolid 600 mg twice daily. She was followed up in the infectious disease ambulatory clinic. She was followed up in the anticoagulation monitoring clinic, and she did not require any alteration in warfarin dose. Glucose monitoring diary maintained by visiting nurse service revealed a controlled diabetes state. There was interval improvement in cellulitis and foot ulcer. She presented to our ER few days after the clinic assessment.\n\nShe had multiple medication allergies. She was allergic to azithromycin, penicillin, moxifloxacin, aspirin, ibuprofen, and ketorolac. She had unclear history of allergy to vancomycin. However, further evaluation during index hospitalization revealed the reaction to be rate dependent infusion reaction.\n\nHer initial vitals were blood pressure of 90/46 mm Hg, oxygen saturation of 97% on room air, heartrate of 110 beats per minute, and she was afebrile. Her physical examination was significant for respiratory distress and drowsiness. The foot exam revealed interval healing of the foot ulcer. There were no meningeal signs. Neurological exam did not reveal any focal deficits. Her abdomen was soft and nontender. Cardiac auscultation did not reveal any new murmur.\n\nInitial laboratory parameters showed lactic acidosis, thrombocytopenia, supra-therapeutic international normalized ratio (INR), low blood glucose, transaminitis, and normal fibrinogen levels (Table 1).\n\nImaging studies did not reveal any infective foci. There was no intracranial bleeding on Computerized tomography (CT) of the head. X-ray chest at the time of admission revealed clear lung fields with no pulmonary infiltrates. Ultrasound of abdomen revealed acalculus gallbladder and normal dimension of the common bile duct.\n\nGiven her altered mentation she required intubation and mechanical ventilation. In view of prior MRSA infection she was managed initially for sepsis. The initial impression of her presentation was sepsis, and required further evaluation for source of infection. Infection disease consultation recommended trough monitored intravenous vancomycin along with polymyxin B and aztreonam. Interdisciplinary discussion between clinical pharmacy, infectious disease consultant, and intensivist recommended further evaluation of records for vancomycin allergy versus allergic reaction. Patient received polymyxin B and aztreonam. She further developed shock. Her periphery was cold; despite fluid resuscitation she required the vasopressor for a brief period. The clinical pharmacist recommended vancomycin use, and her hemodynamic status improved with one day. Lactic acidosis can be from hypotension at presentation, but the improvement was not in conjunction to recovery of shock. This late recovery of serum chemistry led to investigate alternate etiology for lactic acidosis. Infectious disease follow-up recommended vancomycin levels to guide subsequent dose and bacterial cultures for titration of antibiotics. However, her blood culture and wound culture from infection site were negative for any bacterial growth. Both cultures were obtained at time of presentation prior to antibiotics administration. Hematology consultation opined that the hypercoaguable state was warfarin induced rather than sepsis induced. A normal fibrinogen level supported this conclusion. She completed the course of linezolid and hence it was not given at time of admission. She was extubated on Day 5 of admission. Her laboratory parameters showed gradual improvement over 12 days after discontinuation of linezolid (Table 1). Given the absence of septic foci, the clinical scenario supported the presentation to be a constellation of adverse events from linezolid and she did not require the additional antibiotics therapy.\n\n3. Discussion\nLinezolid binds to bacterial RNA and prevents formation of a functional 70S initiation complex which is important for the bacterial translocation process. It has been hypothesized that due to the similarities between human and bacterial ribosomes [9], linezolid inhibits the human mitochondrial ribosome by a similar mechanism. Henceforth, the deficiency of mitochondria encoded proteins can lead to lactic acidosis [10–12]. A longer duration of therapy of more than 6 weeks, has been associated with higher rates of lactic acidosis [1]. A systemic review of 47 cases of linezolid identified male gender as a risk factor for development of lactic acidosis, rather than duration of antimicrobial use and patient age [13]. Sepsis, thiamine deficiency, and liver cirrhosis have been associated with the higher incidence of the linezolid associated lactic acidosis [14]. Tissue hypoxia leads to increase in lactate production. Hypotension affects the lactate clearance and hence leads to hyperlactate state [15]. Although, hypo perfusion can be a cause for lactic acidosis in our patient. Lactic acid levels improve with sepsis management, correction of hypotension, and it is correlated with better prognosis [16, 17]. In our case, the lactate recovery did not correlate to shock management and achievement of re-perfusion status. Lactic acid recovery with linezolid toxicity is prolonged and its can take more than 10 days for the lactate levels to normalize [18]. Metformin is also known to cause lactic acidosis, specifically in patients with the renal and hepatic insufficiency [19]. Metformin can limit mitochondrial cellular respiration leading to lactic acidosis [20]. However, our patient was not on metformin. Hence, possible explanation of a prolonged plateau to normalization of lactate level can be explained by linezolid toxicity.\n\nThe literature has depicted an association of linezolid with myelosuppression [3, 14, 21, 22]. No increased risk of agranulocytosis or other irreversible blood dyscrasias was found [21]. More than 2 weeks of therapy has been found to be a risk factor for linezolid induced thrombocytopenia [21, 22]. Thrombocytopenia secondary to linezolid is reversible upon discontinuation of drug [22]. Patients with renal impairment may develop higher plasma linezolid concentration, and hence more likely to develop thrombocytopenia as result of the linezolid toxicity [3, 14]. Vitamin B6 supplementation has been reported to reverse linezolid associated cytopenia [21]. Frequent blood cell count monitoring is suggested for individuals on more than two weeks of the linezolid therapy.\n\nLinezolid related nonselective monoamine oxidase (MAO) inhibition could induce hypoglycemia [23]. This phenomenon is further supported by the higher incidence of hypoglycemia in the individuals on MAO and insulin or sulfonylurea concurrently [24, 25].Our patient was on insulin for the management of her diabetes, but there was no evidence for the use of MAO inhibitors. The bacterial infection can lead to brittle diabetes status, but we did not identify any active bacterial infection while managing her acute presentation. Her diabetes was well controlled at the time of ambulatory visit assessment prior to ER presentation. Medications with dopamine (D2) receptor agonist activity, like bromocriptine, are utilized for antihyperglycemic effect and can cause side effects of hypoglycemia. Linezolid may increase the levels of dopamine via its MAO inhibition activity, hence leading to hypoglycemia [23]. Another mechanism of the hypoglycemia is from linezolid induced mitochondrial dysfunction leading to pancreatic beta-cell related insulin secretion dysregulation [8].\n\nInitial reports of the potential interaction between warfarin and linezolid surfaced in 2015 [7]. Linezolid can have the antimicrobial activity against Bifidobacterium, hence compromising the vitamin K production in the gut [7]. It is hypothesized that linezolid can decrease vitamin K production and potentiate the warfarin toxicity. Our patient had a stable coagulation profile on a stable dose of warfarin until linezolid initiation and there were no other interaction attractable to the hypercoagulable state.\n\nTransaminitis related to linezolid (drug) induced liver injury has been well reported [6, 10]. The liver histopathology in these cases reveals diffuse microvesicular hepatosteatosis [6]. Ischemic hepatitis can be alternative explanation, but would require the clinical acumen to differentiate between the two etiologies. In ischemic hepatitis there is delayed peaking of bilirubin with ALT/LDH ration of lower than 1.5 [26]. In index case, the bilirubin levels peaked at presentation and ALT/LDH ratio was 1.8. Sepsis can be an alternate explanation, but a clear infectious etiology could not be demonstrated.\n\nThe hemodynamic status in our patient improved rapidly. However, the resolution of other parameters like transaminitis, thrombocytopenia, and hyperlactatemia required multiple days leading to prolonged hospitalization.\n\nIn view of pancytopenia and neuro-toxicity the European Medicines Agency (EMEA) and U.S. Food and Drug Administration have suggested to limit linezolid use to 28 days [27, 28]. Linezolid remains an effective antimicrobial for MRSA related infections. A prolonged duration (>4 weeks) of linezolid use, though not well tolerated, has been reported for management of bone infection [29]. In our patient, in view of her multiple drug allergies and renal insufficiency linezolid remains the preferred antibiotic. We faced challenges in management of possible MRSA infection in view of unclear history of vancomycin allergy. Mitochondrial genetics has been studied in linezolid toxicity , specifically for those related to shorter duration of therapy [30]. In presented cases, mitochondrial genetic can explain presentation of lactic acidosis. However, etiology of other side effect was unrelated.\n\n4. Conclusion\nProlonged use of the linezolid has been associated with lactic acidosis, hypoglycemia, thrombocytopenia, and interaction with warfarin. This case brings to light the need for physicians to be aware of linezolid toxicity being a sepsis mimic during course of management. Alternative antimicrobial agents should be considered for management of suspected bacterial infection.\n\nAbbreviations\nMRSA:Methicillin-resistant Staphylococcus aureus\n\nINR:International normalized ratio.\n\nDisclosure\nNo specific grant from funding agencies in the public, commercial, or not-for-profit sectors was received for writing this case report.\n\nConflicts of Interest\nThe authors have no conflicts of interest to disclose.\n\nTable 1 Demonstrates laboratory parameters at the time of admission and the improvement after discontinuation of linezolid.\n\nParameters\tDay 1\tDay 3\tDay 5\tDay 12\tDay 114\t\nHemoglobin (g/dL)\t8.4\t6.6\t7.9\t7.9\t\t\nWBC (k/µL)\t16\t2.9\t6.7\t21.1\t\t\nPlatelets (k/µL)\t26\t17\t11\t190\t\t\nINR\t8.4\t1.9\t1.6\t1.4\t\t\nCreatinine (mg/dL)\t3.3\t3.1\t2.3\t1.0\t\t\nAST ( U/l)\t1289\t559\t101\t346\t19\t\nALT (U/l)\t897\t688\t418\t669\t33\t\nLDH (units/ml)\t479\t\t\t\t\t\nBilirubin (gm/ml)\t2.1\t1.3\t1.4\t0.9\t\t\nLactic acid (mMol/L)\t12.4\t6.5\t4.4\t\t\t\nBlood gas (pH)\t7.06\t7.4\t7.38\t\t\t\nBlood glucose (mg/dL)\t54\t139\t207\t260\t\t\nFibrinogen (mg/dL)\t225\n==== Refs\n1 Im J. H. Baek J. H. Kwon H. Y. Lee J. S. Incidence and risk factors of linezolid-induced lactic acidosis International Journal of Infectious Diseases 2015 31 47 52 10.1016/j.ijid.2014.12.009 2-s2.0-84921033992 25499040 \n2 Deng J. Su L. X. Liang Z. X. Effects of vitamin B6 therapy for sepsis patients with linezolid-associated cytopenias: a retrospective study Current Therapeutic Research, Clinical and Experimental 2013 74 26 32 10.1016/j.curtheres.2012.12.002 2-s2.0-84879449810 \n3 Echeverria-Esnal D. Retamero A. Pardos S. L. Grau S. Severe thrombocytopenia caused by linezolid poisoning in an underweight critically ill patient with renal impairment treated with the recommended doses Enfermedades Infecciosas y Microbiologia Clinica 2016 34 3 213 214 10.1016/j.eimc.2015.06.012 2-s2.0-84960111222 26211841 \n4 Quinn D. K. Stern T. A. Linezolid and serotonin syndrome Primary Care Companion to The Journal of Clinical Psychiatry 2009 11 6 353 356 10.4088/PCC.09r00853 2-s2.0-77957680315 \n5 Rho J. P. Sia I. G. Crum B. A. Dekutoski M. B. Trousdale R. T. Linezolid-associated peripheral neuropathy Mayo Clinic Proceedings 2004 79 7 927 930 10.4065/79.7.927 2-s2.0-3042856503 15244392 \n6 De Bus L. Depuydt P. Libbrecht L. Severe drug-induced liver injury associated with prolonged use of linezolid Journal of Medical Toxicology 2010 6 3 322 326 10.1007/s13181-010-0047-0 2-s2.0-77956190768 20358416 \n7 Sakai Y. Naito T. Arima C. Potential drug interaction between warfarin and linezolid Internal Medicine 2015 54 5 459 464 10.2169/internalmedicine.54.3146 2-s2.0-84923644139 25758070 \n8 Johnson P. C. Vaduganathan M. Phillips K. M. O’Donnell W. J. A triad of linezolid toxicity: hypoglycemia, lactic acidosis, and acute pancreatitis Baylor University Medical Center Proceedings 2015 28 4 466 468 10.1080/08998280.2015.11929310 26424943 \n9 Santini A. Ronchi D. Garbellini M. Piga D. Protti A. Linezolid-induced lactic acidosis: the thin line between bacterial and mitochondrial ribosomes Expert Opinion on Drug Safety 2017 16 7 833 843 10.1080/14740338.2017.1335305 2-s2.0-85021408121 28538105 \n10 Potolidis E. Gousi E. Delios D. Bei E. Mandros C. Linezolid induced lactic acidosis and hepatic failure International Journal of Case Reports and Images 2012 3 12 79 81 10.5348/ijcri-2012-12-246-LE-19 \n11 De Vriese A. S. Van Coster R. Smet J. Linezolid-induced inhibition of mitochondrial protein synthesis Clinical Infectious Diseases 2006 42 8 1111 1117 10.1086/501356 2-s2.0-33645763684 16575728 \n12 Carson J. Cerda J. Chae J. H. Hirano M. Maggiore P. Severe lactic acidosis associated with linezolid use in a patient with the mitochondrial DNA A2706G polymorphism Pharmacotherapy 2007 27 5 771 774 10.1592/phco.27.5.771 2-s2.0-34247881873 17461714 \n13 Mao Y. Dai D. Jin H. Wang Y. The risk factors of linezolid-induced lactic acidosis: a case report and review Medicine 2018 97 36 p. e12114 10.1097/MD.0000000000012114 2-s2.0-85053299639 \n14 Gould F. K. Linezolid: safety and efficacy in special populations The Journal of Antimicrobial Chemotherapy 2011 4 iv3 iv6 10.1093/jac/dkr071 2-s2.0-79955504717 \n15 Lee S. M. An W. S. New clinical criteria for septic shock: serum lactate level as new emerging vital sign Journal of Thoracic Disease 2016 8 7 1388 1390 10.21037/jtd.2016.05.55 2-s2.0-85027830296 27501243 \n16 Jansen T. C. van Bommel J. Schoonderbeek F. J. Early lactate-guided therapy in intensive care unit patients American Journal of Respiratory and Critical Care Medicine 2010 182 6 752 761 10.1164/rccm.200912-1918OC 2-s2.0-77954930936 20463176 \n17 Suetrong B. Walley K. R. Lactic acidosis in sepsis: it’s not all anaerobic: implications for diagnosis and management Chest 2016 149 1 252 261 10.1378/chest.15-1703 2-s2.0-84954110681 26378980 \n18 Apodaca A. A. Rakita R. M. Linezolid-induced lactic acidosis New England Journal of Medicine 2003 348 1 86 87 10.1056/NEJM200301023480123 2-s2.0-0037413465 12510056 \n19 Salpeter S. R. Greyber E. Pasternak G. A. Salpeter E. E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus The Cochrane Database of Systematic Reviews 2010 1 p. Cd002967 \n20 Kopec K. T. Kowalski M. J. Metformin-associated lactic acidosis: case files of the Einstein Medical Center medical toxicology fellowship Journal of Medical Toxicology 2013 9 1 61 66 10.1007/s13181-012-0278-3 2-s2.0-84874241695 23233435 \n21 French G. Safety and tolerability of linezolid Journal of Antimicrobial Chemotherapy 2003 51 90002 45 53 10.1093/jac/dkg253 12493786 \n22 Gerson S. L. Kaplan S. L. Bruss J. B. Hematologic effects of linezolid: summary of clinical experience Antimicrobial Agents and Chemotherapy 2002 46 8 2723 2726 10.1128/AAC.46.8.2723-2726.2002 2-s2.0-0035992065 12121967 \n23 Bodnar T. Starr K. Halter J. B. Linezolid-associated hypoglycemia in a 64-year-old man with type 2 diabetes The American Journal of Geriatric Pharmacotherapy 2011 9 1 88 92 10.1016/j.amjopharm.2011.02.002 2-s2.0-79953681046 21459312 \n24 Cooper A. J. Ashcroft G. Potentiation of insulin hypoglycaemia by M.A.O.I. antidepressant drugs The Lancet 1966 1 7434 407 409 10.1016/S0140-6736(66)91399-7 \n25 Adnitt P. I. Hypoglycemic action of monoamineoxidase inhibitors Diabetes 1968 17 10 628 633 10.2337/diab.17.10.628 2-s2.0-0014343101 5681080 \n26 Cobbold J. F. L. Summerfield J. A. Friedman L. S. Keeffe E. B. Chapter 22—The liver in systemic disease Handbook of Liver Disease 2012 3rd Philadelpia W. B. Saunders 297 307 \n27 Information. Z-P. Access data food and drug administration 2000 \n28 Bressler A. M. Zimmer S. M. Gilmore J. L. Somani J. Peripheral neuropathy associated with prolonged use of linezolid The Lancet Infectious Diseases 2004 4 8 528 531 10.1016/S1473-3099(04)01109-0 2-s2.0-4043151561 15288827 \n29 Senneville E. Legout L. Valette M. Effectiveness and tolerability of prolonged linezolid treatment for chronic osteomyelitis: a retrospective study Clinical Therapeutics 2006 28 8 1155 1163 10.1016/j.clinthera.2006.08.001 2-s2.0-33748535813 16982292 \n30 Garrabou G. Soriano À. Pinós T. Influence of mitochondrial genetics on the mitochondrial toxicity of linezolid in blood cells and skin nerve fibers Antimicrobial Agents and Chemotherapy 2017 61 9 e00542 e00517 10.1128/AAC.00542-17 2-s2.0-85028327832 28674062\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6420", "issue": "2019()", "journal": "Case reports in critical care", "keywords": null, "medline_ta": "Case Rep Crit Care", "mesh_terms": null, "nlm_unique_id": "101598416", "other_id": null, "pages": "2157674", "pmc": null, "pmid": "31929912", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "15244392;26211841;5681080;21459312;25758070;28674062;20091535;21521705;16575728;23233435;27501243;12510056;12730142;12121967;26424943;17461714;20358416;20098528;25499040;30200095;26378980;16982292;24385027;28538105;15288827;4159787;20463176", "title": "A Case of Linezolid Toxicity Presenting as a Sepsis Mimic.", "title_normalized": "a case of linezolid toxicity presenting as a sepsis mimic" }
[ { "companynumb": "US-HQ-000004", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LINEZOLID" }, "drugadditional": "1", "drugadmini...
{ "abstract": "BACKGROUND\nFor women with left common iliac vein compression (ie, May-Thurner syndrome) who undergo venous stenting and subsequently become pregnant, concerns have been raised regarding a possible compromise of stent patency due to compression from the gravid uterus and the hypercoagulability induced by pregnancy. Only a small body of literature exists on this subject, and limited management guidelines are available. The present study was designed to evaluate the safety of iliac vein stenting for May-Thurner syndrome (MTS) with subsequent pregnancy.\n\n\nMETHODS\nFemale patients who had undergone common iliac vein stenting at our center who were aged 18 to 45 years and had subsequently become pregnant were identified. A retrospective medical record review of eight eligible patients was conducted, recording the demographics, procedural characteristics, and anticoagulation strategies. The primary outcome evaluated was stent patency.\n\n\nRESULTS\nAll eight patients had undergone left common iliac vein stenting for MTS. A total of eight stents were placed, and all demonstrated duplex ultrasound patency throughout pregnancy and postpartum. Seven patients delivered healthy pregnancies, and one experienced a stillbirth. The clinical CEAP (clinical, etiologic, anatomic, pathophysiologic) class remained unchanged or improved from pregnancy to postpartum for all patients. The average age at stent placement was 31 ± 5 years, and the average interval from stent placement to pregnancy was 28 ± 19 months. One patient developed nonobstructive deep vein thrombosis (DVT) of the left femoral vein during pregnancy and was treated with therapeutic enoxaparin. The nonobstructive DVT did not compromise the iliac vein stent. Two patients received low-dose aspirin and prophylactic doses of enoxaparin, one for a history of DVT and factor V Leiden and one for a recent history of fertility treatment. The five remaining patients received no anticoagulation, three received low-dose aspirin, and two received no antiplatelet therapy.\n\n\nCONCLUSIONS\nCommon iliac vein stent patency was not compromised by subsequent pregnancy in our eight patients with MTS. Furthermore, the stents remained patent throughout pregnancy in patients receiving a wide range of anticoagulation and antiplatelet treatments, suggesting that no uniform therapeutic threshold exists and treatment should be individualized. For most patients, low-dose aspirin alone or no treatment was adequate. This could have implications for counseling women who require intervention for MTS and are of child-bearing age.", "affiliations": "New York University Grossman School of Medicine, New York, NY.;Division of Vascular Surgery, New York University Langone Health, New York, NY.;Division of Vascular Surgery, New York University Langone Health, New York, NY. Electronic address: glenn.jacobowitz@nyulangone.org.", "authors": "Speranza|Giancarlo|G|;Sadek|Mikel|M|;Jacobowitz|Glenn|G|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.jvsv.2021.07.018", "fulltext": null, "fulltext_license": null, "issn_linking": null, "issue": null, "journal": "Journal of vascular surgery. Venous and lymphatic disorders", "keywords": "Endovenous stenting; May-Thurner syndrome; Pregnancy", "medline_ta": "J Vasc Surg Venous Lymphat Disord", "mesh_terms": null, "nlm_unique_id": "101607771", "other_id": null, "pages": null, "pmc": null, "pmid": "34438090", "pubdate": "2021-08-23", "publication_types": "D016428:Journal Article", "references": null, "title": "Common iliac vein stenting for May-Thurner syndrome and subsequent pregnancy.", "title_normalized": "common iliac vein stenting for may thurner syndrome and subsequent pregnancy" }
[ { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-328922", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ENOXAPARIN SODIUM" }, ...
{ "abstract": "OBJECTIVE\nThe aim of this study is to present the treatment modalities and associated side effects in a Polish nation-wide ANCA-associated vasculitides (AAV) patients' cohort.\n\n\nMETHODS\nRetrospective analysis of patients diagnosed with AAV between 1990 and 2016, included in the POLVAS registry was performed. Standard descriptive statistic methods were used with an emphasis on the treatment modalities.\n\n\nRESULTS\nThere were 625 patients diagnosed with AAV included in this study: 417 cases of granulomatosis with polyangiitis (GPA; 66.7%), 106 cases of microscopic polyangiitis (MPA; 17.0%) and 102 cases of eosinophilic granulomatosis with polyangiitis (EGPA; 16.3%). The mean age at the date of diagnosis was 50.4 (±15.7) years and the median observational period amounted to 4.0 (2.0-8.0) years. Glucocorticosteroids (GCs) were the medicaments most frequently used for remission induction (593/622; 95.3%), followed by cyclophosphamide (487/622; 78.3%), rituximab (44/622; 7.1%), and methotrexate (39/622; 6.3%). GCs were also most frequently administered for maintenance therapy (499/592; 84.3%), followed by azathioprine (224/592; 37.8%), methotrexate (136/592; 23.0%) and mycophenolate mofetil (99/592; 16.7%). The median cumulative doses of cyclophosphamide and rituximab equalled 7.99 g (4.18-14.0) and 2000 mg (1500-2800), respectively. The most commonly observed adverse events included: infections - 214/551 cases (38.8%), which were associated with the time of observation (OR = 1.05; 95% CI 1.01-1.10), the use of GCs intravenous pulses (OR = 2.76; 95% CI 1.68-4.54) and need for haemodialysis (OR = 1.73; 95% CI 1.10-2.71).\n\n\nCONCLUSIONS\nPolish patients with AAV were predominantly treated according to appropriate guidelines. The most frequent adverse events were typical for usually administered immunosuppressive treatment.", "affiliations": "2nd Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland.;2nd Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland.;2nd Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland.;2nd Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland.;Department of Rheumatology, Raigmore Hospital, Inverness, UK; Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.;Department of Internal Medicine, Connective Tissue Diseases and Geriatrics, Medical University of Gdansk, Gdansk, Poland.;Department of Internal Medicine, Connective Tissue Diseases and Geriatrics, Medical University of Gdansk, Gdansk, Poland.;Department of Internal Medicine, Connective Tissue Diseases and Geriatrics, Medical University of Gdansk, Gdansk, Poland.;Department of Rheumatology and Connective Tissue Diseases, Medical University of Lublin, Lublin, Poland.;Department of Rheumatology and Connective Tissue Diseases, Medical University of Lublin, Lublin, Poland.;Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland; Department of Nephrology, Institute of Medicine University of Opole, Opole University Hospital, Opole, Poland.;Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland.;Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland.;Department of Rheumatology and Internal Diseases, Pomeranian Medical University in Szczecin, Szczecin, Poland.;Department of Rheumatology and Internal Diseases, Pomeranian Medical University in Szczecin, Szczecin, Poland.;Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdansk, Gdansk, Poland.;Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdansk, Gdansk, Poland.;Department of Internal Medicine and Rheumatology, Military Medical Institute, Warszawa, Poland.;Department of Internal Medicine and Rheumatology, Military Medical Institute, Warszawa, Poland.;Department of Internal Diseases and Rheumatology, Central Clinical Hospital of the Ministry of the Interior and Administration, Warszawa, Poland.;Department of Rheumatology and Internal Medicine, Wroclaw Medical University, Wroclaw, Poland.;Department of Internal Medicine and Metabolic Diseases, Medical University of Silesia, Katowice, Poland.;Department of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warszawa, Poland.;Department of Internal Medicine, Rheumatology and Clinical Immunology, Medical University of Silesia, Katowice, Poland.;2nd Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland.;2nd Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland. Electronic address: wojciech.szczeklik@uj.edu.pl.", "authors": "Biedroń|Grzegorz|G|;Włudarczyk|Anna|A|;Wawrzycka-Adamczyk|Katarzyna|K|;Wójcik|Krzysztof|K|;Sznajd|Jan|J|;Zdrojewski|Zbigniew|Z|;Masiak|Anna|A|;Czuszyńska|Zenobia|Z|;Majdan|Maria|M|;Jeleniewicz|Radosław|R|;Klinger|Marian|M|;Jakuszko|Katarzyna|K|;Rowaiye|Olumide Olatubosun|OO|;Brzosko|Marek|M|;Brzosko|Iwona|I|;Dębska-Ślizień|Alicja|A|;Storoniak|Hanna|H|;Tłustochowicz|Witold|W|;Kur-Zalewska|Joanna|J|;Wisłowska|Małgorzata|M|;Madej|Marta|M|;Hawrot-Kawecka|Anna|A|;Głuszko|Piotr|P|;Kucharz|Eugeniusz J|EJ|;Musiał|Jacek|J|;Szczeklik|Wojciech|W|", "chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D000069283:Rituximab; D003520:Cyclophosphamide; D001379:Azathioprine; D008727:Methotrexate", "country": "Netherlands", "delete": false, "doi": "10.1016/j.advms.2020.01.002", "fulltext": null, "fulltext_license": null, "issn_linking": "1896-1126", "issue": "65(1)", "journal": "Advances in medical sciences", "keywords": "ANCA associated vasculitis; Treatment complications; Vasculitis registry; Vasculitis treatment", "medline_ta": "Adv Med Sci", "mesh_terms": "D000328:Adult; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D001379:Azathioprine; D003520:Cyclophosphamide; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D011044:Poland; D011379:Prognosis; D012042:Registries; D012189:Retrospective Studies; D000069283:Rituximab; D015996:Survival Rate", "nlm_unique_id": "101276222", "other_id": null, "pages": "156-162", "pmc": null, "pmid": "31958704", "pubdate": "2020-03", "publication_types": "D016428:Journal Article", "references": null, "title": "Treatment and its side effects in ANCA-associated vasculitides - Study based on POLVAS registry data.", "title_normalized": "treatment and its side effects in anca associated vasculitides study based on polvas registry data" }
[ { "companynumb": "PL-ROCHE-2766911", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", "dru...
{ "abstract": "The aim is to evaluate the efficacy and safety of Sofosbuvir- (SOF-) based direct-acting antiviral agents (DAAs) treatment for patients with genotype (GT) 3/6 hepatitis C virus (HCV) infection.\n\n\n\nPatients infected with GT 3/6 HCV and treated with SOF-based DAAs were enrolled in this prospective, open, single-center, and real-world study. Drugs included Sofosbuvir (SOF), Velpatasvir (VEL), Daclatasvir (DCV), and Ribavirin (RBV). The treatment regimens included SOF + RBV for 24 weeks, SOF + DCV ± RBV for 12/24 weeks, and SOF/VEL ± RBV for 12 weeks.\n\n\n\nA total of 54 patients were included. Age was 42.5 ± 10.4 years. Baseline HCV RNA was 6.29 ± 0.89log10 IU/mL. The numbers of GT 3a, 3b, and 6a patients were 10, 12, and 32, respectively. The numbers of chronic hepatitis, compensated cirrhosis, and decompensated cirrhosis patients were 39, 9, and 6, respectively. In patients with chronic hepatitis C and liver cirrhosis, sustained virological response 12 weeks after the end of treatment (SVR12) was 97.4% and 96.7%, respectively, and rapid virological response (RVR) was 75.0% and 57.1%, respectively. SVR12 of GT3a, GT3b, and GT6a was 100%, 83.3%, and 97%, respectively. ALT normality rate in chronic hepatitis group is higher than that in cirrhosis group at 4 weeks of treatment (89.7% versus 60.0%, p = 0.033) and at 12 weeks after EOT (94.9% versus 66.7%, p = 0.021). The overall incidence rate of adverse events was 44.4%, with fatigue being the most common (13.0%).\n\n\n\nSOF-based DAAs regimen can achieve ideal SVR12 for Chinese patients with both GT3a and GT6a HCV infection. The tolerance and safety of SOF-based DAAs regimen are good.", "affiliations": "Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong, China.;Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong, China.;Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong, China.;Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong, China.;Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong, China.", "authors": "Mei|Yong-Yu|YY|0000-0003-0853-0631;Chen|You-Ming|YM|0000-0002-9599-5850;Wu|Yuan-Kai|YK|0000-0002-0408-9319;Zhang|Xiao-Hong|XH|0000-0002-5041-5234;Xu|Wen-Xiong|WX|0000-0002-0671-697X", "chemical_list": "D000998:Antiviral Agents; D004364:Pharmaceutical Preparations; D012254:Ribavirin; D000069474:Sofosbuvir", "country": "Egypt", "delete": false, "doi": "10.1155/2020/8872120", "fulltext": "\n==== Front\nCan J Gastroenterol Hepatol\nCan J Gastroenterol Hepatol\nCJGH\nCanadian Journal of Gastroenterology & Hepatology\n2291-2789 2291-2797 Hindawi \n\n10.1155/2020/8872120\nResearch Article\nEfficacy and Safety of Sofosbuvir-Based Direct-Acting Antiviral Agents Treatment for Patients with Genotype 3/6 Hepatitis C Virus Infection\nhttps://orcid.org/0000-0003-0853-0631Mei Yong-yu \n1\n\n2\n https://orcid.org/0000-0002-9599-5850Chen You-ming \n1\n\n2\n https://orcid.org/0000-0002-0408-9319Wu Yuan-kai \n1\n\n2\n https://orcid.org/0000-0002-5041-5234Zhang Xiao-hong zhangxh5@mail.sysu.edu.cn\n1\n\n2\n https://orcid.org/0000-0002-0671-697XXu Wen-xiong xwx1983@163.com\n1\n\n2\n \n1Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong, China\n\n2Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong, China\nAcademic Editor: Alessandro Granito\n\n\n2020 \n31 10 2020 \n2020 88721204 7 2020 12 10 2020 16 10 2020 Copyright © 2020 Yong-yu Mei et al.2020This 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.Aims\n The aim is to evaluate the efficacy and safety of Sofosbuvir- (SOF-) based direct-acting antiviral agents (DAAs) treatment for patients with genotype (GT) 3/6 hepatitis C virus (HCV) infection. \n\nMethods\n Patients infected with GT 3/6 HCV and treated with SOF-based DAAs were enrolled in this prospective, open, single-center, and real-world study. Drugs included Sofosbuvir (SOF), Velpatasvir (VEL), Daclatasvir (DCV), and Ribavirin (RBV). The treatment regimens included SOF + RBV for 24 weeks, SOF + DCV ± RBV for 12/24 weeks, and SOF/VEL ± RBV for 12 weeks. \n\nResults\n A total of 54 patients were included. Age was 42.5 ± 10.4 years. Baseline HCV RNA was 6.29 ± 0.89log10 IU/mL. The numbers of GT 3a, 3b, and 6a patients were 10, 12, and 32, respectively. The numbers of chronic hepatitis, compensated cirrhosis, and decompensated cirrhosis patients were 39, 9, and 6, respectively. In patients with chronic hepatitis C and liver cirrhosis, sustained virological response 12 weeks after the end of treatment (SVR12) was 97.4% and 96.7%, respectively, and rapid virological response (RVR) was 75.0% and 57.1%, respectively. SVR12 of GT3a, GT3b, and GT6a was 100%, 83.3%, and 97%, respectively. ALT normality rate in chronic hepatitis group is higher than that in cirrhosis group at 4 weeks of treatment (89.7% versus 60.0%, p = 0.033) and at 12 weeks after EOT (94.9% versus 66.7%, p = 0.021). The overall incidence rate of adverse events was 44.4%, with fatigue being the most common (13.0%). \n\nConclusion\n SOF-based DAAs regimen can achieve ideal SVR12 for Chinese patients with both GT3a and GT6a HCV infection. The tolerance and safety of SOF-based DAAs regimen are good.\n\nGuangzhou Science and Technology Program key projects2014B020212025Science and Technology of Guangdong Province\n==== Body\n1. Introduction\nThere are 71 million chronic hepatitis C (CHC) patients worldwide [1–3], and 350,000 people die of hepatitis C-related diseases every year. In China, 10 million people are infected with hepatitis C virus (HCV) [4]. HCV infection has become a serious public health problem.\n\nGenotype 3 (GT3) and GT6 HCV infections are more common in southeast Asia and south China [5, 6]. People with these two genotypes are at higher risk of developing liver cancer [4, 7–9]. Compared with other genotypes of chronic HCV infection, patients with GT3-CHC have a faster progression in liver disease [7]. Direct-acting antiviral agents (DAAs) are the first choice for HCV by Chinese Medical Association [4], American Association for the Study of Liver Diseases [10], and European Association for the Study of the Liver [11]. The treatment regimens include multiple solutions based on Sofosbuvir (SOF). Compared with GT1-CHC, GT3-CHC patients have a relatively low sustained virological response 12 weeks after the end of treatment (SVR12) by DAAs [12]. Satisfactory SVR12 has been achieved for DAAs treatment in GT6-CHC patients, but the number of patients in clinical trials is limited. Otherwise, there is still lack of data on the efficacy and safety of DAAs treatment in Chinese population in real-world study.\n\nTherefore, we design this prospective and real-world study and aim to compare the efficacy and safety of different DAAs treatments based on SOF for CHC patients with GT 3/6 in China. We hope the results can provide supplementary data for clinical medication.\n\n2. Materials and Methods\n2.1. Study Design and Subjects\nThis was a prospective, open, single-center, and real-world study. Patients, who were infected with GT 3/6 HCV and treated with DAAs based on SOF in Third Affiliated Hospital of Sun Yat-sen University from December 1, 2017, to September 30, 2019, were enrolled in the study. This study complied with the Declaration of Helsinki and was approved by the ethics committee of the Third Affiliated Hospital of Sun Yat-sen University. The ethical approval number was [2018] 02-305-02. All participants provided written informed consent prior to enrollment in the study.\n\nEnrollment criteria were the following: (1) CHC patients [4], (2) age of 18–65 years, (3) GT3 or GT6 HCV infection, (4) treatment with DAAs based on SOF, and (5) voluntarily signing informed consent form and participating in the follow-up cohort of hepatitis C in Third Affiliated Hospital of Sun Yat-sen University.\n\nExclusive criteria were the following: (1) patients with renal disfunction (eGFR < 30 mL/min/1.73 m2), (2) patients taking drugs that had interactions with DAAs, and (3) patients with autoimmune diseases or those who acquired immune deficiency syndrome.\n\n2.2. Treatment Regimens\nDrugs included Sofosbuvir (SOF, oral 400 mg per day), Velpatasvir (VEL, oral 100 mg per day), Daclatasvir (DCV, oral 60 mg per day), and Ribavirin (RBV, oral 10∼15 mg/kg per day). SOF (Sovaldi, GILEAD) was officially launched in China on October 21, 2017. SOF/VEL (Epclusa, GILEAD) was officially launched in China on May 30, 2018. DCV (Daklinza, Bristol-Myers Squibb) was officially launched in China on August 24, 2017. Patients can obtain these drugs about 2 months thereafter.\n\nAccording to guideline [4, 10, 11] of HCV treatment, drug instructions, and drug accessibility in China, the treatment regimens included SOF + RBV for 24 weeks, SOF + DCV ± RBV for 12/24 weeks, and SOF/VEL ± RBV for 12 weeks. RBV was used in singular DAA regimen of SOF for chronic hepatitis and cirrhosis patients or in SOF-based DAAs regimens for cirrhosis patients.\n\n2.3. Follow-Up\nThe patients were followed up at baseline, 4 weeks of treatment, 8 weeks of treatment, end of treatment (EOT), 12 weeks after EOT, and 24 weeks after EOT. At each follow-up, patient's data, including symptoms, signs, and laboratory tests, were recorded. Laboratory tests included blood cells test (white blood cells, red blood cells, hemoglobin, and platelets), blood biochemical test (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBil], blood urea nitrogen [BUN], and creatinine), virological test (anti-hepatitis A virus immunoglobulin M [HAV-IgM], hepatitis B virus surface antigen [HBsAg], HBV DNA, anti-HCV immunoglobulin G [HCV-IgG], HCV RNA, and anti-hepatitis E virus immunoglobulin M and G [HEV-IgM and HEV-IgG]), liver ultrasound, and Fibroscan.\n\nRoutine automated techniques were used for all biochemical tests at our clinical laboratories. Serum HBV DNA levels were measured with real-time PCR using the COBAS AmpliPrep/COBAS TaqMan HBV Test, version 2.0 (detection limit: 20 IU/mL, Roche Molecular Systems, Inc.). Serum HCV RNA levels were measured with real-time PCR using the COBAS AmpliPrep/COBAS TaqMan HCV Test, version 2.0 (detection limit: 15 IU/mL, Roche Molecular Systems, Inc.).\n\n2.4. Definition of Virological Response\nRapid viral response (RVR) is defined as HCV RNA being undetectable after 4 weeks of DAAs treatment. Early viral response (EVR) is defined as HCV RNA being undetectable after 8 weeks of DAAs treatment. End of treatment response (EOTR) is defined as HCV RNA being undetectable at the end of DAAs treatment. Sustained virological response 12 weeks after EOT (SVR12) is defined as HCV RNA being undetectable 12 weeks after the end of DAAs treatment.\n\n2.5. Statistical Analysis\nContinuous data were indicated with mean ± standard deviation (SD), while categorical data were reported as count and percentage (%). Student's independent t-test and one-way ANOVA were used to test the difference of means between 2 groups or among multiple groups (>2). Nonparametric tests including the Mann-Whitney U test and Kruskal-Wallis test were used to compare means between groups for data normality was not assumed. Categorical data were tested with Chi-square test or Fisher's exact test (if any expected value ≤ 5 was found). The statistical significance level for all the tests was set at a p value < 0.05. Statistical analyses were performed using IBM SPSS Version 20 (SPSS Statistics V20, IBM Corporation, Somers, New York).\n\n3. Results\n3.1. Patients Baseline Characteristics\nA total of 58 CHC patients with GT3/6 were enrolled in this prospective study. Two cases had missing data: 1case was treated with SOF and interferon α, and 1 case stopped treatment in one month. Therefore, a total of 54 patients were finally included in this study. The CONSORT diagram of patient enrollment is shown in Figure 1.\n\nThe average age of the 54 patients was 42.5 ± 10.4 years. Forty-two patients were males, while 12 were females. There were 39, 9, and 6 patients with chronic hepatitis, compensated cirrhosis, and decompensated cirrhosis, respectively. In patients with chronic hepatitis, there were 8, 4, and 27 patients with GT3a, GT3b, and GT6a, respectively. In patients with compensated cirrhosis, there were 1, 4, and 4 patients with GT3a, GT3b, and GT6a, respectively. In patients with decompensated cirrhosis, there were 1, 4, and 1 patient with GT3a, GT3b, and GT6a, respectively. In total, there were 10, 12, and 32 patients with GT3a, GT3b, and GT6a, respectively. Baseline level of HCV RNA was 6.29 ± 0.89 log10 IU/mL. The duration from diagnosis to treatment was 40.2 ± 64.4 months. The duration of follow-up was 46.1 ± 23.5 weeks. The demographic information and baseline characteristics of the patients are shown in Table 1.\n\n3.2. Safety of SOF-Based DAAs Treatment\nThe overall incidence of adverse events (AEs) is 44.4% (24/54), including 7 (12.9%) patients with fatigue, 3 (5.6%) patients with rash, 2 (3.7%) patients with itchy skin, 2 (3.7%) patients with headache and dizziness, 1 (1.9%) patient with gastric ulcer, 1 (1.9%) patient with myalgia, 1 (1.9%) patient with prolonged menstruation, and 1 (1.9%) patient with abdominal pain and diarrhea. The laboratory tests abnormalities mainly included 2 (3.7%) patients with elevated TBil, 2 (3.7%) patients with decreased hemoglobin, and 1 (1.9%) patient with decreased platelets. Interestingly, 5 out of 6 (83.3%) patients in decompensated cirrhosis group had AEs. Most of AEs disappeared after proper treatment, unless serious adverse events (SAEs) occurred in 1 patient, who was diagnosed with hepatocellular carcinoma (HCC) at EOT with pathological evidence and received liver cancer resection. Seven patients were coinfected with hepatitis B virus (HBV), and none of them had HBV reactivation in DAAs treatment. One patient had a history of liver transplantation for 5 years, and no AEs occurred in DAAs treatment. None of the 54 patients stopped DAAs treatment due to AEs, and none of them died from AEs in DAAs treatment course.\n\n3.3. Efficacy of SOF-Based DAAs Treatment\nBaseline level of HCV RNA was 6.33 ± 0.81 and 6.17 ± 1.11 log10 IU/mL in patients of chronic hepatitis and cirrhosis, respectively (p > 0.05). After SOF-based DAAs treatment, RVR was 75.0% and 57.1% in patients of chronic hepatitis and cirrhosis, respectively. EVR was 100% and 93.3% in patients of chronic hepatitis and cirrhosis, respectively. EOTR was 100% and 93.3% in patients of chronic hepatitis and cirrhosis, respectively. SVR12 was 97.4% and 96.7% in patients of chronic hepatitis and cirrhosis, respectively. The results are shown in Table 2. For patients with different genotype, EOTR and SVR12 are shown in Figure 2(a). For patients with different diagnosis (chronic hepatitis, compensated cirrhosis, and decompensated cirrhosis), EOTR and SVR12 were shown in Figure 2(b). For patients with different treatment plan, EOTR and SVR12 were shown in Figure 2(c).\n\nThere were 3 patients without SVR12. Among them, Patient A had CHC with GT3b and was treated with SOF and DCV for 12 weeks; Patient B had compensated cirrhosis with GT6a and was treated with SOF and RBV for 24 weeks; Patient C had decompensated cirrhosis with GT3b and was treated with SOF, DCV, and RBV for 24 weeks. Then, as they did not achieve SVR12, Patients A and C changed to be treated with SOF/VEL + RBV for 24 weeks, and Patient B changed to be treated with SOF/VEL + RBV for 12 weeks. All of them achieved SVR12 after that.\n\nFor all the 54 patients, baseline ALT abnormality rate was 66.7%. ALT normality rate in chronic hepatitis group is higher than that in cirrhosis group at 4 weeks of treatment (89.7% versus 60.0%, p < 0.05) and at 12 weeks after EOT (94.9% versus 66.7%, p < 0.05). Baseline level of TBil in cirrhosis group is higher than that in chronic hepatitis group. But there were not statistical differences of the two groups in TBil changes in the treatment course or the follow-up thereafter (all p > 0.05). Meanwhile, there were no statistical differences of the two groups in estimated glomerular filtration rate (eGFR) changes in the treatment course or the follow-up thereafter (all p > 0.05). The biochemical response of DAAs treatment is shown in Table 3.\n\n4. Discussion\nDAAs were officially launched in China in 2017, but there have not been many real-world studies of DAAs treatment in GT3 and GT6 HCV infection in China so far. In our study, the SOF-based DAAs regimen could achieve SVR12 in 94.4% of all the patients included. SVR12 was 100% in patients with GT3a, 97% in patients with GT6a, and 83.3% in patients with GT3b. Otherwise, the overall safety of the SOF-based DAAs regimen was good.\n\nOur study showed that AEs of the SOF-based DAAs regimen were mild. AEs were mainly fatigue and rash. Symptoms relieved after proper treatment, and drug withdrawal was not needed. Abnormal laboratory data, mainly including increased TBil and decreased HGB and PLT, occurred in cirrhosis patients, especially in decompensated ones. The decreased HGB and PLT could recover to normal level after adjusting the dosage of ribavirin. However, the mechanism of PLT decline was unclear. Although patients with HBV coinfection in this study did not have elevated level of HBV DNA, we found cases of HBV activation after SVR in our previous study [13]. The progression of liver disease to cirrhosis and hepatocellular carcinoma is generally faster in CHC patients who are coinfected with HBV, and HCV is usually more predominant. Immunosuppression of the host or eradication of hepatitis C can change this paradigm, causing hepatitis B reactivation [14]. Therefore, CHC patients with HBV coinfection still needed to monitor level of HBV DNA after DAAs treatment. Intrahepatic occupancy was not found at baseline, but hepatocellular carcinoma was found at the end of DAAs treatment in one patient in our study. DAAs treatment can inhibit replication of HCV and achieve SVR. After that, the progression of liver disease may slow down [15]. DAAs treatment cannot directly prevent occurrence of liver cancer. However, underlying liver cirrhosis is present in most patients with HCC, the impact of liver function is relevant to establish treatment approach, and antiviral treatment could prevent worsening of liver function, allowing anti-HCC treatment [16]. Whether DAAs can predispose to HCC or not is still conflicting so far [17]. A study from Taiwan indicated that the risk of HCC recurrence and progression is not increased by DAAs [18]. In patients with HCV-related cirrhosis who had been successfully treated for early HCC, DAAs significantly improved OS compared with no DAA treatment [19]. A meta-analysis [20] showed that lower serum albumin, randomized controlled trial study design, and follow-up were independently associated with higher recurrence risk, whereas tumour size and alpha-fetoprotein levels were associated with higher mortality in patients with successfully treated HCV-related HCC.\n\nALT normality rate in chronic hepatitis group is higher than that in cirrhosis group at 4 weeks of treatment (89.7% versus 60.0%, p < 0.05) and at 12 weeks after EOT (94.9% versus 66.7%, p < 0.05) in our study. It may be due to the change of liver structure in cirrhosis patients. Hepatocellular inflammation may be caused by not only HCV replication but also the immune response to liver cirrhosis. eGFR did not decrease neither in the treatment course nor in the follow-up thereafter, showing good renal tolerance of SOF-based DAAs regimen. It is inconsistent with the research by Liu et al., which found that patients receiving SOF-based DAAs exhibited a quadratic trend, with eGFR worsening on treatment and improving off treatment [21].\n\nIn a large multinational CHC cohort from East Asia, oral DAAs were highly effective (the overall SVR12 was 96%) and well tolerated across the region [22]. Of the all-oral regimens, SVR12 in GT3 CHC patients was 90–95% [12]. SVR12 could achieve 100% in GT6 CHC patients with DAAs regimen in southwest China in a real-world study [23]. In our study, SOF-based DAAs regimen could achieve fast elimination of HCV in most of the CHC patients with GT3a/3b/6a. The overall RVR, EVR, EOTR, and SVR12 were 69.6%, 97.8%, 98.1%, and 94.4%, respectively. SVR of GT3 CHC patients was ideal in the era of combination treatment of peginterferon and Ribavirin before DAAs, as it reached about 70% (68.2–71.5%) and was much higher than that of GT1. However, SVR of GT3 CHC patients was not ideal in the era of SOF-based DAAs treatment, as it reached about 90% and was lower than that of other genotypes in several studies [12, 24–27]. GT3 is regarded as being more difficult to treat as it is a relatively aggressive genotype, associated with greater liver damage and cancer risk; some subgroups of patients with GT3 infection are less responsive to current licensed DAA treatments [12]. In our study, SVR12 was 83.3% with GT3b, lower than that of GT3a (100%) and GT6a (97%). SVR12 was similar in both chronic hepatitis and cirrhosis patients with GT3b (p > 0.05) or in both compensated and decompensated cirrhosis patients with GT3b (p > 0.05). Otherwise, there was a relative high incidence of liver cancer in GT3 CHC patients [8, 9]. So, it was important to choose an adequate DAAs regimen, such as SOF-based DAAs regimens combined with RBV for prolonged duration, or Pibrentasvir + Glecaprevir [28], for patients with GT3b HCV infection.\n\nIn our study, EOTR and SVR12 were 100% in CHC patients with DAAs regimen of SOF/VEL ± RBV. But SVR12 was relatively low in CHC patients with DAAs regimen of SOF + RBV and SOF + DCV ± RBV. SOF/VEL ± RBV seemed to be a prior regimen of initial treatment for GT3/6 CHC patients. Studies have shown that DAAs regimen of SOF/VEL ± RBV can achieve ideal SVR12 [29, 30]. The three patients with initial DAAs treatment failure in our study received sequential DAAs regimen of SOF/VEL + RBV and gained SVR12 after that. DAAs regimen of SOF/VEL + RBV can also be a solution for previous DAAs treatment failure [31].\n\nThere are several limitations in our study. First, the sample size is small, which may lead to statistical bias and influence the result and clinical decision. Clinical studies with large population are needed to confirm our results. Second, there are three different treatment regimens in our study. As a real-world study, treatment regimen decision is based on treatment guidelines, drug accessibility, drug price, patient compliance, and so on. The heterogeneity of patients at baseline makes it difficult to compare the advantages and disadvantages of different treatment regimens.\n\n5. Conclusions\nSOF-based DAAs regimen can achieve ideal SVR12 for Chinese patients with both GT3a and GT6a HCV infection. The tolerance and safety of SOF-based DAAs regimen are good. The results need confirmation on larger populations.\n\nAcknowledgments\nThis study was supported by Science and Technology of Guangdong Province: Special Funds for Public Welfare Research and Capacity Building in Guangdong Province (Grant no. 2014B020212025).\n\nData Availability\nThe data used to support the findings of this study are included within the article.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest.\n\nFigure 1 The CONSORT diagram of patient enrollment.\n\nFigure 2 EOTR and SVR12. (a) EOTR and SVR12 in patients with different genotype. (b) EOTR and SVR12 in patients with different diagnosis. (c) EOTR and SVR12 in patients with different treatment plan.\n\nTable 1 Demographic information and baseline characteristics.\n\n\tAll (n = 54)\tCHC (n = 39)\tCIR (n = 15)\tStatistics\t\np\n\t\nAge (years)\t42.5 ± 10.4\t40.1 ± 10.0\t49.3 ± 8.4\t3.066\t0.003\t\nSex (male/female)\t40/14\t32/7\t10/5\t0.727\t0.394\t\nBMI (kg/m2)\t23.0 ± 4.0\t22.6 ± 3.6\t24.2 ± 4.7\t1.286\t0.205\t\nDecompensated cirrhosis\t6 (11.1%)\t0 (0%)\t6 (40.0%)\t—\t—\t\nGenotype (3a/3b/6a)\t10/12/32\t8/4/27\t2/8/5\t10.789\t0.005\t\nHCV RNA (log10 IU/mL)\t6.29 ± 0.89\t6.33 ± 0.81\t6.17 ± 1.11\t0.988\t0.328\t\nALT (IU/L)\t91.6 ± 68.0\t99.6 ± 75.6\t70.0 ± 35.1\t1.841\t0.072\t\nTBil (μmol/L)\t13.8 ± 7.4\t11.2 ± 4.6\t20.3 ± 9.4\t3.306\t0.005\t\nAlcohol addiction\t16 (29.6%)\t9 (23.1%)\t7 (46.7%)\t1.871\t0.171\t\nRoute of infection\t \t \t \t1.132\t0.568\t\nTransfusion\t8 (14.8%)\t5 (12.8%)\t3 (20.0%)\t \t \t\nIDUs\t16 (29.6%)\t13 (33.3%)\t3 (20.0%)\t \t \t\nUnknown\t30 (55.6%)\t21 (53.8%)\t9 (60.0%)\t \t \t\nHBV coinfection\t7 (13.0%)\t4 (10.3%)\t3 (20.0%)\t0.253\t0.615\t\nDuration from diagnosis to treatment (months)\t40.2 ± 64.4\t35.0 ± 60.9\t54.1 ± 73.5\t0.943\t0.351\t\nFollow-up (weeks)\t46.1 ± 23.5\t44.2 ± 22.5\t51.4 ± 26.2\t0.988\t0.328\t\nCHC: chronic hepatitis C; CIR: cirrhosis; BMI: body mass index; ALT: alanine aminotransferase; TBil: total bilirubin; IDUs: intravenous drugs users.\n\nTable 2 The virological response of DAAs treatment.\n\n\tAll (n = 54)\tCHC (n = 39)\tCIR (n = 15)\tStatistics\t\np\n\t\nRegimen (1/2/3/4/5)\t16/17/12/7/2\t12/16/4/7/0\t4/1/8/0/2\t18.823\t<0.001\t\nRVR\t32/46 (69.6%)\t24/32 (75.0%)\t8/14 (57.1%)\t0.745\t0.388\t\nEVR\t45/46 (97.8%)\t31/31(100%)\t14/15 (93.3%)\t—\t0.326\t\nEOTR\t53 (98.1%)\t39 (100%)\t14 (93.3%)\t—\t0.278\t\nSVR12\t51 (94.4%)\t38 (97.4%)\t13 (86.7%)\t—\t0.183\t\nRelapse\t3 (5.6%)\t1 (2.6%)\t2 (13.3%)\t—\t0.183\t\nCHC: chronic hepatitis C; CIR: cirrhosis; Regimen: 1 = SOF + RBV, 2 = SOF + DCV, 3 = SOF + DCV + RBV, 4 = SOF/VEL, and 5 = SOF/VEL + RBV, 12 weeks or 24 weeks; RVR: rapid virological response; EVR: early virological response; EOTR: end of treatment response; SVR12: sustained virological response 12 weeks after the end of treatment.\n\nTable 3 The biochemical response of DAAs treatment.\n\n\tAll (n = 54)\tCHC (n = 39)\tCIR (n = 15)\tStatistics\t\np\n\t\nALT0 (IU/L)\t91.6 ± 68.0\t99.6 ± 75.6\t70.0 ± 35.1\t1.841\t0.072\t\nBaseline ALT abnormality\t36 (66.7%)\t26 (66.7%)\t10 (66.7%)\t0.000\t1.000\t\nALT normality\t \t \t \t \t \t\nW4\t44 (81.5%)\t35 (89.7%)\t9 (60.0%)\t4.533\t0.033\t\nW12\t49 (90.7%)\t36 (92.3%)\t13 (86.7%)\t0.014\t0.907\t\nEOT\t48 (88.9%)\t36 (92.3%)\t12 (80.0%)\t0.649\t0.420\t\nF12\t47 (87.0%)\t37 (94.9%)\t10 (66.7%)\t5.343\t0.021\t\nTBil0 (μmol/L)\t13.8 ± 7.4\t11.2 ± 4.6\t20.3 ± 9.4\t3.306\t0.005\t\nΔTB4_0\t1.1 ± 5.0\t1.1 ± 4.6\t1.3 ± 5.9\t0.154\t0.878\t\nΔTB12_0\t−0.6 ± 6.1\t−0.4 ± 4.2\t−1.1 ± 9.2\t0.238\t0.815\t\nΔTB_EOT_0\t−1.4 ± 4.5\t−1.3 ± 3.6\t−1.9 ± 6.2\t0.334\t0.743\t\nΔTB_F12_0\t−2.4 ± 6.6\t−3.4 ± 5.0\t0.2 ± 9.5\t1.124\t0.285\t\neGFR0 (ml/min.1.73 m2)\t107.3 ± 19.0\t107.0 ± 21.8\t108.3 ± 9.8\t0.162\t0.872\t\nΔeGFR4_0\t2.4 ± 11.1\t4.6 ± 12.8\t−2.2 ± 4.7\t1.445\t0.163\t\nΔeGFR12_0\t0.5 ± 11.3\t1.6 ± 12.8\t−1.9 ± 7.1\t0.903\t0.372\t\nΔeGFR_EOT_0\t2.3 ± 11.9\t2.8 ± 13.6\t1.3 ± 7.1\t0.324\t0.748\t\nΔeGFR_F12_0\t0.0 ± 12.4\t−0.8 ± 13.9\t1.6 ± 8.9\t0.503\t0.618\t\nCHC: chronic hepatitis C; CIR: cirrhosis; BMI: body mass index; ALT: alanine aminotransferase; TBil: total bilirubin; eGFR: estimated glomerular filtration rate; W4: week 4 of treatment; W12: week 12 of treatment; EOT: end of treatment; F12: 12 weeks after end of treatment; ALT0: ALT at baseline (same for TBil0 and eGFR0); ΔTB4_0 or ΔeGFR4_0: changes of TBil or eGFR from baseline to week 4 (TB4–TB0, or eGFR4–eGFR0); ΔTB12_0 or ΔeGFR12_0: changes of TBil or eGFR from baseline to week 12; ΔTB_EOT_0 or ΔeGFR_EOT_0: changes of TBil or eGFR from baseline to end of treatment; ΔTB_F12_0 or ΔeGFR_F12_0: changes of TBil or eGFR from baseline to 12 weeks after end of treatment.\n==== Refs\n1 World Health Organization Guidelines for the Care and Treatment of Persons Diagnosed with Chronic Hepatitis C Virus Infection 2018 Geneva, Switzerland World Health Organization \n2 Mohd Hanafiah K. 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Real-life effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in hepatitis C patients with previous DAA failure Journal of Hepatology 2019 71 6 1106 1115 10.1016/j.jhep.2019.07.020 2-s2.0-85072690601 31433303\n\n", "fulltext_license": "CC BY", "issn_linking": "2291-2789", "issue": "2020()", "journal": "Canadian journal of gastroenterology & hepatology", "keywords": null, "medline_ta": "Can J Gastroenterol Hepatol", "mesh_terms": "D000998:Antiviral Agents; D002648:Child; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus; D006526:Hepatitis C; D019698:Hepatitis C, Chronic; D006801:Humans; D004364:Pharmaceutical Preparations; D011446:Prospective Studies; D012254:Ribavirin; D000069474:Sofosbuvir; D016896:Treatment Outcome", "nlm_unique_id": "101623613", "other_id": null, "pages": "8872120", "pmc": null, "pmid": "33194875", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": "28397696;24090188;31584833;28061016;29650333;30959157;31819865;20554340;31424972;27935168;30987413;30380166;31433303;29089588;31448717;31463665;30669787;30946776;31816111;31790766;31771822;28440303;31266620;29365309;28214411;29145802;29536554;25069599;23172780", "title": "Efficacy and Safety of Sofosbuvir-Based Direct-Acting Antiviral Agents Treatment for Patients with Genotype 3/6 Hepatitis C Virus Infection.", "title_normalized": "efficacy and safety of sofosbuvir based direct acting antiviral agents treatment for patients with genotype 3 6 hepatitis c virus infection" }
[ { "companynumb": "CN-GILEAD-2020-0504963", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SOFOSBUVIR" }, "drugadditional": "3", ...
{ "abstract": "Introduction: In severe asthma, management of life-threatening air trapping that persists despite initiation of standard asthma treatment is difficult in the absence of extracorporeal membranous oxygenation.Case study: Three children with life-threatening asthma could not be adequately ventilated despite maximum conventional treatment because of severe air trapping. A novel method of active expiration by abdominal compression with a standard ventilator was adopted with immediate effect with significant improvement in ventilation.Conclusion: Synchronized abdominal compression is a novel and simple method that allows an effective treatment of severe air trapping in an intubated paralyzed asthma child.", "affiliations": "Department of Paediatrics, Kwong Wah Hospital, Yau Ma Tei, Hong Kong, China.;Department of Paediatrics, Kwong Wah Hospital, Yau Ma Tei, Hong Kong, China.;Department of Paediatrics, Kwong Wah Hospital, Yau Ma Tei, Hong Kong, China.;Department of Paediatrics, Kwong Wah Hospital, Yau Ma Tei, Hong Kong, China.", "authors": "Chan|Eric Y|EY|;Chan|Pak-Hong|PH|;Yeung|Gerry M|GM|;Ng|Daniel K|DK|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1080/02770903.2019.1606234", "fulltext": null, "fulltext_license": null, "issn_linking": "0277-0903", "issue": "57(7)", "journal": "The Journal of asthma : official journal of the Association for the Care of Asthma", "keywords": "Status asthmaticus; auto-PEEP; child; mechanical ventilation; respiratory acidosis", "medline_ta": "J Asthma", "mesh_terms": "D034861:Abdominal Wall; D002675:Child, Preschool; D045853:Exhalation; D005260:Female; D006801:Humans; D007223:Infant; D007442:Intubation, Intratracheal; D012121:Respiration, Artificial; D012720:Severity of Illness Index; D013224:Status Asthmaticus; D016896:Treatment Outcome", "nlm_unique_id": "8106454", "other_id": null, "pages": "765-768", "pmc": null, "pmid": "31017026", "pubdate": "2020-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Synchronized abdominal compression as a novel treatment of life-threatening preschool asthma.", "title_normalized": "synchronized abdominal compression as a novel treatment of life threatening preschool asthma" }
[ { "companynumb": "HK-TEVA-2021-HK-1971638", "fulfillexpeditecriteria": "1", "occurcountry": "HK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ALBUTEROL" }, "drugadditional": "4", ...
{ "abstract": "By definition, the neurologic impairments of hemiplegic migraine are reversible. However, a few cases of permanent neurologic deficits associated with hemiplegic migraine have been reported. Herein, we present the case of a patient with permanent impairments because of hemiplegic migraine despite normalization of associated brain magnetic resonance imaging abnormalities. Cases like these suggest the need to consider aggressive prophylactic therapy for patients with recurrent hemiplegic migraine attacks.", "affiliations": "Mayo Clinic, Phoenix, AZ, USA.", "authors": "Schwedt|Todd J|TJ|;Zhou|Jiying|J|;Dodick|David W|DW|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1111/head.12232", "fulltext": null, "fulltext_license": null, "issn_linking": "0017-8748", "issue": "54(1)", "journal": "Headache", "keywords": "hemiplegic migraine; migraine; persistent neurologic deficit", "medline_ta": "Headache", "mesh_terms": "D005260:Female; D006801:Humans; D020325:Migraine with Aura; D009422:Nervous System Diseases; D055815:Young Adult", "nlm_unique_id": "2985091R", "other_id": null, "pages": "163-6", "pmc": null, "pmid": "24117121", "pubdate": "2014-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12122185;16054936;9550598;8479146;8898206;20739815;23203776;9371899;14755732;14979299;17883529;17578530;12539047;21458376;15196295", "title": "Sporadic hemiplegic migraine with permanent neurological deficits.", "title_normalized": "sporadic hemiplegic migraine with permanent neurological deficits" }
[ { "companynumb": "US-DRREDDYS-USA/USA/14/0038943", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ZONISAMIDE" }, "drugadditional": null, ...
{ "abstract": "Routes of administration for medications and fluids in the acute care setting have primarily focused on oral, intravenous, or intraosseous routes, but, in many patients, none of these routes is optimal. A novel device (Macy Catheter; Hospi Corp) that offers an easy route for administration of medications or fluids via rectal mucosal absorption (proctoclysis) has recently become available in the palliative care market; we describe here the first known uses of this device in the emergency setting. Three patients presenting to the hospital with conditions limiting more typical routes of medication or fluid administration were treated with this new device; patients were administered water for hydration, lorazepam for treatment of alcohol withdrawal, ondansetron for nausea, acetaminophen for fever, aspirin for antiplatelet effect, and methimazole for hyperthyroidism. Placement of the device was straightforward, absorption of administered medications (judged by immediacy of effects, where observable) was rapid, and use of the device was well tolerated by patients, suggesting that this device may be an appealing alternative route to medication and fluid administration for a variety of indications in acute and critical care settings.", "affiliations": "Department of Pharmacy Services, Advocate Christ Medical Center, Oak Lawn, IL 60453.;Department of Emergency Medicine, Advocate Christ Medical Center, Oak Lawn, IL 60453.;Department of Pharmacy Services, Advocate Christ Medical Center, Oak Lawn, IL 60453.;Department of Pharmacy Services, Advocate Christ Medical Center, Oak Lawn, IL 60453.;Department of Emergency Medicine, Advocate Christ Medical Center, Oak Lawn, IL 60453.;Department of Pharmacy Services, Advocate Christ Medical Center, Oak Lawn, IL 60453.;Department of Emergency Medicine, Advocate Christ Medical Center, Oak Lawn, IL 60453. Electronic address: kulstad@uic.edu.", "authors": "Lyons|Neal|N|;Nejak|Daniel|D|;Lomotan|Nadine|N|;Mokszycki|Robert|R|;Jamieson|Stephen|S|;McDowell|Marc|M|;Kulstad|Erik|E|", "chemical_list": "D058633:Antipyretics; D013956:Antithyroid Agents; D001569:Benzodiazepines", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0735-6757", "issue": "33(8)", "journal": "The American journal of emergency medicine", "keywords": null, "medline_ta": "Am J Emerg Med", "mesh_terms": "D000285:Administration, Rectal; D000328:Adult; D000369:Aged, 80 and over; D020268:Alcohol-Induced Disorders, Nervous System; D058633:Antipyretics; D013956:Antithyroid Agents; D001569:Benzodiazepines; D057785:Catheters; D004636:Emergency Service, Hospital; D005260:Female; D005334:Fever; D005440:Fluid Therapy; D006801:Humans; D006980:Hyperthyroidism; D008297:Male", "nlm_unique_id": "8309942", "other_id": null, "pages": "1113.e5-6", "pmc": null, "pmid": "25662805", "pubdate": "2015-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "An alternative for rapid administration of medication and fluids in the emergency setting using a novel device.", "title_normalized": "an alternative for rapid administration of medication and fluids in the emergency setting using a novel device" }
[ { "companynumb": "US-JNJFOC-20150900930", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, ...
{ "abstract": "OBJECTIVE\nTo report a case of erlotinib-induced breast cancer regression.\n\n\nMETHODS\nA 38-year-old woman developed bilateral locoregional malignant cutaneous lymphangitis following a right subcutaneous mastectomy and 3 months of adjuvant chemotherapy. After several systemic chemotherapy regimens, the lymphangitis worsened rapidly, with progressive skin ulceration. Morphine and dexamethasone were given, with suboptimal pain control. A chemotherapy regimen of gemcitabine and vinorelbine was started. After 2 full-dose administrations, while lymphangitis continued to worsen, erlotinib 150 mg/day was added to the regimen. After 10 weeks of treatment, pain subsided and analgesics were discontinued. Physical examination revealed a partial regression of malignant cutaneous lymphangitis and pulmonary metastases, with resolution of ulceration.\n\n\nCONCLUSIONS\nThere has been increased interest in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in the treatment of breast cancer. Gefitinib has shown a low level of efficacy, while preliminary clinical data on erlotinib were not conclusive and suggested lack of clinical activity. Molecular analysis of the tumor in our patient revealed a profile predictive of response to EGFR selective inhibitors in some patients with lung cancer.\n\n\nCONCLUSIONS\nThe addition of erlotinib to our patient's chemotherapy regimen resulted in antitumor activity in breast cancer in which an activated EGFR pathway was demonstrated. This finding is consistent with available preclinical and clinical data on EGFR tyrosine kinase inhibitors across tumor types and supports the efforts to optimize EGFR selective inhibitors in treating breast cancer and other malignancies.", "affiliations": "Medical Care Unit, Department of Medicine, European Institute of Oncology, Milan, Italy. chiara.catania@ieo.it", "authors": "Catania|Chiara|C|;De Pas|Tommaso Martino|TM|;Pelosi|Giuseppe|G|;Manzotti|Michela|M|;Adamoli|Laura|L|;Nolè|Franco|F|;Goldhirsch|Aron|A|", "chemical_list": "D011799:Quinazolines; D000069347:Erlotinib Hydrochloride", "country": "United States", "delete": false, "doi": "10.1345/aph.1H252", "fulltext": null, "fulltext_license": null, "issn_linking": "1060-0280", "issue": "40(11)", "journal": "The Annals of pharmacotherapy", "keywords": null, "medline_ta": "Ann Pharmacother", "mesh_terms": "D000328:Adult; D001943:Breast Neoplasms; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D011799:Quinazolines; D011859:Radiography; D012074:Remission Induction", "nlm_unique_id": "9203131", "other_id": null, "pages": "2043-7", "pmc": null, "pmid": "17062833", "pubdate": "2006-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Erlotinib-induced breast cancer regression.", "title_normalized": "erlotinib induced breast cancer regression" }
[ { "companynumb": "IT-RANBAXY-2014R1-90642", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MORPHINE" }, "drugadditional": null, ...
{ "abstract": "OBJECTIVE\nWe sought to describe a case of an epidural hematoma after a cervical interlaminar epidural steroid injection (ILESI) performed using contralateral oblique view. We also discuss factors that could have placed this patient at increased risk, including concurrent use of omega-3 fatty acids and non-steroidal anti-inflammatory medications.\n\n\nMETHODS\nA 74-year-old woman returned to the pain clinic, within 15 min of discharge, after an apparent uncomplicated cervical ILESI using the contralateral oblique technique with severe periscapular pain and muscle spasms. Cervical MRI showed a large epidural hematoma which was subsequently emergently evacuated. On postoperative examination, the patient had no neurologic deficits and full resolution of her painful symptoms.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first reported case of cervical epidural hematoma in which the contralateral oblique technique was used. Also, this is the second case in which the combination of non-steroidal anti-inflammatory medications and omega-3 fatty acids has been considered as a contributor to increased hematoma risk. This case underscores the risk of epidural hematoma using a novel fluoroscopic technique and the need for potential discontinuation of supplements like omega-3 fatty acids.", "affiliations": "Department of Anesthesiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;Department of Anesthesiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA jhgoree@uams.edu.", "authors": "Beasley|Drew|D|;Goree|Johnathan H|JH|", "chemical_list": "D015525:Fatty Acids, Omega-3; D005938:Glucocorticoids; D003907:Dexamethasone", "country": "England", "delete": false, "doi": "10.1136/rapm-2018-000005", "fulltext": null, "fulltext_license": null, "issn_linking": "1098-7339", "issue": "44(2)", "journal": "Regional anesthesia and pain medicine", "keywords": null, "medline_ta": "Reg Anesth Pain Med", "mesh_terms": "D000368:Aged; D002574:Cervical Vertebrae; D003907:Dexamethasone; D004824:Epidural Space; D015525:Fatty Acids, Omega-3; D005260:Female; D005938:Glucocorticoids; D046748:Hematoma, Epidural, Spinal; D006801:Humans; D007268:Injections, Epidural", "nlm_unique_id": "9804508", "other_id": null, "pages": "253-255", "pmc": null, "pmid": "30700620", "pubdate": "2019-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cervical epidural hematoma following interlaminar epidural steroid injection via the contralateral oblique view in patient taking omega-3 fatty acids.", "title_normalized": "cervical epidural hematoma following interlaminar epidural steroid injection via the contralateral oblique view in patient taking omega 3 fatty acids" }
[ { "companynumb": "US-MICRO LABS LIMITED-ML2019-01811", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional...
{ "abstract": "BACKGROUND Infliximab, a monoclonal antibody against tumor necrosis factor (TNF) alpha with proven efficacy and known safety profile, is currently widely used in the treatment of inflammatory bowel diseases. Increased risk for serious infections and malignant neoplasms secondary to immunosuppression is a major concern during therapy with this medication. Histoplasmosis is a granulomatous disease caused by the fungus Histoplasma capsulatum. Disseminated forms of the disease have immunodepression as a major risk factor. CASE REPORT A 39-years-old man had been followed with refractory fistulizing ileocolonic Crohn's disease using combination therapy (infliximab plus azathioprine) and also receiving short courses of steroids. After 2 years of this immunosuppressive therapy, the patient presented with high fever (39.5ºC) for 5 days, associated with profuse sweating, and moderate pain in the left hypochondrium. The patient was hospitalized. Diagnoses of tuberculosis, malignancy, autoimmune diseases, and bacterial and viral infections were rapidly discarded after investigation. Clinical, laboratory, and image signs of liver involvement prompted a guided percutaneous biopsy, which revealed granulomatous hepatitis, with the presence of fungal structures suggestive of Histoplasma capsulatum. Upon treatment with liposomal amphotericin followed by itraconazole, the patient showed an impressively positive clinical response. CONCLUSIONS TNF blockers, particularly when associated with other immunosuppressors, are a serious risk factor for opportunistic infections. This unusual case of disseminated histoplasmosis in a patient with Crohn's disease using infliximab in combination with azathioprine and steroids emphasizes the need for surveillance of this uncommon but potentially lethal complication before starting TNF blockers therapy.", "affiliations": "Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.;Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.;Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.;Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.;Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.;Division of Infectious Diseases, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.;Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.;Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.;Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.", "authors": "Ferreira|Sandro da Costa|SDC|;Nóbrega|Fernando Jorge Firmino|FJF|;de Araújo|Roberta Chaves|RC|;de Almeida|Patrícia Holanda|PH|;Villanova|Márcia Guimarães|MG|;Santana|Rodrigo de Carvalho|RC|;Zambelli Ramalho|Leandra Naira|LN|;Martinelli|Ana de Lourdes Candolo|ALC|;Troncon|Luiz Ernesto de Almeida|LEA|", "chemical_list": "D000069285:Infliximab", "country": "United States", "delete": false, "doi": "10.12659/AJCR.925345", "fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n34495947\n10.12659/AJCR.925345\n925345\nArticles\nHistoplasmosis Related to Immunosuppression in a Patient with Crohn’s Disease: A Diagnostic Challenge\nFerreira Sandro da Costa A C D E F 1\nNóbrega Fernando Jorge Firmino B F 1\nde Araújo Roberta Chaves B 1\nde Almeida Patrícia Holanda B 1\nVillanova Márcia Guimarães B 1\nde Carvalho Santana Rodrigo D G 2\nRamalho Leandra Naira Zambelli D G 3\nde Lourdes Candolo Martinelli Ana D G 1\nde Almeida Troncon Luiz Ernesto A D E F G 1\n1 Division of Gastroenterology, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil\n2 Division of Infectious Diseases, Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil\n3 Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil\nCorresponding Author: Sandro da Costa Ferreira, e-mail: sandrocferreira1705@gmail.com\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nThis case report was presented at the Advances in Inflammatory Bowel Diseases meeting on December 12-14, 2019 in Orlando, FL and published with the meeting abstracts in The American Journal of Gastroenterology, 2019;114:S6-S7\n\nConflict of interest: None declared\n\nFinancial support: This research was supported by the Fundação de Apoio ao Ensino e Pesquisa do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto (FAEPA), a local University Hospital foundation that supports scholarship and research\n\n2021\n08 9 2021\n22 e925345-1e925345-6\n22 4 2021\n08 7 2021\n03 8 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Male, 39-year-old\n\nFinal Diagnosis: Disseminated histoplasmosis\n\nSymptoms: Fever • aprofuse sweating • splenomegaly • abdominal pain\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Gastroenterology and Hepatology\n\nObjective:\n\nUnusual clinical course\n\nBackground:\n\nInfliximab, a monoclonal antibody against tumor necrosis factor (TNF) alpha with proven efficacy and known safety profile, is currently widely used in the treatment of inflammatory bowel diseases. Increased risk for serious infections and malignant neoplasms secondary to immunosuppression is a major concern during therapy with this medication. Histoplasmosis is a granulomatous disease caused by the fungus Histoplasma capsulatum. Disseminated forms of the disease have immunodepression as a major risk factor.\n\nCase Report:\n\nA 39-years-old man had been followed with refractory fistulizing ileocolonic Crohn’s disease using combination therapy (infliximab plus azathioprine) and also receiving short courses of steroids. After 2 years of this immunosuppressive therapy, the patient presented with high fever (39.5ºC) for 5 days, associated with profuse sweating, and moderate pain in the left hypochondrium. The patient was hospitalized. Diagnoses of tuberculosis, malignancy, autoimmune diseases, and bacterial and viral infections were rapidly discarded after investigation. Clinical, laboratory, and image signs of liver involvement prompted a guided percutaneous biopsy, which revealed granulomatous hepatitis, with the presence of fungal structures suggestive of Histoplasma capsulatum. Upon treatment with liposomal amphotericin followed by itraconazole, the patient showed an impressively positive clinical response.\n\nConclusions:\n\nTNF blockers, particularly when associated with other immunosuppressors, are a serious risk factor for opportunistic infections. This unusual case of disseminated histoplasmosis in a patient with Crohn’s disease using infliximab in combination with azathioprine and steroids emphasizes the need for surveillance of this uncommon but potentially lethal complication before starting TNF blockers therapy.\n\nKeywords:\n\nCrohn Disease\nHistoplasmosis\nTumor Necrosis Factor-alpha\n==== Body\npmcBackground\n\nDuring the last 2 decades, a new paradigm emerged in the treatment of inflammatory bowel diseases (IBD), leading to the increased use of antibodies against tumor necrosis factor alpha (anti-TNF-α) (infliximab, adalimumab, certolizumab pegol, and golimumab) [1]. They were originally used for the treatment of moderate to severe active Crohn’s disease (CD), but recently were approved for more severe forms of severe ulcerative colitis (UC) [2–5].\n\nHistoplasmosis is a systemic granulomatous disease acquired by inhalation of microconidia from the fungus Histoplasma capsulatum, which is found in soil and in the droppings of birds and bats and is endemic in several regions in Brazil [6,7].\n\nThe disease’s clinical presentation may vary according to the patient’s immunity, and immunodepression is a major risk factor for the development of more severe forms of the disease, such as disseminated histoplasmosis. This may manifest with a variety of symptoms, including fever (91%), cough (65%), hepatosplenomegaly or lymphadenopathy (52%), weight loss (48%), and anemia (39%). Usually, the primary infection in an immunocompetent host is generally asymptomatic or presents as a self-limiting flu-like illness [8].\n\nAmong the most worrisome adverse effects of anti-TNF-α are the increased risk of developing serious infections, such as tuberculosis (TB), other opportunistic bacterial infections, systemic mycoses, such as histoplasmosis, which may appear in the disseminated form, and reactivation of latent viral infections, as well as malignancies. Thus, surveillance before starting TNF blockers therapy and close monitoring of patients afterwards are needed to increase patient safety ]9,10].\n\nWe herein report an unusual case of disseminated histoplasmosis in a patient with Crohn’s disease using anti-TNF-α (infliximab) in combination with azathioprine and corticosteroids.\n\nCase Report\n\nA 39-year-old white man in outpatient follow-up due to ileocolonic CD presented with fever in a routine outpatient visit. CD had been diagnosed 11 years before, after a segmental small bowel resection due to enteric-enteric fistulas. For over 3 years, the patient had been receiving immunosuppressive therapy with azathioprine 150 mg daily (2.0 mg/kg) and infliximab (IFX) maintenance therapy (5 mg/kg every 8 weeks). During follow-up, despite receiving this combo therapy, he had presented a few episodes of disease activity, requiring courses of steroids. He also reported frequent trips to the interior of the Brazilian states of Minas Gerais and Goiás, besides contact with birds and poultry in his residence. In a routine visit, he was found to be in clinical and endoscopic remission of CD but presented with high fever (39.5ºC) for 5 days, with profuse sweating and moderate pain in the left hypochondrium. He denied urinary and respiratory symptoms and reported passing well-formed stools once a day. Physical examination revealed a bulky splenomegaly. The patient was then hospitalized for investigation, and the treatment for IBD was entirely suspended on this occasion. Laboratory data on admission revealed an increase of aspartate amino transferase (AST) of 291 U/L (reference value: 41 U/L), alanine amino transferase (ALT) of 119 U/L (reference value: 38 U/L), normal canalicular enzymes, and slightly elevated C-reactive protein of 3.1 mg/dL and bilirubin (total bilirubin of 1.7 mg/dL, indirect bilirubin of 1.1 mg/dL). Screening by bacterial cultures, tuberculosis (tuberculin test, polymerase chain reaction and culture), serological tests for viral hepatitis, HIV, syphilis, antigenemia, and polymerase chain reaction (PCR) for cytomegalovirus (CMV) and Epstein-Barr virus were negative. Plain chest radiographs did not show any abnormality. Further evaluation included computed tomography (CT) scans of the thorax and abdomen. The chest CT scan evidenced a pulmonary nodule on the right lung with a halo in “frosted glass”, suggesting an infectious process, and right and mediastinal hilar lymph node enlargement. The abdominal CT scan showed hepatosplenomegaly, periaortic abdominal lymph node enlargement, hepatic steatosis, and bilateral renal lithiasis.\n\nThe patient evolved with maintenance of fever and gradual clinical worsening, with onset of mild dyspnea, dry cough, and jaundice with a total bilirubin peak of 23.22 mg/dl (17.13 mg/ dl of direct bilirubin), in addition to elevation of aminotransferases (AST of 336 U/L and ALT of 191 U/L), pancytopenia, and acute renal failure (creatinine of 5.66 mg/dL and urea of 126 mg/dL), which prompted referral to hemodialysis. A bone marrow needle aspiration revealed cytoplasmic inclusion in macrophages, suggesting an infectious process. Further tests included enzyme immunoassay (ELISA) for leptospirosis, serology for toxoplasmosis, and Wright’s reaction, which were all negative. Counterimmunoelectrophoresis (CIE) for fungi was then found positive for Histoplasma until dilution 1: 8. It was then decided to perform a guided needle liver biopsy, which revealed granulomatous hepatitis, with presence of fungal structures suggestive of Histoplasma capsulatum (Figure 1). Therapy with liposomal amphotericin (1.0 mg/kg body weight) was then initiated, with gradual improvement of symptoms and recovery of renal function, as well as resolution of jaundice. After 6 weeks of treatment, the patient was discharged from the hospital and switched to oral itraconazole.\n\nOn 6-month follow-up, the patient was still using oral itraconazole, and the CIE for histoplasmosis was still positive, but only until the 1: 2 dilution. A new chest tomography performed 6 months after starting anti-fungal specific treatment showed complete resolution of the pulmonary nodule located in the right lung. At this time, treatment for CD was resumed with the reintroduction of azathioprine alone. Itraconazole was suspended after 12 months of uninterrupted use, after a new CIE for fungi tested negative.\n\nDiscussion\n\nTNF-α is a proinflammatory cytokine produced by macrophages in response to stimuli such as oxidative stress or endotoxins. This agent has a key function in the immune system, since it stimulates the differentiation of monocytes into macrophages, the recruitment of neutrophils, and the formation of granulomas, thus playing an important role in the host defense system against infectious diseases [11]. Furthermore, TNF-α stimulates the production of interferon, which is crucial for both phagocytosis and fungicidal activity [12]. Inhibition of this cytokine by anti-TNF-α in the context of treatment of IBD may potentially reduce the efficacy of host immune function in defense against infectious organisms, thus leading to an increased risk of infections, including serious infections [13]. In general, the use of anti-TNF-α agents as a treatment option for IBD increases the odds of opportunistic infection by a factor of 3, and with the combination of 2 or 3 drugs, such as immune suppressors or corticosteroids, the odds ratio is increased to 14 [14].\n\nDisseminated histoplasmosis represents a serious clinical condition, associated with dysfunctions of the host immune system and, more specifically, to impairment of cellular immunity that affects the T cells, thus allowing spread of the disease. However, only a small proportion of exposed individuals (<0.1%) actually develop disseminated disease [15].\n\nOther cases of disseminated histoplasmosis associated with the use of infliximab in patients with Crohn’s disease have been reported [10,16–18] in addition to a case of fatal Histoplasma pneumonia in a patient with ulcerative colitis treated with IFX [19]. In a recent review based on medical reports from an area with moderate endemicity for histoplasmosis, a total of 357 cases of disseminated histoplasmosis were identified, 8 (2.2%) of whom were receiving TNF-α inhibitor therapy at the time of diagnosis. Five patients were receiving infliximab and 3 were receiving adalimumab [20]. Therefore, the risk of disseminated histoplasmosis in patients receiving anti-TNF-α is now widely recognized [17]. In these reports, similarly to ours, all patients had received immunosuppressive drugs concomitant with anti-TNF-α agents. A previous review of 19 patients diagnosed throughout a decade in a single academic center [18] showed that symptoms and signs of pulmonary involvement were present in 70-80% of cases. Although hepatic enzyme elevation may occur in dissemination, an overt hepatitis-like presentation is uncommon [18,19]. In the case herein presented, despite the finding of a suspect pulmonary nodule, respiratory clinical manifestations were less impressive and there was overt jaundice. A granulomatous hepatitis, with presence of fungal structures suggestive of Histoplasma capsulatum in the liver tissue, was clearly demonstrated and provided the basis for the etiologic diagnosis and prompted anti-fungal therapy initiation.\n\nOn the other hand, common features between our case and other reports of disseminated histoplasmosis concern the diagnostic difficulty and a complete response to anti-fungal treatment, most likely helped by the cessation of the inciting TNF-α inhibitor [10,15].\n\nUsually, the endogenous reactivation of old, mainly pulmonary, foci during a state of immunosuppression works as a trigger of the disseminated form of histoplasmosis. TNF-α blockade is nonetheless associated with an increase in the risk of infection by intracellular, granuloma-forming pathogens, such as Histoplasma capsulatum [11]. In the present case, the underlying immunosuppressive therapy of our patient (azathioprine and IFX, in addition to courses of corticosteroids) due to the character of Crohn’s disease, in an individual with a history of contacts with birds and travel to areas endemic for histoplasmosis (mold sporulation can be accelerated by bat and bird feces), might have been a risk factor for reactivation of latent disease focus and evolution to disseminated form.\n\nThe diagnosis of disseminated histoplasmosis often presents a great challenge, considering that it can affect any organ, and this circumstance can contribute to a “chameleon-like” clinical image and diagnostic errors. Although with some limitations, such as false-positive reactions that can occur during the course of other fungal infections (eg, blastomycosis and paracoccidioidomycosis) and in the presence of malignant tumors, serological tests are useful adjuncts in the diagnosis of histoplasmosis, especially in the forms where positive cultures are rarely obtained. The complement fixation test (CF) or the immunodiffusion assay (ID) [21], followed by counterimmunoelectrophoresis (CIE), are the most commonly used tests for diagnosing systemic fungal infections, including histoplasmosis. The Histoplasma antigen can be detected in urine, serum, cerebrospinal fluid, or bronchoalveolar lavage [22–24]]. Antigen sensitivity is 90% in urine and 80% in serum [21,23].\n\nIn our case, the diagnosis of disseminated histoplasmosis was made by combining results from CIE (1: 8 after dilution) with findings from histopathology after percutaneous liver biopsy that demonstrated granulomatous hepatitis, with the presence of fungal structures suggestive of Histoplasma capsulatum. We opted for CIE because it is more rapidly performed (approximately 90 min) than the ID or the CF test (both taking at least 24 hours) [22] and it is the most frequently used method in our service for the diagnosis of systemic fungal infections.\n\nCurrently, there are no formal guidelines or absolute recommendations regarding the use of anti-TNF-α agents in patients at risk for systemic fungal infections, such as histoplasmosis [25]. Considering the small number of cases of histoplasmosis reported in association with the use of anti-TNF-α agents in patients with IBD, a routine screening proposal to reliably identify patients at increased risk of reactivation of histoplasmosis has not been so far recommended [14]. Likewise, anti-fungal prophylaxis in this situation is thought to be unnecessary [14].\n\nOn the other hand, patients with active fungal infection should not start treatment with anti-TNF-α agents, and interruption of treatment with anti-TNF-α and immunosuppressive agents is indicated for the established infection, together with the appropriate targeted anti-fungal therapy [25]. In our case, we opted for suspending both infliximab and azathioprine and immediately initiated anti-fungal therapy with amphotericin B after the diagnosis was confirmed. It is difficult to decide to reintroduce anti-TNF therapy in patients previously diagnosed with disseminated histoplasmosis, as the duration of the high-risk period after the end of TNF-α block (weeks or months) is uncertain, even when the infection responds to treatment. Regarding immune suppressors, which would remain as the sole option to control IBD, reintroduction after the infection responds to treatment should be coupled with secondary prophylaxis, as well as with other measures eventually advised by an infectious disease expert [25]. In our case, after the response to anti-fungal treatment was assessed by the decrease of fungal antigens levels, as measured by CEI tests at 2 months, and then approximately every 3 months during therapy and for at least 6 months after treatment is stopped, we opted for the reintroduction of an azathioprine monotherapy regimen, as a specific treatment of inflammatory bowel disease.\n\nThus, it is essential that disseminated histoplasmosis be remembered as a possible diagnosis in patients using immunosuppressive therapies. Current guidelines support screening for bacterial and viral infections, such as tuberculosis, hepatitis B, and varicella zoster, before the onset of anti-TNF-α agents, and this makes screening for fungal infection tempting as well. However, this may not be effective because the reactivation of fungal disease is rare. Our suggestion is that, in view of the seriousness of cases, all patients prior to the use of anti-TNF-α agents should be informed of the risk for acquiring systemic mycoses, such as histoplasmosis, paracoccidioidomycosis, and cryptococcosis, as well as of the type of environment likely to be contaminated, activities to avoid, and symptoms for which they should seek medical attention, especially in endemic areas.\n\nConclusions\n\nThis report calls attention to an unusual case of disseminated histoplasmosis, which is a serious clinical condition, most likely arising from an adverse effect of combined immunosuppression with IFX, azathioprine, and courses of corticosteroids in a patient with Crohn’s disease.\n\nIn this condition, all efforts should be made to recognize this serious infectious complication in patients treated with anti-TNF-α agents, and the specific treatment should be instituted as soon as possible. Diagnosis requires a high degree of suspicion, recognition of the most common forms of disease presentation, and familiarity with the use of specific diagnostic tests.\n\nFigure 1. (A, B) Granulomatous inflammation in the liver, with the presence of clustered macrophages (H&E, 20 and 40×, magnification, respectively). (C, D) Absence of acid-fast bacilli in granulomas (Ziehl-Neelsen, 20 and 40×, magnification, respectively). (E–G) Presence of small rounded, birefringent, and clustered structures (Gomori-Methanamine-Silver, 20, 40 and 100×, magnification, respectively).\n\nConflicts of Interest\n\nNone declared.\n\nDeclaration of Figures Authenticity\n\nAll figures submitted have been created by the authors who confirm that the images are original with no duplication and have not been previously published in whole or in part.\n==== Refs\nReferences:\n\n1. Cohen LB Nanau RM Delzor F Neuman MG Biologic therapies in inflammatory bowel disease Transl Res 2014 163 6 533 56 24467968\n2. Hanauer SB Feagan BG Lichtenstein GR Maintenance infliximab for Crohn’s disease: The ACCENT I randomised trial Lancet 2002 359 9317 1541 49 12047962\n3. Magro F Portela F Management of inflammatory bowel disease with infliximab and other anti-tumor necrosis factor alpha therapies BioDrugs 2010 24 Suppl.1 3 14 21175228\n4. Seo GS Chae S-C Biological therapy for ulcerative colitis: An update World J Gastroenterol 2014 20 37 13234 38 25309060\n5. Hanson RL Gannon MJ Khamo N Improvement in safety monitoring of biologic response modifiers after the implementation of clinical care guidelines by a specialty J Manag Care Pharm 2013 19 1 49 67 23383700\n6. Colombo AL Tobón A Restrepo A Epidemiology of endemic systemic fungal infections in Latin America Med Mycol 2011 49 8 785 98 21539506\n7. Ferreira MS Borges AS [Histoplasmosis.] Rev Soc Bras Med Trop 2009 42 2 192 98 [in Portuguese] 19448941\n8. Wheat LJ Histoplasmosis: A review for clinicians from non-endemic areas Mycoses 2006 49 4 274 82 16784440\n9. Lichtenstein GR Feagan BG Cohen RD Serious infection and mortality in patients with Crohn’s disease: More than 5 years of follow-up in the TREATTM Registry Am J Gastroenterol 2012 107 9 1409 22 22890223\n10. Galandiuk S Davis BR Infliximab-induced disseminated histoplasmosis in a patient with Crohn’s disease Nat Clin Pract Gastroenterol Hepatol 2008 5 5 283 87 18398409\n11. Roach DR Bean AGD TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection J Immunol 2002 168 9 4620 27 11971010\n12. Beaman L Effects of recombinant gamma interferon and tumor necrosis factor on in vitro interactions of human mononuclear phagocytes with Coccidioides immitis Infect Immun 1991 59 11 4227 29 1937779\n13. Lawrance IC Radford-Smith GL Bampton PA Serious infections in patients with inflammatory bowel disease receiving anti-tumor-necrosis-factor-alpha therapy: An Australian and New Zealand experience J Gastroenterol Hepatol 2010 25 11 1732 38 21039834\n14. Toruner M Loftus EV Harmsen WS Risk factors for opportunistic infections in patients with inflammatory bowel disease Gastroenterology 2008 134 4 929 36 18294633\n15. Assi MA Sandid MS Baddour LM Systemic histoplasmosis: A 15-year retrospective institutional review of 111 patients Medicine (Baltimore) 2007 86 3 162 69 17505255\n16. Tschudy J Michail S Disseminated histoplasmosis and pneumocystis pneumonia in a child with Crohn disease receiving infliximab J Pediatr Gastroenterol Nutr 2010 51 2 221 22 20410844\n17. do Valle Pinheiro B de Almeida Delgado A Fonseca Chebli JM Hepatitis and pneumonitis during adalimumab therapy in Crohn’s disease: Mind the histoplasmosis! Arq Gastroenterol 2014 51 1 73 76 24760069\n18. Hage CA Bowyer S Tarvin SE Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy Clin Infect Dis 2010 50 1 85 92 19951231\n19. Dotson JL Crandall W Mousa H Presentation and outcome of histoplasmosis in pediatric inflammatory bowel disease patients treated with antitumor necrosis factor alpha therapy: A case series Inflamm Bowel Dis 2011 17 1 56 61 20645322\n20. Bogorodskaya M El Chakhtoura NG Salata RA Disseminated histoplasmosis in patients receiving tumor necrosis factor-α inhibitors: A case series and review Infect Dis Clin Pract 2016 24 5 261 65\n21. Kauffman CA Histoplasmosis: A clinical and laboratory update Clin Microbiol Rev 2007 20 115 32 17223625\n22. Picardi JL Kauffman CA Schwarz J Phair JP Detection of precipitating antibodies to Histoplasma capsulatum by counterimmunoelectrophoresis Am Rev Respir Dis 1976 114 1 171 76 937834\n23. Yeo SF Wong B Current status of nonculture methods for diagnosis of invasive fungal infections Clin Microbiol Rev 2002 15 3 465 84 12097252\n24. Balada-Llasat J-M Performance of immunodiffusion and complement fixation serology assays for the diagnosis of fungal infections Med Mycol 2018 12 3 127 36\n25. Tsiodras S Samonis G Boumpas DT Kontoyiannis DP Fungal infections complicating tumor necrosis factor α blockade therapy Mayo Clin Proc 2008 83 2 181 94 18241628\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1941-5923", "issue": "22()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D000328:Adult; D003424:Crohn Disease; D006658:Histoplasma; D006660:Histoplasmosis; D006801:Humans; D007165:Immunosuppression Therapy; D000069285:Infliximab; D008297:Male", "nlm_unique_id": "101489566", "other_id": null, "pages": "e925345", "pmc": null, "pmid": "34495947", "pubdate": "2021-09-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "1937779;20645322;21039834;21539506;12097252;18294633;17223625;25309060;11971010;12047962;20410844;937834;19448941;18398409;21175228;22890223;16784440;18241628;24760069;23383700;19951231;24467968;17505255", "title": "Histoplasmosis Related to Immunosuppression in a Patient with Crohn's Disease: A Diagnostic Challenge.", "title_normalized": "histoplasmosis related to immunosuppression in a patient with crohn s disease a diagnostic challenge" }
[ { "companynumb": "BR-MLMSERVICE-20210915-3107997-1", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": "1", ...
{ "abstract": "Splenic rupture is a potentially life-threatening condition and an uncommon short-term complication of granulocyte-colony stimulating factor (G-CSF) administration. It may present as acute abdominal pain or suddenly precipitously worsening anaemia with haemodynamic instability that requires urgent operative intervention for survival. We present a case of an atraumatic idiopathic splenic rupture in University Hospital, Ayr in a patient who received G-CSF treatment for chemotherapy-induced (methotrexate) pancytopenia and was successfully managed by laparoscopic splenectomy.", "affiliations": "General Surgery, University Hospital Ayr, Ayr, UK.;General Surgery, University Hospital Ayr, Ayr, UK.", "authors": "Chinaka|Ugochukwu Chinyere|UC|;Fultang|Joshua|J|http://orcid.org/0000-0002-7192-3668;Pereca|Jelizaveta|J|;Ali|Abdulmajid|A|", "chemical_list": "D016179:Granulocyte Colony-Stimulating Factor", "country": "England", "delete": false, "doi": "10.1136/bcr-2019-232411", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "13(4)", "journal": "BMJ case reports", "keywords": "gastrointestinal surgery; general surgery; haematology (incl blood transfusion)", "medline_ta": "BMJ Case Rep", "mesh_terms": "D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D010535:Laparoscopy; D008875:Middle Aged; D010198:Pancytopenia; D012422:Rupture, Spontaneous; D013154:Spleen; D013156:Splenectomy; D013161:Splenic Rupture; D016896:Treatment Outcome; D006113:United Kingdom", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "32276997", "pubdate": "2020-04-09", "publication_types": "D002363:Case Reports", "references": null, "title": "Atraumatic idiopathic splenic rupture induced by granulocyte-colony stimulating factor (G-CSF) for the treatment of pancytopenia, managed successfully by laparoscopic splenectomy.", "title_normalized": "atraumatic idiopathic splenic rupture induced by granulocyte colony stimulating factor g csf for the treatment of pancytopenia managed successfully by laparoscopic splenectomy" }
[ { "companynumb": "GB-AMGEN-GBRSP2020073387", "fulfillexpeditecriteria": "2", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PENICILLIN V" }, "drugadditional": null, ...
{ "abstract": "OBJECTIVE\nPatients with high-risk neuroblastoma have an increased risk of recurrence and relapse of disease and a very poor prognosis. 131I-metaiodobenzylguanidine (131I-mIBG) in combination with topotecan as a radiosensitizer can be an effective and relatively well-tolerated agent for the treatment of refractory neuroblastoma. The aim of this retrospective study was to evaluate response and outcome of combined therapy with 131I-mIBG and topotecan.\n\n\nMETHODS\nTen patients, between 3 and 20 years of age, were included. Nine patients had been refractory to several lines of chemotherapy and radiotherapy. One patient with a very high-risk neuroblastoma had received only induction therapy. Response was graded according to the International Neuroblastoma Staging System.\n\n\nRESULTS\nRegarding treatment response, two patients achieved complete remission, one with relapse at 16 months, five achieved a partial remission, four showed progression at between 1 and 18 months; two showed stable disease with progression at between 1 and 5 months, and one showed progressive disease. Eight of the ten patients died with overall survival between 4 and 63 months, and two patients were still alive without disease at the time of this report: 52 and 32 months (patient had received only induction therapy). Acute and subacute adverse effects were mainly haematological, and one patient developed a differentiated thyroid cancer.\n\n\nCONCLUSIONS\nIn patients with high-risk refractory neuroblastoma, administration of high activities of 131I-mIBG in combination with topotecan was found to be an effective therapy, increasing overall survival and progression-free survival. Further studies including a larger number of patients and using 131I-mIBG for first-line up-front therapy are warranted.", "affiliations": "Department of Nuclear Medicine, Cruces University Hospital, Plaza de Cruces s/n, 48903, Baracaldo, Vizcaya, Spain. jose.genollasubirats@osakidetza.eus.;Department of Nuclear Medicine, Cruces University Hospital, Plaza de Cruces s/n, 48903, Baracaldo, Vizcaya, Spain.;Department of Medical Physics and Radiation Protection, Cruces University Hospital, Plaza de Cruces s/n, 48903, Baracaldo, Vizcaya, Spain.;Department of Pediatric Oncology and Hematology, Cruces University Hospital, Plaza de Cruces s/n, 48903, Baracaldo, Vizcaya, Spain.;Department of Nuclear Medicine, Cruces University Hospital, Plaza de Cruces s/n, 48903, Baracaldo, Vizcaya, Spain.;Department of Pediatric Oncology and Hematology, Cruces University Hospital, Plaza de Cruces s/n, 48903, Baracaldo, Vizcaya, Spain.", "authors": "Genolla|Jose|J|;Rodriguez|Trinidad|T|;Minguez|Pablo|P|;Lopez-Almaraz|Ricardo|R|;Llorens|Veronica|V|;Echebarria|Aizpea|A|", "chemical_list": "D019797:3-Iodobenzylguanidine; D019772:Topotecan", "country": "Germany", "delete": false, "doi": "10.1007/s00259-019-04291-x", "fulltext": null, "fulltext_license": null, "issn_linking": "1619-7070", "issue": "46(7)", "journal": "European journal of nuclear medicine and molecular imaging", "keywords": "131I-mIBG therapy; Dosimetry; High-risk neuroblastoma; Topotecan", "medline_ta": "Eur J Nucl Med Mol Imaging", "mesh_terms": "D019797:3-Iodobenzylguanidine; D000293:Adolescent; D059248:Chemoradiotherapy; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D009447:Neuroblastoma; D000077982:Progression-Free Survival; D011874:Radiometry; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D012306:Risk; D019772:Topotecan; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "101140988", "other_id": null, "pages": "1567-1575", "pmc": null, "pmid": "30838430", "pubdate": "2019-07", "publication_types": "D016428:Journal Article", "references": "10519894;10604736;11193903;11207038;12960120;14520475;15869455;15935554;16116154;16306521;16421427;1657371;17479288;17627418;1823825;1823827;18819996;19171716;19713562;20179922;2045205;20578835;21387264;21803182;23050139;23484236;23921531;24130233;24333097;26133597;29642099;3657705;4047115;6134943;6589432;6679954;7205383;8336186;8472027;9516844", "title": "Dosimetry-based high-activity therapy with 131I-metaiodobenzylguanidine (131I-mIBG) and topotecan for the treatment of high-risk refractory neuroblastoma.", "title_normalized": "dosimetry based high activity therapy with 131i metaiodobenzylguanidine 131i mibg and topotecan for the treatment of high risk refractory neuroblastoma" }
[ { "companynumb": "ES-PROGENICS PHARMACEUTICALS/LANTHEUS HOLDINGS-LMI-2019-00832", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TOPOTECAN HYDROCHLORIDE" ...
{ "abstract": "OBJECTIVE\nThe study aims to analyze patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ).\n\n\nMETHODS\nTwelve patients treated in the Department of Oral and Maxillofacial Surgery, the First Affiliated Hospital of Me-dical School, Zhejiang University from May 2013 to September 2015 were included. Patients' basic situation, medication, clinical symptoms, therapies, and effects were obtained and analyzed.\n\n\nRESULTS\nThe treatment of nine patients focused on the mandible, whereas that of three patients was on the maxilla. The clinical symptoms appeared from 10 to 80 months, with an average of about (28.00±21.42) months. Nine patients had tooth extraction history. After operation (nine patients), eight were treated, one had stable in bone exposure and three patients received conservative treatment.\n\n\nCONCLUSIONS\nIntravenous infusion of bisphosphonates can induce BRONJ. The mandible is commonly involved and tooth extraction is a big inducement. Treatments nowadays seek to relieve clinical symptoms, but prevention is more important.", "affiliations": "Dept. of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Medical School, Zhejiang University, Hangzhou 310003, China.;Dept. of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Medical School, Zhejiang University, Hangzhou 310003, China.", "authors": "Jiaxing|Gong|G|;Huiming|Wang|W|", "chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates", "country": "China", "delete": false, "doi": "10.7518/hxkq.2016.04.008", "fulltext": null, "fulltext_license": null, "issn_linking": "1000-1182", "issue": "34(4)", "journal": "Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology", "keywords": "bisphosphonate; jaws; osteomyelitis; osteonecrosis", "medline_ta": "Hua Xi Kou Qiang Yi Xue Za Zhi", "mesh_terms": "D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D006801:Humans; D008334:Mandible; D008437:Maxilla; D014081:Tooth Extraction", "nlm_unique_id": "9422648", "other_id": null, "pages": "358-363", "pmc": null, "pmid": "28317352", "pubdate": "2016-08-01", "publication_types": "D016428:Journal Article", "references": "12966493;24051498;18214569;11499860;25254048;17307580;20727997;20369541;24373581;19371809;19165270;19901958;20166976;24758539;19925998;9875874;25476210;14534891;25047929;18423296", "title": "Clinical analysis of bisphosphonate-related osteonecrosis of the jaw.", "title_normalized": "clinical analysis of bisphosphonate related osteonecrosis of the jaw" }
[ { "companynumb": "PHHY2016CN124755", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ZOLEDRONIC ACID" }, "drugadditional": "3", "...
{ "abstract": "OBJECTIVE\nTo assess the response to pexidartinib treatment in six cohorts of adult patients with advanced, incurable solid tumors associated with colony-stimulating factor 1 receptor (CSF1R) and/or KIT proto-oncogene receptor tyrosine kinase activity.\n\n\nMETHODS\nFrom this two-part phase I, multicenter study, pexidartinib, a small-molecule tyrosine kinase inhibitor that targets CSF1R, KIT, and FMS-like tyrosine kinase 3 (FLT3), was evaluated in six adult patient cohorts (part 2, extension) with advanced solid tumors associated with dysregulated CSF1R. Adverse events, pharmacokinetics, and tumor responses were assessed for all patients; patients with tenosynovial giant cell tumor (TGCT) were also evaluated for tumor volume score (TVS) and patient-reported outcomes (PRO). CSF1 transcripts and gene expression were explored in TGCT biopsies.\n\n\nRESULTS\nNinety-one patients were treated: TGCT patients (n = 39) had a median treatment duration of 511 days, while other solid tumor patients (n = 52) had a median treatment duration of 56 days. TGCT patients had response rates of 62% (RECIST 1.1) and 56% (TVS) for the full analysis set. PRO assessments for pain showed improvement in patient symptoms, and 76% (19/25) of TGCT tissue biopsy specimens showed evidence of abnormal CSF1 transcripts. Pexidartinib treatment of TGCT resulted in tumor regression and symptomatic benefit in most patients. Pexidartinib toxicity was manageable over the entire study.\n\n\nCONCLUSIONS\nThese results offer insight into outcome patterns in cancers whose biology suggests use of a CSF1R inhibitor. Pexidartinib results in tumor regression in TGCT patients, providing prolonged control with an acceptable safety profile.", "affiliations": "Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York. tapw@mskcc.org.;UCLA Medical Center, Santa Monica, California.;Evergreen Hematology and Oncology, Spokane, Washington.;Plexxikon Inc., South San Francisco, California.;Plexxikon Inc., South San Francisco, California.;Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.;UCLA Jonsson Comprehensive Cancer Center, Los Angeles, California.;Rocky Mountain Cancer Centers, Denver, Colorado.;Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.;Vanderbilt University Medical Center, Nashville, Tennessee.;UCLA Medical Center, Santa Monica, California.;Roswell Park Comprehensive Cancer Center, Buffalo, New York.;Massachusetts General Hospital, Boston, Massachusetts.;Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.;Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada.;Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.;Plexxikon Inc., South San Francisco, California.;Spire Sciences, Boca Raton, Florida.;Evidera, Bethesda, Maryland.;Daiichi Sankyo Pharma Development, Basking Ridge, New Jersey.;Plexxikon Inc., South San Francisco, California.;Plexxikon Inc., South San Francisco, California.;Plexxikon Inc., South San Francisco, California.;Plexxikon Inc., South San Francisco, California.", "authors": "Tap|William D|WD|https://orcid.org/0000-0001-7779-2796;Singh|Arun S|AS|https://orcid.org/0000-0002-1633-7746;Anthony|Stephen Patrick|SP|;Sterba|Mike|M|;Zhang|Chao|C|;Healey|John H|JH|https://orcid.org/0000-0002-0802-1186;Chmielowski|Bartosz|B|https://orcid.org/0000-0002-2374-3320;Cohn|Allen Lee|AL|;Shapiro|Geoffrey I|GI|https://orcid.org/0000-0002-3331-4095;Keedy|Vicki L|VL|https://orcid.org/0000-0002-7213-7562;Wainberg|Zev A|ZA|;Puzanov|Igor|I|;Cote|Gregory M|GM|https://orcid.org/0000-0003-0181-886X;Wagner|Andrew J|AJ|https://orcid.org/0000-0002-4384-9448;Braiteh|Fadi|F|;Sherman|Eric|E|;Hsu|Henry H|HH|;Peterfy|Charles|C|;Gelhorn|Heather L|HL|;Ye|Xin|X|;Severson|Paul|P|;West|Brian L|BL|;Lin|Paul S|PS|;Tong-Starksen|Sandra|S|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1158/1078-0432.CCR-21-2007", "fulltext": "\n==== Front\nClin Cancer Res\nClin Cancer Res\nClinical Cancer Research\n1078-0432\n1557-3265\nAmerican Association for Cancer Research\n\n34716196\nCCR-21-2007\n10.1158/1078-0432.CCR-21-2007\nVersion of Record\nClinical Trials: Targeted Therapy\nResults from Phase I Extension Study Assessing Pexidartinib Treatment in Six Cohorts with Solid Tumors including TGCT, and Abnormal CSF1 Transcripts in TGCT\nPexidartinib Treatment in Solid Tumors\nhttps://orcid.org/0000-0001-7779-2796\nTap William D. 1*\nhttps://orcid.org/0000-0002-1633-7746\nSingh Arun S. 2\nAnthony Stephen Patrick 3#\nSterba Mike 4\nZhang Chao 4\nhttps://orcid.org/0000-0002-0802-1186\nHealey John H. 1\nhttps://orcid.org/0000-0002-2374-3320\nChmielowski Bartosz 5\nCohn Allen Lee 6\nhttps://orcid.org/0000-0002-3331-4095\nShapiro Geoffrey I. 7\nhttps://orcid.org/0000-0002-7213-7562\nKeedy Vicki L. 8\nWainberg Zev A. 2\nPuzanov Igor 9\nhttps://orcid.org/0000-0003-0181-886X\nCote Gregory M. 10\nhttps://orcid.org/0000-0002-4384-9448\nWagner Andrew J. 7\nBraiteh Fadi 11\nSherman Eric 1\nHsu Henry H. 4#\nPeterfy Charles 12\nGelhorn Heather L. 13\nYe Xin 14\nSeverson Paul 4#\nWest Brian L. 4#\nLin Paul S. 4#\nTong-Starksen Sandra 4#\n1 Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.\n2 UCLA Medical Center, Santa Monica, California.\n3 Evergreen Hematology and Oncology, Spokane, Washington.\n4 Plexxikon Inc., South San Francisco, California.\n5 UCLA Jonsson Comprehensive Cancer Center, Los Angeles, California.\n6 Rocky Mountain Cancer Centers, Denver, Colorado.\n7 Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.\n8 Vanderbilt University Medical Center, Nashville, Tennessee.\n9 Roswell Park Comprehensive Cancer Center, Buffalo, New York.\n10 Massachusetts General Hospital, Boston, Massachusetts.\n11 Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada.\n12 Spire Sciences, Boca Raton, Florida.\n13 Evidera, Bethesda, Maryland.\n14 Daiichi Sankyo Pharma Development, Basking Ridge, New Jersey.\n# S.P. Anthony, H.H. Hsu, P. Severson, B.L. West, P.S. Lin and S. Tong-Starksen at the time of study.\n\n* Corresponding Author: William D. Tap, Sarcoma Medical Oncology Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065. Phone: 646-888-4163; Fax: 646-888-4252; E-mail: tapw@mskcc.org\nClin Cancer Res 2022;28:298–307\n\n15 1 2022\n29 10 2021\n28 2 298307\n09 6 2021\n16 8 2021\n27 10 2021\n©2021 The Authors; Published by the American Association for Cancer Research\n2021\nAmerican Association for Cancer Research\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.\n\nAbstract\n\nPurpose:\n\nTo assess the response to pexidartinib treatment in six cohorts of adult patients with advanced, incurable solid tumors associated with colony-stimulating factor 1 receptor (CSF1R) and/or KIT proto-oncogene receptor tyrosine kinase activity.\n\nPatients and Methods:\n\nFrom this two-part phase I, multicenter study, pexidartinib, a small-molecule tyrosine kinase inhibitor that targets CSF1R, KIT, and FMS-like tyrosine kinase 3 (FLT3), was evaluated in six adult patient cohorts (part 2, extension) with advanced solid tumors associated with dysregulated CSF1R. Adverse events, pharmacokinetics, and tumor responses were assessed for all patients; patients with tenosynovial giant cell tumor (TGCT) were also evaluated for tumor volume score (TVS) and patient-reported outcomes (PRO). CSF1 transcripts and gene expression were explored in TGCT biopsies.\n\nResults:\n\nNinety-one patients were treated: TGCT patients (n = 39) had a median treatment duration of 511 days, while other solid tumor patients (n = 52) had a median treatment duration of 56 days. TGCT patients had response rates of 62% (RECIST 1.1) and 56% (TVS) for the full analysis set. PRO assessments for pain showed improvement in patient symptoms, and 76% (19/25) of TGCT tissue biopsy specimens showed evidence of abnormal CSF1 transcripts. Pexidartinib treatment of TGCT resulted in tumor regression and symptomatic benefit in most patients. Pexidartinib toxicity was manageable over the entire study.\n\nConclusions:\n\nThese results offer insight into outcome patterns in cancers whose biology suggests use of a CSF1R inhibitor. Pexidartinib results in tumor regression in TGCT patients, providing prolonged control with an acceptable safety profile.\n==== Body\npmcTranslational Relevance\n\nThe results in this study extend previously reported observations from phase I clinical trial that treatment of tenosynovial giant cell tumors (TGCT) with pexidartinib resulted in sustained tumor regression in most patients with TGCT. Treatment did not translate into the same level of efficacy in the other cohorts that were selected based on presumptive biology targeted by pexidartinib, demonstrating the complexity of these malignancies as compared with TGCT, a neoplasm almost completely dependent on CSF1R signaling. In addition, the molecular data demonstrated how the alterations may provide a mechanism of sustained CSF1R production in TGCT and an explanation as to why inhibition of CSF1R is an effective therapeutic intervention. Future studies would need to be conducted in order to assess if there is a direct correlation between specific patient tissue sample expressing high levels of CSF1 and efficacy.\n\nIntroduction\n\nTenosynovial giant cell tumor (TGCT), formerly known as pigmented villonodular synovitis (PVNS) or giant cell tumor of tendon sheath (GCT-TS), is a rare and locally aggressive neoplasm that affects joints, tendon sheaths, and bursae and is characterized by synovial proliferation and tumors with multinucleated giant cells (1). Intra-articular cellular overexpression of colony-stimulating factor 1 (CSF1) in TGCT plays an important role in the pathogenesis and propagation of TGCT (1, 2). Inhibitors of the CSF1 receptor (CSF1R) have shown compelling antitumor activity in patients with TGCT (3–8). Pexidartinib is a novel oral small-molecule inhibitor that selectively targets CSF1R, as well as the KIT receptor tyrosine kinase (KIT) and FMS-like tyrosine kinase 3 (FLT3) harboring an internal tandem duplication mutation (8–11). In the phase III ENLIVEN trial, pexidartinib was associated with a robust tumor response and improvements in symptoms and functionality among adult patients with severe symptomatic TGCT (4). Based on these results, pexidartinib was the first approved treatment for adult patients with symptomatic TGCT associated with severe morbidity or functional limitations not amenable to improvement with surgery (9, 12, 13). Pexidartinib is available in the United States only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) because of the risk of hepatotoxicity (9). Prior to the ENLIVEN study, pexidartinib was evaluated in a two-part phase I study. Results from the part 1 dose-escalation portion have been previously reported (8). In the part 2 extension, six cohorts were enrolled comprising patients with: (i) mucoepidermal carcinoma (MEC) of the salivary gland, (ii) TGCT, (iii) gastrointestinal stromal tumor (GIST), (iv) anaplastic thyroid carcinoma (ATC), (v) solid tumors with documented malignant pleural or peritoneal effusions, and (vi) miscellaneous tumor types with scientific evidence supporting the involvement of CSF1R/KIT signaling in tumorigenesis.\n\nThe present analysis reports the results for 91 patients from all six extension cohorts, with emphasis on evaluating long-term efficacy and safety in the TGCT patient cohort. Preliminary results from the first 23 patients in the TGCT cohort were previously reported (8). Owing to those encouraging results as well as the lack of nonsurgical therapy options for patients with advanced diffuse TGCT, this cohort was expanded, and novel tools that might better capture TGCT-specific treatment effect, disease status, and patient-reported outcomes (PRO) were incorporated. These tools included the TVS to measure disease burden more accurately than Response Evaluation Criteria in Solid Tumors (RECIST; refs. 8, 14) and PRO (15, 16) questions to measure symptom improvement; these measures were customized to capture unique aspects of TGCT. Also reported is a post hoc analysis on the CSF1 transcript alterations in patients in the TGCT cohort.\n\nPatients and Methods\n\nStudy design, patients, and procedures\n\nThis is the part 2 extension of a phase I, multicenter, open-label, uncontrolled, two-part study (Supplementary Appendix). Patients with advanced, incurable solid tumors were enrolled in six extension cohorts and treated with the recommended phase II dose (RP2D) of 1,000 mg/day (taken as 600 mg in the morning and 400 mg in the evening), identified in the part 1 dose-escalation study. Patients continued treatment in part 2 until disease progression or unacceptable toxicity occurred. The primary objective of the extension was to evaluate the potential clinical benefit of single-agent pexidartinib in patients with these specific neoplasms. Pharmacokinetics and safety were also assessed; area under the concentration–time curves over time interval 0 to 4 hours (AUC0–4 h) were estimated from data collection at five time points (nominal time 0, 1, 2, 4, and 6 hours). Adult patients (18 years or older) were enrolled at 12 centers in the United States. The first patient was enrolled on November 16, 2011, and as of March 22, 2021, the enrollment was complete. Briefly, eligibility criteria included: (i) for advanced or recurrent MEC of the salivary gland, patients could not be candidates for curative surgery or radiotherapy; (ii) for TGCT, patients had to have a histologically confirmed diagnosis of inoperable progressive or relapsing TGCT; (iii) for GIST, patients had to have progressed on previous therapy with imatinib and sunitinib; (iv) for ATC, patients had to have histologically or cytologically diagnosed advanced ATC; (v) patients must not have been receiving specific therapy for the effusion or have an indwelling drain; and (vi) other solid tumor types could be included in the miscellaneous cohort. Details of patient eligibility, study design, and procedures have been previously described (8), and key eligibility criteria are listed in the Supplementary Appendix. Patients provided written informed consent. Dose adjustments, usually in increments of 200 mg daily, were allowed, as were temporary drug holds for toxicity or other reasons. This interim analysis presents cumulative data for exposure and response to pexidartinib up to the data cutoff of January 31, 2018 (March 3, 2017, for pharmacokinetic analysis).\n\nEfficacy was assessed locally by imaging at baseline and every 2 months using RECIST version 1.1 [primary outcome, best overall tumor response (i.e., complete response, partial response)]. For patients with TGCT, tumor response was also assessed centrally using a TVS specifically developed for this disease (8, 14). For patients with TGCT enrolled after protocol amendment 8 (August 2013), we used five numeric rating scale (NRS) questions targeting symptoms that are relevant for patients with TGCT (i.e., worst pain, stiffness, limited motion, swelling, and instability; ref. 15). Procedures for assessment of TVS, PRO (for pain), and safety are described in the Supplementary Appendix.\n\nThe study protocol was approved by the Institutional Review Board at each study center. All patients provided written informed consent before study eligibility screening. This study was conducted in accordance with Good Clinical Practice guidelines, as provided by the International Conference on Harmonisation and principles of the Declaration of Helsinki, and all applicable regulatory and ethical requirements. This trial is registered with ClinicalTrials.gov, number NCT01004861.\n\nTGCT-targeted RNA sequencing (RNA-seq)\n\nAs part of the protocol, archival TGCT tissue biopsies were collected when possible to study the molecular characteristics of this disease. Samples were collected between June 9, 2015 and April 12, 2017. RNA isolation from formalin-fixed paraffin-embedded (FFPE) TGCT specimens was performed at AltheaDx Inc. using the Qiagen FFPE RNeasy kit. An Anchored Multiplex PCR (AMP) RNA panel consisting of 33 gene-specific primer sets was specifically designed to target CSF1, including at least one primer set to detect each exon/exon boundary as well as primer sets to tile the 3′-untranslated regions (3′UTR). Libraries were prepared from ∼200 ng RNA and sequenced on an Illumina MiSeq at a depth greater than 1 million reads per sample. Sequencing data were analyzed with Archer Analysis software (Archer DX, Inc.) to identify chimeric alignments. Potential rearrangements were manually reviewed with Integrative Genomics Viewer (17) and prioritized based on the number of unique reads supporting each rearrangement. CSF1 gene expression was estimated by counting unique CSF1 reads and normalizing to a set of housekeeping genes.\n\nStatistical analysis\n\nFor the five non-TGCT disease-specific extension cohorts, a sample size of 10 was considered the minimum number of patients required to test the hypothesis that single-agent pexidartinib could provide a clinical benefit in the individual patient population. Additional statistical analysis details are provided in the Supplementary Appendix.\n\nData availability statement\n\nDeidentified individual participant data and applicable supporting clinical trial documents may be available upon request at https://www.clinicalstudydatarequest.com. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo, Inc., will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at https://www.clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-DS.aspx.\n\nResults\n\nPatient characteristics and drug exposure\n\nA total of 91 patients in six cohorts were enrolled in the extension study, including 39 patients with advanced TGCT and 52 patients with other tumor types. Patient demographic and baseline characteristics are provided in Table 1. Mean (± standard deviation) patient age was 51 years (±15.5), with 45 years (±14) for the TGCT cohort and 56 years (±14.9) for the non-TGCT cohorts.\n\nTable 1. Demographics and baseline characteristics of patients in the extension cohorts—safety population.\n\nExtension cohorts (1,000 mg/day)\t\t\n\tPatients with TGCT\tNon-TGCT patientsa\tTotal\t\n\t(n = 39)\t(n = 52)\t(n = 91)\t\nAge, mean (Standard Deviation) (y)\t45.1 (13.99)\t56.2 (14.92)\t51.4 (15.46)\t\nSex, n (%)\t\n Male\t17 (44%)\t31 (60%)\t48 (53%)\t\n Female\t22 (56%)\t21 (40%)\t43 (47%)\t\nRace, n (%)\t\n White\t33 (85%)\t48 (92%)\t81 (89%)\t\n Black\t3 (8%)\t1 (2%)\t4 (4%)\t\n Asian\t3 (8%)\t1 (2%)\t4 (4%)\t\n Native Hawaiian or other Pacific Islander\t0\t1 (2%)\t1 (1%)\t\n Multiple races\t0\t1 (2%)\t1 (1%)\t\nBMI, mean (Standard Deviation) (kg/m2)\t28.03 (5.866)\t26.90 (6.508)\t27.40 (6.225)\t\nTumor location, n\t\n Knee\t21\t—\t—\t\n Foot/ankle\t7\t—\t—\t\n Hip/thigh\t7\t—\t—\t\n Forearm/wrist\t2\t—\t—\t\n Elbow\t1\t—\t—\t\n Gastroc muscle\t1\t—\t—\t\n Upper extremity\t1\t—\t—\t\nPrevious treatment, n (%)\t\n Surgery\t31 (80%)\t—\t—\t\n Radiation\t3 (8%)\t—\t—\t\n TKI\t4 (10%)\t—\t—\t\n Other systemic treatment (denosumab or sirolimus)\t2 (5%)\t—\t—\t\nAbbreviations: ATC, anaplastic thyroid carcinoma; BMI, body mass index; GIST, gastrointestinal stromal tumor; MEC, mucoepidermal carcinoma; TGCT, tenosynovial giant cell tumor; TKI, tyrosine kinase inhibitor.\n\naNon-TGCT patients: The 5 non-TGCT cohorts include the following tumor types: ATC (n = 9), GIST (n = 11), malignant effusion (n = 8), MEC (n = 4), and other tumor types (n = 20). Malignant effusions included mesothelioma (2), colon cancer (2), ovarian adenocarcinoma (1), unknown primary with lung and liver metastases (1), breast cancer (1), and non–small cell lung cancer (1). The category of “other tumor types” included mesothelioma (7), malignant peripheral nerve sheath tumor (3), Erdheim–Chester disease (2), neurofibromatosis (2), leiomyosarcoma (1), adenoid cystic carcinoma (1), pancreatic neuroendocrine tumor (1), acinic cell carcinoma of the parotid (1), familial schwannomatosis (1), and desmoplastic small round cell tumor (1).\n\nAmong the 39 patients with TGCT, 31 had undergone previous surgery, 3 had received radiation, 4 had received prior treatment with a kinase inhibitor (imatinib or nilotinib), and 2 had received other systemic treatment (denosumab or sirolimus). Two patients had metastatic disease. The most common tumor location was in the knee (21 patients).\n\nThe median duration of treatment for all 91 patients was 111 days (4 months, range, 1–1,814 days), with a longer median duration in the TGCT cohort of 511 days (17 months, range, 15–1,814 days) than in the non-TGCT cohorts [56 days (2 months) range, 1–494 days]. Seven non-TGCT patients (13%) received treatment for more than 6 months. Twenty-three patients with TGCT (59%) were treated for 1 year, 17 (44%) of these patients received treatment for 2 years, 14 (36%) patients for 3 years, and 11 (28%) and 5 (13%) for 4 and 5 years, respectively (as of May 31, 2019).\n\nOf the 91 patients, 30 (33%) required dose reduction and 40 (44%) experienced a drug holiday. Of the 39 patients with TGCT, 24 (62%) required dose reduction and 27 (69%) had a drug holiday. The most common reason for dose interruption among the patients with TGCT was missed doses. Missed doses, dose reductions, and drug holidays were often associated with an adverse event (AE).\n\nSafety\n\nAll 91 patients were included in the safety analysis. Treatment-related treatment-emergent AEs (TEAE; ≥10%) are summarized in Supplementary Table S1, and TEAEs (≥20%) are provided in Supplementary Table S2. All 39 patients with TGCT reported at least 1 AE. For patients with TGCT, the most frequently reported treatment-related AEs were fatigue (74%), hair color changes (72%), nausea (56%), periorbital edema (39%), dysgeusia (36%), and pruritus (31%). The most common grade ≥ 3 treatment-related AEs observed in patients with TGCT were hypophosphatemia (10%), alanine aminotransferase increase (10%), and aspartate aminotransferase (AST) increase (8%); all were reversible and well managed with dose interruption or reduction. Two patients with TGCT developed treatment-related serious adverse events (SAE), consisting of hyponatremia and elevated transaminases.\n\nFor non-TGCT patients, the most frequently reported TEAEs were fatigue (40%), decreased appetite (39%), nausea (33%), and hair color changes (31%). The most common treatment-related AE of grade ≥ 3 in these non-TGCT patients included fatigue (6%), AST increase (4%), and hypophosphatemia (4%). Four non-TGCT patients developed treatment-related SAEs that led to permanent drug withdrawal. Both patients with GIST withdrew: 1 due to grade 4 liver hemorrhage (a metastatic liver lesion with possible hemorrhage present at baseline) and 1 due to grade 3 hypoxia. The third treatment-related SAE was febrile neutropenia that resolved with medication in a mesothelioma patient. The fourth was a fatal cerebrovascular accident (CVA) occurring in an Erdheim–Chester disease patient with a history of CVA and intraparenchymal hemorrhage who had been on study for more than a year. The patient died 10 days after the onset of the event. Six other patients (1 MEC, 3 GIST, 1 ATC, and 1 maligant effusion patient) died due to disease progression during the study.\n\nOf the 91 patients, 6 had grade 3 elevations in aminotransferase levels; for 5 of these patients, the increases resolved after temporary drug withdrawals or dose reductions. One patient continued to have intermittent liver transaminase elevations more than 1 year after permanent drug withdrawal and was eventually diagnosed with primary biliary cirrhosis considered unrelated to the study drug. Two clinically distinct types of hepatotoxocity have previously been observed—aminotransferase elevations and mixed or cholestatic hepatotoxicity (4, 18, 19). In all cases of drug-related increases in aminotransferase levels in the current study, total bilirubin levels were normal, and there were no cases that met criteria for Hy's law.\n\nDecreases in platelets, hemoglobin, and white blood cells—specifically, neutrophils and lymphocytes—were also observed. These effects were generally grade 2 or less. No patient had clinically significant electrocardiogram abnormalities.\n\nPharmacokinetics\n\nThe AUC0–4 h was estimated for 78 patients (36 patients with TGCT and 42 non-TGCT patients). There were no significant diffferences between the disease-specific cohorts in geometric mean AUC0–4 h (Supplementary Fig. S1). The geometric mean AUC0–4h averaged over 78 patients was 26,052 ng·h/mL and for the 36 patients with TGCT was 23,581 ng·h/mL.\n\nEfficacy\n\nResponse by tumor assessment\n\nIn the non-TGCT populaiton (n = 52), 1 (Erdheim–Chester disease) was treated for 494 days and had a partial response (PR). Fifteen non-TGCT patients (GIST, n = 4; malignant effusion, n = 3; mesothelioma, n = 2; neurofibromatosis, n = 2; pancreatic neuroendocrine tumor, familial schwannomatosis, MEC, adenoid cystic carcinoma, n = 1 each) had stable disease (SD) as best response (Table 2), 6 of them had prolonged (>6 months) SD while on study drug (Supplementary Table S3). The median progression-free survival (PFS) for patients with TGCT could not be determined [95% confidence interval (CI), 667 days–not applicable; Supplementary Fig. S2], while that for the non-TGCT patients was 56 days (95% CI, 53–161 days; Supplementary Fig. S3).\n\nTable 2. Treatment duration and best response of SD or PR in non-TGCT patients.\n\nTumor\tTotal treatment duration (days)\tBest response\t\nGIST\t80\tSD\t\nGIST\t111\tSD\t\nGIST\t169\tSD\t\nGIST\t345\tSD\t\nMEC\t350\tSD\t\nMalignant effusiona\t55\tSD\t\nMalignant effusionb\t263\tSD\t\nMalignant effusionc\t56\tSD\t\nFamilial schwannomatosis\t187\tSD\t\nNeurofibromatosis\t199\tSD\t\nNeurofibromatosis\t113\tSD\t\nACC\t57\tSD\t\nMesothelioma\t150\tSD\t\nPancreatic neuroendocrine tumor\t413\tSD\t\nErdheim–Chester disease\t494\tPR\t\nMesothelioma\t55\tSD\t\nAbbreviations: ACC, adenoid cystic carcinoma; GIST, gastrointestinal stromal tumor; MEC, mucoepidermal carcinoma; SD, stable disease; PR, partial response; TGCT, tenosynovial giant cell tumor.\n\naNon–small cell lung cancer.\n\nbMesothelioma.\n\ncColon cancer.\n\nOf the 39 TGCT full analysis set (FAS) patients, 37 met the criteria of the efficacy-evaluable subset (i.e., had a baseline and at least 1 post-baseline radiographic scan). As assessed by RECIST 1.1 per local reading, 24 patients with TGCT achieved a response [2 complete response (CR) and 22 PR], for an objective response rate (ORR) of 62% (95% CI, 45%–77%) and 65% (95% CI, 47%–80%) for the FAS (n = 39) and efficacy-evaluable populations (n = 37), respectively (Fig. 1). The 25th percentile for duration of response (DOR) was 943 days (95% CI, 169 days–not applicable). In addition to those that responded, 8 patients had SD that lasted for at least 6 months, for a disease control rate (DCR = CR + PR + SD) of 82% (95% CI, 66%–92%) and 86% (95% CI, 71%–95%) for the FAS patients (n = 39) and efficacy-evaluable patients (n = 37), respectively. Fifteen patients experienced at least a 50% reduction in sum of longest tumor diameter (Supplementary Fig. S4). Many of these patients who continued on treatment for more than a year demonstrated prolonged tumor response by pexidartinib (18). Thirteen patients remained on pexidartinib treatment as of the January 31, 2018, cutoff, all of whom had been receiving treatment for more than 3 years. As of February 2021, the median DOR and PFS for these 13 subjects that remained on pexidartinib treatment was 1,529 and 1,764 days, respectively.\n\nFigure 1. Tumor response assessed by local RECIST, treatment duration, and disposition for patients with TGCT. Data cutoff: January 31, 2018. Each line represents 1 patient in the study. Patients received an initial dose of 1,000 mg/day. Treatment duration in months is calculated as treatment duration in days divided by 30.4167. RECIST, Response Evaluation Criteria in Solid Tumors; TGCT, tenosynovial giant cell tumor.\n\nFigure 1. Tumor response assessed by local RECIST, treatment duration, and disposition for patients with TGCT. Data cutoff: January 31, 2018. Each line represents 1 patient in the study. Patients received an initial dose of 1,000 mg/day. Treatment duration in months is calculated as treatment duration in days divided by 30.4167. RECIST, Response Evaluation Criteria in Solid Tumors; TGCT, tenosynovial giant cell tumor.\n\nResponse by tumor volume score (TVS)\n\nOf the 39 patients with TGCT, 31 were evaluable radiologically by MRI. Similar to RECIST, the TVS assessment showed that the majority of patients experienced a significant decrease in tumor burden (Fig. 2). Of the 31 efficacy-evaluable patients, 7 achieved a CR, and 15 achieved a PR, giving a TVS ORR of 56% (95% CI, 40%–72%) and 71% (95% CI, 52%–86%) for the FAS (n = 39) and efficacy-evaluable (n = 31) patients, respectively. Nine patients had SD that lasted for at least 6 months, giving a DCR of 79% (95% CI, 64%–91%) and 100% (95% CI, 89%–100%) for FAS and efficacy-evaluable patients, respectively.\n\nFigure 2. Maximum percentage change from baseline in TVS for patients with TGCT. The graph shows the maximum percentage change in TVS score from baseline by individual patient for the 31 MRI-evaluable patients with TGCT. Data cutoff: January 31, 2018. CR, complete response; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; TGCT, tenosynovial giant cell tumor; TVS, tumor volume score.\n\nFigure 2. Maximum percentage change from baseline in TVS for patients with TGCT. The graph shows the maximum percentage change in TVS score from baseline by individual patient for the 31 MRI-evaluable patients with TGCT. Data cutoff: January 31, 2018. CR, complete response; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; TGCT, tenosynovial giant cell tumor; TVS, tumor volume score.\n\nPROs\n\nTGCT-related symptoms reported by patients using the NRS [range from 0 (normal) to 10 (extreme)] for TGCT symptoms of worst pain, stiffness, limited motion, swelling, and instability were assessed in 22 patients from baseline and monthly on treatment. All symptoms assessed showed a consistent trend of decreased scores (i.e., symptom improvement) over the course of pexidartinib treatment. Pain has been shown to be one of the most common symptoms in TGCT (15), and the measurement of pain NRS as a tool has been validated in many neoplastic diseases (20). The mean change in the pain NRS from baseline through cycle 39 in the FAS population showed a decrease starting at approximately cycle 1 that was sustained over time, with sustained improvement from cycle 3 through cycle 39 (Fig. 3).\n\nFigure 3. Mean change from baseline: pain by NRS for patients with TGCT. Data cutoff: January 31, 2018. n drops below 10 after cycle 39, and the results are not shown. NRS, numeric rating scale; TGCT, tenosynovial giant cell tumor.\n\nFigure 3. Mean change from baseline: pain by NRS for patients with TGCT. Data cutoff: January 31, 2018. n drops below 10 after cycle 39, and the results are not shown. NRS, numeric rating scale; TGCT, tenosynovial giant cell tumor.\n\nAn assessment of the relationship between TVS and PRO (Brief Pain Inventory NRS Worst Pain item) showed that changes in TVS corresponded with changes in pain in the same direction (Supplementary Fig. S5). Although 31 patients were evaluable by TVS, in this assessment, n = 13, as PRO measurements were assessed toward the end of patient enrollment. Some patients were excluded from TVS of imaging assessment because metal-induced artifacts on MRI.\n\nTargeted RNA-seq identified abnormal CSF1 transcripts and suggested high expression of CSF1 in TGCT biopsy\n\nRNA from 25 TGCT samples was successfully isolated and sequenced, of which 19 (76%) showed evidence of abnormal CSF1 transcripts (Fig. 4A and B). Nine samples showed strong evidence of gene rearrangements at the junctions of CSF1 exon 5 (n = 7), exon 6 (n = 1), or exon 7 (n = 1); 8 of those were predicted to be in frame. Three of the 7 exon 5 fusion events were supported by evidence of the reciprocal fusion event (FN1:CSF1 and CD99:CSF1), no COL6A3-CSF1 fusions were observed. Ten specimens showed evidence of alteration at exon 8 or within the 3′UTR, with 6 supported by strong-evidence events and 4 with low confidence.\n\nFigure 4. TGCT biopsy-targeted RNA-seq identified abnormal CSF1 transcripts. Ten specimens showed evidence of alteration at exon 8 or within the 3′UTR, with 6 strong-evidence events (A) and 4 low-confidence events (B). CA11, carbonic anhydrase 11; CD101, CD101 molecule; CD99, CD99 molecule (Xg blood group); CDH13, cadherin 13; Chr, chromosome; CSF1, colony-stimulating factor 1; ENG, endoglin; FN1, fibronectin 1; SM, sample; TGCT, tenosynovial giant cell tumor; TM, transmembrane; UTR, untranslated region.\n\nFigure 4. TGCT biopsy-targeted RNA-seq identified abnormal CSF1 transcripts. Ten specimens showed evidence of alteration at exon 8 or within the 3′UTR, with 6 strong-evidence events (A) and 4 low-confidence events (B). CA11, carbonic anhydrase 11; CD101, CD101 molecule; CD99, CD99 molecule (Xg blood group); CDH13, cadherin 13; Chr, chromosome; CSF1, colony-stimulating factor 1; ENG, endoglin; FN1, fibronectin 1; SM, sample; TGCT, tenosynovial giant cell tumor; TM, transmembrane; UTR, untranslated region.\n\nThere was no obvious expression difference between the distinct fusion categories that occurred at or near the exon 5 or exon 6–9 junction of CSF1 (Fig. 5A and B). Regardless of CSF1 fusion status, all 25 TGCT libraries exceeded 2× CSF1 expression relative to the lung RNA control library (Fig. 5C).\n\nFigure 5. CSF1 RNA expression in TGCT relative to lung. Relative to the lung RNA control library, all 25 TGCT libraries had higher CSF1 expression; all 25 exceeded 2× lung CSF1 expression (A–C). There was no obvious expression difference between the distinct fusion categories. CSF1, colony-stimulating factor 1; SM, sample; TGCT, tenosynovial giant cell tumor; WT, wild-type.\n\nFigure 5. CSF1 RNA expression in TGCT relative to lung. Relative to the lung RNA control library, all 25 TGCT libraries had higher CSF1 expression; all 25 exceeded 2× lung CSF1 expression (A–C). There was no obvious expression difference between the distinct fusion categories. CSF1, colony-stimulating factor 1; SM, sample; TGCT, tenosynovial giant cell tumor; WT, wild-type.\n\nDiscussion\n\nTGCT is an uncommon neoplasm that can confer significant morbidity, especially the diffuse form of the disease. Though rarely life-threatening or metastatic, TGCT can be a locally invasive, debilitating disease that causes significant suffering and physical impairment. In recent years, systemic therapies, particularly agents that target the CSF1/CSF1R signaling pathways, have shown promising results as novel treatment options for patients with TGCT (3–8, 21–26). Based on the phase III ENLIVEN study, pexidartinib is now approved in the United States for the treatment of adult patients with symptomatic TGCT associated with severe morbidity or functional limitations with surgery at 800-mg total daily dose, reflecting equivalent efficacy and less toxicity (9, 12, 13). Preliminary data from this phase I study enabled the design and conduct of the ENLIVEN study (8). More specifically, to better evaluate the effect of pexidartinib in patients with TGCT, we implemented novel quantitative endpoints, including TVS, a new quantitative radiographical scoring system to fully measure tumor burden, and TGCT-specific PRO questions to understand whether and how a patient's tumor response might correlate with decreased symptoms and improved quality of life (15). These tools were used in ENLIVEN as key secondary endpoints. Overall, the development of these tools represents a step forward for understanding the efficacy and outcomes that are unique to patients with TGCT as they appropriately and longitudinally monitor the effect of a treatment in clinical development.\n\nIn this phase I extension study, response to pexidartinib treatment was assessed in six cohorts of adult patients with advanced, incurable solid tumors associated with CSF1R and/or KIT activity. Efficacy was most notable in patients with TGCT, where a considerable proportion of patients experienced substantial and prolonged tumor reduction, in addition to improvements in pain-related PRO. There was no substantial evidence of responses among the non-TGCT patients in this study. The safety profile was similar among all six cohorts, and no late-emerging safety signals were observed in the TGCT cohort. All TGCT patient samples assessed showed elevated expression of CSF1. A significant proportion (15/25, 60%) of these samples also had sequence alterations that could alter CSF1 gene expression or result in the fusion of CSF1 to another protein.\n\nHere, we evaluated response in our TGCT cohort in several ways. First, we used the standard radiologic response criteria, RECIST 1.1, which showed an ORR of over 60% for both the FAS and efficacy-evaluable populations. Many patients who responded by RECIST continued on treatment for more than 3 years, indicating that pexidartinib may provide prolonged control of TGCT. Of note, 3 of the 4 patients (75%) who had previously received other tyrosine kinase inhibitor (TKI) treatment achieved a RECIST response on pexidartinib (8).\n\nSecond, we evaluated TGCT response by TVS, which showed an ORR of 56% and 71% for the FAS and efficacy-evaluable populations, respectively. These volumetric measurements could potentially be more sensitive in capturing the full magnitude of response in diffuse TGCT as opposed to the unidimensional measurement of RECIST 1.1.\n\nIn addition, we evaluated symptomatic improvement using PRO questions that were created specifically for patients with TGCT. The present study demonstrates a strong relationship between the radiologic outcome (tumor size change) and the patient-reported pain and stiffness outcomes, which highlights both the strength of the relationship between these outcomes and the importance of each of these measures as unique indicators of treatment benefit.\n\nImportantly, our study also gives insight into the long-term application of pexidartinib in patients with TGCT. With pexidartinib, patients usually achieve a radiologic response within 4 months, and the tumor response can be sustained while remaining on drug (4, 13). Additional analysis of tumor response assessment based on modified tumor response criteria showed that only 3 patients progressed while on therapy: 1 with a locally aggressive forearm lesion that never responded and 2 with metastatic TGCT who had either prolonged SD or PR before relapsing. One question to explore is whether tumor reduction and functional improvement would persist after chronic treatment (beyond 1 year) followed by a drug holiday, a dose reduction, or a simple surgery. Currently, a phase IV study is assessing discontinuation and retreatment with pexidartinib in patients with TGCT from multiple studies (NCT02371369, NCT02734433, and NCT03291288), including patients with TGCT from this phase I extension cohort (NCT01004861). The dose used in this phase I extension was calibrated primarily for patients with lethal, end-stage cancers. Based on findings from this study and the ENLIVEN phase III study, the final approved label indication dose was determined to be 800 mg total daily dose, reflecting equivalent efficacy and less toxicity (9).\n\nOverall, short-term safety between patients with TGCT and non-TGCT patients was similar. However, in the TGCT group, dose reductions and holidays were made on a more liberal basis in consideration of the non–life-threatening nature of this disease, the dramatic initial responses, and the longer cumulative duration of therapy. Long-term treatment with pexidartinib demonstrated a tolerable safety profile, with no late-emerging toxicity. Reported TEAEs were mostly low grade, the most frequent being hair color change (18).\n\nLong-term treatment with pexidartinib has been reported to have a predictable effect on hepatic aminotransferases and an unpredictable risk of serious cholestatic or mixed liver injury (19). Prolonged pexidartinib treatment may be associated with hepatic laboratory abnormalities, including hepatic adverse reactions (AR). The vast majority of patients who experienced hepatic ARs had 1 of 2 clinically distinct types. The first type was isolated aminotransferase elevations (> 90%), which were frequent, reversible with dose interruption, and dose dependent. The second type of hepatic AR was mixed or cholestatic hepatotoxicity (< 5%), which, in clinically significant cases, presented as an increase in alkaline phosphatase and total bilirubin with aminotransferase elevations. Notably, all cases of serious liver toxicity observed presented in the first 8 weeks of treatment, and all resolved in patients with TGCT (4, 18, 19).\n\nThis study included an in-depth analysis of the CSF1 gene in TGCT tissues. Previous findings identified gross chromosomal aberrations involving the CSF1 locus using break-apart FISH probes (27). In another study, two cohorts of patients with TGCT were investigated for CSF1 rearrangements using FISH and either RNA-seq or DNA-seq with Sanger validation (28). CSF1 rearrangements were identified by FISH in 30/39 cases, and sequencing confirmed CSF1 breakpoints in 28 cases. Patients with TGCT, in their large cohort, were characterized by variable alterations, all of which led to truncation of the 3′ end of CSF1, instead of the COL6A3–CSF1 fusions previously reported in some TGCTs. Another report suggested the importance of CSF1 exon 9 deletion in the molecular pathogenesis of TGCT (29). This analysis and review of the sequencing data revealed two general patterns of CSF1 rearrangement in the TGCT tissues. The most common pattern was a rearrangement near the exon 8/9 junction or within exon 9 (3′UTR) of CSF1, which typically partnered with intergenic sequences, often downstream of CSF1 on chromosome 1. The other common pattern was gene fusion of CSF1 exon 5/6 junction with exons of various other genes. Both patterns of CSF1 alteration would eliminate the 3′UTR microRNA regulatory sites (30), suggesting a loss of negative regulation of CSF1 gene expression.\n\nAnalysis of the RNA-seq data also suggested that relative to a lung RNA control library, TGCTs have high expression of CSF1. Together, these results suggest that somatic CSF1 alterations may provide a mechanism of sustained CSF1 production in TGCT and an explanation as to why inhibition of CSF1R is an effective therapeutic intervention.\n\nWe note several limitations of this study. First, the study design is open-label and uncontrolled; this especially affects interpretation of the PRO findings for pain. Second, dose reductions were made based on the clinical judgment of the investigators, which led to substantial dose variation. Third, the RECIST results were based on local readings not blinded to visit order. In contrast, assessments by TVS were based on centralized, time-blinded reading, but as a post hoc analysis. Last, for the RNA-seq study, lung RNA is not the most appropriate control. However, lung samples have the fifth highest median CSF1 expression of all tissues in the public GTEx database (> 50 tissues; ref. 31).\n\nSupplementary appendix\n\nAdditional data and information about this study are provided in the Supplementary Appendix.\n\nAuthors' Disclosures\n\nW.D. Tap reports grants from Plexxikon during the conduct of the study, as well as personal fees from Eli Lilly, EMD-Serono, Mundipharma, C4 Therapeutics, Daiichi Sankyo, Blueprint, Agios Pharmaceuticals, NanoCarrier, Deciphera, Adcendo, Ayala, Kowa, Servier, Bayer, Epizyme, Cogent, Medpactor, and Foghorn outside the submitted work. In addition, W.D. Tap has a patent for Companion Diagnostic for CDK4 inhibitors 14/854,329 pending to MSK/SKI and a patent for Enigma and CDH18 as companion diagnostics for CDK4 inhibition SKI2016-021-03 pending to MSK/SKI; reports scientific advisory board membership for Certis Oncology Solutions and Innova Therapeutics; reports stock ownership from Certis Oncology Solutions and Atropos Therapeutics; and is co-founder of Atropos Therapeutics. A.S. Singh reports grants and personal fees from Daiichi Sankyo during the conduct of the study. A.S. Singh also reports personal fees from Eli Lilly, OncLive, and Expert Perspectives; grants and personal fees from Deciphera, Eisai, Roche, and Blueprint Medicines; grants from NanoCarrier; and other support from Certis Oncology Solutions outside the submitted work. S.P. Anthony reports grants from Plexxikon during the conduct of the study. M. Sterba reports personal fees from Plexxikon Inc. outside the submitted work. J.H. Healey reports personal fees from Daiichi Sankyo during the conduct of the study, as well as personal fees from Daiichi Sankyo outside the submitted work. B. Chmielowski reports grants from Daiichi Sankyo during the conduct of the study, as well as personal fees from Iovance Biotherapeutics, Sanofi Genzyme, OncoSec, IDEAYA Biosciences, Epizyme, Nektar, Regeneron, Biothera, Novartis, Genentech, and Deciphera outside the submitted work. G.I. Shapiro reports other support from Plexxikon during the conduct of the study. G.I. Shapiro also reports grants and personal fees from Eli Lilly, Merck KGaA/EMD-Serono, Sierra Oncology, and Pfizer; personal fees from G1 Therapeutics, Roche, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Daiichi Sankyo, Seattle Genetics, Boehringer Ingelheim, ImmunoMet, Almac, Ipsen, Bayer, Angiex, Asana, Artios, Atrin, Concarlo Holdings, Syros, Zentalis, CytomX Therapeutics, Blueprint Medicines, and Kymera; and grants from Merck & Co outside the submitted work. In addition, G.I. Shapiro has a patent for dosage regimen for sapacitabine and seliciclib issued to Cyclacel Pharmaceuticals and Geoffrey Shapiro and a patent for compositions and methods for predicting response and resistance to CDK4/6 inhibition pending to Liam Cornell and Geoffrey Shapiro. V.L. Keedy reports grants from Plexxikon during the conduct of the study. V.L. Keedy also reports grants from Medpacto, Lilly, Immune Design, GSK, Tracon, Advenchen, Deciphera, and Springworks; grants and personal fees from Daiichi Sankyo; and personal fees from Karyopharm outside the submitted work. Z.A. Wainberg reports grants from AbbVie; Z.A. Wainberg also reports personal fees from Amgen, Bayer, AstraZeneca, Roche, Merck, Incyte, BMS, Seagen, and Genentech, as well as grants and personal fees from Daiichi, Novartis, Ipsen, and Plexxikon outside the submitted work. I. Puzanov reports personal fees from Merck, Nouscom, Oncorus, Amgen, Nektar, and Iovance outside the submitted work. G.M. Cote reports other support from Daiichi Sankyo during the conduct of the study. G.M. Cote also reports other support from Agios, Eisai, Macrogenics, Merck KGaA/EMD-Serono Research and Development Institute, SpringWorks Therapeutics, Bayer, and Repare; personal fees and other support from Epizyme, Foghorn, and PharmaMar; and personal fees from Ikena and C4 Therapeutics outside the submitted work. A.J. Wagner reports grants from Plexxikon and Daiichi Sankyo during the conduct of the study. A.J. Wagner also reports grants and personal fees from Aadi Bioscience, Deciphera, Eli Lilly, Five Prime, and Foghorn; personal fees from Mundipharma, Boehringer Ingelheim, Cogent Biosciences, and NanoCarrier; and grants from Karyopharm outside the submitted work. F. Braiteh reports personal fees from Lilly, AstraZeneca, BMS, Incyte, Deciphera, Eisai, Seagen, Daiichi Sankyo, Boehringer Ingelheim, Pfizer, Amgen, Genentech, and Regeneron outside the submitted work. E. Sherman reports grants and non-financial support from Daiichi Sankyo during the conduct of the study. E. Sherman also reports grants and personal fees from Regeneron; personal fees from Eisai and Exelixis; and grants, personal fees, and non-financial support from Eli Lilly/Loxo and Roche outside the submitted work. H.H. Hsu reports personal fees from Plexxikon during the conduct of the study. C. Peterfy reports personal fees from Daiichi Sankyo during the conduct of the study, as well as personal fees from Five Prime, Deciphera, AmMax, and SynOx outside the submitted work. H.L. Gelhorn reports other support from DSI during the conduct of the study. X. Ye reports other support from Daiichi Sankyo, Inc. during the conduct of the study, as well as other support from Daiichi Sankyo, Inc. outside the submitted work. P.S. Lin reports other support from Plexxikon Inc. during the conduct of the study, as well as a patent for US 9358235 B2 issued and a patent for US 9730918 B2 issued. No disclosures were reported by the other authors.\n\nSupplementary Material\n\nSupplementary Data Click here for additional data file.\n\nSupplementary Data Click here for additional data file.\n\nSupplementary Data Click here for additional data file.\n\nSupplementary Data Click here for additional data file.\n\nSupplementary Data Click here for additional data file.\n\nSupplementary Data Click here for additional data file.\n\nAcknowledgments\n\nWe thank the patients who volunteered to participate in this study, their family members and caregivers, and the study center staff members who cared for the patients. Medical writing assistance was provided by Phillip Giannopoulos and Shruthi Satish of SciStrategy Communications and funded by Daiichi Sankyo, Inc. We also thank Karen Getz for her support with writing the manuscript. Research sponsored by Daiichi Sankyo, Inc. and Plexxikon Inc., a subsidiary of Daiichi Sankyo, Inc.; ClinicalTrials.gov number: NCT01004861. W.D. Tap and J.H. Healey acknowledge that all research funding for Memorial Sloan Kettering is supported in part by a grant from the NIH/NCI (#P30 CA008748). Manuscript writing support was sponsored by Daiichi Sankyo, Inc.\n\nThe publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.\n\nAuthors' Contributions\n\nW.D. Tap: Conceptualization, resources, supervision, investigation, visualization, methodology, writing–original draft, project administration, writing–review and editing. A.S. Singh: Investigation, writing–review and editing. S.P. Anthony: Resources, writing–review and editing. M. Sterba: Data curation, supervision, project administration, writing–review and editing. C. Zhang: Conceptualization, formal analysis, supervision, investigation, writing–review and editing. J.H. Healey: Conceptualization, investigation, writing–review and editing. B. Chmielowski: Formal analysis, supervision, validation, investigation, writing–review and editing. A.L. Cohn: Data curation, supervision, investigation, writing–review and editing. G.I. Shapiro: Resources, supervision, investigation, writing–review and editing. V.L. Keedy: Resources, investigation, writing–review and editing. Z.A. Wainberg: Investigation, writing–review and editing. I. Puzanov: Resources, validation, investigation, writing–review and editing. G.M. Cote: Investigation, writing–review and editing. A.J. Wagner: Resources, investigation, writing–review and editing. F. Braiteh: Resources, data curation, investigation, writing–review and editing. E. Sherman: Resources, investigation, writing–review and editing. H.H. Hsu: Conceptualization, supervision, investigation, methodology, project administration, writing–review and editing. C. Peterfy: Resources, formal analysis, writing–review and editing. H.L. Gelhorn: Investigation, methodology, writing–review and editing. X. Ye: Conceptualization, visualization, methodology, project administration, writing–review and editing. P. Severson: Data curation, formal analysis, writing–review and editing. B.L. West: Conceptualization, data curation, supervision, investigation, writing–review and editing. P.S. Lin: Conceptualization, supervision, writing–review and editing. S. Tong-Starksen: Conceptualization, formal analysis, investigation, project administration, writing–review and editing.\n\nNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).\n==== Refs\nReferences\n\n1. Cassier PA , ItalianoA, Gomez-RocaCA, Le TourneauC, ToulmondeM, CannarileMA, . CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study. Lancet Oncol 2015;16 :949–56.26179200\n2. 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Available from: https://gtexportal.org/home/gene/CSF1.\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1078-0432", "issue": null, "journal": "Clinical cancer research : an official journal of the American Association for Cancer Research", "keywords": null, "medline_ta": "Clin Cancer Res", "mesh_terms": null, "nlm_unique_id": "9502500", "other_id": null, "pages": null, "pmc": null, "pmid": "34716196", "pubdate": "2021-10-29", "publication_types": "D016428:Journal Article", "references": null, "title": "Results from Phase I Extension Study Assessing Pexidartinib Treatment in Six Cohorts with Solid Tumors including TGCT, and Abnormal CSF1 Transcripts in TGCT.", "title_normalized": "results from phase i extension study assessing pexidartinib treatment in six cohorts with solid tumors including tgct and abnormal csf1 transcripts in tgct" }
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{ "abstract": "A 31-year-old woman, who had been diagnosed with craniopharyngioma (CP) at the age of 13, suffered secondary hypopituitarism after two surgical resections of CP, receiving supplement of levothyroxine, cortisone, and sequential estrogen and progesterone because of primary amenorrhea. She managed to conceive after ovulation induction with human menopausal gonadotropin. Luteal phase deficiency (LPD) was found during the first trimester, as the progesterone stayed at a low level between 0.07 and 1.63 ng/ml within seven gestational weeks, followed by a gradual rise from 4.01 up to 34.70 ng/ml in the 11th week, which was mainly secreted by the placenta. Estrogen and progesterone were administered to the patient as luteal support until the 12th week, who succeeded in delivering a healthy baby at term. In conclusion, the patient with hypopituitarism who develops severe LPD during the early pregnancy may need luteal support until 12th week.", "affiliations": "Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.;Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.", "authors": "Xia|Hexia|H|https://orcid.org/0000-0002-5260-1073;Zhang|Wei|W|https://orcid.org/0000-0001-7187-108X", "chemical_list": "D006063:Chorionic Gonadotropin; D011374:Progesterone", "country": "Australia", "delete": false, "doi": "10.1111/jog.14892", "fulltext": "\n==== Front\nJ Obstet Gynaecol Res\nJ Obstet Gynaecol Res\n10.1111/(ISSN)1447-0756\nJOG\nThe Journal of Obstetrics and Gynaecology Research\n1341-8076\n1447-0756\nJohn Wiley & Sons Australia, Ltd Kyoto, Japan\n\n34219314\n10.1111/jog.14892\nJOG14892\nCase Report\nCase Reports\nLuteal phase deficiency during the early trimester in a case with secondary hypopituitarism following craniopharyngioma resection\nLPD in a case with hypopituitarism\nXia and Zhang\nXia Hexia https://orcid.org/0000-0002-5260-1073\nxhx0101@hotmail.com\n\n1 2\nZhang Wei https://orcid.org/0000-0001-7187-108X\n2 3 zhangwei623@hotmail.com\n\n1 Department of Gynecology, Obstetrics and Gynecology Hospital Fudan University Shanghai China\n2 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases Shanghai China\n3 Department of Reproductive Endocrinology, Obstetrics and Gynecology Hospital Fudan University Shanghai China\n* Correspondence: Wei Zhang, 419 Fangxie Road, Shanghai 200011, China. Email: zhangwei623@hotmail.com\n\n04 7 2021\n9 2021\n47 9 10.1111/jog.v47.9 33793384\n29 5 2021\n03 12 2020\n01 6 2021\n© 2021 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.\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\nA 31‐year‐old woman, who had been diagnosed with craniopharyngioma (CP) at the age of 13, suffered secondary hypopituitarism after two surgical resections of CP, receiving supplement of levothyroxine, cortisone, and sequential estrogen and progesterone because of primary amenorrhea. She managed to conceive after ovulation induction with human menopausal gonadotropin. Luteal phase deficiency (LPD) was found during the first trimester, as the progesterone stayed at a low level between 0.07 and 1.63 ng/ml within seven gestational weeks, followed by a gradual rise from 4.01 up to 34.70 ng/ml in the 11th week, which was mainly secreted by the placenta. Estrogen and progesterone were administered to the patient as luteal support until the 12th week, who succeeded in delivering a healthy baby at term. In conclusion, the patient with hypopituitarism who develops severe LPD during the early pregnancy may need luteal support until 12th week.\n\ncraniopharyngioma\ndydrogesterone\nhypopituitarism\ninfertility\nluteal phase deficiency\nsource-schema-version-number2.0\ncover-dateSeptember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.7 mode:remove_FC converted:22.09.2021\n==== Body\npmcIntroduction\n\nCraniopharyngioma (CP) is one of the rare embryonic malformations in the sellar and parasellar area, in which the quality of life is frequently impaired in the long‐term survivors due to the sequelae caused by the anatomical proximity of the tumor to the optic nerve/chiasma and hypothalamic‐pituitary axes.1 The endocrine dysfunction of pituitary impairment or loss and subsequent hypopituitarism usually occurs, especially after CP resection, with an incidence up to 78%–100%.2 Gonadotropin‐releasing hormone, luteinizing hormone (LH), follicle‐stimulating hormone (FSH), thyroid‐stimulating hormone (TSH), and adrenocorticotropic hormone all decrease significantly in hypopituitarism; therefore, a diagnose of any hormone deficiency and an appropriate replacement are within the disease‐specific considerations for CP.3 True, secondary hypogonadotropic hypogonadism (HH) always leads to amenorrhea and infertility. A few cases of successful pregnancy following CP resection have been reported.4 As the German cross‐sectional study reported in 2018, 79 patients were followed up for 15 years with regard to growth hormone substitution therapy, and only 11 (13.9%) got married and 2 (2.5%) conceived or had children.5 A recent review summarized six successful pregnancies after CP resection.6 However, there have been few reports on luteal phase deficiency (LPD) and luteal support during pregnancy after the ovulation induction in the CP patients.6 LPD is a condition of progesterone not sufficient enough to maintain a normal secretory endometrium and to allow for normal embryo implantation and growth.\n\nIn the current study, we presented a case of severe LPD during the first trimester in a female patient, who successfully conceived after ovulation induction at our hospital in 2018, and who, because of secondary HH following CP resection, succeeded in delivering a healthy term baby, thanks to the continuous luteal support beginning in the 12th gestational week.\n\nCase presentation\n\nA 31‐year‐old female, who complained of primary amenorrhea and 2‐year infertility after marriage, had been diagnosed with CP at the age of 13, for which she underwent surgical resection of CP in the department of neurosurgery before receiving supplement of levothyroxine and cortisone because of postoperative hypopituitarism. When she was 16 years old, she had a CP recurrence so that she underwent the second resection. She continued her postoperative treatment with levothyroxine and cortisone. She developed primary amenorrhea, initiating estrogen and progesterone supplement intermittently, from her age of 18 on. In 2016 when she was 29 years old, she got married. As recommended, she was put on sequential estrogen and progesterone supplement, withdrawing vaginal bleeding periodically.\n\nThe patient came to our hospital on January 16, 2018, complaining of 2‐year infertility. She was prescribed another laboratory test for sex hormone concentrations after treatment, its results showing FSH to be 1.21 mIU/ml; LH, 0.57 mIU/ml; estradiol (E2), 14 pg/ml; testosterone (T), 0.01 ng/m; TSH, 0.06 ng/ml; progesterone (P), 0.56 ng/ml; and anti‐muller hormone, 2.4 ng/ml. The image of Mode‐B ultrasonography (Aloka SSD 5500 ultrasonoscope, Aloka Inc.) demonstrated bilateral shrunken ovaries and normal uterus. Her karyotype was 46, XX, and her husband's semen examination was normal.\n\nThe patient signed the written consent, permitting us to use her medical records and results without mentioning her name in the current case report.\n\nThe patient was initially treated with Climen® (Complex packing Estradiol Valerate Tablets, Estradiol Valerate and Cyproterone Acetate Tablets, Climen®, Bayer, German), besides levothyroxine and cortisone. Because of her infertility, she accepted ovulation induction through a routine human menopausal gonadotropin (HMG) increasing program. She experienced two cycles of ovulation induction. In the first cycle, the dominant follicles developed when the total amount of HMG was up to 75 IU*45, from 75 to 150 IU/day, and then up to 225 IU/day, which was associated with Progynova® (Estradiol Valerate Tablets, Progynova®, Bayer, German) 1 mg/day. On April 17, 2018, human chorionic gonadotropin (hCG) at 10 000 IU was injected when two mature follicles (diameter: 18 mm) were observed in the ultrasonic image. Three days later after the injection of hCG, the luteal support started with combined Progynova® (1 mg/day) and Duphaston® (20 mg/day), which lasted only 10 days. Fourteen days later, serum β‐hCG was detected, which indicated pregnancy. Two days later, however, the patient suspended the luteal support, complaining of vaginal bleeding. Thus she ended with a biochemical pregnancy (Figure 1(a)).\n\nFigure 1 The dynamic ultrasonic image during the two cycles of ovulation induction with progynova and HMG injection; (a) Luteal support was withdrawn in the late luteal phase, with the first cycle ending in biochemical pregnancy; (b) Luteal support continued during the early pregnancy, with the second cycle ending in a delivery of a healthy baby. HMG, human menopausal gonadotropin\n\nIn the second cycle, a mature follicle appeared when the total amount of HMG reached 75 IU*45. The luteal support started from the third day after an injection of hCG as before. Thirteen days later, serum β‐hCG was detected to be 14.77 mIU/ml. Then Duphaston® was adjusted to be 30 mg/day, and Progynova® was added to 20 mg/day for the continuous luteal support until the 12th gestational week (Figure 1(b)). As a result, the patient succeeded in delivering a term healthy baby girl. In this case, the gestational age was recalculated according to the ovulation date of July 31, 2018; therefore, August 11, 2018 must have been the 27th day of the gestation.\n\nAs indicated in Figure 2, the levels of serum progesterone and β‐hCG were monitored regularly. During the first 8 weeks of gestation, the level of β‐hCG doubled every 3–4 days, until a peak was maintained at over 260 000 mIU/ml, which was consistent with the level of the normal dynamic β‐hCG during the gestation (Figure 2(a)). However, the level of serum progesterone was as low as 0.07–1.63 ng/ml in early pregnancy, which began to increase in the seventh gestational week, and reached a peak at 4.01–34.70 ng/ml around the 11th week (Figure 2(b)). Since Duffton®, an isomer of progesterone, having a strong affinity with the progesterone receptor, cannot be measured from serum, the level of progesterone truly indicated the ovarian luteal function in the early trimester. However, the level of the patient's serum progesterone was significantly low within 7 weeks of pregnancy, indicating that the patient had a deficient luteal function. Therefore, the supplementation of estrogen and progesterone was performed as luteal support until the 12th gestational week.\n\nFigure 2 The dynamic serum β‐ human chorionic gonadotropin (β‐hCG) and progesterone levels during the early trimester; (a) During the first 8 weeks of gestation, the β‐hCG levels doubled every 3–4 days, maintaining a peak of more than 260 000 mIU/ml after that; (b) The serum progesterone level was as low as 0.07 ng/mg in the early pregnancy, which began to increase from about 7 weeks of gestation, reaching a peak around the 11th week\n\nAfter all this, the patient entered a routine obstetric checkup before delivering a healthy baby girl.\n\nDiscussion\n\nIn the current case, we presented the fluctuating levels of serum estrogen, progesterone, and β‐hCG during the first trimester in a female patient, who successfully conceived after ovulation induction because of secondary HH following CP resection, which indicated severe LPD in the early pregnancy.\n\nIt was reported that the luteal and placental function switched in the seventh week of gestation, after which the placenta began secreting progesterone, and that the placenta completely replaced the corpus luteum between the 10th and 12th gestational week.7 In the current case, the level of the patient's serum progesterone elevated gradually, reaching a peak in the 11th gestational week, exactly the time when the placenta started to produce progesterone. Progestogen is known to be essential for embryo implantation and pregnancy maintenance. With the LH surge following ovulation, the luteal granulocytes were reported to secrete a large amount of estrogen and progesterone, thus regulating the endometrial receptivity and embryo implantation.8 The increasing amount of estrogen and progesterone is well known to be secreted by pregnant corpus luteum to maintain pregnancy. Clinically, LPD has been associated with abnormal estradiol (E2) and progesterone production, shortening the luteal phase,9, 10 and with pregnancy‐related disorders such as infertility and early pregnancy loss.11 It was reported that LPD with a short luteal phase duration, defined as less than 10 days, or with suboptimal luteal progesterone, defined as less than 5 ng/ml maximum progesterone, affected 8.9% and 8.4% of the ovulatory cycles, as the primary clinical and biochemical diagnostic criteria,12 thus leading to a decreased implantation rate or miscarriage.13 Both pilot cohorts of 119 and 360 women showed that serum progesterone <35 nmol/L (11 ng/ml) between 6 and 10 gestational weeks was prognostic of spontaneous miscarriage by the 16th week in women with threatened miscarriage in early pregnancy.14, 15 In the current case, therefore, the patient's biochemical pregnancy might have been related to the lack of timely luteal support. From the continuous dynamic monitoring of hormones in the second pregnancy, we learned that the patient had severe LPD. Thanks to the estrogen and progesterone therapy as luteal support during the early trimester, followed by a healthy placental function, the pregnancy was successfully maintained until the full term childbirth.\n\nThe relevant guidelines and consensuses have recommended that since LPD exists in ovulation‐induced pregnancy, routine luteal support should be administered in these patients, including progesterone supplementation and hCG injection.16, 17 Most of progesterone preparations, such as progesterone injection, progesterone capsules, and vaginal progesterone gel pills, can be measured from serum; consequently, the level of serum progesterone cannot accurately indicate the changes of endogenous progesterone. Therefore, it is difficult to measure the severity of LPD. However, dydrogesterone, an isomer of natural progesterone, can specifically be combined with the progesterone receptor, but cannot be detected from serum.18Therefore we examined the level of endogenous progesterone while the patient was on estradiol and progesterone supplement, which could uncover the severe LPD in this patient, thus developing a clinical therapy accordingly.\n\nIt is a complicated process to treat female infertility following hypogonadotropic amenorrhea, which includes the promotion of reproductive‐organ development through estrogen and progesterone replacement, and a HMG injection to induce ovulation. In the current case, we found that the patient developed a significantly low level of progesterone between 0.07 and 1.63 ng/ml within seven gestational weeks. After ovulation, luteum formation and progesterone secretion were achieved by regulating FSH and LH, especially pulsatile LH secretion. Long‐term LH deficiency due to impaired pituitary function could lead to loss of LH receptors on the granulocytes, abnormal secretion of granulocytes, and consequently complete loss of luteal function in early pregnancy; moreover, exogenous gonadotropins directly stimulated the ovaries to produce and secrete E2, thus resulting in negative feedback at the levels of the hypothalamus and pituitary.19 This could impair progesterone secretion from the corpus luteum.20 As previously reported, a shortened luteal phase could occur after ovulation induction with gonadotropins, which could be explained in terms of a low level of serum progesterone in luteal phase.22 Therefore, there exists biologic plausibility for the benefit of exogenous progesterone to luteal phase support in ovulation induction cycles with gonadotropin.\n\nIn summary, for the first time we reported the dynamic LH and progesterone level of severe LPD during the first trimester in a patient, who conceived successfully through hormone supplementation and ovulation induction with HMG despite her hypopituitarism following CP resection. It is still worth mentioning that adequate luteal hormone support should be provided until the 12th gestational week when the placental function returns to normal completely.\n\nConflict of interest\n\nThe authors declare no potential conflict of interest.\n\nAuthor contributions\n\nWei Zhang provided the treatments and collected the data regarding the patient. Hexia Xia was responsible for the manuscript, which was examined and confirmed by Wei Zhang.\n\nAcknowledgment\n\nThe authors would like to thank Professor Zhengliu Liang of Fudan University for his grateful support in English‐language polishment and revision.\n\nData availability statement\n\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nReferences\n\n1 MullerHL. Craniopharyngioma. Endocr Rev. 2014;35 :513–43.24467716\n2 WijnenM, van den Heuvel‐EibrinkMM, JanssenJAMJL, Catsman‐BerrevoetsCE, MichielsEMC, van Veelen‐VincentM, et al. Very long‐term sequelae of craniopharyngioma. Eur J Endocrinol. 2017;176 :755–67.28325825\n3 ThompsonCJ, CostelloRW, CrowleyRK. Management of hypothalamic disease in patients with craniopharyngioma. Clin Endocrinol. 2019;90 :506–16.\n4 HayashiM, TomobeK, HoshimotoK, OhkuraT. Successful pregnancy following gonadotropin therapy in a patient with hypogonadotropic hypogonadism resulting from craniopharyngioma. Int J Clin Pract. 2002;56 :149–51.11926704\n5 BoekhoffS, BoguszA, SterkenburgAS, EveslageM, MüllerHL. Long‐term effects of growth hormone replacement therapy in childhood‐onset: results of the German Craniopharyngioma Registry (HIT‐Endo). Eur J Endocrinol. 2018;179 :331–41.30139824\n6 SowithayasakulP, BoekhoffS, BisonB, MüllerHL. Pregnancies after childhood craniopharyngioma: results of KRANIOPHARYNGEOM 2000/2007 and review of the literature. Neuroendocrinology. 2021;111 :16–26.32074615\n7 CsapoAI, PulkkinenMO, RuttnerB, SauvageJP, WiestWG. The significance of the human corpus luteum in pregnancy maintenance. I. Preliminary studies. Am J Obstet Gynecol. 1972;112 :1061–7.5017636\n8 PatelB, ElgueroS, ThakoreS, DahoudW, BedaiwyM, MesianoS. Role of nuclear progesterone receptor isoforms in uterine pathophysiology. Hum Reprod Update. 2015;21 :155–73.25406186\n9 Practice Committee of the American Society for Reproductive Medicine . The clinical relevance of luteal phase deficiency: a committee opinion. Fertil Steril. 2012;98 :1112–7.22819186\n10 FritzMA. The modern infertility evaluation. Clin Obstet Gynecol. 2012;55 :692–705.22828101\n11 JonesHW. Luteal‐phase defect: the role of Georgeanna Seegar Jones. Fertil Steril. 2008;90 :e5–7.18001720\n12 SchliepKC, MumfordSL, HammoudAO, StanfordJB, KissellKA, SjaardaLA, et al. Luteal phase deficiency in regularly menstruating women: prevalence and overlap in identification based on clinical and biochemical diagnostic criteria. J Clin Endocrinol Metab. 2014;99 :E1007–14.24606080\n13 KolibianakisEM, DevroeyP. The luteal phase after ovarian stimulation. Reprod Biomed Online. 2002;5 :26–35.\n14 LekSM, KuCW, AllenJCJr, MalhotraR, TanNS, ØstbyeT, et al. Validation of serum progesterone <35 nmol/L as a predictor of miscarriage among women with threatened miscarriage. BMC Pregnancy Childbirth. 2017;17 :78–84.28264669\n15 KuCW, AllenJCJr, MalhotraR, ChongHC, TanNS, ØstbyeT, et al. How can we better predict the risk of spontaneous miscarriage among women experiencing threatened miscarriage? Gynecol Endocrinol. 2015;31 :647–51.26036717\n16 van der LindenM, BuckinghamK, FarquharC, KremerJA, MetwallyM. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev. 2015;2015 :CD009154.\n17 GreenKA, ZoltonJR, SchermerhornSM, LewisTD, HealyMW, TerryN, et al. Progesteroneluteal support after ovulation induction and intrauterineinsemination: an updated systematic review and metaanalysis. Fertil Steril. 2017;107 :924–33.28238492\n18 GriesingerG, TournayeH, MacklonN, PetragliaF, ArckP, BlockeelC, et al. Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction. Reprod Biomed Online. 2019;38 :249–59.30595525\n19 TavaniotouA, SmitzJ, BourgainC, DevroeyP. Ovulation induction disrupts luteal phase function. Ann N Y Acad Sci. 2001;943 :55–63.11594558\n20 RossmanithWG, LaughlinGA, MortolaJF, JohnsonML, VeldhuisJD, YenSS. Pulsatile cosecretion of estradiol and progesterone by the midluteal phase corpus luteum: temporal link to luteinizing hormone pulses. J Clin Endocrinol Metab. 1990;70 :990–5.2318954\n21 ErdemA, ErdemM, AtmacaS, GulerI. Impact of luteal phase support on pregnancy rates in intrauterine insemination cycles: a prospective randomized study. Fertil Steril. 2009;91 :2508–13.18692788\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1341-8076", "issue": "47(9)", "journal": "The journal of obstetrics and gynaecology research", "keywords": "craniopharyngioma; dydrogesterone; hypopituitarism; infertility; luteal phase deficiency", "medline_ta": "J Obstet Gynaecol Res", "mesh_terms": "D000328:Adult; D006063:Chorionic Gonadotropin; D003397:Craniopharyngioma; D005260:Female; D006801:Humans; D007018:Hypopituitarism; D007247:Infertility, Female; D008183:Luteal Phase; D010062:Ovulation Induction; D010911:Pituitary Neoplasms; D011247:Pregnancy; D011374:Progesterone", "nlm_unique_id": "9612761", "other_id": null, "pages": "3379-3384", "pmc": null, "pmid": "34219314", "pubdate": "2021-09", "publication_types": "D002363:Case Reports", "references": "18692788;28325825;32074615;22819186;28264669;28238492;25406186;18001720;22828101;30595525;30614015;11594558;2318954;24467716;26148507;11926704;24606080;26036717;30139824;12537779;5017636", "title": "Luteal phase deficiency during the early trimester in a case with secondary hypopituitarism following craniopharyngioma resection.", "title_normalized": "luteal phase deficiency during the early trimester in a case with secondary hypopituitarism following craniopharyngioma resection" }
[ { "companynumb": "CN-LUPIN PHARMACEUTICALS INC.-2021-23266", "fulfillexpeditecriteria": "2", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditio...
{ "abstract": "Fatal anaphylactic reactions to lignocaine are very rare. In this review of published reports, the main objective is to determine the characteristics of fatal allergic reactions to lignocaine and describe the forensic investigations of anaphylaxis related deaths. From 1957 to 2012, there were seven reports of single case and one report of 8 cases with sufficient information for review. Fatal anaphylactic reactions to lignocaine were generally characterised by fast onset of symptoms (within seconds to <30min of drug exposure) and rapid progression to cardiopulmonary arrest and death (23min to ∼1h). Features of cardiovascular, respiratory and neurological system involvements were often seen. Autopsy might reveal laryngeal oedema, pulmonary oedema, cerebral oedema, eosinophil infiltrates in many organs and other changes. Elevated blood tryptase level caused by mast cell degranulation was also used to diagnose acute anaphylaxis.", "affiliations": "Division of Clinical Pharmacology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China; Centre for Food and Drug Safety, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. Electronic address: tykchan@cuhk.edu.hk.", "authors": "Chan|Thomas Y K|TYK|", "chemical_list": "D008012:Lidocaine", "country": "Ireland", "delete": false, "doi": "10.1016/j.forsciint.2016.07.006", "fulltext": null, "fulltext_license": null, "issn_linking": "0379-0738", "issue": "266()", "journal": "Forensic science international", "keywords": "Anaphylaxis; Fatal outcome; Lignocaine", "medline_ta": "Forensic Sci Int", "mesh_terms": "D000707:Anaphylaxis; D001344:Autopsy; D006801:Humans; D008012:Lidocaine", "nlm_unique_id": "7902034", "other_id": null, "pages": "449-452", "pmc": null, "pmid": "27458994", "pubdate": "2016-09", "publication_types": "D016428:Journal Article; D016454:Review", "references": null, "title": "Fatal anaphylactic reactions to lignocaine.", "title_normalized": "fatal anaphylactic reactions to lignocaine" }
[ { "companynumb": "CN-DENTSPLY-2018SCDP000094", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROMORPHONE" }, "drugadditional": null, ...
{ "abstract": "Dementia with Lewy bodies (DLB) is a neurodegenerative condition that results in loss of mesopontine cholinergic neurons and sympathetic deinnervation. Although acetylcholinesterase inhibitors have been shown to improve cognitive and behavioral deficits in DLB, these patients may be more susceptible to bradyarrhythmic side effects from this class of drugs due to the autonomic insufficiency associated with the disease. We present a patient who experienced a dose-dependent, symptomatic sinus bradyarrhythmia with donepezil doses at and greater than 5 mg. Owing to underlying autonomic dysfunction, patients with DLB may be at increased risk of bradyarrhythmia resulting from treatment with acetylcholinesterase inhibitors.", "affiliations": "Department of Neurology, University of California, San Francisco Memory and Aging Center, San Francisco, CA, USA. mrosenbloom@memory.ucsf.edu", "authors": "Rosenbloom|Michael H|MH|;Finley|Richard|R|;Scheinman|Melvin M|MM|;Feldman|Mitchell D|MD|;Miller|Bruce L|BL|;Rabinovici|Gil D|GD|", "chemical_list": "D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil", "country": "United States", "delete": false, "doi": "10.1097/WAD.0b013e3181b7642b", "fulltext": null, "fulltext_license": null, "issn_linking": "0893-0341", "issue": "24(2)", "journal": "Alzheimer disease and associated disorders", "keywords": null, "medline_ta": "Alzheimer Dis Assoc Disord", "mesh_terms": "D000368:Aged; D001919:Bradycardia; D002800:Cholinesterase Inhibitors; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007189:Indans; D020961:Lewy Body Disease; D008297:Male; D010880:Piperidines", "nlm_unique_id": "8704771", "other_id": null, "pages": "209-11", "pmc": null, "pmid": "20505440", "pubdate": "2010", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "16163744;10390778;10466911;11385013;15616167;16237129;15246845;16805745;14753643;16858101", "title": "Donepezil-associated bradyarrhythmia in a patient with dementia with Lewy bodies (DLB).", "title_normalized": "donepezil associated bradyarrhythmia in a patient with dementia with lewy bodies dlb" }
[ { "companynumb": "US-RANBAXY-2013US-66464", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": null, ...
{ "abstract": "Natalizumab treatment of multiple sclerosis (MS) is associated with a risk of developing progressive multifocal leukoencephalopathy (PML), a rare opportunistic viral demyelinating disease caused by reactivation of John Cunningham virus (JCV). Herein, we report a case of a 40-year-old woman who developed refractory temporal lobe epilepsy; one year after recovery form Natalizumab-induced PML. Localisation related epilepsy, which may be refractory in nature, as in this case report, is a potential chronic disabling complication of PML. Epilepsy in this context, likely reflects grey matter involvement, which may then act as cortical epileptogenic zone.", "affiliations": "Department of Neurology, Galway University Hospital, Galway, Ireland. Electronic address: tarig1982@hotmail.com.;Department of Neurology, Galway University Hospital, Galway, Ireland.;Department of Neurology, Galway University Hospital, Galway, Ireland.", "authors": "Abkur|Tarig Mohammed|TM|;Kearney|Hugh|H|;Hennessy|Michael J|MJ|", "chemical_list": "D007155:Immunologic Factors; D000069442:Natalizumab", "country": "Netherlands", "delete": false, "doi": "10.1016/j.msard.2017.12.004", "fulltext": null, "fulltext_license": null, "issn_linking": "2211-0348", "issue": "20()", "journal": "Multiple sclerosis and related disorders", "keywords": "Multiple sclerosis; Natalizumab; PML; Refractory epilepsy", "medline_ta": "Mult Scler Relat Disord", "mesh_terms": "D000328:Adult; D001921:Brain; D003937:Diagnosis, Differential; D000069279:Drug Resistant Epilepsy; D004833:Epilepsy, Temporal Lobe; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007968:Leukoencephalopathy, Progressive Multifocal; D009103:Multiple Sclerosis; D000069442:Natalizumab", "nlm_unique_id": "101580247", "other_id": null, "pages": "1-2", "pmc": null, "pmid": "29253743", "pubdate": "2018-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Refractory epilepsy following natalizumab associated PML.", "title_normalized": "refractory epilepsy following natalizumab associated pml" }
[ { "companynumb": "IE-BIOGEN-2012BI053755", "fulfillexpeditecriteria": "1", "occurcountry": "IE", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "EVENING PRIMROSE OIL\\HERBALS\\TOCOPHEROL" }, "...
{ "abstract": "To examine the effectiveness of pegylated liposomal doxorubicin (PLD) maintenance therapy (intravenous administration at dose 40 mg/m2 on day 1, repeated every 4 weeks) after first-line salvage chemotherapy for platinum-sensitive recurrent epithelial ovarian cancer.\n\n\n\nThis retrospective cohort study examined women with a first recurrence of platinum-sensitive epithelial ovarian cancer diagnosed between 2005 and 2015. Eligible cases had PLD maintenance following the first-line salvage chemotherapy (n = 28). Outcomes of interest included adverse events related to PLD maintenance therapy and survival outcome after the first recurrence.\n\n\n\nThe median number of PLD maintenance cycles was 7.5 (range 2-26), and 11 (40%) women received ≥ 12 cycles. The median cumulative dose of PLD was 432.5 mg/m2 (range 120-1200 mg/m2). No women developed cardiotoxicity or secondary malignancies. There were 16 (57%) women who developed any grade of adverse events, including 3 (11%) women who developed grade 3 adverse events. There were no grade 4 adverse events. The most common adverse event was mucositis (n = 7, 25%). Dose reduction due to adverse events occurred in 14 (50%) women including 3 (11%) women with discontinuation due to toxicity. Median progression-free survival and overall survival after the initiation of PLD maintenance was 14.5 months (2-year rate 21.1%) and 51.2 months (5-year rate 43.4%), respectively.\n\n\n\nOur study suggests that PLD maintenance therapy for platinum-sensitive recurrent ovarian cancer is relatively well tolerated with the use of dose reduction to manage toxicity. Our study suggests that PLD maintenance therapy may be effective for women with platinum-sensitive recurrent epithelial ovarian cancer.", "affiliations": "Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, 2020 Zonal Avenue, IRD520, Los Angeles, CA, 90089, USA.;Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, 2020 Zonal Avenue, IRD520, Los Angeles, CA, 90089, USA.;Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, 2020 Zonal Avenue, IRD520, Los Angeles, CA, 90089, USA.;Division of Medical Oncology, Department of Medicine, New York University, New York, NY, USA.;Section of Hematology/Oncology, Department of Medicine, Louisiana State University, New Orleans, LA, USA.;Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, 2020 Zonal Avenue, IRD520, Los Angeles, CA, 90089, USA.;Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, 2020 Zonal Avenue, IRD520, Los Angeles, CA, 90089, USA. koji.matsuo@med.usc.edu.", "authors": "Blake|Erin A|EA|;Bradley|Chrystal A|CA|;Mostofizadeh|Sayedamin|S|;Muggia|Franco M|FM|;Garcia|Agustin A|AA|;Roman|Lynda D|LD|;Matsuo|Koji|K|0000-0002-6232-8701", "chemical_list": "D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D010984:Platinum; D004317:Doxorubicin", "country": "Germany", "delete": false, "doi": "10.1007/s00404-019-05104-0", "fulltext": null, "fulltext_license": null, "issn_linking": "0932-0067", "issue": "299(6)", "journal": "Archives of gynecology and obstetrics", "keywords": "Liposomal doxorubicin; Maintenance; Ovarian neoplasms; Platinum sensitive; Recurrence; Survival", "medline_ta": "Arch Gynecol Obstet", "mesh_terms": "D000903:Antibiotics, Antineoplastic; D000077216:Carcinoma, Ovarian Epithelial; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010984:Platinum; D011092:Polyethylene Glycols; D012189:Retrospective Studies", "nlm_unique_id": "8710213", "other_id": null, "pages": "1641-1649", "pmc": null, "pmid": "30824986", "pubdate": "2019-06", "publication_types": "D016428:Journal Article", "references": "28916367;28976446;27717299;23813336;11454878;27025186;22203755;22529265;17301073;22836511;23485623;27049967;20498395;23263923;17947786;21859991;19581533;23835762;28438473;22204724;20815774;16809933;20802015;26271155;28754483", "title": "Efficacy of pegylated liposomal doxorubicin maintenance therapy in platinum-sensitive recurrent epithelial ovarian cancer: a retrospective study.", "title_normalized": "efficacy of pegylated liposomal doxorubicin maintenance therapy in platinum sensitive recurrent epithelial ovarian cancer a retrospective study" }
[ { "companynumb": "US-JNJFOC-20190629789", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, ...
{ "abstract": "The study aimed to determine the characteristics and circumstances of cases sudden or unnatural death (n = 61) with evidence of pathological hoarding, their major organ pathology and toxicology. The mean age was 65·8 yrs (a mean of 16.1 years of potential life lost), 62·3% were male, and 28·2% were obese. 95·1% lived alone, and 96·7% died in their residence, with no medical intervention. In all cases severe squalor and extensive hoarding were noted. The direct cause of death was attributed to disease in 75·4%, heart disease being a significant factor in 52·5%. Accidents causing death directly related to hoarding occurred in two cases. Autopsy revealed extensive pathology: severe coronary artery narrowing (42·4%), myocardial replacement fibrosis (44·1%), emphysema (39·0%), nephrosclerosis (46·6%). Signs of hypothermia were present in 14·8%, and diabetes was diagnosed in 21·3%. The most commonly detected substance was alcohol (32·1%). Medications for heart disease (5·4%) or diabetes (7·1%) were rare. The overall clinical picture was of an isolated group, with a heavy burden of physical disease and, in all probability, a high level of psychiatric disorders, who died alone in their homes.", "affiliations": "National Drug & Alcohol Research Centre, University of New South Wales, Australia. Electronic address: s.darke@unsw.edu.au.;National Drug & Alcohol Research Centre, University of New South Wales, Australia; Sydney Medical School, University of Sydney, NSW, Australia.", "authors": "Darke|Shane|S|;Duflou|Johan|J|", "chemical_list": "D000067401:Blood Alcohol Content", "country": "England", "delete": false, "doi": "10.1016/j.jflm.2016.11.004", "fulltext": null, "fulltext_license": null, "issn_linking": "1752-928X", "issue": "45()", "journal": "Journal of forensic and legal medicine", "keywords": "Circumstances; Demographics; Hoarding; Pathology; Toxicology", "medline_ta": "J Forensic Leg Med", "mesh_terms": "D000061:Accidents, Home; D000368:Aged; D001315:Australia; D000067401:Blood Alcohol Content; D002423:Cause of Death; D003645:Death, Sudden; D003920:Diabetes Mellitus; D004646:Emphysema; D005260:Female; D049429:Forensic Pathology; D005555:Forensic Psychiatry; D006331:Heart Diseases; D000067836:Hoarding Disorder; D006801:Humans; D007035:Hypothermia; D007674:Kidney Diseases; D008297:Male; D009765:Obesity; D012934:Social Isolation", "nlm_unique_id": "101300022", "other_id": null, "pages": "36-40", "pmc": null, "pmid": "27987415", "pubdate": "2017-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Characteristics, circumstances and pathology of sudden or unnatural deaths of cases with evidence of pathological hoarding.", "title_normalized": "characteristics circumstances and pathology of sudden or unnatural deaths of cases with evidence of pathological hoarding" }
[ { "companynumb": "AU-INDIVIOR LIMITED-INDV-097610-2016", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE" }, "drugadditional"...
{ "abstract": "Fentanyl is a synthetic opioid with analgesic potency 75-100 times higher than that of morphine, and its analgesic effect is used for pain treatment, mostly in cancer patients. Using fentanyl patches may reduce misuse potential due to the transdermal route of administration, long-acting action, sustained release delivery property, and maintenance of steady-state serum concentration of the drug. Although there have been reports of transdermal fentanyl patches (TFPs) misuse via transmucosal, trans-nasal, intravenous, and oral routes of administration, fentanyl use disorder via the transdermal route is very rare.\nIn this case report, we present a patient with a history of substance use disorder who developed fentanyl use disorder via transdermal route after using unprescribed TFP in order to quit opium gum. The CARE guidance was followed in the preparation of this case report.\nThe risk of use disorder may be higher, especially in individuals with a history of substance use disorders. This risk should be taken into account when clinicians prescribe this medication.", "affiliations": "Alcohol and Substance Treatment Center, Moodist Hospital, Istanbul, Turkey.;Alcohol and Substance Treatment Center, Moodist Hospital, Istanbul, Turkey.;Alcohol and Substance Treatment Center, Moodist Hospital, Istanbul, Turkey.", "authors": "Guliyev|Cavid|C|https://orcid.org/0000-0002-1398-8164;Tuna|Zehra Olcay|ZO|https://orcid.org/0000-0002-7076-4394;Ögel|Kültegin|K|https://orcid.org/0000-0002-6945-0961", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1080/10550887.2021.1971940", "fulltext": null, "fulltext_license": null, "issn_linking": "1055-0887", "issue": null, "journal": "Journal of addictive diseases", "keywords": "Fentanyl; case report; opioid; substance use disorder; transdermal patch", "medline_ta": "J Addict Dis", "mesh_terms": null, "nlm_unique_id": "9107051", "other_id": null, "pages": "1-6", "pmc": null, "pmid": "34445944", "pubdate": "2021-08-27", "publication_types": "D016428:Journal Article", "references": null, "title": "Fentanyl use disorder characterized by unprescribed use of transdermal patches: a case report.", "title_normalized": "fentanyl use disorder characterized by unprescribed use of transdermal patches a case report" }
[ { "companynumb": "TR-ALVOGEN-2021-ALVOGEN-117585", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, ...
{ "abstract": "A ring-shaped ulcer was observed in the ileum of a 70-year-old male patient with capsule endoscopy of the small intestine performed for detailed investigation of black stools and iron deficiency anemia. Non-steroidal anti-inflammatory drugs (NSAIDs) use in patch form was considered as the etiology. The NSAIDs patches were discontinued, and protective therapy for small intestinal mucosa was initiated. The anemia improved;however, ileus originating from the site of the ulcer required surgical resection. The resected specimen showed no specific pathological findings. Based on the clinical findings, the patient was diagnosed with NSAIDs-induced small intestinal ulcer. The use of NSAIDs patches should be considered as a potential cause of injury to gastrointestinal mucosa.", "affiliations": "Department of Gastroenterology, Kagawa Prefectural Central Hospital.;Department of Gastroenterology, Kagawa Prefectural Central Hospital.;Department of Gastroenterology, Kagawa Prefectural Central Hospital.;Department of Gastroenterology, Kagawa Prefectural Central Hospital.;Department of Pathology, Kagawa Prefectural Central Hospital.", "authors": "Aoyama|Yuki|Y|;Takahashi|Sakuma|S|;Inaba|Tomoki|T|;Izumikawa|Koichi|K|;Nakamura|Satoko|S|", "chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal", "country": "Japan", "delete": false, "doi": "10.11405/nisshoshi.116.145", "fulltext": null, "fulltext_license": null, "issn_linking": "0446-6586", "issue": "116(2)", "journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology", "keywords": null, "medline_ta": "Nihon Shokakibyo Gakkai Zasshi", "mesh_terms": "D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D053704:Capsule Endoscopy; D006801:Humans; D007410:Intestinal Diseases; D007413:Intestinal Mucosa; D007421:Intestine, Small; D008297:Male; D014456:Ulcer", "nlm_unique_id": "2984683R", "other_id": null, "pages": "145-152", "pmc": null, "pmid": "30745552", "pubdate": "2019", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A case of small intestinal ulcer caused by non-steroidal anti-inflammatory drugs patch.", "title_normalized": "a case of small intestinal ulcer caused by non steroidal anti inflammatory drugs patch" }
[ { "companynumb": "JP-TEVA-2019-JP-1058543", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SITAGLIPTIN" }, "drugadditional": "3", ...
{ "abstract": "I present a case of an adenocarcinoma in a retrorectal cyst in a 63-year-old female with a prior history of a congenital cyst excised as a newborn. The patient had a resection with positive margins, followed by chemotherapy and radiotherapy at progression. Her disease did not respond to chemotherapy or radiotherapy and she died with systemic manifestations related to her disease 28 months after diagnosis.", "affiliations": "Department of Radiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.", "authors": "Ujaimi|Reem|R|0000-0002-2386-2493", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/IMCRJ.S294090", "fulltext": "\n==== Front\nInt Med Case Rep J\nInt Med Case Rep J\nimcrj\nimcrj\nInternational Medical Case Reports Journal\n1179-142X\nDove\n\n294090\n10.2147/IMCRJ.S294090\nCase Report\nAdenocarcinoma in a Recurrent Retrorectal Cyst: A Case Report\nUjaimi\nUjaimi\nhttp://orcid.org/0000-0002-2386-2493\nUjaimi Reem 1\n1 Department of Radiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia\nCorrespondence: Reem Ujaimi King Abdulaziz University, Jeddah, Saudi ArabiaTel +966 555608014 Email rkujaimi@kau.edu.sa\n07 4 2021\n2021\n14 223228\n14 12 2020\n11 3 2021\n© 2021 Ujaimi.\n2021\nUjaimi.\nhttps://creativecommons.org/licenses/by-nc/3.0/ 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).\nAbstract\n\nI present a case of an adenocarcinoma in a retrorectal cyst in a 63-year-old female with a prior history of a congenital cyst excised as a newborn. The patient had a resection with positive margins, followed by chemotherapy and radiotherapy at progression. Her disease did not respond to chemotherapy or radiotherapy and she died with systemic manifestations related to her disease 28 months after diagnosis.\n\nKeywords\n\nadenocarcinoma\nrecurrent\nretrorectal cyst\ntailgut cyst\n==== Body\nBackground\n\nRetrorectal cysts, also known as tailgut cysts or retrorectal cystic hamartomas, are developmental cysts that arise from the residue of the tailgut of the intestine during the embryonic period,1,2 and are located in the retrorectal space.3 The retrorectal space is found behind the rectum, in front of the sacrum, with the ureters, iliac blood vessels, sacral nerves, and lateral stalks of the rectum serving as its lateral walls, which makes both the diagnosis and surgical approaches used to address these lesions difficult.4 These tumors are extremely rare, with hospital admissions data estimating their incidence at 1 in 40,000 to 60,000 admissions.5 They have a female predominance, as they are five times more common in females than in males.6,7 These cysts present at any age, but are more common between the ages of 30 and 60 years.6 They are usually asymptomatic and might be identified as an incidental finding on examination, but they may present as a mass in the perianal area,8 and may be associated with changes in bowel movements or perineal pain.9 Affected patients may also present with varied symptoms that can mimic other proctological disorders.10 In the literature, cases presenting with lower back pain have been reported.11 Tailgut cysts are usually benign, but can undergo malignant transformation.12 Seven percent (7%) of those cysts undergo malignant transformation, with adenocarcinoma being one of the most common histological variants.12,13\n\nDiagnosis is usually performed using computed tomography (CT), magnetic resonance imaging (MRI), biochemical analysis, and histological findings following excision.1 Radiological tests are essential in differentiating between benign and malignant lesions; however, a definitive diagnosis is supported by surgical and histological findings.12 Neither fine-needle aspirate nor ultrasound-guided biopsy is recommended, as these procedures may lead to complications that include the formation of fistulae and may lead to the potential spread of malignant cells, if present.9 Elevated tumor markers, including carcinoembryonic antigen (CEA), at the time of diagnosis are useful in assessing the possibility of malignant transformation.2\n\nComplete resection with negative margins is usually the treatment of choice.4 Complete excision usually leads to a favorable prognosis. Excision also prevents recurrent drainage.1,9,10 Where there is malignant transformation, resection and chemotherapy are usually recommended. Other supplemental therapy includes adjuvant radiotherapy.12 We present a case of a retrorectal cyst in a 63-year-old female with a prior cyst excised at birth. The deceased patient’s son provided his informed consent to write and publish this case report. Institutional ethical approval is not required for publication of case reports at our institution.\n\nCase Presentation\n\nThis is a 63-year-old female who was referred to the radiotherapy clinic at our tertiary hospital in December 2016, for consideration of adjuvant radiotherapy for a resected retrorectal adenocarcinoma with a positive margin.\n\nThe patient provided a remote history of a congenital cyst that had been surgically removed when she was a newborn. Her past surgical history was also significant for a hysterectomy and unilateral oophorectomy, which were performed to address a fibroid and benign ovarian cyst more than 17 years prior to this presentation. Her past medical history was significant for diabetes, high blood pressure, high cholesterol and acid reflux. Her current presentation was that of a recent, progressive gluteal swelling associated with chronic lower back pain, which has progressed in the few months prior to presentation. Upon presentation, a cystic mass was felt in the gluteal area and needle aspiration was attempted. Over the following couple of weeks, the cystic fluid reaccumulated and she apparently developed multiple abscesses and fistulas.\n\nThe patient underwent surgical resection of the cystic mass through a posterior approach and recovered well from her surgery. Her back pain had completely resolved. At her first visit to our tertiary center, the only finding in her exam was that of thickening in the gluteal area scar.\n\nLaboratory Investigations\n\nHer initial blood work revealed normal blood counts, and normal liver and renal profiles. CEA and CA 19–9 levels were not obtained at her initial presentation. The initial fluid aspirate was negative for malignancy. The final pathology of the resected mass was positive for mucinous adenocarcinoma arising within a cystic hamartoma. A review of the slides at another private tertiary hospital revealed a mucinous adenocarcinoma; primary ovarian or cervical primaries were to be excluded.\n\nA review of the slides was performed at our hospital. The microscopic description was that of an invasive mucinous adenocarcinoma, as evident throughout the provided tissue samples. The mucin had extravasated to the surrounding tissue and elicited a histiocytic reaction (Figure 1). The tumor was seen at the margin and reached the skin’s surface with ulceration. Features associated with teratoma, epidermoid, duplication, or tailgut cyst were not seen.Figure 1 (A) Histopathologic photo with 20× magnification showing malignant cells floating in mucin. (B) Histopathologic photo with 4× magnification showing extravasated mucin with histiocytic reaction.\n\nImmunohistochemistry was positive for CK7 (diffuse, strong cytoplasmic), CEA (diffuse, moderately strong, cytoplasmic), and CDX2 (focally strong, nuclear), and negative for 4CK 20, P 16, GCDFP, ER, and p63.\n\nRadiological Investigations\n\nAt presentation, an MRI scan of the pelvis was obtained and revealed a large, multiloculated cyst in the ischiorectal fossa, with a clear fat plane between the cyst and the rectum. No other abnormality was noted on MRI. The uterus and ovaries could not be visualized on MRI. Unfortunately, we could not retrieve the first MRI image from the other hospital.\n\nStaging CT scan of the chest, abdomen, and pelvis, as well as a postoperative MRI of the pelvis, were obtained after referral to our hospital. The CT of the chest was unremarkable for any metastatic disease. The CT of the abdomen revealed an ill-defined, solid mass at the right adnexa measuring 3.2 cm that could represent ovarian metastases or a metastatic lymph node; an inguinal lymph node measuring 1.6 cm was also noted on the left side (Figure 2). As a result, an ultrasound of the pelvis was obtained and revealed a solid mass arising from the right adnexa, but no further characterization was possible. An MRI scan of the pelvis revealed fluid collection with high signal intensity and no enhancement on postcontrast images at the presacral region, likely representing a hematoma at the surgical area. The surgical bed demonstrated diffuse, soft-tissue edema and muscular edema, primarily involving the gluteus muscle associated with enhancement. There was circumferential wall thickening involving the rectum. The right ovary was well visualized and appeared unremarkable. There was a left inguinal lymph node measuring 1.4 cm, most likely representing a metastatic lymph node.Figure 2 Axial cut of a computed tomography scan of the pelvis showing a left inguinal lymph node (white arrow).\n\nSince the question arose of whether a gynecological or gastrointestinal primary mass was present, the patient was referred to a gastroenterologist and a gynecologist. The patient underwent a colonoscopy, which did not reveal any perianal, rectal, or colonic masses. As the MRI did not reveal any abnormality in the ovary and given that the patient was examined by a gynecologist who did not find any abnormalities, a gynecological malignancy had also been ruled out.\n\nManagement and Clinical Course\n\nThe patient was discussed at the tumor board. Given the remote history of the cyst and the absence of a clear primary gastrointestinal mass, the potential diagnosis of an adenocarcinoma arising in a recurrent cyst was thought to be likely, with the main differential being an occult adenocarcinoma of the rectum. The decision was made to proceed with chemotherapy. The patient received five cycles of XELOX chemotherapy (capecitabine and oxaliplatin), starting 6 weeks after her surgery.\n\nOnce the patient completed her chemotherapy course, a repeat staging work-up was obtained. The CT of the abdomen and pelvis revealed heterogeneous soft tissue thickening of the rectum, and clinical examination and proctoscopy/biopsy to exclude recurrent disease in the rectum was recommended. A mild reduction in the size of the metastatic left inguinal lymph node was noted. The chest CT scan did not reveal any mediastinal or pulmonary metastases. The patient was again discussed at the tumor board and the recommendation was to have her assessed by a surgical oncologist, and to repeat the colonoscopy to exclude rectal or colonic disease. The repeat colonoscopy did not reveal any masses, and a few polyps were removed and were benign. The patient was seen by the surgical oncologist and thickening at the sacrum in proximity to the previous resection was again noted, as was the inguinal lymph node. Fine-needle aspiration of the inguinal lymph node was obtained and was positive for metastatic adenocarcinoma. A CT-guided biopsy of the thickened sacral area was also obtained and revealed adenocarcinoma (Figure 3).Figure 3 Axial cut of a computed tomography scan of the pelvis at recurrence showing thickened sacral area (Black dot).\n\nFour months after the completion of chemotherapy, a repeat MRI scan was done. It showed a large, speculated, intense, enhancing, soft-tissue mass at the surgical bed. It measured 9 cm×5.3 cm (Figure 4). The tumor was inseparable from the coccyx and was associated with multiple enlarged mesorectal lymph nodes measuring up to 5 mm. There was a large, pelvic lymph node on the left-side wall. Multiple foci of cystic components were also identified adjacent to the tumor. The rectum was unremarkable. In conclusion, there was significant Interval progression at the surgical bed of the tumor, in keeping with recurrence. The patient was again discussed at the tumor board, and the surgical oncologist advised that she had unresectable disease. The patient with then referred to the radiation oncology service for palliative radiotherapy, as she started complaining of pain at this time.Figure 4 Speculated, intense, enhancing, soft-tissue mass at the surgical bed on MRI (sagittal, T1 with contrast).\n\nIn October 2017 (10 months after diagnosis), the patient completed a long course of high-dose palliative radiation therapy. She received a dose of 45 Gy in 28 fractions to the entire pelvis and inguinal area, with concomitant 58.8 Gy delivered to the sacral mass and the enlarged inguinal lymph node (Figure 5).Figure 5 Radiotherapy dose distribution with high dose areas in green.\n\nIn January 2018, the patient repeated the MRI scan, and no significant interval change was noted. She continued to suffer from moderate to severe pain and was referred to the pain clinic, as her pain was not responding to regular narcotics. A superior hypogastric nerve block was administered to her.\n\nA repeat MRI in March 2018 revealed stable disease in the pelvis; however, now in the field of view of this MRI scan were new bone lesions at the level of the lumbar spine. In April 2018, a repeat CT scan of the abdomen and pelvis, as well as a CT scan of the chest revealed no distant metastatic disease apart from the bone metastasis. At this point, the patient’s clinical presentation included non-healing ulcers in the sacral area with skin nodules. Her CEA measured 21.9 and her carcinoembryonic antigen (CA)19.9 measured 4767. She was re challenged with maintenance capecitabine. Figure 6 reflects the change in her CEA level over the clinical course.Figure 6 Changes in levels of CEA and CA 19–9 over the clinical course.\n\nThe patient was last seen at our hospital in December 2018. At that time, she demonstrated major clinical progression and had a poor performance status. Her chemotherapy was stopped, as she had refused further treatment apart from pain and symptom management.\n\nThe patient was last seen in our hospital in December 2018. According to her family, she died on March 26, 2019 (28 months after her diagnosis). She had suffered from severe anemia and went into a coma secondary to a major stroke, potentially having suffered from disseminated intravascular coagulation.\n\nDiscussion\n\nI present the case of an elderly female patient with longstanding back pain and a <1-year history of gluteal swelling that was initially aspirated. Later, the cyst was excised, but with positive margins, and adjuvant chemotherapy was provided. Unfortunately, the patient’s condition advanced and she received radiotherapy and chemotherapy, as her disease was not resectable She succumbed to death due to the systemic effects associated with her disease a few months after completing second-line chemotherapy.\n\nThe challenges of diagnosing a retrorectal cyst include its nonspecific symptoms. Although our case had a short history of gluteal swelling, her 10–15-year history of back pain was relieved following excision of the cyst. Since symptom relief usually follows surgical excision,14 it is possible that the cyst had been there prior to the gluteal swelling. Our case had a cyst that was excised at birth, but in the absence of definitive information about the congenital cyst, it is challenging to know whether this is a recurrent cyst. It is possible that our patient experienced cyst recurrence, as recurrence has been reported up to 58 years following excision.15\n\nConflicting information exists about the use of fine-needle aspirates to manage retrorectal cysts.4 For this reason, CT or MRI imaging is recommended for their diagnosis. Aspiration and biopsy, which are the most accurate diagnostic methods, can only be used after all differential diagnoses have been carefully considered, or when managing cysts where the preoperative finding of malignant degeneration may affect management.2 Furthermore, where aspiration has been performed and the cysts has been deemed operable, it is important to resect the biopsy tract during surgery.10 Cyst aspiration in this patient possibly led to the formation of fistulas and abscesses, and potentially resulted in the spread of malignant cells.\n\nAlthough retrorectal cysts usually have a good prognosis, this is dependent on timely diagnosis and appropriate management. As our patient had multiple aspirations of what was thought to be a benign cyst and given that the excision was not complete (as based on the positive margin and questionable residual noted on images), this may or may not have affected her outcome, as she presented with lymph node metastasis soon after. Due to the rarity of her disease, it is not clear which adjuvant treatment is optimal and should be instituted; as such, multidisciplinary team management of the disease is of paramount importance. The treatment of choice for retrorectal cysts with adenocarcinomatous transformation is surgery followed often times by chemotherapy,12 which our patient received. This can also be combined with radiotherapy, if needed, to sterilize the site of origin of the tumor.16 Because of the rarity of the disease, no evidence is available to dictate the use of adjuvant chemotherapy or radiotherapy, however one modality or the combination is usually offered similar to the management of rectal cancer.17\n\nIn conclusion, tailgut cysts should be considered as a potential diagnosis for any presacral cysts that are present at any age ranging from childbirth to the 8th decade of life.18 An exhaustive workup is essential to establish the diagnosis, exclude the involvement of other pelvic organs, and initiate appropriate, individualized patient management. This requires a high index of suspicion and timely referral of patients to tertiary centers. Additionally, future research should focus on identifying feasible schedules and the investigation requirements for the follow up of asymptomatic patients following the excision of tailgut cysts.\n\nAcknowledgments\n\nThe author acknowledges Dr Salwa Baksh, MD, FRCPC, Dr Nora Trabulsi, MD, FRCSC, and Dr Marwan Al-Hajeili, MD.\n\nDisclosure\n\nThe author reports no conflicts of interest for this work.\n==== Refs\nReferences\n\n1. Wang M, Liu G, Mu Y, He H, Wang S, Li J. Tailgut cyst with adenocarcinoma transition: a rare case report. Medicine (Baltimore). 2020;99 (27 ):e20941. doi:10.1097/MD.0000000000020941 32629697\n2. Zhao XR, Gao C, Zhang Y, Yu YH. The malignant transformation of retrorectal cystic hamartomas with blood irregular antibodies positive: a case report. Medicine (Baltimore). 2015;94 (49 ):e2253. doi:10.1097/MD.0000000000002253 26656372\n3. de Castro Gouveia G, Okada LY, Paes BP, Moura TM, da Conceição Júnior AH, Pinheiro RN. Tailgut cyst: from differential diagnosis to surgical resection-case report and literature review. J Surg Case Rep. 2020;2020 (7 ):rjaa205. doi:10.1093/jscr/rjaa205 32728413\n4. Chand P, Bhatnagar S, Kumar A, Rani N, Rare A. Presentation of lower back swelling as tailgut cyst. Niger J Surg. 2016;22 (2 ):134–137. doi:10.4103/1117-6806.189023 27843281\n5. Jao SW, Beart RW Jr, Spencer RJ, Reiman HM, Ilstrup DM. Retrorectal tumors. Mayo Clinic experience, 1960–1979. Dis Colon Rectum. 1985;28 (9 ):644–652. doi:10.1007/BF02553440 2996861\n6. Haydar M, Griepentrog K. Tailgut cyst: a case report and literature review. Int J Surg Case Rep. 2015;10 :166–168. doi:10.1016/j.ijscr.2015.03.031 25853843\n7. Sloan M, Fantus RJ, Paner GP, Faris S. Perineal dermoid cyst in a young male. Urol Case Rep. 2020;33 :101358. doi:10.1016/j.eucr.2020.101358 33102057\n8. Al-Shoura R, Malaekah H, Al Bassam W. Giant retrorectal epidermoid cyst masquerading as a perianal swelling. Case Rep Surg. 2020;2020 :5750382. doi:10.1155/2020/5750382 32257498\n9. Yalav O, Topal U, Eray İC, Deveci MA, Gencel E, Rencuzogullari A. Retrorectal tumor: a single-center 10-years’ experience. Ann Surg Treat Res. 2020;99 (2 ):110–117. doi:10.4174/astr.2020.99.2.110 32802816\n10. Martins P, Canotilho R, Peyroteo M, Afonso M, Moreira A, de Sousa A. Tailgut cyst adenocarcinoma. Autops Case Rep. 2019;10 (1 ):e2019115. doi:10.4322/acr.2019.115 32039057\n11. Joyce EA, Kavanagh DO, Winter DC. A rare cause of low back pain: report of a tailgut cyst. Case Rep Med. 2012;2012 :623142. doi:10.1155/2012/623142 22431937\n12. Liang F, Li J, Yu K, Zhang K, Liu T, Li J. Tailgut cysts with malignant transformation: features, diagnosis, and treatment. Med Sci Monit. 2020;26 :e919803. doi:10.12659/MSM.919803 31926113\n13. Almeida Costa NA, Rio G. Adenocarcinoma within a tailgut cyst. BMJ Case Rep. 2018;bcr2018226107 . doi:10.1136/bcr-2018-226107\n14. Au E, Anderson O, Morgan B, Alarcon L, George M. Tailgut cysts: report of two cases. Int J Colorectal Dis. 2008;24 (3 ):345–350. doi:10.1007/s00384-008-0598-6 18931850\n15. Kearney D, Valente M. Excision of a recurrent retrorectal tailgut cyst after 58 years. BMJ Case Rep. 2019;12 (5 ):e230286. doi:10.1136/bcr-2019-230286\n16. Chhabra S, Wise S, Maloney-Patel N, Rezac C, Poplin E. Adenocarcinoma associated with tail gut cyst. J Gastrointest Oncol. 2013;4 (1 ):97–100. doi:10.3978/j.issn.2078-6891.2012.043 23450681\n17. Kaistha S, Gangavatiker R, Harsoda R, Kinra P. A case of adenocarcinoma in a tail gut cyst and review of literature. Med J Armed Forces India. 2018;74 (4 ):390–393. doi:10.1016/j.mjafi.2017.06.002 30449930\n18. Alhasani AA, Shamaon RS. Tailgut cyst: a case report in a female neonate. MOJ Surg. 2015;2 (2 ):44–45. doi:10.15406/mojs.2015.02.00016\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1179-142X", "issue": "14()", "journal": "International medical case reports journal", "keywords": "adenocarcinoma; recurrent; retrorectal cyst; tailgut cyst", "medline_ta": "Int Med Case Rep J", "mesh_terms": null, "nlm_unique_id": "101566269", "other_id": null, "pages": "223-228", "pmc": null, "pmid": "33854384", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "2996861;31926113;26656372;25853843;32629697;30108121;32039057;32257498;27843281;33102057;30449930;32728413;22431937;23450681;18931850;32802816;31092499", "title": "Adenocarcinoma in a Recurrent Retrorectal Cyst: A Case Report.", "title_normalized": "adenocarcinoma in a recurrent retrorectal cyst a case report" }
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{ "abstract": "We illustrate 2 cases of pneumonia associated with Bordetella pertussis infection in 72-year-old and 61-year-old patients with cancer receiving myelosuppressive therapy after hematopoietic stem cell transplantation. Bacterial infections are a significant cause of morbidity and mortality in patients with cancer, and those receiving hematopoietic stem cell transplant, solid organ transplant, or myelosuppressive therapy are at increased risk. The infection was detected and the 2 patients had good outcomes following azithromycin treatment. Pertussis, also known as whooping cough, is a contagious respiratory illness that has become a public health challenge due to decreased immunity of the pertussis vaccine. Therefore, it is critical to recognize pertussis early in the course of the disease.", "affiliations": "Department of Infectious Diseases, Moffitt Cancer Center, Tampa, FL 33612-9497, USA. John.Greene@Moffitt.org.", "authors": "Yacoub|Abraham|A|;Nanjappa|Sowmya|S|;Janz|Tyler|T|;Greene|John N|JN|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/107327481602300211", "fulltext": null, "fulltext_license": null, "issn_linking": "1073-2748", "issue": "23(2)", "journal": "Cancer control : journal of the Moffitt Cancer Center", "keywords": null, "medline_ta": "Cancer Control", "mesh_terms": "D000368:Aged; D001886:Bordetella pertussis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms", "nlm_unique_id": "9438457", "other_id": null, "pages": "163-6", "pmc": null, "pmid": "27218794", "pubdate": "2016-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Infectious Disease Report: Bordetella pertussis Infection in Patients With Cancer.", "title_normalized": "infectious disease report bordetella pertussis infection in patients with cancer" }
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{ "abstract": "Management of prosthetic vascular graft infections caused by Pseudomonas aeruginosa can be a significant challenge to clinicians. These infections often do not resolve with antibiotic therapy alone due to antibiotic resistance/tolerance by bacteria, poor ability of antibiotics to permeate/reduce biofilms and/or other factors. Bacteriophage OMKO1 binding to efflux pump proteins in P. aeruginosa was consistent with an evolutionary trade-off: wildtype bacteria were killed by phage whereas evolution of phage-resistance led to increased antibiotic sensitivity. However, phage clinical-use has not been demonstrated. Here, we present a case report detailing therapeutic application of phage OMKO1 to treat a chronic P. aeruginosa infection of an aortic Dacron graft with associated aorto-cutaneous fistula. Following a single application of phage OMKO1 and ceftazidime, the infection appeared to resolve with no signs of recurrence.", "affiliations": "Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA.;Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA.;Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale School of Medicine, New Haven, CT, USA.;Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, USA.;Section of Cardiac Surgery, Department of Surgery, Yale School of Medicine, New Haven, CT, USA.;Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale School of Medicine, New Haven, CT, USA.", "authors": "Chan|Benjamin K|BK|;Turner|Paul E|PE|;Kim|Samuel|S|;Mojibian|Hamid R|HR|;Elefteriades|John A|JA|;Narayan|Deepak|D|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/emph/eoy005", "fulltext": "\n==== Front\nEvol Med Public HealthEvol Med Public HealthemphEvolution, Medicine, and Public Health2050-6201Oxford University Press 2958885510.1093/emph/eoy005eoy005Case StudyPhage treatment of an aortic graft infected with Pseudomonas aeruginosa Chan Benjamin K 1Turner Paul E 12Kim Samuel 3Mojibian Hamid R 4Elefteriades John A 5Narayan Deepak 31 Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA2 Program in Microbiology, Yale School of Medicine, New Haven, CT, USA3 Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale School of Medicine, New Haven, CT, USA4 Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, USA5 Section of Cardiac Surgery, Department of Surgery, Yale School of Medicine, New Haven, CT, USACorresponding author. Department of Ecology and Evolutionary Biology, Yale University, P.O. Box 208106, New Haven, CT 06520, USA. Tel: +203-432-5918. E-mail: paul.turner@yale.edu2018 08 3 2018 08 3 2018 2018 1 60 66 29 9 2017 28 1 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.2018This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract\nManagement of prosthetic vascular graft infections caused by Pseudomonas aeruginosa can be a significant challenge to clinicians. These infections often do not resolve with antibiotic therapy alone due to antibiotic resistance/tolerance by bacteria, poor ability of antibiotics to permeate/reduce biofilms and/or other factors. Bacteriophage OMKO1 binding to efflux pump proteins in P. aeruginosa was consistent with an evolutionary trade-off: wildtype bacteria were killed by phage whereas evolution of phage-resistance led to increased antibiotic sensitivity. However, phage clinical-use has not been demonstrated. Here, we present a case report detailing therapeutic application of phage OMKO1 to treat a chronic P. aeruginosa infection of an aortic Dacron graft with associated aorto-cutaneous fistula. Following a single application of phage OMKO1 and ceftazidime, the infection appeared to resolve with no signs of recurrence.\n\nphage therapyprosthetic vascular graft infectionPseudomonas aeruginosaantibiotic resistanceNational Institutes of Health10.13039/100000002#R01-HD028016\n==== Body\nINTRODUCTION\nThe widespread evolution of multi-drug-resistant (MDR) bacterial infections poses an escalating global threat to human health, highlighted by the recent World Health Organization’s first ever list of antibiotic resistant ‘priority pathogens’ [1]. Consequently, the increasing failure of traditional antibiotics has necessitated the development of novel antibacterial strategies, especially new therapies that target MDR bacteria which frequently colonize prosthetics associated with common surgeries. However, it is inevitable that pathogenic bacteria will evolve resistance against novel therapeutic intervention. Thus, new approaches ideally should target MDR bacterial pathogens while acknowledging that their further evolution would be unavoidable. In particular, these newly developed strategies could be designed to exert selection pressure on the bacteria to respond evolutionarily to therapy, by becoming on-average less biomedically problematic (e.g. reduced virulence, pathogenicity and/or transmissibility) [2–5]. This approach could be capable of successfully limiting MDR bacterial infections and additionally directing evolution of the pathogen in a clinically meaningful way.\n\nProsthetic vascular graft infections (PVGI) are catastrophic events which present serious challenges to surgeons and place heavy economic burdens on patients and the healthcare system. The reported incidence ranges from 0.6% to 9.5% depending on graft site [6, 7] and there are currently no readily identifiable or practical algorithms for their management. Traditional intervention strategies involve systemic antibiotics, debridement of infected tissue, partial-to-complete graft excision and secondary revascularization [8]. However, many patients presenting with vascular graft infections have significant comorbidities and are often critically ill, complicating surgical intervention and reducing likelihood of a positive clinical outcome. Despite best management, mortality and morbidity rates remain high with conservative estimates for both over 20% [9, 10]. Reinfection rates are also significant, highlighting the inadequacy of current treatment modalities at eradicating the infecting organism. As the number of procedures involving vascular grafts continues to increase with an aging population and prevalence of atherosclerosis and diabetes, new approaches to the management of PVGI are needed.\n\nA common source of PVGIs is Pseudomonas aeruginosa, a ubiquitous Gram-negative, rod-shaped bacterium prevalent in natural and artificial environments [11] and listed as an increasingly antibiotic resistant priority pathogen [1]. Adaptation to myriad habitats has allowed P. aeruginosa to persist in many human-associated environments, most notably in hospitals, where it is increasingly associated with nosocomial infections [12]. These infections are difficult to manage, in part due to intrinsic antibiotic resistance resulting from decreased membrane permeability, active antibiotic efflux and other chromosomally encoded enzymes. Further complicating the problem of P. aeruginosa infections is their ability to form biofilms. Biofilm-mediated infections are notoriously difficult to manage, due to their generally greater resistance to chemical antimicrobials [13] and formation following sub-lethal concentrations of antibiotics [14]. Furthermore, slow-growing cells present in the biofilm (e.g. persister cells) may have sufficiently reduced metabolisms, resulting in resistance to bacteriostatic antibiotics that target metabolically active bacteria [15]. As a result, biofilms may also act as a reservoir for the dissemination of infections throughout the body which could greatly prolong infection duration and severity.\n\nOne potential alternative approach to using traditional antibiotics for prevention/treatment of bacterial infections is ‘phage therapy,’ the application of lytic bacteriophages (or ‘phages;’ viruses of bacteria) for the bio-control of bacteria. As one of the first classes of antimicrobials discovered in the modern era, their application has had a controversial past and their clinical use has not been fully accepted in Westernized countries. However, studies performed in the latter half of the 20th century [16], recent clinical trials [17, 18] and individual case reports [19] that demonstrate safety and potential efficacy have renewed interest in phage therapy as a possible mechanism by which antibiotic resistant and biofilm-associated infections might be controlled. As a class of antibacterials, phages are distinct from traditional chemical antibiotics in four seemingly beneficial ways: they are self-amplifying/limiting in the presence/absence of substrate (i.e. susceptible bacteria); they are often able to penetrate biofilms to reach infectious bacteria [20–22]; they are capable of infecting/killing persister cells; and their killing mechanism is distinct from those of traditional antibiotics. Exploiting the differences between antibiotics and phage therapy has been a driving force for continued research into the potential clinical utility of phage therapy.\n\nHowever, one obvious drawback to phage therapy is the clear evidence that bacteria can readily evolve resistance to phage infection [23, 24]. For example, phage attachment to a receptor binding-site exerts selection pressure for altered or down-regulated expression of the receptor, thereby allowing bacteria to escape phage infection [23]. Because evolved phage-resistance is virtually certain, modern approaches to phage therapy must acknowledge and capitalize on this inevitability. Trade-offs are often observed in biology, where organisms evolve one trait that improves fitness (a relative reproduction or survival advantage), while simultaneously suffering reduced performance in another trait [25–29]. Thus, phage therapy could be developed as an ‘evolutionary-based strategy’ that forces a trade-off of greatest relevance to the problem of widespread antibiotic resistance: utilize phages that drive MDR bacterial pathogens to evolve increased phage resistance by suffering increased sensitivity to chemical antibiotics (Fig. 1). This approach to phage therapy should be doubly effective; success is achieved when phage kills the target bacterium, and success is also achieved when bacteria evolve phage resistance because they suffer increased sensitivity to clinically approved antibiotics.\n\n\nFigure 1. An ‘evolutionary-based strategy’ in phage therapy should be doubly effective. Top: if phage binding to surface-exposed proteins of efflux pumps causes lysis (killing) of infected cells, this simultaneously should exert selection pressure for bacteria to evolve phage resistance that concomitantly increases sensitivity to co-administered antibiotics due to inefficient efflux. Bottom: phage OMKO1 selects for increased sensitivity of MDR P. aeruginosa to antibiotics by forcing the desired trade-off [30]. Bacteria are either sensitive to the phage (and more resistant to antibiotics), left; or resistant to the phage (and more sensitive to antibiotics), right. Data previously reported in [30]\n\nWe recently identified phage OMKO1 that appears to utilize the outer membrane protein M of the mexAB- and mexXY-multidrug efflux systems of P. aeruginosa [30], exerting selection pressure for bacteria to evolve increased phage resistance that ‘trades-off’ with bacterial ability to maintain resistance to antibiotics (Fig. 1). These data suggest that bacteria evolve resistance to phage OMKO1 via mutations that alter efflux-pump proteins as binding sites for phage, thereby decreasing the ability for bacteria to extrude antibiotics and causing them to become antibiotic sensitive. This outcome is consistent with an evolutionary trade-off, which should allow phage OMKO1 to act synergistically with antibiotics in combination therapy. The use of this phage therapeutically, however, has not been previously tested. Numerous studies have examined the impact of phages on biofilms [21], but we are unaware of a case involving therapeutic application of phages to disrupt biofilms in a PVGI caused by MDR pathogen. Although methods to best leverage a phage-resistance/antibiotic-sensitivity trade-off in a clinical setting would be informed by consideration of dosage strategies (simultaneous vs alternating administration of phage and antibiotic); of pharmacokinetics and pharmacodynamics to optimize the trade-off; and of the possibility that MDR P. aeruginosa can simultaneously evolve resistance to phage and antibiotics, these questions are the targets of ongoing studies. Nevertheless, based on in vitro evidence that phage OMKO1 selects for re-sensitization to antibiotics in clinically relevant P. aeruginosa strains [30], we report the outcome of a single emergency case of phage therapy to treat a PVGI (chronic aortic Dacron graft) caused by P. aeruginosa.\n\nLABORATORY ASSAYS\nBased on previous results [30], we hypothesized that additive effects, and potential synergy, between phage OMKO1 and ceftazidime could be utilized to disrupt P. aeruginosa biofilms when concentrations of antibiotic alone were too low to destroy the biofilm but sufficient to eliminate planktonic bacteria. Figure 2A illustrates this hypothetical synergy whereby phage-sensitive (antibiotic-resistant) cells in the biofilm are lysed, disrupting biofilm stability and exposing cells to lethal concentrations of antibiotic that kills phage-resistant (antibiotic-sensitive) bacteria. To examine potential synergy or additive effects and exclude concerns of phage/antibiotic antagonism prior to emergency application of phage OMKO1, we performed in vitro biofilm reduction assays using the strain isolated from fistular discharge of the patient.\n\n\nFigure 2. (A) Therapeutic concentrations of antibiotics are unable to penetrate biofilms due to poor permeability and depressed metabolism of biofilm constituents. Phage OMKO1, however, is able to replicate within bacteria present in biofilm. Next, biofilm instability occurs as phage OMKO1 replicates. Finally, with the biofilm disrupted, therapeutic concentrations of antibiotic can better reach target bacteria, and any cells resistant to phage OMKO1 infection are expected to be more susceptible to antibiotics (i.e., less capable of efflux). (B) Mean densities of bacteria previously grown for 72-h as biofilms on Dacron sections, following 24-h exposure to either ciprofloxacin or ceftazidime with and without phage OMKO1. (C) Mean densities of bacteria previously grown for 72-h as biofilms on Dacron sections, following 24-h exposure to differing amounts of phage OMKO1. The black horizontal line represents density equal to the reliable limit of detection (OD600 = 0.1). See text for details\n\nBiofilms were grown on 3 mm × 3 mm sections of Dacron by inoculating each section in 150 µl 0.1 × LB broth in a 96-well dish with 50 µl of an overnight culture of P. aeruginosa isolated from fistular discharge of our patient. Dacron sections were removed from growth media after 72-h and rinsed with 200 µl of 0.1 × LB three times to remove planktonic cells. Following rinse, sections were added to 200 µl of LB medium containing treatment (phage OMKO1, ceftazidime or ciprofloxacin at 2 × MIC, antibiotic at 2 × MIC + phage OMKO1, or blank control). Following exposure to treatment for 24 h, Dacron sections were placed in fresh LB medium and allowed to incubate at 37°C for an additional 24 h without agitation. Dacron sections were then removed and cell density (optical density at absorbance wavelength 600 nm; OD600) was measured with an automated spectrophotometer (Tecan model Infinite F200 microplate-reader). Results (Fig. 2B) showed that phage OMKO1 combined with either ciprofloxacin or ceftazidime caused mean (n = 3) cell densities grown on Dacron sections to be statistically significantly lower than those exposed to either antibiotic alone (t-test with P < 0.001, ciprofloxacin; and P < 0.007, ceftazidime). Furthermore, treatment with phage alone was observed to significantly reduce mean cell densities relative to no treatment (P < 0.001). However, neither ciprofloxacin nor ceftazidime at 2 × MIC was sufficient to eliminate 72 h biofilms (P = 0.074, ciprofloxacin; P = 0.357, ceftazidime). These data indicated that the antibiotics were incapable of reducing cell densities in biofilms, whereas phage OMKO1 alone or in combination with antibiotic significantly reduced bacterial densities. The experiment also confirmed that phage OMKO1 and antibiotic showed no evidence of antagonistic interactions, suggesting that their co-administered treatment would not adversely affect biofilm reduction in the patient.\n\nWe then determined the minimum dose of phage OMKO1 required to remove biofilms in the absence of antibiotic to provide guidance for the in vivo efficacy, under the conservative assumption that possible phage-antibiotic synergy would not necessarily benefit the patient during treatment. To do so, we conducted replicated (n = 3) assays measuring minimum bactericidal titer, where differing concentrations of phage OMKO1 were used to attack biofilms initiated with constant cell densities identical to those used in the above-described biofilm reduction assays. Assay treatments consisted of serial 10-fold dilutions of phage OMKO1 starting at 10e10 plaque forming units (PFU) per ml. Cell densities (OD600) were then used to estimate the minimum multiplicity of infection (MOI: phage particles per cell) required to reduce biofilms on Dacron sections to a value less than OD600 = 0.1 (our limit of detection of viable bacterial cells using these methods). Results (Fig. 2C) showed that target biofilm reduction was achieved at MOI ≥ 0.00001, indicating that phage OMKO1 was highly effective at reducing biofilm densities even at very low relative frequencies of phage particles. The data suggested that a single treatment using 1,000 PFU of phage OMKO1 might be sufficient to effectively reduce a biofilm of ∼1e8 CFU of the P. aeruginosa patient strain, even if phage-antibiotic synergy per se could not be achieved during treatment.\n\nCASE PRESENTATION\nIn July 2012, our 76-year old male patient underwent aortic arch replacement surgery with a Dacron graft for an aortic aneurysm. This was complicated by a P. aeruginosa mediastinal and aortic graft infection (confirmed by blood and deep wound culture) for which the patient returned to the operating room on multiple occasions for debridement and washout of the infected chest wall (Fig. 3A). The chest wall was eventually closed with omental and bilateral pectoralis major flaps. The patient was admitted again in early 2013 for recurrent P. aeruginosa infection (confirmed by blood and deep wound culture) and a new mediastinal fistula which drained purulent material. The patient was deemed too high risk for surgical replacement of his infected aortic graft after extensive discussions with his treating cardiac surgeon and multiple other consulting surgeons from other institutions. Therefore, the patient was conservatively treated with IV ceftazidime and superficial chest wall debridement. The patient was successfully discharged from the hospital, completed his multi-week course of intravenous ceftazidime (2 g IV q8h), and was switched to oral ciprofloxacin (750 mg q12h) as the isolated P. aeruginosa was susceptible to ciprofloxacin at this time. Over the course of the next year into 2014 the patient was admitted three more times for P. aeruginosa bacteremia (confirmed by cultures) which always began with subjective fevers and increased purulent drainage from his mediastinal fistula. CT imaging during the patient’s admission in October of 2013 showed increased perigraft fluid near the aortic root with surrounding phlegmonous changes in continuation with the mediastinal fistula tract (Fig. 3B). This poorly organized phlegmonous collection was thought to be the source of the mediastinal fistula discharge. However, the collection never became organized enough on subsequent CT scans to attempt drainage. During these admissions, his P. aeruginosa sample showed intermediate resistance to ciprofloxacin; therefore, the patient was treated with several week courses of intravenous ceftazidime that successfully suppressed the infection. Between each admission, attempts were made to restart oral ciprofloxacin after discussions with the infectious disease physician, but the patient eventually became septic after each attempt, necessitating intravenous ceftazidime treatment. The patient stayed abroad for over a year after his last hospital admission in May of 2014 where the patient continued to receive intravenous ceftazidime treatment. The patient presented to our clinic in late 2015 complaining of increased serosanguinous drainage from his mediastinal fistula. While the fistula had intermittently expressed mild serosanguinous drainage, the patient grew troubled because the fluid appeared to have become bloodier in nature. Based on this history, we became concerned that the perigraft, phlegmonous collection could be eroding into the aorta itself. The patient was not a candidate for elective surgical management and the patient, himself, wished to explore options other than indefinite antibacterial treatment. It was deemed at this time that the patient would make an ideal candidate for exploration of phage therapy with phage OMKO1.\n\n\nFigure 3. (A) Intraoperative photograph showing aortic graft and P. aeruginosa infection (arrow) over myocardium, taken during operation to debride and to wash out infected tissues. (B) Comparative CT image showing infected collection (arrow) and site of targeted aspiration during therapy\n\nCASE MANAGEMENT AND OUTCOME\nWe proposed a procedure in which we would directly access the perigraft collection anterior to the aortic root by needle puncture using image guidance. At this site, we would distribute a mixture of phage OMKO1 and ceftazidime that had demonstrated synergism in a previous study [30]. This strategy was further supported by data in the current study (Fig. 2B and C) that used the strain isolated from the fistular discharge and confirmed re-sensitization to antibiotic in bacteria with evolved resistance to phage OMKO1. Importantly, these assays approximated the efficacy of in vivo biofilm breakdown, as it was unlikely that subsequent applications of phage OMKO1 would have been possible due to the complicated involvement of the proposed procedure.\n\nPurification and preparation of phage OMKO1\nApplication of phage OMKO1 required removal of endotoxins present in the phage lysate, because endotoxemia (and associated septic shock) was perceived as the greatest possible risk to the patient’s health. This endotoxin removal was accomplished via spin column (Pierce High Capacity Endotoxin Removal Spin Columns, Thermo Fisher) followed by dialysis in phosphate buffered saline. Limulus amebocyte lysate (LAL) testing was then performed by a third-party laboratory (Associates of Cape Cod, East Falmouth, MA) to determine endotoxin concentrations. Upon receiving endotoxin levels, dilution of the preparation was performed in injectable saline to produce a final concentration of 12.5 EU/ml and titer of 10e7 plaque forming units per ml (PFU/ml). This administered titer was determined to be acceptable and to likely exceed the minimum MOI capable of effectively reducing 72-h-old biofilms of the fistular-discharge strain in preliminary bactericidal titer assays (Fig. 2C), although the exact MOI at time of treatment was unknowable.\n\nProcedure\nAfter the risks and benefits of the experimental procedure were discussed, the patient consented to the procedure. The Food and Drug Administration and Yale University Human Investigation Committee gave their approval for the use of phage OMKO1 as an emergency investigational new drug (FDA IND#16827). In January of 2016, pre-procedure CT imaging reconfirmed the perigraft, phlegmonous collection near the left-anterior aortic root which was first imaged in 2013. The collection had remained stable, but due to the chronicity of the infection and inflammation seen on imaging, heavy scarring was predicted to hinder our attempts at needle aspiration. The chest wall was punctured with a needle (away from the site of the mediastinal fistula) and advanced to the perigraft collection under direct CT guidance and in sterile fashion. Fluid could not be aspirated back or injected, confirming the heavy scarring in this area. Therefore, we withdrew the needle from the chest and applied 10 ml of phage OMKO1 (10e7 PFU/ml) and ceftazidime (0.2 g/ml) solution into the mediastinal fistula which was in continuity with the perigraft collection. A sterile dressing was placed over the fistula and the patient was admitted to a telemetry monitored bed for observation. The following day, the patient had no complaints, exhibited stable vital signs and had laboratory values within normal limits. We were confident that no injury to the aorta had occurred, and the patient was discharged still on his ceftazidime regimen. The patient returned to his home country shortly, thereafter.\n\nApproximately 4 weeks post-procedure, the patient developed significant bleeding from the mediastinal wound. Due to serious concerns that an aortic perforation had occurred, the patient underwent emergency exploratory surgery. By operative report, aortic perforation was confirmed under direct visualization, caused by severe adhesions between the aorta and ectopic bone from remnants of the sternum. The patient underwent a partial (3 × 7 cm) aorta and graft excision and replacement, and repair of the mediastinal fistula. The entire graft could not be removed despite attempts to do so. Cultures taken during this time only revealed growth of Candida from the superficial chest wound which was appropriately treated. Ceftazidime was discontinued shortly after the surgery, and the patient has not had any evidence of recurrent infection despite remaining off of antibiotics (based on blood cultures, clinical symptoms and CT imaging).\n\nDISCUSSION\nThe argument for use of phage therapy in biofilm-associated infections is old and has a storied past. However, phage ability to disrupt biofilms where traditional antibiotics fail is a significant advantage (Fig. 2A) and should be considered for infections refractory to standard management practices. Phage such as OMKO1 that appear to force a clinically relevant trade-off may present an effective solution to the inevitable evolution of resistance by pathogenic bacteria. We verified the ability of phage OMKO1 to re-sensitize bacteria to antibiotics in vitro [14] prior to application, which provided valuable insight into the potential clinical outcome. This prior work provided preliminary data that suggested synergy could occur between phage OMKO1 and chemical antibiotics. Interestingly, the current study demonstrates the phage alone is capable of reducing bacterial biofilm densities in the presence/absence of antibiotic, suggesting phage-antibiotic antagonism should not be a concern during treatment against P. aeruginosa biofilms. Future work will further examine the conditions in which phage OMKO1 is effective alone versus in synergy with antibiotics in killing bacterial pathogens.\n\nThe long history of phage therapy in the former Soviet Union suggests that few, if any, side effects are associated with therapeutic application of bacteriophages [17, 18, 31, 32], and we did not anticipate any negative effects following use of phage OMKO1. In this case study, we did not observe any noticeable side effects associated with phage OMKO1. It appears to have been effective at biofilm reduction on prosthetic graft material, contributing to eradicating the P. aeruginosa infection. The standard of care for an infected thoracic aortic graft is complete removal of the infected graft, debridement of the surrounding infected tissue, and graft replacement [33]. However, this is many times deemed too risky, leading to more conservative treatments and/or lifelong suppressive antibiotic therapy [34]. Despite treatment, mortality rates for thoracic aortic graft infection range between 25% and 75% [34], and there is an approximately 20% risk of reinfection if the patient survives graft replacement [35]. In our case, only partial removal of the aortic graft was possible, greatly increasing the reinfection risk and necessitating continued lifelong suppressive antibiotics. Yet, the patient has not had a recurrent infection in the 18 months since discontinuing antibiotics after the emergent surgery. Due to these circumstances, we argue that the phage therapy played a significant role in contributing to the eradication of the P. aeruginosa infection. Eventual controlled trials examining phage application as adjunctives may reveal improved clinical outcomes in cases of recalcitrant infection, and we hope that exploratory studies such as this one can provide preliminary evidence suggesting that phage OMKO1 can greatly improve the effects of antibiotics for the removal of P. aeruginosa biofilms in PVGI.\n\nBoth the current case study and a recently reported treatment of an Acinetobacter baumanii infection highlight why the understanding of evolutionary biology is vital to the development and administration of phage therapy in humans. Schooley et al. reported the personalized phage-based therapy in a 68-year-old diabetic patient with necrotizing pancreatitis complicated by a MDR A. baumanii infection [19]. Nine different phages with lytic activity on the patient strain were identified, and were administered intravenously and percutaneously into abscess cavities using combinations (cocktails) of phages. However, the rise of phage resistance in the infecting bacterial population necessitated an iterative process of phage cocktail formulation, because of recurrent failure [19]. Although the patient’s infection ultimately resolved, this evolutionary process demonstrates one obvious challenge of phage therapy, where evolution of phage resistance occurs after treatment is administered [23, 24]. In contrast, the current case study indicates the fortuitous possibility for a single phage to apparently resolve the bacterial infection, where pre-treatment understanding of the evolutionary mechanism (phage-resistance/antibiotic-sensitivity trade-off) underlying bacterial resistance informed the choice of phage used in experimental therapy. Together, the two studies illustrate that improved understanding of both pre- and post-treatment mechanisms of phage resistance are crucial for further development of phage therapy strategies, for clinical medicine to capitalize on the general utility of phage therapy as an alternative to traditional antibiotics.\n\nACKNOWLEDGEMENTS\nWe thank the patient in this case for his willingness to participate and provide detailed medical data; two anonymous reviewers for helpful comments on the manuscript; L. Gogokhia, S. Abedon, J. Wertz and J. Daniels for insightful discussion and support; A.N. Chan and M.L. Chan for providing inspiration and motivation to pursue studies such as this; C. Fiore and P. Marks at the FDA for their invaluable assistance; and S. Mao and K. Kortright for assistance with laboratory assays. Our sources of funding include grants made possible by the Project High Hopes Foundation (Turner), the U.S. National Science Foundation grant #DEB-1051093 (Turner) and the NIH grant #R01-HD028016 (Narayan).\n\n\nConflict of interest: None declared.\n==== Refs\nREFERENCES\n1 \nTacconelli E , Magrini N , Kahlmeter G. \nGlobal Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery, and Development of New Antibiotics.\nWorld Health Organization Report \n2017 .\n2 \nAllen RC , Popat R , Diggle SP \n\nTargeting virulence: can we make evolution-proof drugs? . Nat Rev Microbiol 2014 ; 12 :300 –8 .24625893 \n3 \nMühlen S , Dersch P. \nAnti-virulence strategies to target bacterial infections . Curr Top Microbiol Immunol 2016 ; 398 :147 –83 .26942418 \n4 \nClatworthy AE , Pierson E , Hung DT. \nTargeting virulence: a new paradigm for antimicrobial therapy . Nat Chem Biol 2007 ; 3 :541 –8 .17710100 \n5 \nChan BK , Brown K , Kortright KE \n\nExtending the lifetime of antibiotics: how can phage therapy help? . Future Microbiol 2016 ; 11 :1105 –7 .27545690 \n6 \nKieffer E , Sabatier J , Plissonnier D \n\nProsthetic graft infection after descending thoracic/thoracoabdominal aortic aneurysmectomy: management with in situ arterial allografts . J Vasc Surg 2001 ; 33 :671 –8 .11296316 \n7 \nSchild AF , Perez E , Gillaspie E \n\nArteriovenous fistulae vs. arteriovenous grafts: a retrospective review of 1,700 consecutive vascular access cases . J Vasc Access 9 :231 –5 .19085891 \n8 \nBunt TJ. \nVascular graft infections: an update . Cardiovasc Surg 2001 ; 9 :225 –33 .11336845 \n9 \nO’Connor S , Andrew P , Batt M \n\nA systematic review and meta-analysis of treatments for aortic graft infection . J Vasc Surg 2006 ; 44 :38 –45 .16828424 \n10 \nPerera GB , Fujitani RM , Kubaska SM. \nAortic graft infection: update on management and treatment options . Vasc Endovascular Surg 2006 ; 40 :1 –10 .16456600 \n11 \nRemold SK , Brown CK , Farris JE \n\nDifferential habitat use and niche partitioning by Pseudomonas species in human homes . Microb Ecol 2011 ; 62 :505 –17 .21503776 \n12 \nEmori TG , Gaynes RP. \nAn overview of nosocomial infections, including the role of the microbiology laboratory . Clin Microbiol Rev 1993 ; 6 :428 –42 .8269394 \n13 \nStewart PS , Costerton JW. \nAntibiotic resistance of bacteria in biofilms . Lancet 2001 ; 358 :135 –8 .11463434 \n14 \nHoffman LR , D'Argenio DA , MacCoss MJ \n\nAminoglycoside antibiotics induce bacterial biofilm formation . Nature 2005 ; 436 :1171 –5 .16121184 \n15 \nLewis K. \nPersister cells and the riddle of biofilm survival . Biochemistry 2005 ; 70 :267 –74 .15807669 \n16 \nSmith HW , Huggins MB. \nEffectiveness of phages in treating experimental Escherichia coli diarrhoea in calves, piglets and lambs . J Gen Microbiol 1983 ; 129 :2659 –75 .6355391 \n17 \nWright A , Hawkins CH , Änggård EE , Harper DR. \nA controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy . Clin Otolaryngol 2009 ; 34 :349 –57 .19673983 \n18 \nRhoads DD , Wolcott RD , Kuskowski MA \n\nBacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial . J Wound Care 2009 ; 18 :237 –8 .19661847 \n19 \nSchooley RT , Biswas B , Gill JJ. \nDevelopment and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection . Antimicrob Agents Chemother 2017 ; 61 . pii: e00954-17. DOI: 10.1128/AAC.00954-17.\n20 \nHarper D , Parracho H , Walker J \n\nBacteriophages and biofilms . Antibiotics 2014 ; 3 :270 –84 .\n21 \nChan BK , Abedon ST. \nBacteriophages and their enzymes in biofilm control . Curr Pharm Des 2015 ; 21 :85 –99 .25189866 \n22 \nAbedon ST. \nEcology of anti-biofilm agents i: antibiotics versus bacteriophages . Pharmaceuticals (Basel) 2015 ; 8 :525 –58 .26371010 \n23 \nLabrie SJ , Samson JE , Moineau S. \nBacteriophage resistance mechanisms . Nat Rev Microbiol 2010 ; 8 :317 –27 .20348932 \n24 \nVale PF , Little TJ. \nCRISPR-mediated phage resistance and the ghost of coevolution past . Proc Biol Sci 2010 ; 277 :2097 –103 .20236977 \n25 \nWright S. \n1968 \nEvolution and the Genetics of Populations , Vol. 1 \nChicago : University of Chicago Press .\n26 \nLenski RE. \nExperimental studies of pleiotropy and epistasis in Escherichia coli. I. Variation in competitive fitness among mutants resistant to virus T4 . Evolution 1988 ; 42 :425 –32 .28564005 \n27 \nCrill WD , Wichman HA , Bull JJ. \nEvolutionary reversals during viral adaptation to alternating hosts . Genetics 2000 ; 154 :27 –37 .10628966 \n28 \nDessau M , Goldhill D , McBride RL \n\nSelective pressure causes an RNA virus to trade reproductive fitness for increased structural and thermal stability of a viral enzyme . PLoS Genet 2012 ; 8 :e1003102 .23209446 \n29 \nGoldhill DH , Turner PE. \nThe evolution of life history trade-offs in viruses . Curr Opin Virol 2014 ; 8 :79 –84 .25087040 \n30 \nChan BK , Sistrom M , Wertz JE \n\nPhage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa . Sci Rep 2016 ; 6 :26717 .27225966 \n31 \nAbedon ST , Kuhl SJ , Blasdel BG \n\nPhage treatment of human infections . Bacteriophage 2011 ; 1 :66 –85 .22334863 \n32 \nHousby JN , Mann NH. \nPhage therapy . Drug Discov Today 2009 ; 14 :536 –40 .19508915 \n33 \nFujii T , Watanabe Y. \nMultidisciplinary treatment approach for prosthetic vascular graft infection in the thoracic aortic area . Ann Thorac Cardiovasc Surg 2015 ; 21 :418 –27 .26356686 \n34 \nCoselli JS , Köksoy C , LeMaire SA. \nManagement of thoracic aortic graft infections . Ann Thorac Surg 1999 ; 67 :1990 .10391355 \n35 \nYoung RM , Cherry KJ , Davis PM \n\nThe results of in situ prosthetic replacement for infected aortic grafts . Am J Surg 1999 ; 178 :136 –40 10487266\n\n", "fulltext_license": "CC BY", "issn_linking": "2050-6201", "issue": "2018(1)", "journal": "Evolution, medicine, and public health", "keywords": "Pseudomonas aeruginosa; antibiotic resistance; phage therapy; prosthetic vascular graft infection", "medline_ta": "Evol Med Public Health", "mesh_terms": null, "nlm_unique_id": "101616698", "other_id": null, "pages": "60-66", "pmc": null, "pmid": "29588855", "pubdate": "2018", "publication_types": "D002363:Case Reports", "references": "20348932;10487266;26942418;27225966;20236977;21503776;23209446;25189866;28564005;15807669;27545690;26371010;16456600;25087040;22334863;8269394;11463434;19085891;19508915;19661847;28807909;6355391;10391355;16121184;17710100;26356686;11336845;11296316;24625893;16828424;19673983;10628966", "title": "Phage treatment of an aortic graft infected with Pseudomonas aeruginosa.", "title_normalized": "phage treatment of an aortic graft infected with pseudomonas aeruginosa" }
[ { "companynumb": "US-DRREDDYS-USA/USA/18/0097829", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null...
{ "abstract": "BACKGROUND\nThe supply of unregulated \"new psychoactive substances\" (NPS) has shown a steady increase over the past six years. This report from the Swedish STRIDA project describes analytically confirmed non-fatal intoxications involving butyrfentanyl (butyrylfentanyl) or 4-fluorobutyrfentanyl (para-fluorobutyrfentanyl), two fentanyl analogues recently introduced as NPS opioids.\n\n\nMETHODS\nObservational case series of consecutive patients with suspected acute NPS exposure and requiring hospital care from all over Sweden.\n\n\nMETHODS\nFrom May 2014 to January 2015, blood and urine samples were obtained from four intoxication cases involving butyrfentanyl and one case involving 4-fluorobutyrfentanyl (men, 19-30 years) presenting in emergency departments (ED) or intensive care units (ICU). Laboratory analysis of serum and/or urine samples was performed by multi-component liquid chromatography-mass spectrometry methods. Data on clinical features were collected during consultations with the Poisons Information Centre and retrieved from medical records.\n\n\nMETHODS\nOf the five patients, two were discharged home from the ED and three were admitted to the ICU, of whom two required intubation and mechanical ventilation. Clinical features included typical opioid symptoms such as unconsciousness, respiratory depression, and apnea. In one case, naloxone successfully countered the effects. All patients were discharged the same or the following day. Butyrfentanyl was detected in two serum (0.6 and 0.9 ng/mL) and three urine (2.0-65.6 ng/mL) samples from three of four cases; three cases also contained fentanyl. In the 4-fluorobutyrfentanyl case, the substance was detected in serum (∼15 ng/mL) and urine (∼10 ng/mL). In four cases, other NPS and/or classical drugs were also detected. Analysis of two \"butyrfentanyl\" NPS products (nasal spray and powder) brought to hospital by patients showed that the 10-fold more potent fentanyl was the main active ingredient (∼7.5-10-fold higher amount) in both.\n\n\nCONCLUSIONS\nTypical and potentially life-threatening opioid toxicity was seen in acute intoxications involving butyrfentanyl, 4F-butyrfentanyl, and fentanyl. The incorrect labelling of butyrfentanyl NPS products which instead mainly contained fentanyl is alarming, given the narrow range between a safe and a lethal dose for opioids.", "affiliations": "Swedish Poisons Information Centre , Stockholm , Sweden.", "authors": "Bäckberg|Matilda|M|;Beck|Olof|O|;Jönsson|Karl-Henrik|KH|;Helander|Anders|A|", "chemical_list": "D000701:Analgesics, Opioid; D013287:Illicit Drugs; D009270:Naloxone; D005283:Fentanyl", "country": "England", "delete": false, "doi": "10.3109/15563650.2015.1054505", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-3650", "issue": "53(7)", "journal": "Clinical toxicology (Philadelphia, Pa.)", "keywords": "Butyrfentanyl; Butyrylfentanyl; Fentanyl analogue; Internet drugs; Mass spectrometry methods; NPS; New psychoactive substances; Opioid analgesic drug; para-Fluorobutyrfentanyl", "medline_ta": "Clin Toxicol (Phila)", "mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D001049:Apnea; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D004636:Emergency Service, Hospital; D005283:Fentanyl; D006801:Humans; D013287:Illicit Drugs; D007362:Intensive Care Units; D008297:Male; D013058:Mass Spectrometry; D009270:Naloxone; D012131:Respiratory Insufficiency; D012189:Retrospective Studies; D013548:Sweden; D014474:Unconsciousness; D055815:Young Adult", "nlm_unique_id": "101241654", "other_id": null, "pages": "609-17", "pmc": null, "pmid": "26083809", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Opioid intoxications involving butyrfentanyl, 4-fluorobutyrfentanyl, and fentanyl from the Swedish STRIDA project.", "title_normalized": "opioid intoxications involving butyrfentanyl 4 fluorobutyrfentanyl and fentanyl from the swedish strida project" }
[ { "companynumb": "SE-MYLANLABS-2016M1000050", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREGABALIN" }, "drugadditional": null, ...
{ "abstract": "Studies have reported that statin usage before stroke can increase the incidence of intracerebral hemorrhage after thrombolytic treatment. However, whether the administration of statin at an early stage of ischemic stroke increases hemorrhage occurrence is unknown. The aim of this study was to assess the effect of statin on neurological imaging and functional outcomes after intravenous alteplase treatment, within 24 h of acute ischemic stroke attack. A total of 119 consecutive acute ischemic stroke patients treated by intravenous alteplase were recruited, of which 71 patients (59.7 %) were given statin therapy within 24 h of stroke onset. The physiological parameters, including demography, vascular risk factors, and clinical characteristics were recorded. The occurrence of intracerebral hemorrhage (ICH), symptomatic intracerebral hemorrhage (sICH), 90-day functional outcomes, and mortality in the patients were further analyzed. There were 24 occurrences of ICH after alteplase treatment (20.2 %) and there was no difference when patients were treated with statin (p = 0.280). Multivariate logistic regression analysis showed no significant correlation between the administration of statin and the occurrence of ICH (p = 0.230) or sICH (p = 0.949). There was a trend toward better neurological function with higher statin dose. The use of statin in the early stage of ischemic stroke is safe and does not increase the risk of intracerebral hemorrhage after alteplase treatment, suggesting that a clinical trial of early statin treatment on a large scale following thrombolysis is needed for further evaluation.", "affiliations": "Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China.;Department of Neurology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, 1630 Dongfang Road, Shanghai, 200127, China.;Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China.;Department of Neurology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, 1630 Dongfang Road, Shanghai, 200127, China.;Department of Neurology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, 1630 Dongfang Road, Shanghai, 200127, China.;Department of Neurology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, 1630 Dongfang Road, Shanghai, 200127, China.;Department of Neurology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, 1630 Dongfang Road, Shanghai, 200127, China.;Department of Neurology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, 1630 Dongfang Road, Shanghai, 200127, China.;Department of Neurology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, 1630 Dongfang Road, Shanghai, 200127, China.;Department of Neurology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, 1630 Dongfang Road, Shanghai, 200127, China.;Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China. gyyang0626@gmail.com.;Department of Neurology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, 1630 Dongfang Road, Shanghai, 200127, China. lliyans@hotmail.com.", "authors": "Geng|Jieli|J|;Song|Yeping|Y|;Mu|Zhihao|Z|;Xu|Qun|Q|;Shi|Guowen|G|;Sun|Yameng|Y|;Chen|Ying|Y|;Lin|Yan|Y|;Pan|Yuanmei|Y|;Yu|Lin|L|;Yang|Guo-Yuan|GY|;Li|Yansheng|Y|", "chemical_list": "D005343:Fibrinolytic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000069059:Atorvastatin; D010959:Tissue Plasminogen Activator", "country": "Austria", "delete": false, "doi": "10.1007/978-3-319-18497-5_47", "fulltext": null, "fulltext_license": null, "issn_linking": "0065-1419", "issue": "121()", "journal": "Acta neurochirurgica. Supplement", "keywords": "Acute; Hemorrhage; Ischemic stroke; Statins; Thrombolysis", "medline_ta": "Acta Neurochir Suppl", "mesh_terms": "D000368:Aged; D000069059:Atorvastatin; D002545:Brain Ischemia; D002543:Cerebral Hemorrhage; D061345:Early Medical Intervention; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D020521:Stroke; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome", "nlm_unique_id": "100962752", "other_id": null, "pages": "269-75", "pmc": null, "pmid": "26463960", "pubdate": "2016", "publication_types": "D016428:Journal Article", "references": null, "title": "Early Use of Statin in Patients Treated with Alteplase for Acute Ischemic Stroke.", "title_normalized": "early use of statin in patients treated with alteplase for acute ischemic stroke" }
[ { "companynumb": "CN-ROCHE-1664895", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": null, "drug...
{ "abstract": "BACKGROUND\nIn recurrent head and neck squamous cell carcinoma ineligible for resection or irradiation, treatment aims primarily at symptom control and quality of life enhancement with an expected outcome of 6-12 months.\n\n\nMETHODS\nIn 2005, a male patient, born in 1944, with a second local recurrence of human papillomavirus negative tonsil cancer was enrolled in the EXTREME trial, and randomized to platinum/5-fluorouracil/cetuximab arm resulting in partial remission with progression-free survival of 12 months. The second-line systemic therapy comprised 5 cycles of 3-weekly docetaxel/cisplatin/5-fluorouracil regimen plus weekly cetuximab.\n\n\nRESULTS\nAs confirmed on imaging and repeated biopsies, complete response was achieved with disease-free survival of 8 years and follow-up period of 12 years. Severe acute toxicities during the taxane-based chemotherapy plus cetuximab included grade 4 anorexia and grade 3 febrile neutropenia.\n\n\nCONCLUSIONS\nPoor tumor differentiation, no weight loss, oropharyngeal location, white race, and particularly the induced complete response were most likely the key favorable prognostic factors in the reported patient. The possibility of a synergistic interaction between taxanes and cetuximab should be further explored.", "affiliations": "Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium. petr.szturz@fnbrno.cz.;Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.;Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.;Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.;Department of Radiology, Antwerp University Hospital, Edegem, Belgium.;Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium.;Department of Pathology, Antwerp University Hospital, Edegem, Belgium.;Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.;Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.", "authors": "Szturz|Petr|P|;Specenier|Pol|P|;Van Laer|Carl|C|;Van Den Weyngaert|Danielle|D|;Corthouts|Bob|B|;Carp|Laurens|L|;Van Marck|Eric|E|;Vanderveken|Olivier|O|;Vermorken|Jan B|JB|", "chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D000068818:Cetuximab; D002945:Cisplatin; D005472:Fluorouracil", "country": "Germany", "delete": false, "doi": "10.1007/s00405-015-3673-y", "fulltext": null, "fulltext_license": null, "issn_linking": "0937-4477", "issue": "273(6)", "journal": "European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery", "keywords": "Epidermal growth factor receptor inhibitor; Positron emission tomography; Targeted therapy; Taxanes; Tonsil cancer", "medline_ta": "Eur Arch Otorhinolaryngol", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D000068818:Cetuximab; D002945:Cisplatin; D018572:Disease-Free Survival; D000077143:Docetaxel; D005472:Fluorouracil; D006258:Head and Neck Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D000072078:Positron Emission Tomography Computed Tomography; D011788:Quality of Life; D012074:Remission Induction; D043823:Taxoids; D013997:Time Factors; D014067:Tonsillar Neoplasms; D016896:Treatment Outcome", "nlm_unique_id": "9002937", "other_id": null, "pages": "1629-36", "pmc": null, "pmid": "26044403", "pubdate": "2016-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "16951222;11283932;25105871;1634913;2414023;8402640;2022478;23147544;872136;12085250;24577117;15805872;21861540;21352589;20943624;18784101;17538161;10776971;17442661;24899223;19704061;23835714;9625170;15452834", "title": "Long-term remission of locally recurrent oropharyngeal cancer after docetaxel-based chemotherapy plus cetuximab.", "title_normalized": "long term remission of locally recurrent oropharyngeal cancer after docetaxel based chemotherapy plus cetuximab" }
[ { "companynumb": "BE-MYLANLABS-2016M1029322", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": "1", ...
{ "abstract": "Alcohol use disorder (AUD) frequently co-occurs with other psychiatric disorders, including personality disorders, which are pervasive, persistent, and impairing. Personality disorders are associated with myriad serious outcomes, have a high degree of co-occurrence with substance use disorders, including AUD, and incur significant health care costs. This literature review focuses on co-occurring AUD and personality disorders characterized by impulsivity and affective dysregulation, specifically antisocial personality disorders and borderline personality disorders. Prevalence rates, potential explanations and causal models of co-occurrence, prognoses, and the status of existing treatment research are summarized. Several important future research considerations are relevant to these complex, co-occurring conditions. Research assessing mechanisms responsible for co-occurring AUD and antisocial personality disorder or borderline personality disorder will further delineate the underlying developmental processes and improve understanding of onset and courses. In addition, increased focus on the efficacy and effectiveness of treatments targeting underlying traits or common factors in these disorders will inform future prevention and treatment efforts, as interventions targeting these co-occurring conditions have relatively little empirical support.", "affiliations": "Ashley C. Helle, Ph.D., is a Postdoctoral fellow in the Department of Psychological Sciences, University of Missouri-Columbia, Columbia, Missouri.;Ashley L. Watts, Ph.D., is a Postdoctoral fellow in the Department of Psychological Sciences, University of Missouri-Columbia, Columbia, Missouri.;Timothy J. Trull, Ph.D., is a Curators' Distinguished Professor and a Byler Distinguished Professor in the Department of Psychological Sciences, University of Missouri-Columbia, Columbia, Missouri.;Kenneth J. Sher, Ph.D., is a Curators' Distinguished Professor in the Department of Psychological Sciences, University of Missouri-Columbia, Columbia, Missouri.", "authors": "Helle|Ashley C|AC|;Watts|Ashley L|AL|;Trull|Timothy J|TJ|;Sher|Kenneth J|KJ|", "chemical_list": "D000927:Anticonvulsants; D000928:Antidepressive Agents; D014150:Antipsychotic Agents", "country": "United States", "delete": false, "doi": "10.35946/arcr.v40.1.05", "fulltext": "\n==== Front\nAlcohol ResAlcohol ResAlcohol Research : Current Reviews2168-34922169-4796National Institute on Alcohol Abuse and Alcoholism 10.35946/arcr.v40.1.05arcr.v40.1.05Alcohol ResearchCurrent ReviewsAlcohol Use Disorder and Antisocial and Borderline Personality Disorders Helle Ashley C. Ashley C. Helle, Ph.D., is a Postdoctoral fellow in the Department of Psychological Sciences, University of Missouri-Columbia, Columbia, MissouriWatts Ashley L. Ashley L. Watts, Ph.D., is a Postdoctoral fellow in the Department of Psychological Sciences, University of Missouri-Columbia, Columbia, Missouri.Trull Timothy J. Timothy J. Trull, Ph.D., is a Curators’ Distinguished Professor and a Byler Distinguished Professor in the Department of Psychological Sciences, University of Missouri-Columbia, Columbia, MissouriSher Kenneth J. Kenneth J. Sher, Ph.D., is a Curators’ Distinguished Professor in the Department of Psychological Sciences, University of Missouri-Columbia, Columbia, Missouri2019 30 12 2019 40 1 arcr.v40.1.052019Unless otherwise noted in the text, all material appearing in this journal is in the public domain and may be reproduced without permission. Citation of the source is appreciated.Alcohol use disorder (AUD) frequently co-occurs with other psychiatric disorders, including personality disorders, which are pervasive, persistent, and impairing. Personality disorders are associated with myriad serious outcomes, have a high degree of co-occurrence with substance use disorders, including AUD, and incur significant health care costs. This literature review focuses on co-occurring AUD and personality disorders characterized by impulsivity and affective dysregulation, specifically antisocial personality disorders and borderline personality disorders. Prevalence rates, potential explanations and causal models of co-occurrence, prognoses, and the status of existing treatment research are summarized. Several important future research considerations are relevant to these complex, co-occurring conditions. Research assessing mechanisms responsible for co-occurring AUD and antisocial personality disorder or borderline personality disorder will further delineate the underlying developmental processes and improve understanding of onset and courses. In addition, increased focus on the efficacy and effectiveness of treatments targeting underlying traits or common factors in these disorders will inform future prevention and treatment efforts, as interventions targeting these co-occurring conditions have relatively little empirical support.\n\nalcohol use disorderantisocial personality disorderborderline personality disordercomorbidity\n==== Body\nIntroduction\nThe quest to understand the etiology, course, and treatment of alcohol use disorder (AUD) has given rise to an extensive body of work on identifying factors that contribute to these phenomena. Many of these factors, such as temperament and personality traits, are common to multiple psychiatric conditions, and some, such as variants of alcohol metabolizing genes, are specific to AUD. This review describes the co-occurrence of AUD with antisocial personality disorder (ASPD) and borderline personality disorder (BPD). The prevalence and effects of these personality disorders, their co-occurrence with AUD through the lens of several current models, and the treatment and overall implications of these complex co-occurrences are discussed.\n\nThe conceptualization and diagnostic criteria for AUD has evolved over the years and through editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM). For example, in the text revision of the fourth edition of the DSM (DSM-IV-TR) the conceptualization included alcohol abuse and dependence, which were categories that comprised two different symptom sets and required a number of criteria for diagnosis.1 More recent conceptualizations of AUD are seen in the fifth edition of the DSM (DSM-5), which describes AUD as a single disorder with 11 criteria and includes a severity gradient designated by the number of criteria met (e.g., two to three symptoms constitute mild AUD).2 Although this conceptualization inherently is still categorical, the changes are consistent with a transition toward dimensional approaches (e.g., severity can be graded across one set of symptoms).3 Additional work needs to be done to capture a fully dimensional diagnosis for AUD.\n\nOther diagnostic systems, such as the 11th revision of the International Classification of Diseases (ICD-11), have implemented new conceptualizations of AUD that differ from the alcohol abuse and dependence categories and that attempt to capture potential features of severity (e.g., harmful use diagnosis and recurrent problems).4 Note that many of the studies reported in this review focus on previous DSM conceptualizations of AUD, such as the categories of alcohol abuse and dependence from the DSM-IV-TR. In addition, much of the work described here conceptualizes AUD as a categorical diagnosis, either present or absent, although support for a categorical AUD taxonomy is declining.1 Differing AUD conceptualizations may affect the general consensus of research findings.\n\nPersonality disorder diagnoses and, more generally, psychopathology are migrating toward a dimensional classification system. For example, the ICD-11 includes a dimensional approach to personality disorder diagnosis.4 For classifying personality disorders, there has been a call for and transition to dimensional approaches, and a number of the proposed models largely align with robust and well-validated models of personality.5–8 The DSM-IV-TR personality disorder categories were retained in the DSM-5, but the DSM-5 (Section III: Emerging Measures and Models) proposes a new model that integrates dimensional aspects (e.g., dimensional personality traits) into a more traditional categorical classification model.2 This hybrid categorical-dimensional model, the alternative DSM-5 model for personality disorders, is described in more detail in the following section.\n\nPersonality Disorders\nAlthough the long-standing research aimed at identifying an “alcoholic personality”9 has not been particularly fruitful, these efforts have nevertheless identified some personality traits, or constellations thereof, that are associated with increased risk for alcohol use and misuse. ASPD and BPD, both characterized by impulsivity, negative emotionality, and antagonism, are two such constellations. This review focuses on ASPD and BPD; however, personality disorders in general are the focus of some research presented and are noted throughout.\n\nASPD is characterized by behavior patterns that show a lack of regard for and violation of the rights of others, deceit, manipulation, and impulsivity that have occurred since age 15, in addition to evidence of conduct disorder before age 15.2 BPD is conceptualized as a disorder of emotion dysregulation, impulsivity, suicidality, identity disturbance, and difficulties in interpersonal relationships. Although the DSM-5 classifies personality disorders categorically, the DSM-5 alternative, hybrid dimensional-categorical model of personality disorder describes these disorders in terms of broad personality domains (negative affectivity, detachment, antagonism, disinhibition, and psychoticism) and facets that are largely consistent with popular models of general personality, namely the five-factor model (see the section Trait Explanations for a detailed explanation of this model).5 Individual personality disorders such as BPD are then characterized by specific traits, resulting in a hybrid model that describes the disorders in terms of both dimensional trait features (e.g., disinhibition) and categories (e.g., BPD).\n\nWithin the alternative DSM-5 model for personality disorders, ASPD and BPD are characterized by high levels of disinhibition, with BPD additionally associated with high levels of negative affectivity, and ASPD additionally associated with high levels of antagonism. The ICD-11 conceptualizes personality disorders in a manner similar to the DSM-5 alternative model, such that dimensional traits (e.g., negative affectivity and disinhibition) are included in the diagnosis.4 Further, in the ICD-11, these traits accompany a general diagnosis for mild, moderate, or severe personality disorder.\n\nPrevalence\nEpidemiological, community, and clinical psychiatric samples across all 10 categorical personality disorders have yielded prevalences ranging from 9% to 21% in community (nonclinical) samples10 to approximately 31% in psychiatric outpatient samples,11 with many individuals receiving diagnoses of more than one personality disorder. Across epidemiological studies, community prevalences for ASPD and BPD, individually, range from 1% to 4% and 1% to 6%, respectively.10\n\nASPD and BPD manifest in a broad array of maladaptive behaviors, including suicide, self-harm, aggression, criminal behavior, and substance misuse. Moreover, ASPD and BPD are associated with profound economic costs.12–15 ASPD is associated with criminal offenses, with ASPD prevalence as large as 60% in prison populations,12 and BPD is associated with higher suicide rates than those among the general population.13 Both conditions are associated with higher rates of chronic illness, sleep disturbances, and health care utilization when compared to rates among individuals with no diagnosis of personality disorder.14,15 Evidence shows that ASPD and BPD are related, and that they are serious psychiatric disorders associated with significant consequences, including consequences undergirded by poor emotional and behavioral control (e.g., excessive alcohol use), making the disorders likely to co-occur with AUD.\n\nDiagnosis limitations and considerations\nBecause the literature on co-occurrence is largely based on categorical diagnoses, the limitations and biases of the current diagnosis classification system for personality disorders should be considered. A few well-documented limitations include lack of coverage of an individual’s presenting concerns within the existing personality disorders, an arbitrary number of symptoms required for a diagnosis, large variation of presentation and symptoms within each personality disorder, and high co-occurrence of personality disorder categories.7 Although substantial evidence supports dimensional as opposed to categorical conceptualizations of personality disorders, such as the five-factor model and the DSM-5 alternative model for personality disorders,6 the current exploration of co-occurrence inherently relies on categorical diagnoses.16\n\nConsequently, some apparent co-occurrence may be misleading because of overlapping features and aspects of diagnostic bias. Moreover, subthreshold levels of alcohol or personality pathology, such as binge drinking and impulsivity, which are not diagnostic categories, may co-occur before co-occurring alcohol and personality disorders can be detected. Thus, an association between personality disorders and AUD may manifest before formal diagnoses of either condition and may occur at varying levels of pathology. These factors should be considered when examining the conceptualization and diagnosis of co-occurring AUD and personality disorders.\n\nEpidemiology of Co-Occurring AUD and Personality Disorders\nData from large epidemiological studies of psychopathology highlight the intertwined nature of AUD and personality disorders. In the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), which was a large, population-based study, 42% of participants who met the diagnostic criteria for any personality disorder also met the criteria for DSM-IV alcohol dependence.10 Diagnostic co-occurrence tended to be most pronounced for Cluster B personality disorders, particularly ASPD and BPD, which are characterized by disinhibited and antagonistic forms of externalizing traits and behaviors. Recent reviews have indicated that of those individuals who met diagnostic criteria for BPD, 46% to 49% also met diagnostic criteria for current AUD, and 59% met diagnostic criteria for lifetime AUD.17 The prevalence of AUD among those diagnosed with ASPD was about 68%.18 Among the general population or clinical samples of individuals with a current diagnosis of AUD or alcohol dependence, the prevalence of a BPD diagnosis was approximately 12% to 17%.17 Among individuals with an AUD diagnosis, especially clinical samples, ASPD diagnoses were slightly more prevalent than BPD diagnoses, ranging from 19% to 22%.18 Overall, AUD and ASPD and BPD overlap to a high degree.\n\nNevertheless, it is important to consider co-occurrence estimates in the context of their sampling limitations and interpretive challenges. For instance, many studies that establish populationwide estimates are cross-sectional, which precludes investigating the temporal relations among onset of AUD and personality disorders. Moreover, epidemiological data tend to rely on retrospective self-reports and lifetime diagnoses, which may be influenced by an individual’s current emotional state (e.g., momentary affect) and general personality traits (e.g., level of negative emotionality).\n\nIn addition, when assessing for AUD, interviewers ask about the various consequences of alcohol use. In practice, establishing alcohol as a cause or contributor to a criterion (e.g., hazardous use) can be extremely challenging, but the assumption that alcohol played a causal or consequential role is often the default.19 For example, if an individual routinely drinks while driving, is this behavior best understood as caused by AUD or by a more general pattern of rule-breaking and risky behavior? Therefore, some ostensible co-occurrence could be due to imprecision in the diagnostic criteria and how those criteria are assessed.\n\nExplanations and Models of Co-Occurrence\nRelevant to developing effective treatment and prevention are the mechanisms responsible for co-occurring AUD and personality disorders, that is, how or why personality disorders relate to AUDs. Explanations or models of co-occurring AUD and ASPD or BPD include common third-variable (e.g., trait) explanations and causal (e.g., AUD leads to personality disorder or personality disorder leads to AUD) explanations.\n\nTrait explanations\nMeta-analytic research suggests that personality disorders can be conceptualized as combinations, or even configurations, of extreme variants of general personality traits, which often are based on or correspond with the five-factor model.8 The five-factor model encompasses the broad personality domains of neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness, each of which includes narrower traits, termed “facets.” Five-factor model domains and facets are dimensional, such that variability in personality lies on a continuum, with each pole reflecting an extreme of a basic trait. For simplicity, the two poles are described as high and low. For example, social cooperativeness and affiliation reflect high agreeableness, which is the opposite pole of antagonism. ASPD and BPD reflect low levels of agreeableness and conscientiousness and high levels of antagonism and impulsivity, respectively. ASPD and BPD have key associations with neuroticism and extraversion, although the personality trait associations are different for each disorder. BPD is characterized by high levels of neuroticism, whereas ASPD is not robustly associated with neuroticism but is characterized by high levels of two of neuroticism’s facets: anger and impulsiveness. ASPD is characterized by high levels of the excitement-seeking facet of extraversion, whereas BPD is characterized by low levels of the warmth and positive emotionality facets of extraversion.\n\nFrom a trait perspective, BPD and ASPD tend to relate similarly to AUD. This similarity can be explained by their overlapping profiles of general personality traits, particularly antagonism and impulsivity (disinhibition).8 Although AUD often is conceptualized as an episodic condition rather than a chronic (trait-like) condition, it is increasingly apparent that AUD is related to several personality traits, and that these traits are similar to the traits that undergird ASPD, BPD, and other psychopathology in general. Trull and Sher first established that alcohol abuse and dependence were characterized by high levels of neuroticism and low levels of agreeableness and conscientiousness.20 Even with no diagnosis of AUD, features or patterns of alcohol use (e.g., ever using alcohol, quantity of alcohol use, and problematic use of alcohol) have been characterized by the same general personality traits (e.g., low conscientiousness).21\n\nOf note, typologies for AUD have shown similar patterns of personality dimensions. Cloninger conceptualized two subtypes of AUD.22 Type I had later onset (after age 25) and was associated with more anxious rather than impulsive features. Type II was more common in men and represented individuals who had early onset of alcohol use and frequent aggressive behaviors or arrests. Cloninger examined Type II AUD22 and ASPD23 separately and posited that they both had high novelty-seeking, low harm avoidance, and low reward dependence. This literature converges evidence that AUD on one hand and BPD and ASPD on the other have comparable relationships with general personality traits. Personality traits associated with aggressive, impulsive, and neurotic tendencies coalesce into the trait complexes of ASPD and BPD. These same trait complexes may contribute to a broad swath of externalizing forms of psychopathology, including alcohol and other substance misuse, risky sex, and other antisocial behavior.24,25\n\nDevelopmental explanations\nAdolescence and emerging adulthood are crucial developmental periods for understanding the sources and trajectory of AUD. In addition to being a period of heightened alcohol use,26 adolescence tends to be associated with increased independence and acquisition of adult roles, exploration, and reward-seeking, as well as heightened levels of impulsivity, sensation-seeking, and, to a lesser extent, neuroticism.27 Declines in alcohol use and reductions in personality trait levels across development have been called “maturing out”28 and the “maturity principle,”29 respectively. For example, late adolescence and emerging adulthood are associated with heightened prevalence of alcohol use and associated problems, the risk for which tends to decline with age. Although personality traits are believed to reflect a person’s stable, internal disposition,30 the transition from emerging to young adulthood is associated with normative changes in personality that reflect development toward psychological maturity, such as increases in emotional stability, self-control, and affiliation, and a shift to adult roles, such as committed relationships and parenthood.27\n\nResearchers have empirically linked these developmental changes in personality and alcohol use.31–33 Specifically, changes in impulsivity, neuroticism, and problematic alcohol use tend to correlate. Across adolescence and early adulthood, individuals with steeper declines in impulsivity and neuroticism demonstrated steeper declines in problematic alcohol use.33 Individuals with a less substantial decline (or even an increase) in impulsivity and neuroticism had either increases, or smaller decreases, in problematic alcohol use. In the same vein, increases in risk-taking behavior across development are associated with increases in alcohol use among adolescents.34,35 Still, there are individual differences in these general developmental trends, and some research suggests that personality may moderate AUD trajectories such that individuals who exhibit more impulsivity and neuroticism are more likely to experience more severe or chronic problems with alcohol. Relatedly, other research suggests variability in the developmental course of personality and alcohol use. Some individuals do not exhibit the maturity principle or mature out of alcohol use and instead exhibit chronic and stable alcohol, emotional, and behavioral control issues.36,37\n\nCausal models\nAt least four major co-occurrence models, each of which contains different assumptions, explain how AUD relates to ASPD and BPD: the predisposition (or vulnerability) model, the complication (or scar) model, the exacerbation model, and the spectrum model.38 The predisposition model purports that existing personality disorder elicits environmental responses, such as interpersonal or occupational problems, that provoke the onset of AUD. The temporal relationship between AUD and ASPD or BPD is reversed in the complication model, whereby AUD “scars” an individual’s personality. For instance, neuroadaptation due to excessive alcohol consumption across time might result in increased impulsivity or negative emotionality. The exacerbation model purports that ASPD and BPD add to or modify the manifestation, course, or expression of AUD, resulting in a distinctive AUD symptom profile. For instance, the presence of ASPD or BPD might increase the longevity of AUD or the extent of impairment. The spectrum model posits that the two disorders share common etiology.\n\nUnfortunately, there is a relative paucity of empirical data for comparing these causal models. Existing data tend to support the predisposition model, in which the personality traits that undergird ASPD or BPD, particularly impulsivity, novelty-seeking, and neuroticism, tend to predict later alcohol problems, including AUD diagnosis39 and onset.40 Tracing the prospective, longitudinal relationships between impulsivity, neuroticism, and AUD across adolescence, Elkins and colleagues demonstrated that, after accounting for preexisting AUD, impulsivity and negative emotionality uniquely predicted new onset of AUD at age 20 after a baseline at age 17.40\n\nStill other research suggests that personality may contribute to AUD by means of “niche-picking,” whereby those with higher levels of certain personality traits select into high-risk environments for AUD. Park and colleagues found that undergraduates who scored highly on extraversion, despite not drinking heavily before college, were more likely to enter into the Greek system and thus were at increased risk for alcohol problems later in college.41 Novelty-seeking (a facet of extraversion) also has been shown to have a proximal association with alcohol use, such that enhancement motives for drinking (to “get high” or enhance positive affect) were associated with sensation-seeking.42 Together, these findings suggest that traits associated with ASPD and BPD, namely impulsivity and negative emotionality, appear to reflect broad liability for precocious alcohol use and AUD. Other traits associated with ASPD, namely novelty-seeking, tend to be associated with AUD both directly and indirectly by influencing selection into high-risk environments and motives for drinking.\n\nThe exacerbation model has some limited support, in that individuals with higher levels of outgoingness, impulsivity, aggression, and antisociality have been shown to be more likely to experience reinforcing, stress-dampening effects of alcohol.43 The complication model also has some limited support, as demonstrated by research in which chronic, heavy-drinking adolescents exhibited short-term (1 year) increases in impulsive behavior.35 Research also has implicated alcohol use as a predictor of aggressive and violent behavior.24\n\nOf note, the temporal relatedness of alcohol use to changes in personality is relevant, such that “proximal, but not necessarily distal, alcohol use influences subsequent changes in personality.”44(p363) Barnes wrote about the directionality of these relationships, noting that neuroticism tended to increase from “prealcoholic” to “clinical alcoholism,” suggesting that such a change in personality may be a result of heavy or chronic drinking.45\n\nThe increase in neuroticism as alcohol use progresses aligns with neurobiological models of addiction, such as the allostatic model. This model posits that as addiction and compulsion for a substance progresses, negative affect increases in the absence of the substance, thereby contributing to substance use as negative reinforcement and becoming a continuing cyclical process.46 The result is progressive allostatic changes of less positive and more negative mood. The persistence and reversibility of such presumed allostatic effects in the absence of continued heavy drinking is unclear.45 Together, these findings highlight the intertwined, bidirectional connections between AUD and personality disorders, which likely cannot be described by one causal model.\n\nThe predisposition, complication, and exacerbation models presume independent etiology and onset of AUD and personality disorders. The spectrum model, in contrast, contains two major assumptions: Personality disorders and AUD are not distinct and rise, at least in part, from a set of common etiological factors. In addition, each disorder exists on a continuum or comprises multiple components along a continuum, ranging from subclinical traits to full-blown psychopathology. This model has received considerable support and also has historical roots. Cloninger first proposed that personality mediated genetic risk for AUD,23 a theory that Slutske and colleagues later instantiated empirically.47 Using a multivariate behavioral genetic twin design, these researchers found that the genetic variance associated with the broad trait of behavioral undercontrol, which included impulsivity, novelty-seeking, and aggression, accounted for 40% of the genetic variance in alcohol dependence. These findings highlight the notion that the overlap of impulsivity and AUD originates from shared genetic mechanisms. Other work has demonstrated the same for AUD and BPD.48 This shared genetic mechanism appears to give rise to externalizing behavior and psychopathology generally,25 including AUD, other substance use disorder (SUD), conduct disorder, and antisocial behavior, rather than to impulsivity and AUD specifically.\n\nThese findings align with burgeoning evidence that internalizing and externalizing are two broad, heritable spectra of psychopathology. Internalizing is characterized by elevated negative emotionality, and externalizing is characterized by behavioral undercontrol and novelty-seeking. These two spectra are responsible for well-documented co-occurrence of psychiatric conditions that share phenomenological similarities.49,50\n\nContemporary taxonomies organize psychopathology dimensionally and hierarchically, with signs and symptoms of psychiatric conditions at the bottom of the hierarchy and externalizing and internalizing toward the top.51 Much research places AUD, ASPD, and BPD squarely within externalizing. Externalizing can be broken down into disinhibited and antagonistic forms. Disinhibited externalizing comprises all substance-related disorders, whereas antagonistic externalizing comprises BPD as well as narcissistic, histrionic, and paranoid personality disorders. Notably, an antisocial behavior subfactor is believed to contribute to both the disinhibited and antagonistic externalizing subspectra and includes ASPD, conduct disorder, oppositional defiant disorder, attention deficit hyperactivity disorder, and intermittent explosive disorder. Some research suggests that BPD contributes to both externalizing and internalizing spectra,52 although this possibility warrants more research attention.\n\nTully and Iacono proposed a hierarchical common liabilities model, which suggests that disorders (e.g., SUD and ASPD) that load onto the same psychopathology spectrum (e.g., externalizing) share common etiologic mechanisms.50 As noted previously, a significant amount of evidence demonstrates that genes influence the covariation among disorders within externalizing and internalizing spectra, likely because of the common neurobiological mechanisms within each spectrum. These researchers offered that neurobiological mechanisms responsible for behavioral control and negative emotionality give rise to externalizing and internalizing, respectively, and likely are responsible for the co-occurrence among AUD, ASPD, and BPD. Specific genetic and other neurobiological mechanisms responsible for the development of AUD, ASPD, and BPD remain elusive. Further research is needed to identify more specific neurobiological mechanisms and biologically based endophenotypes implicated in the covariation among AUD, ASPD, and BPD, as well as those that are unique to each condition.53\n\nClosely aligned to the spectrum perspective is the notion that AUD is heterogeneous and has two or more subtypes, each one associated with a different spectrum.54,55 A number of these subtypes, such as Knight’s “essential” type,54 Babor’s Type B,55 and Cloninger’s Type II,22 are characterized by early onset and antisocial features. Thus, a relevant consideration is the possibility that the apparent co-occurrence between AUD and ASPD, for example, could be viewed as a subtype of AUD associated with the externalizing spectrum. Other subtypes, such as Knight’s “reactive alcoholism,” Babor’s Type A, and Cloninger’s Type I, are associated more with the internalizing spectrum. The subtyping literature highlights that the phenomenon of co-occurrence need not be viewed as the overlap of two relatively homogeneous conditions but could represent a single, relatively homogeneous, subtype of a heterogeneous condition.\n\nPrognosis and Course\nThe course of AUD has much variation, with some cases limited to a specific period of time, others showing a relapsing and remitting pattern, and still others showing a persistent, chronic pattern.56 Given the chronic nature of personality disorders, it seems likely that the presence of a co-occurring personality disorder would be associated with a more pernicious course of AUD. Relatively little research has used community-based samples to examine the course of AUD and personality disorders. However, existing data suggest co-occurring personality disorders augur poor prognoses. For example, in a general population sample, ASPD and BPD were significantly associated with persistence of alcohol dependence.57\n\nFew in-depth investigations focus on the course of co-occurring AUD and ASPD. One study investigated the prevalence and course of SUD, including AUD, in a treatment-seeking sample that included a small number (n = 54) of individuals diagnosed with ASPD and a comparison sample (n = 552) of individuals with no ASPD diagnosis.58 The investigators found that individuals diagnosed with ASPD started drinking alcohol at younger ages. However, AUD diagnosis and indicators of course (i.e., years of alcohol use, days of alcohol use in the past year, and days of abstinence) were not significantly different between the ASPD and non-ASPD groups.\n\nA prospective, 10-year study focused on the course of BPD in a clinical sample and demonstrated a few major themes relevant to the course of SUD, including alcohol abuse and dependence.59 The study included two groups of participants: those diagnosed with BPD and those diagnosed with another personality disorder. First, diagnoses of alcohol abuse and dependence were more common among participants who were diagnosed with BPD when compared with participants diagnosed with another personality disorder. Second, the prevalence of alcohol disorders similarly decreased over time for both groups, but it remained more common among those diagnosed with BPD.\n\nThe course of alcohol and substance disorders was examined more closely within the BPD group. The findings indicated that a vast majority (about 90%) of participants diagnosed with BPD had a remission of alcohol abuse or dependence by the 10-year follow-up.59 Further, participants with BPD were more likely to experience remission than recurrences of use, and individuals who had BPD but no alcohol diagnosis at baseline were unlikely to develop an alcohol-related diagnosis during the study. Although this was not a treatment-specific study, the participants were recruited from inpatient samples and were in treatment for most of the study period.\n\nIn a review of treatment outcomes for individuals with co-occurring AUD and ASPD, Newton-Howes and colleagues concluded that alcohol outcomes and psychosocial functioning improved for those who stayed in treatment, although attrition was high.60 The prognosis of co-occurring AUD and BPD is complex and difficult to disentangle given the varied pathways of each disorder. Intensive longitudinal studies are critical to assess variations in course and prognosis and can potentially provide indicators of co-occurrence and severity. Additional research in this area is needed.\n\nTreatment\nClinical approaches to and research on treatment for personality disorders and SUD (including AUD) have often been tackled from a silo approach, such that one condition (e.g., addiction) is addressed separately from other psychological symptoms and disorders. Addressing personality disorders and SUD independently may be necessary in the clinical realm because of active substance use or threats of relapse thwarting treatment progress. Also, this approach may be necessary for research trials to maximize internal validity.\n\nDepending on the severity of AUD, the detoxification period may first be necessary for the most accurate assessment of mood and personality. For example, increased irritability, anxiety, and low mood may be present primarily during heavy use or during withdrawal and may resolve if substance induced.2,46 Assessment of affective symptoms after withdrawal or detoxification, incorporating known information about premorbid emotional and behavioral functioning when available, may help with diagnosis decisions and may serve to disentangle substance use from symptoms that may be associated with other disorders. However, some individuals do not receive treatment following detoxifications, as it is estimated that approximately 50% of detoxifications are followed by other treatment.61\n\nAlthough co-occurring AUD or SUD and personality disorders understandably can make the assessment and intervention process challenging, it may be unrealistic to require that treatment focus on only one aspect at a time (e.g., target only substance use and then treat the personality disorder). For co-occurring AUD and BPD, a number of complications may arise, such as suicidal thoughts or behavior associated with the personality disorder, potentially undermining the ability to continue with AUD treatment. Thus, it may not always be possible or ideal to treat only the AUD or personality disorder and then proceed to treat the co-occurring disorder. These complexities are evident throughout the research literature, as few studies specifically examine co-occurring conditions.\n\nAlthough treatments have been developed or adapted for AUD, SUD, BPD, and ASPD, there is limited empirical support for these treatments among samples of individuals diagnosed with AUD and co-occurring ASPD or BPD. Treatment research involving those with AUD and psychiatric disorders other than personality disorders also is limited, highlighting a major gap in empirical and intervention fields.62 However, studies examining various disorder-specific treatments may be useful for treating the co-occurring disorders. It should be noted that a number of treatments may be effective for AUD and ASPD or BPD, but they have not been established as efficacious because of limited trials, small samples, or a broad focus on SUD or outcomes rather than AUD.63 Regardless, research in which SUD is the focus may provide a starting point for further treatment research on alcohol use and AUD in the context of BPD and ASPD. (See Table 1 for brief descriptions of the treatments discussed in this article.)\n\nPsychosocial treatments\nThere is modest support for treatments that show reductions in substance use while primarily treating BPD (i.e., dialectical behavior therapy, dynamic deconstructive psychotherapy, and dual-focused schema therapy) or while treating SUD in the context of BPD.63,76 For example, one study examined dialectical behavior therapy for SUD and included medication assistance (e.g., replacing opiates with methadone) in the initial phases of treatment, called “transitional maintenance.”64 The investigators reported that at the end of treatment and at a 16-month follow-up, this treatment was more effective at reducing substance use than treatment as usual.\n\nOther studies have found dialectical behavior therapy to be as effective at treating BPD symptoms for those with BPD and SUD as it is for participants with no SUD.77 However, for the reduction of substance-related symptoms, no difference was found between the dialectical behavior therapy group and the treatment as usual group.77 Although dialectical behavior therapy is primarily used for BPD, it was found to be acceptable in a clinical trial intended to treat men with both BPD and ASPD, most of whom also reported substance use.78 Rates of alcohol and substance use did not change substantially in this trial, however. A review examining effective treatments for BPD determined that other treatments, such as mentalization-based therapy, showed promise, although the small number of studies limited the strength of possible recommendations.79\n\nEffective treatments for ASPD are limited because few trials with sufficient evidence have been identified.80 ASPD treatments showing promise, such as treatment with contingency management, often were originally developed for SUDs, further highlighting the possibility of a common thread across interventions for co-occurring AUD and ASPD or BPD.\n\nAs noted by Garofalo and Wright, treatment approaches based on transdiagnostic constructs such as neuroticism and disinhibition may target changes in the constructs.24 Transdiagnostic factors, which have been described as “psychological constructs that are observed across a range of disorders” and “functionally causal mechanisms that inform the development of classes of disorders,” align with a dimensional approach to both understanding and treating psychopathology.81(p135) Some treatment packages that use a transdiagnostic approach are acceptance and commitment therapy,71 dialectical behavior therapy,64 and the unified protocol.72 Through various treatments and across an array of disorders, including BPD and SUD, research has supported changes related to transdiagnostic constructs, such as increases in emotion regulation.82 In addition, indirect evidence supporting transdiagnostic approaches comes from research on personality and alcohol, which has revealed that using alcohol to cope with negative emotions mediates the association between personality traits, such as neuroticism and impulsivity, and reported alcohol problems.83\n\nThe integration of relevant treatment components such as emotion regulation skills, as opposed to stand-alone, single-disorder treatment, is highly compatible with transdiagnostic approaches. For example, contingency management, an effective treatment for AUD that uses behavioral principles to decrease ineffective and increase effective behaviors, has been incorporated into treatment for other disorders, such as dialectical behavior therapy.70 Integrated treatment for personality disorders proposes using key treatment components from multiple therapies and developing a treatment adapted to a patient’s needs.74 This approach inherently integrates key transdiagnostic components such as emotion regulation.\n\nResearch specific to co-occurring SUD and personality disorders (not exclusively ASPD and BPD) has concluded that using evidence-based strategies across therapies (e.g., combining contingency management with pharmacotherapy) tends to be most effective.84 Research on AUD treatment has suggested that targeting specific traits, such as impulsiveness, using a matched treatment approach may effectively reduce alcohol use.85 Mindfulness and modification therapy, which is another transdiagnostic treatment that targets behavioral dysregulation, has been shown to be related to decreased alcohol use and aggression among voluntary and court-ordered participants.75 Collectively, the research suggests that identifying transdiagnostic features and treating conditions using evidence-supported treatment components that target those features may be a useful approach for treating co-occurring AUD and personality disorders.\n\nImportant to note is attrition during treatment for co-occurring AUD or SUD and personality disorders (e.g., 40% in a sample of SUD and BPD), and some evidence shows higher dropout rates for participants who had AUD and a personality disorder, as compared to those with AUD and no personality disorder.60,64 This attrition is not surprising given that this population faces many challenges and complexities with the presenting problem and related to the broader environment and context. However, some studies have pointed to factors and existing strategies that may improve retention rates, such as making treatment enrollment contingent on predetermined attendance rules and establishing strong therapeutic relationships.64 Other research has called for a focus on improving dual-diagnosis treatments and retention strategies for people with AUD.60\n\nPharmacological interventions\nComprehensive treatment for people with co-occurring AUD and ASPD or BPD often adopts a multifaceted approach using psychosocial and pharmacological interventions, including medication-assisted treatment for AUD and for BPD. Treatment for AUD may include acamprosate, naltrexone, disulfiram, or off-label medications such as topiramate,86 and treatment for BPD may include naltrexone or topiramate.87,88 This review focuses on studies of personality disorders and AUD outcomes and is organized by class of medication (i.e., alcohol-specific medications, anticonvulsants, and psychoactive drugs).\n\nAn investigation of the effectiveness of medications among individuals with alcohol dependence found that treatment with naltrexone, naltrexone plus disulfiram, or disulfiram plus placebo was just as effective for alcohol use outcomes among individuals who had co-occurring BPD or ASPD as it was among those with no ASPD or BPD.89 In another study, Rohsenow and colleagues identified that the presence of antisocial traits was associated with increased effectiveness of naltrexone when compared to placebo.90\n\nBefore discussing pharmacotherapy for personality disorders, it should be noted that no medications for ASPD or BPD have been approved by the U.S. Food and Drug Administration. Further, no clinical trials have directly examined the efficacy of medications for people with co-occurring AUD and ASPD or BPD. Most studies have focused on one medication that targets similar mechanisms (e.g., impulsivity) across co-occurring conditions.\n\nResearch supporting specific pharmacotherapy for BPD is mixed, largely because the quality and quantity of studies provide insufficient evidence to evaluate efficacy.91 Although the evidence regarding pharmacotherapy approaches for BPD is equivocal, certain medications, such as mood stabilizers and antipsychotics, matched to specific symptom presentations, such as affective lability, may show improvement for BPD symptoms, whereas selective serotonin reuptake inhibitors (SSRIs) demonstrate little to no efficacy.87 Similarly, studies have preliminarily supported use of naltrexone for symptoms in the impulsive behavior domain and have reported reductions in self-injurious thoughts and behaviors.87,88 The general recommendation is to use psychotherapy as the primary treatment with pharmacotherapy as an adjunctive treatment, since the efficacy of specific medications for BPD is not currently robust. Regarding ASPD, little evidence supports pharmacotherapy, and medications are often used to treat symptoms but not as a stand-alone treatment.92\n\nAnticonvulsants such as topiramate and lamotrigine and atypical, second-generation antipsychotics such as olanzapine have been investigated for the treatment of AUD and BPD. Topiramate has been identified as a possible off-label medication for AUD and BPD separately, suggesting a mechanism of action (of increased inhibitory control) applicable to both conditions.93 A review of the medications for co-occurring AUD and BPD noted that topiramate was associated with fewer drinking days for participants who had AUD and with decreased anger intensity and reactions for those who had BPD.63 In addition, topiramate and lamotrigine have demonstrated some effectiveness for decreasing craving, and lamotrigine has been associated with a decrease in impulsivity and anger symptoms of BPD.63\n\nThe atypical antipsychotics aripiprazole and olanzapine have been associated with impulsivity changes in BPD.94,95 The effect of atypical antipsychotics on alcohol-related outcomes is mixed. An inconsistent effect for outcomes such as craving or abstinence has been reported across studies, and some research has suggested that genetic influences may act as primary moderators.96,97\n\nThe literature on antidepressants has demonstrated mixed results across studies and conditions. As previously mentioned, SSRIs generally have been ineffective in the treatment of BPD. On the other hand, research investigating AUD and ASPD has found more promising results. For instance, one study concluded that people with AUD and ASPD who also had another mood disorder benefited from antidepressants, whereas those with no additional mood disorder did not.98 In a review of pharmacotherapy for ASPD, the tricyclic antidepressant nortriptyline was identified as one of the medications that was superior to placebo on at least one alcohol-related outcome (i.e., drinking days).92 However, only one study reported this result, and several other outcomes, such as patient drinking ratings and craving, did not differ between the nortriptyline and placebo groups.92 As with the atypical antipsychotics, antidepressants have been associated with different pharmacological outcomes across the traditional alcohol typologies. For individuals in the Type A typology group compared with those in the Type B group, the SSRI sertraline was more effective for the outcomes of fewer drinking days, time to relapse, and continuous abstinence period.99\n\nConsiderations and future directions for treatment\nASPD and BPD are complex and heterogeneous disorders often accompanied by other disorders, such as anxiety or depression. Therefore, as with psychosocial approaches, pharmacotherapy has focused on transdiagnostic dimensions or assumed neurophysiology rather than diagnosis categories for treatment of these disorders.100 This focus has led to the investigation of medications specific to affective dysregulation or impulsive behavioral dysregulation instead of medications specific to a diagnosis.\n\nOther treatment complexities include determining level of care based on severity of presentation and addressing barriers to accessible care. For individuals with severe AUD, inpatient or detoxification treatment may be a necessary component of treatment. For individuals with BPD, hospitalization or specific safety measures may be necessary if suicide is a risk. For those with ASPD, incarceration or other related limitations may be barriers to treatment. When any of these disorders occur independently or simultaneously, the risks of addiction, intentional or accidental overdose, and self-harm are heightened and may affect the course of treatment, particularly pharmacotherapy decisions.\n\nStepped care is an approach that can potentially help navigate the complex and evolving nature of co-occurring AUD and ASPD or BPD. Stepped care, or continuing care, has been associated with positive outcomes and longer treatment engagement for individuals with AUD or SUD.101 Stepped care is an adaptive approach, evolving as the patient’s needs change over time. For example, intensive in-person treatment may be necessary at times, whereas other modes of treatment with varying levels of intensity, such as telephone-based care or medication, may be more appropriate over the period of treatment. A flexible treatment team is necessary for a stepped care approach to work effectively. Time in treatment has been positively associated with better outcomes for people who have been diagnosed with co-occurring AUD and other psychopathology,84 further highlighting the potential utility of stepped care approaches for these co-occurring conditions.\n\nIn conclusion, future research investigating pharmacotherapies specific to co-occurring conditions is needed. The extant research, often limited to a few studies per finding, generally concludes:\n\nPharmacotherapies for AUD do not produce different outcomes for individuals with a co-occurring personality disorder.\n\nSome anticonvulsants and atypical antipsychotics may be useful for the treatment of AUD, BPD, and their co-occurrence.\n\nResearch is mixed on the effectiveness of antidepressants for ASPD alone and for co-occurring AUD and ASPD, and effectiveness often depends on important moderating variables.\n\nEvidence-based treatments for co-occurring AUD and personality disorders, in addition to realistic implementation and dissemination strategies that accommodate the treatments to these multifaceted disorders, need to be explored further.\n\nConclusion and Future Research\nExisting research on ASPD and BPD has important implications for AUD, likely because the conditions have overlapping symptoms, personality correlates, course, and etiology. Research examining shared mechanisms can contribute to both prevention and targeted intervention efforts. In addition, using new and advanced methodological approaches to assess risk factors and precursors to misuse or relapse can advance understanding of mechanisms that contribute to initial and continued use along the developmental course.26\n\nKey aspects of these disorders, such as affect disturbance, reflect volatility. Momentary changes in affect may be challenging to recall or assess using traditional methodological approaches such as asking individuals to rate their mood from a week ago. For example, craving and affect are episodic and may be assessed more accurately when they occur with natural cues. Precise assessment of such symptoms or constructs is relevant to diagnosis, because a comprehensive assessment of important criteria across relevant contexts can provide a full and more accurate picture of the individual’s presenting concerns and symptoms. Research incorporating methodological approaches, such as ambulatory assessment and ecological momentary assessment, to assess mood and craving in the moment can resolve critical within-person patterns of response to evocative cues, allowing for a more nuanced and individual evaluation of associations between the behaviors (e.g., drinking) and traits (e.g., impulsivity) commonly related to personality disorders. These methods can facilitate the assessment of an individual’s experience (e.g., mood and behaviors) in the moment.\n\nFuture research should also continue to focus on assessing and implementing the best methods, times, and places for providing treatment to individuals with co-occurring AUD and ASPD or BPD. For example, individuals with both AUD and a personality disorder tend to seek substance-specific treatment later than those with only AUD, although, on average, they use substances earlier, have greater impairment, and have shorter time to relapse.102 Research must also address:\n\nScreening (where and when people get referred to treatment)\n\nBarriers to treatment entry (factors that influence failure to enter treatment)\n\nIdentification of treatment approaches for co-occurring conditions\n\nDissemination and implementation of effective treatment approaches\n\nAll three disorders have many similarities, including impulsivity and negative affect, externalizing correlates, and a likely potential for serious consequences and negative outcomes. Nevertheless, the ability to reach people diagnosed with these conditions and to treat them successfully is lacking in many ways. Individuals diagnosed with co-occurring AUD and ASPD, BPD, or another personality disorder clearly have an influential presence across health and legal systems.12,15 However, people diagnosed with AUD alone have a surprisingly low treatment-seeking rate.62 In the National Comorbidity Survey, results specific to treatment-seeking behaviors among individuals with co-occurring AUD and a psychiatric condition indicated that this population was more likely to receive specialty mental health treatment not focused on substance use (41%) than substance-specific interventions (16%).62\n\nThe contrast between patterns of treatment-seeking behaviors is stark for people diagnosed with AUD alone versus those diagnosed with co-occurring conditions. Further understanding of the barriers to treatment for those with co-occurring conditions may provide points of change that positively influence the consumer’s ability to access care that targets relevant transdiagnostic factors. Hopefully, as more investigators focus on the common factors underlying these conditions, newer assessment and treatment approaches can be developed, evaluated, and ultimately disseminated to settings and clinicians that serve these individuals.\n\nAcknowledgments\nThis article was supported by National Institutes of Health grant T32AA013526.\n\nFinancial Disclosure\n\nTimothy J. Trull is a scientific adviser for Boehringer Ingelheim.\n\nTable 1 Treatment Descriptions\n\nTreatment\tKey Concepts\t\nDialectical Behavior Therapy for SUD64\t\nUses primarily behavioral approaches to target problematic behaviors organized within a predetermined hierarchy: life-threatening behaviors, behaviors that interfere with treatment, and behaviors that interfere with quality of life.\n\nTargets substance use as the top behavior within the quality-of-life level of the hierarchy.\n\nIncludes skills training in four domains: mindfulness, emotion regulation, distress tolerance, and interpersonal effectiveness.\n\nIncludes 12 months of weekly individual therapy and group skills training, telephone coaching, and therapist consultation.\n\nEmphasizes attachment strategies and dialectical abstinence.\n\nTargets BPD and AUD simultaneously.\n\n\t\nDynamic Deconstructive Psychotherapy65\t\nIncludes weekly individual therapy for 12 months.\n\nEmphasizes alliance building, emotion identification, polarization awareness, judgment awareness and modification, and distance from idealizing fantasies.\n\nTargets AUD and BPD simultaneously.\n\n\t\nDual-Focused Schema Therapy66\t\nIncludes 6 months of individual and group therapies.\n\nEmphasizes relapse prevention, stimulus control, interpersonal and emotion regulation skills, coping with craving, and identification and obstruction of maladaptive schemas.\n\nAddresses substance use as a coping mechanism for emotions and conflicts related to schemas.\n\nTargets AUD and BPD simultaneously.\n\n\t\nMentalization-Based Therapy67\t\nUses psychodynamic-oriented treatment in group and individual formats.\n\nEmphasizes improvement of mentalization within a safe, collaborative, and attached therapy relationship and focuses on internal states of self and others, with a goal of improving interpersonal relatedness, emotion regulation, and identity.\n\n\t\nMetacognitive Treatment68,69\t\nEmphasizes metacognitive mastery, which is the “ability to use knowledge about mental states of self and others to cope with distress and solve social problems.”6(p22)\n\nTargets the cognitive attentional syndrome to modify unhelpful thinking patterns.\n\n\t\nContingency Management70\t\nUses behavioral economics and operant conditioning principles to modify behaviors.\n\nEmphasizes the use of reinforcements and consequences to increase desired (e.g., abstinence) and decrease undesired (e.g., substance use) behaviors.\n\n\t\nAcceptance and Commitment Therapy71\t\nEmphasizes acceptance, values, and psychological flexibility through approaches such as mindfulness, identification of values and congruent living, and thought diffusion.\n\nOffers individual and group formats.\n\n\t\nUnified Protocol Therapy72\t\nUses transdiagnostic treatment for emotional disorders.\n\nEmphasizes emotional and physical awareness, appraisal flexibility, exposure, and emotion-driven behaviors.\n\n\t\nEmotion-Regulation Therapy73\t\nUses an acceptance-based approach to emotion regulation and is delivered in group format as an adjunctive treatment.\n\nIncludes participation in groups focused on improving skills such as, among others, impulse control and increasing awareness of emotions and their functions.\n\n\t\nIntegrated Therapy74\t\nUses a coordinated, goal-oriented approach integrating evidence-based components of other treatments (e.g., dialectical behavior therapy and cognitive behavioral therapy) and follows a sequential process of therapy stages, beginning with establishing safety.\n\nEmphasizes therapeutic relationships, motivation for change, and self-observation.\n\n\t\nMindfulness and Modification Therapy75\t\nIncludes individual or group transdiagnostic treatment targeting behavioral dysregulation.\n\nEmphasizes mindfulness and components of other treatments (e.g., acceptance and commitment therapy and dialectical behavior therapy).\n\n\t\nNote: This table does not include all the available treatment approaches, and these descriptions are not intended to be comprehensive descriptions of the treatments or their components.\n==== Refs\nReferences\n1 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 4th ed Text rev. 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J Abnorm Psychol 2010 119 93 105 20141246 \n84 Kelly TM Daley DC Douaihy AB Treatment of substance abusing patients with comorbid psychiatric disorders Addict Behav 2012 37 11 24 21981788 \n85 Conrod PJ Personality-targeted interventions for substance use and misuse Curr Addict Rep 2016 3 426 436 27909645 \n86 Jonas DE Amick HR Feltner C Pharmacotherapy for adults with alcohol use disorders in outpatient settings: A systematic review and meta-analysis JAMA 2014 311 1889 1900 24825644 \n87 Lieb K Völlm B Rücker G Pharmacotherapy for borderline personality disorder: Cochrane systematic review of randomised trials Br J Psychiatry 2010 196 4 12 20044651 \n88 Sonne S Rubey R Brady K Naltrexone treatment of self-injurious thoughts and behaviors J Nerv Ment Dis 1996 184 192 195 8600226 \n89 Ralevski E Ball S Nich C The impact of personality disorders on alcohol-use outcomes in a pharmacotherapy trial for alcohol dependence and comorbid Axis I disorders Am J Addict 2007 16 443 449 18058408 \n90 Rohsenow DJ Miranda R Jr McGeary JE Family history and antisocial traits moderate naltrexone’s effects on heavy drinking in alcoholics Exp Clin Psychopharmacol 2007 15 272 281 17563214 \n91 Stoffers J Völlm BA Rücker G Pharmacological interventions for borderline personality disorder Cochrane Database Syst Rev 2010 6 CD005653 20556762 \n92 Khalifa N Duggan C Stoffers J Pharmacological interventions for antisocial personality disorder Cochrane Database Syst Rev 2010 8 CD007667 20687091 \n93 Rubio G Ponce G Jiménez-Arriero MA Effects of topiramate in the treatment of alcohol dependence Pharmacopsychiatry 2004 38 37 40 14750047 \n94 Soler J Pascual JC Campins J Double-blind, placebo-controlled study of dialectical behavior therapy plus olanzapine for borderline personality disorder Am J Psychiatry 2005 162 1221 1224 15930077 \n95 Zanarini MC Frankenburg FR Olanzapine treatment of female borderline personality disorder patients: A double-blind, placebo-controlled pilot study J Clin Psychiatry 2001 62 849 854 11775043 \n96 Hutchison KE Wooden A Swift RM Olanzapine reduces craving for alcohol: A DRD4 VNTR polymorphism by pharmacotherapy interaction Neuropsychopharmacology 2003 28 1882 1888 12888781 \n97 Martinotti G DiNicola M Di Giannantonio M Aripiprazole in the treatment of patients with alcohol dependence: A double-blind comparison trial vs. naltrexone J Psychopharmacol 2009 23 123 129 18515460 \n98 Penick EC Powell BJ Campbell J Pharmacological treatment for antisocial personality disorder alcoholics: A preliminary study Alcohol Clin Exp Res 1996 20 477 484 8727240 \n99 Pettinati HM Volpicelli JR Kranzler HR Sertraline treatment for alcohol dependence: Interactive effects of medication and alcoholic subtype Alcohol Clin Exp Res 2000 24 1041 1049 10924008 \n100 Soloff PH Algorithms for pharmacological treatment of personality dimensions: Symptom-specific treatments for cognitive-perceptual, affective, and impulsive-behavioral dysregulation Bull Menninger Clin 1998 62 195 214 9604516 \n101 McKay JR Continuing care in the treatment of addictive disorders Curr Psychiatry Rep 2006 8 355 362 16968615 \n102 Zikos E Gill KJ Charney DA Personality disorders among alcoholic outpatients: Prevalence and course in treatment Can J Psychiatry 2010 55 65 73 20181301\n\n", "fulltext_license": "CC0", "issn_linking": "2168-3492", "issue": "40(1)", "journal": "Alcohol research : current reviews", "keywords": "alcohol use disorder; antisocial personality disorder; borderline personality disorder; comorbidity", "medline_ta": "Alcohol Res", "mesh_terms": "D000437:Alcoholism; D000927:Anticonvulsants; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D000987:Antisocial Personality Disorder; D001521:Behavior Therapy; D001883:Borderline Personality Disorder; D015897:Comorbidity; D006801:Humans; D007175:Impulsive Behavior; D010554:Personality Disorders; D011379:Prognosis", "nlm_unique_id": "101594475", "other_id": null, "pages": null, "pmc": null, "pmid": "31886107", "pubdate": "2019", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D016454:Review", "references": "1637250;27909645;2882604;20556783;24913314;16351376;15061343;26461047;22642461;3579504;17645399;15930077;28333488;20141246;12369475;18058408;26287444;28077216;28829989;10924008;18370620;16459936;28915400;22065531;17034434;15768573;18515460;14750047;20687091;9604516;16563205;19413401;20491737;26541558;10653513;18708274;29226598;17716092;22122362;20491733;30250740;17563214;22369165;16199838;28385703;17716066;12755325;25919396;11775043;20556762;20044651;12888781;20695803;16300724;19413410;16968615;16492093;21981788;12867203;11871377;28941927;11120394;16435954;30355023;8727240;7473043;8040504;20836905;7142573;385996;22895952;21851441;15709943;24825644;9801723;16942958;24342856;10598211;26772405;10396164;20181301;21083831;11497032;8600226;22686496;21073485", "title": "Alcohol Use Disorder and Antisocial and Borderline Personality Disorders.", "title_normalized": "alcohol use disorder and antisocial and borderline personality disorders" }
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{ "abstract": "Background: The aim of this study was to describe biochemical, virological features and Mother-to child-transmission (MTCT) rate in chronic hepatitis B (CHB) women who stopped antiviral therapy before or in the early pregnancy. Methods: This was a single-center, retrospective study. Forty-three CHB women who stopped treatment before or in the early pregnancy and 103 CHB women with tenofovir disoproxil fumarate (TDF) treatment throughout pregnancy were enrolled. The virological and biochemical flares during pregnancy and postpartum period were studied. MTCT rates were also compared. Results: During pregnancy, ALT flares (43.9% vs 1.0%) and viral rebound (31.7% vs 0) were more common in women who stopped treatment (P<0.001). Postpartum ALT flares were less frequent in women with treatment than those stopped treatment (0 vs 6/35, P = 0.001). The birth defect rate in the mothers who stopped treatment did not statistically differ from that of mothers treated throughout pregnancy (4.9 % vs 3.9 %, P = 1.000). There were no significant differences of gestational complications between the two groups, except intrahepatic cholestasis of pregnancy (12.2% vs 0, P = 0.002). The rate of MTCT in mothers who discontinued treatment was higher (2.4% vs 0, P = 0.285), although there was no statistically significant. Conclusion: ALT flares were common in mothers who discontinued antiviral therapy. Thus, these pregnant women should be monitored closely. Cessation of treatment was not recommended although no hepatic failure was observed. Larger studies are needed to evaluate the safety of discontinuation before pregnancy.", "affiliations": "Department of General Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China.;Department of General Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China.;Hepatology clinic, Beijing Ditan Hospital, Capital Medical University, Beijing, China.;Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.;Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.;Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.;Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.;Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.;Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.", "authors": "Gao|Xuesong|X|;Duan|Xuefei|X|;Cai|Haodong|H|;Hu|Yuhong|Y|;Liu|Min|M|;Kang|Kai|K|;Zhou|Mingfang|M|;Fu|Dong|D|;Yi|Wei|W|", "chemical_list": "D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D000068698:Tenofovir", "country": "Australia", "delete": false, "doi": "10.7150/ijms.38410", "fulltext": "\n==== Front\nInt J Med SciInt J Med SciijmsInternational Journal of Medical Sciences1449-1907Ivyspring International Publisher Sydney 10.7150/ijms.38410ijmsv17p0170Research PaperPregnancy Outcome of Women with Chronic Hepatitis B who Discontinued Antiviral Treatment before or in the Early Pregnancy Gao Xuesong 1Duan Xuefei 1Cai Haodong 2Hu Yuhong 3Liu Min 3Kang Kai 3Zhou Mingfang 3Fu Dong 3Yi Wei 3✉1 Department of General Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China.2 Hepatology clinic, Beijing Ditan Hospital, Capital Medical University, Beijing, China.3 Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.✉ Corresponding author: Wei Yi, No. 8 Jingshun East Street, Chaoyang District, Beijing, China. Tel: +86 13683687062; E-mail: yiwei1215@163.comCompeting Interests: The authors have declared that no competing interest exists.\n\n2020 1 1 2020 17 2 170 175 14 7 2019 12 12 2019 © The author(s)2020This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.Background: The aim of this study was to describe biochemical, virological features and Mother-to child-transmission (MTCT) rate in chronic hepatitis B (CHB) women who stopped antiviral therapy before or in the early pregnancy.\n\nMethods: This was a single-center, retrospective study. Forty-three CHB women who stopped treatment before or in the early pregnancy and 103 CHB women with tenofovir disoproxil fumarate (TDF) treatment throughout pregnancy were enrolled. The virological and biochemical flares during pregnancy and postpartum period were studied. MTCT rates were also compared.\n\nResults: During pregnancy, ALT flares (43.9% vs 1.0%) and viral rebound (31.7% vs 0) were more common in women who stopped treatment (P<0.001). Postpartum ALT flares were less frequent in women with treatment than those stopped treatment (0 vs 6/35, P = 0.001). The birth defect rate in the mothers who stopped treatment did not statistically differ from that of mothers treated throughout pregnancy (4.9 % vs 3.9 %, P = 1.000). There were no significant differences of gestational complications between the two groups, except intrahepatic cholestasis of pregnancy (12.2% vs 0, P = 0.002). The rate of MTCT in mothers who discontinued treatment was higher (2.4% vs 0, P = 0.285), although there was no statistically significant.\n\nConclusion: ALT flares were common in mothers who discontinued antiviral therapy. Thus, these pregnant women should be monitored closely. Cessation of treatment was not recommended although no hepatic failure was observed. Larger studies are needed to evaluate the safety of discontinuation before pregnancy.\n\nchronic hepatitis Bpregnancy complicationsinfantantiviral agentsalanine transaminase\n==== Body\nIntroduction\nThere were approximately 257 million persons with chronic hepatitis B in the world, including 65 million women of childbearing age who can potentially transmit HBV to their babies 1. Mother-to child-transmission (MTCT) remains an important mode of viral transmission in high prevalence areas 2. An association between high maternal levels of HBV viral load and increased risk of MTCT has been identified. The China national hepatitis B sero-epidemiologic surveys in 2006 showed that the prevalence of hepatitis B surface antigen (HBsAg) positivity among childbearing women was 6.6% 3. Typically, antiviral treatment is not indicated in women of childbearing age because they are more likely to be in the immune-tolerant phase. Therefore, the current guideline recommends starting antiviral therapy for women in the immune-tolerant phase with HBV DNA > 2 × 106 IU/mL during the third trimester of pregnancy to further reduce the risks of perinatal transmission 4. However, patients with significant liver injury who meet the standard indications for HBV therapy should consider the antiviral treatment. If a woman becomes pregnant during long-term oral nucleos(t)ide analogues (NAs) treatment, careful consideration needs to be made on whether to stop or to continue antiviral therapy. Previous studies demonstrated that antiviral therapy throughout pregnancy was safe 5-8. However, some women choose to discontinue therapy concerning the safety of medications. There is no consensus on safe cessation of long-term NAs therapy. With relatively longer consolidation therapy, safe discontinuation of NAs seems to be a feasible way in a substantial proportion of patients 9, 10. Nevertheless, treatment cessation could also lead to serious complications and even death in a few patients with advanced fibrosis or cirrhosis 11. Kim et al investigated 12 pregnant women on antiviral therapy discontinued drugs as soon as the awareness of the pregnancy to avoid utero exposure. They reported 66.7% patients (8/12) had a virological relapse, 50% (6/12) had severe ALT flares. All patients recovered without an event of hepatic decompensation 12. However, limited information is available in pregnant women with chronic hepatitis B (CHB).\n\nTherefore, we evaluated the pregnancy outcomes of withdrawal of antiviral treatment before pregnancy in women with CHB.\n\nMethods\nStudy population\nWe performed a retrospective study of consecutive CHB women evaluated during pregnancy in Beijing Ditan Hospital, Captital Medical University between 2010 and 2018. Patients were diagnosed with CHB according to AASLD guideline.4 Women were excluded if they met any of the following criteria: evidence of hepatocellular carcinoma, or hepatic decompensation; systemic diseases such as cardiopulmonary, neurological or renal disease; co-infection with human immunodeficiency virus, hepatitis C virus, hepatitis D virus, toxoplasmosis, syphilis, rubella or cytomegalovirus; history of amniocentesis during pregnancy; a familial history of genetic disease in either member of a couple; previous delivery of a child with a deformity.\n\nThey were divided into two groups. The pregnant women who stopped antiviral treatment by themselves were included in Group 1. They discontinued the antiviral therapy after a careful consideration of the risks of hepatitis flares and HBV MTCT against fetal exposure during the pregnancy. Group 2 included patients who had tenofovir disoproxil fumarate (TDF) treatment throughout pregnancy. Ethical approval for this study was granted by the institutional review board of Beijing Ditan Hospital, which waived the need for informed consent for this observational study.\n\nWe abstracted data from obstetric records of Beijing Ditan Hospital. Information included maternal demographic data, serum alanine transaminase (ALT) levels, serum creatinine (Cr), HBV serologic markers, HBV DNA levels, pregnancy complications, gestation time (weeks), delivery mode. The following infant data were collected: birth weight, birth length, Apgar score (1 minute) at birth, infant adverse events, birth defect, HBV virological testing at birth and after completion of the three hepatitis B vaccination doses.\n\nImmunoprophylaxis schedule and laboratory tests\nAll infants were given standard immunoprophylaxis: 200 IU HBIG (Chengdu Rongsheng Pharmaceuticals, Chengdu, China) and 10 μg recombinant hepatitis B vaccine (Hansenula Polymorpha, Dalian Hissen Bio-pharm, Dalian, China) injected within 2 hours after birth. The vaccine was boosted at 1 and 6 months after birth. The serum of infants was collected before vaccination and HBIG injection at birth and at 7 months after birth.\n\nAll of the parameter testing was performed in the laboratory of Beijing Ditan hospital. HBsAg, hepatitis B surface antibody (anti-HBs) and HBeAg were measured using a chemiluminescent microparticle immunoassay (Architect i2000 analyser; Abbott Diagnostics, Abbott Park, IL, USA). The serum HBV DNA level was quantified using real-time polymerase chain reaction (PCR) (Shanghai Kehua Bioengineering Co. Ltd., Shanghai, China), with a lower limit of 100 IU/mL. The ALT level was tested using a Hitachi 7600 fully automatic biochemical analyser (Wako Pure Chemical Industries, Ltd., Tokyo, Japan, ULN ≤ 40U/L). Serum creatinine (normal 0.46-0.83 mg/dl), CK (normal 40-200 U/L), and phosphorus (normal 2.74-4.88 mg/dl) were measured using an automatic analyser (Hitachi 7600- 020, Hitachi High Technologies Co., Tokyo, Japan).\n\nOutcomes assessment\nThe primary outcomes were: miscarriage, premature (<37w), and birth defect. Other outcomes included preeclampsia, gestational diabetes (GDM), placenta previa, placental abruption, and preterm premature rupture of the membranes; neonatal outcomes for singleton pregnancy included weight, length and 1- min Apgar score; the rates of HBV MTCT, defined by HBsAg seropositivity or HBV DNA positivity at 7 months.\n\nStatistical methods\nContinuous variables normally distributed were expressed as mean ± standard deviation (SD) and compared by Student's t test. Quantitative data non-normally distributed were presented as median and range and compared by Man-Whitney U test. Categorical variables were presented as numbers and percentages and compared by chi-square analysis or Fisher' s exact test. P < 0.05 was considered statistically significant. All data were analyzed using SPSS (version 22.0; IBM Corp Ltd., Armonk, NY).\n\nResults\nBaseline characteristics\nDuring the period from January 1, 2010 through June 30, 2018, a total of 147 women with active CHB were retrospectively enrolled at 12 weeks of gestational age. Maternal characteristics and outcomes are summarized in Table 1. In Group 1, there were 43 women with 43 pregnancies and 41 live births. They discontinued antiviral therapy before or during first trimester. A total of 110 pregnancies in 104 CHB women were included in Group 2. There were 103 live births. All women became pregnant while receiving TDF treatment and continued their TDF treatment throughout pregnancy. In Group 1, six women discontinued antiviral treatment at the median gestational age of 5 weeks and 37 stopped treatment before pregnancy. The pregnant women were older in Group 1 than those in Group 2 (29.5 ± 3.4 years vs 30.9 ± 3.8 years, P = 0.042). In Group 1, one pregnant woman had stillbirth and one was induced because of dead fetus. There were 3 cases of stillbirths, 3 cases of miscarriages and one case of induced labour in Group 2. The rate of live birth in mothers who discontinued antiviral therapy was similar with that in mothers on TDF treatment (41/43 or 95.3% vs 103/110 or 93.6%, P = 0.982).\n\nAt baseline, HBV DNA was higher in women who had already discontinued therapy as compared with those on treatment (5.1 ± 1.9 log10 IU/mL vs 3.6 ± 0.9 log10 IU/mL, P = 0.010). Most women were HBeAg-positive (35/43, 81.4% vs 85/104, 81.7%, P = 0.962). ALT was also higher in women who stopped treatment (35.9 U/L vs 20.4 U/L, P < 0.001), whereas serum creatinine (Cr) was higher in women on TDF treatment (0.51 mg/dl vs 0.55 mg/dl, P = 0.001).\n\nMaternal and infant safety\nThe mean gestational weeks of the mothers who discontinued treatment were shorter than the mothers with TDF treatment throughout pregnancy (38 vs 39 weeks, P = 0.005). There were no significant differences in the rate of infants' weights, heights, Apgar scores (1 min) or cesarean rates between the two groups. In Group 1, one infant was diagnosed with renal duplication and one infant was diagnosed with congenital aortic dysplasia. Four cases of birth defects were found at birth in Group 2: one case of right-side cryptorchidism, one case of congenital localized absence of skin, one case of G6PD deficiency. Another case of birth defect was diagnosed with mitochondrial respiratory chain complex I deficiency at the 7-month follow-up. The birth defect rate in Group 1 did not statistically differ from Group 2 (2/41 or 4.9 % vs 4/103 or 3.9 %, P = 1.000) (Table 2). There were no significant differences of adverse birth outcomes between the two groups, except the rate of intrahepatic cholestasis of pregnancy (5/41,12.2% vs 0, P = 0.002) (Table 3). Elevated Cr levels were more frequent in TDF-treated versus mothers with off-treatment (0.58 ± 0.09 mg/dl vs 0.54 ± 0.08 mg/dl, P = 0.047), though the difference was not assessed as clinically significant.\n\nALT flares and HBV DNA levels during pregnancy\nA viral rebound of increase in HBV DNA > 2 log10 IU/mL was found in 13 women (31.7%). Among women who discontinued treatment, ALT flares (120.5 U/L to 694.6 U/L) were observed in 43.9% (18/41) of women and an increase in HBV DNA of > 2 log IU/mL was observed in 38.9% (7/18) of women. It should be noted that three woman who discontinued treatment before pregnancy had ALT flares during the second trimester and achieved undetectable serum HBV DNA (< 100 IU/mL) before delivery. None of women developed hepatic failure or hepatic decompensation. Resolution of ALT flares occurred spontaneously in 38.9% (7/18) of women. Improved ALT was observed in 22.2% (4/18) of women, in whom ALT decreased to nearly normal values (<2 × ULN).\n\nALT flares were less likely to occur in women on TDF treatment throughout pregnancy than those in women who stopped treatment (1/103 or 1.0% vs 18/41 or 43.9%, P < 0.001). The other women remained normal to mildly elevated ALT (8 to 87 U/L). No HBV DNA rebound occurred. Most of women (99/103) achieved HBV DNA undetectable (< 100 IU/mL) and the other four women maintained low HBV DNA levels (< 2000 IU/mL). No viral rebound observed (0 vs 31.7%, P < 0.001).\n\nEfficacy assessment for mothers and infants\nAt delivery, the median HBV DNA level for mothers in Group 1 was significantly higher than that in Group 2 (6.0 ± 1.4 log10 IU/mL vs 2.3 ± 0.4 log10 IU/mL, P < 0.001). Although the levels of ALT were higher and Cr were lower in the mothers in Group 1 when compared with the mothers in Group 2, all the mothers had normal ALT, CK, Cr and phosphorus at delivery (Table 4). Virological features and MTCT rates of infants in two groups are presented in Table 5. At birth, the infants in the two groups had similar rates of peripheral blood HBsAg positivity (9/41 or 22.0% vs 17/103 or 16.5%, P = 0.443). The levels of HBV DNA were undetectable in the two groups. At 28 weeks of age, one infant born to mother who stopped treatment was positive for serum HBsAg and HBV DNA (1/41 or 2.4%). The MTCT rate of HBV in the mothers who discontinued treatment was higher than the mothers with TDF treatment throughout pregnancy (1/41 or 2.4% vs 0, P = 0.285), although there was no statistically significant.\n\nALT flares and HBV DNA levels at postpartum 28 weeks\nSix women who discontinued treatment in Group 1 and 21 mothers who treated throughout pregnancy in Group 2 were excluded from the analysis of postpartum flares for insufficient data. No ALT flares were observed at postpartum 28 weeks in women with TDF treatment throughout pregnancy. The frequency of ALT flares was significantly lower in women with TDF treatment throughout pregnancy than in mothers who discontinued treatment (0 vs 6/35 or 17.1%, P = 0.001). One new ALT flares were observed during postpartum in women untreated throughout pregnancy (n=35). Fourteen mothers reinitiated antiviral therapy during postpartum 1-3 months, of whom 11 mothers had viral suppression at postpartum 28 weeks and none achieved HBeAg seroconversion. Among those women who did not reinitiate treatment, one who was HBV DNA undetectable before delivery achieved HBeAg seroconversion before 28 weeks postpartum. Furthermore, one achieved HBeAg seroconversation spontaneously 2 years postpartum later.\n\nThe mothers with TDF treatment throughout pregnancy had lower levels of viremia (2.7 ± 0.3 log IU/mL vs 5.5 ± 1.5 log IU/mL, P < 0.001) and ALT levels (18.8 U/L vs 38.2 U/L, P < 0.001) as compared with those mothers who discontinued antiviral therapy at 28 weeks postpartum (Table 6). Among mothers who received antiviral treatment throughout pregnancy, one achieved HBeAg seroconversation and stopped treatment one month postpartum. She remained HBV DNA undetectable and HBeAg negtive at 28 weeks postpartum. One mother achieved HBsAg seroconversation one and half years postpartum.\n\nDiscussion\nCessation of NAs is generally not recommended among CHB patients due to the risk of viral relapse and clinical exacerbation. Similarly, the safety of ceasing therapy needs to be carefully considered for the increased risk of viral rebound and hepatitis flares among pregnant women. However, the recent studies revealed although virological relapses occurred in the majority of off-treatment patients, they are not necessarily followed by ALT elevations and the probability of liver decompensation was low 10, 13. Therefore, discontinuation of treatment before pregnancy maybe a feasible option, especially to a woman with younger age, undetectable HBV DNA levels, low serum HBsAg levels, without advanced fibrosis, and the long duration of on-therapy virological remission. However, little data is available regarding the potential adverse pregnancy outcomes.\n\nThe previous studies had focused on the maternal safety. ALT flares during pregnancy and postpartum were observed and they did not evaluate rates of MTCT or the safety of infants 12, 14. In current study, the birth defect rate among mothers who discontinued treatment was not significantly higher when compared with mothers with TDF treatment throughout pregnancy (4.9% vs 3.9%, P = 1.000). The congenital abnormality rates for infants born to mothers with HBV infection were reported to be 1.1%-10.9% 15, 16. Our finding was consistent with these previous studies. Furthermore, renal duplication and congenital aortic dysplasia are congenital malformation. Its aetiology remains unknown and it does not seem to be associated with HBV in pregnancy. Hepatitis flares during the pregnancy or postpartum periods were reported to be linked to maternal mortality 17. The increasing corticosteroid levels to prevent rejection could explain much of the viral relapses and ALT flares 5. The other interpretation issue is the discontinuation of NAs treatment. Fortunately, the clinical outcomes were not severe and none of pregnant women developed hepatic failure in our study, although virological rebound and hepatic flares were common.\n\nNo significant differences were noted in the rates of most adverse pregnancy outcomes. An exception is the prevalence of intrahepatic cholestasis (ICP) of pregnancy. A systematic review and meta-analysis from UK to quantify the adverse pregnancy outcome in women with ICP found that serum bile acids of 100 µmol/L or more was association with increased risk of stillbirth in women with ICP and singleton pregnancies (Hazard ratio 30.50 [95% CI 8.83-105.30]) 18. Hu et al showed the rates of HBV infection in the new-borns, fetal distress, neonatal asphyxia, and birth defects, and infant Apgar scores were higher in ICP pregnancies with HBV than the control groups (P < 0.05) 19. No association was reported between ICP and antiviral therapy to date. We inferred that antiviral treatment improved liver function, therefore, reduced the risk of ICP.\n\nThis study has several limitations. It was retrospective study and not all patients had sufficient data. In fact, we do not recommend to stop antiviral treatment before pregnancy regarding to the infant safety. The decisions to stop treatment should be considered carefully and individualized. In addition, the clinical implications have been limited by the small sample size.\n\nIn conclusion, nearly half of women who stopped antiviral treatment experienced ALT flares and viral rebounds throughout the course of their pregnancy. However, all patients recovered during pregnancy. We do not recommend to stop antiviral treatment before pregnancy. The women who withdraw antiviral treatment before pregnancy should be monitored closely during pregnancy and postpartum.\n\nDeclaration of funding interests: This study was funded in part by Beijing Hospitals Authority Incubating Program (PX2019064), China's National Science and Technology Major Project (2018ZX10715-005-003-002, 2018ZX10715-005-003-005).\n\nTable 1 Baseline demographic and clinical characteristics of pregnant women\n\nVariable\tGroup 1\tGroup 2\tP\t\nMothers (n)\t43\t104\t\t\nPregnancies (n)\t43\t110\t\t\nLive births, n (%)\t41 (95.3)\t103 (93.6)\t0.982\t\nAge (years)\t29.5 ± 3.4\t30.9 ± 3.8\t0.042\t\nHBeAg positive, n (%)\t35 (81.4)\t85 (81.7)\t0.962\t\nALT (U/L)\t35.9 (25.0-77.6)\t20.4 (15.2-26.7)\t< 0.001\t\nCK (U/L)\t43.3 (34.1-81.2)\t61.1 (46.3-78.7)\t0.094\t\nCr (mg/dl)\t0.51 (0.47-0.56)\t0.55 (0.51-0.62)\t0.001\t\nPhosphorus (mg/dl)\t3.5 (3.1-3.8)\t3.4 (3.1-3.7)\t0.729\t\nHBV DNA (log10 IU/mL)\t5.1 ± 1.9\t3.6 ± 0.9\t0.010\t\nValues presented as median (range) or mean ± SD. ALT, alanine aminotransferase; CK, creatine kinase; Cr, serum creatinine; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus.\n\nTable 2 Neonatal clinical characteristics\n\nVariable\tGroup 1 (n=41)\tGroup 2 (n=103)\tP\t\nApgar (1 min)\t10.0 (10.0-10.0)\t10.0 (10.0-10.0)\t0.116\t\nWeight (kg)\t3.4 (3.2-3.6)\t3.3 (3.1-3.5)\t0.051\t\nLength (cm)\t50.0 (50.0-50.0)\t50.0 (50.0-50.0)\t0.054\t\nGestational age (weeks)\t38.0 (37.5-39.0)\t39.0 (38.0-40.0)\t0.005\t\nCaesarean section, n (%)\t22 (53.7)\t49 (47.6)\t0.510\t\nBirth defect, n (%)\t2 (4.9)\t4 (3.9)\t1.000\t\nTable 3 Complications and adverse events of pregnancy\n\nVariable\tGroup 1\n (n=41)\tGroup 2\n (n=103)\tP\t\nPremature birth, n (%)\t3 (7.3)\t3 (2.9)\t0.464\t\nPostpartum haemorrhage, n (%)\t1 (2.4)\t4 (3.9)\t1.000\t\nOligohydramnios, n (%)\t2 (4.9)\t8 (7.8)\t0.801\t\nGestational diabetes mellitus, n (%)\t14 (34.1)\t20 (19.4)\t0.060\t\nMeconium staining of the amniotic fluid (III degree), n (%)\t2 (4.9)\t6 (5.8)\t1.000\t\nPremature rupture of membranes, n (%)\t7 (17.1)\t11 (10.7)\t0.295\t\nGestational hypertension, n (%)\t2 (4.9)\t0 (0.0)\t0.080\t\nPre-eclampsia, n (%)\t1 (2.4)\t0 (0.0)\t0.285\t\nHypothyroidism, n (%)\t3 (7.3)\t4 (3.9)\t0.663\t\nIntrahepatic cholestasis of pregnancy, n (%)\t5 (12.2)\t0 (0.0)\t0.002\t\nPlacenta previa, n (%)\t1 (2.4)\t3 (2.9)\t1.000\t\nTable 4 Changes in HBV DNA and biochemical markers at delivery for the two groups\n\nVariable\tGroup 1 (n=41)\tGroup 2 (n=103)\tP\t\nALT (U/L)\t25.6 (16.9-56.7)\t16.1 (12.5-20.5)\t< 0.001\t\nCK (U/L)\t60.3 (35. 3-87.7)\t57.4 (48.9-81.0)\t0.764\t\nCr (mg/dl)\t0.54 ± 0.08\t0.58 ± 0.09\t0.047\t\nPhosphorus (mg/dl)\t3.4 ± 0.5\t3.5 ± 0.5\t0.363\t\nHBV DNA (log10 IU/mL)\t6.0 ± 1.4\t2.3 ± 0.4\t< 0.001\t\nALT, alanine aminotransferase; CK, creatine kinase; Cr, serum creatinine; HBV, hepatitis B virus.\n\nTable 5 Virological features and MTCT rates of infants in TDF treated group and untreated group.\n\nVariable\tGroup 1 (n=41) \tGroup 2 (n=103) \tP\t\nAt birth\n\t\t\t\t\nHBsAg+, n (%)\t9 (22.0)\t17 (16.5)\t0.443\t\nHBV DNA ≥100 IU/mL, n (%)\t2 (4.9)\t0 (0.0)\t0.079\t\nPostpartum 28 weeks\n\t\t\t\t\nHBsAg+, n (%)\t1 (2.4)\t0 (0.0)\t0.285\t\nHBV DNA ≥100 IU/mL, n (%)\t1 (2.4)\t0 (0.0)\t0.285\t\nTable 6 HBV DNA and biochemical markers at 28 weeks postpartum for the two groups\n\nVariable\tGroup 1 (n=35)\tGroup 2 (n=82)\tP\t\nALT\t38.2 (20.6-100.8)\t18.8 (14.7-21.7)\t< 0.001\t\nHBeAg, n (%)\t25 (71.4)\t51 (62.2)\t0.338\t\nHBV positive, n (%)\t20 (57.1)\t3 (3.7)\t< 0.001\t\nHBV DNA (log10 IU/mL)\t5.5 ± 1.5\t2.7 ± 0.3\t< 0.001\t\nALT, alanine aminotransferase; CK, creatine kinase; Cr, serum creatinine; HBV, hepatitis B virus.\n==== Refs\n1 WHO GLOBAL HEPATITIS REPORT https://www.who.int/hepatitis/publications/global-hepatitis-report2017/en/ \n2 Ayoub W Cohen E Hepatitis B Management in the Pregnant Patient: An Update J Clin Transl Hepatol 2016 4 241 247 27777892 \n3 Zheng H Cui FQ Gong XH Status of the hepatitis B virus surface antigen and e antigen prevalence among reproductive women in China Chinese J Vaccines Immun 2010 16 496 499 (Chinese) \n4 Terrault NA Lok ASF McMahon BJ Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance Hepatology 2018 67 1560 1599 29405329 \n5 Yi W Liu M Cai HD Safety of lamivudine treatment for chronic hepatitis B in early pregnancy World J Gastroenterol 2012 18 6645 6650 23236240 \n6 Yi W Li MH Xie Y Prospective cohort study on the efficacy and safety of telbivudine used throughout pregnancy in blocking mother-to-child transmission of hepatitis B virus J Viral Hepat 2017 24 Suppl 1 49 56 29082650 \n7 Liu M Cai H Yi W Safety of telbivudine treatment for chronic hepatitis B for the entire pregnancy J Viral Hepat 2013 20 Suppl 1 65 70 \n8 He T Bai Y Cai H Safety and efficacy of lamivudine or telbivudine started in early pregnancy for mothers with active chronic hepatitis B Hepatol Int 2018 12 118 125 29344772 \n9 Papatheodoridis G Vlachogiannakos I Cholongitas E Discontinuation of oral antivirals in chronic hepatitis B: A systematic review Hepatology 2016 63 1481 1492 27100145 \n10 Chang ML Liaw YF Hadziyannis SJ Systematic review: cessation of long-term nucleos(t)ide analogue therapy in patients with hepatitis B e antigen-negative chronic hepatitis B Aliment Pharmacol Ther 2015 42 243 257 26151841 \n11 Van Hees S Bourgeois S Van Vlierberghe H Stopping nucleos(t)ide analogue treatment in Caucasian hepatitis B patients after HBeAg seroconversion is associated with high relapse rates and fatal outcomes Aliment Pharmacol Ther 2018 47 1170 1180 29498078 \n12 Kim HY Choi JY Park CH Outcome after discontinuing antiviral agents during pregnancy in women infected with hepatitis B virus J Clin Virol 2013 56 299 305 23273664 \n13 Papatheodoridi M Papatheodoridis G Can we stop nucleoside analogues before HBsAg loss? J Viral Hepat 2019 26 936 941 30803099 \n14 Chang CY Aziz N Poongkunran M Serum Aminotransferase Flares in Pregnant and Postpartum Women with Current or Prior Treatment for Chronic Hepatitis B J Clin Gastroenterol 2018 52 255 261 28323748 \n15 Tan J Huang S He G Maternal hepatitis B surface antigen carrier status and its impact on neonatal outcomes: a cohort study of 21 947 singleton newborns in China J Matern Fetal Neonatal Med 2017 30 2219 2224 27696914 \n16 Safir A Levy A Sikuler E Maternal hepatitis B virus or hepatitis C virus carrier status as an independent risk factor for adverse perinatal outcome Liver Int 2010 30 765 770 20214739 \n17 Nguyen G Garcia RT Nguyen N Clinical course of hepatitis B virus infection during pregnancy Aliment Pharmacol Ther 2009 29 755 764 19183158 \n18 Ovadia C Seed PT Sklavounos A Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses Lancet 2019 393 899 909 30773280 \n19 Hu Y DY Yu L The impact of intrahepatic cholestasis of pregnancy with hepatitis B virus infection on perinatal outcomes Ther Clin Risk Manag 2014 10 381 385 24920912\n\n", "fulltext_license": "CC BY", "issn_linking": "1449-1907", "issue": "17(2)", "journal": "International journal of medical sciences", "keywords": "alanine transaminase; antiviral agents; chronic hepatitis B; infant; pregnancy complications", "medline_ta": "Int J Med Sci", "mesh_terms": "D000328:Adult; D004279:DNA, Viral; D005260:Female; D006513:Hepatitis B e Antigens; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D049590:Postpartum Period; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011256:Pregnancy Outcome; D000068698:Tenofovir; D019562:Viral Load", "nlm_unique_id": "101213954", "other_id": null, "pages": "170-175", "pmc": null, "pmid": "32038100", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": "27100145;23458527;30803099;28323748;26151841;29344772;29405329;23273664;19183158;30773280;24920912;27696914;23236240;29082650;27777892;29498078;20214739", "title": "Pregnancy Outcome of Women with Chronic Hepatitis B who Discontinued Antiviral Treatment before or in the Early Pregnancy.", "title_normalized": "pregnancy outcome of women with chronic hepatitis b who discontinued antiviral treatment before or in the early pregnancy" }
[ { "companynumb": "CN-GILEAD-2020-0447975", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE" }, "drugadditiona...
{ "abstract": "OBJECTIVE\nTo determine an optimal biologic dose (OBD) of decitabine as a single agent and then the maximum-tolerated dose (MTD) of valproic acid (VA) combined with decitabine in acute myeloid leukemia (AML).\n\n\nMETHODS\nTwenty-five patients (median age, 70 years) were enrolled; 12 were untreated and 13 had relapsed AML. To determine an OBD (based on a gene re-expression end point), 14 patients received decitabine alone for 10 days. To determine the MTD, 11 patients received decitabine (at OBD, days 1 through 10) plus dose-escalating VA (days 5 through 21).\n\n\nRESULTS\nThe OBD of decitabine was 20 mg/m(2)/d intravenously, with limited nonhematologic toxicity. In patients treated with decitabine plus VA, dose-limiting encephalopathy occurred in two of two patients at VA 25 mg/kg/d and one of six patients at VA 20 mg/kg/d. Drug-induced re-expression of estrogen receptor (ER) was associated with clinical response (P < or = .05). ER promoter demethylation, global DNA hypomethylation, depletion of DNA methyltransferase enzyme, and histone hyperacetylation were also observed. In an intent-to-treat analysis, the response rate was 44% (11 of 25). Of 21 assessable patients, 11 (52%) responded: four with morphologic and cytogenetic complete remission (CR; each had complex karyotype), four with incomplete CR, and three with partial remission. In untreated AML, four of nine assessable patients achieved CR. Clinical responses appeared similar for decitabine alone or with VA.\n\n\nCONCLUSIONS\nLow-dose decitabine was safe and showed encouraging clinical and biologic activity in AML, but the addition of VA led to encephalopathy at relatively low doses. On the basis of these results, additional studies of decitabine (20 mg/m(2)/d for 10 days) alone or with an alternative deacetylating agent are warranted.", "affiliations": "Department of Medicine, Division of Hematology and Oncology, The Ohio State University, Columbus, OH 43210, USA. william.blum@osumc.edu", "authors": "Blum|William|W|;Klisovic|Rebecca B|RB|;Hackanson|Bjoern|B|;Liu|Zhongfa|Z|;Liu|Shujun|S|;Devine|Hollie|H|;Vukosavljevic|Tamara|T|;Huynh|Lenguyen|L|;Lozanski|Gerard|G|;Kefauver|Cheryl|C|;Plass|Christoph|C|;Devine|Steven M|SM|;Heerema|Nyla A|NA|;Murgo|Anthony|A|;Chan|Kenneth K|KK|;Grever|Michael R|MR|;Byrd|John C|JC|;Marcucci|Guido|G|", "chemical_list": "D014635:Valproic Acid; D000077209:Decitabine; D001374:Azacitidine", "country": "United States", "delete": false, "doi": "10.1200/JCO.2006.09.4169", "fulltext": null, "fulltext_license": null, "issn_linking": "0732-183X", "issue": "25(25)", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "keywords": null, "medline_ta": "J Clin Oncol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine; D001927:Brain Diseases; D000077209:Decitabine; D005221:Fatigue; D006801:Humans; D007239:Infections; D015470:Leukemia, Myeloid, Acute; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia; D012074:Remission Induction; D017211:Treatment Failure; D014635:Valproic Acid", "nlm_unique_id": "8309333", "other_id": null, "pages": "3884-91", "pmc": null, "pmid": "17679729", "pubdate": "2007-09-01", "publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia.", "title_normalized": "phase i study of decitabine alone or in combination with valproic acid in acute myeloid leukemia" }
[ { "companynumb": "US-OTSUKA-2019_012226", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DECITABINE" }, "drugadditional": null, ...
{ "abstract": "Worldwide, the consumption of dietary supplements for the enhancement of sexual performance is common. Consumers are generally fond of these products because they often want to avoid drugs, preferring \"natural\" than \"chemical\" solutions. This is challenging, as many of these supplements labelled \"herbal\" or \"natural\" are actually adulterated with drugs, mainly phosphodiesterase-5 inhibitors. This phenomenon is facilitated by fewer demanding regulations for marketing supplements. Thus, consumers may be widely exposed to serious adverse events, such as acute liver injury, kidney failure, pulmonary embolism, stroke or even death. We aim to warn physicians about this issue. This multidisciplinary review simultaneously deals with clinical consequences of this phenomenon, analytical toxicology and regulation. Indeed, after outlining this worldwide issue and highlighting that a drug-adulterated dietary supplement is actually a falsified drug, we discuss its main contributing factors. Then, we describe some examples of adverse events of which a case of sildenafil-tadalafil-induced ischaemic stroke that benefited medical care in our hospital. Furthermore, we present some means to avoid adulteration and discuss their limitations that may be explained by the heterogeneity of the regulation of dietary supplements between countries. Doing so, we point out the requirement of a global harmonization of this regulation for an efficient eradication of this public health threat. Meanwhile, dietary supplements should be considered adulterated until proven otherwise. Thus, we encourage physicians to investigate these products in the drug histories of their patients, especially when clinical conditions cannot be explained by classical aetiologies.", "affiliations": "CHRU-Nancy, Department of Clinical Pharmacology, Toxicology and Pharmacovigilance, Regional University Hospital of Nancy, Université de Lorraine, Nancy, France.;CHRU-Nancy, Department of Clinical Pharmacology, Toxicology and Pharmacovigilance, Regional University Hospital of Nancy, Université de Lorraine, Nancy, France.;Department of Neurology, CHRU-Nancy, Nancy, France.;Poison Control Centre of Eastern France, CHRU-Nancy, Nancy, France.;Université de Lorraine, CNRS, IMoPA, Nancy, France.;CHRU-Nancy, Department of Clinical Pharmacology, Toxicology and Pharmacovigilance, Regional University Hospital of Nancy, Université de Lorraine, Nancy, France.;CHRU-Nancy, Department of Clinical Pharmacology, Toxicology and Pharmacovigilance, Regional University Hospital of Nancy, Université de Lorraine, Nancy, France.;Department of Clinical Pharmacology, Toxicology and Pharmacovigilance, CHRU-Limoges, Limoges, France.;CHRU-Nancy, Department of Clinical Pharmacology, Toxicology and Pharmacovigilance, Regional University Hospital of Nancy, Université de Lorraine, Nancy, France.", "authors": "Yéléhé-Okouma|Mélissa|M|https://orcid.org/0000-0002-9096-5898;Pape|Elise|E|;Humbertjean|Lisa|L|;Evrard|Marion|M|;El Osta|Rabih|R|;Petitpain|Nadine|N|https://orcid.org/0000-0003-0225-3178;Gillet|Pierre|P|https://orcid.org/0000-0002-0598-7508;El Balkhi|Souleiman|S|;Scala-Bertola|Julien|J|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1111/fcp.12653", "fulltext": null, "fulltext_license": null, "issn_linking": "0767-3981", "issue": "35(5)", "journal": "Fundamental & clinical pharmacology", "keywords": "adverse events; dietary supplement regulation; dietary supplements adulteration; erectile dysfunction; herbal supplements; phosphodiesterase 5 inhibitors; sexual enhancement; stroke", "medline_ta": "Fundam Clin Pharmacol", "mesh_terms": null, "nlm_unique_id": "8710411", "other_id": null, "pages": "792-807", "pmc": null, "pmid": "33484004", "pubdate": "2021-10", "publication_types": "D016428:Journal Article; D016454:Review", "references": null, "title": "Drug adulteration of sexual enhancement supplements: a worldwide insidious public health threat.", "title_normalized": "drug adulteration of sexual enhancement supplements a worldwide insidious public health threat" }
[ { "companynumb": "FR-ALKEM LABORATORIES LIMITED-FR-ALKEM-2021-00601", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SILDENAFIL" }, "druga...
{ "abstract": "We describe a case of multiple desmoid tumors (DT) that developed in an ileal J pouch, which were successfully treated by low-dose combination chemotherapy using vinblastine (VBL) and methotrexate (MTX). Serial changes in the serum D-dimer levels reflected the treatment response. DT involving both the abdominal wall and the ileal pouch developed after total proctocolectomy with ileoanal anastomosis for familial adenomatous polyposis in a 26-year-old female who was treated in an outpatient unit with low-dose VBL and MTX biweekly for 12 months. The treatment response was assessed at routine intervals by physical examination and abdominal computer tomography (CT) imaging. We assessed serial changes in plasma D-dimers, a potential marker for angiogenic activity, during the low-dose VBL and MTX treatment. DT were successfully treated with low-dose VBL and MTX chemotherapy without any significant side effects or pouch sacrifice. Abdominal CT imaging revealed a decrease in tumor size, and the plasma D-dimer levels decreased in association with tumor regression. This case report shows the efficacy of a low-dose combination chemotherapeutic regimen of VBL and MTX for the treatment of ileoanal pouch mesenteric DT in an outpatient setting. In addition, plasma D-dimers may be a marker for desmoid tumor treatment efficacy.", "affiliations": "Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.;Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.;Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.;Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.;Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.;Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.;Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. kusunoki@clin.medic.mie-u.ac.jp.", "authors": "Toiyama|Yuji|Y|;Konishi|Naomi|N|;Inoue|Yasuhiro|Y|;Yoshiyama|Shigeyuki|S|;Araki|Toshimitsu|T|;Miki|Chikao|C|;Kusunoki|Masato|M|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.1007/s12328-008-0055-7", "fulltext": null, "fulltext_license": null, "issn_linking": "1865-7265", "issue": "2(3)", "journal": "Clinical journal of gastroenterology", "keywords": "Chemotherapy; D-dimer; Desmoid; FAP; Ileal pouch", "medline_ta": "Clin J Gastroenterol", "mesh_terms": null, "nlm_unique_id": "101477246", "other_id": null, "pages": "170-174", "pmc": null, "pmid": "26192289", "pubdate": "2009-06", "publication_types": "D016428:Journal Article", "references": "3568326;1562974;8605563;12562642;10826436;10071306;11571741;9164373;9738571;14719159;8395084;2917130;9823798;14745880;14617246;8150351;1651563;2766217;1323382;8876270;7519966;11875705;16769149;10653875;2540254;3729590;8453544;11401062;3719103", "title": "Successful treatment of ileal pouch desmoids using multimodal chemotherapy with low-dose vinblastine and methotrexate in a patient with familial adenomatous polyposis.", "title_normalized": "successful treatment of ileal pouch desmoids using multimodal chemotherapy with low dose vinblastine and methotrexate in a patient with familial adenomatous polyposis" }
[ { "companynumb": "JP-PFIZER INC-2016383438", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, ...
{ "abstract": "Graft-versus-host-disease after orthotopic liver transplant is a rare and life-threatening complication. The diagnosis is challenging and usually confirmed by chimerism and skin biopsies. The most common cause of death is sepsis (60%), and broad-spectrum antibiotics and antifungal prophylaxis are strongly recommended. We present a case of a 61-year-old man with hepatocellular carcinoma and a previous history of metabolic and alcoholic cirrhosis who underwent orthotopic liver transplant. The immunosuppression regimen consisted of corticosteroids, calcineurin inhibitor, and mammalian target of rapamycin complex 1 inhibitor. Nine days after surgery, the patient developed leukopenia and skin rash. After confirmation of graft-versus-host disease by chimerism and skin biopsy, etanercept, a novel anti-tumor necrosis factor-alpha drug used for patients with hematologic and rheumatologic disease, was administrated. Unfortunately, no clinical improvements or bone marrow recovery were noted, and the patient had subsequent fatal sepsis due to Enterococcus faecium, Aspergillus fumigatus, and viral superinfection. There are no US Food and Drug Administration-approved treatments for graft-versus-host disease after orthotopic liver transplant. The main risk factors are recipients > 50 years old, patients with glucose intolerance, patients transplanted due to hepatocellular carcinoma, donor-recipient age difference of > 20 years, and any HLA-class I match. In accordance with the literature, we suggest early use of broad-spectrum antibiotics and antifungal drugs during etanercept treatment. In addition, because of substantially higher risk for severe sepsis, we strongly recommend adding an antiviral prophylaxis to prevent Cytomegalovirus reactivation or unexpected superinfection.", "affiliations": "From the UOC Anesthesia and Intensive Care Unit, Department of Medicine-DIMED, Padua Hospital, Padua, Italy.", "authors": "Boscolo|Annalisa|A|;Menin|Eugenia|E|;Zelaschi|Beatrice|B|;Albertoni|Laura|L|;Zanus|Giacomo|G|;Baratto|Fabio|F|", "chemical_list": "D000935:Antifungal Agents; D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D000079424:Tumor Necrosis Factor Inhibitors; D000068800:Etanercept", "country": "Turkey", "delete": false, "doi": "10.6002/ect.2017.0231", "fulltext": null, "fulltext_license": null, "issn_linking": "1304-0855", "issue": "18(1)", "journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation", "keywords": null, "medline_ta": "Exp Clin Transplant", "mesh_terms": "D000328:Adult; D019072:Antibiotic Prophylaxis; D000935:Antifungal Agents; D000998:Antiviral Agents; D000068800:Etanercept; D017809:Fatal Outcome; D006086:Graft vs Host Disease; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D012307:Risk Factors; D018805:Sepsis; D016896:Treatment Outcome; D000079424:Tumor Necrosis Factor Inhibitors", "nlm_unique_id": "101207333", "other_id": null, "pages": "123-127", "pmc": null, "pmid": "29619911", "pubdate": "2020-02", "publication_types": "D002363:Case Reports", "references": null, "title": "Early Use of Etanercept for Graft-Versus-Host Disease After Liver Transplant: the Importance of Broad Spectrum Infective Prophylaxis.", "title_normalized": "early use of etanercept for graft versus host disease after liver transplant the importance of broad spectrum infective prophylaxis" }
[ { "companynumb": "PHHY2018IT045963", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "4", "druga...
{ "abstract": "A man in his 40s developed a severe cutaneous adverse reaction following treatment of septic arthritis with flucloxacillin. The eruption had overlap features of cutaneous vasculitis and acute generalised exanthematous pustulosis which was complicated by renal and liver impairment. This case heightens the variation in presentation of a severe drug eruption.", "affiliations": "Dermatology Department, University College Hospital Galway, Galway, Ireland.;Dermatology Department, University College Hospital Galway, Galway, Ireland.", "authors": "Murad|Aizuri|A|;Murphy|Annette|A|", "chemical_list": "D000900:Anti-Bacterial Agents; D005436:Floxacillin", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2014()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000328:Adult; D000900:Anti-Bacterial Agents; D001170:Arthritis, Infectious; D001706:Biopsy; D003937:Diagnosis, Differential; D003875:Drug Eruptions; D005436:Floxacillin; D006801:Humans; D008297:Male; D012867:Skin; D018366:Vasculitis, Leukocytoclastic, Cutaneous", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "25404248", "pubdate": "2014-11-17", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "21690532;23009177;11168761;17854366;23855377", "title": "Cutaneous vasculitis overlap with acute generalised exanthematous pustulosis (AGEP).", "title_normalized": "cutaneous vasculitis overlap with acute generalised exanthematous pustulosis agep" }
[ { "companynumb": "PHHY2015IE000995", "fulfillexpeditecriteria": "1", "occurcountry": "IE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLINDAMYCIN\\CLINDAMYCIN PHOSPHATE" }, "drugadditional...
{ "abstract": "BACKGROUND\nIatrogenic cervical spondylodiscitis is rare, but may occur after various medical interventions.\n\n\nMETHODS\nWe report a case of a diabetic 70-years-old female with C5-C6 spondylodiscitis and symptomatic epidural abscess with neck pain and upper limb paresis after endoscopic botulinum toxin injection for the treatment of dysphagia. Treatment included antibiotic therapy with amoxicillin and later on benzylpenicillin for the next ten weeks and corporectomy with spondylodesis.\n\n\nRESULTS\nThe patient made an excellent recovery, with complete resolution of paresis and only minor residual hypoesthesia at one year after operation.\n\n\nCONCLUSIONS\nCervical spondylodiscitis should be considered early, in patients with neck pain after endoscopic cricopharyngeal injection, as timely diagnosis and treatment can prevent serious and irreversible neurological deficit.", "affiliations": "Department of Neurosurgery, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. Electronic address: j.n.m.lukassen@umcg.nl.;Department of Neurosurgery, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.;Department of Neurosurgery, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.;Department of Neurosurgery, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.", "authors": "Lukassen|J N M|JNM|;Aalbers|M W|MW|;Coppes|M H|MH|;Groen|R J M|RJM|", "chemical_list": "D009498:Neurotoxins; D001905:Botulinum Toxins", "country": "France", "delete": false, "doi": "10.1016/j.anorl.2018.03.010", "fulltext": null, "fulltext_license": null, "issn_linking": "1879-7296", "issue": "136(4)", "journal": "European annals of otorhinolaryngology, head and neck diseases", "keywords": "Botulinum toxin injection; Corporectomy; Cricopharyngeal muscles; Dysphagia; Epidural abscess; Spondylodiscitis", "medline_ta": "Eur Ann Otorhinolaryngol Head Neck Dis", "mesh_terms": "D000368:Aged; D001905:Botulinum Toxins; D002574:Cervical Vertebrae; D003680:Deglutition Disorders; D015299:Discitis; D020802:Epidural Abscess; D049631:Esophageal Sphincter, Upper; D005260:Female; D006801:Humans; D007049:Iatrogenic Disease; D007273:Injections, Intramuscular; D019547:Neck Pain; D009498:Neurotoxins; D010291:Paresis; D013117:Spinal Cord Compression; D013290:Streptococcal Infections", "nlm_unique_id": "101531465", "other_id": null, "pages": "313-316", "pmc": null, "pmid": "30910364", "pubdate": "2019-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cervical spondylodiscitis following cricopharyngeal botulinium toxin injection.", "title_normalized": "cervical spondylodiscitis following cricopharyngeal botulinium toxin injection" }
[ { "companynumb": "NL-MERZ PHARMACEUTICALS GMBH-19-01606", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BOTULINUM TOXIN TYPE A" }, "drug...
{ "abstract": "BACKGROUND Long QT syndrome (LQTS) is an arrhythmogenic heart condition that can be congenital or acquired. Prolonged ventricular repolarizations in individuals with the disorder can cause fatal arrhythmias. Abnormal functioning of cardiac ion channels leads to arrhythmias such as torsades de pointes (TdP) and may be triggered by stress or medications. Many medications used in the perioperative period are triggers for the arrythmia. CASE REPORT A 7-year-old patient with known congenital LQTS type 2 presented for bilateral myringotomy and tube placement. The patient was otherwise healthy and taking propranolol daily. Preoperative midazolam was administered for anxiolysis, and induction of anesthesia was uneventful. He sustained an episode of TdP immediately following general anesthetic induction after failure of an in situ automatic implantable cardioverter-defibrillator (AICD). External defibrillation succeeded, and the patient was stabilized in the Postanesthesia Recovery Unit before transfer to the Pediatric Intensive Care Unit. Interrogation of the AICD revealed several undelivered defibrillation attempts. A chest X-ray showed an area suggestive of an epicardial electrode fracture. The following day, the AICD was replaced with no arrythmias noted. The patient had an uneventful recovery. CONCLUSIONS In patients with a known history of LQTS, preparation and prevention are cornerstones of anesthesia care. Minimizing the use of triggering medications and emotional stress in the perioperative period, combined with ready equipment and medications to respond to arrythmias, are essential. In children, there is a greater chance of lead fracture and resulting device failure. Preoperative history of device function or interrogation of the AICD and possibly a chest X-ray are essential to ensure the integrity of the leads.", "affiliations": "Department of Anesthesiology and Perioperative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.;Department of Pediatrics, Division of Pediatric Cardiology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.;Department of Pediatrics, Division of Pediatric Cardiology, University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA.;Department of Pediatrics, Division of Pediatric Cardiology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.;Department of Anesthesiology and Perioperative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.;Department of Anesthesiology and Perioperative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.", "authors": "Coleman|Melissa|M|;Imundo|Jason R|JR|;Cortez|Daniel|D|;Cohen|Mark H|MH|;Dhar|Padmani|P|;Dalal|Priti G|PG|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.12659/AJCR.925602", "fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n10.12659/AJCR.925602\n925602\nArticles\nTorsades de Pointes During Myringotomy in a Child with Congenital Long QT Syndrome: A Case Report\nColeman Melissa ADEFG1 Imundo Jason R. DEF2 Cortez Daniel DEF3 Cohen Mark H. E2 Dhar Padmani EF1 Dalal Priti G. ADE1 \n1 Department of Anesthesiology and Perioperative Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, U.S.A.\n\n2 Department of Pediatrics, Division of Pediatric Cardiology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, U.S.A.\n\n3 Department of Pediatrics, Division of Pediatric Cardiology, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN, U.S.A.\nCorresponding Author: Melissa Coleman, e-mail: mcoleman@pennstatehealth.psu.eduAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n15 10 2020 \n21 e925602-1 e925602-5\n01 5 2020 31 7 2020 07 9 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 7-year-old\n\nFinal Diagnosis: Torsades de pointes\n\nSymptoms: Ventricular tachycardia\n\nMedication: Propranolol • Magnesium\n\nClinical Procedure: Bilateral myringotomy tubes\n\nSpecialty: Anesthesiology • Cardiology • Pediatrics and Neonatology\n\nObjective:\nCongenital defects/diseases\n\nBackground:\nLong QT syndrome (LQTS) is an arrhythmogenic heart condition that can be congenital or acquired. Prolonged ventricular repolarizations in individuals with the disorder can cause fatal arrhythmias. Abnormal functioning of cardiac ion channels leads to arrhythmias such as torsades de pointes (TdP) and may be triggered by stress or medications. Many medications used in the perioperative period are triggers for the arrythmia.\n\nCase Report:\nA 7-year-old patient with known congenital LQTS type 2 presented for bilateral myringotomy and tube placement. The patient was otherwise healthy and taking propranolol daily. Preoperative midazolam was administered for anxiolysis, and induction of anesthesia was uneventful. He sustained an episode of TdP immediately following general anesthetic induction after failure of an in situ automatic implantable cardioverter-defibrillator (AICD). External defibrillation succeeded, and the patient was stabilized in the Postanesthesia Recovery Unit before transfer to the Pediatric Intensive Care Unit. Interrogation of the AICD revealed several undelivered defibrillation attempts. A chest X-ray showed an area suggestive of an epicardial electrode fracture. The following day, the AICD was replaced with no arrythmias noted. The patient had an uneventful recovery.\n\nConclusions:\nIn patients with a known history of LQTS, preparation and prevention are cornerstones of anesthesia care. Minimizing the use of triggering medications and emotional stress in the perioperative period, combined with ready equipment and medications to respond to arrythmias, are essential. In children, there is a greater chance of lead fracture and resulting device failure. Preoperative history of device function or interrogation of the AICD and possibly a chest X-ray are essential to ensure the integrity of the leads.\n\nMeSH Keywords:\nAnesthesia, GeneralAnesthesia, InhalationLong QT SyndromePediatricsTorsades de Pointes\n==== Body\nBackground\nCongenital long QT syndrome (LQTS) results from mutations in cardiac ion channels [1]. On electrocardiogram (ECG), prolonged QT intervals and T-wave abnormalities from extended ventricular repolarization are hallmarks of the disease. The condition can present as recurrent episodes of syncope, seizure-like episodes, or cardiac arrest. If untreated, sudden death may result from torsades de pointes (TdP) degenerating to ventricular fibrillation [2]. We present a case of a 7-year-old child with known congenital LQTS and an automatic implantable cardioverter-defibrillator (AICD) in situ who sustained an episode of TdP after anesthetic induction for a scheduled minor surgical procedure. Written authorization (under the Health Insurance Portability and Accounting Act) to use existing protected health information was obtained from the patient’s guardian for publication of this case.\n\nCase Report\nA 7-year-old child (weight 26 kg, height 124 cm) presented for myringotomy and ear tube placement. He had a past history of LQTS type 2, and an epicardial dual-chamber/epicardial patch AICD had been implanted 2 years prior without any anesthesia complications. No history of the AICD firing was noted during his cardiology follow-up since its placement. He had no other medical issues. Family history was positive for LQTS in the mother and sister. The child’s routine medications included propranolol. His preoperative vital signs were stable, and examination findings were normal. The pacemaker clinic recommended no changes to the AICD programming, and no interrogation was performed the day of surgery because use of surgical cautery was not planned. No ECG was performed preoperatively on the day of surgery. His ECG from more than 1 year ago revealed normal sinus rhythm with QT and QTc intervals of 482 and 559 milliseconds, respectively. All previous ECGs had a QTc interval of greater than 500 milliseconds. An echocardiogram, approximately 1 year ago, revealed normal biventricular size and function.\n\nThe child received oral midazolam for preoperative anxiolysis. In the operating room, following application of standard American Society of Anesthesiologists monitoring, inhalational induction was achieved with a 50: 50 mixture of nitrous oxide/oxygen and sevoflurane. The patient remained in normal sinus rhythm (Figure 1A). Shortly after anesthesia induction, the ECG monitor revealed a pattern of bigeminy (Figure 1B) and trigeminy, followed by 5 beats of ventricular tachycardia, which resolved spontaneously to normal sinus rhythm. Sevoflurane was immediately discontinued; 100% oxygen was administered in preparation of awakening the patient. External defibrillator pads were applied. Two minutes later, the ECG monitor revealed ventricular bigeminy followed by a pattern suggestive of TdP. The episode of TdP resolved spontaneously. Intravenous access was established during this episode. Laboratory results revealed a serum potassium level of 4.1 mmEq/L. Two minutes later, a sustained episode of TdP was noted (Figure 1C), and external cardiac defibrillation was successfully attempted (50 J) due to the failure of the in situ AICD to respond. Following defibrillation, narrow complex tachycardia was noted (130–150 bpm) with return of spontaneous circulation. Magnesium sulfate (30 mg/kg) was administered intravenously. The child was transported to the Postanesthesia Care Unit (PACU) with a normal sinus rhythm and in stable condition.\n\nThe cardiology team performed AICD device interrogation in the PACU. Evaluation of the device revealed 6 failed attempted therapies during this incident. The chest X-ray revealed an area suggestive of epicardial electrode fracture (Figure 2).\n\nThe child was admitted to the Pediatric Intensive Care Unit. He was monitored on telemetry, and defibrillation pads remained in place overnight. A transvenous single-chamber single-coil AICD was placed under general anesthesia the following day. The patient made an uneventful recovery and was discharged to home.\n\nDiscussion\nWe have presented the case of a child with congenital LQTS type 2 and an AICD device, who received anesthesia. Device malfunction resulted in cardiac arrest requiring treatment with defibrillation and intravenous magnesium therapy. This case presents 2 important learning points: (1) preoperative preparation of a child with an AICD, and (2) anesthetic management of a child with congenital LQTS.\n\nLQTS can be congenital or acquired, although up to 30% of carriers of LQTS are asymptomatic and have a normal QT interval and Schwartz score [3]. Acquired LQTS denotes patients with normal QTc at baseline who may develop fatal arrhythmias when exposed to triggering agents. Due to the complex nature of LQTS genetics, patients may appear to have a normal phenotype unless their reserve is sufficiently depleted by stress or medications [4,5]. Medications that may induce TdP include certain antiarrhythmics, antibiotics, antiemetics, and induction agents [6]. The mutations in congenital LQTS mainly relate to dysfunctional proteins that disrupt the ion channel function or change the voltage threshold [4]. There are 15 major types of LQTS identified, but LQTS types 1, 2, and 3 are the most common [3]. Our patient was a known carrier of LQTS type 2, but any patient with latent disease may suddenly present with symptoms of LQTS due to the stress and pharmacology of an anesthetic.\n\nAnesthesia management must include strategies for both prevention and treatment of arrhythmias that can lead to cardiac arrest. Preoperative prevention includes maintaining therapy with beta-blockers up to the day of surgery. Beta-blockers are the mainstay of prophylactic therapy for LQTS, but efficacy varies depending on the genotype. LQTS type 1 responds best to beta-blockers, which are less protective in LQTS types 2 and 3. Maintaining serum potassium levels in the high-normal range of 4.5 to 5 mEq/L may be protective, especially in patients with LQTS type 2 whose ion channel abnormality is sensitive to serum potassium levels [3,7]. Adequate premedication to reduce anxiety, and thereby sympathetic activation, is of paramount importance. Premedication with midazolam is preferred over dexmedetomidine because there are mixed reports in the literature about the effects of dexmedetomi-dine on QTc [8].\n\nThe Heart Rhythm Society, along with the American Society of Anesthesiologists, recommends communication with the heart rhythm team prior to any procedure and a thorough review of the records [9]. In patients with a well-established congenital LQTS diagnosis, a prolonged QTc is a known finding. In the above case, a preoperative ECG was not performed on the day of surgery because the patient had previously diagnosed congenital LQTS type 2 with a QTc greater than 500 milliseconds on all previous ECGs.\n\nInterrogation of the device in question may or may not be necessary depending on the record of recent device checks [9]. Generally, implanted pacemakers and defibrillators are checked by technicians when electrocautery is planned because AICD tachycardia therapies would need to be turned off in this setting. Devices of pacemaker-dependent patients should be placed in an asynchronous pacing mode, preventing inhibition of their device and subsequent asystole from cautery [9]. Patients typically receive an identification card with the type of device they have (company), thus making interrogation of the device more straightforward. Ideally, a child with an AICD should have the device function confirmed before undergoing a surgical procedure. In the above case, a preoperative interrogation of the AICD would have indicated lead malfunction. There may be an increased rate of lead fracture in children compared with adults because of growth and a greater activity level [10,11]. Several strategies are used in this instance, including review of preoperative chest X-ray, recent device interrogation, and medical records. If none are available, pre-operative consultation along with a device check is warranted [9] (Table 1).\n\nIntraoperatively, the main objectives are to prevent sympathetic excitation and to avoid factors that prolong QT interval [4]. An extensive list exists of medications that prolong the QT interval, and various drugs used in the perianesthesia period may need to be avoided [6]. In general, anesthetic agents have depressive effects on cardiovascular physiology. All volatile agents can prolong the QTc interval, although they do so to varying degrees, likely depending on the genotype of the individual [4]. Generally, patients with LQTS are not triggered by volatile agents if they are appropriately beta-blocked. Isoflurane is the agent of choice because there it may shorten QT interval [7,12]. Narcotics assist in reducing adrenergic stimulation and fentanyl is preferred, especially over sufentanil, which may increase the QTc interval [12]. Muscle relaxants such as succinylcholine and pancuronium can stimulate sympathetic responses and increase the QT interval, and therefore, they should be avoided [4]. Rocuronium and vecuronium are preferred neuromuscular blocking agents. Propofol may be beneficial because it either causes no change or shortens the QTc interval [12]. For nausea and vomiting prophylaxis, droperidol is known to prolong the QTc interval. Ondansetron is considered to be a possible risk; however, its safety profile is better [12].\n\nIf an arrhythmia is triggered, medications and equipment must be immediately available. First, discontinue the triggering agent, which during an anesthetic, is likely the volatile agent. TdP is treated with magnesium 30 mg/kg bolus over 2 to 3 minutes followed by an infusion [4,13]. In stable patients with TdP resistant to magnesium, transcutaneous or transvenous pacing can be used to increase the heart rate and shorten the QT interval [7,14]. Some LQTS patients do benefit from overdrive pacing when the TdP is induced by bradycardia or pause episodes. It is unclear, specifically, in patients with LQTS type 2 if ventricular overdrive pacing would shorten the QTc interval prophylactically. Any unstable patient should receive unsynchronized defibrillation and initiation of chest compressions. Some reports discuss using isoproterenol or dobutamine in patients with acquired LQTS who do not respond to magnesium; however, this is not indicated in patients with congenital LQTS because the increased adrenergic state may worsen the arrhythmia [12]. Any patient experiencing serious complications of LQTS should have immediate consultation and assessment with a pediatric electrophysiologist. Long-term therapy often includes AICD placement or left cardiac sympathetic denervation.\n\nConclusions\nAlthough LQTS syndrome is not a common disorder, it affects about 1 in every 2000 individuals, making it a disorder the anesthesiologist may frequently encounter [3]. Beta-blockade, anxiolytics, and pain control will minimize the risk of triggering sustained perioperative arrhythmias in LQTS patients. In children, specifically, there is greater chance of lead fracture and resulting device failure. Documented history of device function or interrogation of the AICD and possibly a chest X-ray are also essential to ensure the integrity of the leads. Having magnesium and a defibrillator on standby will minimize treatment delays if a ventricular arrhythmia occurs. In patients with a known history of LQTS, preparation and prevention are the cornerstones of anesthesia care.\n\nDepartment and Institution where work was done\n\nDepartment of Anesthesiology and Perioperative Medicine, Penn State Children’s Hospital, Hershey, PA, U.S.A.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Electrocardiogram demonstrating the progression of the arrythmia. (A) Sinus rhythm with prolonged QT interval. (B) Bigeminy. (C) Ventricular tachycardia with transition to torsades de pointes.\n\nFigure 2. Anterior-posterior radiograph illustrating the fractured leads of the automatic implantable cardioverterdefibrillator (arrows).\n\nTable 1. Preoperative checklist for child with an AICD.\n\n□ Identify type of AICD\t\n□ Review AICD device\t\n□ Review medical records\t\n□ Consult Pediatric Cardiology\t\n□ Check electrolytes on day of procedure\t\n□ Consider chest X-ray\t\nAICD – automatic implantable cardioverter-defibrillator.\n==== Refs\nReferences:\n1. Ackerman M The long QT syndrome: Ion channel diseases of the heart Mayo Clin Proc 1998 73 3 250 69 9511785 \n2. Ackerman M Porter C Identification of a family with inherited long QT syndrome following a pediatric near-drowning Pediatrics 1998 101 306 8 9445509 \n3. Mizsawa Y Horie M Wilde A Genetic and clinical advances in congenital long QT syndrome Circ J 2014 78 12 2827 33 25274057 \n4. Booker P Whyte S Ladusans E Long QT syndrome and anaesthesia Br J Anaesth 2003 90 349 66 12594150 \n5. Yang P Kanki H Drolet B Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes Circulation 2002 105 16 1943 48 11997281 \n6. Kannankeril P Roden D Darbar D Drug-induced long QT syndrome Pharmacol Rev 2010 62 4 760 81 21079043 \n7. Kaye AD Volpi-Abadie J Bensler J QT interval abnormalities: Risk factors and perioperative management in long QT syndromes and torsades de pointes J Anesth 2013 27 4 575 78 23412014 \n8. Görges M Whyte S Sanatani S Changes in QTc associated with a rapid bolus dose of dexmedetomidine in patients receiving TIVA: A retrospective study Paediatr Anaesth 2015 25 12 1287 93 26507917 \n9. Crossley G Poole J Rozner M The Heart Rhythm Society (HRS)/ American Society of Anesthesiologists (ASA) Expert Consensus Statement on the perioperative management of patients with implantable defibrillators, pacemakers and arrhythmia monitors: Facilities and patient management Heart Rhythm 2011 8 7 1114 52 21722856 \n10. Link M Hill S Cliff D Comparison of frequency of complications of implantable cardioverter defibrillators in children versus adults Am J Cardiol 1999 83 2 263 66 10073833 \n11. Eicken A Kolb C Lange S Implantable cardioverter defibrillator (ICD) in children Int J Cardiol 2006 107 1 30 35 16337494 \n12. Kies S Pabelick C Hurley H Anesthesia for patients with congenital long QT syndrome Anesthesiology 2005 102 1 204 10 15618804 \n13. Tzivoni D Banai S Schuger C Treatment of torsade de pointes with magnesium sulfate Circulation 1988 77 2 392 97 3338130 \n14. Thomas S Behr E Pharmacological treatment of acquired QT prolongation and torsades de pointes Br J Clin Pharmacol 2016 81 3 420 27 26183037\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1941-5923", "issue": "21()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D000768:Anesthesia, General; D002648:Child; D004562:Electrocardiography; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D016171:Torsades de Pointes", "nlm_unique_id": "101489566", "other_id": null, "pages": "e925602", "pmc": null, "pmid": "33056945", "pubdate": "2020-10-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10073833;21079043;9511785;11997281;21722856;25274057;26507917;9445509;15618804;16337494;23412014;26183037;3338130;12594150", "title": "Torsades de Pointes During Myringotomy in a Child with Congenital Long QT Syndrome: A Case Report.", "title_normalized": "torsades de pointes during myringotomy in a child with congenital long qt syndrome a case report" }
[ { "companynumb": "US-PFM-2021-05524", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", ...
{ "abstract": "Brugada pattern is a well-known pathological finding on electrocardiogram (ECG) which increases the likelihood of cardiac arrest due to ventricular arrhythmia. These cases generally present in younger patients without evidence of an electrolyte abnormality, structural heart disease, or cardiac ischemia. In many instances, this pattern is either hidden on initial presentation or presents as an incidental finding on an EKG. Often times the Brugada syndrome leads to sudden cardiac death or more rarely can be unmasked with a class 1A or 1C anti-arrhythmic agent. Here, we present a distinctive case in which the pattern was exposed by amiodarone during the emergent treatment of Ventricular Tachycardia (VT).\n\n\n\nA 34-year-old female, without significant cardiac history, presented to the Emergency Department after multiple near syncopal episodes at home. Initial ECG showed VT vs. SVT. After a failed trial of adenosine, the patient was treated with 150 mg amiodarone and became hypotensive needing an electrical cardioversion. After becoming bradycardic, the amiodarone drip was discontinued and she was admitted to the MICU. An echocardiogram and left heart catheterization showed no evidence of coronary artery disease or decreased ejection fraction. The patient's ECG now showed a subtle Brugada Type 3 pattern and she received a dual chamber AICD upon discharge.\n\n\n\nThis case emphasizes the awareness needed to seek out this pattern on subsequent ECG's. With the high lethality of Brugada, the emergency physician must recognize that multiple drugs can evoke this pattern after initial presentation.", "affiliations": "Carl R. Darnall Army Medical Center, Emergency Medicine Residency, 36065 Santa Fe Ave, Fort Hood, TX 76544, United States of America. Electronic address: Douglas.Robinson@rvu.edu.;Carl R. Darnall Army Medical Center, Emergency Medicine Residency, 36065 Santa Fe Ave, Fort Hood, TX 76544, United States of America. Electronic address: gregory.r.hand2.mil@mail.mil.;Carl R. Darnall Army Medical Center, Emergency Medicine Residency, 36065 Santa Fe Ave, Fort Hood, TX 76544, United States of America.;Carl R. Darnall Army Medical Center, Emergency Medicine Residency, 36065 Santa Fe Ave, Fort Hood, TX 76544, United States of America. Electronic address: ahackett@nyit.edu.", "authors": "Robinson|Douglas|D|;Hand|Gregory|G|;Ausman|Jason|J|;Hackett|Anthony|A|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D000638:Amiodarone", "country": "United States", "delete": false, "doi": "10.1016/j.ajem.2018.10.050", "fulltext": null, "fulltext_license": null, "issn_linking": "0735-6757", "issue": "37(2)", "journal": "The American journal of emergency medicine", "keywords": "Amiodarone; Brugada syndrome; Emergency medicine; SCNA5 gene; Sudden cardiac death; Ventricular tachycardia", "medline_ta": "Am J Emerg Med", "mesh_terms": "D000328:Adult; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D053840:Brugada Syndrome; D017147:Defibrillators, Implantable; D004562:Electrocardiography; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D017180:Tachycardia, Ventricular", "nlm_unique_id": "8309942", "other_id": null, "pages": "376.e3-376.e7", "pmc": null, "pmid": "30415983", "pubdate": "2019-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Brugada pattern exposed with administration of amiodarone during emergent treatment of ventricular tachycardia.", "title_normalized": "brugada pattern exposed with administration of amiodarone during emergent treatment of ventricular tachycardia" }
[ { "companynumb": "PHHY2019US034920", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": null, "drug...
{ "abstract": "BACKGROUND\nData on the novel oral anticoagulants (NOACS) during catheter ablation (CA) of atrial fibrillation (AF) are still limited. This study evaluated the periprocedural major complications (MC) of CA of AF, and compared Apixaban, Dabigatran, and Rivaroxaban with continuous phenoprocoumon.\n\n\nRESULTS\nA total of 444 patients (mean age = 65.1 ± 9.4 years; 283 [64%] male) with paroxysmal (n = 180 [41%]), persistent (n = 256 [58%]), or longstanding-persistent AF were enrolled. CA was performed in all patients using radiofrequency energy in conjunction with a 3D-mapping system. MCs were defined according to the current guidelines. Continuous phenprocoumon-therapy was administered in 120/444 (27%) patients (group 1) and 324/444 (73%) patients were treated with NOACs (group 2; Dabigatran: n = 51 [15.7%]; Rivaroxaban: n = 193 [59.6%]; Apixaban: n = 80 [24.7%]). Procedure times were comparable between groups 1 and 2 (128.2 ± 39.7 minutes vs. 129.7 ± 51.2 minutes; P = 0.77). CHA2 DS2-Vasc (3.0 [2.0, 4.0)] vs. 2.0 [1.0, 3.0]; P < 0.01) and HASBLED scores (2.0 [2.0, 2.5] vs. 2.0 [1.0, 2.0]; P = 0.002) were higher in group 1 patients. The incidence of MCs in the overall group was 8/444 (2%) and was equally distributed between groups 1 and 2 (2/120 [2%] vs. 6/324 [2%], P = 0.90). The incidence of MCs was comparable between the three different NOACs. There were no significant differences between patients with and without MCs with regard to age, CHA2 DS2-Vasc-score or HASBLED-score.\n\n\nCONCLUSIONS\nThe major complication rate between all three NOACs currently available and continuous phenprocoumon during AF ablation seem to be comparable. Complication rates were similar between patients treated with the three different available NOACs.", "affiliations": "Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany.;Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany.;Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany.;Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany.;Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany.;Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany.;Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany.;Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany.;Asklepios Proresearch, Hamburg, Germany.;Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany.;Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany.;Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany.", "authors": "Rillig|Andreas|A|;Lin|Tina|T|;Plesman|Joaquina|J|;Heeger|Christian-H|CH|;Lemes|Christine|C|;Metzner|Andreas|A|;Mathew|Shibu|S|;Wissner|Erik|E|;Wohlmuth|Peter|P|;Ouyang|Feifan|F|;Kuck|Karl-Heinz|KH|;Tilz|Roland Richard|RR|", "chemical_list": "D000925:Anticoagulants; D000991:Antithrombins; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D000069552:Rivaroxaban; D000069604:Dabigatran; D010644:Phenprocoumon", "country": "United States", "delete": false, "doi": "10.1111/jce.12856", "fulltext": null, "fulltext_license": null, "issn_linking": "1045-3873", "issue": "27(2)", "journal": "Journal of cardiovascular electrophysiology", "keywords": "anticoagulation; apixiban; atrial fibrillation; bleeding; catheter ablation; complication; dabigatran; novel oral anticoagulant; pulmonary vein isolation; rivaroxaban", "medline_ta": "J Cardiovasc Electrophysiol", "mesh_terms": "D000200:Action Potentials; D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants; D000991:Antithrombins; D001281:Atrial Fibrillation; D017115:Catheter Ablation; D000069604:Dabigatran; D004334:Drug Administration Schedule; D022062:Electrophysiologic Techniques, Cardiac; D065427:Factor Xa Inhibitors; D005260:Female; D006339:Heart Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D010644:Phenprocoumon; D011183:Postoperative Complications; D011720:Pyrazoles; D011728:Pyridones; D012042:Registries; D000069552:Rivaroxaban; D020521:Stroke; D013997:Time Factors; D016896:Treatment Outcome", "nlm_unique_id": "9010756", "other_id": null, "pages": "147-53", "pmc": null, "pmid": "26464027", "pubdate": "2016-02", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Apixaban, Rivaroxaban, and Dabigatran in Patients Undergoing Atrial Fibrillation Ablation.", "title_normalized": "apixaban rivaroxaban and dabigatran in patients undergoing atrial fibrillation ablation" }
[ { "companynumb": "DE-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-59399BI", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" ...
{ "abstract": "Neutropenic enterocolitis (NE) is a life-threatening infection of the immunocompromised. NE ubiquitously affects the cecum, often with involvement of the ascending colon and ileum. Classically, NE is associated with high mortality leading to the frequent use of aggressive treatment strategies including surgery. Although conservative approaches are often successful, there are currently no standardized treatment guidelines for NE and it is unclear when such strategies should be implemented. Here, we describe a patient with suspected chemotherapy-associated NE despite having previously undergone a right hemicolectomy. As computed tomography imaging failed to provide a conclusive diagnosis, we performed a gentle endoscopic evaluation that affirmed a diagnosis of NE of the transverse colon, and suggested the patient would benefit from conservative treatment. This case demonstrates that endoscopy can be a safe and useful tool in the diagnosis of NE, and is an important reminder that NE can affect any part of the gastrointestinal tract.", "affiliations": "Medical Scientist Training Program, University of Illinois College of Medicine, Chicago, IL, USA.;University of Illinois College of Medicine, Chicago, IL, USA.;Medical Scientist Training Program, University of Illinois College of Medicine, Chicago, IL, USA.;Metropolitan Group Hospitals General Surgery Residency, Advocate Illinois Masonic Hospital, University of Illinois, Chicago, IL, USA.", "authors": "Principe|Daniel R|DR|;Koch|Regina M|RM|;Bergsten|Tova M|TM|;Rubin|Jonathan|J|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/omcr/omz140", "fulltext": "\n==== Front\nOxf Med Case Reports\nOxf Med Case Reports\nomcr\nOxford Medical Case Reports\n2053-8855 Oxford University Press \n\n10.1093/omcr/omz140\nomz140\nCase Report\nChemotherapy-associated neutropenic enterocolitis of the transverse colon post right hemicolectomy\nPrincipe Daniel R 1 Koch Regina M 2 Bergsten Tova M 1 Rubin Jonathan 3 1 \nMedical Scientist Training Program, University of Illinois College of Medicine, Chicago, IL, USA\n2 \nUniversity of Illinois College of Medicine, Chicago, IL, USA\n3 \nMetropolitan Group Hospitals General Surgery Residency, Advocate Illinois Masonic Hospital, University of Illinois, Chicago, IL, USA\nCorrespondence address. Medical Scientist Training Program, University of Illinois College of Medicine, 840 South Wood Street, 601 CSB, Chicago, IL 60612, USA. Tel: (312) 996-7473; E-mail: principe@illinois.edu\n1 2020 \n31 1 2020 \n31 1 2020 \n2020 1 omz1406 11 2019 20 11 2019 28 11 2019 © The Author(s) 2020. Published by Oxford University Press.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nNeutropenic enterocolitis (NE) is a life-threatening infection of the immunocompromised. NE ubiquitously affects the cecum, often with involvement of the ascending colon and ileum. Classically, NE is associated with high mortality leading to the frequent use of aggressive treatment strategies including surgery. Although conservative approaches are often successful, there are currently no standardized treatment guidelines for NE and it is unclear when such strategies should be implemented. Here, we describe a patient with suspected chemotherapy-associated NE despite having previously undergone a right hemicolectomy. As computed tomography imaging failed to provide a conclusive diagnosis, we performed a gentle endoscopic evaluation that affirmed a diagnosis of NE of the transverse colon, and suggested the patient would benefit from conservative treatment. This case demonstrates that endoscopy can be a safe and useful tool in the diagnosis of NE, and is an important reminder that NE can affect any part of the gastrointestinal tract.\n\nNational Institutes of Health10.13039/1000000021F30CA236031\n==== Body\nINTRODUCTION\nNeutropenic enterocolitis (NE) is a life-threatening infection affecting the immunocompromised. Although the precise etiology varies, most cases involve the overgrowth of Clostridium septicum causing severe inflammation and thickening of the cecum, often involving the ascending colon and terminal ileum. In some instances, this can lead to life-threatening complications including perforation, peritonitis and septicemia [1]. Diagnosis of NE is often challenging due to its nonspecific presentation and a lack of consensus regarding diagnostic criteria [2]. Patients generally present complaining of vague GI symptoms including abdominal pain, distention, vomiting, diarrhea and fever [1]. As such, diagnosis is dependent on physical exam, imaging and clinical context. With no standardized treatment guidelines for NE, outcomes can be poor with some estimates suggesting a mortality rate of ~50% [1, 3].\n\nHere, we present the case of a patient presenting with severe neutropenia and diffuse abdominal pain following chemotherapy. Although her symptoms were concerning for NE, her cecum and ascending colon had been previously resected and she had no clinical signs of the right iliac fossa. Imaging showed the presence of gas in the wall of the transverse colon, and based on the results of cautious endoscopy, the patient was diagnosed with atypical NE and managed conservatively. This case serves as an important reminder that NE can affect any part of the gastrointestinal tract, and that diagnosis is not excluded by the absence of right-sided symptoms. Further, this case demonstrates that if performed cautiously, endoscopy can be an important and minimally invasive tool in the management of NE, expediting diagnosis and guiding treatment decisions.\n\nCASE PRESENTATION\nA 70-year-old woman presented to the emergency department complaining of severe, diffuse abdominal pain of 2 days. Her medical history was significant for right-sided stage 3 colon cancer status post open right hemicolectomy with end-to-end ileocolic anastomosis. She had been receiving adjuvant FOLFOX (folinic acid, fluorouracil and oxaliplatin) at a different institution with her last chemotherapy infusion 5 days prior to the time of presentation. On physical exam the patient was afebrile, normotensive and mildly tachycardic. Her abdomen was distended and tender with focal peritoneal signs in the epigastric region, but there was no tenderness in the right iliac fossa. A complete blood count showed a white blood cell (WBC) count of 2300/μl with an absolute neutrophil count (ANC) of 600/μl with 44% bands.\n\nComputed tomography imaging showed the presence of gas in the wall of the transverse colon with associated lymphedema and patent mesenteric vessels (Fig. 1). Due to the degree of neutropenia and clinical context, we strongly suspected an atypical NE. However, imaging alone was unable to exclude the possibility of another etiology such as an infective enterocolitis. Therefore, and we elected for endoscopy with cautious, gentle insufflation to ensure no further damage to the transverse colon. Although the transverse colon was edematous, the patient did not show signs of vascular compromise, necrosis or transmural thickening (Fig. 2). Biopsies were obtained from the diseased colonic segment, which showed normal mucosa with edema. Based on these results, as well as negative stool cultures for infectious processes including C. difficile, the patient was diagnosed with NE of the transverse colon. She was managed conservatively with bowel rest, IV fluid resuscitation, antibiotics (vancomycin and meropenem) and filgrastim-sndz to stimulate leukocyte production. The patient’s symptoms improved rapidly and her WBC count increased to 5000/μl with an ANC of 2500/μl. She was discharged on hospital day four with oral antibiotics and has had no further issues.\n\nFigure 1 CT imaging showing the presence of gas in the wall of the transverse colon with associated lymphedema.\n\nFigure 2 Endoscopy showing edema of the transverse colon consistent with NE.\n\nDISCUSSION\nHere, we present the unusual case of NE originating in the transverse colon. To date, there has only been one reported case of chemotherapy-associated NE affecting the transverse colon, in which the cecum was intact but uninvolved [4]. Hence, ours in the first documented case of a NE in a patient lacking a cecum, serving as an important clinical reminder that, although NE has been long thought to ubiquitously involve the cecum, it can originate in any part of the GI tract and should be suspected in any myelosuppressed patient presenting with vague abdominal pain.\n\nAs mentioned, there are currently no standardized treatment guidelines for NE, particularly for non-classic cases such as ours. In the previously reported case identifying NE of the transverse colon, the patient developed bowel perforation and required immediate surgical correction [4]. However, there are no current standards to determine when surgery is and is not indicated, with most reserving surgery for cases with more severe complications including persistent bleeding, pneumoperitoneum suggestive of perforation or clinical deterioration [5, 6]. As our patient had gas within the wall of the transverse colon but no obvious signs of perforation, it was unclear whether she would benefit from surgery particularly given her history of hemicolectomy. As such, we elected for a minimally invasive approach to better evaluate her condition, which not only affirmed the diagnosis, but also led us to believe that she would benefit most from conservative treatment.\n\nAlthough we had success using careful endoscopy with gentle insufflation, others have cautioned against endoscopy for fear of further injury to the intestine or increasing the spread of bacteria [7]. Hence, endoscopy should be reserved for patients such as ours with mild-to-moderate disease and hemodynamic stability, after other non-invasive imaging modalities have failed to adequately inform the treatment plan or rule out other potential etiologies. These techniques include CT, which is the preferred imaging modality in adults due to its high sensitivity and superior accuracy compared to plain radiography [1]. Bedside ultrasound sonography (US) is also an important tool in the diagnosis of NE [8]. For instance, in a small study, early bedside US at the onset of a single symptom was able to diagnose NE in 100% of patients evaluated. However, US was significantly less effective later during disease course [9]. In this study, US identified two patients at risk for wall rupture who were eventually taken for surgery, although these were still confirmed by CT [9]. Hence, while diagnostic guidelines are not standardized at this time, we recommend CT as the first approach when NE is suspect, with additional tools reserved for cases in which this fails to fully determine the treatment plan. However, regardless of the diagnostic tools used, it is imperative that patients suspected for NE receive coordinated, multidisciplinary care to ensure rapid diagnosis and management of what can quickly progress to a life-threatening condition.\n\nConflict of interest statement\nNone declared.\n\nFunding\nThis work was supported by the National Institutes of Health (grant 1F30CA236031 to D.R. Principe).\n\nConsent for publication\nThe patient provided fully informed, written consent to have her clinical information and imaging shared in this report. Additional information is available upon request.\n\nGuarantor\nDaniel R. Principe.\n==== Refs\nReferences\n1. \nRodrigues FG , Dasilva G , Wexner SD \nNeutropenic enterocolitis\n. World J Gastroenterol 2017 ;23 :42 –7\n.28104979 \n2. \nMachado NO \nNeutropenic enterocolitis: a continuing medical and surgical challenge\n. N Am J Med Sci 2010 ;2 :293 –300\n.22558577 \n3. \nUllery BW , Pieracci FM , Rodney JR , Barie PS \nNeutropenic enterocolitis\n. Surg Infect (Larchmt) 2009 ;10 :307 –14\n.19566419 \n4. \nRamsingh J , Bolln C , Hodnett R , Al-Ani A \nNeutropenic enterocolitis affecting the transverse colon: an unusual complication of chemotherapy\n. BMJ Case Rep 2014 ;2014 . doi: 10.1136/bcr-2014-204035 .\n5. \nNesher L , Rolston KV \nNeutropenic enterocolitis, a growing concern in the era of widespread use of aggressive chemotherapy\n. Clin Infect Dis 2013 ;56 :711 –7\n.23196957 \n6. \nShamberger RC , Weinstein HJ , Delorey MJ , Levey RH \nThe medical and surgical management of typhlitis in children with acute nonlymphocytic (myelogenous) leukemia\n. Cancer 1986 ;57 :603 –9\n.3484659 \n7. \nWilliams N , Scott AD \nNeutropenic colitis: a continuing surgical challenge\n. Br J Surg 1997 ;84 :1200 –5\n.9313695 \n8. \nDietrich CF , Hermann S , Klein S , Braden B \nSonographic signs of neutropenic enterocolitis\n. World J Gastroenterol 2006 ;12 :1397 –402\n.16552808 \n9. \nBenedetti E , Simonetti F , Caracciolo F , Papineschi F , Bruno B , Pelosini M , et al. \nEarly diagnosis of neutropenic enterocolitis by ultrasound Sonography\n. Blood 2009 ;114 :4742 –2\n.\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2053-8855", "issue": "2019(11)", "journal": "Oxford medical case reports", "keywords": null, "medline_ta": "Oxf Med Case Reports", "mesh_terms": null, "nlm_unique_id": "101642070", "other_id": null, "pages": "omz140", "pmc": null, "pmid": "31879565", "pubdate": "2019-11", "publication_types": "D002363:Case Reports", "references": "23196957;22558577;19566419;9313695;24792023;3484659;28104979;16552808", "title": "Chemotherapy-associated neutropenic enterocolitis of the transverse colon post right hemicolectomy.", "title_normalized": "chemotherapy associated neutropenic enterocolitis of the transverse colon post right hemicolectomy" }
[ { "companynumb": "US-MYLANLABS-2020M1040057", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": "3", ...
{ "abstract": "Background  Drug-induced liver injury is a common cause of transaminitis, occurring in up to 5% of patients who are hospitalized for liver failure. In pregnancy, transaminitis is seen in conditions which may require expedited delivery. Case  A 39-year-old G2P0010 at 27 2/7 weeks' gestation with chronic hypertension on labetalol was found to have elevated transaminases. Evaluation for preeclampsia, acute fatty liver, nonalcoholic steatohepatitis, cholelithiasis, infections, and autoimmune conditions were all negative. Labetalol was then discontinued, and liver biopsy was performed. After discontinuation of labetalol, her hepatitis improved, and she was discharged on hospital day 12 and went on to deliver at term. Conclusion  Labetalol-induced hepatitis should be considered in the differential for transaminitis during pregnancy to prevent iatrogenic preterm delivery.", "affiliations": "Department of Obstetrics and Gynecology, University of Illinois College of Medicine at Chicago, Chicago, Illinois.;Department of Obstetrics and Gynecology, University of Illinois College of Medicine at Chicago, Chicago, Illinois.;Department of Gastroenterology, Advocate Christ Medicine Center, Oak Lawn, Illinois.;Department of Pathology, Advocate Christ Medical Center, Oak Lawn, Illinois.;Department of Maternal-Fetal Medicine, Advocate Christ Medical Center, Oak Lawn, Illinois.", "authors": "Whelan|Anna|A|;Izewski|Joanna|J|;Berkelhammer|Charles|C|;Walloch|Jami|J|;Kay|Helen H|HH|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1055/s-0040-1713789", "fulltext": "\n==== Front\nAJP Rep\nAJP Rep\n10.1055/s-00000169\nAJP Reports\n2157-6998 2157-7005 Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. \n\n10.1055/s-0040-1713789\n200009\nCase Report\nLabetalol-Induced Hepatotoxicity during Pregnancy: A Case Report\nWhelan Anna MD1 Izewski Joanna MD1 Berkelhammer Charles MD2 Walloch Jami MD3 Kay Helen H. MD4 1 Department of Obstetrics and Gynecology, University of Illinois College of Medicine at Chicago, Chicago, Illinois\n2 Department of Gastroenterology, Advocate Christ Medicine Center, Oak Lawn, Illinois\n3 Department of Pathology, Advocate Christ Medical Center, Oak Lawn, Illinois\n4 Department of Maternal-Fetal Medicine, Advocate Christ Medical Center, Oak Lawn, Illinois\nAddress for correspondence Anna Whelan, MD Department of Obstetrics and Gynecology, University of Illinois College of Medicine at Chicago840 S. Wood Street, M/C 808, Chicago, IL 60612Anna.whelan.md@gmail.com\n7 2020 \n04 8 2020 \n10 3 e210 e212\n15 2 2020 07 3 2020 This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.\nBackground\n Drug-induced liver injury is a common cause of transaminitis, occurring in up to 5% of patients who are hospitalized for liver failure. In pregnancy, transaminitis is seen in conditions which may require expedited delivery.\n\n\n\nCase\n A 39-year-old G2P0010 at 27\n2/7\nweeks' gestation with chronic hypertension on labetalol was found to have elevated transaminases. Evaluation for preeclampsia, acute fatty liver, nonalcoholic steatohepatitis, cholelithiasis, infections, and autoimmune conditions were all negative. Labetalol was then discontinued, and liver biopsy was performed. After discontinuation of labetalol, her hepatitis improved, and she was discharged on hospital day 12 and went on to deliver at term.\n\n\n\nConclusion\n Labetalol-induced hepatitis should be considered in the differential for transaminitis during pregnancy to prevent iatrogenic preterm delivery.\n\n\nKeywords\nlabetalolhypertension in pregnancyhepatotoxicitytransaminitis\n==== Body\nTransaminitis in pregnancy is a serious and ominous finding for clinicians. It is often a sign of severe preeclampsia, hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome or acute fatty liver of pregnancy (AFLP). When present, these can lead to severe maternal and neonatal consequences. However, in the absence of other signs and symptoms of these diseases, it is important to examine other potential causes of hepatotoxicity.\n\n\nDrug-induced liver injury is an often overlooked, yet fairly common cause of hepatic damage. As many as 20% of patients who are hospitalized for symptoms of liver failure in the United States can be attributed to medication exposure.\n1\n2\nThe overall incidence of drug-induced liver injury is approximately 1 in 10,000 to 1 in 100,000 patients.\n2\n3\n\n\n\nLabetalol is a selective α-adrenergic antagonist and nonselective β-adrenergic antagonist that is commonly used in the treatment of hypertension. It has an excellent safety profile and is one of the first-line medications to treat hypertension in pregnancy.\n4\nCommon side effects reported include orthostatic hypotension, headache, dizziness, and nausea.\n1\n2\n3\nSerious side effects may include severe bradycardia, hypotension, cardiac impairment, bronchospasm, respiratory distress, and hypoglycemia.\n5\nBut since the 1980s, there have been few reports underlining serious hepatic injury in patients taking labetalol.\n1\n6\n7\n8\nDue to its rarity, physicians may be unaware of this possible cause of hepatotoxicity.\n\n\nCase Report\n\nA 39-year-old G2P1011 at 27\n2/7\nweeks' gestation with a history of chronic hypertension and myomectomy presented to the emergency room with severe left lower quadrant pain. She denied headache, blurred vision, shortness of breath, or right upper quadrant pain. Her vital signs were normal except for blood pressure of 159/92. Exam showed tenderness to palpation in the left lower quadrant, normal neurologic exam, and normal uterine and cervical exam. Fetal heart tracing was reassuring.\n\n\nAfter arrival, blood pressures were elevated with some in the severe range, 144 to 173 systolic over 92 to 109 diastolic. Review of the patient's prenatal records indicated that she had been started on labetalol 1 month prior to conception. She required intravenous labetalol 20 mg once and was restarted on prescribed labetalol dose of 200 mg twice a day, although she reported taking only 100 mg twice a day, and had not taken any medication for 3 days prior to presentation. She had elevated liver enzymes with alanine transaminase (ALT) of 206 U/L and aspartate transaminase (AST) of 524 U/L. Alkaline phosphatase was normal at 86 U/L and total bilirubin was normal at 0.5 mg/dL. The urine protein/creatinine ratio was 171. An ammonia level was sent to assess for fatty liver of pregnancy and was normal at 14 μmol/L. Blood smear showed no signs of hemolysis and lactate dehydrogenase was normal. The patient denied alcohol or acetaminophen use or abuse. She was admitted for further evaluation of her elevated transaminases. Delivery was held due to her overall stable clinical picture which did not support a diagnosis of severe preeclampsia.\n\nExtensive serological testing for causes of hepatitis were negative including: hepatitis A/B/C/E, cytomegalovirus, Epstein–Barr virus, herpes simplex virus, autoimmune hepatitis (antinuclear antibodies, smooth muscle antibodies, antineutrophil cytoplasmic antibodies, lupus anticoagulant, liver–kidney microsomal antibodies, antiphospholipid antibodies), and bile acids. Liver ultrasound scan and magnetic resonance imaging showed no evidence of hepatic necrosis or fatty liver. Doppler ultrasound showed patent hepatic veins and echocardiogram was normal.\n\n\nOn hospital day 4, with transaminase levels still rising and all testing negative to date, labetalol was discontinued, even though she was on a relatively low dose at 200 mg Q12 hours, and she was switched to nifedipine for her hypertension. Her left lower quadrant pain was attributed to a degenerating 5 cm myoma and improved during hospitalization. On hospital day 8, her transaminases peaked with an AST of 360 U/L and ALT of 1,099 U/L. Due to the uncertainty of her diagnosis, the patient underwent a liver core biopsy without complications. Over the next 4 days, her AST and ALT downtrended (\nFig. 1\n). At discharge on hospital day 12, her AST improved to 215 U/L and ALT to 754 U/L.\n\n\nFig. 1 \nTrend of transaminase levels from admission to hospital discharge.\n\n\n\nThe liver biopsy, with input from consulting hepatopathologists, was reported as normal liver architecture without fibrosis, steatosis, or cholestasis (\nFig. 2\n). No viral inclusions were observed, and inflammatory cells were predominantly mononuclear without large numbers of eosinophils. There was no evidence for autoimmune hepatitis, HELLP or AFLP. No centrilobular necrosis was observed which would be observed with acetaminophen toxicity. The diagnosis of drug-induced liver injury was made. Prompt improvement in liver enzymes after discontinuation of labetalol supported this diagnosis. The patient subsequently presented at term 9 weeks later and underwent a normal delivery. Liver enzymes by that time had improved to near normal with AST of 42 U/L and ALT of 83 U/L.\n\n\nFig. 2 \nLiver biopsy: The histologic features include a central vein (\nA\n), debris-laden macrophages (\nB\n), admixed with eosinophils (\nC\n), the sinusoids with increased Kupffer cells with debris (\nD\n), and rare acidophil bodies—eosinophilic necrotic hepatocytes (\nE\n).\n\n\nDiscussion\n\nDue to the overall safety profile of labetalol and the rarity of idiosyncratic reactions, it is currently one of the first-line drugs used to treat hypertension in pregnancy.\n4\nWe describe a case of labetalol-induced hepatitis occurring in pregnancy. We believe that this case report is important as a reminder that there may be other explanations for transaminitis in a pregnant patient aside from preeclampsia, HELLP or AFLP. Our patient was spared a potential iatrogenic preterm delivery when a thorough investigation suggested labetalol toxicity.\n\n\n\nLabetalol is primarily cleared in the liver. It is rapidly taken up and approximately 80 to 90% of the drug in blood is removed in a single pass.\n6\nLabetalol can cause transaminitis and in rare occasions may lead to significant hepatotoxicity, hepatocellular injury, hepatocellular necrosis, liver failure, and death.\n1\n2\n3\n7\n8\nThe hepatotoxicity is most often considered an idiosyncratic response due to a presentation at therapeutic doses along with an indolent and variable latency period which can range from 5 to 90 days.\n2\nIdiosyncratic drug reactions account for approximately 20% of cases with liver injury severe enough for hospitalization and occur more commonly in women than men.\n2\nIn a multicenter open label trial, labetalol was shown to cause reversible asymptomatic transaminase elevations in 8% of patients using the drug.\n7\nSome of these patients were rechallenged with the drug and again showed an elevation in transminases.\n7\nSince case reports emerged in the 1980s, the hepatotoxicity of labetalol has been documented in multiple reports.\n2\n3\n7\n8\nThis is significant, as rarely this can progress to hepatic failure in pregnancy.\n8\n\n\n\nThe pathogenesis of labetalol hepatotoxicity is not completely known but is attributed to several intracellular pathways, of which one is the mitochondrial cytochrome P450 enzymatic pathway. Patients with isoenzyme differences or mutations in this enzyme gene may be more susceptible to its hepatotoxic effects. Other mechanisms may include an autoimmune and inflammatory response.\n3\n7\n8\n\n\n\nLiver biopsies in patients diagnosed with labetalol hepatoxicity typically show scant amounts of lymphocytes and diffuse findings of variable degrees of necrosis and apoptosis. In contrast, specimens from patients with autoimmune or infectious hepatitis show lymphocytic infiltration.\n3\nIt has been argued that the hepatotoxicity from labetalol may represent an allergic reaction. However, the lack of eosinophils in our patient's biopsy, as well as the indolent time course makes an allergic etiology less likely.\n3\nOur patient's biopsy was consistent with idiosyncratic drug toxicity in that it showed “sparse” inflammatory cells without other overwhelming etiologies such as centrilobular necrosis due to acetaminophen toxicity or intracellular fat deposits due to nonalcoholic steatohepatitis.\n\n\n\nLabetalol liver damage can occur even at average doses of 200 mg/d (range from 50–600 mg daily). Our patient had been prescribed a dose of 200 mg twice daily, but was taking less than that per her admission. Patients with hepatotoxicity most commonly present with a combination of jaundice and anorexia.\n2\n3\nIn reported cases, ALT and AST can rise 10 to 100 times from baseline.\n2\n3\n7\n8\n\n\nAlthough there is no practical means to prevent labetalol toxicity, aside from awareness and close monitoring, we recommend that all patients with chronic hypertension undergo baseline liver evaluation with complete blood count and a comprehensive metabolic panel either preconception or at their first prenatal visit. It is important to assess their baseline transaminase levels prior to starting labetalol during pregnancy for patients with hypertension.\n\nConclusion\nDrug-induced liver injury secondary to the use of labetalol is rare but a well-described reaction in the general, nonpregnant population. Its presentation may be confused with other diseases in pregnancy which can lead to iatrogenic preterm delivery. It is important to include drug-induced liver injury in the differential when assessing pregnant patients with elevated liver enzymes.\n\nConflict of Interest None declared.\n\nDisclosure\nThe authors have nothing to disclose.\n\nNote\nThis case report was presented as a poster at the ACOG 2019 Annual Meeting on May 3–6, 2019, in Nashville, TN.\n==== Refs\nReferences\n1 Stronkhorst A Bosma A van Leeuwen D J A case of labetalol-induced hepatitis\nNeth J Med 1992 40 (3-4):200 202\n1603212 \n2 Lee W M Drug-induced hepatotoxicity\nN Engl J Med 2003 349 05 474 485\n12890847 \n3 Douglas D D Yang R D Jensen P Thiele D L Fatal labetalol-induced hepatic injury\nAm J Med 1989 87 02 235 236\n2757062 \n4 ACOG Practice Bulletin No. 203: chronic hypertension in pregnancy\nObstet Gynecol 2019 133 01 e26 e50\n30575676 \n5 Grassin Delyle S Duverneuil-Mayer C Abe E Fatal intoxication with labetalol (Trandate)\nForensic Sci Int 2008 178 (2-3):e19 e21\n18406090 \n6 McNeil J J Louis W J Clinical pharmacokinetics of labetalol\nClin Pharmacokinet 1984 9 02 157 167\n6370541 \n7 Clark J A Zimmerman H J Tanner L A Labetalol hepatotoxicity\nAnn Intern Med 1990 113 03 210 213\n2375555 \n8 Long R C Wofford M R Harkins K G Minor D S Hepatocellular necrosis associated with labetalol\nJ Clin Hypertens (Greenwich) 2007 9 04 287 290\n17396073\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2157-7005", "issue": "10(3)", "journal": "AJP reports", "keywords": "hepatotoxicity; hypertension in pregnancy; labetalol; transaminitis", "medline_ta": "AJP Rep", "mesh_terms": null, "nlm_unique_id": "101569862", "other_id": null, "pages": "e210-e212", "pmc": null, "pmid": "33094006", "pubdate": "2020-07", "publication_types": "D002363:Case Reports", "references": "2375555;12890847;18406090;1603212;30575676;6370541;2757062;17396073", "title": "Labetalol-Induced Hepatotoxicity during Pregnancy: A Case Report.", "title_normalized": "labetalol induced hepatotoxicity during pregnancy a case report" }
[ { "companynumb": "NVSC2020US327906", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LABETALOL\\LABETALOL HYDROCHLORIDE" }, "drugadditional...
{ "abstract": "In a subset analysis of data from a 6-month, multicenter, non-interventional study, we compared change in symptoms and quality of life (QoL), and treatment tolerability, in men with moderate to severe lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) receiving tamsulosin (TAM, 0.4 mg/day) or the hexanic extract of Serenoa repens (HESr, 320 mg/day) as monotherapy. Symptoms and QoL were assessed using the IPSS and BII questionnaires, respectively. Patients in the treatment groups were matched using two statistical approaches (iterative and propensity score matching). Within the iterative matching approach, data was available from a total of 737 patients (353 TAM, 384 HESr). After 6 months, IPSS scores improved by a mean (SD) of 5.0 (4.3) points in the TAM group and 4.5 (4.7) points in the HESr group (p = 0.117, not significant). Improvements in QoL were equivalent in the two groups. TAM patients reported significantly more adverse effects than HESr patients (14.7% vs 2.1%; p < 0.001), particularly ejaculation dysfunction and orthostatic hypotension. These results show that HESr is a valid treatment option for men with moderate/severe LUTS/BPH; improvements in urinary symptoms and QoL were similar to those observed for tamsulosin, but with considerably fewer adverse effects.", "affiliations": "Urology Department, Hospital Clínic, Universitat de Barcelona, IDIBAPS, Barcelona, Spain.;Urology Department, Research Group in Men's Integral Health, Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain.;Urology Department, Hosp. Univ. Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain.;Urology Department, Hosp. Univ. de Canarias, Tenerife, Spain.;Urology Department, Research Group in Men's Integral Health, Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain.;Urology Department, Hosp. Univ. Central de Asturias, Oviedo, Spain.;Urology Department, University of Messina, Messina, Italy.;Urology Department, Fundació Puigvert, Autonoma University of Barcelona, Barcelona, Spain.;Urology Department, Fundació Puigvert, Autonoma University of Barcelona, Barcelona, Spain.;Urology Department, Hosp. Univ. de Getafe. Getafe, Madrid, Spain.;Urology Department, Hosp. Nal. de Parapléjicos, Toledo, Spain.;Urology Department, Hosp. Univ. Virgen de Las Nieves, Granada, Spain.;Gran Sol Primary Care Center, Badalona, Barcelona, Spain.;San Andrés Primary Care Center, Madrid, Spain.;Menasalbas Primary Care Center, Toledo, Spain.;SEMERGEN Nefro-Urology Working Group, Barcelona, Spain.;Pierre Fabre Ibérica S.A., Barcelona, Spain. jose.manasanch@pierre-fabre.com.", "authors": "Alcaraz|Antonio|A|;Rodríguez-Antolín|Alfredo|A|;Carballido-Rodríguez|Joaquín|J|;Castro-Díaz|David|D|;Medina-Polo|José|J|;Fernández-Gómez|Jesús M|JM|;Ficarra|Vincenzo|V|;Palou|Joan|J|;Ponce de León Roca|Javier|J|;Angulo|Javier C|JC|;Esteban-Fuertes|Manuel|M|;Cózar-Olmo|José M|JM|;Pérez-León|Noemí|N|;Molero-García|José M|JM|;Fernández-Pro Ledesma|Antonio|A|;Brenes-Bermúdez|Francisco J|FJ|;Manasanch|José|J|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1038/s41598-021-98586-5", "fulltext": "\n==== Front\nSci Rep\nSci Rep\nScientific Reports\n2045-2322\nNature Publishing Group UK London\n\n98586\n10.1038/s41598-021-98586-5\nArticle\nEfficacy and tolerability of the hexanic extract of Serenoa repens compared to tamsulosin in moderate-severe LUTS-BPH patients\nAlcaraz Antonio 1\nRodríguez-Antolín Alfredo 2\nCarballido-Rodríguez Joaquín 3\nCastro-Díaz David 4\nMedina-Polo José 2\nFernández-Gómez Jesús M. 5\nFicarra Vincenzo 6\nPalou Joan 7\nPonce de León Roca Javier 7\nAngulo Javier C. 8\nEsteban-Fuertes Manuel 9\nCózar-Olmo José M. 10\nPérez-León Noemí 11\nMolero-García José M. 12\nFernández-Pro Ledesma Antonio 13\nBrenes-Bermúdez Francisco J. 14\nManasanch José jose.manasanch@pierre-fabre.com\n\n15\n1 grid.10403.36 Urology Department, Hospital Clínic, Universitat de Barcelona, IDIBAPS, Barcelona, Spain\n2 grid.144756.5 0000 0001 1945 5329 Urology Department, Research Group in Men’s Integral Health, Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain\n3 grid.73221.35 0000 0004 1767 8416 Urology Department, Hosp. Univ. Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain\n4 grid.411220.4 0000 0000 9826 9219 Urology Department, Hosp. Univ. de Canarias, Tenerife, Spain\n5 grid.411052.3 0000 0001 2176 9028 Urology Department, Hosp. Univ. Central de Asturias, Oviedo, Spain\n6 grid.10438.3e 0000 0001 2178 8421 Urology Department, University of Messina, Messina, Italy\n7 grid.5841.8 0000 0004 1937 0247 Urology Department, Fundació Puigvert, Autonoma University of Barcelona, Barcelona, Spain\n8 Urology Department, Hosp. Univ. de Getafe. Getafe, Madrid, Spain\n9 Urology Department, Hosp. Nal. de Parapléjicos, Toledo, Spain\n10 grid.411380.f 0000 0000 8771 3783 Urology Department, Hosp. Univ. Virgen de Las Nieves, Granada, Spain\n11 Gran Sol Primary Care Center, Badalona, Barcelona, Spain\n12 San Andrés Primary Care Center, Madrid, Spain\n13 Menasalbas Primary Care Center, Toledo, Spain\n14 SEMERGEN Nefro-Urology Working Group, Barcelona, Spain\n15 Pierre Fabre Ibérica S.A., Barcelona, Spain\n29 9 2021\n29 9 2021\n2021\n11 1940127 5 2021\n23 8 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This 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/.\nIn a subset analysis of data from a 6-month, multicenter, non-interventional study, we compared change in symptoms and quality of life (QoL), and treatment tolerability, in men with moderate to severe lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) receiving tamsulosin (TAM, 0.4 mg/day) or the hexanic extract of Serenoa repens (HESr, 320 mg/day) as monotherapy. Symptoms and QoL were assessed using the IPSS and BII questionnaires, respectively. Patients in the treatment groups were matched using two statistical approaches (iterative and propensity score matching). Within the iterative matching approach, data was available from a total of 737 patients (353 TAM, 384 HESr). After 6 months, IPSS scores improved by a mean (SD) of 5.0 (4.3) points in the TAM group and 4.5 (4.7) points in the HESr group (p = 0.117, not significant). Improvements in QoL were equivalent in the two groups. TAM patients reported significantly more adverse effects than HESr patients (14.7% vs 2.1%; p < 0.001), particularly ejaculation dysfunction and orthostatic hypotension. These results show that HESr is a valid treatment option for men with moderate/severe LUTS/BPH; improvements in urinary symptoms and QoL were similar to those observed for tamsulosin, but with considerably fewer adverse effects.\n\nSubject terms\n\nProstate\nBenign prostatic hyperplasia\nUrological manifestations\nPierre Fabre Ibérica S.A.issue-copyright-statement© The Author(s) 2021\n==== Body\npmcIntroduction\n\nBenign prostatic hyperplasia (BPH) is a non-malignant growth of the prostate tissue and is a frequent cause of lower urinary tract symptoms (LUTS) in men1,2. Prevalence of BPH has been estimated at between 50 to 60% for men in their 60s3, while prevalence of LUTS associated with BPH (LUTS/BPH) increases from approximately 3% in those aged 45–49 years to over 30% in men aged ≥ 85 years4.\n\nThe European Association of Urology (EAU) guidelines on the management of LUTS note that symptoms can be divided into 3 types, i.e. storage, voiding and post-micturition symptoms1, with voiding symptoms being the most prevalent, but storage symptoms the most bothersome5. Several studies have also indicated that LUTS and LUTS/BPH can have a significant impact on patients’ quality of life (QoL)6,7 and on the QoL of patients’ partners5,8.\n\nMedical treatments most frequently used for LUTS/BPH include alpha-1-adrenergic receptors blockers (AB) and 5-alpha-reductase inhibitors (5ARI), or a combination of both in some patients. Although such treatments have demonstrated their effectiveness in reducing symptoms, they can also negatively affect sexual function, especially ejaculatory function9. Other medical treatments also used to treat LUTS/BPH include 5-phosphodiesterase inhibitors, antimuscarinic drugs, beta-3 agonists and phytotherapy. The hexanic extract of Serenoa repens (S. repens) (HESr) is a phytotherapeutic treatment for LUTS/BPH which has been shown to have anti-inflammatory10–13, antiandrogenic14–17, and antiproliferative effects17.\n\nImprovements in symptoms and QoL in patients treated with the HESr treatment were observed in the non-interventional Quality of Life in Benign Prostatic Hyperplasia, or QUALIPROST study18, which assessed the effectiveness and tolerability of commonly used treatments for LUTS/BPH in clinical practice. QUALIPROST provided further evidence that HESr appears to be as effective as AB and 5ARI for the treatment of moderate to severe LUTS/BPH when used as monotherapy or in combination with one of the other treatments over a six-month treatment period18 and confirmed the low level of adverse effects associated with HESr treatment, especially in comparison to AB and 5ARI. In the original QUALIPROST publication18, it was not possible to analyze in-depth the outcomes in patients treated with tamsulosin (TAM) and compare them with patients receiving the HESr after applying matching techniques.\n\nIn this subset analysis of data from the QUALIPROST study, we compared changes in urinary symptoms (overall, voiding and storage) and QoL in men with moderate to severe LUTS/BPH receiving TAM or HESr as monotherapy using two different matching approaches to optimize comparability of the treatment groups. Treatment tolerability was also evaluated and compared.\n\nMethods\n\nPatients and study design\n\nData for this analysis was from the QUALIPROST study (ISRCTN11815680)18, a multicenter study to evaluate change in symptoms and QoL in patients with moderate to severe LUTS/BPH (baseline IPSS score > 7 points) managed in a urological setting. The study conformed to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines19 and is described in detail in Alcaraz A et al18. Briefly, the study used a longitudinal, prospective, non-interventional design in which participants were followed up for a 6-month period. Patients were excluded from QUALIPROST if they had received a medical treatment for BPH in the 6 months prior to inclusion, if they had received any drug treatment with a known effect on BPH symptoms (i.e., diuretics, antihistamines, or tricyclic antidepressants) at any time in the 4 weeks prior to inclusion, if they had other urinary disorders, or if they had previously undergone surgery of the lower urinary tract. As QUALIPROST was a real-world study of patient management, investigators could prescribe any of the commercially available treatments according to their usual practice. A range of treatments were prescribed to manage LUTS/BPH, including monotherapy and combination treatments. The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of the Puerta de Hierro Majadahonda University Hospital in Madrid, Spain. Informed consent was obtained individually from all patients included in the study.\n\nFor the present sub-analysis, data was used from patients ≥ 40 years of age with a diagnosis of LUTS/BPH and an IPSS score of > 7 points who had received either TAM (OMNIC, UROLOSIN or generics, at a recommended dose [RD] of 0.4 mg/day) or HESr (PERMIXON; RD: 320 mg/day, 160 mg morning and evening) as monotherapy. PERMIXON contains: free fatty acids, 80.7% (mainly lauric, oleic, myristic and palmitic acids); glycerides, 6.8%; methyl and ethyl esters, 2.5%; unsaponified matter, 2.27%; long-chain esters, 1.36%20.\n\nStudy variables\n\nKey endpoints in the QUALIPROST study were change in LUTS evaluated by means of the International Prostate Symptom Score (IPSS) and impact on QoL assessed using the Benign Prostatic Hyperplasia Impact Index (BII). The IPSS includes 8 questions, seven of which assess symptoms of LUTS/BPH, while the eighth assesses QoL associated with the condition. The symptom items assess problems with both storage (urgency, frequency, nocturia) and voiding (incomplete emptying, intermittency, weak stream and straining to void). The overall score on the IPSS ranges from 0 to 35 for the symptom items, with a higher score indicating more severe symptoms, and from 0 to 5 for the QoL item (item 8). An improvement of > 3.1 points on the IPSS questionnaire is considered clinically relevant21. Separate sub-scores can also be calculated for the storage and voiding symptoms.\n\nThe BII is a self-administered questionnaire consisting of 4 questions measuring the impact of urinary symptoms on physical discomfort, worries about health, symptom bother, and interference with usual activities during the past month22,23. Items are answered on a Likert scale, with 4 or 5 response options per item and scores range from 0 (best QoL) to 13 (worst QoL). An improvement of > 0.4 points on the BII questionnaire is considered clinically relevant, as perceived by the patient21. Both the BII and the IPSS were self-completed by patients at baseline and at the 6-month follow-up visit.\n\nSociodemographic data collected at baseline also included age, weight and height, date of onset of urinary symptoms, year of LUTS/BPH diagnosis, results from diagnostic tests when carried out (digital rectal exam, prostate volume, maximum urinary flow, urine analysis, serum analysis, prostate-specific antigen), treatment received (yes/no, alpha-blockers, 5-alpha-reductase inhibitors, phytotherapy, other), and information on co-morbidities and their treatment. Adverse effects potentially associated with treatment were recorded at follow-up.\n\nTreatment compliance was assessed using the validated Spanish version of the Haynes-Sackett questionnaire24 which asks about (a) patients’ difficulty taking the medication and (b) the number of tablets they have taken in the previous month. Patients taking 80% or over of the prescribed dose are considered to show good adherence.\n\nStatistical analysis\n\nOptimising comparability: iterative and propensity score matching\n\nTo optimise comparability between the TAM and HESr groups, we used two different approaches to select the sample to be included from each group. Initially, an iterative matching procedure was used to ensure comparable group mean scores for baseline IPSS (total score, and voiding and storage subscores), QoL (IPSS item 8) and BII scores, maximum urinary flow (Qmax), prostate-specific antigen (PSA), and prostate volume. The iterative matching procedure is intended to ensure that two or more study groups are comparable in terms of a given set of variables. This approach selects individuals consecutively from one or more of the groups in such a way that when the means of specific variables are compared between groups, the result is not significant (i.e. when performing a t-test, the resulting p value is not significant, using a type I error of 10%). Thus, the two groups are matched in terms of means of the variables used to guide the iterative matching (IPSS, BII, etc.). Unlike propensity score matching (another standard technique to select individuals and make groups comparable), with iterative matching the groups may contain different numbers of patients, which helps to guarantee the largest possible sample size. In line with this methodology, therefore, patients were removed one by one from one of the two groups and the two groups continually compared until there were no statistically significant differences (p > 0.1) between them on any of the selected baseline characteristics listed above.\n\nAs further confirmation of the study results, we carried out a propensity score matching procedure, whereby a propensity score was calculated for each patient for inclusion in either treatment group, again based on baseline IPSS (total score, and voiding and storage subscores), QoL (IPSS item 8) and BII scores, Qmax, PSA, and prostate volume. Each patient in the TAM group was then paired with a patient from the HESr group with a similar propensity score (within a pre-established range of ± 0.2 SD), giving groups of equal size for comparison.\n\nThe iterative matching procedure was performed using t-tests to compare treatment groups in each elimination round and Student’s t-test was used to determine the success of the matching procedure, by testing for post-matching baseline between-group differences on the IPSS and BII total scores, the IPSS voiding and storage sub-scores, and IPSS item 7 (nocturia). Matching was done at both the level of the overall sample and for sub-groups of patients defined by IPSS severity.\n\nAssessing change over time\n\nChange over time within the different treatment groups was assessed using paired t-tests and between-group differences in the size of change on the IPSS and BII was assessed by t-tests for independent samples. Changes on items 1–7 on the IPSS, which assess symptom severity, were analyzed separately from item 8, which assesses QoL. Outcomes on the IPSS storage and voiding sub-scores were also analyzed and compared between groups.\n\nResponder analysis\n\nA responder analysis of patients was performed using results on IPSS items 1–7 and the results compared between groups using the chi-squared test. Responders were defined as patients who improved by 3.1 points or more on the IPSS questionnaire, a change which is considered clinically relevant21. The same analysis was repeated for patients showing an improvement of ≥ 25% in their IPSS score and for patients showing a worsening in symptoms (increase of 4 points or more on the IPSS overall score).\n\nAdverse effects\n\nAdverse effects were analyzed in terms of frequencies and proportions and compared between groups using the chi-square or exact Fisher test as appropiate.\n\nSub-group analysis\n\nAll analyses were performed for the sample as a whole and for two sub-groups defined by baseline severity of urinary symptoms, i.e. a moderate group with a baseline IPSS score of 8–19 and a more severe group with a baseline IPSS score of ≥ 20 points.\n\nPatients with any missing data on the IPSS and BII at any visit were excluded from the analysis as were any patients who were lost to follow-up or that stopped or changed treatment. In all comparisons, results were considered statistically significant at p < 0.05. Statistical analyzes were carried out using R 3.5.2 statistical software25.\n\nResults\n\nResults based on iterative matching: available data and study flow chart\n\nAfter the iterative matching procedure, data was available from 737 patients (353 for TAM and 384 for HESr). The number and proportion of patients reporting moderate or severe IPSS at baseline in the TAM and the HESr groups are shown in Fig. 1.Figure 1 Study flow-chart: iterative matching based on IPSS (total, voiding and storage sub-scores, and item 8) and BII scores, maximum urinary flow rate (Qmax), prostate-specific antigen (PSA), and prostate volume at baseline. TAM: tamsulosin; HESr: hexanic extract of Serenoa repens.\n\nSociodemographic and clinical characteristics of the sample after iterative matching\n\nTable 1 shows the sociodemographic and clinical characteristics for the treatment groups at baseline for the matched samples. At baseline, mean IPSS (SD) was 17.4 (4.8) in the tamsulosin group and 16.8 (5.2) in the HESr group (p = 0.105) There were no statistically significant differences between the two groups on any of the clinical parameters analyzed, either overall or when analyzed according to baseline IPSS intensity (moderate or severe). Similarly, there were no statistically significant differences between groups in the frequency of recorded concomitant diseases (Supplementary Table S1). Mean total baseline IPSS was slightly higher in older patients, with a mean (SD) IPSS score of 16.3 (4.7) points in patients ≤ 65 years compared to a mean of 17.6 (5.1) points in those aged > 65 years.Table 1 Patient baseline characteristics by treatment group (iterative matching sample).\n\n\tTAM\tHESr\tp value\t\nn\tMean (SD)\tn\tMean (SD)\t\nAge, mean (SD) years\t318\t64.6 (8.4)\t335\t63.5 (9.1)\t0.112\t\nBMI (kg/m2), mean (SD)\t311\t26.8 (2.9)\t332\t26.7 (2.9)\t0.487\t\nIPSS, mean (SD)\t353\t17.4 (4.8)\t384\t16.8 (5.2)\t0.105\t\nIPSS voiding subscore\t353\t10.0 (3.3)\t384\t9.6 (3.4)\t0.109\t\nIPSS storage subscore\t353\t7.4 (2.2)\t384\t7.2 (2.4)\t0.232\t\nNocturia\t353\t2.4 (1.0)\t384\t2.4 (1.0)\t0.539\t\nBII, mean (SD)\t353\t7.2 (2.3)\t384\t6.9 (2.3)\t0.107\t\nIPSS 8 (QoL)\t353\t3.7 (1.1)\t384\t3.6 (1.1)\t0.163\t\nTime since diagnosis (years)\t317\t1.0 (2.3)\t334\t1.3 (2.9)\t0.167\t\nQmax (ml/s)\t159\t11.8 (3.4)\t158\t12.4 (3.6)\t0.111\t\nProstate volume (cm3)\t301\t51.7 (19.5)\t324\t49.3 (17.0)\t0.109\t\nPSA (ng/ml)\t325\t2.5 (1.3)\t351\t2.4 (1.2)\t0.375\t\nTAM: tamsulosin; HESr: hexanic extract of Serenoa repens. BMI: body mass index; IPSS: International Prostate Symptom Score; BII: Benign Prostatic Hyperplasia Impact Index; QoL: quality of life; Qmax: maximum urinary flow rate; PSA: prostate-specific antigen.\n\nChange in symptoms, QoL and clinical parameters after 6 months (iterative matching sample)\n\nTable 2 shows the change in symptoms, QoL and clinical parameters for the TAM and HESr groups after 6 months of treatment. The mean (SD) change in IPSS score was 5.0 (4.3) points for those treated with tamsulosin and 4.5 (4.7) for patients receiving HESr (p = 0.117); mean (SD) improvement on the BII improvement was 2.3 (2.4) and 2.2 (2.5) points, respectively (p = 0.417). Analysis of IPSS scores showed similar improvements in voiding and storage symptoms for both treatments. There were no statistically significant differences between the groups in any of these outcomes.Table 2 Improvements from baseline to 6-month follow-up in symptoms and quality of life by treatment group (iterative matching sample).\n\n\tTAM\tHESr\tp value\t\nn\tMean (SD)\tn\tMean (SD)\t\nIPSS total\t335\t5.0 (4.3)\t369\t4.5 (4.7)\t0.117\t\nIPSS voiding sub-score\t335\t2.9 (2.8)\t369\t2.5 (3.1)\t0.051\t\nIPSS storage sub-score\t335\t2.1 (2.1)\t369\t2.0 (2.3)\t0.527\t\nNocturia\t335\t0.6 (0.9)\t369\t0.6 (1.0)\t0.539\t\nBII total\t335\t2.3 (2.4)\t369\t2.2 (2.5)\t0.417\t\nIPSS 8 (QoL)\t335\t1.3 (1.2)\t369\t1.1 (1.2)\t0.129\t\nTAM: tamsulosin; HESr: hexanic extract of Serenoa repens; IPSS: International Prostate Symptom Score; BII: Benign Prostatic Hyperplasia Impact Index; QoL: quality of life.\n\nData on change in Qmax, prostate volume and PSA for patients who underwent these tests at both baseline and the 6-month follow-up visit in the two study groups is provided in Table 3. Given that this was an observational study in which clinicians applied their usual criteria for requesting Qmax and PSA analysis, patient numbers with available data for those tests were considerably lower than those with available data on the IPSS and BII, both at baseline and follow-up. Based on the available results, the mean improvement in Qmax ranged from 3.1 to 3.2 ml/s and the mean change in prostate volume was about − 2.6 cm3 for both arms. Similarly, the change in PSA values between the study groups available at follow-up was 0.2 and 0.1 ng/ml for the TAM and the HESr groups, respectively. No statistically significant differences were found in these outcomes.Table 3 Change from baseline to 6-month follow-up in PSA, Qmax and prostate volume for the study groups (iterative matching sample).\n\n\tTAM\tHESr\tp value\t\nn*\tMean (SD)\tn*\tMean (SD)\t\nPSA total (ng/ml)\t116\t− 0.2 (1.3)\t128\t− 0.1 (0.8)\t0.771\t\nQmax (ml/sec)\t62\t3.2 (3.4)\t79\t3.1 (3.6)\t0.849\t\nProstate volume (cm3)\t61\t− 2.6 (9.3)\t89\t− 2.7 (11.6)\t0.961\t\nTAM: tamsulosin; HESr: hexanic extract of Serenoa repens; Qmax: maximum urinary flow rate; PSA: prostate-specific antigen.\n\n*Number of patients vary according to the test and the personal clinical practice of the investigators.\n\nChange in IPSS score based on baseline symptom severity (iterative matching sample)\n\nWhen change in IPSS scores was analyzed by baseline symptom severity (Fig. 2 and Table 4), patients in both the moderate and severe baseline symptom groups showed improvement, with no statistically significant differences between the TAM and HESr groups. Gains were larger in patients with more severe baseline symptoms (IPSS mean improvement of 7.8 and 7.9 points for TAM and HESr, respectively, in the more severe group, compared to 3.7 and 3.3 points, respectively, in patients with moderate baseline symptoms). Baseline and follow-up IPSS scores according to sub-groups defined by baseline severity (IPSS moderate or severe) are provided in Supplementary Figure S2.Figure 2 Mean change (95% CI) in IPSS total score from baseline to 6 months for the treatment groups based on baseline symptom severity (iterative matching sample). TAM: tamsulosin; HESr: hexanic extract of Serenoa repens; IPSS: International Prostate Symptom Score.\n\nTable 4 Improvements from baseline to 6-month follow-up in symptoms, quality of life, and clinical parameters by treatment group, in patients with severe (IPSS > 19) baseline symptoms (iterative matching sample).\n\n\tTAM\tHESr\tp value\t\nn\tMean (SD)\tn\tMean (SD)\t\nIPSS total\t106\t7.8 (4.9)\t93\t7.9 (5.3)\t0.964\t\nIPSS voiding sub-score\t106\t4.7 (3.1)\t93\t4.7 (3.2)\t0.977\t\nIPSS storage sub-score\t106\t3.1 (2.4)\t93\t3.2 (2.5)\t0.955\t\nNocturia\t106\t1.0 (1.0)\t93\t1.1 (1.1)\t0.673\t\nBII total\t106\t2.8 (2.7)\t93\t2.8 (3.2)\t0.968\t\nIPSS 8 (QoL)\t106\t1.6 (1.2)\t93\t1.3 (1.3)\t0.184\t\nHESr: hexanic extract of Serenoa repens; TAM: tamsulosin; IPSS: International Prostate Symptom Score; BII: Benign Prostatic Hyperplasia Impact Index; QoL: quality of life.\n\nA similar pattern was seen when results were analyzed by symptom type (storage or voiding). In patients with moderate baseline symptoms, the IPSS storage symptom sub-score improved by 1.6 points (p = 0.947) in both treatment groups, compared to an improvement of 3.1 and 3.2 points (p = 0.955) in the TAM and HESr groups, respectively, in patients with more severe baseline symptoms. On the voiding sub-score, patients with moderate baseline symptoms treated with TAM and HESr showed improvements of 2.1 and 1.8 points (p = 0.098), respectively, while those with more severe baseline symptoms showed an improvement of 4.7 points (p = 0.977) in both treatment groups. There were no statistically significant differences between the groups on these analyses. When change in IPSS score was analysed across different age groups according to treatment type, no statistically significant differences were observed between tamsulosin and the HESr in terms of efficacy in any of the age groups (50–60; 61–70; 71–80 years).\n\nBased on the iterative matching samples, QoL improved to a similar degree in both treatment groups, both when patients were assessed overall (mean [SD] improvement in BII score of 2.3 [2.4] points for TAM and 2.2 [2.5] points for HESr) and when analyzed by baseline symptom severity. As shown in Fig. 3, patients with more severe baseline symptoms showed greater improvement. Supplementary Figure S3 shows the mean baseline and follow-up BII scores according to sub-groups defined by baseline symptom severity (IPSS 8—19; IPSS > 19).Figure 3 Mean improvement (95% CI) in mean BII total score by baseline symptom severity and treatment group, baseline to 6 months (iterative matching sample). TAM: tamsulosin; HESr: hexanic extract of Serenoa repens; BII: Benign Prostatic Hyperplasia Impact Index; IPSS: International Prostate Symptom Score.\n\nA similar pattern was observed when item 8 of the IPSS was used to assess QoL, with a mean [SD] improvement of 1.1 [1.2] and 1.0 [1.2] points in the TAM and HESr groups, respectively, in patients with moderate baseline symptoms (p = 0.535), and an improvement of 1.6 [1.2] and 1.3 [1.3] points, respectively, in the more severe baseline patients (p = 0.184). A statistically significant (p < 0.001) correlation of 0.570 and 0.569 for the TAM and HESr arms, respectively, was observed between the BII total score and question 8 of the IPSS.\n\nResults of the IPSS responder analysis showed that 240 (71.6%) patients in the TAM group improved by at least 3 points on the IPSS compared to 242 (65.6%) of patients in the HESr group (p = 0.100).\n\nTreatment compliance\n\nWith respect to treatment compliance, 31 (9.4%) of TAM patients reported difficulty taking the medication compared to 35 HESr patients (9.7%), with no statistically significant difference between the two groups (p = 0.976). Among the patients that did report any difficulty taking the medication, over 93.5% and 91.4% for the TAM and HESr groups, respectively, reported good treatment adherence, with no statistically significant differences between them (p = 1.000).\n\nAdverse effects\n\nTable 5 shows the incidence of adverse effects (AE) overall and for the two treatment groups. 52 (14.7%) patients reported at least one AE in the TAM group compared to 8 (2.1%) patients in the HESr group (p < 0.001). The most frequent AE was anejaculation (reported by 8.5% of patients receiving TAM, compared to 0 patients on HESr; p < 0.001). This was followed by reduced ejaculatory volume (5.1% of patients on TAM and 0.5% of HESr patients; p < 0.001), and orthostatic hypotension (reported by 2% of TAM patients and no HESr patients; p = 0.006).Table 5 Reported adverse effects for the study sample overall and by treatment group.\n\n\tOverall\tTAM\tHESr\tp value\t\nn = 737\tn = 353\tn = 384\t\nAny adverse effect\t60 (8.1%)\t52 (14.7%)\t8 (2.1%)\t< 0.001*\t\nAnejaculation\t30 (4.1%)\t30 (8.5%)\t0\t< 0.001*\t\nReduced ejaculatory volume\t20 (2.7%)\t18 (5.1%)\t2 (0.5%)\t< 0.001*\t\nOrthostatic hypotension\t7 (1.0%)\t7 (2.0%)\t0\t0.006*\t\nDizziness\t7 (1.0%)\t4 (1.1%)\t3 (0.8%)\t0.715\t\nReduced libido\t5 (0.7%)\t4 (1.1%)\t1 (0.3%)\t0.199\t\nOnly AE with an incidence of ≥ 1% in any of the groups are reported (iterative matching sample).\n\nTAM: tamsulosin; HESr: hexanic extract of Serenoa repens.\n\n*Statistically significant.\n\nResults based on propensity matched samples\n\nAfter propensity matching, data was available for a total of 128 patients each for TAM and HESr. Of those, 93 patients had moderate symptoms and 35 had severe symptoms at baseline in the TAM group, compared to 100 and 28 patients, respectively, in the HESr group (Supplementary Figure S1). Mean (SD) baseline IPSS was 16.7 (4.5) and 16.3 (4.9) points in the TAM and HESr groups, respectively, with no statistically significant differences between the groups at baseline (p = 0.579). Mean (SD) baseline BII was 7.2 (2.2) and 7.0 (2.4) points, respectively, for TAM and HESr, with no statistically significant differences between the groups at baseline (p = 0.499). There were no statistically significant differences between the two treatment groups on any other baseline characteristics (Supplementary Table S2).\n\nAs in the analysis based on the iterative matching procedure, overall IPSS and BII scores showed a similar level of improvement in symptoms and QoL, with no statistically significant differences between the groups in terms of the size of the improvement. Mean (SD) change on the IPSS was 5.1 (4.6) points in the TAM group and 4.9 (4.6) in HESr patients (p = 0.718 for the difference in the size of the change between the two groups). On the BII, mean change was 2.6 (2.4) points for TAM patients and 2.4 (2.5) points for HESr patients (p = 0.494 for the difference in the size of the change between the two groups). There were no statistically significant differences between the treatment groups on any of the other outcomes analysed (Supplementary Table S3).\n\nIn patients with more severe baseline symptoms (IPSS > 19), similar levels of change were observed in both treatment groups on all endpoints assessed, with no statistically significant differences between groups (Supplementary Table S4). For example, mean (SD) improvement in IPSS total score was 9.1 (5.3) in the TAM group and 9.0 (5.4) in the HESr group (p = 0.929 for the difference in the size of the change between the two groups), while mean (SD) change on the BII was 3.3 (2.8) in the TAM group and 3.6 (2.8) in the HESr group (p = 0.593 for the difference in the size of the change between the two groups). Likewise, the overall incidence of AEs was higher in the TAM group (21 patients, 16.4%) than in the HESr group (3 patients, 2.3%) and the difference was statistically significant at p < 0.001 (Supplementary Table S5). Anejaculation and reduced ejaculatory volume were the two individual AEs showing statistically significant between-group differences in incidence favoring the HESr (p = 0.002 and p = 0.014, respectively).\n\nDiscussion\n\nAs far as we know, this is the first prospective, non-interventional, 6-month follow-up study to compare TAM and HESr in current clinical practice which includes an specific assessment of change in QoL using the BII questionnaire. Investigating treatment effectiveness in conditions of usual clinical practice is important because it provides complementary evidence to that obtained in randomized controlled trials (RCTs)26. RCTs reported by Debruyne et al27, which showed similar efficacy for the HESr (PERMIXON) and tamsulosin in providing relief from symptoms, or that reported by Latil et al28, which showed that HESr reduced inflammatory activity in the prostate to a greater extent than tamsulosin, are clearly important but the results may not always translate to clinical practice. The QUALIPROST Study was performed in the conditions and with the type of patients regularly found in clinical practice. On the other hand, as real-world studies like QUALIPROST are not performed under such controlled conditions as RCTs, between-group matching techniques are useful in reducing possible bias when comparing results across treatments.\n\nThe present subset analysis is also relevant because it analyzes one specific Serenoa repens extract, in line with the 2020 European Association of Urology guidelines on the management of LUTS1 which recommended that results from different clinical trials should be compared strictly according to the same validated extraction technique and/or content of active compounds29. The recommendation is based on the fact that the pharmacokinetic properties of different preparations can vary significantly so extracts of the same plant produced by different companies may not have the same biological or clinical effects1. Indeed, Habib and colleagues have shown that different Serenoa repens extracts can vary considerably in composition20. Potency has also been shown to vary across commercially available plant extracts, with some being no more effective than placebo30 The HESr is the only S. repens extract which the European Medicines Agency (EMA) considers as having sufficient evidence to support its use as treatment for LUTS/BPH31. In support of the EMA’s position, two recently published, exhaustive systematic reviews showed that the hexanic extract of S. repens (HESr) reduces nocturia and improves Qmax compared with placebo, and that, in terms of efficacy, it is similar to tamsulosin and short-term 5ARI in relieving LUTS32,33 and the recently published 2021 EAU guidelines on the management of LUTS recommends offering hexane extracted Serenoa repens to men with LUTS who want to avoid any potential adverse events especially related to sexual function34.\n\nThe present subset analysis of matched data from the QUALIPROST Study provides evidence that men with moderate/severe LUTS/BPH treated for 6 months with HESr show similar levels of improvement in urinary symptoms and QoL as those treated with tamsulosin, but that the HESr was associated with fewer adverse effects. These results further demonstrate the HESr’s efficacy and support findings from RCTs that have compared HESr and TAM. In an RCT comparing TAM and the HESr in men with a baseline IPSS ≥ 10, Debruyne et al27 reported a 4.4-point improvement in total IPSS in both groups after 12 months of treatment, which is very similar to our findings of a mean improvement in IPSS of 4.5 points in the HESr group and 5 points in the TAM group after 6 months of treatment. In the CombAT trial, Barkin et al35 also observed improvements of 4.7 points in total IPSS after 9 months of treatment with tamsulosin.\n\nIn further analysis focusing on patients with severe baseline urinary symptoms, Debruyne et al36 found that total IPSS improved by 7.8 points with PERMIXON after 12 months of treatment compared to 5.8 points with tamsulosin. These results align with our finding of a mean improvement of 7.9 points for patients in the HESr group, though we observed a mean improvement of 8.8 points in the severe patients treated with TAM. All of the improvements seen on the IPSS in our study, in both the overall sample and the more severe patients, exceed the minimal relevant difference of 3.1 points which has been established for the IPSS total score21. Similarly, the mean decrease of ≥ 2.2 points reported on the BII questionnaire in all the groups in this analysis represents a marked clinical improvement in QoL experienced by the patients, according to the Barry et al. threshold21.\n\nThe improvements in QoL presented here are also similar to those observed in earlier studies. In the CombAT trial, after 6 months of treatment with tamsulosin (mean baseline BII score: 5.3 points) the BII showed an adjusted mean improvement of 1.5 points35 compared to a mean improvement of 2.3 points for TAM (mean baseline BII score: 7.2 points) and of 2.2 points for the HESr (mean baseline BII score: 6.9 points) in our study. The adjusted mean improvement on IPSS Q8 in the CombAT study was 0.9 points in the tamsulosin arm (mean baseline IPSS for Q8: 3.6 points), compared to 1.3 in our study for tamsulosin (mean baseline BII score: 3.7 points) and 1.1 points for the HESr (mean baseline BII score: 3.6 points).\n\nThe difference between our study and many of the results reported previously is that we observed these changes in conditions of usual clinical practice, for example in patients with concomitant diseases, rather than in the carefully controlled conditions of an RCT. Those controlled conditions, and the fact that RCTs are often carried out in a narrower range of patients than is seen in usual practice, can limit the external validity of their results. Real world studies, on the other hand, are useful because they provide complementary evidence on treatments in conditions where factors such as poor adherence, or the presence of concomitant conditions can impact effectiveness26. This is of relevance in the present analysis, as tamsulosin is the most commonly prescribed alpha-blocker in recent years37.\n\nAs observed in several previous studies, one advantage of the HESr is the low rate of associated adverse effects. Indeed, 2.1% of patients receiving HESr in this study reported any AE compared to 14.7% in the TAM group. Adverse effects in the TAM group primarily affected sexual function, which may be an area of particular concern to the men who take the medication. In terms of treatment safety, alpha-blockers such as tamsulosin or silodosin are considered in the FORTA (LUTS-Fit fOr The Aged) 2014 classification38 to be of questionable use (FORTA C) in patients aged 65 or over, and it is suggested that other alpha-blockers, including alfuzosin, doxazosin, or terazosin, should be avoided in that age group (FORTA D). The HESr and other phytotherapeutic drugs were not evaluated in the 2014 FORTA classification, as only the most widely used drugs for LUTS-BPH were included in this classification. Furthermore, in a recent cohort study among patients aged ≥ 65 years and diagnosed with BPH, the tamsulosin cohort (n = 253,136 patients) was associated with a significantly higher risk of dementia when compared with no-BPH-medication cohort and with the other alternative-BPH-medication cohorts evaluated39.\n\nAs treatment strategy should aim to maximise clinical benefit while limiting side effects, then treatment for LUTS/BPH should be tailored to the individual patient’s symptomatology, comorbidities, and preferences, and take into account treatment tolerability. Discussion of the risk of adverse effects with patients prior to prescription treatments for LUTS/BPH is clearly important. Tamsulosin treatment has been associated with ejaculatory dysfunction (EjD)9,40, with a higher rate of EjD than the nonselective alpha-1-adrenergic receptor antagonists41 and an incidence of EjD up to 26% depending on dose and treatment duration42. It has also been reported that almost 90% of healthy volunteers taking 0.8 mg of tamsulosin showed decreased ejaculate volume and 35.4% had complete anejaculation43, which is particularly important if preservation of fertility is desired.\n\nStrengths of the present study include the matching approach, which, as indicated by the lack of any statistically significant differences between groups at baseline, ensured a high level of comparability between the treatment arms. The inclusion of the propensity score analysis helps to further reduce the possibility of bias in the study and provides additional support for the robustness of the results.\n\nThe present study has some limitations. Data were obtained using a non-interventional design without randomization or blinding. Patients were therefore allocated to a specific management approach based on clinician judgement, which could lead to a selection bias. Nevertheless, as noted, considerable steps were taken in analysis to reduce the risk of bias. The 6-month follow-up period could also be considered a study limitation. Nevertheless, this time period is likely to be sufficient to observe the effects of TAM, as it has been reported to have a rapid onset of action, with maximum effect observed within the first 3 months of treatment27,44. In the case of the HESr, the results observed appear to be due to a combination of its proven anti-inflammatory, 5-alpha-reductase inhibition and antiproliferative mechanisms of action, although more time might be required to observe the full effect of the 5-alpha-reductase inhibition mechanism. In fact, a 2-year clinical study showed that results after 24 months of treatment with the HESr were 10.5% better than those observed at 6-months45. Therefore, although clinically relevant improvements in IPSS were seen in the HESr group after 6 months in the current study, a longer follow-up could potentially achieve slightly better results. It is also of note that some in vitro studies in rodents have shown Serenoa repens to have a smooth muscle relaxant effect in the prostate46 and bladder47, which might also contribute to its efficacy. Finally, it would be of interest to investigate whether the extension of the symptoms and QoL improvements over a longer period could be associated with a reduction in the risk of progression and whether the higher rate of AEs in the TAM group could affect long-term quality of life, cost of treatment, and treatment adherence.\n\nIn conclusion, a range of treatment options are available for patients with moderate-severe LUTS/BPH, with differing characteristics in terms of the degree of symptom relief achieved, tolerability, and impact on QoL. The availability of different options means that treatment of LUTS/BPH can be customised to the individual patient’s symptomatology, comorbidities, and preferences. Beginning treatment with the least aggressive option in terms of tolerability is a reasonable approach to symptom management, as long as that option aligns with patient preferences and has demonstrated effectiveness. In the present analysis, the hexanic extract of S. repens appears to have similar efficacy to tamsulosin but with better tolerability which likely makes it a good first-line treatment choice for many patients.\n\nSupplementary Information\n\nSupplementary Information.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1038/s41598-021-98586-5.\n\nAcknowledgements\n\nWe would like to thank all the members of the Qualiprost Study Group (listed in the Supplementary Information) for their contribution to data collection, without which the study would not have been possible, Isaac Subirana for his help with the statistical analysis and Michael Herdman for translating and reviewing the manuscript.\n\nAuthor contributions\n\nV.F., A.A. and J.M. conceived the study and analysis design. V.F. and J.M developed the methodology and the formal analysis. A.A., V.F. and J.M. wrote the original draft. J.C.A., J.P.L.R., N.P.L. and J.M.P., reviewed, edited and completed the original manuscript. All authors revisited the paper critically and approved the final version of the manuscript.\n\nFunding\n\nThis analysis was funded by an unrestricted grant by Pierre Fabre Ibérica S.A.\n\nData availability\n\nThe data presented in this study are available on reasonable request from the corresponding author.\n\nCompeting interests\n\nJ.M. is a medical advisor with Pierre Fabre Ibérica S.A., a company that commercializes an extract of Serenoa repens. The other authors declare no potential conflict of interest.\n\nPublisher's note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Gravas, S. et al. EAU guidelines on management of non-neurogenic male LUTS including benign prostatic obstruction. 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Vienna, Austria. https://www.R-project.org (2018).\n26. Berger ML Good practices for real-world data studies of treatment and/or comparative effectiveness: Recommendations from the joint ISPOR-ISPE Special Task Force on real-world evidence in health care decision making Pharmacoepidemiol. Drug Saf. 2017 26 1033 1039 10.1002/pds.4297 28913966\n27. Debruyne F Comparison of a phytotherapeutic agent (Permixon) with an alpha-blocker (Tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study Eur. Urol. 2002 41 497 506 10.1016/S0302-2838(02)00066-0 12074791\n28. Latil A Pétrissans MT Rouquet J Robert G de la Taille A Effects of hexanic extract of Serenoa repens (Permixon 160 mg) on inflammation biomarkers in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia Prostate 2015 75 16 1857 1867 10.1002/pros.23059 26306400\n29. 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Novara G Efficacy and safety of hexanic lipidosterolic extract of Serenoa repens (Permixon) in the treatment of lower urinary tract symptoms due to benign prostatic hyperplasia: systematic review and meta-analysis of randomized controlled trials Eur. Urol. Focus. 2016 2 553 561 10.1016/j.euf.2016.04.002 28723522\n34. Gravas, S. et al. EAU guidelines on management of non-neurogenic male LUTS incl. benign prostatic obstruction. https://uroweb.org/wp-content/uploads/EAU-Guidelines-on-Management-of-Non-Neurogenic-Male-LUTS-2021.pdf (2021) (accessed on 9 April 2021).\n35. Barkin J Effect of dutasteride, tamsulosin and the combination on patient-reported quality of life and treatment satisfaction in men with moderate-to-severe benign prostatic hyperplasia: 2-year data from the CombAT trial BJU Int. 2009 103 919 926 10.1111/j.1464-410X.2009.08196.x 19239460\n36. Debruyne F Evaluation of the clinical benefit of permixon and tamsulosin in severe BPH patients-PERMAL study subset analysis Eur. Urol. 2004 45 773 780 10.1016/j.eururo.2004.01.015 15149751\n37. Moon HW Prescription pattern of alpha-blockers for management of lower urinary tract symptoms/benign prostatic hyperplasia Sci. Rep. 2018 8 1 13223 10.1038/s41598-018-31617-w 30185936\n38. Oelke M Appropriateness of oral drugs for long-term treatment of lower urinary tract symptoms in older persons: results of a systematic literature review and international consensus validation process (LUTS-FORTA 2014) Age Ageing 2015 44 745 755 10.1093/ageing/afv077 26104505\n39. Duan Y Grady JJ Albertsen PC Helen Wu Z Tamsulosin and the risk of dementia in older men with benign prostatic hyperplasia Pharmacoepidemiol. Drug Saf. 2018 27 340 348 10.1002/pds.4361 29316005\n40. Kaplan SA Re: The Effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT Study J. Urol. 2011 185 1384 1385 10.1016/j.juro.2010.12.080 22115487\n41. Bell JR Laborde E Update on the sexual impact of treatment for benign prostatic hyperplasia Curr, Urol, Rep. 2012 13 433 440 10.1007/s11934-012-0278-5 23065462\n42. Gandhi J The impact and management of sexual dysfunction secondary to pharmacological therapy of benign prostatic hyperplasia Transl. Androl. Urol. 2017 6 295 304 10.21037/tau.2017.03.57 28540239\n43. Hellstrom WJ Sikka SC Effects of acute treatment with tamsulosin versus alfuzosin on ejaculatory function in normal volunteers J. Urol. 2006 176 4 Pt 1 1529 1533 10.1016/j.juro.2006.06.004 16952675\n44. Roehrborn CG The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study Eur. Urol. 2010 57 123 131 10.1016/j.eururo.2009.09.035 19825505\n45. Pytel YA Long-term clinical and biologic effects of the lipidosterolic extract of Serenoa repens in patients with symptomatic benign prostatic hyperplasia Adv. Ther. 2002 19 297 306 10.1007/BF02853175 12665050\n46. Chua T Eise NT Simpson JS Ventura S Pharmacological characterization and chemical fractionation of a liposterolic extract of saw palmetto (Serenoa repens): Effects on rat prostate contractility J. Ethnopharmacol. 2014 152 283 291 10.1016/j.jep.2013.12.030 24463033\n47. Gutierrez M García de Boto MJ Cantabrana B Hidalgo A Mechanisms involved in the spasmolytic effect of extracts from Sabal serrulata fruit on smooth muscle Gen. Pharmacol. 1996 27 171 176 10.1016/0306-3623(95)00094-1 8742517\n\n", "fulltext_license": "CC BY", "issn_linking": "2045-2322", "issue": "11(1)", "journal": "Scientific reports", "keywords": null, "medline_ta": "Sci Rep", "mesh_terms": null, "nlm_unique_id": "101563288", "other_id": null, "pages": "19401", "pmc": null, "pmid": "34588509", "pubdate": "2021-09-29", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "28723522;19302497;10420151;26104505;25112532;24463033;12074791;26810324;73694;16985902;29316005;22520557;12180222;30185936;16467543;29694707;9759701;22774395;17947786;30027406;12665050;24708055;23065462;28540239;15289814;8742517;23094219;23846725;28913966;16952675;22115487;18849646;15149751;9072592;19825505;7536866;18409474;7563343;19239460;26306400;14572753;24656222", "title": "Efficacy and tolerability of the hexanic extract of Serenoa repens compared to tamsulosin in moderate-severe LUTS-BPH patients.", "title_normalized": "efficacy and tolerability of the hexanic extract of serenoa repens compared to tamsulosin in moderate severe luts bph patients" }
[ { "companynumb": "ES-ASTELLAS-2021US037910", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TAMSULOSIN HYDROCHLORIDE" }, "drugadditional":...
{ "abstract": "A 33-year-old patient was diagnosed with acute Vogt-Koyanagi-Harada (VKH) disease and was prescribed prednisolone (1 mg/kg/day) and azathioprine (2.5 mg/kg/day). She mistakenly took an excessively high dose (4 mg/kg/day) of prednisolone for 14 days. The erroneous dose of corticosteroids was progressively corrected. Several weeks after initial presentation, the patient developed a polymerase chain reaction-proven bilateral cytomegalovirus retinitis, with extensive occlusive arteritis in the right eye. Systemic immunosuppressive therapy was temporarily discontinued and viral retinitis was successfully managed with systemic and intravitreal ganciclovir. Corticosteroids were reintroduced to control recurrent VKH disease. Final visual acuity was 20/1000 in the right eye and 20/50 in the left eye.", "affiliations": "Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia.;Department of Ophthalmology, Farhat Hached University Hospital, Faculty of Medicine, University of Sousse, Sousse, Tunisia.;Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia.;Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia.;Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia.;Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia.", "authors": "Khochtali|Sana|S|;Mahjoub|Ahmed|A|;Dridi|Tarek|T|;Ksiaa|Imen|I|;Abroug|Nesrine|N|;Khairallah|Moncef|M|", "chemical_list": "D007166:Immunosuppressive Agents; D001379:Azathioprine", "country": "India", "delete": false, "doi": "10.4103/ijo.IJO_628_20", "fulltext": "\n==== Front\nIndian J Ophthalmol\nIndian J Ophthalmol\nIJO\nIndian Journal of Ophthalmology\n0301-4738 1998-3689 Wolters Kluwer - Medknow India \n\n32823462\nIJO-68-2012\n10.4103/ijo.IJO_628_20\nCase Reports\nCytomegalovirus retinitis following corticosteroid overdose for Vogt-Koyanagi-Harada disease\nKhochtali Sana Mahjoub Ahmed 1 Dridi Tarek Ksiaa Imen Abroug Nesrine Khairallah Moncef Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia\n1 Department of Ophthalmology, Farhat Hached University Hospital, Faculty of Medicine, University of Sousse, Sousse, Tunisia\n\nCorrespondence to: Dr. Moncef Khairallah, Department of Ophthalmology, Fattouma Bourguiba University Hospital, 5019 Monastir, Tunisia. E-mail: moncef.khairallah@rns.tn\n9 2020 \n20 8 2020 \n68 9 2012 2014\n21 3 2020 07 5 2020 17 7 2020 Copyright: © 2020 Indian Journal of Ophthalmology2020This 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.A 33-year-old patient was diagnosed with acute Vogt-Koyanagi-Harada (VKH) disease and was prescribed prednisolone (1 mg/kg/day) and azathioprine (2.5 mg/kg/day). She mistakenly took an excessively high dose (4 mg/kg/day) of prednisolone for 14 days. The erroneous dose of corticosteroids was progressively corrected. Several weeks after initial presentation, the patient developed a polymerase chain reaction-proven bilateral cytomegalovirus retinitis, with extensive occlusive arteritis in the right eye. Systemic immunosuppressive therapy was temporarily discontinued and viral retinitis was successfully managed with systemic and intravitreal ganciclovir. Corticosteroids were reintroduced to control recurrent VKH disease. Final visual acuity was 20/1000 in the right eye and 20/50 in the left eye.\n\nCorticosteroidscytomegalovirus retinitisimmunosuppressive agentsretinal vasculitisVogt-Koyanagi- Harada disease\n==== Body\nCytomegalovirus (CMV) retinitis is a sight-threatening ocular infection, typically affecting immunocompromised individuals. It may present as fulminant hemorrhagic retinitis characterized by full thickness necrotizing retinitis and prominent retinal haemorrhages, as indolent granular retinitis, or as frosted branch angiitis.[12] It is commonly seen in patients with human immunodeficiency virus (HIV) infection and a low CD4 count (<50 cells/mm3). It can also occur as an opportunistic condition in patients with systemic non-HIV-related immunosuppression mainly including hematologic malignancies, immunosuppressive therapy, and organ transplantation.[12] It has also been reported following intraocular or periocular steroid administration.[3]\n\nWe herein report the case of a patient with acute Vogt-Koyanagi-Harada (VKH) disease who developed bilateral CMV retinitis after accidentally using an excessive dose of corticosteroids in association with an immunosuppressant agent.\n\nCase Report\nA 33-year-old woman with unremarkable medical history was referred to our department with a one-month history of bilateral blurring of vision. At presentation, best-corrected visual acuity (BCVA) was 20/500 in both eyes. The anterior chamber was quiet and there were 2+ vitreous cells in both eyes. Fundus examination showed bilateral multifocal exudative retinal detachment (ERD) [Fig. 1a and b]. Fluorescein angiography revealed early delayed choroidal perfusion and late multilobular subretinal dye pooling OU [Fig. 1c-f]. Swept-source optical coherence tomography (SS-OCT) showed bilateral extensive ERD with subretinal septa, retinal pigment epithelium (RPE) undulations, and a marked choroidal thickening [Fig. 1g and h].\n\nFigure 1 (a and b). Colour fundus photographs at presentation show bilateral multifocal exudative retinal detachments (ERD), OU. (c and d). Early-phase fluorescein angiograms reveal focal areas of delayed choroidal perfusion. (e and f). Late-phase fluorescein angiograms show multilobular subretinal dye pooling. (g and h). Initial structural swept-source OCT shows bilateral extensive ERD with subretinal septa, retinal pigment epithelium undulations, and a marked choroidal thickening\n\nA diagnosis of acute VKH disease was made. Results of pre-treatment investigations including complete blood count (CBC), erythrocyte sedimentation rate (ESR), liver and renal functions tests, syphilis serology, and chest X-ray was normal or negative. The patient was prescribed oral prednisolone 1 mg/kg/day and azathioprine 2.5 mg/kg/day. Three weeks after presentation, BCVA was 20/100 in both eyes and there was a significant improvement of ERD, OU. However, the patient reported having mistakenly received four times the prescribed dose (4 mg/kg/day) of prednisolone for 14 days. CBC showed elevated leukocyte count at 15100 cells/mL with high neutrophil count at 13000 cells/mL. Haemoglobin was 13 g/dL and platelet count was 400000 cells/mL. The erroneous dose of corticosteroids was progressively corrected with the help of endocrinologists.\n\nSix weeks later, the patient complained of decrease in vision in the right eye (RE). BCVA was 20/1000 in the RE and 20/80 in the left eye (LE). Slit-lamp examination showed granulomatous keratic precipitates, 1+ cells in the anterior chamber, and 2+ cells in the vitreous in the RE. The anterior chamber was quiet and there were 2+ cells in the vitreous in the LE. Fundus examination revealed sunset-glow fundus OU, a diffuse vascular sheathing and narrowing with multiple retinal haemorrhages in the RE. It also showed areas of small granular punctate yellowish retinal lesions predominantly in the inferonasal periphery of the LE [Fig. 2a and b]. Fluorescein angiography revealed marked retinal arterial occlusions in the RE, and optic disc hyperfluorescence in the LE [Fig. 2c and d]. SS-OCT angiography showed a diffuse loss of microvasculature in the superficial and deep retinal capillary plexuses in the RE [Fig. 2e and f]. SS-OCT demonstrated hyperreflectivity and thickening of the inner retinal layers, with a few intraretinal cysts and some shallow RPE undulations in the RE. It showed no obvious macular abnormalities in the LE [Fig. 2g and h].\n\nFigure 2 (a and b). Composite colour fundus photographs, nine weeks after presentation, shows bilateral sunset-glow fundus, bilateral peripapillary subretinal fibrosis associated with retinal pigment epithelium (RPE) proliferation, diffuse vascular sheathing and narrowing with multiple retinal haemorrhages in the right eye (RE), and a patch of granular retinitis in the inferonasal periphery of the left eye (LE), consistent with CMV retinitis. (c and d). Late-phase fluorescein angiograms reveal occlusion of the main retinal arterial branches in the RE, and optic disc hyperfluorescence OU. Note the presence of a peripapillary hypofluoresence due to the masking effect of peripapillary RPE proliferation. (e and f). Swept-source OCT angiography shows a diffuse loss of microvasculature in the superficial and deep retinal capillary plexuses in the RE, and projection of superficial vessels onto the deep capillary plexus in the LE. (g and h). Swept-source OCT shows hyperreflectivity and thickening of the inner retinal layers, with a few intraretinal cysts and some shallow RPE undulations in the RE, with no obvious macular abnormalities in the LE\n\nThe newly developed clinical and multimodal imaging findings, except for the sunset-glow fundus, were considered to be atypical for VKH disease. Alternative diagnoses were considered including a masquerade syndrome, infectious disease initially mimicking VKH disease, and superimposed infectious condition. Systemic corticosteroids and azathioprine were withdrawn. An extensive work-up including CBC, syphilis serology, C-reactive protein, ESR, serum protein electrophoresis, chest X-ray, Mantoux test, QuantiFERON-TB Gold, human immunodeficiency virus serology, thoraco-abdominopelvic computed tomography scan, and MRI of the brain was performed. Results were all normal or negative. Real-time polymerase chain reaction (PCR) on aqueous sample for CMV, varicella zoster virus, herpes simplex virus 1, and herpes simplex virus 2 was performed. It was positive for CMV DNA (2000 copies/ml), confirming opportunistic CMV retinitis.\n\nThe patient was given intravenous ganciclovir treatment (5 mg/kg twice a day) for 6 weeks and 2 intravitreal ganciclovir injections (2 mg/0.1 ml) in the RE. CMV retinitis was controlled, but the patient developed a VKH disease recurrence with bilateral choroidal thickening, RPE folds in both eyes, and a shallow ERD in the RE on SS-OCT. Repeated PCR on aqueous sample showed a significant reduction in viral load (200 CMV DNA copies/ml). VKH disease recurrence was managed with oral prednisolone, at an initial dose of 0.5 mg/kg/day introduced while the patient was still receiving intravenous antiviral treatment. Systemic steroids were then progressively tapered.\n\nOne year after initial presentation, the patient was receiving 5 mg/day of prednisolone and dexamethasone drops twice a day, OU. BCVA was 20/1000 in the RE and 20/50 in the LE. There was a marked fundus depigmentation without associated anterior chamber or vitreous inflammatory reaction [Fig. 3]. The patient developed no CMV retinitis recurrence.\n\nFigure 3 (a and b). Composite colour fundus photographs, one year after initial presentation, show a sunset-glow fundus with peripapillary subretinal fibrosis associated with retinal pigment epithelium proliferation OU, and residual gliotic sheathing of vessels around the optic disc in the right eye. (c and d). Swept-source OCT shows some degree of residual retinal atrophy in the macular area in the right eye, and quite normal findings in the left eye\n\nDiscussion\nThis patient, initially diagnosed with acute VKH disease, developed bilateral CMV retinitis after using by mistake an overdose of corticosteroids in association with azathioprine. CMV retinitis was indolent in type, and was associated with moderate vitritis, and unilateral major retinal arterial occlusions. It occurred in combination with pre-existing inflammatory changes related to VKH disease, and therefore diagnosis was challenging. Such infectious sight-threatening condition could be overlooked or misinterpreted as a worsening of the primary non-infectious uveitis.[4] However, the unusual occurrence of retinal vasculitis mainly manifesting as occlusive arteritis was highly suspicious in our patient.\n\nActive CMV retinitis has rarely been reported in HIV-negative patients under systemic immunosuppression for chronic non-infectious uveitis including Behçet uveitis, VKH disease, and idiopathic uveitis. It developed in all these cases following intraocular or periocular corticosteroid injection in one side.[3456] Although our patient did not receive any local steroids, she mistakenly took excessively high doses of systemic steroids for a couple of weeks, in association with azathioprine.\n\nCMV retinitis in HIV-patients is classically characterized by areas of retinitis typically in a perivascular distribution, associated with venous sheathing in areas of retinitis and mild anterior chamber and vitreous inflammation.[12] A recent study by Ho M et al. showed that non-HIV patients are more likely to have prominent vitritis, retinal arteritis, and extensive vascular occlusions beyond the site of retinitis.[7] All these distinctive features were seen in the present case. The spectrum of clinical manifestations of CMV retinitis in non-HIV patients is wide, probably due to varying degrees of immunocompromise between affected patients. Timely recognition of such manifestations is of utmost importance to avoid misdiagnosis and subsequent delay in initiating appropriate treatment.[7]\n\nOccurrence of CMV retinitis in HIV-negative patients under systemic immunosuppressive therapy requires adjustments to their initial corticosteroid and/or non-corticosteroid immunomodulating therapy to be adequately made. Furthermore, antiviral therapy should be maintained at least until regression of the retinitis lesions and recovery of patients'immune status.[3] Both oral prednisolone and azathioprine were temporarily discontinued in our patient. She was treated with intravenous and intravitreal ganciclovir. But, oral valganciclovir is not available in our country. Transient withdrawal of immunosuppressive therapy resulted in VKH disease recurrence, and this led to the reintroduction of medium-dose oral corticosteroid therapy in combination with antiviral agent to control intraocular inflammation. No recurrence of CMV retinitis or related retinal detachment occurred, but a severe visual loss persisted in the RE due to extensive arterial occlusions involving the macula.\n\nConclusion\nIn summary, CMV retinitis may occur in patients with non-infectious uveitis as a consequence of highly aggressive systemic immunosuppressive therapy. Signs of viral retinitis overlap with signs of the pre-existing non-infectious uveitis. Both diagnosis and management are challenging.\n\nDeclaration of patient consent\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\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgments\nThis work has been supported by the Ministry of Higher Education and Research of Tunisia.\n==== Refs\n1 Jabs DA Cytomegalovirus retinitis and the acquired immunodeficiency syndrome--bench to bedside: LXVII Edward Jackson Memorial Lecture Am J Ophthalmol 2011 151 198 216e1 21168815 \n2 Port AD Orlin A Kiss S Patel S D'Amico DJ Gupta MP Cytomegalovirus retinitis: A review J Ocul Pharmacol Ther 2017 33 224 34 28355091 \n3 Takakura A Tessler HH Goldstein DA Guex-Crosier Y Chan CC Brown DM Viral retinitis following intraocular or periocular corticosteroid administration: A case series and comprehensive review of the literature Ocul Immunol Inflamm 2014 22 175 82 24655372 \n4 Tugal-Tutkun I Araz B Cagatay A CMV retinitis after intravitreal triamcinolone acetonide injection in a patient with Behçet's uveitis Int Ophthalmol 2010 30 591 3 20033756 \n5 Ufret-Vincenty RL Singh RP Lowder CY Kaiser PK Cytomegalovirus retinitis after fluocinolone acetonide (Retisert) implant Am J Ophthalmol 2007 143 334 5 17258523 \n6 Zaborowski AG Cytomegalovirus retinitis following intravitreal triamcinolone acetonide in a patient with chronic uveitis on systemic immunosuppression Ocul Immunol Inflamm 2013 21 148 9 23282087 \n7 Ho M Invernizzi A Zagora S Tsui J Oldani M Lui G Presenting features, treatment and clinical outcomes of cytomegalovirus retinitis: Non-HIV patients vs HIV patients Ocul Immunol Inflamm 2020 28 651 8 31166809\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0301-4738", "issue": "68(9)", "journal": "Indian journal of ophthalmology", "keywords": "Corticosteroids; Vogt-Koyanagi- Harada disease; cytomegalovirus retinitis; immunosuppressive agents; retinal vasculitis", "medline_ta": "Indian J Ophthalmol", "mesh_terms": "D000328:Adult; D001379:Azathioprine; D017726:Cytomegalovirus Retinitis; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D014607:Uveomeningoencephalitic Syndrome; D014792:Visual Acuity", "nlm_unique_id": "0405376", "other_id": null, "pages": "2012-2014", "pmc": null, "pmid": "32823462", "pubdate": "2020-09", "publication_types": "D002363:Case Reports", "references": "24655372;31166809;28355091;21168815;17258523;20033756;23282087", "title": "Cytomegalovirus retinitis following corticosteroid overdose for Vogt-Koyanagi-Harada disease.", "title_normalized": "cytomegalovirus retinitis following corticosteroid overdose for vogt koyanagi harada disease" }
[ { "companynumb": "TR-ALKEM LABORATORIES LIMITED-TR-ALKEM-2020-05910", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "dru...
{ "abstract": "Livedoid vasculopathy is a rare thrombotic cutaneous disease. This observational study aimed to assess the clinical and biological features of livedoid vasculopathy and the efficacy of treatments. Patients enrolled had typical livedoid vasculopathy both clinically and histologically. Investigation of thrombophilia was performed. Electromyography was undertaken in the presence of symptoms suggesting peripheral neuropathy. Eighteen women and 8 men were included, with a mean age of 35.5 years at onset. Twenty patients had at least one thrombophilia factor. Ten patients had a peripheral neuropathy with 2 of these patients demonstrating a specific thrombo-occlusive vasculopathy on muscle biopsy. Anticoagulation with low molecular weight heparin was the most prescribed therapy and was associated with the best outcome (effective in 14 patients). Eight patients had severe disease refractory to anticoagulation and required intravenous immunoglobulins, producing a good response in 6 patients.", "affiliations": "Department of Dermatology, Hôpital Tenon, APHP, Paris, France.", "authors": "Gardette|Emma|E|;Moguelet|Philippe|P|;Bouaziz|Jean-David|JD|;Lipsker|Dan|D|;Dereure|Olivier|O|;Le Pelletier|Francois|F|;Lok|Catherine|C|;Maisonobe|Thierry|T|;Bessis|Didier|D|;Conard|Jacqueline|J|;Francès|Camille|C|;Barete|Stéphane|S|", "chemical_list": "D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors", "country": "Sweden", "delete": false, "doi": "10.2340/00015555-2965", "fulltext": null, "fulltext_license": null, "issn_linking": "0001-5555", "issue": "98(9)", "journal": "Acta dermato-venereologica", "keywords": "intravenousimmunoglobulins; livedoidvasculopathy; lowmolecularweightheparin; peripheralneuropathy; thrombophilia; throm­bosisofdermalvessels", "medline_ta": "Acta Derm Venereol", "mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000925:Anticoagulants; D001777:Blood Coagulation; D002648:Child; D005260:Female; D005602:France; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D054068:Livedo Reticularis; D008297:Male; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases; D012307:Risk Factors; D019851:Thrombophilia; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "0370310", "other_id": null, "pages": "842-847", "pmc": null, "pmid": "29738044", "pubdate": "2018-10-10", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study", "references": null, "title": "Livedoid Vasculopathy: A French Observational Study Including Therapeutic Options.", "title_normalized": "livedoid vasculopathy a french observational study including therapeutic options" }
[ { "companynumb": "FR-MYLANLABS-2018M1086917", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FONDAPARINUX" }, "drugadditional": "3", ...
{ "abstract": "Acute Chagas disease reactivation (CDR) after cardiac transplantation is a well-known phenomenon in endemic countries of Central and South America and Mexico, but is rare outside of those countries. In this report, we describe a case of a 49 year old male who presented 25 weeks after heart transplant with clinical features concerning for acute rejection, including malaise, anorexia, weight loss, and fever. His immunosuppression therapy included tacrolimus, mycophenolate, and prednisone. An endomyocardial biopsy revealed lymphocytic and eosinophilic inflammation, myocyte damage, and rare foci of intracellular organisms consistent with Trypanosoma cruzi amastigotes. The patient had no known history of Chagas disease. Upon additional questioning, the patient endorsed bites from reduviid bugs during childhood in El Salvador. Follow-up serum PCR testing was positive for T. cruzi DNA. Tests for other infectious organisms and donor specific antibodies were negative. This case illustrates the striking clinical and histologic similarities between acute cellular rejection and acute CDR with cardiac involvement in heart transplant patients, and thus emphasizes the importance of pre-transplant testing for Chagas in patients with epidemiologic risk factors.", "affiliations": "The University of North Carolina at Chapel Hill, School of Medicine.;The University of North Carolina at Chapel Hill, Department of Medicine, Division of Infectious Diseases.;The University of North Carolina at Chapel Hill, Department of Medicine, Division of Cardiology, Heart Failure and Cardiac Transplantation.;The University of North Carolina at Chapel Hill, Department of Medicine, Division of Infectious Diseases.;The University of North Carolina at Chapel Hill, Department of Medicine, Division of Infectious Diseases.;The University of North Carolina at Chapel Hill, Department of Medicine, Division of Infectious Diseases.;The University of North Carolina at Chapel Hill, Department of Medicine, Division of Cardiology, Heart Failure and Cardiac Transplantation.;The University of North Carolina at Chapel Hill, Department of Medicine, Division of Cardiology, Heart Failure and Cardiac Transplantation.;The University of North Carolina at Chapel Hill, Department of Medicine, Division of Cardiology, Heart Failure and Cardiac Transplantation.;The University of North Carolina at Chapel Hill, Department of Pathology and Laboratory Medicine. Electronic address: bart_singer@med.unc.edu.", "authors": "Hamilton|Madeleine M|MM|;Sciaudone|Michael|M|;Chang|Patricia P|PP|;Bowman|Natalie M|NM|;Andermann|Tessa M|TM|;Bartelt|Luther A|LA|;Jaganathan|Sudha P|SP|;Rose-Jones|Lisa J|LJ|;Andrews|Megan E|ME|;Singer|Bart|B|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.carpath.2021.107394", "fulltext": null, "fulltext_license": null, "issn_linking": "1054-8807", "issue": null, "journal": "Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology", "keywords": "Chagas Disease Reactivation; endomyocardial biopsy; heart transplant pathology", "medline_ta": "Cardiovasc Pathol", "mesh_terms": null, "nlm_unique_id": "9212060", "other_id": null, "pages": "107394", "pmc": null, "pmid": "34742866", "pubdate": "2021-11-03", "publication_types": "D002363:Case Reports", "references": null, "title": "Unexpected Case of Chagas Disease Reactivation in Endomyocardial Biopsy for Evaluation of Cardiac Allograft Rejection.", "title_normalized": "unexpected case of chagas disease reactivation in endomyocardial biopsy for evaluation of cardiac allograft rejection" }
[ { "companynumb": "US-MYLANLABS-2022M1006670", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "...
{ "abstract": "OBJECTIVE\nAcute corneal hydrops is a rare complication of keratoconus and may be a risk factor for further complications such as microbial keratitis.\n\n\nMETHODS\nRetrospective, case series.\n\n\nRESULTS\nSix eyes developed microbial keratitis during acute corneal hydrops. Risk factors for the development of microbial keratitis included epithelial defect, contact lens wear, trichiasis, and use of topical steroids. Two eyes developed corneal perforation and 1 eye was treated for possible endophthalmitis. All eyes developed marked scarring and neovascularization with final visual acuity of 20/200 or less. Three eyes received penetrating keratoplasty, and each experienced endothelial rejection with 1 eye developing graft failure.\n\n\nCONCLUSIONS\nMicrobial keratitis is a rare complication that may develop during acute corneal hydrops. The infection may rapidly appear and spread throughout the cornea and can lead to severe corneal scarring, neovascularization, and loss of vision and may prejudice subsequent keratoplasty. Prophylactic topical antibiotics should always be considered when treating acute corneal hydrops.", "affiliations": "Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.", "authors": "Meyer|Jay J|JJ|;McGhee|Charles N J|CN|", "chemical_list": "D000900:Anti-Bacterial Agents", "country": "United States", "delete": false, "doi": "10.1097/ICO.0000000000000883", "fulltext": null, "fulltext_license": null, "issn_linking": "0277-3740", "issue": "35(7)", "journal": "Cornea", "keywords": null, "medline_ta": "Cornea", "mesh_terms": "D000208:Acute Disease; D000328:Adult; D000900:Anti-Bacterial Agents; D001419:Bacteria; D002648:Child; D015715:Corneal Edema; D003320:Corneal Ulcer; D004359:Drug Therapy, Combination; D015818:Eye Infections, Bacterial; D005260:Female; D006801:Humans; D015948:Keratoplasty, Penetrating; D008297:Male; D011379:Prognosis; D012307:Risk Factors; D014792:Visual Acuity", "nlm_unique_id": "8216186", "other_id": null, "pages": "1019-22", "pmc": null, "pmid": "27191669", "pubdate": "2016-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Acute Corneal Hydrops Complicated by Microbial Keratitis: Case Series Reveals Poor Immediate and Long-Term Prognosis.", "title_normalized": "acute corneal hydrops complicated by microbial keratitis case series reveals poor immediate and long term prognosis" }
[ { "companynumb": "NZ-ALLERGAN-1663893US", "fulfillexpeditecriteria": "1", "occurcountry": "NZ", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LATANOPROST" }, "drugadditional": null, ...
{ "abstract": "Neurological immune-related adverse events (irAEs) are rare toxicities that occur following immune checkpoint inhibitor therapy. We propose that patients with thymic malignancies and graft-versus-host disease (GVHD) are predisposed to irAEs. We present two asymptomatic patients, one with thymoma and another with GVHD, who developed abnormal brain MRIs after treatment with programmed cell death protein 1 inhibitors. The first patient, with thymic cancer and thymoma, developed pontine enhancing MRI lesions following treatment with pembrolizumab. The second patient, with prior GVHD, developed pachymeningeal enhancement following treatment with nivolumab. IrAEs with abnormal MRI studies, despite asymptomatology, have significant impact on the treatment strategy for these patients.", "affiliations": "Department of Neurology, University of Chicago Medical Center, Chicago, IL 60637, USA.;Department of Neurology, University of Chicago Medical Center, Chicago, IL 60637, USA.;Department of Neurology, University of Chicago Medical Center, Chicago, IL 60637, USA.;Department of Neurology, University of Chicago Medical Center, Chicago, IL 60637, USA.", "authors": "Yuen|Carlen A|CA|;Rezania|Kourosh|K|;Park|Deric M|DM|;Reder|Anthony T|AT|0000-0002-6423-1495", "chemical_list": null, "country": "England", "delete": false, "doi": "10.2217/imt-2020-0186", "fulltext": null, "fulltext_license": null, "issn_linking": "1750-743X", "issue": "13(1)", "journal": "Immunotherapy", "keywords": "CLIPPERS; GVHD; NMO; chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids; graft-versus-host-disease; immune-related adverse events; neuromyelitis optica; nivolumab; pachymeningeal enhancement; pembrolizumab", "medline_ta": "Immunotherapy", "mesh_terms": null, "nlm_unique_id": "101485158", "other_id": null, "pages": "11-17", "pmc": null, "pmid": "33023359", "pubdate": "2021-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Asymptomatic brainstem lesions and pachymeningeal enhancement after anti-PD-1 therapy.", "title_normalized": "asymptomatic brainstem lesions and pachymeningeal enhancement after anti pd 1 therapy" }
[ { "companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-092182", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "NIVOLUMAB" }, "drugaddi...
{ "abstract": "Autosomal-dominant hypocalcemia with hypercalciuria (ADHH) is a genetic disease characterized by hypoparathyroidism with hypercalciuria. Most patients with ADHH have calcium-sensing receptor (CaSR) gene mutations. The CaSR gene controls parathyroid secretions, and mutations in this gene can be detected via changes in serum calcium level. The activating mutation of the CaSR gene results in familial or sporadic ADHH. Most activating mutations of the CaSR gene are reportedly de novo missense mutations. This is the first case report of a novel activating variant of the CaSR gene in a neonate with congenital hypoparathyroidism with hypomagnesemia and hypercalciuria. We also report the 3-month follow-up management of the patient.", "affiliations": "Department of Pediatrics, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea.;Department of Pediatrics, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea.;Department of Pediatrics, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Pediatrics, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea.", "authors": "Moon|Jung-Eun|JE|;Lee|Su-Jeong|SJ|;Park|Suk-Hyun|SH|;Kim|Jinsup|J|;Jin|Dong-Kyu|DK|;Ko|Cheol Woo|CW|", "chemical_list": null, "country": "Korea (South)", "delete": false, "doi": "10.6065/apem.2018.23.2.107", "fulltext": "\n==== Front\nAnn Pediatr Endocrinol MetabAnn Pediatr Endocrinol MetabAPEMAnnals of Pediatric Endocrinology & Metabolism2287-10122287-1292Korean Society of Pediatric Endocrinology 2996988410.6065/apem.2018.23.2.107apem-2018-23-2-107Case ReportDe novo a novel variant of CaSR gene in a neonate with congenital hypoparathyroidism Moon Jung-Eun MD1Lee Su-Jeong MD1Park Suk-Hyun MDPhD1Kim Jinsup MD2Jin Dong-Kyu MDPhD2http://orcid.org/0000-0002-0643-7233Ko Cheol Woo MDPhD1\n1 Department of Pediatrics, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea\n2 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, KoreaAddress for correspondence: Cheol Woo Ko, MD, PhD Division of Pediatric Endocrinology, Kyungpook National University Children’s Hospital, 130 Dongdeokro, Jung-gu, Daegu 41944, Korea Tel: +82-53-420-5715 Fax: +82-53-425-6683 E-mail: cwko@knu.ac.kr6 2018 20 6 2018 23 2 107 111 27 11 2017 22 12 2017 28 12 2017 © 2018 Annals of Pediatric Endocrinology & Metabolism2018This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Autosomal-dominant hypocalcemia with hypercalciuria (ADHH) is a genetic disease characterized by hypoparathyroidism with hypercalciuria. Most patients with ADHH have calcium-sensing receptor (CaSR) gene mutations. The CaSR gene controls parathyroid secretions, and mutations in this gene can be detected via changes in serum calcium level. The activating mutation of the CaSR gene results in familial or sporadic ADHH. Most activating mutations of the CaSR gene are reportedly de novo missense mutations. This is the first case report of a novel activating variant of the CaSR gene in a neonate with congenital hypoparathyroidism with hypomagnesemia and hypercalciuria. We also report the 3-month follow-up management of the patient.\n\nHypercalciuric hypocalcemiaHypoparathyroidismCalcium-sensing receptorsMutation\n==== Body\nIntroduction\nAutosomal-dominant hypocalcemia with hypercalciuria (ADHH) is a genetic disease characterized by hypoparathyroidism with hypercalciuria [1]. Patients with ADHH show varying degrees of hypocalcemia. Although convulsions due to hypocalcemia can occur, most patients are asymptomatic or show intermittent limb numbness, muscular contractions, and laryngeal spasms [2]. Most patients with ADHH are known to have mutations of the calcium-sensing receptor (CaSR) gene [3]. Bartter syndrome, which is accompanied by hypocalcemia, hypomagnesemia, hypercalciuria, secondary hyperaldosteronism, and hypokalemia, can also develop due to activating mutation of CaSR gene [4]. CaSR is a G-protein-coupled receptor in cell membranes, which is predominantly located in the parathyroid gland and renal tubule; it detects minute changes in serum calcium levels and, consequently, controls parathyroid secretions. In addition, it participates in the renal regulation of positive ion concentrations through intracellular signaling pathways [5,6]. Generally, when the calcium concentration in the blood is lowered, the secretion of parathyroid hormone (PTH) increases, which then increases the reabsorption of calcium in the kidneys, ultimately leading to elevated blood calcium levels. As such, the parathyroid glands play a pivotal role in regulating systemic calcium homeostasis. Further, there is an inverse relationship between the secretion of PTH and extracellular calcium concentrations. When this homeostasis is disturbed, complications such as hypercalcemia and hypocalcemia can arise [7]. In patients with chronic hypocalcemia, CaSR actions increase the expression of the PTH gene and stimulate the proliferation of parathyroid cells, thereby maintaining the homeostasis of parathyroid functions. In contrast, in patients with hypercalcemia, the synthesis and secretion of PTH are suppressed.\n\nDepending on the actions (inactivating or activating) of CaSR, hyper- or hypoparathyroidism can occur [1]. Hannan et al. [8] reported that 70 CaSR mutations had been confirmed at the time of their study, and 25 mutations associated with ADHH were reported. Activating mutations of CaSR gene, which are also referred to as heterozygous gain-of-function, result in familial or sporadic ADHH [9]. Most activating mutations of CaSR gene have been reported to be missense mutations. In 2004, Hu et al. [10] reported a de novo variant of CaSR gene in monozygotic twins. This study reports a novel activating variant of CaSR gene that occurred de novo in a Korean neonate who had congenital hypoparathyroidism with hypomagnesemia and hypercalciuria.\n\nCase report\nA 5-day-old female neonate was transferred to the neonatal intensive care unit (NICU) at the Kyungpook National University Children’s Hospital because of seizures. The patient was born through normal vaginal delivery at 39 weeks and weighed 3.2 kg. There was no notable finding during previously conducted prenatal care. Facial convulsions and muscular contractions in the limbs were observed on postnatal day 2. The patient was transferred to the NICU on postnatal day 5 because the symptoms persisted. Laboratory investigations revealed a serum calcium level of 4.7 mg/dL (normal range, 9.0–10.6 mg/dL), ionized calcium level of 2.2 mg/dL (normal range, 4.8–4.92 mg/dL), phosphate level of 13.2 mg/dL (normal range, 4.8–8.2 mg/dL), serum magnesium level of 1.29 mEq/L (normal range, 1.44–3.12 mEq/L), intact PTH (i-PTH) level of 2.6 pg/mL (normal range, 10–65 pg/mL), and 25-hydroxyvitamin D3 level of 13.95 ng/mL (normal range, 8.0–51.9 ng/mL) (Fig. 1).\n\nThe morphology of the patient's face, limbs, and fingers did not show any abnormalities. An atrial septal defect of 3.4-mm size was noted on cardiac ultrasonography, and the results of renal ultrasonography were normal. Although the patient’s thymus glands were normal on chest ultrasonography, we tested for a 22q11.2 microdeletion because of the neonatal hypocalcemia. The result was negative. No abnormal finding was observed in auditory tests. The neonate's parents did not have a history of convulsions and muscular contractions, and nobody in her family had a history of kidney stones.\n\nBecause the patient presented with convulsions at the time of admission, calcium (10-mg/kg bolus) and magnesium (2.5 mg/kg/day) was also administered intravenously. And she was also administered elemental calcium (75 mg/kg) in the form of oral calcium carbonate. Until postnatal day 7, the convulsions continued intermittently and the hypocalcemia (serum calcium level, 6.9 mg/dL) and hypomagnesemia (serum magnesium level, 1.4 mEq/L) remained unresolved. Thus, calcium was administered continuously through intravenous injections and the magnesium dose was doubled to 5 mg/kg/day. The convulsions disappeared on postnatal day 8; therefore, the continuous intravenous calcium and magnesium administration was stopped. Because the hypocalcemia persisted (serum calcium level, 6.0–7.1 mg/dL), the dose of elemental calcium was increased to 180 mg/kg/day. Nevertheless, on postnatal day 11, the hypomagnesemia (serum magnesium level, 1.49 mEq/L) and hypocalcemia (serum calcium level, 6.4 mg/dL) did not improve. Intravenous magnesium injections (5 mg/kg/day) and calcitriol (0.25 μg/day) were added (Fig. 1). The patient was maintained on a low-phosphate diet formula because of hyperphosphatemia (phosphate level, 8.0–9.0 mg/dL). In blood tests repeated during the follow-up period, inappropriately low PTH levels (i-PTH, 0–6 pg/mL) were observed. Therefore, tests were conducted to screen for gene mutations associated with hypoparathyroidism, calcium abnormalities, and magnesium abnormalities (GCMB, GATA3, TBCE, CaSR, GNA11, preproPTH, and TRPM6 genes). The dose of calcitriol was increased gradually (from 0.25 μg/day to 1.5 μg/day). Because the spot urine calcium/urinary creatinine ratio (mg%: mg%) was elevated (1.0–2.02 [normal level, <0.8 for neonates]) at 1 month old, thiazide (0.5 mg/kg/day) was additionally administered to decrease urinary calcium excretion. The patient was subsequently followed up for 2 weeks in the NICU and discharged.\n\nTargeted exome sequencing in the patient was performed using the TruSight One Sequencing Panel, resulting in a heterozygous novel variant c.2474A>T(p.Tyr825Phe) in exon 7 of CaSR gene confirmed by Sanger sequencing. No same variant was noted in the Sanger sequencing conducted for the parents. Thus, the patient was found to have a de novo novel activating vatiant of CaSR gene (Fig. 2). The in-silico analysis score of the variant yielded a SIFT score of 0 and a Polyphen-2 HVAR score of 0.994.\n\nWhen the results were obtained, the patient had been discharged and was taking calcium carbonate (elemental calcium dose of 180 mg/kg/day), calcitriol (0.75 μg bid), magnesium (0.25 mEq/kg/day), and thiazide (0.5 mg/kg/day). The patient was rehospitalized to modify and manage the doses. At the time of readmission, the patient was 2 months old. In a blood test conducted upon readmission, the following measurements were obtained: serum calcium level of 8.0 mg/dL (normal range, 9.0–10.6 mg/dL), ionized calcium level of 4.2 mg/dL (normal range, 4.8–4.92 mg/dL), phosphate level of 8.1 mg/dL (normal range, 4.8–8.2 mg/dL), magnesium level of 2.2 mEq/L (normal range, 1.92–3.12 mEq/L, at age 7 days–2 years), i-PTH level of 0.34 pg/mL (normal range, 10–65 pg/mL), and 25-hydroxyvitamin D3 level of 36.89 ng/mL (normal range, 8.0–51.9 ng/mL) (Fig. 1). In the spot urine test, the calcium/urinary creatinine ratio (mg%: mg%) was 1.31.\n\nIn a renal ultrasonography conducted because of persistent hypercalciuria, multiple small calyceal stones in both kidneys and a 0.6-cm stone in the left renal pelvis were newly observed, and hydronephrosis was absent (Fig. 3). Except for the dose of thiazide, the doses of the other drugs (calcium carbonate, magnesium, and calcitriol) were decreased. We carefully monitored the neonate for convulsions, and the serum calcium, phosphorus, magnesium, and urinary calcium excretion rate were checked regularly. On day 7 after readmission, calcitriol dose was decreased from 1.5 to 0.125 μg/day and the calcium dose was decreased to 20 mg/kg/day. In a blood test conducted 2 days later, the serum calcium level was found to be low (6.6 mg/dL). Consequently, the calcium carbonate dose was increased and maintained at 40 mg/kg. Due to hypercalciuria (spot urine calcium/creatinine ratio, 1.03), the thiazide dose was increased from 0.5 to 1.5 mg/kg, and the patient was discharged after we decided to control the doses in an outpatient setting.\n\nIn an outpatient blood test conducted on day 10 after discharge (when the patient was 3 months old), the serum calcium level was 7.5 mg/dL, the phosphate level was 7.6 mg/dL, and the spot urine calcium/creatinine ratio was 0.9. No neurological symptom was present. Hypercalciuria improved slightly during the administration of thiazide. However, hypocalcemia and hyperphosphatemia continued. Because of the persistent hypercalciuria and kidney stones, calcitriol administration was stopped. The patient had a history of neonatal hypocalcemic convulsions; hence, calcium carbonate was maintained at 40 mg/kg. The patient is currently being followed up and we are considering regulating the doses, with blood monitoring blood, urine tests, and renal ultrasonography.\n\nThis case was approved by the Institutional Review Board of Kyungpook National University Chilgok Hospital (approval number: 2017-11-008). Informed consent was obtained from both parents for the publishing of this case report.\n\nDiscussion\nIn the present case, a de novo novel variant of CaSR gene was confirmed in a neonatal patient who presented with convulsions that were caused by hypocalcemia. The patient also presented with hypoparathyroidism, hypocalcemia, and hypomagnesemia.\n\nGenerally, the causes of hypocalcemia within the first 72 hours after birth include preterm birth, fetal growth retardation, maternal diabetes, neonatal asphyxia, hypoparathyroidism, phosphorus overconsumption and hypomagnesemia [11,12]. Because genetic mutations are rare causes of hypocalcemia, blood tests to measure PTH, phosphate, magnesium, and vitamin D are conducted in neonatal and young patients with hypocalcemia [13,14]. Hypomagnesemia reduces parathyroid secretions and vitamin D synthesis, and it results in unresponsiveness or hyporesponsiveness in the organs on which PTH acts [15]. This is why the hypomagnesemia was corrected preferentially. Furthermore, the activating actions of CaSR can increase the renal excretion of calcium and the excretion of serum magnesium, thereby, decreasing parathyroid actions [16,17]. Thus, if hypocalcemia persists during the correction of hypomagnesemia and hypocalcemia or presents with hypoparathyroidism and hypercalciuria, activating mutations of CaSR gene should be considered.\n\nMost activating mutations of CaSR gene have been reported to be missense mutations in patients with ADHH [8]. Hu et al. [10] reported a de novo mutation of CaSR gene in monozygotic twins. A variant of CaSR gene found in our patient (c.2474A>T [p.Tyr825Phe]) is an unreported de novo novel variant. The variant corresponds to the transmembrane-spanning domains. CaSR, which is composed of 1,078 amino acids, consists of a large extracellular domain comprising seven transmembrane-spanning domains and an intracellular tail and is coded by six exons of the CaSR gene that are located on chromosome 3q13.3–21 [3]. Although the patient in our report had a novel variant of CaSR gene, she showed the same clinical features (hypocalcemia, hyperphosphatemia, and hypercalciuria) noted in previously reported cases of CaSR gene mutations. If conservation scores are reliable in disease prediction, the c.2474A>T (p.Tyr825Phe) variant could be disease causing, as both Phastcon and GERP scores are high (0.994 and 5.89, respectively). Also, the patient's variant was not found in the control population and occurred at p.T825P, a similar location as in other pathogenic variants (p.A824P and p.T828N) [8]. Thus, the patient's variant is likely to be a pathogenic variant.\n\nRegarding treatment, activating mutations of CaSR gene may cause the body to recognize low calcium concentrations as normal and, thus, influence parathyroid secretions [18]. Subsequently, the administration of calcium can aggravate hypercalciuria. The administration of calcium should be minimized in patients with an activating variant of CaSR gene; although calcitriol can be used, it can also cause hypercalciuria [19]. In particular, activating mutations of CaSR gene in patients with ADHH are sensitive to calcitriol, resulting in hypercalciuria after low doses of calcitriol. Therefore, hydrochlorothiazide (0.5–2.0 mg/kg/day) should be administered alongside, leading to the increased reabsorption of calcium in the renal tubules and, thus, a dose-sparing effect of calcitriol.\n\nIn the present case, renal stones were observed only 2 months after the administration of calcium and calcitriol. We planned to stop calcium carbonate and minimize the use of calcitriol to prevent severe hypercalciuria. The patient had a history of hypocalcemic convulsions and persistent hyperphosphatemia. It a reason that calcium carbonate could not be stopped. Only calcitriol was stopped, but the thiazide treatment was continued. Blood and urine tests along with renal ultrasonography will be regularly performed during the patient’s follow-up for the dosage monitoring and modification.\n\nIn conclusion, we report a de novo novel variant of CaSR gene (c.2474A>T [p.Tyr825Phe]) in a patient who presented with hypoparathyroidism with hypomagnesemia and hypercalciuria. A functional study regarding this variant is necessary.\n\nConflict of interest: No potential conflict of interest relevant to this article was reported.\n\nFig. 1. The serial changes in serum phosphate, magnesium, calcium, ionized calcium, i-PTH, and u-Ca/Cr ratio, and medication for 3 months, are shown. IV Cal, intravenous calcium; PO Cal, calcium carbonate per oral; IV Mg, intravenous magnesium; PO Mg, elemental magnesium per oral; i-PTH, intact parathyroid hormone; u-Ca/Cr, spot urine calcium/creatinine.\n\nFig. 2. We identified a novel variant of calcium-sensing receptor (CaSR) gene in the patient and no variant in her parents. A heterozygous A to T transition is shown at position 2474 in exon 7 of CaSR gene, changing Tyr to Phe (T825P).\n\nFig. 3. (A) Kidney ultrasonography shows multiple tiny calyceal stones(white arrows) in right kidney. (B) A 0.6-cm stone filling the left renal pelvis(white arrow). (A,B) There was no evidence of obstructive uropathy.\n==== Refs\nReferences\n1 Pollak MR Brown EM Estep HL McLaine PN Kifor O Park J Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation Nat Genet 1994 8 303 7 7874174 \n2 D'Souza-Li L Yang B Canaff L Bai M Hanley DA Bastepe M Identification and functional characterization of novel calcium-sensing receptor mutations in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia J Clin Endocrinol Metab 2002 87 1309 18 11889203 \n3 Janicic N Soliman E Pausova Z Seldin MF Rivière M Szpirer J Mapping of the calcium-sensing receptor gene (CaSR) to human chromosome 3q13.3-21 by fluorescence in situ hybridization, and localization to rat chromosome 11 and mouse chromosome 16 Mamm Genome 1995 6 798 801 8597637 \n4 Choi KH Shin CH Yang SW Cheong HI Autosomal dominant hypocalcemia with Bartter syndrome due to a novel activating mutation of calcium sensing receptor, Y829C Korean J Pediatr 2015 58 148 53 25932037 \n5 Hendy GN D'Souza-Li L Yang B Canaff L Cole DE Mutations of the calcium-sensing receptor (CaSR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia Hum Mutat 2000 16 281 96 11013439 \n6 Hofer AM Brown EM Extracellular calcium sensing and signalling Nat Rev Mol Cell Biol 2003 4 530 8 12838336 \n7 Brown EM Clinical lessons from the calcium-sensing receptor Nat Clin Pract Endocrinol Metab 2007 3 122 33 17237839 \n8 Hannan FM Nesbit MA Zhang C Cranston T Curley AJ Harding B Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites Hum Mol Genet 2012 21 2768 78 22422767 \n9 Thakker RV Diseases associated with the extracellular calcium-sensing receptor Cell Calcium 2004 35 275 82 15200151 \n10 Hu J Mora S Weber G Zamproni I Proverbio MC Spiegel AM Autosomal dominant hypocalcemia in monozygotic twins caused by a de novo germline mutation near the amino-terminus of the human calcium receptor J Bone Miner Res 2004 19 578 86 15005845 \n11 Arora NK Paul VK Singh M Morbidity and mortality in term infants with intrauterine growth retardation J Trop Pediatr 1987 33 186 9 3669134 \n12 Tsang RC Chen I Hayes W Atkinson W Atherton H Edwards N Neonatal hypocalcemia in infants with birth asphyxia J Pediatr 1974 84 428 33 4811993 \n13 Thomas TC Smith JM White PC Adhikari S Transient neonatal hypocalcemia: presentation and outcomes Pediatrics 2012 129 e1461 7 22614771 \n14 Clarke BL Brown EM Collins MT Jüppner H Lakatos P Levine MA Epidemiology and diagnosis of hypoparathyroidism J Clin Endocrinol Metab 2016 101 2284 99 26943720 \n15 Rude RK Oldham SB Singer FR Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency Clin Endocrinol (Oxf) 1976 5 209 24 182417 \n16 Watanabe S Fukumoto S Chang H Takeuchi Y Hasegawa Y Okazaki R Association between activating mutations of calcium-sensing receptor and Bartter's syndrome Lancet 2002 360 692 4 12241879 \n17 Gong Y Renigunta V Himmerkus N Zhang J Renigunta A Bleich M Claudin-14 regulates renal Ca++ transport in response to CaSR signalling via a novel microRNA pathway EMBO J 2012 31 1999 2012 22373575 \n18 Pearce SH Bai M Quinn SJ Kifor O Brown EM Thakker RV Functional characterization of calcium-sensing receptor mutations expressed in human embryonic kidney cells J Clin Invest 1996 98 1860 6 8878438 \n19 Pearce SH Williamson C Kifor O Bai M Coulthard MG Davies M A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor N Engl J Med 1996 335 1115 22 8813042\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2287-1012", "issue": "23(2)", "journal": "Annals of pediatric endocrinology & metabolism", "keywords": " Calcium-sensing receptors; Hypoparathyroidism; Mutation; Hypercalciuric hypocalcemia", "medline_ta": "Ann Pediatr Endocrinol Metab", "mesh_terms": null, "nlm_unique_id": "101588279", "other_id": null, "pages": "107-111", "pmc": null, "pmid": "29969884", "pubdate": "2018-06", "publication_types": "D016428:Journal Article", "references": "15005845;17237839;15200151;7874174;25932037;22422767;8813042;11013439;8878438;11889203;8597637;182417;4811993;22373575;26943720;12838336;22614771;12241879;3669134", "title": "De novo a novel variant of CaSR gene in a neonate with congenital hypoparathyroidism.", "title_normalized": "de novo a novel variant of casr gene in a neonate with congenital hypoparathyroidism" }
[ { "companynumb": "KR-VALIDUS PHARMACEUTICALS LLC-KR-2018VAL000925", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CALCIUM CARBONATE" }, "...
{ "abstract": "Tumor necrosis factor-α (TNF-α) inhibitors and ustekunimab are widely used in autoimmune diseases. It is known that these biological agents cause the reactivation of hepatitis B virus (HBV). There is no standardized strategy to prevent the reactivation in patients with evidence of a previous HBV infection. In our study, anti-HBc IgG-positive patients who received a biological agent were evaluated in terms of HBV reactivation.\n\n\n\nPatients who were followed up for the use of biological agents in our clinic were evaluated retrospectively. Patients with isolated anti-HBc IgG positivity were included in the study. The HBV reactivation data were recorded from the patients' files retrospectively.\n\n\n\nTwo hundred and seventy-eight patients who received biological treatment were evaluated. Twenty-nine patients with isolated anti-HBc IgG positivity or resolved HBV infection were included in the study. The HBV reactivation was seen in 5 patients (17.2%). Of these patients, 3 were using adalimumab, 1 infliximab, and 1 ustekunimab. It was controlled by antiviral therapy that was started in the early period.\n\n\n\nDrugs that block TNF-α and ustekunimab cause an increase in viral replication. In literature, the HBV reactivation rate was approximately 1% in HBsAg-negative, anti-HBC IgG-positive cases, whereas it was found to be as high as 17.2% in our study. Patients receiving the immunomodulator therapy should be evaluated for HBV serology before treatment and carefully monitored for HBV reactivation during and after treatment.", "affiliations": "Department of Infection Disease and Clinical Microbiology, Health Sciences University, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey.;Department of Infection Disease and Clinical Microbiology, Health Sciences University, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey.;Department of Infection Disease and Clinical Microbiology, Health Sciences University, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey.;Department of Infection Disease and Clinical Microbiology, Çukurova University School of Medicine, Adana, Turkey.;Department of Infection Disease and Clinical Microbiology, Health Sciences University, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey.;Department of Infection Disease and Clinical Microbiology, Health Sciences University, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey.;Department of Infection Disease and Clinical Microbiology, Health Sciences University, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey.;Department of Infection Disease and Clinical Microbiology, Health Sciences University, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey.", "authors": "Solay|Aslı Haykır|AH|;Acar|Ali|A|;Eser|Fatma|F|;Kuşcu|Ferit|F|;Tütüncü|Emin Ediz|EE|;Kul|Gülnur|G|;Şentürk|Gönül Çiçek|GÇ|;Gürbüz|Yunus|Y|", "chemical_list": "D018501:Antirheumatic Agents; D000998:Antiviral Agents; D001685:Biological Factors; D006510:Hepatitis B Antibodies; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000069549:Ustekinumab; D000068879:Adalimumab", "country": "Turkey", "delete": false, "doi": "10.5152/tjg.2018.18032", "fulltext": null, "fulltext_license": null, "issn_linking": "1300-4948", "issue": "29(5)", "journal": "The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology", "keywords": null, "medline_ta": "Turk J Gastroenterol", "mesh_terms": "D000068879:Adalimumab; D018501:Antirheumatic Agents; D000998:Antiviral Agents; D001685:Biological Factors; D005260:Female; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006515:Hepatitis B virus; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha; D000069549:Ustekinumab; D014775:Virus Activation", "nlm_unique_id": "9515841", "other_id": null, "pages": "561-565", "pmc": null, "pmid": "30260778", "pubdate": "2018-09", "publication_types": "D023362:Evaluation Study; D016428:Journal Article", "references": "10719836;12551985;12871214;15479865;19330727;20556450;22273662;22436845;23111095;23746170;24495663;25195983;25447850;25447852;25776200;25848463;25937860;26274393;26420955;8574849", "title": "Reactivation rates in patients using biological agents, with resolved HBV infection or isolated anti-HBc IgG positivity.", "title_normalized": "reactivation rates in patients using biological agents with resolved hbv infection or isolated anti hbc igg positivity" }
[ { "companynumb": "TR-JNJFOC-20181009899", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "USTEKINUMAB" }, "drugadditional": "3", ...
{ "abstract": "Human T-cell leukemia virus type I (HTLV-1) infection and adult T-cell leukemia-lymphoma (ATL) have been shown to cause immunodeficiency. However, only a few cases have been reported on the development of Epstein-Barr virus positive-diffuse large B-cell lymphoma (EBV-DLBCL) in HTLV-1 carriers or in patients with ATL. Here we report a case of a female HTLV-1 carrier who developed cytomegalovirus (CMV) retinitis. During the CMV retinitis treatment, she developed a liver tumor. The diagnosis of composite ATL and EBV-DLBCL was made by tumor biopsy. The patient also suffered from pulmonary cryptococcosis and invasive pulmonary aspergillosis at the time of chemotherapy initiation. She had repeated CMV antigenemia and bacterial sepsis during the course of chemotherapy, and she died of bacterial sepsis. HTLV-1 carriers who are complicated with opportunistic infections should be carefully observed not only for ATL development but also for the development of EBV-DLBCL and associated infectious complications.", "affiliations": "Department of Hematology, Nagasaki University Hospital.;Department of Hematology, Nagasaki University Hospital.;Department of Pathology, Sasebo City General Hospital.;Department of Pathology, Kurume University School of Medicine.;Department of Infectious Diseases, Nagasaki University Hospital.;Department of Hematology, Nagasaki University Hospital.;Department of Hematology, Nagasaki University Hospital.;Tissue and Histopathology Section, Atomic Bomb Disease Institute, Nagasaki University.;Department of Hematology, Nagasaki University Hospital.;Department of Hematology, Nagasaki University Hospital.;Department of Hematology, Nagasaki University Hospital.;Department of Pathology, Kurume University School of Medicine.;Department of Hematology, Nagasaki University Hospital.", "authors": "Sakamoto|Hikaru|H|;Imaizumi|Yoshitaka|Y|;Niino|Daisuke|D|;Takeuchi|Mai|M|;Matsui|Kosuke|K|;Horai|Makiko|M|;Sato|Shinya|S|;Akazawa|Yuko|Y|;Ando|Koji|K|;Sawayama|Yasushi|Y|;Hata|Tomoko|T|;Ohshima|Koichi|K|;Miyazaki|Yasushi|Y|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.11406/rinketsu.61.305", "fulltext": null, "fulltext_license": null, "issn_linking": "0485-1439", "issue": "61(4)", "journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology", "keywords": "Adult T-cell leukemia/lymphoma; Diffuse large B-cell lymphoma; Epstein-Barr virus; Opportunistic infection", "medline_ta": "Rinsho Ketsueki", "mesh_terms": "D000328:Adult; D020031:Epstein-Barr Virus Infections; D005260:Female; D004854:Herpesvirus 4, Human; D015368:Human T-lymphotropic virus 1; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell; D016403:Lymphoma, Large B-Cell, Diffuse", "nlm_unique_id": "2984782R", "other_id": null, "pages": "305-311", "pmc": null, "pmid": "32378571", "pubdate": "2020", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Composite adult T-cell leukemia/lymphoma and Epstein-Barr virus-positive diffuse large B-cell lymphoma.", "title_normalized": "composite adult t cell leukemia lymphoma and epstein barr virus positive diffuse large b cell lymphoma" }
[ { "companynumb": "JP-CHEPLA-C20201734", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", ...
{ "abstract": "Antidepressant discontinuation syndrome occurs in approximately 20 percent of patients after abrupt discontinuation of an antidepressant medication that was taken for at least six weeks. Typical symptoms of antidepressant discontinuation syndrome include flu-like symptoms, insomnia, nausea, imbalance, sensory disturbances, and hyperarousal. These symptoms usually are mild, last one to two weeks, and are rapidly extinguished with reinstitution of antidepressant medication. Antidepressant discontinuation syndrome is more likely with a longer duration of treatment and a shorter half-life of the treatment drug. A high index of suspicion should be maintained for the emergence of discontinuation symptoms, which should prompt close questioning regarding accidental or purposeful self-discontinuation of medication. Before antidepressants are prescribed, patient education should include warnings about the potential problems associated with abrupt discontinuation. Education about this common and likely underrecognized clinical phenomenon will help prevent future episodes and minimize the risk of misdiagnosis.", "affiliations": "Winn Army Community Hospital, Fort Stewart, Georgia, USA. Christopher.h.warner@us.army.mil", "authors": "Warner|Christopher H|CH|;Bobo|William|W|;Warner|Carolynn|C|;Reid|Sara|S|;Rachal|James|J|", "chemical_list": "D000928:Antidepressive Agents", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0002-838X", "issue": "74(3)", "journal": "American family physician", "keywords": null, "medline_ta": "Am Fam Physician", "mesh_terms": "D000928:Antidepressive Agents; D003937:Diagnosis, Differential; D006801:Humans; D012307:Risk Factors; D013375:Substance Withdrawal Syndrome; D013577:Syndrome", "nlm_unique_id": "1272646", "other_id": null, "pages": "449-56", "pmc": null, "pmid": "16913164", "pubdate": "2006-08-01", "publication_types": "D016428:Journal Article; D016454:Review", "references": null, "title": "Antidepressant discontinuation syndrome.", "title_normalized": "antidepressant discontinuation syndrome" }
[ { "companynumb": "MY-LUPIN PHARMACEUTICALS INC.-2022-05678", "fulfillexpeditecriteria": "2", "occurcountry": "MY", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PAROXETINE" }, "drugadditional...
{ "abstract": "BACKGROUND\nManagement of refractory status epilepticus (SE) involves administration of intravenous γ-aminobutyric acid (GABA(A)) receptor agonists, such as benzodiazepines, barbiturates, or propofol. Animal models suggest that reductions in synaptic GABA(A) receptors may cause these drugs to become less effective as the duration of SE increases. This may explain the large doses that are commonly required to control seizures, which in turn contributes to a high incidence of complications, including hypotension and the need for vasopressors. In contrast, expression of excitatory N-methyl-D-aspartate (NMDA) receptors increases with prolonged SE and their stimulation by glutamate may propagate seizure activity. Ketamine is a NMDA-receptor antagonist that is considered promising as treatment for refractory SE. Compared with other anaesthetic drugs, ketamine produces less hypotension.\n\n\nMETHODS\nThis report describes a patient who developed worsening hypotension with escalating doses of midazolam and propofol in the context of non-convulsive SE. He was therefore treated with ketamine within hours of being diagnosed.\n\n\nRESULTS\nKetamine was immediately efficacious at reducing the frequency, amplitude, and duration of seizures. The dose was rapidly titrated upwards using quantitative continuous EEG monitoring, until seizures were completely abolished. SE did not recur with weaning of sedatives and he went on to have an excellent recovery. A small number of previous reports have found ketamine to abort late SE. In most cases, ketamine was administered several days into the course, and outcomes were poor even though seizures were controlled.\n\n\nCONCLUSIONS\nLarger series and phase I clinical trial(s) of ketamine for treatment of refractory SE seem warranted.", "affiliations": "Department of Critical Care Medicine, University of Calgary, ICU Administration, Ground Floor, McCaig Tower, 3134 Hospital Dr NW, Calgary, AB T2N 2T9, Canada. andreas.kramer@albertahealthservices.ca", "authors": "Kramer|Andreas H|AH|", "chemical_list": "D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine", "country": "United States", "delete": false, "doi": "10.1007/s12028-011-9668-7", "fulltext": null, "fulltext_license": null, "issn_linking": "1541-6933", "issue": "16(2)", "journal": "Neurocritical care", "keywords": null, "medline_ta": "Neurocrit Care", "mesh_terms": "D018691:Excitatory Amino Acid Antagonists; D006801:Humans; D007649:Ketamine; D008297:Male; D008875:Middle Aged; D016194:Receptors, N-Methyl-D-Aspartate; D013226:Status Epilepticus", "nlm_unique_id": "101156086", "other_id": null, "pages": "299-305", "pmc": null, "pmid": "22237581", "pubdate": "2012-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "20098301;11074184;15230698;15944379;21939901;9015485;21724423;12609230;18851928;21576693;21987548;18804344;9239591;12904852;10659851;17941842;11903460;2158437;12967577;10327162;20861452;9855547;12609394;15832606;19661801", "title": "Early ketamine to treat refractory status epilepticus.", "title_normalized": "early ketamine to treat refractory status epilepticus" }
[ { "companynumb": "CA-RANBAXY-2012US-58819", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, ...
{ "abstract": "OBJECTIVE\nThe aim of this study was to evaluate utilization, efficacy, and side effects of flecainide treatment as first-line agent in patients with fetal supraventricular tachycardia (SVT).\n\n\nMETHODS\nThis retrospective review was conducted on 23 consecutive fetal tachyarrhythmia cases that met inclusion criteria. If the treatment was necessary, then flecainide was used as first-line treatment in all cases.\n\n\nRESULTS\nAmong the study group, there were 21 (91.3%) cases of SVT and 2 (8.6%) cases of Atrial Flutter (AF). Sixteen fetuses had persistent SVT and five fetuses had intermittent SVT. We treated 17 fetuses with flecainide monotherapy and 15 of them converted to sinus rhythm and remaining two fetuses were refractory to monotherapy. The median time to conversion to sinus rhythm was 3.8 ± 1.6 days. Only one fetus (20%) among the intermittent SVT cases required anti-arrhythmic treatment.\n\n\nCONCLUSIONS\nOur study has demonstrated that flecainide is an effective first-line treatment for fetal SVT with high success rate (88.2%), low side effect profile and relatively easy utilization. Based on the current study and recently published article results, flecainide can be recommended as the drug of first choice for treatment of fetal SVT cases.", "affiliations": "a Department of Obstetrics and Gynecology, Maternal-Fetal Medicine Unit , Kanuni Sultan Suleyman Training and Research Hospital , Istanbul , Turkey.;a Department of Obstetrics and Gynecology, Maternal-Fetal Medicine Unit , Kanuni Sultan Suleyman Training and Research Hospital , Istanbul , Turkey.;b Department of Pediatric Cardiology , Kanuni Sultan Suleyman Training and Research Hospital , Istanbul , Turkey.;a Department of Obstetrics and Gynecology, Maternal-Fetal Medicine Unit , Kanuni Sultan Suleyman Training and Research Hospital , Istanbul , Turkey.;a Department of Obstetrics and Gynecology, Maternal-Fetal Medicine Unit , Kanuni Sultan Suleyman Training and Research Hospital , Istanbul , Turkey.;c Department of Obstetrics and Gynecology , Kanuni Sultan Suleyman Training and Research Hospital , Istanbul , Turkey.;a Department of Obstetrics and Gynecology, Maternal-Fetal Medicine Unit , Kanuni Sultan Suleyman Training and Research Hospital , Istanbul , Turkey.", "authors": "Ekiz|Ali|A|;Kaya|Basak|B|;Bornaun|Helen|H|;Acar|Deniz Kanber|DK|;Avci|Muhittin Eftal|ME|;Bestel|Aysegul|A|;Yildirim|Gokhan|G|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D005424:Flecainide", "country": "England", "delete": false, "doi": "10.1080/14767058.2017.1286317", "fulltext": null, "fulltext_license": null, "issn_linking": "1476-4954", "issue": "31(4)", "journal": "The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians", "keywords": "Fetus; arrhythmia; flecainide; supraventricular tachycardia", "medline_ta": "J Matern Fetal Neonatal Med", "mesh_terms": "D000328:Adult; D000889:Anti-Arrhythmia Agents; D004452:Echocardiography; D005260:Female; D005315:Fetal Diseases; D005318:Fetal Heart; D005424:Flecainide; D005865:Gestational Age; D006801:Humans; D015160:Hydrops Fetalis; D007231:Infant, Newborn; D011247:Pregnancy; D012189:Retrospective Studies; D013617:Tachycardia, Supraventricular; D016896:Treatment Outcome; D018608:Ultrasonography, Doppler; D055815:Young Adult", "nlm_unique_id": "101136916", "other_id": null, "pages": "407-412", "pmc": null, "pmid": "28114840", "pubdate": "2018-02", "publication_types": "D016428:Journal Article", "references": null, "title": "Flecainide as first-line treatment for fetal supraventricular tachycardia.", "title_normalized": "flecainide as first line treatment for fetal supraventricular tachycardia" }
[ { "companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-166121", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIGOXIN" }, "drugadd...
{ "abstract": "Congress and the FDA have strongly suggested that tranquilizers and antipsychotics not be used in agitated demented frail elderly patients. The medical profession has not moved away from the tradition of antipsychotic sedation of such patients. Use of 'modern second generation low dose' antipsychotics continue to be the standard of care. Propranolol, a non-selective beta-blocker with good penetration of the CNS, is a reasonable and safe alternative to sedatives and antipsychotics. Anti-dementia drugs are complementary to propranolol. A case study which contrasts the two pharmacologic approaches is detailed. A method of estimating delirium-agitation risk in dementia patients (DRN method) is described.", "affiliations": "Alzheimer's Corporation, 6000 Uptown Blvd, Suite 308, Albuquerque, NM 87110-4148, USA. aca@swcp.com", "authors": "Summers|William K|WK|", "chemical_list": "D014150:Antipsychotic Agents; D011433:Propranolol", "country": "Netherlands", "delete": false, "doi": "10.3233/jad-2006-9107", "fulltext": null, "fulltext_license": null, "issn_linking": "1387-2877", "issue": "9(1)", "journal": "Journal of Alzheimer's disease : JAD", "keywords": null, "medline_ta": "J Alzheimers Dis", "mesh_terms": "D000368:Aged; D014150:Antipsychotic Agents; D001986:Bronchial Spasm; D003704:Dementia; D019468:Disease Management; D006801:Humans; D008297:Male; D011433:Propranolol; D011595:Psychomotor Agitation; D012135:Respiratory Sounds; D014481:United States; D014486:United States Food and Drug Administration", "nlm_unique_id": "9814863", "other_id": null, "pages": "69-75", "pmc": null, "pmid": "16627936", "pubdate": "2006-03", "publication_types": "D002363:Case Reports; D003160:Comparative Study; D016428:Journal Article", "references": null, "title": "The management of agitation in demented patients with propranolol.", "title_normalized": "the management of agitation in demented patients with propranolol" }
[ { "companynumb": "US-PFIZER INC-2018134426", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "RISPERIDONE" }, "drugadditional": null, ...
{ "abstract": "We present an atypical case of tuberculosis in an immunocompetent man from west Africa living in Europe. The patient entered the hospital with a painful lump of 3 cm on his right clavicule which he noticed 2 weeks before and back pain. During the examinations for further evaluation his condition deteriorated within short time. Tuberculosis was diagnosed, treatment started but he needed mechanical ventilation at the intensive care unit and had kidney failure. The further evolvement was favourable in the end but needed intensive treatment for over 4 weeks. Tuberculosis cases with such severe evolution are rather known with immunodeficient patients. Extrapulmonary tuberculosis, especially skeletal tuberculosis is seen more frequent in young immunocompetent migrants. The migrating persons seem to be more at risk to get sick than the ones staying in their origin country. We suppose the course of our patient's disease is miliary or septic, of which both are rather rare entities.", "affiliations": "Department of Internal Medicine, Sonnenhof, Bern, Bern, Switzerland.", "authors": "Albrecht|Nicole|N|;Cottagnoud|Philippe|P|;Chatterjee|Bidisha|B|", "chemical_list": null, "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2014()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000328:Adult; D000354:Africa, Western; D054242:Emigrants and Immigrants; D005060:Europe; D006801:Humans; D007121:Immunocompetence; D008159:Lumbar Vertebrae; D008297:Male; D012128:Respiratory Distress Syndrome; D014057:Tomography, X-Ray Computed; D014391:Tuberculosis, Miliary; D014397:Tuberculosis, Pulmonary; D014399:Tuberculosis, Spinal", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "24654236", "pubdate": "2014-03-20", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "21420653;17166963;16789468;17607348;18369480;18564694;15114055;10919306;14600128;15162540;18173355;16488649;17398230;10609064;16020892;7881684;16477032;16938198;15378263;16258876;16509557;16586317;11230395;7065732;11371265;12783178;17980121;12141971;15228896;9197219;11339471;18614559;12447531;17439685;15164258;3584648;12324902;18834315;620556;8825004;16860392", "title": "Miliary tuberculosis with atypical presentation in an immunocompetent young African man.", "title_normalized": "miliary tuberculosis with atypical presentation in an immunocompetent young african man" }
[ { "companynumb": "PHHY2014CH126084", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": null, "druga...
{ "abstract": "Invasive mucormycosis in patients with hematological diseases mostly occurs in the lungs. Invasive mucormycosis of other anatomical sites is relatively infrequent and its pathogenesis has not so far been well elucidated. Here, we describe an autopsy case of pulmonary invasive mucormycosis complicated by cerebral embolism with infarct. A 77-year-old Japanese woman with relapsed acute myeloid leukemia complained of left visual disturbance and weakness of the lower limbs. The diagnosis of leukemic infiltration to the central nervous system was made. Repeated intrathecal injection of methotrexate plus cytarabine resulted in partial amelioration of the neurologic symptoms. However, the patient then developed fever, dyspnea, and subsequent right hemiparesis. A computed tomography (CT) scan showed a consolidative shadow with halo sign in the left lung field, which was compatible with either invasive pulmonary aspergillosis or mucormycosis. These findings accounted for fever and dyspnea, but not hemiparesis. Despite antifungal therapy, the patient succumbed to death after two weeks. Autopsy revealed pulmonary invasive mucormycosis with a fungal ball in the lumina of the adjacent ascending aorta. Intriguingly, autopsy and postmortem CT scan identified left cerebral infarct due to mucormycosis, which accounted for the right hemiparesis. It is likely that the fungal ball caused the cerebral embolism through hematogenous dissemination. We should suspect hematogenous dissemination when we see a patient with pulmonary invasive mucormycosis developing neurologic symptoms.", "affiliations": "Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo Japan.;Department of Pathology, Graduate School of Medicine, The University of Tokyo Japan.;Department of Radiology, Graduate School of Medicine, The University of Tokyo Japan.;Department of Radiology, Graduate School of Medicine, The University of Tokyo Japan.;Department of Radiology, Sanraku Hospital Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo Japan.;Department of Pathology, Graduate School of Medicine, The University of Tokyo Japan.;Department of Radiology, Graduate School of Medicine, The University of Tokyo Japan.;Department of Pathology, Graduate School of Medicine, The University of Tokyo Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo Japan.", "authors": "Higo|Takashi|T|;Kobayashi|Takashi|T|;Yamazaki|Sho|S|;Ando|Sumiyo|S|;Gonoi|Wataru|W|;Ishida|Masanori|M|;Okuma|Hidemi|H|;Nakamura|Fumihiko|F|;Ushiku|Tetsuo|T|;Ohtomo|Kuni|K|;Fukayama|Masashi|M|;Kurokawa|Mineo|M|", "chemical_list": "D003561:Cytarabine; D008727:Methotrexate", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1936-2625", "issue": "8(10)", "journal": "International journal of clinical and experimental pathology", "keywords": "Cerebral embolism; hematogenous dissemination; invasive mucormycosis; relapsed acute myeloid leukemia", "medline_ta": "Int J Clin Exp Pathol", "mesh_terms": "D000368:Aged; D001344:Autopsy; D003561:Cytarabine; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D020766:Intracranial Embolism; D055744:Invasive Pulmonary Aspergillosis; D015470:Leukemia, Myeloid, Acute; D008168:Lung; D008727:Methotrexate; D009091:Mucormycosis", "nlm_unique_id": "101480565", "other_id": null, "pages": "13639-42", "pmc": null, "pmid": "26722589", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10961535;14748801;15003897;8115954;16080086;16885047;21622653", "title": "Cerebral embolism through hematogenous dissemination of pulmonary mucormycosis complicating relapsed leukemia.", "title_normalized": "cerebral embolism through hematogenous dissemination of pulmonary mucormycosis complicating relapsed leukemia" }
[ { "companynumb": "JP-ACCORD-037089", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drug...
{ "abstract": "Anaphylaxis is rare but life-threatening. Its incidence during pediatric procedural sedation outside of the operating room is unknown. We used data from the Pediatric Sedation Research Consortium (PSRC) to determine the incidence and nature of allergic and anaphylactic reactions in this practice.\n\n\n\nA retrospective observational study of prospectively collected information in the PSRC's multicenter database was performed. Cases of allergic reaction were identified. Because anaphylaxis is not a listed complication in the PSRC database, all cases for which allergic reaction was noted were reviewed for the occurrence of other complications or interventions that would suggest at least 2 organ system derangements consistent with anaphylaxis as well as for practitioner commentary stating the occurrence of anaphylaxis. Descriptive analyses of demographic information and summary statistics were performed, and multiple logistic regression analysis was used to evaluate associations between the occurrence of allergic reactions and medications.\n\n\n\nDuring the study period, 227 833 cases were entered into the PSRC database. There were 54 cases of allergic reaction (incidence 1:4219); 6 were consistent with anaphylaxis (incidence 1:37 972). A significant association between the development of allergic reaction and 4 sedative and/or analgesic medications was noted: midazolam (odds ratio [OR] 2.2; confidence interval [CI] 1.2-3.9), ketamine (OR 3.8; CI 2.1-7.1), methohexital (OR 48.8; CI 14.9-159.9), and morphine (OR 4.4; CI 1.04-18.2). There were no mortalities.\n\n\n\nAllergic reactions and anaphylaxis during pediatric procedural sedation are rare. In this study, the development of allergic reactions was significantly associated with the use of midazolam, ketamine, methohexital, and morphine.", "affiliations": "Division of Critical Care Medicine, Department of Pediatrics, Nemours Alfred I. duPont Hospital for Children, Wilmington, Delaware; jhertzog@nemours.org.;Departments of Hospital Medicine and Anesthesiology, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas; and.;Department of Pediatrics, Herman and Walter Samuelson Children's Hospital at Sinai, Baltimore, Maryland.", "authors": "Hertzog|James H|JH|;Preisberga|Krista|K|;Penfil|Scott|S|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1542/hpeds.2018-0089", "fulltext": null, "fulltext_license": null, "issn_linking": "2154-1671", "issue": "9(1)", "journal": "Hospital pediatrics", "keywords": null, "medline_ta": "Hosp Pediatr", "mesh_terms": "D000707:Anaphylaxis; D000758:Anesthesia; D002648:Child; D016208:Databases, Factual; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D011446:Prospective Studies; D012189:Retrospective Studies", "nlm_unique_id": "101585349", "other_id": null, "pages": "16-23", "pmc": null, "pmid": "30541918", "pubdate": "2019-01", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study", "references": null, "title": "The Incidence and Nature of Allergic and Anaphylactic Reactions During Pediatric Procedural Sedation: A Report From the Pediatric Sedation Research Consortium.", "title_normalized": "the incidence and nature of allergic and anaphylactic reactions during pediatric procedural sedation a report from the pediatric sedation research consortium" }
[ { "companynumb": "US-FRESENIUS KABI-FK201901433", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": "3", ...
{ "abstract": "Sorafenib is a promising agent for treating pediatric refractory acute myeloid leukemia (AML) exhibiting FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD); however, its optimal use needs to be established. We report 2 cases of refractory pediatric FLT3-ITD-positive AML treated with sorafenib. Case 1 underwent stem cell transplantation (SCT) without entering remission, despite the use of chemotherapy. This patient relapsed despite receiving post-SCT sorafenib. Chemotherapy combined with sorafenib successfully achieved complete remission in case 2. This patient received post-SCT sorafenib and remains in complete remission. The combination of pre-SCT and post-SCT sorafenib may thus be effective for pediatric refractory FLT3-ITD-positive AML.", "affiliations": "*Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto †Department of Pediatrics, Matsushita Memorial Hospital, Moriguchi, Japan.", "authors": "Osone|Shinya|S|;Imamura|Toshihiko|T|;Kanayama|Takuyo|T|;Tsuma|Yusuke|Y|;Kawashima-Goto|Sachiko|S|;Nakatani|Takuya|T|;Sugimoto|Atsuya|A|;Takai|Akari|A|;Miyachi|Mitsuru|M|;Tamura|Shinichi|S|;Ishida|Hiroyuki|H|;Hosoi|Hajime|H|", "chemical_list": "D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D051941:fms-Like Tyrosine Kinase 3", "country": "United States", "delete": false, "doi": "10.1097/MPH.0000000000000672", "fulltext": null, "fulltext_license": null, "issn_linking": "1077-4114", "issue": "39(4)", "journal": "Journal of pediatric hematology/oncology", "keywords": null, "medline_ta": "J Pediatr Hematol Oncol", "mesh_terms": "D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009154:Mutation; D009536:Niacinamide; D010671:Phenylurea Compounds; D016879:Salvage Therapy; D000077157:Sorafenib; D020080:Tandem Repeat Sequences; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3", "nlm_unique_id": "9505928", "other_id": null, "pages": "e199-e202", "pmc": null, "pmid": "27571118", "pubdate": "2017-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Sorafenib Therapy for Pediatric Acute Myeloid Leukemia with FMS-like Tyrosine Kinase 3-internal Tandem Duplication Mutations: 2 Case Reports.", "title_normalized": "sorafenib therapy for pediatric acute myeloid leukemia with fms like tyrosine kinase 3 internal tandem duplication mutations 2 case reports" }
[ { "companynumb": "JP-FRESENIUS KABI-FK201706239", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "IDARUBICIN" }, "drugadditional": null, ...
{ "abstract": "A 12-year-old boy presented to the emergency department with findings concerning for multisystem inflammatory syndrome in children. After clinical stabilization following treatment with antibiotics, remdesivir, and anakinra, the patient was noted to have episodes of altered mentation. Video electroencephalogram revealed status epilepticus, which was subsequently controlled with antiepileptic medications.", "affiliations": "New York University Grossman School of Medicine, New York, NY; Hassenfeld Children's Hospital, NYU Langone Medical Center, New York, NY. Electronic address: Jennifer.Shenker@nyulangone.org.;New York University Grossman School of Medicine, New York, NY; Hassenfeld Children's Hospital, NYU Langone Medical Center, New York, NY.;New York University Grossman School of Medicine, New York, NY; Hassenfeld Children's Hospital, NYU Langone Medical Center, New York, NY.;New York University Grossman School of Medicine, New York, NY; Hassenfeld Children's Hospital, NYU Langone Medical Center, New York, NY.;New York University Grossman School of Medicine, New York, NY; Hassenfeld Children's Hospital, NYU Langone Medical Center, New York, NY.", "authors": "Shenker|Jennifer|J|;Trogen|Brit|B|;Schroeder|Laura|L|;Ratner|Adam J|AJ|;Kahn|Philip|P|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.jpeds.2020.07.062", "fulltext": null, "fulltext_license": null, "issn_linking": "0022-3476", "issue": "227()", "journal": "The Journal of pediatrics", "keywords": null, "medline_ta": "J Pediatr", "mesh_terms": "D002648:Child; D006801:Humans; D008297:Male; D013226:Status Epilepticus; D018746:Systemic Inflammatory Response Syndrome", "nlm_unique_id": "0375410", "other_id": null, "pages": "300-301", "pmc": null, "pmid": "32712284", "pubdate": "2020-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "31432001;11587880;14625166;22528274;32240762;32374370;23320006;32275288;32410759", "title": "Multisystem Inflammatory Syndrome in Children Associated with Status Epilepticus.", "title_normalized": "multisystem inflammatory syndrome in children associated with status epilepticus" }
[ { "companynumb": "US-BIOVITRUM-2020US4955", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FOSPHENYTOIN" }, "drugadditional": null, ...
{ "abstract": "We present a 42-year-old woman with no history of diabetes or glucose intolerance who had a 5-year history of ulcerative necrobiosis lipoidica (NL). Despite failure of multiple medications, she experienced clearing of her ulcers after her treatment was changed to ustekinumab. We discuss our patient's disease course and elaborate upon mechanistic reasons for her improvement related to ustekinumab therapy.", "affiliations": "Department of Dermatology, University of California Davis School of Medicine, Sacramento, California.", "authors": "Hassoun|Lauren A|LA|;Sivamani|Raja K|RK|;Sharon|Victoria R|VR|;Silverstein|Marc A|MA|;Burrall|Barbara A|BA|;Tartar|Danielle M|DM|", "chemical_list": "D003879:Dermatologic Agents; D018664:Interleukin-12; D000069549:Ustekinumab", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1087-2108", "issue": "23(7)", "journal": "Dermatology online journal", "keywords": null, "medline_ta": "Dermatol Online J", "mesh_terms": "D000328:Adult; D003879:Dermatologic Agents; D005260:Female; D006099:Granuloma; D006801:Humans; D018664:Interleukin-12; D009335:Necrobiosis Lipoidica; D012883:Skin Ulcer; D000069549:Ustekinumab", "nlm_unique_id": "9610776", "other_id": null, "pages": null, "pmc": null, "pmid": "29469709", "pubdate": "2017-07-15", "publication_types": "D002363:Case Reports; D016422:Letter", "references": null, "title": "Ustekinumab to target granulomatous dermatitis in recalcitrant ulcerative necrobiosis lipoidica: case report and proposed mechanism.", "title_normalized": "ustekinumab to target granulomatous dermatitis in recalcitrant ulcerative necrobiosis lipoidica case report and proposed mechanism" }
[ { "companynumb": "US-TEVA-808599USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "d...
{ "abstract": "We report a case of a relapsed hemophagocytic intramedullary plasmacytoma, previously non-phagocytic, in conjunction with development of a new clone with different cytogenetic abnormalities forming a solitary plasmacytoma.", "affiliations": "Department of Medicine, The Mount Sinai Hospital, New York, NY, 10029, USA.;Department of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Center, New York, NY, 10029, USA.;Department of Pathology, Molecular and Cell-Based Medicine, The Mount Sinai Hospital, Icahn School of Medicine, Tisch Cancer Institute, Annenberg 15-78A, One Gustave L. Levy Place, Box 1194, New York, NY, 10029-6574, USA. julie.feldstein@mssm.edu.", "authors": "Mouhieddine|Tarek H|TH|;Barlogie|Bart|B|;Teruya-Feldstein|Julie|J|http://orcid.org/0000-0003-0033-445X", "chemical_list": "D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D009842:Oligopeptides; D003561:Cytarabine; C556306:daratumumab; D013792:Thalidomide; D000069286:Bortezomib; D005047:Etoposide; C524865:carfilzomib; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D002945:Cisplatin; D008558:Melphalan; D002330:Carmustine", "country": "Japan", "delete": false, "doi": "10.1007/s12185-019-02817-5", "fulltext": null, "fulltext_license": null, "issn_linking": "0925-5710", "issue": "111(6)", "journal": "International journal of hematology", "keywords": "Hemophagocytic; Intramedullary; Plasmacytoma; Relapsed", "medline_ta": "Int J Hematol", "mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D001859:Bone Neoplasms; D000069286:Bortezomib; D002330:Carmustine; D002945:Cisplatin; D003520:Cyclophosphamide; D003561:Cytarabine; D003907:Dexamethasone; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008558:Melphalan; D009364:Neoplasm Recurrence, Local; D009842:Oligopeptides; D010954:Plasmacytoma; D000072078:Positron Emission Tomography Computed Tomography; D011630:Pubic Bone; D035583:Rare Diseases; D033581:Stem Cell Transplantation; D013792:Thalidomide; D014182:Transplantation, Autologous; D016896:Treatment Outcome", "nlm_unique_id": "9111627", "other_id": null, "pages": "888-890", "pmc": null, "pmid": "31900879", "pubdate": "2020-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Hemophagocytic relapsed intramedullary plasmacytoma.", "title_normalized": "hemophagocytic relapsed intramedullary plasmacytoma" }
[ { "companynumb": "US-AMGEN-USASP2020093353", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DARATUMUMAB" }, "drugadditional": null, ...
{ "abstract": "Inflammatory linear verrucous epidermal nevus (ILVEN) is a chronic, a linear, or whorled array of inflammatory, following the lines of Blaschko. Treatment of ILVEN is challenging with numerous therapies of varying degrees of success reported. We present a case of ILVEN in a 5-year-old-boy, treated successfully with crisaborole 2% ointment. This brief report suggests that there may be additional cellular immunologic pathways responsible for the presentation of ILVEN that may be explained by management with crisaborole use.", "affiliations": "Duke University School of Medicine, Durham, North Carolina.;Duke University School of Medicine, Durham, North Carolina.;Duke University School of Medicine, Durham, North Carolina.", "authors": "Barney|Emily|E|https://orcid.org/0000-0003-3586-5752;Prose|Neil S|NS|;Ramirez|Mary|M|", "chemical_list": "D001896:Boron Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; C543085:crisaborole", "country": "United States", "delete": false, "doi": "10.1111/pde.13793", "fulltext": null, "fulltext_license": null, "issn_linking": "0736-8046", "issue": "36(3)", "journal": "Pediatric dermatology", "keywords": "crisaborole; inflammatory linear verrucous epidermal nevus", "medline_ta": "Pediatr Dermatol", "mesh_terms": "D001896:Boron Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002675:Child, Preschool; D006801:Humans; D008297:Male; D054000:Nevus, Sebaceous of Jadassohn", "nlm_unique_id": "8406799", "other_id": null, "pages": "404-405", "pmc": null, "pmid": "30838675", "pubdate": "2019-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Inflammatory linear verrucous epidermal nevus treated successfully with crisaborole ointment in a 5-year-old boy.", "title_normalized": "inflammatory linear verrucous epidermal nevus treated successfully with crisaborole ointment in a 5 year old boy" }
[ { "companynumb": "US-STRIDES ARCOLAB LIMITED-2019SP007151", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional...
{ "abstract": "Oxaliplatin, a third-generation platinum agent, has been used for the treatment of colon, pancreatic, and stomach cancers in recent years. It carries a reduced risk of acute kidney injury (AKI) compared to the previous platinum agents, including cisplatin and carboplatin. Several cases of oxaliplatin-induced acute tubular necrosis (ATN) have been reported; however, only one case has been reported as acute tubulointerstitial nephritis (ATIN) histopathologically. Here, we present a case of biopsy-proven and dialysis-dependent ATIN, which dramatically resolved with steroid therapy. The patient was a 67-year-old male who had undergone chemotherapy for colon adenocarcinoma. He suddenly developed shaking chills, fever, and hot flashes at the end of the 18th 5-fluorouracil (5-FU)/L-leucovorin/oxaliplatin administration, and was admitted to our hospital. On the 4th day of hospitalization, severe renal dysfunction (creatinine 6.5 mg/dL) was observed. As oliguria continued, we initiated hemodialysis therapy on the 6th day of hospitalization. Drug-induced ATIN was strongly suspected due to the history of multiple exposures to oxaliplatin with allergic reaction and sterile pyuria. We began steroid therapy on the 8th day of hospitalization. Subsequently, renal biopsy was performed and the diagnosis of ATIN was made. The patient's renal function gradually improved, and 6 months later, it had returned to baseline. Our case demonstrates that we should consider not only ATN, but also ATIN, as potential presentations of oxaliplatin-induced AKI.", "affiliations": "Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, 216-8511, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, 216-8511, Japan. masahikoyazawa@gmail.com.;Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, 216-8511, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, 216-8511, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, 216-8511, Japan.;Department of Pathology, Kawasaki Municipal Tama Hospital, 1-30-37 Syukugawara, Tama-Ku, Kawasaki, 214-8525, Japan.;Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-Ku, Kawasaki, 216-8511, Japan.", "authors": "Yamada|Shohei|S|;Yazawa|Masahiko|M|0000-0002-3907-5347;Yamamoto|Makoto|M|;Koitabashi|Kenichiro|K|;Ichikawa|Daisuke|D|;Koike|Jyunki|J|;Shibagaki|Yugo|Y|", "chemical_list": "D000970:Antineoplastic Agents; D000077150:Oxaliplatin", "country": "Japan", "delete": false, "doi": "10.1007/s13730-019-00390-8", "fulltext": null, "fulltext_license": null, "issn_linking": "2192-4449", "issue": "8(3)", "journal": "CEN case reports", "keywords": "Acute interstitial nephritis; Drug-induced acute kidney injury; Oxaliplatin; Platinum agent", "medline_ta": "CEN Case Rep", "mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000743:Anemia, Hemolytic; D000970:Antineoplastic Agents; D003110:Colonic Neoplasms; D006801:Humans; D007668:Kidney; D008297:Male; D009395:Nephritis, Interstitial; D000077150:Oxaliplatin; D013921:Thrombocytopenia", "nlm_unique_id": "101636244", "other_id": null, "pages": "188-193", "pmc": null, "pmid": "30827015", "pubdate": "2019-08", "publication_types": "D002363:Case Reports", "references": "12453866;16914559;24691017;15230812;24927897;15827046;10561172;25859355;20336051;22450906;25984004;8441839;21144842;19033714;24052222;15175436;17582384;21685026;24350092;24615628;26844777", "title": "A case of biopsy-proven oxaliplatin-induced acute tubulointerstitial nephritis with thrombocytopenia and anemia.", "title_normalized": "a case of biopsy proven oxaliplatin induced acute tubulointerstitial nephritis with thrombocytopenia and anemia" }
[ { "companynumb": "JP-BAUSCH-BL-2019-021425", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": "3", ...
{ "abstract": "This is a case of nontraumatic shoulder pain initially diagnosed on x-ray as an anterior dislocation. The patient was on anticoagulants and, in actuality, had severe hemarthrosis that caused the subluxation. Attempts to reduce the dislocation in this situation might have resulted in worsening of the intra-articular bleed. There has been only 1 similar reported case in the European Journal of Emergency Medicine in 2013 of a 53-year-old woman who was thought to have a nontraumatic anterior shoulder dislocation, and attempts were unsuccessful at reduction. Definitive therapy involved hemarthrosis aspiration. Others have reported spontaneous hemarthrosis due to anticoagulants; however, only 1 has reported an initial mistaken joint dislocation diagnosis. Nontraumatic hemarthrosis do occur in patients on anticoagulant therapy, and it is important to recognize that this can be misdiagnosed as a joint dislocation requiring reduction. In a patient who is on anticoagulants presenting with nontraumatic joint pain and anterior shoulder or possibly other dislocations on plain radiographs, it is pertinent to consider hemarthrosis.", "affiliations": "Henry Ford Hospital, Department of Emergency Medicine, Detroit, MI. Electronic address: christineMAVISDAVIS@GMAIL.COM.;Henry Ford Hospital, Department of Emergency Medicine, Detroit, MI.", "authors": "Davis|Christine B|CB|;Nowak|Richard M|RM|", "chemical_list": "D000925:Anticoagulants", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0735-6757", "issue": "32(12)", "journal": "The American journal of emergency medicine", "keywords": null, "medline_ta": "Am J Emerg Med", "mesh_terms": "D000925:Anticoagulants; D004636:Emergency Service, Hospital; D005260:Female; D006395:Hemarthrosis; D006801:Humans; D008875:Middle Aged; D011859:Radiography; D012783:Shoulder Dislocation; D012785:Shoulder Joint; D020069:Shoulder Pain", "nlm_unique_id": "8309942", "other_id": null, "pages": "1562.e3-4", "pmc": null, "pmid": "25043625", "pubdate": "2014-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Anticoagulant-induced hemarthrosis presenting as anterior shoulder dislocation.", "title_normalized": "anticoagulant induced hemarthrosis presenting as anterior shoulder dislocation" }
[ { "companynumb": "US-MYLANLABS-2014M1016111", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, ...
{ "abstract": "Doxycycline is a commonly prescribed antibiotic with growing evidence suggesting a possible linkage with drug-induced acute pancreatitis. We present an elderly female presenting with severe acute pancreatitis likely secondary to doxycycline therapy after thorough investigation. We reviewed the evidence linking doxycycline-inducing acute pancreatitis and signs and symptoms for severe disease. Early recognition and intervention are critical for positive patient outcomes.", "affiliations": "Department of Internal Medicine, NYU Langone Hospital - Long Island, Mineola, New York, USA neal.shah@nyulangone.org.;Department of Gastroenterology and Hepatology, NYU Langone Hospital - Long Island, Mineola, New York, USA.;Department of Gastroenterology and Hepatology, NYU Langone Hospital - Long Island, Mineola, New York, USA.", "authors": "Shah|Neal|N|http://orcid.org/0000-0001-6875-929X;Razzano|Anthony|A|;Grendell|James|J|", "chemical_list": "D000900:Anti-Bacterial Agents; D004318:Doxycycline", "country": "England", "delete": false, "doi": "10.1136/bcr-2020-239640", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "14(2)", "journal": "BMJ case reports", "keywords": "gastrointestinal system; pancreatitis", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D004318:Doxycycline; D005260:Female; D005440:Fluid Therapy; D006801:Humans; D010195:Pancreatitis; D017582:Renal Replacement Therapy", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "33547098", "pubdate": "2021-02-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Doxycycline Induced Severe Acute Pancreatitis: A Rare Finding To A Common Medication.", "title_normalized": "doxycycline induced severe acute pancreatitis a rare finding to a common medication" }
[ { "companynumb": "US-MYLANLABS-2021M1014867", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": "1", ...
{ "abstract": "Sorafenib is an oral multikinase inhibitor approved by the United States Food and Drug Administration for the treatment of advanced hepatocellular and renal cell carcinoma. Cases of sorafenib-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome have been reported in the literature. DRESS syndrome is a potentially fatal, drug-induced hypersensitivity reaction that occurs 2-8 weeks after drug exposure. DRESS syndrome presents with generalized morbilliform eruption, facial edema, eosinophilia, and end-organ damage. We present the first reported case of sorafenib toxicity mimicking DRESS syndrome in a patient with metastatic adrenocortical carcinoma presenting with fever, morbilliform rash, and transaminitis in the absence of eosinophilia three days following initiation of sorafenib therapy. It is critical that clinicians are equipped to accurately diagnose DRESS syndrome due to its high mortality rate and the morbidity associated with prolonged steroid therapy.\n\nJ Drugs Dermatol. 2019;18(5):468-469.", "affiliations": null, "authors": "Salame|Nicole|N|;Chow|Maggie L.|ML|;Ochoa|Maria T.|MT|;Compoginis|Goli|G|;Crew|Ashley B.|AB|", "chemical_list": "D000970:Antineoplastic Agents; D000077157:Sorafenib", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1545-9616", "issue": "18(5)", "journal": "Journal of drugs in dermatology : JDD", "keywords": null, "medline_ta": "J Drugs Dermatol", "mesh_terms": "D000306:Adrenal Cortex Neoplasms; D018268:Adrenocortical Carcinoma; D000970:Antineoplastic Agents; D003937:Diagnosis, Differential; D063926:Drug Hypersensitivity Syndrome; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000077157:Sorafenib", "nlm_unique_id": "101160020", "other_id": null, "pages": "468-469", "pmc": null, "pmid": "31141856", "pubdate": "2019-05-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Sorafenib Toxicity Mimicking Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) Syndrome", "title_normalized": "sorafenib toxicity mimicking drug reaction with eosinophilia and systemic symptoms dress syndrome" }
[ { "companynumb": "US-BAYER-2019-127080", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "d...
{ "abstract": "A 67-year-old man with a medical history of multiorgan sarcoidosis was admitted to the hospital with skin ulceration and a superimposed polymicrobial infection that had failed outpatient management. The patient's outpatient regimen included doxycycline, ciprofloxacin and moderate-dose prednisone therapy for a coinfection with Pseudomonas aeruginosa and methicillin-susceptible Staphylococcus aureus The patient presented after a syncopal episode initially thought to be due to severe dehydration. Owing to concern for cardiac sarcoidosis as well as worsening skin lesions, he was admitted to the hospital for cardiac monitoring and intravenous antibiotics. On admission, we broadened antibiotic coverage and initiated high-dose steroids at 1 mg/kg/day of prednisone. He was discharged on intravenous antibiotics and a slow steroid taper 3 days later. At the patient's 1-month and 5-month follow-up clinic visits, he demonstrated remarkable improvement of his scalp and facial wounds.", "affiliations": "Henry Ford Hospital, Detroit, Michigan, USA gfram1@hfhs.org.;Henry Ford Hospital, Detroit, Michigan, USA.;Henry Ford Hospital, Detroit, Michigan, USA.;Henry Ford Hospital, Detroit, Michigan, USA.", "authors": "Fram|Georgi|G|;Kohli|Smita|S|;Jiang|Angela|A|;Kaatz|Scott|S|", "chemical_list": "D000900:Anti-Bacterial Agents; D013256:Steroids", "country": "England", "delete": false, "doi": "10.1136/bcr-2019-231769", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "12(11)", "journal": "BMJ case reports", "keywords": "dermatology; medical management; skin", "medline_ta": "BMJ Case Rep", "mesh_terms": "D061605:Administration, Intravenous; D000368:Aged; D000900:Anti-Bacterial Agents; D060085:Coinfection; D003937:Diagnosis, Differential; D005145:Face; D006801:Humans; D008297:Male; D011550:Pseudomonas aeruginosa; D012507:Sarcoidosis; D012535:Scalp; D012883:Skin Ulcer; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus; D013256:Steroids; D013575:Syncope; D016896:Treatment Outcome", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "31748362", "pubdate": "2019-11-19", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "3819097;7212741;17560307;17560311;3026601;7069023;11312418;29232421;17190623;22116891;25265873;23742283;9041836;18032765", "title": "Sarcoidosis presenting as facial and scalp ulceration with secondary bacterial infection of the skin.", "title_normalized": "sarcoidosis presenting as facial and scalp ulceration with secondary bacterial infection of the skin" }
[ { "companynumb": "US-BAYER-2019-219395", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": null, ...
{ "abstract": "Development of autoimmune hepatitis (AIH) has been sporadically reported in patients with multiple sclerosis (MS) either concurrently or after treatment with immunomodulatory drugs, including interferon-beta (IFN-β) and steroids.\n\n\n\nTo report a large cohort of 14 patients with MS diagnosed with AIH during an assessment of deranged liver function tests (LFTs).\n\n\n\nFrom 2005 to 2017, we prospectively identified 14 (13 women) patients with MS who suffered also from AIH after investigation in our department for the presence of deranged LFTs. Age at diagnosis of MS was 36.7 ± 9.3 years while at diagnosis of AIH 43.1 ± 12 years.\n\n\n\nAIH diagnosis was based on elevation of aminotransferases in all patients [alanine aminotransferase: 520 IU/L (range: 115-1219)], elevation of IgG in 6, compatible autoantibody profile in all, including 5 patients with liver-specific autoantibodies and typical or compatible histological features in 11 patients. 5 patients were under treatment with IFN-β plus methylprednisolone pulses, 3 with IFN-β plus oral steroids, 1 with IFN-β, 4 with methylprednisolone pulses whereas 1 patient was free of treatment. The median time from IFN-β initiation to the development of hepatitis was 12 months (range:1-120). Treatment for AIH was initiated in 13 patients with prednisolone (0.5-1 mg/kg/day) plus mycophenolate myfetil (2 g/day) in 10 and prednisolone plus azathioprine in 3 with complete and partial response in 11 and 2 patients, respectively.\n\n\n\nThe differential diagnosis of hepatitis in MS patients should include AIH and in particular when immunomodulatory treatment has been preceded. Autoantibody testing and liver histology play fundamental role in establishing a prompt diagnosis of AIH in these patients. Treatment of AIH in patients with MS seems safe and efficient as complete or partial response was recorded in all of our patients.", "affiliations": "Institute of Internal Medicine and Hepatology, Larissa, Greece; Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece.;Institute of Internal Medicine and Hepatology, Larissa, Greece.;Institute of Internal Medicine and Hepatology, Larissa, Greece; Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece.;Department of Neurology, School of Medicine, University of Thessaly, Larissa, Greece.;Department of Pathology, School of Medicine, University of Thessaly, Larissa, Greece.;Department of Neurology, School of Medicine, University of Thessaly, Larissa, Greece.;Institute of Internal Medicine and Hepatology, Larissa, Greece; Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece. Electronic address: georgedalekos@gmail.com.", "authors": "Rigopoulou|Eirini I|EI|;Gyftaki|Sofia|S|;Arvaniti|Pinelopi|P|;Tsimourtou|Vana|V|;Koukoulis|George K|GK|;Hadjigeorgiou|Georgios|G|;Dalekos|George N|GN|", "chemical_list": "D001323:Autoantibodies; D005938:Glucocorticoids; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D016899:Interferon-beta; D011239:Prednisolone; D009173:Mycophenolic Acid; D001379:Azathioprine; D008775:Methylprednisolone", "country": "France", "delete": false, "doi": "10.1016/j.clinre.2018.12.002", "fulltext": null, "fulltext_license": null, "issn_linking": "2210-7401", "issue": "43(3)", "journal": "Clinics and research in hepatology and gastroenterology", "keywords": "Autoimmune hepatitis; IFN-β; Immunomodulatory treatment; Multiple sclerosis", "medline_ta": "Clin Res Hepatol Gastroenterol", "mesh_terms": "D000328:Adult; D001323:Autoantibodies; D001379:Azathioprine; D005260:Female; D005938:Glucocorticoids; D019693:Hepatitis, Autoimmune; D006801:Humans; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D016899:Interferon-beta; D008111:Liver Function Tests; D008297:Male; D008775:Methylprednisolone; D009103:Multiple Sclerosis; D009173:Mycophenolic Acid; D011239:Prednisolone", "nlm_unique_id": "101553659", "other_id": null, "pages": "e25-e32", "pmc": null, "pmid": "30594597", "pubdate": "2019-06", "publication_types": "D016428:Journal Article", "references": null, "title": "Autoimmune hepatitis in patients with multiple sclerosis: The role of immunomodulatory treatment.", "title_normalized": "autoimmune hepatitis in patients with multiple sclerosis the role of immunomodulatory treatment" }
[ { "companynumb": "GR-PFIZER INC-2019043294", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INTERFERON BETA-1A" }, "drugadditional": "3", ...
{ "abstract": "OBJECTIVE\nTo report the case of a patient receiving itraconazole for the treatment of histoplasmosis and his subsequent reduction in pancreatic tumor size.\n\n\nMETHODS\nA 64-year-old male was diagnosed with Stage III locally advanced unresectable pancreatic adenocarcinoma. The patient was administered radiation plus chemotherapy, which included cisplatin and capecitabine. Upon restaging, the patient's tumor was again determined to be unresectable; therefore, palliative chemotherapy treatments were initiated, which included gemcitabine and erlotinib. After two gemcitabine cycles, he was admitted to the hospital because of loss of motor function due to spinal cord hemisection. After the surgery, the patient became neutropenic because of previous chemotherapy cycle and developed disseminated histoplasmosis. After he received his nine-month course of itraconazole, the pancreatic cancer was readdressed and he was then deemed to be resectable and had a Whipple procedure. Over the next several years, he showed no evidence of pancreatic metastases or relapse.\n\n\nCONCLUSIONS\nItraconazole has been shown to have many mechanisms by which it could potentially suppress tumor cell growth, which includes inhibition of the Hedgehog pathway, vascular endothelial growth factor receptor-2, and P-glycoprotein efflux pump. This azole antifungal has been studied in small patient populations with various types of cancers. Studies of basal cell carcinoma, nonsmall cell lung cancer, ovarian cancer, and malignant pleural mesothelioma have shown favorable results suggesting that more study of itraconazole is warranted to decide its clinical utility.\n\n\nCONCLUSIONS\nThere would need to be much more research performed to determine if this agent had a role as a chemotherapy agent; however, health care professionals should be aware of itraconazole's potential antineoplastic mechanisms.", "affiliations": "College of Pharmacy, University of Tennessee, Signal Mountain, TN, USA nny323@uthsc.edu.;College of Pharmacy, University of Tennessee, Knoxville, TN, USA.;East Tennessee Medical Group, Alcoa, TN, USA.", "authors": "Lockhart|Nicholas R|NR|;Waddell|James Aubrey|JA|;Schrock|Nathan Eric|NE|", "chemical_list": "D000935:Antifungal Agents; D000970:Antineoplastic Agents; D017964:Itraconazole", "country": "England", "delete": false, "doi": "10.1177/1078155215572931", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1552", "issue": "22(3)", "journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners", "keywords": "Cancer; antifungal; histoplasmosis; infection; itraconazole; oncology", "medline_ta": "J Oncol Pharm Pract", "mesh_terms": "D000230:Adenocarcinoma; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D006801:Humans; D017964:Itraconazole; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms", "nlm_unique_id": "9511372", "other_id": null, "pages": "528-32", "pmc": null, "pmid": "25670260", "pubdate": "2016-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Itraconazole therapy in a pancreatic adenocarcinoma patient: A case report.", "title_normalized": "itraconazole therapy in a pancreatic adenocarcinoma patient a case report" }
[ { "companynumb": "US-ACTAVIS-2016-09910", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, ...
{ "abstract": "BACKGROUND\nOlanzapine 10 mg is recommended for breakthrough chemotherapy-induced nausea and vomiting. However, there is a possibility that 5 mg can be expected to be sufficiently effective. We aimed to investigate the efficacy and safety of olanzapine 5 mg for breakthrough chemotherapy-induced nausea and vomiting.\n\n\nMETHODS\nA single-arm prospective trial of olanzapine 5 mg every 24 h for 72 h was conducted to treat breakthrough chemotherapy-induced nausea and vomiting in patients receiving carboplatinbased chemotherapy. The primary endpoint was total control (i.e., no emesis, no nausea, and no rescue medications) over 72 h. The secondary endpoints were early efficacy using the nausea scores at 30, 60, and 120 min after taking olanzapine from baseline and adverse events.\n\n\nRESULTS\nAmong 84 potentially eligible patients, 19 patients who took olanzapine for breakthrough chemotherapy-induced nausea and vomiting were examined. The total control rate was 32% (95% CI: 13- 57%), 65% (95% CI: 38-89%), 65% (95% CI: 38-89%), and 29% (95% CI: 10-56%) during 2-24, 24-48, 48-72 h, and overall period, respectively. The nausea scale significantly reduced after 30 min (P=0.0078), and the scale had been reduced by 67% from the baseline after 60 min. The adverse event of somnolence of any grade was observed in 13 (68%) patients, 6 (32%) of whom had grade 2 and 1 (5%) grade 3 somnolence.\n\n\nCONCLUSIONS\nOlanzapine 5 mg did not show the expected effect on the complete disappearance of breakthrough chemotherapy-induced nausea and vomiting within 24 h.", "affiliations": "Department of Pharmacy, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan. m.akimitsu@aichi-cc.jp.;Department of Pharmacy, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Aichi 466-8650, Japan.;Department of Pharmacy, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi 460-0001, Japan.;Department of Pharmacy, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.;Department of Pharmacy, Chubu Rosai Hospital, Minato-ku Nagoya, Aichi 455-8530, Japan.;Department of Pharmacy, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Aichi 453- 8511, Japan.;Department of Pharmacy, Komaki City Hospital, Komaki, Aichi 485-8520, Japan.;Department of Clinical Pharmacy, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.;Department of Pharmacy, Nagoya City West Medical Center, Nagoya, Aichi 462- 8508, Japan.;Department of Pharmacy, Nagoya City University Hospital, Nagoya, Aichi 467-8602, Japan.;Department of Pharmacy, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan.;Department of Pharmacy, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Aichi 466-8650, Japan.;Department of Pharmacy, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi 460-0001, Japan.;Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan.;Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan.", "authors": "Maeda|Akimitsu|A|;Yoshida|Hiroki|H|;Inoue|Hirotaka|H|;Ejiri|Masayuki|M|;Yamaguchi|Satoe|S|;Kushihara|Hideyuki|H|;Yamamoto|Yoshihiro|Y|;Ando|Yosuke|Y|;Sato|Yumiko|Y|;Tashiro|Yuusuke|Y|;Hasegawa|Ayako|A|;Takahara|Yuko|Y|;Mizutani|Mika|M|;Oze|Isao|I|;Shimizu|Junichi|J|", "chemical_list": "D000932:Antiemetics; D000970:Antineoplastic Agents; D001569:Benzodiazepines; D016190:Carboplatin; D000077152:Olanzapine", "country": "China", "delete": false, "doi": "10.21037/apm-20-1784", "fulltext": null, "fulltext_license": null, "issn_linking": "2224-5820", "issue": "10(3)", "journal": "Annals of palliative medicine", "keywords": "Breakthrough; carboplatin; nausea; olanzapine; vomiting", "medline_ta": "Ann Palliat Med", "mesh_terms": "D000932:Antiemetics; D000970:Antineoplastic Agents; D001569:Benzodiazepines; D016190:Carboplatin; D006801:Humans; D009325:Nausea; D000077152:Olanzapine; D011446:Prospective Studies; D014839:Vomiting", "nlm_unique_id": "101585484", "other_id": null, "pages": "2699-2708", "pmc": null, "pmid": "33615803", "pubdate": "2021-03", "publication_types": "D016428:Journal Article", "references": null, "title": "Effects of 5-mg dose of olanzapine for breakthrough nausea and vomiting in patients receiving carboplatin-based chemotherapy: a prospective trial.", "title_normalized": "effects of 5 mg dose of olanzapine for breakthrough nausea and vomiting in patients receiving carboplatin based chemotherapy a prospective trial" }
[ { "companynumb": "JP-MYLANLABS-2021M1040573", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OLANZAPINE" }, "drugadditional": "3", ...
{ "abstract": "Strongyloidiosis is usually an asymptomatic chronic nematodal disease. The term hyperinfection is used to denote autoinfection, a phenomenon in which the number of worms increases enormously. Development or exacerbation of gastrointestinal and pulmonary symptoms is seen, (A) and the detection of increased numbers of larvae in stool and or sputum is the hallmark. It is known to occur with a change in immune status of the host; this can occur due to immunosuppressants. Cytomegalovirus (CMV) is also known to suppress host immunity. Due to the nonspecific presentation, the diagnosis is frequently missed, and the outcome remains poor with 15-87% mortality despite therapy. We report here a case of Strongyloides stercoralis hyperinfection following immunosuppressive therapy for autoimmune hepatitis and concomitant CMV infection with purpura fulminance and frank sepsis, with fatal outcome.", "affiliations": "Department of Microbiology, Institute of Liver and Biliary Sciences, New Delhi, India.;Department of Microbiology, Institute of Liver and Biliary Sciences, New Delhi, India.;Department of Gastroenterology, Institute of Liver and Biliary Sciences, New Delhi, India.", "authors": "Rathor|Neha|N|;Khillan|Vikas|V|;Sarin|S K|SK|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/0972-5229.173694", "fulltext": "\n==== Front\nIndian J Crit Care MedIndian J Crit Care MedIJCCMIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine0972-52291998-359XMedknow Publications & Media Pvt Ltd India IJCCM-20-5210.4103/0972-5229.173694Case ReportStrongyloides stercoralis hyperinfection in patient with autoimmune hepatitis and purpura fulminans Rathor Neha Khillan Vikas Sarin S. K. 1From: Department of Microbiology, Institute of Liver and Biliary Sciences, New Delhi, India1 Department of Gastroenterology, Institute of Liver and Biliary Sciences, New Delhi, IndiaCorrespondence: Dr. Neha Rathor, Department of Microbiology, Institute of Liver and Biliary Sciences, New Delhi, India. E-mail: neharathor.s@gmail.com1 2016 20 1 52 54 Copyright: © 2016 Indian Journal of Critical Care Medicine2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Strongyloidiosis is usually an asymptomatic chronic nematodal disease. The term hyperinfection is used to denote autoinfection, a phenomenon in which the number of worms increases enormously. Development or exacerbation of gastrointestinal and pulmonary symptoms is seen, (A) and the detection of increased numbers of larvae in stool and or sputum is the hallmark. It is known to occur with a change in immune status of the host; this can occur due to immunosuppressants. Cytomegalovirus (CMV) is also known to suppress host immunity. Due to the nonspecific presentation, the diagnosis is frequently missed, and the outcome remains poor with 15–87% mortality despite therapy. We report here a case of Strongyloides stercoralis hyperinfection following immunosuppressive therapy for autoimmune hepatitis and concomitant CMV infection with purpura fulminance and frank sepsis, with fatal outcome.\n\nAutoimmune hepatitispurpura fulminancestrongyloides\n==== Body\nIntroduction\nStrongyloides hyperinfection is a well-known entity; however this is the first case report of a North Indian patient with autoimmune hepatitis and purpura fulminance. In India, the epicenter lies in southern states, with a paucity of cases reports from northern states.[1] To our knowledge, this is the first case report of strongyloides hyperinfection with concurrent cytomegalovirus (CMV) infection and gram-negative sepsis from North India.\n\nCase Report\nA 59-year-old Indian female presented to our hospital, with c/o abdominal distension for last 2 months, generalized weakness, productive cough, and purpuric rashes over both lower limbs and fever for 2 days. The patient was a known hypertensive and hypothyroid on medications and past history of cholecystectomy 17 years back.\n\nShe was recently diagnosed as a case of chronic liver disease due to autoimmune hepatitis 3 months back was being treated for the same. She was started on wysolone 60 mg for last 3 months and azoran 100 mg for past 1 month.\n\nOn general examination, she was conscious, oriented, and afebrile. Physical examination revealed pallor, pedal edema, palpable purpuric spots on both the lower limbs. Her blood pressure was low (80/50 mm of Hg), progesterone receptor - 118/min, and risk ratio - 20/min. Chest examination revealed bilateral normal air entry with basal crepitations. Abdomen was distended and tender with sluggish bowel sounds.\n\nInitial laboratory investigation confirmed anemia (hemoglobin - 9.3 g/dl), total lung capacity 8.9 × 109/L with neutrophilia, (neutrophil - 83%, lymphocyte - 11%, and eosinophil - 1%), and platelets 139 × 109/L.\n\nHer kidney function were deranged - urea 120 mg/dl, creatinine 2.08 mg/dl, sodium 133 mmol/L, and potassium 4.39 mmol/L. Liver function tests were also deranged, (total bilirubin - 1.4 mg/dl, aspartate aminotransferase - 98 IU/L, alanine aminotransferase - 82 IU/L, serum alkaline phosphatase - 519 IU/L, gamma glutamyl transferase - 800 IU/L, albumin - 2.0 g/dl, and globulin - 3.3 g/dl).\n\nArterial blood gas revealed respiratory acidosis and lactate 3.2 (pH - 7.30, HCO3 - 20 mm Hg, PCO2 - 46 mm Hg, and PO2 -87 mm Hg.) C reactive protein 144 mg/L, because of the worsening respiratory status and altered sensorium she was intubated and put on a mechanical ventilator. She also had paralytic ileus (high RT aspirate 600 ml/24 h).\n\nChest X-ray showed bilateral fluffy alveolar opacities with infiltrates, left side consolidation and right homogenous opacities with ground glass appearance. Baseline ECHO with 50%, no regional wall motion abnormality, inferior vena cava 20. Ultrasonography showed liver with irregular outlines and coarse echotexture, minimal interloop ascites, few dilated fluid filled small bowel loops were seen with sluggish peristaltic movement.\n\nCytologic examination of the bronchial wash and lavage comprised benign respiratory epithelial cells, few polymorphs and histiocytes over hemorrhagic background. A wet mount was seen which revealed motile larvae resembling larvae of Strongyloides stercoralis [Figures 1–4].\n\nFigure 1 Coiled up strongyloides larvae\n\nFigure 2 Double bulb esophagus\n\nFigure 3 Primordial genital primordium\n\nFigure 4 Embryonated egg\n\nInterestingly bronchoalveolar lavage culture grew Klebsiella pneumoniae. Other cultures were sterile. CMV DNA quant 1.81 × 106/ml.\n\nAbsolute eosinophil count was −55/cumm (reference range 40–440) Serum immunoglobulin E was 319 (reference range 100). Skin biopsy showed occasional thrombi in dermal vessels with extravasation of red blood cells; epidermis was largely unremarkable which is compatible with purpura fulminans. No larvae were seen.\n\n\nTreatment\nAntibiotics were added as per sensitivity reports. Ivermectin 12 mg once daily was added. A high ionotropic support was given to maintain mean arterial pressure of 65 mmHg.\n\nFurther course\nShe had a sudden onset of cardiac arrest and despite best possible effort. She could not be revived. Postmortem liver biopsy features were consistent with liver cirrhosis with features of sepsis. Muscle biopsy showed transversely and longitudinally cut muscle fibers with a focal group of atrophic muscles.\n\nDiscussion\nFatal S. stercoralis hyperinfection with immune suppression was first reported in 1966 by Cruz et al.[2] Immunosuppression may occur due to steroids and other immunosuppressants. Some viruses such as CMV, also lower immunity. Female worms produce more eggs in the presence of exogenous steroids; this further facilitates worm growth and development.[34] In our patient, all the above factors got together to deliver the fatal blow.\n\nHyperinfection may develop as early as 20 days after the onset of corticosteroid therapy and as late as several years in immunocompetent persons.[56] Symptoms may include dyspnea, cough, pleuritic chest pain, hemoptysis, infiltrates of varying character on chest imaging, and mild blood eosinophilia. Concomitant use of corticosteroids or bacterial coinfection, as seen in our patient, suppresses the eosinophilia. Respiratory failure may occur in severe cases.[7] Purpura fulminance has been described in both sepsis and strongyloidiasis. In Strongyloidiasis, it is periumbilical and thumbprinting in appearance. In such cases strongyloidiasis larvae is seen in the skin biopsy, this was absent in our case. Therefore, Purpura in our case could be due to underlying sepsis. Strongyloid larvae carry gastrointestinal flora, while it migrates, causing sepsis.[89]\n\nParalytic ileus, caused by obstruction resulting from heavy parasite burdens may be a subtle pointer.[10]\n\nIronically, an inverse relationship between autoimmune liver diseases and S. stercoralis infection, has been proposed, a possible link between deworming and the emergence of immunological disease has been described, with some authors suggesting helminths, safe and effective in the treatment of inflammatory bowel disease: A possible example of Th2 conditioning of the mucosal immune response.[1112]\n\nHowever, a high mortality despite therapy warrants, not only screening and monitoring but, a state of constant, high alert as concurrent sepsis may further obscure the presentation and waylays the clinician.\n\nAs stool studies are often negative, aspiration of duodenojejunal fluid and enzyme-linked immunosorbent assay serologic testing may be used as adjunct diagnostic tools.[13] Patients who have positive serologic tests and an exposure history, regardless of a negative stool results, should receive a course of treatment (ivermectin, 200 μg/kg/day for 2 days, and repeat after 2 weeks).[14]\n\nSubsequent decisions about screening and prophylactic ivermectin must be individualized, but at the very least, a low threshold for performing stool exams should be maintained. Persons residing in strongyloidiasis-endemic areas or in high-risk occupations need to be educated about modes of parasite transmission to avoid recurrent infection.\n\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Singh S Sharma MP Strongyloid stercoralis in Northern India Indian J Microbiol 1992 10 197 203 \n2 Cruz T Reboucas G Rocha H Fatal strongyloidiasis in patients receiving corticosteroids N Engl J Med 1966 275 1093 6 5925209 \n3 Spencer JV Lockridge KM Barry PA Lin G Tsang M Penfold ME Potent immunosuppressive activities of cytomegalovirus-encoded interleukin-10 J Virol 2002 76 1285 92 11773404 \n4 Hunter CJ Petrosyan M Asch M Dissemination of Strongyloides stercoralis in a patient with systemic lupus erythematosus after initiation of albendazole: A case report J Med Case Rep 2008 2 156 18479527 \n5 Debussche X Toublanc M Camillieri JP Assan R Overwhelming strongyloidiasis in a diabetic patient following adrenocorticotropin treatment and keto-acidosis Diabetes Metab 1988 14 294 8 \n6 Rivera E Maldonado N Vélez-García E Grillo AJ Malaret G Hyperinfection syndrome with Strongyloides stercoralis Ann Intern Med 1970 72 199 204 4904675 \n7 Mani RK Sardana R Chawla R Bansal A Bansal MS Kansal S Respiratory failure, coma and cutaneous lesions due to disseminated strongyloidiosis Indian J Crit Care Med 2003 7 132 6 \n8 Bank DE Grossman ME Kohn SR Rabinowitz AD The thumbprint sign: Rapid diagnosis of disseminated strongyloidiasis J Am Acad Dermatol 1990 23 2 Pt 1 324 6 2212133 \n9 Link K Orenstein R Bacterial complications of strongyloidiasis: Streptococcus bovis meningitis South Med J 1999 92 728 31 10414486 \n10 Mori S Konishi T Matsuoka K Deguchi M Ohta M Mizuno O Strongyloidiasis associated with nephrotic syndrome Intern Med 1998 37 606 10 9711888 \n11 Aoyama H Hirata T Sakugawa H Watanabe T Miyagi S Maeshiro T An inverse relationship between autoimmune liver diseases and Strongyloides stercoralis infection Am J Trop Med Hyg 2007 76 972 6 17488925 \n12 Garg SK Croft AM Bager P Helminth therapy (worms) for induction of remission in inflammatory bowel disease Cochrane Database Syst Rev 2014 1 CD009400 24442917 \n13 Loutfy MR Wilson M Keystone JS Kain KC Serology and eosinophil count in the diagnosis and management of strongyloidiasis in a non-endemic area Am J Trop Med Hyg 2002 66 749 52 12224585 \n14 Zaha O Hirata T Kinjo F Saito A Fukuhara H Efficacy of ivermectin for chronic strongyloidiasis: Two single doses given 2 weeks apart J Infect Chemother 2002 8 94 8 11957127\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0972-5229", "issue": "20(1)", "journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine", "keywords": "Autoimmune hepatitis; purpura fulminance; strongyloides", "medline_ta": "Indian J Crit Care Med", "mesh_terms": null, "nlm_unique_id": "101208863", "other_id": null, "pages": "52-4", "pmc": null, "pmid": "26955218", "pubdate": "2016-01", "publication_types": "D002363:Case Reports", "references": "11773404;9711888;24442917;2212133;18479527;17488925;12224585;10414486;5925209;4904675;2842205;11957127", "title": "Strongyloides stercoralis hyperinfection in patient with autoimmune hepatitis and purpura fulminans.", "title_normalized": "strongyloides stercoralis hyperinfection in patient with autoimmune hepatitis and purpura fulminans" }
[ { "companynumb": "IN-CONCORDIA PHARMACEUTICALS INC.-E2B_00008328", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugad...
{ "abstract": "To describe patient characteristics, audiometric outcomes, and magnetic resonance imaging (MRI) signal patterns in patients with suspected labyrinthine hemorrhage.\n\n\n\nRetrospective review.\n\n\n\nTertiary medical center.\n\n\n\nRadiology database was queried for terms related to labyrinth hemorrhage or labyrinthitis and then selected for patients in which labyrinthine hemorrhage was suspected in the report. Eleven patients were identified and all treated at our institution. Blinded assessment of temporal bone MRI by 2 experienced neuroradiologists was performed and interrater reliability assessed. Patient demographics, medical comorbidities, and audiometric outcomes are described.\n\n\n\nOf the 11 patients identified, the median patient age was 60 years; 7 were female and 4 male. Ten of 11 patients presented with unilateral sudden sensorineural hearing loss (SNHL), and 8 of 11 had associated vertigo. One patient experienced vertigo without hearing loss. Of those presenting with sudden SNHL, 82% were left with nonserviceable American Academy of Otolaryngology-Head and Neck Surgery class D hearing. Interrater reliability for detecting T1 signal abnormalities was moderate but very good for detecting fluid attenuation inversion recovery (FLAIR) signal abnormalities. Most patients had existing hypertension. Average follow-up was 13.3 months.\n\n\n\nWe present the largest cohort of patients with radiographic diagnosis of labyrinthine hemorrhage using T1 and FLAIR signal abnormalities on MRI. Most patients presented with a profound unilateral sudden SNHL that did not recover. Our findings are consistent with prior reports that abnormal FLAIR signal on MRI is a reliable marker for detecting inner ear injury and can potentially be used as a marker for poor prognosis.", "affiliations": "1 Department of Otolaryngology-Head & Neck Surgery, Emory University, Atlanta, Georgia, USA.;1 Department of Otolaryngology-Head & Neck Surgery, Emory University, Atlanta, Georgia, USA.;2 Department of Radiology, Emory University, Atlanta, Georgia, USA.", "authors": "Vivas|Esther X|EX|;Panella|Nicholas J|NJ|;Baugnon|Kristen L|KL|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/0194599818785900", "fulltext": null, "fulltext_license": null, "issn_linking": "0194-5998", "issue": "159(5)", "journal": "Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery", "keywords": "MRI; hemorrhagic labyrinthitis; labyrinthine hemorrhage; sudden sensorineural hearing loss", "medline_ta": "Otolaryngol Head Neck Surg", "mesh_terms": "D017677:Age Distribution; D000368:Aged; D001299:Audiometry; D015331:Cohort Studies; D016208:Databases, Factual; D005260:Female; D006319:Hearing Loss, Sensorineural; D003639:Hearing Loss, Sudden; D006470:Hemorrhage; D006801:Humans; D021621:Imaging, Three-Dimensional; D015994:Incidence; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D015588:Observer Variation; D011379:Prognosis; D012189:Retrospective Studies; D018570:Risk Assessment; D017678:Sex Distribution; D062606:Tertiary Care Centers", "nlm_unique_id": "8508176", "other_id": null, "pages": "908-913", "pmc": null, "pmid": "29966483", "pubdate": "2018-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Spontaneous Labyrinthine Hemorrhage: A Case Series.", "title_normalized": "spontaneous labyrinthine hemorrhage a case series" }
[ { "companynumb": "US-CIPLA LTD.-2019US01414", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", ...
{ "abstract": "We present the case report of an 80-year-old woman with chronic kidney disease stage G5 admitted to the hospital with fluid overload and hyperkalaemia. Sodium polystyrene sulfonate (SPS, Kayexalate) in sorbitol suspension was given orally to treat her hyperkalaemia, which precipitated an episode of SPS in sorbitol-induced ischaemic colitis with the subsequent complication of vancomycin-resistant Enterococcus (VRE) bacteraemia. SPS (Kayexalate) in sorbitol suspension has been implicated in the development of intestinal necrosis. Sorbitol, which is added as a cathartic agent to decrease the chance of faecal impaction, may be primarily responsible through several proposed mechanisms. The gold standard of diagnosis is the presence of SPS crystals in the colon biopsy. On a MEDLINE search, no previous reports of a VRE bacteraemia as a complication of biopsy-confirmed SPS in sorbitol ischaemic colitis were found. To the best of our knowledge, ours would be the first such case ever reported.", "affiliations": "Department of Internal Medicine, SBH Health System, Bronx, New York, USA.;Department of Internal Medicine, SBH Health System, Bronx, New York, USA.;Department of Radiology, SBH Health System, Bronx, New York, USA.;Department of Internal Medicine, SBH Health System, Bronx, New York, USA.", "authors": "Cerrud-Rodriguez|Roberto Christian|RC|;Alcaraz-Alvarez|Diego|D|;Chiong|Brian Bobby|BB|;Ahmed|Abdurhman|A|", "chemical_list": "D011137:Polystyrenes; D013012:Sorbitol; C003321:polystyrene sulfonic acid", "country": "England", "delete": false, "doi": "10.1136/bcr-2017-221790", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2017()", "journal": "BMJ case reports", "keywords": "contraindications and precautions; drugs: gastrointestinal system; endoscopy; gi bleeding; infectious diseases", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000369:Aged, 80 and over; D016470:Bacteremia; D017091:Colitis, Ischemic; D005260:Female; D006801:Humans; D007008:Hypokalemia; D011137:Polystyrenes; D051436:Renal Insufficiency, Chronic; D013012:Sorbitol; D014057:Tomography, X-Ray Computed; D065507:Vancomycin-Resistant Enterococci", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "29127125", "pubdate": "2017-11-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "11418881;7249508;19751641;2404568;27573805;19373153;20167700;26244026;8990142;21463839", "title": "Vancomycin-resistant Enterococcus faecium bacteraemia as a complication of Kayexalate (sodium polystyrene sulfonate, SPS) in sorbitol-induced ischaemic colitis.", "title_normalized": "vancomycin resistant enterococcus faecium bacteraemia as a complication of kayexalate sodium polystyrene sulfonate sps in sorbitol induced ischaemic colitis" }
[ { "companynumb": "US-VIVIMED-2018SP004058", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ALBUTEROL" }, "drugadditional": null, ...
{ "abstract": "We describe four patients with chronic renal failure (CRF) who developed significant neurotoxicity after receiving short-term ciprofloxacin. Three of them had developed encephalopathy with myoclonic jerks and one patient had delirium. All patients had advanced chronic renal failure (mean estimated creatinine clearance 16 +/- 6 ml/minute), although they were not yet on renal replacement therapy. The mean received dose of ciprofloxacin was 2150 +/- 1300 mg and symptoms started to appear after the first 24 hours of drug intake. Investigations ruled out other possible causes of these neurological presentations, and withdrawal of ciprofloxacin was followed by complete resolution, after a mean of 8.5 +/- 4 days. Advanced renal failure in all patients and underlying neurologic diseases in two patients may have predisposed them to the neurotoxicity. The report of these cases should help to draw the attention of clinicians to the potential occurrence of these adverse effects in patients with CRF.", "affiliations": "Renal Unit, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia.", "authors": "Al-Ghamdi|Saeed Mg|SM|", "chemical_list": null, "country": "Saudi Arabia", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1319-2442", "issue": "13(2)", "journal": "Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia", "keywords": null, "medline_ta": "Saudi J Kidney Dis Transpl", "mesh_terms": null, "nlm_unique_id": "9436968", "other_id": null, "pages": "163-70", "pmc": null, "pmid": "17660656", "pubdate": "2002", "publication_types": "D016428:Journal Article", "references": null, "title": "Reversible Encephalopathy and Delirium in Patients with Chronic Renal Failure who had Received Ciprofloxacin.", "title_normalized": "reversible encephalopathy and delirium in patients with chronic renal failure who had received ciprofloxacin" }
[ { "companynumb": "SA-RANBAXY-2014R1-86916", "fulfillexpeditecriteria": "1", "occurcountry": "SA", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, ...
{ "abstract": "OBJECTIVE\nIntravitreal melphalan is emerging as an effective treatment for refractory vitreous seeds in retinoblastoma, but there is limited understanding regarding its toxicity. This study evaluates the retinal and systemic toxicity of intravitreal melphalan in retinoblastoma patients, with preclinical validation in a rabbit model.\n\n\nMETHODS\nClinical and preclinical, prospective, cohort study.\n\n\nMETHODS\nIn the clinical study, 16 patient eyes received 107 intravitreal injections of 30 μg melphalan given weekly, a median of 6.5 times (range, 5-8). In the animal study, 12 New Zealand/Dutch Belt pigmented rabbits were given 3 weekly injections of 15 μg of intravitreal melphalan or vehicle to the right eye.\n\n\nMETHODS\nElectroretinogram (ERG) responses were recorded in both humans and rabbits. For the clinical study, ERG responses were recorded at baseline, immediately before each injection, and at each follow-up visit; 82 of these studies were deemed evaluable. Median follow-up time was 5.2 months (range, 1-11). Complete blood counts (CBCs) were obtained on the day of injection at 46 patient visits. In the animal study, ERG responses were obtained along with fluorescein angiography, CBCs, and melphalan plasma concentration. After humane killing, the histopathology of the eyes was evaluated.\n\n\nMETHODS\nFor the clinical study, we measured peak-to-peak ERG amplitudes in response to 30-Hz photopic flicker stimulation with comparisons between ERG studies before and after intravitreal melphalan. For the animal study, we collected ERG parameters before and after intravitreal melphalan injections with histopathologic findings.\n\n\nRESULTS\nBy linear regression analysis, over the course of weekly intravitreal injections in retinoblastoma patients, for every additional injection, the ERG amplitude decreased by approximately 5.8 μV. The ERG remained stable once the treatment course was completed. In retinoblastoma patients, there were no grade 3 or 4 hematologic events. One week after the second injection in rabbits, the a- and b-wave amplitude declined significantly in the melphalan treated eyes compared with vehicle-treated eyes (P<0.05). Histopathology revealed severely atrophic retina.\n\n\nCONCLUSIONS\nWeekly injections of 30 μg of melphalan can result in a decreased ERG response, which is indicative of retinal toxicity. These findings are confirmed at an equivalent dose in rabbit eyes by ERG measurements and by histopathologic evidence of severe retinal damage. Systemic toxicity with intravitreal melphalan at these doses in humans or rabbits was not detected.", "affiliations": "Ophthalmic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York. Electronic address: francij1@mskcc.org.;Unidad de Farmacocinética Clínica, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina; CONICET: National Scientific and Technical Research Council, Buenos Aries, Argentina.;Unidad de Farmacocinética Clínica, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina.;Laboratorio de Farmacologia, CIVETAN-CONICET, Facultad de Veterinaria, Universidad Nacional del Centro de Buenos Aires, Tandil, Argentina.;Laboratorio de Investigaciones Oculares, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.;Fundación Oftalmológica Argentina Jorge Malbrán, Buenos Aires, Argentina.;Ophthalmic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York.;Ophthalmology, Mount Sinai School of Medicine, New York, New York.;Laboratorio de Investigaciones Oculares, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.;Servicio de Hematología-Oncología, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina.;Ophthalmic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York.", "authors": "Francis|Jasmine H|JH|;Schaiquevich|Paula|P|;Buitrago|Emiliano|E|;Del Sole|María José|MJ|;Zapata|Gustavo|G|;Croxatto|J Oscar|JO|;Marr|Brian P|BP|;Brodie|Scott E|SE|;Berra|Alejandro|A|;Chantada|Guillermo L|GL|;Abramson|David H|DH|", "chemical_list": "D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0161-6420", "issue": "121(9)", "journal": "Ophthalmology", "keywords": null, "medline_ta": "Ophthalmology", "mesh_terms": "D000818:Animals; D018906:Antineoplastic Agents, Alkylating; D001772:Blood Cell Count; D002648:Child; D002675:Child, Preschool; D004353:Drug Evaluation, Preclinical; D004596:Electroretinography; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D007223:Infant; D058449:Intravitreal Injections; D008297:Male; D008558:Melphalan; D009366:Neoplasm Seeding; D011446:Prospective Studies; D011817:Rabbits; D012044:Regression Analysis; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D014822:Vitreous Body", "nlm_unique_id": "7802443", "other_id": null, "pages": "1810-7", "pmc": null, "pmid": "24819859", "pubdate": "2014-09", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Local and systemic toxicity of intravitreal melphalan for vitreous seeding in retinoblastoma: a preclinical and clinical study.", "title_normalized": "local and systemic toxicity of intravitreal melphalan for vitreous seeding in retinoblastoma a preclinical and clinical study" }
[ { "companynumb": "US-APOPHARMA USA, INC.-2017AP012348", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": nul...
{ "abstract": "Coronavirus disease (COVID-19)-associated coagulopathy is most often characterized by elevated D-dimer, interleukin-6, and plasma fibrinogen concentrations as well as hypercoagulability in thromboelastometry with increased clot firmness in the EXTEM, INTEM, and FIBTEM assays. Clinically, it manifests with a very high incidence of thrombosis, particularly in the pulmonary system, whereas bleeding complications are infrequent.\n\n\n\nHere, we describe two critically ill patients with COVID-19 admitted to our intensive care unit demonstrating different thromboelastometry and biomarker patterns. One patient presented with hypercoagulability and the other patient with hypocoagulability and fibrinolysis shutdown in thromboelastometry. The pathophysiology and the potential impact on treatment options are discussed.\n\n\n\nA combination of biomarkers and thromboelastometry results can be helpful in the future to decide which therapeutic strategy might be most appropriate for critically ill patients with COVID-19. This would be an important step to establish precision medicine in this high-risk patient population.", "affiliations": "Department of Anesthesia, Brighton and Sussex University Hospitals NHS Trust, Brighton, UK.;Department of Anesthesia, Brighton and Sussex University Hospitals NHS Trust, Brighton, UK.;Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, Essen, and Tem Innovations, Munich, Germany.", "authors": "Kong|Robert|R|;Hutchinson|Nevil|N|;Görlinger|Klaus|K|", "chemical_list": null, "country": "Korea (South)", "delete": false, "doi": "10.4097/kja.20327", "fulltext": "\n==== Front\nKorean J Anesthesiol\nKorean J Anesthesiol\nKJA\nKorean Journal of Anesthesiology\n2005-6419\n2005-7563\nKorean Society of Anesthesiologists\n\n32773727\n10.4097/kja.20327\nkja-20327\nCase Report\nHyper- and hypocoagulability in COVID-19 as assessed by thromboelastometry -two case reports-\nThromboelastometry in COVID-19\nhttp://orcid.org/0000-0002-8598-9991\nKong Robert 1\nhttp://orcid.org/0000-0002-6326-0067\nHutchinson Nevil 1\nhttp://orcid.org/0000-0002-7315-9528\nGörlinger Klaus 2\n1 Department of Anesthesia, Brighton and Sussex University Hospitals NHS Trust, Brighton, UK\n2 Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, Essen, and Tem Innovations, Munich, Germany\nCorresponding author: Klaus Görlinger, M.D. Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, and Tem Innovations, Martin-Kollar-Strasse 13-15, Munich 81829, GermanyTel: +49-172-6596-069Fax: +49-89-9981-8487 Email: kgoerlinger@ilww.com\n8 2021\n10 8 2020\n74 4 350354\n21 6 2020\n5 8 2020\n5 8 2020\nCopyright © The Korean Society of Anesthesiologists, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground\n\nCoronavirus disease (COVID-19)-associated coagulopathy is most often characterized by elevated D-dimer, interleukin-6, and plasma fibrinogen concentrations as well as hypercoagulability in thromboelastometry with increased clot firmness in the EXTEM, INTEM, and FIBTEM assays. Clinically, it manifests with a very high incidence of thrombosis, particularly in the pulmonary system, whereas bleeding complications are infrequent.\n\nCase\n\nHere, we describe two critically ill patients with COVID-19 admitted to our intensive care unit demonstrating different thromboelastometry and biomarker patterns. One patient presented with hypercoagulability and the other patient with hypocoagulability and fibrinolysis shutdown in thromboelastometry. The pathophysiology and the potential impact on treatment options are discussed.\n\nConclusions\n\nA combination of biomarkers and thromboelastometry results can be helpful in the future to decide which therapeutic strategy might be most appropriate for critically ill patients with COVID-19. This would be an important step to establish precision medicine in this high-risk patient population.\n\nAnticoagulants\nCOVID-19\nFibrinolysis\nHemostasis\nThrombelastography\nThrombosis\n==== Body\nCoronavirus disease (COVID-19)-associated coagulopathy is most often characterized by elevated D-dimer, interleukin-6 (IL-6), and plasma fibrinogen concentrations as well as hypercoagulability in thromboelastometry with increased clot firmness in the EXTEM, INTEM, and FIBTEM assays [1]. Clinically, it manifests with a very high incidence of thrombosis, particularly in the pulmonary system, whereas bleeding complications are infrequent [2]. In contrast, sepsis-associated coagulopathy due to bacterial infection is characterized by hypocoagulability in thromboelastometry which has been shown to be a good predictor of increased mortality [3]. Here, we describe two critically ill patients with COVID-19 admitted to our intensive care unit (ICU) at Brighton and Sussex University Hospitals NHS Trust presenting with different thromboelastometry phenotypes, clinical courses, and outcomes.\n\nCase Reports\n\nThe NHS Institutional Review Board waived the requirement of informed consent from each patient.\n\nCase 1\n\nA 48-year-old South Asian woman (Patient A) from Bangladesh (height 168 cm, weight 80 kg) was admitted to the medical ward for three days after which she was transferred to the ICU; she had cough and increasing dyspnea for three days before hospital admission. Comorbidities included hypertension, hypercholesterinemia, coronary artery disease, previous stroke (fully recovered), and type 2 diabetes. On admission, her laboratory results were as follows: hemoglobin (Hb): 143 g/L, white blood cells (WBC): 9.0 × 109/L, lymphocytes: 1.4 × 109/L, platelets: 261 × 109/L, international normalized ratio (INR): 1.1, D-dimer: 510 μg/L, fibrinogen plasma concentration: 8.4 g/L, and C-reactive protein (CRP): 52 mg/L. Her chest radiograph showed cardiomegaly and extensive bilateral peripherally predominant ground-glass opacities. Polymerase chain reaction (PCR) result was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and negative for influence/respiratory syncytial virus (RSV). Blood cultures were negative. The patient was treated with nasal oxygen therapy and antibiotics (ceftriaxone and doxycycline, according the hospital’s COVID-19 protocol). Antiviral therapy and dexamethasone were not administered. Later, CRP increased to 137 mg/L on the second day of hospitalization. The patient was transferred to the ICU on the third day because of increased respiratory rate and oxygen requirement. ROTEM performed 2 hours after ICU admission (Fig. 1A) revealed that Patient A was hypercoagulable with the EXTEM assay showing an increased clot firmness with an amplitude of clot firmness 5 minutes after coagulation time (CT) (A5) of 65 mm and a maximum clot firmness (MCF) of 78 mm, indicating hypercoagulability with a high risk of thrombosis [4]. FIBTEM also showed increased clot firmness (A5 41 mm and MCF 50 mm), indicating increased fibrinogen concentration and fibrin polymerization. Furthermore, the EXTEM lysis index 60 minutes after CT (LI60) was 97%, i.e., in the physiologic range (82–97.9%), whereas FIBTEM LI60 was 100% [5]. Treatment consisted of continuation of antibiotics, enoxaparin 40 mg twice a day in view of ROTEM results, and high flow nasal oxygen and intermittent face mask continuous positive airway pressure (CPAP) therapies. The patient did not need intermittent positive pressure ventilation (IPPV) or any vasoactive support. Laboratory results on the second day in the ICU were as follows: Hb: 131 g/L, WBC: 10.8 × 109/L, platelet count: 307 × 109/L, INR: 1.1, activated partial thromboplastin time (APTT) ratio: 1.3, D-dimer: 510 μg/L, and CRP: 196 mg/L. The patient recovered well and was transferred from the ICU to the medical ward after two days in the ICU with a CRP of 73 mg/L and was discharged three days later with a prescription of her usual medication plus enoxaparin 40 mg once daily for 2 weeks. The patient did not show any clinical signs of thrombosis during her hospital stay.\n\nCase 2\n\nA 68-year-old Caucasian man (Patient B) from the United Kingdom (height 177 cm, weight 85 kg) was admitted with cough and a week-long increasing dyspnea, before which he was healthy. His wife and daughter probably had COVID-19 with resolving symptoms, and they were all living in the same house. The patient markedly experienced shortness of breath on the day of admission to the emergency department (ED) and, therefore, called an ambulance. His laboratory results on admission were as follows: Hb: 140 g/L, creatinine: 117 μmol/L, WBC: 8.6 × 109/L, lymphocytes: 0.2 × 109/L, platelet count: 126 × 109/L, INR: 1.4, APTT ratio: 1.3, D-dimer > 20,000 μg/L (i.e., higher than the upper limit of the measurement range), fibrinogen plasma concentration: 6.8 g/L, and CRP: 336 mg/L. His chest radiograph showed dense bilateral mid-zone and right lower zone consolidation. PCR result was positive for SARS-CoV-2 and negative for influenza/RSV. Blood cultures showed coagulase-negative staphylococci. The patient was treated with antibiotics (ceftriaxone and doxycycline, according the hospital’s COVID-19 protocol). Antiviral therapy and dexamethasone were not administered. As the patient was severely hypoxemic in the ED, he was transferred directly to the ICU. Orotracheal intubation and IPPV (positive end-expiratory pressure 15 mmHg) were performed about 3 hours after ICU admission as respiratory effort was not improved by face mask CPAP therapy. Chest radiography repeated after intubation showed bilateral interstitial lung changes similar to the imaging conducted earlier on the same day. Prone position did not improve oxygenation. Laboratory results on the next day were as follows: Hb: 133 g/L, creatinine: 265 μmol/L, WBC: 16.3 × 109/L, platelet count: 56 × 109/L, INR: 1.6, APTT ratio: 1.5, D-dimer: 4,340 μg/L, fibrinogen plasma concentration: 2.9 g/L, and CRP: 478 mg/L. By ROTEM, Patient B presented with hypocoagulability in the EXTEM assay with a prolonged CT of 99 s, clot formation time (CFT) of 253 s, and decreased clot firmness amplitudes (A5, 22 mm and MCF, 48 mm) (Fig. 1B). Furthermore, EXTEM and FIBTEM analyses demonstrated a complete fibrinolysis shutdown [5]. Both hypocoagulability and fibrinolysis shutdown have been shown to be associated with increased mortality in bacterial sepsis [3,6]. The FIBTEM trace was within normal limits which may be owing to impaired fibrin polymerization, given that fibrinogen concentration was elevated. The patient deteriorated within a few hours of ICU admission and died the following day despite invasive ventilation, norepinephrine for hypotension, and renal replacement therapy for acute kidney failure. Patient B did not show any clinical signs of thrombosis during his hospital stay.\n\nDiscussion\n\nWe have presented two cases that illustrate the additional value of using thromboelastometry to monitor patients with COVID-19. Increased clot firmness in EXTEM and INTEM (amplitude of clot firmness 10 minutes after CT (A10) > 61.5 mm or MCF > 68 mm) assays has been shown to be associated with an increased incidence of thrombosis in adults and neonates undergoing cardiac and non-cardiac surgery [4]. Furthermore, increased clot firmness in the FIBTEM assay (MCF > 25 mm) has been shown to be associated with an increased incidence of thrombosis in patients with cirrhosis and hepatocellular carcinoma as well as in patients with thrombophilic predisposition after liver transplantation [7,8]. Thromboelastometry in Patient A showed hypercoagulability despite upper normal ranged D-dimer levels and a normal INR. Patients with D-dimer > 3,000 µg/L and/or sepsis-induced coagulopathy score ≥ 4 seem to benefit from increased anticoagulation [9]. However, in critically ill patients with COVID-19, the incidence of thrombosis and pulmonary embolism is high despite pharmacological thromboprophylaxis [2].\n\nThe case of Patient B demonstrated that not all critically ill patients with COVID-19 present the same thromboelastometric pattern. This might be attributed to ethnic and genetic difference, such as gene polymorphisms, bacterial superinfection, or the phase of the disease. Both hypocoagulability and fibrinolysis shutdown, as presented by Patient B, have been shown to be associated with increased mortality in cases involving bacterial sepsis [3,6]. Furthermore, lymphocytopenia has been shown to be associated with poor outcomes in COVID-19 [10]. Although thrombocytopenia, which is an important determinant of clot firmness, is rare in COVID-19, it is associated with poor outcomes in the patient population [7,11]. Furthermore, the mismatch between FIBTEM MCF (14 mm) and Clauss fibrinogen plasma concentration (6.8 g/L) in Patient B might reflect an acquired factor XIII deficiency, which often occurs in sepsis, cirrhosis, acute renal failure, and malignancies [12]. Unfortunately, factor XIII activity is not available for Patient B, which leaves this interpretation speculative. The rapid deterioration of Patient B with acute renal failure and a fatal outcome is in-line with the data published by Wright et al. [13] showing that patients with the combination of high D-dimer (> 2,600 µg/L, here > 20,000 µg/L) and fibrinolysis shutdown (lysis 30 minutes after maximum amplitude in thrombelastography (TEG LY30) of 0% or ROTEM LI60 of 100%) are associated with the highest incidence of thrombosis (50%) and acute renal failure (80%). Here, increased D-dimers and fibrinolysis shutdown may reflect an imbalance in hemostasis with increased clot formation but impaired fibrinolysis – similar to disseminated intravascular coagulation. It remains to be determined whether fibrinolytic therapy with recombinant tissue plasminogen activator (rtPA) has a therapeutic role in critically ill patients with COVID-19 who cannot be oxygenated adequately despite mechanical ventilation and prone positioning. Notably, extracorporeal membrane oxygenation is associated with very high mortality in patients with COVID-19, particularly in patients with hyperinflammation characterized by high IL-6 levels. Although this might support the use of fibrinolytic therapy with rtPA in these patients, Campello et al. [14] demonstrated that a FIBTEM MCF < 14.5 mm is highly predictive of bleeding complications (such as hemorrhagic stroke) after rtPA. Therefore, hypocoagulability in thromboelastometry, particularly a FIBTEM MCF < 14.5 mm should be considered a contraindication for fibrinolytic therapy in critically ill patients with COVID-19.\n\nNevertheless, this case report has several limitations. First, no follow-up ROTEM analyses are available for these patients. Accordingly, the presented ROTEM analyses only represent a snapshot of the COVID-19-associated coagulopathy that can be considered as a dynamic process. Here, different thromboelastometric phenotypes may represent different conditions of the patients or different phases of the coagulopathy. Second, the cut-off values for fibrinolysis shutdown established in trauma and bacterial sepsis cases have been used as clear cut-off values for fibrinolysis shutdown in COVID-19-associated coagulopathy have not been established yet. Further studies are needed to characterize COVID-19-associated coagulopathy and its differences from trauma- and sepsis-induced coagulopathy.\n\nThese two cases demonstrate that the thromboelastometric phenotype can be different and thromboelastometry can easily distinguish between hyper- and hypocoagulability in critically ill patients with COVID-19. Furthermore, thromboelastometry can identify patients with fibrinolysis shutdown [5,6]. The combination of thromboelastometry parameters (EXTEM and FIBTEM CT, CFT, A5, A10, MCF and LI60) and conventional biomarkers (D-dimer, Clauss fibrinogen, and IL-6) might be superior in predicting clinical outcomes such as thrombosis, renal failure and death in patients with COVID-19 than each diagnostic test alone. Therefore, these test combinations can be helpful in the future to decide which therapeutic strategy might be the most appropriate one in critically ill patients with COVID-19. This would be an important step to establish precision medicine not only in thromboelastometry-guided bleeding management but also in this high-risk patient population [15].\n\nFig. 1. ROTEM graphs and results of Patient A and Patient B. (A) Critically ill Patient A with COVID-19, with a hypercoagulable phenotype. (B) Critically ill Patient B with COVID-19 with a hypocoagulable phenotype. EXTEM: extrinsically activated (tissue factor) thromboelastometric assay, FIBTEM: extrinsically activated thromboelastometric assay with the addition of cytochalasin to eliminate platelet contribution to clot firmness, CT: coagulation time, CFT: clot formation time, alpha: alpha angle, A5: amplitude of clot firmness 5 minutes after CT, A10: amplitude of clot firmness 10 minutes after CT, MCF: maximum clot firmness, LI60: lysis index in percentage of maximum clot firmness 60 minutes after CT, ML: maximum lysis during run time, *Reference range for physiological fibrinolysis in EXTEM as published by Stettler et al. [5].\n\nConflicts of Interest\n\nKlaus Görlinger is working as the Medical Director of Tem Innovations since July 2012. Robert Kong and Nevil Hutchinson reported no potential conflict of interest relevant to this article.\n\nAuthor Contributions\n\nRobert Kong (Conceptualization; Investigation; Writing – review & editing)\n\nNevil Hutchiinson (Conceptualization; Investigation; Writing – review & editing)\n\nKlaus Görlinger (Conceptualization; Writing – original draft)\n==== Refs\nReferences\n\n1 Spiezia L Boscolo A Poletto F Cerruti L Tiberio I Campello E COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure Thromb Haemost 2020 120 998 1000 32316063\n2 Dolhnikoff M Duarte-Neto AN de Almeida Monteiro RA da Silva LFF de Oliveira EP Saldiva PH Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19 J Thromb Haemost 2020 18 1517 9 32294295\n3 Adamzik M Langemeier T Frey UH Görlinger K Saner F Eggebrecht H Comparison of thrombelastometry with simplified acute physiology score II and sequential organ failure assessment scores for the prediction of 30-day survival: a cohort study Shock 2011 35 339 42 21068699\n4 Hincker A Feit J Sladen RN Wagener G Rotational thromboelastometry predicts thromboembolic complications after major non-cardiac surgery Crit Care 2014 18 549 25292221\n5 Stettler GR Moore EE Moore HB Nunns GR Silliman CC Banerjee A Redefining postinjury fibrinolysis phenotypes using two viscoelastic assays J Trauma Acute Care Surg 2019 86 679 85 30562328\n6 Adamzik M Eggmann M Frey UH Görlinger K Bröcker-Preuss M Marggraf G Comparison of thromboelastometry with procalcitonin, interleukin 6, and C-reactive protein as diagnostic tests for severe sepsis in critically ill adults Crit Care 2010 14 R178 20929576\n7 Zanetto A Senzolo M Vitale A Cillo U Radu C Sartorello F Thromboelastometry hypercoagulable profiles and portal vein thrombosis in cirrhotic patients with hepatocellular carcinoma Dig Liver Dis 2017 49 440 5 28109767\n8 Kamel Y Hassanin A Ahmed AR Gad E Afifi M Khalil M Perioperative thromboelastometry for adult living donor liver transplant recipients with a tendency to hypercoagulability: a prospective observational cohort study Transfus Med Hemother 2018 45 404 12 30574058\n9 Tang N Bai H Chen X Gong J Li D Sun Z Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy J Thromb Haemost 2020 18 1094 9 32220112\n10 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 JAMA 2020 323 1061 9 32031570\n11 Lippi G Plebani M Henry BM Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis Clin Chim Acta 2020 506 145 8 32178975\n12 Bedreli S Sowa JP Malek S Blomeyer S Katsounas A Gerken G Rotational thromboelastometry can detect factor XIII deficiency and bleeding diathesis in patients with cirrhosis Liver Int 2017 37 562 8 27634287\n13 Wright FL Vogler TO Moore EE Moore HB Wohlauer MV Urban S Fibrinolysis shutdown correlation with thromboembolic events in severe COVID-19 infection J Am Coll Surg 2020 231 193 203.e1 32422349\n14 Campello E Farina F Spiezia L Maggiolo S Palmieri A Sartorello F Thromboelastometry profiles in patients undergoing thrombolytic therapy for acute ischaemic stroke Thromb Haemost 2016 115 1231 4 26864700\n15 Görlinger K Pérez-Ferrer A Dirkmann D Saner F Maegele M Calatayud ÁA The role of evidence-based algorithms for rotational thromboelastometry-guided bleeding management Korean J Anesthesiol 2019 72 297 322 31096732\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2005-6419", "issue": "74(4)", "journal": "Korean journal of anesthesiology", "keywords": "Anticoagulants; COVID-19; Fibrinolysis; Hemostasis; Thrombelastography; Thrombosis", "medline_ta": "Korean J Anesthesiol", "mesh_terms": "D000368:Aged; D001778:Blood Coagulation Disorders; D000086382:COVID-19; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000086402:SARS-CoV-2; D013916:Thrombelastography; D019851:Thrombophilia", "nlm_unique_id": "101502451", "other_id": null, "pages": "350-354", "pmc": null, "pmid": "32773727", "pubdate": "2021-08", "publication_types": "D002363:Case Reports", "references": "32294295;32316063;32178975;32031570;28109767;30562328;32422349;21068699;26864700;31096732;30574058;27634287;20929576;25292221;32220112", "title": "Hyper- and hypocoagulability in COVID-19 as assessed by thromboelastometry -two case reports.", "title_normalized": "hyper and hypocoagulability in covid 19 as assessed by thromboelastometry two case reports" }
[ { "companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-325162", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "dru...
{ "abstract": "BACKGROUND\nClinical manifestations of extraneural infection with the pork tapeworm Taenia solium typically affect the muscles, eyes, alimentary canal, and/or subcutaneous tissues. Children living with HIV are at increased risk for more widespread and severe manifestations of food-borne opportunistic infections, including T. solium, due to fluctuating levels of immunosuppression. We present a case of disseminated T. solium in a HIV-positive child with Kaposi sarcoma living in Tanzania with cysticercosis presenting as widespread subcutaneous nodules.\n\n\nMETHODS\nA 4-year-old HIV-positive boy in Southern Tanzania presented for evaluation of > 30 violaceous skin lesions, few subcutaneous nodules, and a circumferential violaceous penile lesion which rapidly grew after initiation of ART. The patient was clinically diagnosed with Kaposi sarcoma and started on chemotherapy with bleomycin, vincristine, and doxorubicin. He completed 10 cycles of chemotherapy, with full resolution of the violaceous skin and penile lesions but persistence of his subcutaneous nodules, thus paclitaxel was added. After 12 additional cycles of paclitaxel, his subcutaneous nodules enlarged, and biopsy of a scapular subcutaneous nodule was performed. Histopathology revealed a cystic structure with a central larval scolex and serrated spiral canal consistent with T. solium, which confirmed a diagnosis of disseminated cysticercosis. He completed a 10-day course of praziquantel and albendazole with resolution of the subcutaneous nodules.\n\n\nCONCLUSIONS\nDisseminated cysticercosis is an unusual opportunistic infection which can present as subcutaneous nodules without other typical cysticercosis symptoms. Immunosuppression - from HIV and/or chemotherapy - may unmask cysticercosis in children in endemic regions and result in more severe manifestations of this disease. Cysticercosis should remain on a clinician's differential for subcutaneous nodules, especially in children living with HIV. Cysticercosis can mimic Kaposi sarcoma, and histopathology is essential to accurately diagnose and manage patients with concerning skin lesions.", "affiliations": "Baylor College of Medicine, 1 Baylor Plaza BCM 620, Houston, TX, 77030-3411, USA. David.McCormick2@bcm.edu.;Baylor College of Medicine, 1 Baylor Plaza BCM 620, Houston, TX, 77030-3411, USA.;Baylor College of Medicine - Texas Children's Cancer and Hematology Centers, Houston, TX, USA.;Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.;Baylor College of Medicine - Texas Children's Cancer and Hematology Centers, Houston, TX, USA.;Baylor College of Medicine, 1 Baylor Plaza BCM 620, Houston, TX, 77030-3411, USA.", "authors": "McCormick|David W|DW|;Bacha|Jason M|JM|;El-Mallawany|Nader K|NK|;Kovarik|Carrie L|CL|;Slone|J S|JS|;Campbell|Liane R|LR|", "chemical_list": "D000923:Anticestodal Agents; D011223:Praziquantel; D015766:Albendazole", "country": "England", "delete": false, "doi": "10.1186/s12879-020-05039-x", "fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect. Dis\nBMC Infectious Diseases\n1471-2334 BioMed Central London \n\n5039\n10.1186/s12879-020-05039-x\nCase Report\nDisseminated cysticercosis and Kaposi sarcoma in a child with HIV/AIDS: A case report\nMcCormick David W. David.McCormick2@bcm.edu 1 Bacha Jason M. 123 El-Mallawany Nader K. 4 Kovarik Carrie L. 5 Slone J. S. 4 Campbell Liane R. 123 1 grid.39382.330000 0001 2160 926XBaylor College of Medicine, 1 Baylor Plaza BCM 620, Houston, TX 77030-3411 USA \n2 grid.39382.330000 0001 2160 926XBaylor International Pediatric AIDS Initiative (BIPAI) at Texas Children’s Hospital, Baylor College of Medicine, Houston, TX USA \n3 Baylor College of Medicine Children’s Foundation - Tanzania, Pediatrics, Mbeya, Tanzania \n4 grid.39382.330000 0001 2160 926XBaylor College of Medicine - Texas Children’s Cancer and Hematology Centers, Houston, TX USA \n5 grid.25879.310000 0004 1936 8972Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA USA \n25 4 2020 \n25 4 2020 \n2020 \n20 30924 1 2020 16 4 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/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nClinical manifestations of extraneural infection with the pork tapeworm Taenia solium typically affect the muscles, eyes, alimentary canal, and/or subcutaneous tissues. Children living with HIV are at increased risk for more widespread and severe manifestations of food-borne opportunistic infections, including T. solium, due to fluctuating levels of immunosuppression. We present a case of disseminated T. solium in a HIV-positive child with Kaposi sarcoma living in Tanzania with cysticercosis presenting as widespread subcutaneous nodules.\n\nCase presentation\nA 4-year-old HIV-positive boy in Southern Tanzania presented for evaluation of > 30 violaceous skin lesions, few subcutaneous nodules, and a circumferential violaceous penile lesion which rapidly grew after initiation of ART. The patient was clinically diagnosed with Kaposi sarcoma and started on chemotherapy with bleomycin, vincristine, and doxorubicin. He completed 10 cycles of chemotherapy, with full resolution of the violaceous skin and penile lesions but persistence of his subcutaneous nodules, thus paclitaxel was added. After 12 additional cycles of paclitaxel, his subcutaneous nodules enlarged, and biopsy of a scapular subcutaneous nodule was performed. Histopathology revealed a cystic structure with a central larval scolex and serrated spiral canal consistent with T. solium, which confirmed a diagnosis of disseminated cysticercosis. He completed a 10-day course of praziquantel and albendazole with resolution of the subcutaneous nodules.\n\nConclusions\nDisseminated cysticercosis is an unusual opportunistic infection which can present as subcutaneous nodules without other typical cysticercosis symptoms. Immunosuppression – from HIV and/or chemotherapy – may unmask cysticercosis in children in endemic regions and result in more severe manifestations of this disease. Cysticercosis should remain on a clinician’s differential for subcutaneous nodules, especially in children living with HIV. Cysticercosis can mimic Kaposi sarcoma, and histopathology is essential to accurately diagnose and manage patients with concerning skin lesions.\n\nKeywords\nKaposi sarcomaCysticercosisTaenia soliumHIVAIDSOpportunistic infectionissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nCysticercosis is an infection with the larval form of Taenia solium, the pork tapeworm. Cysticercosis is transmitted through fecal contamination of food or water or autoinfection, and persons with taeniasis (the intestinal form) serve as the reservoir. Poor food preparation and hand hygiene increases the risk of cysticercosis [1]. While mild or asymptomatic intestinal infection commonly occurs following ingestion of contaminated pork, there are two important, more severe clinical manifestations of cysticercosis that can occur following ingestion of food or water contaminated with cysts, depending on the site of larval encystation. Neurocysticercosis (NCC) refers to encystation of cysticerci within the brain parenchyma or subarachnoid space, and is the leading cause of seizures in low- and middle-income countries (LMIC) [2]. Disseminated cysticercosis (DC) refers to cysticerci migrating to and encystation in skeletal muscle, cardiac muscle, eyes, and/or subcutaneous tissues.\n\nCysticercosis is one of the most prevalent helminth infections globally, with an estimated 370,000 persons affected by NCC [3]. Data specific to sub-Saharan Africa (SSA) are limited; however, regional SSA data suggest a higher prevalence than in South America and the Indian subcontinent [4], and a major cause of disability-adjusted life-years in SSA [3]. In Tanzania, recent estimates suggest that approximately 16% of the population have DC or NCC, and 2–5% of the population has taeniasis [5].\n\nDisseminated cysticercosis is an uncommon manifestation of infection with T. solium and most commonly presents as subcutaneous and intramuscular nodules, although any organ can be infected [6–10]. Among people living with HIV, a recent case-control study did not find any association between HIV infection and NCC in Tanzania [11], and to date, no unique relationship between NCC and HIV has been reported [12]. We present a case of disseminated cysticercosis in a HIV positive child being treated for Kaposi sarcoma in Tanzania that presented as widespread subcutaneous lesions following initiation of antiretroviral therapy (ART) and chemotherapy.\n\nCase presentation\nAn HIV-positive 4-year-old boy presented to clinic for evaluation of worsening skin lesions after starting ART. His absolute (percentage) CD4 count at the time of ART initiation was 32 cells/μL (3%) (Fig. 1), and he was started on ART with zidovudine-lamivudine-nevirapine. Approximately 3 months after ART initiation, he developed > 30 violaceous papules and plaques, a necrotic edematous circumferential plaque on the distal shaft and glans of the penis, and scattered small subcutaneous nodules in his submandibular and cervical regions (Fig. 2, panel a). He was clinically diagnosed with Kaposi sarcoma secondary to the immune reconstitution inflammatory syndrome due to the classic appearance of his cutaneous lesions. His ART was shifted to abacavir-lamivudine-lopinavir/ritonavir due to anemia (hemoglobin 7.2 g/dL) and potential activity of protease inhibitors against human herpes virus-8 [13, 14]. He was started on a chemotherapy regimen of bleomcyin (15 U/m2) and vincristine (1.4 mg/m2) every 2 weeks. Biopsy was not obtained initially due to logistical and resource constraints.\nFig. 1 Timeline of clinical course from day of presentation showing absolute CD4 count and major clinical events\n\nFig. 2 Clinical images showing lesions (a) at the time of diagnosis of KS-IRIS, (b) following antineoplastic therapy, and (c) following antihelminthic therapy\n\n\n\nAfter five cycles of this chemotherapeutic regimen, doxorubicin (25–35 mg/m2) was added based on failure to achieve complete clinical remission. The patient completed an additional 10 cycles of bleomycin-vincristine-doxorubicin every 3 weeks without complete remission of the violaceous lesions or penile nodule. During the course of chemotherapy, he achieved full virologic suppression and his CD4 count had increased to 265 cells/μL (13%) after 143 days of antiretroviral therapy (Fig. 1). However, his KS lesions continued to persist, and chemotherapy was shifted to monthly paclitaxel. He eventually completed 12 cycles of paclitaxel monotherapy with dexamethasone as a premedication and showed improvement and full resolution of the violaceous skin and penile lesion. However, during this time he developed numerous additional subcutaneous nodules on his trunk, tongue, and extremities that rapidly and progressively increased in size in number (Fig. 2, panel b).\n\nA biopsy was taken for further investigation. Histopathology of the nodule revealed a cystic structure with a central larval scolex and serrated spiral canal consistent with T. solium, which confirmed the diagnosis of DC (Fig. 3). Additional history taking with the caregiver revealed that the patient and his family consumed pork frequently as a regular part of their diet.\nFig. 3 Biopsy of the patient's subcutaneous nodule (4x magnification, hemtoxylin and eosin stain) showing a Taenia solium cysticercus. Cysticerci are fluid-filled cystic structures consisting of a thin bladder wall (red arrow) and a parenchymatous portion containing a scolex surrounded by a convoluted spiral canal (blue arrow). The hooks of the scolex are often only seen in few tissue sections\n\n\n\nChemotherapy was stopped and he was treated for DC with albendazole 7.5 mg/kg twice daily and praziquantel 25 mg/kg twice daily for 10 days. Prednisone was administered as an adjunctive treatment to limit the possibility of cerebral edema as NCC could not be ruled out (computed tomography scans of the head were unavailable). He had almost complete resolution of all subcutaneous nodules during his 10-day treatment course (Fig. 2, panel c). All treatment was well-tolerated with minor toxicity (anemia). A small sublingual nodule persisted acutely following treatment, fully resolving several months later. He has not had recurrence of KS or DC after 42 months of follow-up.\n\nDiscussion and conclusions\nGiven the limited diagnostic capabilities, it is difficult to determine if the DC in this patient was a complication of primary infection with T. solium, or secondary to underlying immunodeficiency secondary to HIV/AIDS, chemotherapy, steroid administration, or reconstitution of the immune system following ART initiation. Infection with HIV has not been associated with increased prevalence of cysticercosis or increased severity of disease; however, prevalence of helminth infections seems to peak with a CD4 count of 200–500 [11, 12, 15].There is no clear association between HIV infection and cysticercosis [11, 12], and it is difficult to determine if the subcutaneous nodules seen in our patient represent primary infection or unmasking of extant lesions following reconstitution of the immune system.\n\nThe presentation of DC following ART and chemotherapy is a reminder that clinicians need to consider DC in the differential for CLHIV living in areas with high burden of cysticercosis and/or other helminthic disease who develop widespread subcutaneous nodules during treatment. The differential diagnosis for cutaneous cestode infections in children in SSA includes sparganosis and echinococcosis, which should be also be considered when an immunocompromised person’s clinical course worsens or fails to improve [16, 17]. Clinicians in endemic regions must be familiar with the signs and symptoms of all forms of T. solium infection in CLHIV, which include taeniasis, subcutaneous nodules, NCC, or otherwise unexplained nodules or lesions in muscle, organs, or other soft tissue. Biopsy of lesions not responding as expected to treatment is recommended to make a definitive diagnosis and identify the most appropriate treatment.\n\nAbbreviations\nARTAntiretroviral therapy\n\nAIDSAcquired Immunodeficiency Syndrome\n\nCD4Cluster of Differentiation 4 cell\n\nCLHIVChildren living with HIV\n\nDCDisseminated cysticercosis\n\nKSKaposi Sarcoma\n\nHIVHuman Immunodeficiency Virus\n\nLMICLow- and middle-income countries\n\nNCCNeurocysticertosis\n\nSSASub-Saharan Africa\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nDavid W. McCormick and Jason M. Bacha contributed equally to this work.\n\nAcknowledgements\nWe thank the patient and his family for participation in the case report, and we thank the staff at the Baylor College of Medicine Center of Excellence in Mbeya, Tanzania.\n\nWe are grateful to the staff at Baylor College of Medicine Children’s Foundation – Tanzania Centre of Excellence for their relentless dedication to bettering the lives of our patients and families. We would also like to recognize the courage and fortitude of our patients and their families as they survive and thrive despite their diagnosis of HIV.\n\nAuthors’ contributions\nDWM, JMB, and LRC were responsible for data extraction, patient chart review, and creating and writing of the initial manuscript drafts. DWM, JMB, LRC, NE, CLK, and JSS were all involved in the clinical care, treatment, and follow up aspects for the case presented. DWM, JMB, LRC, NE, CLK, and JSS all were involved in reviewing/revising of manuscript drafts, have agreed to be accountable for all aspects of the work, and have given final approval of the final manuscript version to be published.\n\nFunding\nThe authors have no sources of funding to declare.\n\nAvailability of Data and materials\nThe data used and/or analysed during this case report are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nApproval was obtained from the Mbeya Medical Research and Ethics Committee and the Medical Research Coordinating Committee (MRCC) of the National Institute for Medical Research (NIMR) in Tanzania, and the Institutional Review Board, Baylor College of Medicine in Houston, Texas, USA (H-32491). Waiver of patient informed consent was approved by all committees as this retrospective study analyzed only de-identified data.\n\nConsent for publication\nWaiver of patient informed consent was approved by all committees as this retrospective study analyzed only de-identified data. However, written (and verbal) caregiver consent was obtained from the patient’s parent to take and share photographs for clinical educational purposes during the course of care and treatment at the Baylor Mbeya COE.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Qavi A Garg RK Malhotra HS Jain A Kumar N Malhotra KP Disseminated cysticercosis : clinical spectrum 2016 \n2. Reddy DS Volkmer R II Neurocysticercosis as an infectious acquired epilepsy worldwide Seizure Eur J Epilepsy 2017 52 176 181 10.1016/j.seizure.2017.10.004 \n3. Torgerson PR Devleesschauwer B Praet N Speybroeck N Willingham AL Kasuga F World Health Organization Estimates of the Global and Regional Disease Burden of 11 Foodborne Parasitic Diseases, 2010: A Data Synthesis PLoS Med 2015 12 12 e1001920 10.1371/journal.pmed.1001920 26633705 \n4. Coral-Almeida M Gabriël S Abatih EN Praet N Benitez W Dorny P Taenia solium human cysticercosis: A systematic review of sero-epidemological data from endemic zones around the world PLoS Negl Trop Dis 2015 9 7 1 20 10.1371/journal.pntd.0003919 \n5. Aminiel H Id N Winkler AS Braae UC Mdegela H Mkupasi EM Taenia solium taeniosis and cysticercosis literature in Tanzania provides research evidence justification for control : A systematic scoping review 2019 1 17 \n6. Prasad R Kapoor K Mishra D Disseminated Cysticercosis in a Child 2012 1389 1391 \n7. Singh UK Prasad R Bhushan P Mishra OP Disseminated cysticercosis with a right common femoral vein thrombosis 2013 3 6 \n8. Heller T Wallrauch C Kaminstein D Phiri S Case Report : Cysticercosis : Sonographic Diagnosis of a Treatable Cause of Epilepsy and Skin Nodules Am J Trop Med Hyg 2017 97 6 1827 1829 10.4269/ajtmh.17-0257 29016298 \n9. Qavi A Garg RK Malhotra HS Jain A Kumar N Malhotra KP Disseminated cysticercosis Medicine (Baltimore) 2016 95 39 e4882 10.1097/MD.0000000000004882 27684822 \n10. Duvignaud A Receveur M-C Pistone T Malvy D Disseminated cysticercosis revealed by subcutaneous nodules in a migrant from Cameroon Travel Med Infect Dis 2014 12 5 551 552 10.1016/j.tmaid.2014.07.005 25138603 \n11. Schmidt V, Kositz C, Herbinger K, Carabin H, Ngowi B, Naman E, et al. Association between Taenia solium infection and HIV / AIDS in northern Tanzania : a matched cross sectional-study. Infect Dis Poverty. 2016:1–15. Available from:. 10.1186/s40249-016-0209-7.\n12. Vazquez OH Romo ML Neurocysticercosis and HIV Infection : what can we learn from the published literature ? 2019 357 365 \n13. Sgadari C Monini P Barillari G Ensoli B Use of HIV protease inhibitors to block Kaposi’s sarcoma and tumour growth Lancet Oncol 2003 4 9 537 547 10.1016/S1470-2045(03)01192-6 12965274 \n14. Gantt S Cattamanchi A Krantz E Magaret A Selke S Kuntz SR Reduced human herpesvirus-8 oropharyngeal shedding associated with protease inhibitor-based antiretroviral therapy J Clin Virol 2014 60 2 127 132 10.1016/j.jcv.2014.03.002 24698158 \n15. Mascaro C Noormahomed EV Mauaie MN Buene T Funzamo CA Benson CA A Cross-sectional Serological Study of Cysticercosis , Schistosomiasis , Toxocariasis and Echinococcosis in HIV- 1 Infected People in Beira , Mozambique PLoS Negl Trop Dis 2014 8 9 e3121 10.1371/journal.pntd.0003121 25188395 \n16. Raether W Hanel H Epidemiology, clinical manifestations and diagnosis of zoonotic cestode infections: an update Parasitol Res [Internet] 2003 91 5 412 438 10.1007/s00436-003-0903-9 \n17. Eberhard ML Thiele EA Yembo GE Yibi MS Cama VA Ruiz-Tiben E Case report: thirty-seven human cases of sparganosis from Ethiopia and South Sudan caused by spirometra Spp Am J Trop Med Hyg 2015 93 2 350 355 10.4269/ajtmh.15-0236 26055739\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2334", "issue": "20(1)", "journal": "BMC infectious diseases", "keywords": "AIDS; Cysticercosis; HIV; Kaposi sarcoma; Opportunistic infection; Taenia solium", "medline_ta": "BMC Infect Dis", "mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000163:Acquired Immunodeficiency Syndrome; D015766:Albendazole; D000818:Animals; D000923:Anticestodal Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002675:Child, Preschool; D003551:Cysticercosis; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D011223:Praziquantel; D012514:Sarcoma, Kaposi; D040521:Subcutaneous Tissue; D041201:Taenia solium; D013636:Tanzania", "nlm_unique_id": "100968551", "other_id": null, "pages": "309", "pmc": null, "pmid": "32334521", "pubdate": "2020-04-25", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "29016298;26147942;25188395;26055739;25138603;22392264;26633705;12965274;13680371;23391957;24698158;29055271;31166983;27684822;31189001;27903304", "title": "Disseminated cysticercosis and Kaposi sarcoma in a child with HIV/AIDS: A case report.", "title_normalized": "disseminated cysticercosis and kaposi sarcoma in a child with hiv aids a case report" }
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{ "abstract": "Paroxetine, a selective serotonin reuptake inhibitor (SSRI) may be given in severe cases of maternal depression and panic disorders during pregnancy. However, it may lead to severe withdrawal symptoms: respiratory distress, jitteriness, convulsions, hypoglycaemia, an impaired muscle tone and necrotising enterocolitis. These symptoms, also called neonatal withdrawal syndrome, may last up to one month. We report a girl born at 37 weeks of gestation presenting 12 hours after birth with hypopnea, bradycardia and a decreased muscular tone of unknown origin. The child was transferred to the NICU and was intubated and ventilated mechanically. Within the first days the patient also developed cerebral seizures. The EEG showed severe abnormalities. Later we learned that the patient's mother had been treated with Paroxetine during pregnancy. The patient recovered after two days of ventilation and anticonvulsive medication with phenobarbital. The EEG result showed a siginificant improvement. At day 10 she was discharged in good condition. Recognition and treatment of the presented neonatal problems could have been more effective and faster, if the attending pediatricians had been informed earlier about the maternal medication with SSRIs. Neonates of mothers who were treated with SSRIs during pregnancy should be monitored. Paroxetine withdrawal syndrome should be considered as one of the differential diagnosis of neonatal encephalopathy.", "affiliations": "Zentrum für Kinderheilkunde und Jugendmedizin, Universitätsklinikum Giessen. Friederike.Herbst@pediat.med.uni-giessen.de", "authors": "Herbst|F|F|;Gortner|L|L|", "chemical_list": "D017367:Serotonin Uptake Inhibitors; D017374:Paroxetine", "country": "Germany", "delete": false, "doi": "10.1055/s-2003-45176", "fulltext": null, "fulltext_license": null, "issn_linking": "0948-2393", "issue": "207(6)", "journal": "Zeitschrift fur Geburtshilfe und Neonatologie", "keywords": null, "medline_ta": "Z Geburtshilfe Neonatol", "mesh_terms": "D000328:Adult; D001008:Anxiety Disorders; D003937:Diagnosis, Differential; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D009357:Neonatal Abstinence Syndrome; D020258:Neurotoxicity Syndromes; D017374:Paroxetine; D011247:Pregnancy; D011248:Pregnancy Complications; D017367:Serotonin Uptake Inhibitors; D013036:Spasms, Infantile", "nlm_unique_id": "9508901", "other_id": null, "pages": "232-4", "pmc": null, "pmid": "14689334", "pubdate": "2003", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "Paroxetine withdrawal syndrome as differential diagnosis of acute neonatal encephalopathy?.", "title_normalized": "paroxetine withdrawal syndrome as differential diagnosis of acute neonatal encephalopathy" }
[ { "companynumb": "DE-MYLANLABS-2018M1020880", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PAROXETINE" }, "drugadditional": null, ...
{ "abstract": "BACKGROUND\nAutoimmune polyglandular syndrome type 2 (APS-2) is a rare and complex clinical entity, and little is known about its etiology and progression.\n\n\nMETHODS\nA 52-year-old woman with autoimmune hepatitis (AIH) and bronchial asthma was diagnosed with APS-2; autoimmune Addison's disease (AD), and Hashimoto's thyroiditis (HT), and she underwent prednisolone (PSL) treatment. Five months later, she presented ptosis and was diagnosed with thymoma-associated myasthenia gravis (MG). Thymectomy and PSL treatment with immuno-suppressants appeared to ameliorate MG, AD, AIH, HT, and bronchial asthma. HLA typing analysis revealed that the patient had susceptible HLA alleles to MG, AIH, and HT in a Japanese population.\n\n\nCONCLUSIONS\nThis case suggests common endocrinological and autoimmune aspects of APS-2 and AIH with thymoma-associated MG, which are considered to be extremely rare complications.", "affiliations": "The First Department of Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan. inaba@wakayama-med.ac.jp.;The First Department of Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan.;Department of Neurology, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan.;Thoracic and Cardiovascular Surgery, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan.;Department of Neurology, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan.;Thoracic and Cardiovascular Surgery, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan.", "authors": "Inaba|Hidefumi|H|http://orcid.org/0000-0002-7718-734X;Ariyasu|Hiroyuki|H|;Iwakura|Hiroshi|H|;Kurimoto|Chiaki|C|;Ueda|Yoko|Y|;Uraki|Shinsuke|S|;Takeshima|Ken|K|;Furukawa|Yasushi|Y|;Morita|Shuhei|S|;Nakayama|Yoshiaki|Y|;Ohashi|Takuya|T|;Ito|Hidefumi|H|;Nishimura|Yoshiharu|Y|;Akamizu|Takashi|T|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s12902-020-0498-5", "fulltext": "\n==== Front\nBMC Endocr Disord\nBMC Endocr Disord\nBMC Endocrine Disorders\n1472-6823 BioMed Central London \n\n498\n10.1186/s12902-020-0498-5\nCase Report\nAutoimmune polyglandular syndrome type 2 and autoimmune hepatitis with thymoma-associated myasthenia gravis: case report\nhttp://orcid.org/0000-0002-7718-734XInaba Hidefumi inaba@wakayama-med.ac.jp 1 Ariyasu Hiroyuki ariyasu@wakayama-med.ac.jp 1 Iwakura Hiroshi hiwaku@wakayama-med.ac.jp 1 Kurimoto Chiaki chiakikr@wakayama-med.ac.jp 1 Ueda Yoko yokoued@wakayama-med.ac.jp 1 Uraki Shinsuke shinnojo@wakayama-med.ac.jp 1 Takeshima Ken kt10948@wakayama-med.ac.jp 1 Furukawa Yasushi y-furuka@wakayama-med.ac.jp 1 Morita Shuhei smorita@wakayama-med.ac.jp 1 Nakayama Yoshiaki yoshi-n@wakayama-med.ac.jp 2 Ohashi Takuya t-ohashi@wakayama-med.ac.jp 3 Ito Hidefumi ito@wakayama-med.ac.jp 2 Nishimura Yoshiharu nishim-y@wakayama-med.ac.jp 3 Akamizu Takashi akamizu@wakayama-med.ac.jp 1 1 0000 0004 1763 1087grid.412857.dThe First Department of Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan \n2 0000 0004 1763 1087grid.412857.dDepartment of Neurology, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan \n3 0000 0004 1763 1087grid.412857.dThoracic and Cardiovascular Surgery, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan \n7 4 2020 \n7 4 2020 \n2020 \n20 4716 5 2019 24 1 2020 © The Author(s). 2020Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAutoimmune polyglandular syndrome type 2 (APS-2) is a rare and complex clinical entity, and little is known about its etiology and progression.\n\nCase presentation\nA 52-year-old woman with autoimmune hepatitis (AIH) and bronchial asthma was diagnosed with APS-2; autoimmune Addison’s disease (AD), and Hashimoto’s thyroiditis (HT), and she underwent prednisolone (PSL) treatment. Five months later, she presented ptosis and was diagnosed with thymoma-associated myasthenia gravis (MG). Thymectomy and PSL treatment with immuno-suppressants appeared to ameliorate MG, AD, AIH, HT, and bronchial asthma. HLA typing analysis revealed that the patient had susceptible HLA alleles to MG, AIH, and HT in a Japanese population.\n\nConclusions\nThis case suggests common endocrinological and autoimmune aspects of APS-2 and AIH with thymoma-associated MG, which are considered to be extremely rare complications.\n\nKeywords\nAutoimmune polyglandular syndrome type 2 (APS-2)Autoimmune Addison’s diseaseHashimoto’s thyroiditisAutoimmune hepatitisThymoma-associated myasthenia gravisBronchial asthmaThis work was supported in part by Takeda Science Foundation.issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nAutoimmune polyglandular syndrome type 2 (APS-2) is a rare complex clinical entity. It is defined as autoimmune Addison’s disease (AD) concomitant with autoimmune thyroid diseases such as Graves’ disease and Hashimoto’s thyroiditis (HT), and/or type 1 diabetes mellitus, in the absence of hypoparathyroidism [1]. The prevalence of APS-2 is 1.4–4.5 per 100,000 and it most commonly affects middle-aged women [1].\n\nMyasthenia gravis (MG) is a neuromuscular junction disease that is mostly associated with autoimmune antibodies, such as anti-acetylcholine receptor (AChR)-antibody (Ab) [2, 3]. Autoimmune hepatitis (AIH) is characterized by autoimmunity to hepatocytes with increase of antinuclear antibody (ANA) [4]. Co-existence of MG and AIH is rare [3, 5]. Moreover, cases of APS-2 with thymoma-associated MG and AIH are extremely rare, and their common etiology has been unclear [1]. Here, we report a case of APS2 accompanied by thymoma-associated MG and AIH. We also examined the HLA of the patient, including disease-susceptible allele.\n\nCase presentation\nA 52-year-woman was admitted to our hospital because of 3-month history of loss of appetite, fatigue, and 2-month history of pigmentation of the oral mucosa and the tongue. She had been treated for bronchial asthma for 9 years by budesonide formoterol fumarate hydrate inhalation and oral theophylline. She had also had been diagnosed with AIH and had been taking azathioprine (50 mg/day) for 5 years.\n\nShe had no familial history of autoimmune disease. Her height was 144.5 cm, and body weight was 57.0 kg (BMI: 27.3 kg/m2). There was no apparent loss of body weight. Blood pressure was 88/63 mmHg. Her thyroid gland was firm and diffusely enlarged. In laboratory tests (Table 1), serum sodium and potassium levels were normal (under treatment of oral furosemide: 10 mg/day), and eosinophilia and hypoglycemia were not observed. In endocrinological examinations (Table 2), serum cortisol level at 06:00 was remarkably decreased, < 1.0 μg/dL (normal range: 2.9–19.4) and plasma adrenocorticotropic hormone (ACTH) level was elevated, 800.0 pg/mL (normal range: 7.2–63.3). Adrenal cortex autoantibodies (ACA) were positive, × 40 (normal range: < × 10). Abdominal CT showed that bilateral adrenal glands were slightly atrophied (Fig. 1a). Based on clinical findings and endocrinological data, she was diagnosed with autoimmune AD. She also had HT. Her anti-thyroglobulin antibody (TgAb) was elevated, 231.9 IU/mL (normal range: < 28.0) (Table 3). Ultrasonography examination showed diffusely enlarged thyroid gland, with coarse and hypoechogenic pattern. Both serum calcium level, 8.9 mg/dL (8.8–10.1), and plasma intact PTH level, 31 pg/dL (9.3–74.9) were normal (Tables 1, 2 and 3). Based on these findings, she was diagnosed with APS-2. In order to treat AIH and autoimmune AD, PSL was considered to be better than hydrocortisone. Therefore, PSL (10 mg/day) and fludrocortisone (0.1 mg/day) were started for autoimmune AD. The pigmentation of the oral mucosa and the tongue, the loss of appetite, the fatigue, and the hypotension disappeared within 3 months.\nTable 1 Laboratory data on admission\n\n\tResults\tUnit\tNormal range\t\nWBC\t3330\t/μL\t(3500–9800)\t\n(Neutro 51.1%, Eos 0%, Baso 0%, Lym 42.6%)\t\n Hb\t12\tg/dL\t(12–15)\t\n Plt\t21.7 × 104\t/μL\t(13–37)\t\n TP\t6.2\tg/dL\t(6.7–8.1)\t\n Alb\t3.4\tg/dL\t(3.9–4.9)\t\n AST\t35\tIU/L\t(7–38)\t\n ALT\t14\tIU/L\t(4–44)\t\n ALP\t262\tIU/L\t(115–359)\t\n G-GTP\t19\tIU/L\t(9–35)\t\n LDH\t157\tIU/L\t(106–220)\t\n BUN\t13\tmg/dL\t(8–20)\t\n Cr\t0.53\tmg/dL\t(0.43–0.72)\t\n T-bil\t0.7\tmg/dL\t(0.2–1.2)\t\n Ca\t8.9\tmg/dL\t(8.8–10.1)\t\n P\t3.2\tmg/dL\t(2.7–4.6)\t\n Na\t137\tmEq/L\t(135–145)\t\n K\t3.7\tmEq/L\t(3.5–5.0)\t\n Cl\t101\tmEq/L\t(98–107)\t\n PG\t80\tmg/dL\t(70–109)\t\n HbA1c\t5\t%\t(4.6–6.2)\t\n ANA\t80\tx\t(< 40)\t\n ds-DNA\tnegative\t\t\t\n RNP\tnegative\t\t\t\n Sm\tnegative\t\t\t\n SS-A\tnegative\t\t\t\n SS-B\tnegative\t\t\t\n Scl-70\tnegative\t\t\t\n C3\t102\tmg/dL\t(65–135)\t\n C4\t19\tmg/dL\t(13–35)\t\nUrinary analysis\t\n SG\t1.02\t\t\t\n Protein\t(−)\t\t\t\n Occult blood\t(−)\t\t\t\n Sugar\t(−)\t\t\t\n\nTable 2 Endocrinological data on admission\n\n\tResults\tUnit\tNormal range\t\nTSH\t2.515\tμIU/mL\t(0.35–4.94)\t\nFT3\t3.51\tpg/mL\t(1.71–3.71)\t\nFT4\t0.93\tng/dL\t(0.70–1.55)\t\nTRAb\t< 1.0\tIU/mL\t(< 2.0)\t\nTgAb\t231.9\tIU/mL\t(< 28.0)\t\nTPOAb\t< 5.0\tU/mL\t(< 16.0)\t\nF\t< 1.0\tμg/dL\t(2.9–19.4)\t\nACTH\t800\tpg/mL\t(7.2–63.3)\t\nPAC\t1.2\tng/dL\t(3.6–24)\t\nPRA\t14\tng/mL/H\t(0.2–3.9)\t\ni-PTH\t31\tpg/d\tL (9.3–74.9)\t\nACA\t40\tx\t(< 10)\t\nGADAb\t< 1.3\tU/mL\t(0–1.4)\t\nIA-2Ab\tnegative\t\t\t\nUrinary examination\t\n free F\t< 1\tμg/day\t(43–176)\t\n GH\t0.6\tng/mL\t(0–2.1)\t\n IGF-I\t39\tng/mL\t(78–213)\t\n LH\t5.7\tmIU/mL\t(1.7–11.2)\t\n FSH\t7.9\tmIU/mL\t(2.1–18.6)\t\n E2\t461\tpg/mL\t\t\n PRL\t38\tng/mL\t(< 15)\t\n\nFig. 1 a On an abdominal CT, atrophy of the bilateral adrenal glands was seen (arrows). b A solid mass was seen in the anterior mediastinum (arrow) on a chest CT, suspected to be thymoma (34 × 34 mm in size)\n\n\nTable 3 Results of HLA typing test of the patient\n\nHLA\tPatient allele\tSusceptible autoimmune disease (References)\t\nA\t11:01/24:02\t\t\nB\t39:01/51:01\t\t\nC\t07:02/14:02\t\t\nDRB1\t04:05/11:01\tAIH Ref [4]. Other APS-2 case Ref [6]\t\nDRB3\t02:02\t\t\nDRB4\t01:03\tHT Ref [7], AIH Ref [4]\t\nDQA1\t03:03/05:05\t\t\nDQB1\t03:01/04:01\tAIH Ref [4], MG Ref [8]\t\nDPA1\t01:03/02:02\t\t\nDPB1\t02:01/05:01\tMG Ref [8]\t\nFootnotes:\n\nHLA-DRB1*04:05, DRB4, and DQB1*04:01 for AIH ref. [4], DRB4 for HT ref. [7], and DQB1*03 and DPB1*02:01 for MG ref. [8] were reported as disease-susceptible alleles\n\nKonno, et al. reported a case of APS-2 similar to the current case; AD, HT and AIH with MG without thymoma and bronchial asthma who had HLA-A23, B52/62, and DR11/15 ref. [6]\n\n\n\nFive months after diagnosis of APS-2, she noticed ptosis in both eyes which worsened in the evening. There was no muscle weakness, dysarthria, or dysphagia. She was readmitted to hospital. On readmission, anti-AChR-Ab level was increased, 4.4 nmol/L (normal range: 0–0.3). Anti-titin antibody was not measured. The repetitive nerve stimulation test at 3 Hz of the right facial nerve revealed decremental response. On chest CT, an anterior mediastinal mass (34 × 34 mm) was observed, which was suspected to be thymoma (Fig.1b). She was thus diagnosed with thymoma-associated ocular MG. Pyridostigmine treatment was begun, but due to adverse events including abdominal pain and skin rash, it was withdrawn. Since symptoms of the ocular MG were very slight, PSL (10 mg/day) for autoimmune AD and ocular MG was continued. Azathioprine (50 mg/day) for AIH was continued by the hepatologist. Subsequently, total thymectomy was conducted. The surgical specimen of mediastinal mass exhibited thymoma: histological type B2, pT2, R0. After the thymectomy, PSL and immuno-suppressant treatment was continued (Fig. 2). The level of anti-AchR-Ab for MG then decreased. Ptosis also improved within 5–6 months. After 42 months, immuno-suppressant treatment was ceased, but even after 10 months, MG had not worsened. Normalized ACA levels (< 10) at 53 months might suggest improvement of AD or atrophy of the adrenal glands. Although serum levels of TgAb and anti-thyroperoxidase antibody (TPOAb) increased during the course, thyroid function stayed normal during the entire course, thus HT had not worsened.\nFig. 2 Clinical course after diagnosis of APS-2. Five months after this diagnosis, she was diagnosed with thymoma-associated MG. Anti-AchR-Ab titer gradually decreased. * Immuno-suppressants: Under treatment with azathioprine (50 mg/day), total thymectomy was conducted. After thymectomy, tacrolimus (3 mg/day) was started instead of azathioprine, and 25 months later, it was changed to cyclosporine (50 mg/day). Ten months later, the treatment was changed to ambenonium (5 mg/day), and ceased after 10 months (at 52 months)\n\n\n\nSince multiple concurrent autoimmune diseases were seen, the patient underwent HLA typing tests. She had HLA-A*11:01/24:02, B*39:01/51:01, C*07:02/14:02, DRB1*04:5/11:01, DRB3*02:02, DRB4*01:03, DQA1*03:03/05:05, DQB1*03:01/04:01, DPA1*01:03/02:02, and DPB1*02:01/05:01 (Table 3).\n\nDiscussion and conclusion\nAPS is divided into 4 types, and APS-2 with autoimmune AD and HT is referred to as Schmidt’s syndrome [1]. Thymoma is reported in 15% of cases of MG, and half of cases of thymoma have concomitant MG [2, 6]. The prevalence of AIH in APS-2 is reported to be 4%, and MG in APS-2 is considered to be even more rare [3].\n\nIn the current case, based on the typical endocrinological findings, autoimmune AD and HT were diagnosed. The absence of hypoparathyroidism led to diagnosis of APS-2. Thymoma-associated MG concomitant with AIH and bronchial asthma was also observed. Although cases of APS-2 have been reported, to the best of our knowledge, cases of APS-2 with thymoma-associated MG are rare, and their complication with AIH and bronchial asthma has not been reported until now.\n\nMultiple genetic and environmental factors seem to be associated with the development of APS-2, but its etiology is not understood [1]. In the current case, MG developed despite the patient receiving PSL and azathioprine therapy. The reason for this is unclear, but enlarged thymoma might affect the development of MG.\n\nHLA has been reported to be a major genetic factor for APS-2. HLA-DR3/DR4 alleles or its haplotype are reported to be one of the large risk factors for APS-2 in Western people [1]. To date, however, predisposition of HLA alleles to APS-2 in Japanese has not been reported.\n\nIn Japanese cohorts, disease-predisposing alleles are as follows: HLA-DRB4 for HT [7], HLA-DRB1*04:05, DRB4 and DQB1*04:01 for AIH [4], and DQB1*03 and DPB1*02:01 for MG [8]. All of these alleles were seen in the current case. Konno, et al. reported a case of APS-2 similar to the current case; their patient had AD, HT and AIH with MG without thymoma and with no bronchial asthma but had HLA-A23, B52/62, and DR11/15 [9]. DR11 was also seen in the current case. Seker, et al. also reported a case of AD and MG with thymoma, but without HT or AIH [10]. They did not examine HLA typing. HLA typing test could be useful for patients with multiple autoimmune diseases to determine a common immunological factor. HLA typing test would reveal various disease-susceptible and disease-protective alleles. Thus, early prediction and intervention of the diseases may be possible, and such information could help patient care in the long-term.\n\nGiven that development of bronchial asthma is reported to be associated with HLA inheritance [11], concomitance of AD, HT, thymoma-associated MG, and possibly bronchial asthma, could be related to common HLA allele or haplotypes. Since autoantigen is presented on the surface of antigen-presenting cells with HLA-class I (cytotoxic effects of CD8+ T-cells) or HLA-class II (effector effects of CD4+ T-cells), common antigen may also be involved in multiple diseases. A common antigen among AD, HT, AIH, MG, and possibly bronchial asthma, may cause cross presentation and cross immuno-reactions, and this may in part explain the etiology in our case.\n\nInterestingly, thymoma is often related to autoimmune diseases [2, 3, 9, 12]. In a long-term follow up (60 months) of 85 patients with thymoma, 47 patients had autoimmune diseases, 33 patients had MG, 4 patients had HT, and 1 patient had AIH [12].\n\nSerum levels of TgAb and TPOAb were increased, in contrast with the decreased levels of anti-AchR-Ab during the course, suggesting that TgAb and TPOAb were not indicators for progression of HT [13]. Indeed, thyroid function had been normal during the long course, and HT did not worsen after thymectomy.\n\nIn conclusion, our long-term observation highlighted the autoimmune aspects of a patient with very rare concomitant presentation of APS-2 and AIH with thymoma-associated MG, and with bronchial asthma. Early steroid intervention and thymectomy seemed to be effective treatment. This case suggests common endocrinological and autoimmune aspects of APS-2 and AIH with thymoma-associated MG.\n\nAbbreviations\nACAAdrenal cortex autoantibodies\n\nAchRAcetylcholine receptor\n\nACTHAdrenocorticotropic hormone\n\nADAddison’s disease\n\nAIHAutoimmune hepatitis\n\nANAAntinuclear antibody\n\nAPS-2Autoimmune polyglandular syndrome type 2\n\nHTHashimoto’s thyroiditis\n\nMGMyasthenia gravis\n\nPSLPrednisolone\n\nTgAbAnti-thyroglobulin antibody\n\nTPOAbAnti-thyroperoxidase antibody\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors thank the patient and her daughter for their participation. All authors have adhered to CARE guidelines/methodology. We acknowledge proofreading and editing by Benjamin Phillis (Wakayama Medical University).\n\nAuthors’ contributions\nHIN, HA, HIK, CK, YU, SU, YF, YNY, and TO participated in the diagnosis and treatment of the patient, collected data, interpreted data, and wrote the manuscript. KT and SM drafted work, conducted investigations, reviewed publications, and helped in reviewing the manuscript. HIT, YNM, and TA played an important role in the management of the patient, and substantively revised the manuscript. All of the authors read and approved the final manuscript.\n\nFunding\nThe study was supported by Takeda Science Foundation in the collection of data and in writing the manuscript.\n\nAvailability of data and materials\nAll data related to this report are stored at Wakayama Medical University (Wakayama, Japan), and are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent for publication of the case was obtained from the patient. A copy of the consent form is available for review by the editor of the journal.\n\nCompeting interests\nAll authors (HIN, HA, HIK, CK, YU, SU, KT, YF, SM, YNY, TO, HIT, YNM, and TA) have no competing interests.\n==== Refs\nReferences\n1. Betterle C Dal Pra C Mantero F Zanchetta R Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction Endocr RevEndocr Rev 2002 23 3 327 364 10.1210/edrv.23.3.0466 \n2. Romi F. Thymoma in Myasthenia Gravis: From Diagnosis to Treatment. Autoimmune Dis. 2011;474512. 10.4061/2011/474512.\n3. Mao ZF Yang LX Mo XA Qin C Lai YR He NY Li T Hackett ML Frequency of autoimmune diseases in myasthenia gravis: a systematic review Int J Neurosci 2011 121 3 121 129 10.3109/00207454.2010.539307 21142828 \n4. Yoshizawa K Ota M Katsuyama Y Ichijo T Matsumoto A Tanaka E Kiyosawa K Genetic analysis of the HLA region of Japanese patients with type 1 autoimmune hepatitis J HepatolJ Hepatol 2005 42 4 578 584 10.1016/j.jhep.2004.12.019 15763345 \n5. Asakawa H Kashihara T Fukuda H Yamamoto M A patient with thymoma and four different organ-specific autoimmune diseases Neth J MedNeth J Med 2002 60 292 295 \n6. Konno S Ichijo T Murata M Toda T Nakazora H Nomoto N Sugimoto H Nemoto H Kurihara T Wakata N Autoimmune polyglandular syndrome type 2 with myasthenia gravis crisis Neurologist 2009 15 6 361 363 10.1097/NRL.0b013e3181945437 19901721 \n7. Ueda S Oryoji D Yamamoto K Noh JY Okamura K Noda M Kashiwase K Kosuga Y Sekiya K Inoue K Identification of independent susceptible and protective HLA alleles in Japanese autoimmune thyroid disease and their epistasis J Clin Endocrinol MetabJ Clin Endocrinol Metab 2014 99 2 E379 E383 10.1210/jc.2013-2841 24285682 \n8. Horiki T Inoko H Moriuchi J Ichikawa Y Arimori S Combinations of HLA-DPB1 and HLA-DQB1 alleles determine susceptibility to early-onset myasthenia gravis in Japan Autoimmunity 1994 19 1 49 54 10.3109/08916939409008008 7749041 \n9. Müller-Hermelink HK Marx A Pathological aspects of malignant and benign thymic disorders Ann MedAnn Med 1999 31 Suppl 2 5 14 \n10. Seker M Gozu HI Oven Ustaalioğlu BB Sonmez B Erkal FY Kocak M Barisik NO Orbay E Sargin M Sargin H Myasthenia gravis and autoimmune Addison disease in a patient with thymoma Clin Lung Cancer 2009 10 5 367 370 10.3816/CLC.2009.n.051 19808197 \n11. Yao Y Zhu L Li J Jin Y He L Association of HLA-DRB1 gene polymorphism with risk of asthma: a meta-analysis Med Sci Monit Basic ResMed Sci Monit Basic Res 2016 22 80 86 10.12659/MSMBR.900193 \n12. Bernard C Frih H Pasquet F Kerever S Jamilloux Y Tronc F Guibert B Isaac S Devouassoux M Chalabreysse L Thymoma associated with autoimmune diseases: 85 cases and literature review Autoimmun RevAutoimmun Rev 2016 15 1 82 92 10.1016/j.autrev.2015.09.005 \n13. Akamizu T Amino N Feingold KR Anawalt B Boyce A Chrousos G Dungan K Grossman A Hershman JM Kaltsas G Koch C Kopp P Hashimoto’s Thyroiditis Endotext [Internet] 2000 South Dartmouth (MA) MDText.com, Inc\n\n", "fulltext_license": "CC BY", "issn_linking": "1472-6823", "issue": "20(1)", "journal": "BMC endocrine disorders", "keywords": "Autoimmune Addison’s disease; Autoimmune hepatitis; Autoimmune polyglandular syndrome type 2 (APS-2); Bronchial asthma; Hashimoto’s thyroiditis; Thymoma-associated myasthenia gravis", "medline_ta": "BMC Endocr Disord", "mesh_terms": "D005260:Female; D019693:Hepatitis, Autoimmune; D006801:Humans; D008875:Middle Aged; D009157:Myasthenia Gravis; D016884:Polyendocrinopathies, Autoimmune; D011379:Prognosis; D013945:Thymoma; D013953:Thymus Neoplasms", "nlm_unique_id": "101088676", "other_id": null, "pages": "47", "pmc": null, "pmid": "32264857", "pubdate": "2020-04-07", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12050123;21860784;7749041;27503745;19901721;24285682;10574149;12430577;26408958;15763345;19808197;21142828", "title": "Autoimmune polyglandular syndrome type 2 and autoimmune hepatitis with thymoma-associated myasthenia gravis: case report.", "title_normalized": "autoimmune polyglandular syndrome type 2 and autoimmune hepatitis with thymoma associated myasthenia gravis case report" }
[ { "companynumb": "JP-NAPPMUNDI-GBR-2020-0076686", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUDESONIDE\\FORMOTEROL FUMARATE" }, "drug...
{ "abstract": "Specific genetic deficiencies are a rare cause that should be included in the diagnostic algorithm of disseminated herpetic lesions. The aim of this article is to describe the ocular herpetic manifestations in a rare genetic disorder called GATA2 deficiency. We present the clinical case of a 26-year-old male with dendritic ulcers in his cornea, marrow aplasia and idiopathic chronic lymphedema. He was diagnosed with GATA2 deficiency. GATA2 gene is critical for the genesis and function of hematopoietic stem cells. Its deficiency can cause myelodysplastic syndromes, congenital lymphedema and severe viral infections. Our patient presented these three manifestations, added to a deletion in 20q12 that confirmed the suspicion of GATA2 mutation. A bone marrow transplant was suggested as definitive treatment. The corneal herpetic epithelial lesion was analogous to a regular hepetic keratitis with none stromal keratitis.", "affiliations": "12 de Octubre University Hospital, Ophthalmology Department, Complutense University, Madrid, Spain.;12 de Octubre University Hospital, Ophthalmology Department, Complutense University, Madrid, Spain.;12 de Octubre University Hospital, Ophthalmology Department, Complutense University, Madrid, Spain.;12 de Octubre University Hospital, Ophthalmology Department, Complutense University, Madrid, Spain.", "authors": "Ortueta-Olartecoechea|Ana I|AI|;Torres-Peña|José L|JL|;Palacios-Hípola|Ana I|AI|;Mencia-Gutierrez|Enrique|E|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.1016/j.sjopt.2017.11.001", "fulltext": "\n==== Front\nSaudi J OphthalmolSaudi J OphthalmolSaudi Journal of Ophthalmology1319-4534Elsevier S1319-4534(17)30140-610.1016/j.sjopt.2017.11.001Case ReportHerpetic ocular manifestations in a patient with GATA2 deficiency Ortueta-Olartecoechea Ana I. Torres-Peña José L. jos_luit@hotmail.com⁎Palacios-Hípola Ana I. Mencia-Gutierrez Enrique 12 de Octubre University Hospital, Ophthalmology Department, Complutense University, Madrid, Spain⁎ Corresponding author. jos_luit@hotmail.com13 11 2017 Apr-Jun 2018 13 11 2017 32 2 164 166 16 10 2016 4 11 2017 5 11 2017 © 2017 The Authors. Production and hosting by Elsevier B.V. on behalf of Saudi Ophthalmological Society, King Saud University.2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Specific genetic deficiencies are a rare cause that should be included in the diagnostic algorithm of disseminated herpetic lesions. The aim of this article is to describe the ocular herpetic manifestations in a rare genetic disorder called GATA2 deficiency. We present the clinical case of a 26-year-old male with dendritic ulcers in his cornea, marrow aplasia and idiopathic chronic lymphedema. He was diagnosed with GATA2 deficiency. GATA2 gene is critical for the genesis and function of hematopoietic stem cells. Its deficiency can cause myelodysplastic syndromes, congenital lymphedema and severe viral infections. Our patient presented these three manifestations, added to a deletion in 20q12 that confirmed the suspicion of GATA2 mutation. A bone marrow transplant was suggested as definitive treatment. The corneal herpetic epithelial lesion was analogous to a regular hepetic keratitis with none stromal keratitis.\n\nKeywords\nGATA2 deficiencyHerpetic keratitisHIVMyelodysplastic syndrome20q12 deletionFoscarnetHerpetic disseminated infection\n==== Body\nIntroduction\nCutaneous and ocular disseminated herpetic lesions have many causes, such as human immunodeficiency virus (HIV) infection, chemotherapy treatment or primary immunodeficiency. Specific genetic deficiencies are an unusual cause that should be included in the diagnostic algorithm. The lack of an effective cell mediated immune response in immunocompromised patients may result in a huge viral load, may be implicated in a prolonged course of cutaneous infection and resistance to antiviral treatment.1, 2\n\nWe present a clinical case of a young man with periocular, ocular and systemic herpetic lesions, due to a deficiency in GATA2 gene. This is a human gene encoding a protein called GATA binding protein 2, which is a transcription factor that regulates hematopoietic stem cell homeostasis. There are few cases that can be found in literature.\n\nCase report\nA 26-year-old male came to our clinics, referred with red eye, pain and superior eyelid swelling in his left eye for 1 week. He had previously been diagnosed with cellulitis because of cutaneous erythematous lesions in his left leg and he had been treated with oral amoxicillin.\n\nIn his medical background, a diagnosis of bone marrow aplasia from four years ago was found. It had been treated with danazol; in addition, there was an idiopathic chronic lymphedema diagnosis from 13 years ago.\n\nIn the ophthalmological examination, he presented with upper left eyelid edema and reactive conjunctival chemosis; the cornea was clear. He was treated for an external hordeulum with hydrocortisone-oxytetracycline-polymyxin B ointment. Two days later he developed two paracentral dendritic ulcers that stained with fluorescein but with no underlying stromal involvement in his left cornea (Fig. 1), and the upper eyelid edema persisted. At that point his best corrected visual acuity (BCVA) on the decimal scale was 0.3, which improved to 0.5 with pinhole in his right eye and 0.5 without improvement with pinhole in his left eye. Intraocular pressure was 15 mmHg in both eyes. The hydrocortisone-oxytetracycline-polymyxin B ointment was suspended and treatment with acyclovir ointment 5 times a day and a topical lubrication ointment 3 times a day was then started.Fig. 1 Herpes keratitis in his left eye.\n\n\n\nAt the same time, he presented herpetic lesions in his left leg, fever and massive aphthous-like ulcerations in oral mucosa with pseudomembranes (Fig. 2). His blood tests detected leukopenia 800 cel/µl (4000–11,300), neutropenia and prothrombin activity of 43% (75–140). Also the ALT 2 963 UI (5–45) and the AST 2 667 UI (5–37) were elevated, as the PCR was 33.2 mg/dl (0.10–0.50).Fig. 2 Herpetic lesions in his left leg (A); and massive aphthous-like ulcerations in oral mucosa with pseudomembranes (B).\n\n\n\nThe treatment with amoxicillin was suspended as no improvement of the cutaneous lesions was detected and treatment with meropenem, acyclovir and nystatin was started, as a prophylaxis for his leukopenia. Several serology tests for cytomegalovirus, Epstein-Barr virus, herpes zoster, herpes simplex, syphilis and hepatitis A, B and C were performed, all of them with negative results. The skin and oral lesions biopsy were positive for herpes simplex virus type 2 (HSV–2). The corneal dendritic ulcer persisted despite topical acyclovir. A bone marrow biopsy was informed for myelodysplastic syndrome with multilineage dysplasia, and a severe decrease in the Natural Killer (NK) cell activity, monocytopenia, and a B leukocyte deficit. For these reasons, it was suspected that the patient carried a GATA2 deficiency; this was confirmed by a deletion in 20q12. Tests for deletions 5q31 and 7q31 were negative.\n\nThe skin lesions continued despite systemic acyclovir treatment. Three weeks later, the treatment was changed to systemic foscarnet, with good clinical response in the skin and oral lesions. After the resolution of the dendritic ulcers, the BCVA in his left eye was 0.7.\n\nA bone marrow transplant was suggested, but the patient refused, as he wanted to be followed up in his country of origin.\n\nDiscussion\nSystemic herpetic lesions are associated with primary or secondary immunodeficiency syndromes, with the secondary being more frequent. Previous studies have documented a high prevalence of HSV-1 and HSV-2 in HIV-infected homosexual men and have shown that HSV manifestations may become chronic in such patients.3 Regarding primary causes, gene deficiency is rare, and needs high level of suspicion to be recognized. Our patient presented a deficiency in GATA2 gene, which was detected after a complete systemic study.\n\nThe GATA gene belongs to a family of zinc finger transcription factors that regulates stem cell homeostasis.4 There are 3 types of GATA. GATA1 works primarily in erythropoiesis and megakaryopoiesis and GATA3 in T-cell lymphopoiesis. GATA2 is particularly critical for hematopoietic stem and progenitor cells genesis and function and, thus, all subsequent blood cell lineages.\n\nThe clinical hallmarks of GATA2 deficiency include infections with human papillomaviruses (HPV) and nontuberculous mycobacteria (NTM), predisposition to myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML), pulmonary alveolar proteinosis (PAP), and congenital lymphedema.5\n\nInitial clinical presentations are variable: severe viral infections, disseminated NTM infections, MDS/AML, lymphedema, and invasive fungal infections. From those, our patient presented a severe HSV infection, MDS and lymphedema.\n\nSevere viral infections are the most common presentation, particularly with HPV and herpesvirus reactivations that include keratitis, herpes stomatitis, esophagitis or genital lesions and varicella.\n\nThis susceptibility may be attributed to deficiency and/or dysfunction of NK cells, which are critical for antiviral immunity.6\n\nIn patients with primary immunodeficiency, we have to consider an increased treatment resistance.7 That is what happened to our patient, who had a poor response to acyclovir but a good one to foscarnet.\n\nThe ophthalmological management of these patients is similar to those with no inmunodeficency. Our patient received treatment with acyclovir ointment and a topical lubrication ointment with a good outcome. The corneal epithelial lesion is not different from other herpetic keratitis; which is attributed to the cytopathic effect of the virus. Furthermore, the vision impairment in stromal keratitis is believed to represent an immunopathological response to virus. Stromal disease appears, at least in part, to be an immunological lymphocyte response to HSV antigens in the cornea. It is thus conceivable that the lymphocyte dysfunction associated with immunosuppression by immunodeficiencies might have actually protected this patient against developing stromal keratitis.7\n\nCongenital immune deficiencies are rare; that is why both a high degree of suspicion and the work of a multidisciplinary team are required to reach a clinical diagnosis which later becomes a genetic one. In this case the herpetic keratitis was an early manifestation of the systemic viral infection, which had a good response to a second line treatment with foscarnet.\n\nConflict of interest\nThe authors declared that there is no conflict of interest.\n\nPeer review under responsibility of Saudi Ophthalmological Society, King Saud University.\n==== Refs\nReferences\n1 Hoppenjans W.B. Bibler M.R. Orme R.L. Solinger A.M. Prolongated cutaneus herpes zoster in acquired immunodeficiency syndrome Arch Dermatol 126 1990 1048 1050 2166483 \n2 Dilley D. Chandler R.G. Gupta A. Resistant herpes infection of the palm in a patient with acquired immunodeficiency syndrome: a case report J Hand Surg Am 22 1997 650 652 9260621 \n3 Safrin S. Ashley R. Houlihan C. Cusick P.S. Mills J. Clinical and serologic features of herpes simplex virus infection in patients with AIDS AIDS 5 1991 1107 1110 1657040 \n4 Chou J. Lutskiy M. Tsitsikov E. Notarangelo L.D. Geha R.S. Dioun A. Presence of hypogammaglobulinemia and abnormal antibody responses in GATA 2 deficiency J Allergy Clin Immunol 134 2014 223 226 24726394 \n5 Dickinson R.E. Milne P. Jardine L. Zandi S. Swierczek S.I. McGovern N. The evolution of cellular deficiency in GATA 2 mutation Blood 123 2014 863 874 24345756 \n6 Spinner M.A. Sanchez L.A. Hsu A.P. Shaw P.A. Zerbe C.S. Calvo K.R. GATA 2 deficiency: a protean disorder of hematopoiesis, lymphatics and immunity Blood 123 2014 809 821 24227816 \n7 Pramod N.P. Hari R. Sudhamathi K. Ananadakannan K. Thyagarajan S.P. Influence of human immunodeficiency virus status on the clinical history of herpes simplex keratitis Ophthalmologica 214 2000 337 340 10965247\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1319-4534", "issue": "32(2)", "journal": "Saudi journal of ophthalmology : official journal of the Saudi Ophthalmological Society", "keywords": "20q12 deletion; Foscarnet; GATA2 deficiency; HIV; Herpetic disseminated infection; Herpetic keratitis; Myelodysplastic syndrome", "medline_ta": "Saudi J Ophthalmol", "mesh_terms": null, "nlm_unique_id": "9425601", "other_id": null, "pages": "164-166", "pmc": null, "pmid": "29942189", "pubdate": "2018", "publication_types": "D016428:Journal Article", "references": "1657040;9260621;10965247;2166483;24345756;24726394;24227816", "title": "Herpetic ocular manifestations in a patient with GATA2 deficiency.", "title_normalized": "herpetic ocular manifestations in a patient with gata2 deficiency" }
[ { "companynumb": "ES-BAUSCH-BL-2018-018878", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": "3", ...
{ "abstract": "BACKGROUND\nDelayed ipsilateral intraparenchymal hemorrhage (IPH) has been reported following technically successful treatment of intracranial aneurysms using flow-diverting stents in up to 8.5% of patients. We report a similar, though less frequent phenomenon in the setting of stent-assisted coil embolization.\n\n\nMETHODS\nInstitutional review board approval was obtained. A retrospective analysis of a prospective neurointerventional procedure registry was performed to review all IPHs that occurred in aneurysm patients within 90 days of endovascular treatment performed between November 2002 and November 2014 at one institution. Age, sex, hypertension, dual antiplatelet therapy, and technical details of the procedure were recorded.\n\n\nRESULTS\nA total of 1697 patients underwent endovascular treatment of an intracranial aneurysm without a flow diverter at our institution during the study period. Among these, 138 patients underwent stent-assisted coiling (8.1%). Of these, three patients (2.2%) suffered a delayed IPH within the vascular territory distal to the treated lesion (one woman, median age 60 years).\n\n\nCONCLUSIONS\nRecently described in the setting of flow diversion, delayed ipsilateral IPH is not limited to flow-diverting stents. Though less frequent, a potential for this complication may exist following any intracranial stenting procedure, possibly related to hemorrhagic conversion of microembolic phenomena in the setting of dual antiplatelet or anticoagulation therapy.", "affiliations": "Division of Interventional Neuroradiology, Neuroscience Institute, Abbott Northwestern Hospital, Consulting Radiologists Ltd, Mail Route 11113, 800 E. 28th Street, Minneapolis, MN, 55407, USA. yasha.kayan@crlmed.com.;Division of Interventional Neuroradiology, Neuroscience Institute, Abbott Northwestern Hospital, Consulting Radiologists Ltd, Mail Route 11113, 800 E. 28th Street, Minneapolis, MN, 55407, USA.;Division of Interventional Neuroradiology, Neuroscience Institute, Abbott Northwestern Hospital, Consulting Radiologists Ltd, Mail Route 11113, 800 E. 28th Street, Minneapolis, MN, 55407, USA.;Division of Interventional Neuroradiology, Neuroscience Institute, Abbott Northwestern Hospital, Consulting Radiologists Ltd, Mail Route 11113, 800 E. 28th Street, Minneapolis, MN, 55407, USA.;Division of Interventional Neuroradiology, Neuroscience Institute, Abbott Northwestern Hospital, Consulting Radiologists Ltd, Mail Route 11113, 800 E. 28th Street, Minneapolis, MN, 55407, USA.;Division of Interventional Neuroradiology, Neuroscience Institute, Abbott Northwestern Hospital, Consulting Radiologists Ltd, Mail Route 11113, 800 E. 28th Street, Minneapolis, MN, 55407, USA.", "authors": "Kayan|Yasha|Y|http://orcid.org/0000-0002-7747-0188;Delgado Almandoz|Josser E|JE|;Fease|Jennifer L|JL|;Tran|Kira|K|;Milner|Anna M|AM|;Scholz|Jill M|JM|", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.1007/s00234-015-1624-3", "fulltext": null, "fulltext_license": null, "issn_linking": "0028-3940", "issue": "58(3)", "journal": "Neuroradiology", "keywords": "Aneurysm; Complication; Hemorrhage; Intervention; Stent", "medline_ta": "Neuroradiology", "mesh_terms": "D000368:Aged; D015984:Causality; D002533:Cerebral Angiography; D002543:Cerebral Hemorrhage; D015897:Comorbidity; D057510:Endovascular Procedures; D005260:Female; D061847:Hospitals, High-Volume; D006801:Humans; D015994:Incidence; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D008910:Minnesota; D011183:Postoperative Complications; D012307:Risk Factors; D015607:Stents; D016896:Treatment Outcome", "nlm_unique_id": "1302751", "other_id": null, "pages": "261-6", "pmc": null, "pmid": "26615534", "pubdate": "2016-03", "publication_types": "D016428:Journal Article", "references": "21990807;23803136;22821921;16235046;20150304;19349825;11158880;22403783;15276392;23521463;25340018;23314576;23828107;24320006;26251427;25355814;23418004;24353331;25352581", "title": "Incidence of delayed ipsilateral intraparenchymal hemorrhage after stent-assisted coiling of intracranial aneurysms in a high-volume single center.", "title_normalized": "incidence of delayed ipsilateral intraparenchymal hemorrhage after stent assisted coiling of intracranial aneurysms in a high volume single center" }
[ { "companynumb": "US-BAYER-2016-070907", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "dr...
{ "abstract": "A 20-year-old man with end-stage renal disease was scheduled to have an ABO-incompatible living kidney transplantation donated by his mother. His complete blood count including differential white blood cell count was normal before preoperative immunosuppressive therapy including mycophenolate mofetil (MMF), tacrolimus (FK506), and prednisolone was started 3 weeks before the operation. The dosage of MMF was initially 2,000 mg/day, but was reduced to 500 mg/day due to diarrhea 10 days before the operation. He received rituximab 13 days before the operation. The neutrophil (Neu) count was 3,100/μl a day before the operation. Transplant surgery was finished without any complications. The Neu count was found to be 300/μl on the day and 80/μl the next day. Granulocyte colony-stimulating factor was administered daily. Then the Neu count increased to 9,100/μl on postoperative day (POD) 2, and was maintained within the normal range. MMF was re-started on POD 12. The dosage was 500 mg, and was increased to 1,000 mg on POD 21. On POD 30 the 12-hr blood concentration of MMF was 117.2 mg× hr/l, which was almost double the adequate target dose. Then the dosage was reduced to 500 mg. In this case MMF is the most suspected drug for drug-induced agranulocytosis. Although MMF-induced neutropenia is frequently observed in transplant recipients, it usually happens three months after transplantation or later. The present case is a rare case as it occurred on the day of transplantation. The pharmacokinetics of MMF varies with the individual. Although routine monitoring of blood concentration of MMF is not recommended, specific attention to prevent overdosage should be given particularly in a patient presenting possible adverse effects including diarrhea and depilation.", "affiliations": "The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.", "authors": "Matsumoto|Keiyu|K|;Kobayashi|Takashi|T|;Murakami|Kaoru|K|;Okubo|Kazutoshi|K|;Negoro|Hiromitsu|H|;Terada|Naoki|N|;Sugino|Yoshio|Y|;Yamasaki|Toshinari|T|;Matsui|Yoshiyuki|Y|;Inoue|Takahiro|T|;Kamba|Tomomi|T|;Yoshimura|Koji|K|;Ogawa|Osamu|O|", "chemical_list": "D007166:Immunosuppressive Agents; D011239:Prednisolone; D009173:Mycophenolic Acid; D016559:Tacrolimus", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0018-1994", "issue": "60(6)", "journal": "Hinyokika kiyo. Acta urologica Japonica", "keywords": null, "medline_ta": "Hinyokika Kiyo", "mesh_terms": "D000380:Agranulocytosis; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D019520:Living Donors; D008297:Male; D009173:Mycophenolic Acid; D059035:Perioperative Period; D011239:Prednisolone; D016559:Tacrolimus; D055815:Young Adult", "nlm_unique_id": "0421145", "other_id": null, "pages": "275-8", "pmc": null, "pmid": "25001642", "pubdate": "2014-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Perioperative agranulocytosis induced by immunosuppressants in a renal graft recipient : a case report.", "title_normalized": "perioperative agranulocytosis induced by immunosuppressants in a renal graft recipient a case report" }
[ { "companynumb": "JP-ACCORD-024914", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, ...
{ "abstract": "The clinical and neurodevelopmental features are presented of four children--two sibling pairs--who were exposed in utero to valproic acid. One of each pair of children presented for diagnosis and assessment of developmental delay; the other sibling was examined at a later date. Three of the children were globally developmentally delayed with marked speech disability, and had dysmorphic features consistent with fetal valproate syndrome. One also had features of infantile autism. The fourth child had some of the dysmorphic features connected with fetal valproate syndrome, but had normal intellect, with his verbal ability being significantly below his non-verbal ability. He currently attends a school for learning-disabled children.", "affiliations": "Department of Paediatrics, University of the Witwatersrand, Johannesburg, South Africa.", "authors": "Christianson|A L|AL|;Chesler|N|N|;Kromberg|J G|JG|", "chemical_list": "D002998:Clonazepam; D014635:Valproic Acid", "country": "England", "delete": false, "doi": "10.1111/j.1469-8749.1994.tb11858.x", "fulltext": null, "fulltext_license": null, "issn_linking": "0012-1622", "issue": "36(4)", "journal": "Developmental medicine and child neurology", "keywords": null, "medline_ta": "Dev Med Child Neurol", "mesh_terms": "D000328:Adult; D001321:Autistic Disorder; D002675:Child, Preschool; D002998:Clonazepam; D002658:Developmental Disabilities; D004827:Epilepsy; D005190:Family; D005260:Female; D005385:Fingers; D006801:Humans; D007361:Intelligence Tests; D007859:Learning Disabilities; D008297:Male; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects; D013577:Syndrome; D014635:Valproic Acid", "nlm_unique_id": "0006761", "other_id": null, "pages": "361-9", "pmc": null, "pmid": "7512516", "pubdate": "1994-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Fetal valproate syndrome: clinical and neuro-developmental features in two sibling pairs.", "title_normalized": "fetal valproate syndrome clinical and neuro developmental features in two sibling pairs" }
[ { "companynumb": "ZA-MYLANLABS-2018M1045294", "fulfillexpeditecriteria": "1", "occurcountry": "ZA", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, ...
{ "abstract": "Sydenham's chorea (SC) is an immune-mediated hyperkinetic movement disorder, developing after group A Beta-hemolytic streptococcal (GABHS) infection. Aside from conventional symptomatic treatment (carbamazepine, valproate, neuroleptics), the use of steroids has also been advocated, mainly in severe, drug-resistant cases or if clinically disabling side effects develop with first line therapies. Based on the description of 5 cases followed in the Child Neurology Unit of Santa Maria Nuova Hospital in Reggio Emilia and on the available medical literature on this topic, we propose considering the use of corticosteroids therapy in children with SC, with the administration of IV methyl-prednisolone followed by oral deflazacort in severe cases and of oral deflazacort alone in mild and moderate degrees of involvement. In our experience this therapy is effective both in the short and long-term period, in different clinical presentations (chorea paralytica, distal chorea, hemichorea, \"classic\" chorea, association with mood disorder or dyspraxia) and very well tolerated (no significant side effects were recorded).", "affiliations": "Department of Pediatrics, Child Neurology and Psychiatry Unit, Arcispedale Santa Maria Nuova, IRCCS, Viale Risorgimento 80, 42123 Reggio Emilia, Italy. Electronic address: fusco.carlo@asmn.re.it.;Department of Pediatrics, Child Neurology and Psychiatry Unit, Arcispedale Santa Maria Nuova, IRCCS, Viale Risorgimento 80, 42123 Reggio Emilia, Italy.", "authors": "Fusco|C|C|;Spagnoli|C|C|", "chemical_list": "D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D011282:Pregnenediones; C021988:deflazacort; D008775:Methylprednisolone", "country": "England", "delete": false, "doi": "10.1016/j.ejpn.2017.11.011", "fulltext": null, "fulltext_license": null, "issn_linking": "1090-3798", "issue": "22(2)", "journal": "European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society", "keywords": "Corticosteroids; Deflazacort; Methyl-prednisolone; Outcome; Sydenham's chorea; Treatment", "medline_ta": "Eur J Paediatr Neurol", "mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D002648:Child; D002675:Child, Preschool; D002819:Chorea; D005260:Female; D006801:Humans; D008297:Male; D008775:Methylprednisolone; D011282:Pregnenediones", "nlm_unique_id": "9715169", "other_id": null, "pages": "327-331", "pmc": null, "pmid": "29287833", "pubdate": "2018-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Corticosteroid treatment in Sydenham's chorea.", "title_normalized": "corticosteroid treatment in sydenham s chorea" }
[ { "companynumb": "IT-TEVA-2018-IT-872236", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CHLORPROMAZINE" }, "drugadditional": "3", ...
{ "abstract": "Stomatitis is a class effect associated with the inhibition of mTOR and is associated with everolimus therapy for breast cancer. Topical steroids might reduce stomatitis incidence and severity, and the need for dose reductions and interruptions of everolimus. Anecdotal use of topical steroid oral prophylaxis has been reported in patients with breast cancer. We aimed to assess dexamethasone-based mouthwash for prevention of stomatitis in patients with breast cancer.\n\n\n\nThis US-based, multicentre, single-arm, phase 2 prevention study enrolled women aged 18 years and older with postmenopausal status who had histologically or cytologically confirmed metastatic hormone receptor-positive, HER2-negative breast cancer. Beginning on day 1 of cycle 1, patients received everolimus 10 mg plus exemestane 25 mg daily, with 10 mL of alcohol-free dexamethasone 0·5 mg per 5 mL oral solution (swish for 2 min and spit, four times daily for 8 weeks). After 8 weeks, dexamethasone mouthwash could be continued for up to eight additional weeks at the discretion of the clinician and patient. The primary endpoint was incidence of grade 2 or worse stomatitis by 8 weeks assessed in the full analysis set (patients who received at least one dose of everolimus and exemestane and at least one confirmed dose of dexamethasone mouthwash) versus historical controls from the BOLERO-2 trial (everolimus and exemestane treatment in patients with hormone receptor-positive advanced breast cancer who were not given dexamethasone mouthwash for prevention of stomatitis). This trial is registered at ClinicalTrials.gov, number NCT02069093.\n\n\n\nBetween May 28, 2014, and Oct 8, 2015, we enrolled 92 women; 85 were evaluable for efficacy. By 8 weeks, the incidence of grade 2 or worse stomatitis was two (2%) of 85 patients (95% CI 0·29-8·24), versus 159 (33%) of 482 patients (95% CI 28·8-37·4) for the duration of the BOLERO-2 study. Overall, 83 (90%) of 92 patients had at least one adverse event. The most frequently reported grade 3 and 4 adverse events in the safety set were hyperglycaemia (seven [8%] of 92 patients), rash (four [4%]), and dyspnoea (three [3%]). Serious adverse events were reported in 20 (22%) patients; six (7%) were deemed treatment related, with dyspnoea (three [3%]) and pneumonia (two [2%]) reported most frequently. 12 (13%) of 92 patients had adverse events suspected to be related to treatment that led to discontinuation of everolimus and exemestane (the most common were rash, hyperglycaemia, and stomatitis, which each affected two [2%] patients).\n\n\n\nProphylactic use of dexamethasone oral solution substantially reduced the incidence and severity of stomatitis in patients receiving everolimus and exemestane and could be a new standard of oral care for patients receiving everolimus and exemestane therapy.\n\n\n\nNovartis Pharmaceuticals Corporation.", "affiliations": "University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA. Electronic address: hope.rugo@ucsf.edu.;Los Angeles Cancer Network, Los Angeles, CA, USA.;Highlands Oncology Group, Fayetteville, AR.;University of California Los Angeles School of Medicine, Los Angeles, CA, USA.;Oncology Consultants PA, Department of Research, Houston, TX, USA.;St Luke's Cancer Institute, Kansas City, MO, USA.;Cancer Treatment Centers of America, Atlanta, GA, USA.;Kaiser Permanente Mid-Atlantic States, Gaithersburg, MD, USA.;UC Irvine Health Chao Family Comprehensive Cancer Center, Orange, CA, USA.;Vanderbilt-Ingram Comprehensive Cancer Center, Nashville, TN, USA.;Oncology and Diagnostic Sciences, Dental School and The Marlene and Stewart Greenebaum Comprehensive Cancer Center University of Maryland Medical Center, Baltimore, MD, USA.;The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.;Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.;The University of Texas MD Anderson Cancer Center, Houston, TX, USA.", "authors": "Rugo|Hope S|HS|;Seneviratne|Lasika|L|;Beck|J Thaddeus|JT|;Glaspy|John A|JA|;Peguero|Julio A|JA|;Pluard|Timothy J|TJ|;Dhillon|Navneet|N|;Hwang|Leon Christopher|LC|;Nangia|Chaitali|C|;Mayer|Ingrid A|IA|;Meiller|Timothy F|TF|;Chambers|Mark S|MS|;Sweetman|Robert W|RW|;Sabo|J Randy|JR|;Litton|Jennifer K|JK|", "chemical_list": "D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D009067:Mouthwashes; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D003907:Dexamethasone; D000068338:Everolimus; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; C056516:exemestane", "country": "England", "delete": false, "doi": "10.1016/S1470-2045(17)30109-2", "fulltext": null, "fulltext_license": null, "issn_linking": "1470-2045", "issue": "18(5)", "journal": "The Lancet. Oncology", "keywords": null, "medline_ta": "Lancet Oncol", "mesh_terms": "D000287:Administration, Topical; D000368:Aged; D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D003907:Dexamethasone; D003875:Drug Eruptions; D004417:Dyspnea; D000068338:Everolimus; D005260:Female; D006801:Humans; D006943:Hyperglycemia; D008875:Middle Aged; D009067:Mouthwashes; D009362:Neoplasm Metastasis; D011014:Pneumonia; D018719:Receptor, ErbB-2; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D012720:Severity of Illness Index; D013280:Stomatitis", "nlm_unique_id": "100957246", "other_id": null, "pages": "654-662", "pmc": null, "pmid": "28314691", "pubdate": "2017-05", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial.", "title_normalized": "prevention of everolimus related stomatitis in women with hormone receptor positive her2 negative metastatic breast cancer using dexamethasone mouthwash swish a single arm phase 2 trial" }
[ { "companynumb": "US-MYLANLABS-2017M1042549", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": null, ...
{ "abstract": "Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant tumor that is commonly associated with biallelic alterations of SMARCB1. Recurrent or refractory AT/RT has not been molecularly characterized as well. We present the case of a child with recurrent AT/RT who underwent clinically integrated molecular profiling (germline DNA and tumor DNA/RNA sequencing). This demonstrated a somatic lesion in CDKN1C alongside hallmark loss of SMARCB1. This data allowed us to explore potential personalized therapies for this patient and expose a molecular driver that may be involved in similar cases.", "affiliations": "Departments of *Pediatrics, Division of Pediatric Hematology-Oncology †Pathology §Pediatrics, Division of Neurology, University of Michigan, Ann Arbor ‡Division of Pediatric Hematology-Oncology, Beaumont Hospital, Royal Oak, MI.", "authors": "Tran|Dustin|D|;Camelo-Piragua|Sandra|S|;Gupta|Avneesh|A|;Gowans|Kate|K|;Robertson|Patricia L|PL|;Mody|Rajen|R|;Koschmann|Carl|C|", "chemical_list": "C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57", "country": "United States", "delete": false, "doi": "10.1097/MPH.0000000000000873", "fulltext": null, "fulltext_license": null, "issn_linking": "1077-4114", "issue": "39(8)", "journal": "Journal of pediatric hematology/oncology", "keywords": null, "medline_ta": "J Pediatr Hematol Oncol", "mesh_terms": "D001706:Biopsy; D001921:Brain; D003131:Combined Modality Therapy; D050761:Cyclin-Dependent Kinase Inhibitor p57; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008279:Magnetic Resonance Imaging; D009154:Mutation; D012008:Recurrence; D018335:Rhabdoid Tumor; D017422:Sequence Analysis, DNA; D013724:Teratoma; D016896:Treatment Outcome", "nlm_unique_id": "9505928", "other_id": null, "pages": "e466-e469", "pmc": null, "pmid": "28731921", "pubdate": "2017-11", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": "25542864;25496315;15769941;27157931;21521802;24853101;15254056;25262539;26755072;12142780;25688119;19064966;14964309;20137775;16099835;9892189;26923874;19221586;27095948", "title": "Loss of CDKN1C in a Recurrent Atypical Teratoid/Rhabdoid Tumor.", "title_normalized": "loss of cdkn1c in a recurrent atypical teratoid rhabdoid tumor" }
[ { "companynumb": "US-009507513-1801USA003857", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": null, ...
{ "abstract": "A 69-year-old man was admitted to our hospital in October 2003, for further examination of two liver tumors. He was diagnosed with hepatocellular carcinoma (HCC) arising from decompensated hepatitis B virus (HBV)-related cirrhosis. Long-term lamivudine administration improved liver function dramatically despite repeated treatment for HCC. His Child-Pugh score was 9 points at start of lamivudine treatment, improving to 5 points after 1 year. His indocyanine green at 15 min after injection test score was 48% before lamivudine treatment, improving to 22% after 2 years and to 5% after 4 years. Radiofrequency ablation controlled the HCC foci and maintained his liver function. In April 2009, abdominal computed tomography revealed a tumor thrombus in the right portal vein. Since his indocyanine green test results had improved to less than 10%, we performed a right hepatectomy, which was successful. To our knowledge, there have been no documented reports of patients undergoing successful right hepatectomy for HCC arising from decompensated cirrhosis. The findings observed in our patient indicate the importance of nucleoside analogs for treating HBV-related HCC.", "affiliations": "First Department of Internal Medicine, Oita University, Oita 879-5593, Japan. hondak@oita-u.ac.jp", "authors": "Honda|Koichi|K|;Seike|Masataka|M|;Maehara|Shin-ichiro|S|;Tahara|Koichiro|K|;Anai|Hideaki|H|;Moriuchi|Akira|A|;Muro|Toyokichi|T|", "chemical_list": "D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine", "country": "United States", "delete": false, "doi": "10.3748/wjg.v18.i20.2586", "fulltext": null, "fulltext_license": null, "issn_linking": "1007-9327", "issue": "18(20)", "journal": "World journal of gastroenterology", "keywords": "Decompensated cirrhosis; Hepatectomy; Hepatitis B virus; Hepatocellular carcinoma; Lamivudine", "medline_ta": "World J Gastroenterol", "mesh_terms": "D000368:Aged; D006528:Carcinoma, Hepatocellular; D006498:Hepatectomy; D019694:Hepatitis B, Chronic; D006801:Humans; D019259:Lamivudine; D008103:Liver Cirrhosis; D008113:Liver Neoplasms; D008297:Male; D018894:Reverse Transcriptase Inhibitors", "nlm_unique_id": "100883448", "other_id": null, "pages": "2586-90", "pmc": null, "pmid": "22654459", "pubdate": "2012-05-28", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "14699491;14699490;17914972;14697813;9654535;16521207;15985009;12512035;17295771;7814813;10952248;19789837;10952249;12563138;12514773;15841454;9138281;10421670;10613747;18086120;21278701;1426884;16024289;15470215;15754094;19731239;10365796;20006394;18662281;8646675;12793712;17300703;12198698;6486592", "title": "Lamivudine treatment enabling right hepatectomy for hepatocellular carcinoma in decompensated cirrhosis.", "title_normalized": "lamivudine treatment enabling right hepatectomy for hepatocellular carcinoma in decompensated cirrhosis" }
[ { "companynumb": "JP-GLAXOSMITHKLINE-JP2016GSK192547", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": n...
{ "abstract": "The objectives were to determine the prevalence of and to identify risk factors associated with constriction of the fetal ductus arteriosus (DA) following perioperative indomethacin use for fetal myelomeningocele (MMC) repair. Study design A retrospective chart review study included 100 consecutive fetuses who underwent fetal MMC repair between 2011 and 2018. All patients had fetal echocardiography (FE) on postoperative day (POD)#1 and 2 to detect constriction of the DA. All patients received indomethacin for tocolysis using a standardized protocol. Multivariate regression analysis was carried out to identify the predictors for fetal ductal constriction.\n\n\n\nEighty patients met our study eligibility criteria. Median gestational age at time of surgery was 25 (24-25) weeks. Constriction of the DA was detected in 14 fetuses (17.5%). In five fetuses, this was observed on POD# 1, in seven on POD# 2, and in two on both days. The only independent risk factor for predicting DA constriction was maternal body mass index (BMI) <25 kg/m2 (P = .002).\n\n\n\nIndomethacin therapy following fetal MMC surgery requires careful daily FE surveillance. The association of DA constriction and low BMI suggests that BMI-based dosing of indomethacin may be recommended for perioperative tocolysis in fetal MMC surgery.", "affiliations": "Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Fetal Center, Houston, TX, USA.;Division of Pediatric Cardiology, Baylor College of Medicine and Texas Children's Fetal Center, Houston, TX, USA.;Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Fetal Center, Houston, TX, USA.;Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Fetal Center, Houston, TX, USA.;Department of Neurosurgery, Baylor College of Medicine and Texas Children's Fetal Center, Houston, TX, USA.;Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Fetal Center, Houston, TX, USA.;Department of Pediatric Anesthesiology, Baylor College of Medicine and Texas Children's Fetal Center, Houston, TX, USA.;Department of Pediatric Anesthesiology, Baylor College of Medicine and Texas Children's Fetal Center, Houston, TX, USA.;Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Fetal Center, Houston, TX, USA.;Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Fetal Center, Houston, TX, USA.;Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Fetal Center, Houston, TX, USA.", "authors": "Nassr|Ahmed A|AA|0000-0002-1924-7965;Furtun|Betul Y|BY|;Cortes|Magdalena Sanz|MS|0000-0002-0265-9859;Erfani|Hadi|H|;Whitehead|William E|WE|;Donado|Mayel Y|MY|;Olutoye|Olutoyin|O|;Velez|Mario P|MP|;Espinoza|Jimmy|J|;Belfort|Michael A|MA|;Shamshirsaz|Alireza A|AA|0000-0001-6333-3177", "chemical_list": "D016861:Cyclooxygenase Inhibitors; D007213:Indomethacin", "country": "England", "delete": false, "doi": "10.1002/pd.5655", "fulltext": null, "fulltext_license": null, "issn_linking": "0197-3851", "issue": "40(6)", "journal": "Prenatal diagnosis", "keywords": null, "medline_ta": "Prenat Diagn", "mesh_terms": "D000328:Adult; D015992:Body Mass Index; D015331:Cohort Studies; D003251:Constriction, Pathologic; D016861:Cyclooxygenase Inhibitors; D004373:Ductus Arteriosus; D004452:Echocardiography; D005260:Female; D046128:Fetal Therapies; D005332:Fetoscopy; D005865:Gestational Age; D006801:Humans; D007213:Indomethacin; D008591:Meningomyelocele; D019635:Neurosurgical Procedures; D011247:Pregnancy; D011673:Pulsatile Flow; D012189:Retrospective Studies; D012307:Risk Factors; D016137:Spina Bifida Cystica; D014262:Tricuspid Valve Insufficiency", "nlm_unique_id": "8106540", "other_id": null, "pages": "669-673", "pmc": null, "pmid": "32003478", "pubdate": "2020-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Maternal low body mass index is a risk factor for fetal ductal constriction following indomethacin use among women undergoing fetal repair of spina bifida.", "title_normalized": "maternal low body mass index is a risk factor for fetal ductal constriction following indomethacin use among women undergoing fetal repair of spina bifida" }
[ { "companynumb": "NVSC2020US175009", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MAGNESIUM" }, "drugadditional": "3", "drugad...
{ "abstract": "We report a case of a paediatric patient undergoing urological procedure in which a possible inadvertent intravascular or intraosseous injection of bupivacaine with adrenaline in usual doses caused subsequent cardiac arrest, completely reversed after administration of 20% intravenous lipid emulsion. Early diagnosis of local anaesthetics toxicity and adequate cardiovascular resuscitation manoeuvres contribute to the favourable outcome.", "affiliations": "Edgard Santos Professor University Hospital, Federal University of Bahia, Salvador, BA, Brazil.;Edgard Santos Professor University Hospital, Federal University of Bahia, Salvador, BA, Brazil.;Edgard Santos Professor University Hospital, Federal University of Bahia, Salvador, BA, Brazil.", "authors": "Torres de Araújo Azi|Liana Maria|LM|0000-0002-9466-6537;Figueroa|Diego Grimaldi|DG|;Simas|Ana Amélia Souza|AA|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2016/7826280", "fulltext": "\n==== Front\nCase Rep AnesthesiolCase Rep AnesthesiolCRIACase Reports in Anesthesiology2090-63822090-6390Hindawi Publishing Corporation 10.1155/2016/7826280Case ReportCardiac Arrest after Local Anaesthetic Toxicity in a Paediatric Patient http://orcid.org/0000-0002-9466-6537Torres de Araújo Azi Liana Maria \n*\nFigueroa Diego Grimaldi Simas Ana Amélia Souza Edgard Santos Professor University Hospital, Federal University of Bahia, Salvador, BA, Brazil*Liana Maria Torres de Araújo Azi: liana.araujo@ufba.brAcademic Editor: Kuang-I Cheng\n\n2016 31 10 2016 2016 782628027 8 2016 10 10 2016 Copyright © 2016 Liana Maria Torres de Araújo Azi 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.We report a case of a paediatric patient undergoing urological procedure in which a possible inadvertent intravascular or intraosseous injection of bupivacaine with adrenaline in usual doses caused subsequent cardiac arrest, completely reversed after administration of 20% intravenous lipid emulsion. Early diagnosis of local anaesthetics toxicity and adequate cardiovascular resuscitation manoeuvres contribute to the favourable outcome.\n==== Body\n1. Introduction\nThe caudal block is a procedure often used as a complementary method of analgesia in paediatric surgery. Possible complications of the procedure include intravascular, subarachnoid, or intraosseous injections, all with catastrophic consequences for patients. Intravascular injection occurs in about 1.3 to 10.000 caudal blocks [1].\n\nOverdose toxicity of local anaesthetics has long been known, but its therapy has gained a new ally with the use of lipid emulsions in their treatment [2].\n\nAcceptable theories by which lipid therapy reverses local anaesthetic cardiotoxicity are the “lipid sink” (increasing the clearance of the local anaesthetic from cardiac tissue) and the inhibition of myocardial fatty acid oxidation by the phospholipid [2].\n\nConsent was obtained from the patient for publication of this case.\n\n2. Case Presentation\nA 6-year-old male child, 22 kg, with congenital glaucoma (using Timolol drops for three years) was posted for hypospadias repair. Uneventful general anaesthesia (GA) induction with fentanyl 100 mcg, Propofol 60 mg, and Rocuronium 15 mg occurred and he was intubated with a 5.5 cuffed. Volume-controlled mechanical ventilation (TV = 200 mL and RR = 18 rpm, PEEP = 5 cmH2O, O2 60% in 1,6% sevoflurane) was started and a caudal block in lateral position was performed without difficulty with 12 mL of 0.5% bupivacaine with epinephrine (lack of resistance technique) after negative aspiration for blood or CSF. After supine position, the patient immediately presented hypotension (BP = 60 × 32 mmHg) and cardiac rhythm of ventricular tachycardia with pulse (HR = 176 bpm). Amiodarone hydrochloride 50 mg and epinephrine 20 mcg reverted the rhythm to sinus (HR = 148 bpm, BP = 80 × 45 mmHg). FiO2 was raised to 100%. Local anaesthetic intoxication was hypothesized and lipid emulsion was requested. About two minutes later, the patient had cardiac arrest (pulseless ventricular tachycardia interspersed with ventricular fibrillation) and cardiopulmonary resuscitation was initiated. Amiodarone 50 mg + epinephrine 40 mcg was given and a three-time one-minute intravenous bolus injection of 20% lipid emulsion 1.0 mL·kg−1 was given, with prompt reversion to sinus rhythm. Then, an intravenous infusion of 20% lipid emulsion at 0.25 mL·kg−1·min−1 was administered in the next 30 minutes. Surgery was cancelled.\n\nThe patient also had two new cardiac arrests in pulseless electrical activity about four and nine minutes later from the previous reversal, treated with effective cardiac resuscitation and 40 mcg bolus of adrenaline. Adrenaline infusion at doses 0.1–0.4 mcg·kg−1·min−1 was begun. Thereafter, the patient had no further episodes of arrests. Left femoral artery was punctured and urinary catheterization for diuresis monitoring was done. Blood gas analysis showed pH = 7.09, pO2 = 86 mmHg, pCO2 = 46 mmHg, HCO3 = 14 mEq/L, BE = −15.8, and Sat = 93%. Despite respiratory acidosis, lactate concentration was nearly normal (1.7 mmol·L−1). He was transferred to the Intensive Care Unit and the adrenaline was turned off after 5 hours of its onset (Figure 1). As perfusion improved, respiratory acidosis disappeared blood lactate level decreased to 0.8 mmol·L−1. The patient was kept sedated until normalization of pulmonary and tissue perfusion parameters. Computed tomography of the brain showed no brain damage. He was extubated without sequelae thirty hours after the episode and was discharged home three days later. Formal consent for publication was obtained from patient's mother.\n\n3. Discussion\nLocal anaesthetic toxicity has been reported with almost all kind of regional blocks, including peripheral blockades [3] and caudal blocks [4]. The caudal block is the most easily learned of all regional anaesthetic techniques. It has relatively low risk of complications and a high rate of success. A testing dose can be used to exclude intravascular injection and although desirable it is not commonly performed by most anaesthesiologists. In this case, the ease of injection was used as a parameter for correct placement. The choice of a longer-acting amide LA, such as bupivacaine, improves analgesia after surgery but its cardiotoxicity limits its use [5]. Addition of vasoconstrictors such as epinephrine can dramatically slow its absorption, improving its safety and prolonging the anaesthesia [1]. In this case, the limit dose (3 mg·kg−1) was not achieved and the typical description of progressive biphasic symptoms affecting first the CNS and then CVS [6] was not seen, as he was sedated and curarized.\n\nBeta blockade with Timolol drops before surgery may have difficult cardiac arrest reversion and it could also justify the increasing necessities of adrenaline to maintain hemodynamic stable status.\n\nIntravenous lipid emulsion is a method for rescue for cardiovascular collapse after an inadvertent intravenous injection of local anaesthetics [7]. In cardiac arrest caused by bupivacaine intoxication, first-line rescue with epinephrine and epinephrine + intravenous lipid emulsion (ILE) was more effective with regard to survival [8]. There are several case reports of successful resuscitation after cardiovascular collapse in the adult population but examples in children are scarce and this case seems to be the second one showing features of ventilation/perfusion (V/P) mismatch after ILE in child [4]. The doses used in this case followed the ASRA Practice Advisory [9, 10] and resulted in a complete stop of the arrests about 20 minutes after the beginning of its infusion.\n\nIf ventilation or perfusion is unstable, a ventilation/perfusion (V/Q) mismatch can occur. It can be caused by blood shunting, for example, during atelectasis, or by dead space in the lungs, for example, with a pulmonary embolism, hypovolemia, or on postarrest period in an intubated and well-ventilated patient. Gas analysis just after cardiac recovery showed respiratory acidosis due to V/Q mismatch. Inadequate pulmonary perfusion (yet) to adequately ventilated areas of the lung impairs gas exchange and leads to hypoxia [11]. FiO2 was set to 100% to target SaO2 to 90–94% in the postcardiac arrest period.\n\nDespite the fact that it would have resulted in the same consequences (subsequently pulseless electrical activity cardiac arrest), defibrillation using 2 Joules·kg−1 would be more suitable than amiodarone as the first choice for treatment of the second cardiac arrest. Induced hypothermia was not performed according to PALS guideline [12].\n\nThis case is remarkable because due to the rapid onset of cardiac symptoms intraosseous injection cannot be ruled out. Appropriate conduction of the case favoured a postarrest period without complications.\n\nEthical Approval\nThe responsible institutional review board of our institution gave permission to publish this report.\n\nDisclosure\nThis report was previously presented, in part, at the Medically Challenging Case poster presentation at the ASA Annual Meeting 2013.\n\nCompeting Interests\nAll the authors declare that there is no conflict of interests regarding this publication.\n\nFigure 1\n==== Refs\n1 Giaufré E. Caudal anesthesia in children Cah Anesthesiol 1995 43 3 281 286 7583894 \n2 Ciechanowicz S. Patil V. Lipid emulsion for local anesthetic systemic toxicity Anesthesiology Research and Practice 2012 2012 11 131784 10.1155/2012/131784 2-s2.0-81555204104 \n3 Kamel I. Trehan G. Barnette R. Intralipid therapy for inadvertent peripheral nervous system blockade resulting from local anesthetic overdose Case Reports in Anesthesiology 2015 2015 3 486543 10.1155/2015/486543 \n4 Shenoy U. Paul J. Antony D. Lipid resuscitation in pediatric patients—need for caution? Paediatric Anaesthesia 2014 24 3 332 334 10.1111/pan.12285 2-s2.0-84895063705 24219431 \n5 Lönnqvist P.-A. Morton N. S. Postoperative analgesia in infants and children British Journal of Anaesthesia 2005 95 1 59 68 10.1093/bja/aei065 2-s2.0-21344437523 15668207 15668207 \n6 Mulroy M. F. Systemic toxicity and cardiotoxicity from local anesthetics: incidence and preventive measures Regional Anesthesia and Pain Medicine 2002 27 6 556 561 10.1053/rapm.2002.37127 2-s2.0-0036854808 12430104 \n7 Ozcan M. S. Weinberg G. Update on the use of lipid emulsions in local anesthetic systemic toxicity: a focus on differential efficacy and lipid emulsion as part of advanced cardiac life support International Anesthesiology Clinics 2011 49 4 91 103 10.1097/aia.0b013e318217fe6f 2-s2.0-80053541858 21956080 \n8 Mauch J. Jurado O. M. Spielmann N. Bettschart-Wolfensberger R. Weiss M. Resuscitation strategies from bupivacaine-induced cardiac arrest Paediatric Anaesthesia 2012 22 2 124 129 10.1111/j.1460-9592.2011.03688.x 2-s2.0-84855344838 21883659 \n9 Neal J. M. Bernards C. M. Butterworth J. F. ASRA practice advisory on local anesthetic systemic toxicity Regional Anesthesia and Pain Medicine 2010 35 2 152 161 10.1097/AAP.0b013e3181d22fcd 2-s2.0-77952348314 20216033 20216033 \n10 Neal J. M. Mulroy M. F. Weinberg G. L. American Society of Regional Anesthesia and Pain Medicine checklist for managing local anesthetic systemic toxicity: 2012 version Regional Anesthesia and Pain Medicine 2012 37 1 16 18 10.1097/aap.0b013e31822e0d8a 2-s2.0-84855173510 22189574 \n11 Donoso F. A. Arriagada S. D. Díaz R. F. Cruces R. P. Ventilation strategies in the child with severe hypoxemic respiratory failure Gaceta Medica de Mexico 2015 151 1 75 84 25739487 \n12 Kleinman M. E. De Caen A. R. Chameides L. Special report—pediatric basic and advanced life support: 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations Pediatrics 2010 126 5 e1261 e1318 10.1542/peds.2010-2972a 2-s2.0-78049448034 20956433\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6390", "issue": "2016()", "journal": "Case reports in anesthesiology", "keywords": null, "medline_ta": "Case Rep Anesthesiol", "mesh_terms": null, "nlm_unique_id": "101581025", "other_id": null, "pages": "7826280", "pmc": null, "pmid": "27872765", "pubdate": "2016", "publication_types": "D016428:Journal Article", "references": "7583894;20956433;15668207;22189574;20216033;24219431;21956080;21883659;12430104;25739487;21969824;25767725", "title": "Cardiac Arrest after Local Anaesthetic Toxicity in a Paediatric Patient.", "title_normalized": "cardiac arrest after local anaesthetic toxicity in a paediatric patient" }
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{ "abstract": "Allo-SCT can result in long-term remission in patients with multiple myeloma (MM), although its overall role in disease management remains controversial. We evaluated lenalidomide monotherapy response and tolerability among 18 patients with MM who progressed or relapsed after Allo-SCT, who were enrolled a median of 12 months (range 3-104) following transplant. Treatment duration of lenalidomide was 8 months (range 1-57). Ten patients required dose reductions from 25 to 5-20 mg at a median of three cycles (range 1-12): eight for neutropenia, one for thrombocytopenia and one for myalgias and weakness. Serious adverse events (N=5) included H1N1 influenza (2), bacterial pneumonia (2) and fever, myalgia and hypoxia. Two patients died at 3 and 5 months of gastrointestinal or hepatic GVHD occurring within 1 month of dosing. Responses included complete response (CR) (5), very good partial response (2), partial response (PR) (3), minimal response (1) and stable disease (2) for an overall response rate (≥ PR) of 56%. Ten patients discontinued therapy for progressive disease (PD) at a median of 8.5 (1-43) months. Six patients died from PD. Five patients remained on therapy at 39 months (range 14-57), with four in CR. Lenalidomide for relapse of MM after Allo-SCT can result in extended disease control (>12 months) in 50% of patients.", "affiliations": "1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA [2] Department of Medicine, University of Washington, Seattle, WA, USA.;1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA [2] Department of Medicine, University of Washington, Seattle, WA, USA.;1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA [2] Department of Medicine, University of Washington, Seattle, WA, USA.;1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA [2] Department of Medicine, University of Washington, Seattle, WA, USA.", "authors": "Bensinger|W I|WI|;Green|D J|DJ|;Burwick|N|N|;Becker|P S|PS|", "chemical_list": "D020533:Angiogenesis Inhibitors; D013792:Thalidomide; D000077269:Lenalidomide", "country": "England", "delete": false, "doi": "10.1038/bmt.2013.219", "fulltext": null, "fulltext_license": null, "issn_linking": "0268-3369", "issue": "49(4)", "journal": "Bone marrow transplantation", "keywords": null, "medline_ta": "Bone Marrow Transplant", "mesh_terms": "D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors; D018450:Disease Progression; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009364:Neoplasm Recurrence, Local; D011446:Prospective Studies; D012074:Remission Induction; D013792:Thalidomide; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous", "nlm_unique_id": "8702459", "other_id": null, "pages": "492-5", "pmc": null, "pmid": "24419523", "pubdate": "2014-04", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "18784738;9753033;22442350;23144198;21730266;16757975;23151215;18056678;19682891;15361911;20038719;19471019;16397129;23085463;21690556;17360989;21962393;21269237;22446605;19487069;18070719;12456509", "title": "A prospective study of lenalidomide monotherapy for relapse after Allo-SCT for multiple myeloma.", "title_normalized": "a prospective study of lenalidomide monotherapy for relapse after allo sct for multiple myeloma" }
[ { "companynumb": "US-CELGENE-163-21880-14013158", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null,...
{ "abstract": "Bullous pemphigoid (BP) is a blistering skin disorder infrequent in infancy and rarely reported in medical literature.\n\n\n\nHere we describe three cases of BP which were referred to our department in the last 15 years. Two of them developed an eruption of bullous lesions just a few days after vaccination for diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B and Haemophilus influenzae B. The third patient developed the same blistering lesions shortly after herpetic stomatitis. In all three cases, clinical diagnosis was confirmed by histological examination which showed subepidermal bullae with a dermal inflammatory infiltrate, and direct immunofluorescence of perilesional skin showed linear IgG and C3 deposits along the basement membrane zone. Immunoblot assay was positive for BP antigen 180. Treatment with oral prednisone was instituted and the lesions resolved in two out of three patients; the third one was treated with an immunosuppressive agent (tacrolimus) and corticosteroid and subsequently with intravenous immunoglobulin and plasmapheresis, due to an underlying complex autoimmune disease.\n\n\n\nAlthough the mechanism of induction of BP is still unclear, the close relationship between trigger events (immunization or viral infection) and onset of the disease arises a possible association.", "affiliations": "Dipartimento di Pediatria 1, Ospedale Infantile Regina Margherita, Regina Margherita Children's Hospital, Citta' della Salute e della Scienza di Torino, Piazza Polonia 94, 10126, Turin, Italy.;Dipartimento di Pediatria 1, Ospedale Infantile Regina Margherita, Regina Margherita Children's Hospital, Citta' della Salute e della Scienza di Torino, Piazza Polonia 94, 10126, Turin, Italy.;Dipartimento di scienze mediche, Università degli studi di Torino, Torino, Italy.;Pediatric Department, Chelsea and Westminster Hospital, London, UK.;Dipartimento di Pediatria 1, Ospedale Infantile Regina Margherita, Regina Margherita Children's Hospital, Citta' della Salute e della Scienza di Torino, Piazza Polonia 94, 10126, Turin, Italy. francesco.savino@unito.it.", "authors": "Baroero|Luca|L|;Coppo|Paola|P|;Bertolino|Laura|L|;Maccario|Stefano|S|;Savino|Francesco|F|", "chemical_list": "D016756:Immunoglobulins, Intravenous", "country": "England", "delete": false, "doi": "10.1186/s12887-017-0813-0", "fulltext": "\n==== Front\nBMC PediatrBMC PediatrBMC Pediatrics1471-2431BioMed Central London 81310.1186/s12887-017-0813-0Case ReportThree case reports of post immunization and post viral Bullous Pemphigoid: looking for the right trigger Baroero Luca luca.baroero@gmail.com 1Coppo Paola coppo.paola@gmail.com 1Bertolino Laura laura.bertolino@unito.it 2Maccario Stefano Stefano.Maccario@chelwest.nhs.uk 3Savino Francesco 0039 0113135618francesco.savino@unito.it 11 grid.415778.8Dipartimento di Pediatria 1, Ospedale Infantile Regina Margherita, Regina Margherita Children’s Hospital, Citta’ della Salute e della Scienza di Torino, Piazza Polonia 94, 10126 Turin, Italy 2 0000 0001 2336 6580grid.7605.4Dipartimento di scienze mediche, Università degli studi di Torino, Torino, Italy 3 grid.439369.2Pediatric Department, Chelsea and Westminster Hospital, London, UK 23 2 2017 23 2 2017 2017 17 6011 5 2016 16 2 2017 © The Author(s). 2017\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\nBullous pemphigoid (BP) is a blistering skin disorder infrequent in infancy and rarely reported in medical literature.\n\nCase Presentation\nHere we describe three cases of BP which were referred to our department in the last 15 years. Two of them developed an eruption of bullous lesions just a few days after vaccination for diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B and Haemophilus influenzae B. The third patient developed the same blistering lesions shortly after herpetic stomatitis. In all three cases, clinical diagnosis was confirmed by histological examination which showed subepidermal bullae with a dermal inflammatory infiltrate, and direct immunofluorescence of perilesional skin showed linear IgG and C3 deposits along the basement membrane zone. Immunoblot assay was positive for BP antigen 180. Treatment with oral prednisone was instituted and the lesions resolved in two out of three patients; the third one was treated with an immunosuppressive agent (tacrolimus) and corticosteroid and subsequently with intravenous immunoglobulin and plasmapheresis, due to an underlying complex autoimmune disease.\n\nConclusion\nAlthough the mechanism of induction of BP is still unclear, the close relationship between trigger events (immunization or viral infection) and onset of the disease arises a possible association.\n\nKeywords\nCase reportInfantBullous PemphigoidDrug therapyVaccinationissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nBullous pemphigoid (BP) is an autoimmune blistering skin disorder associated with presence of tissue-bound and circulating IgG autoantibodies directed against hemidesmosomal proteins, called BP antigen 180 and BP antigen 230 [1]. Bullous pemphigoid usually affects the elderly and is rare in childhood and infancy. BP is diagnosed on the basis of clinical, histologic and immunologic findings [2, 3]. Among possible trigger factors of BP, immunization and viral infections are mentioned in literature. Some cases of BP have been reported soon after vaccine administration, although the immunological mechanism underneath is still unclear [4–6].\n\nThe clinical presentation of BP amongst children differs from that seen in adults, notably in terms of acral involvement with predominance of palmoplantar lesions, sparing the mucosa and genital area, in children aged less than 1 year. Unlike in adults, childhood BP has usually a good prognosis and resolves quite rapidly after initiation of treatment [7].\n\nAlthough a clear trigger is not well established for BP, especially in infancy, a combination of multiple factors can be postulated. We present here 3 cases of children younger than 2 years who were referred to our Hospital in the last 15 years after developing BP related in time with a previous episode of vaccination or viral infection.\n\nCase Presentation\nA previously healthy 3-month-old boy was referred to our Hospital with a 15-day history of a blistering eruption on his hands and feet. He received a first dose of combined vaccination against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B and Haemophilus influenzae B 2 days before the onset of the bullous rash. He had been previously treated at home with topical gentamicin and oral co-amoxiclavulante, without resolution of the skin eruption. There was no relevant family history for autoimmune or blistering disorders and no risk factors during pregnancy or delivery had been identified. Infant was breast-fed and growing normally. Clinically he presented with blistering lesions with a prevailing acral distribution: large vesicles and tense bullae with surrounding erythema were seen on the palms and soles, whereas widespread smaller blisters on erythematous skin could be noticed on the trunk and abdomen (Figs. 1 and 2). Mucous membranes were not involved and other systems’ examination was unremarkable. Observations were within normal limits and the patient was afebrile. Results of laboratory investigations showed that the patient had a mild eosinophilia (1.47 × 109/L, 12% of WBC count); inflammatory markers and complement components were normal. Bacteriology analysis of the fluid inside blisters revealed no infections and blood virological tests were negative. A first biopsy for histologic study was taken from a recent vesicular lesion and showed subepidermal blister with a mixed superficial perivascular inflammatory infiltrate with abundant eosinophils. A second biopsy for direct immunofluorescence (DIF) was taken from uninvolved perilesional skin: the results of DIF showed linear deposition of immunoglobulin G (IgG, faint deposits) and complement component 3 (C3, intense deposits) along the basement membrane zone leading to the diagnosis of bullous pemphigoid (Fig. 3). The immunoblot assay was positive for BP antigen 180. Oral steroids have been started with prednisone at 1.5 mg/kg/day for ten days. Once the development of blisters was stopped and erythema had subsided, a careful tapering of prednisone was started, following an alternate day scheme. Considering the severity of the disease and the young age of infants, we started with a higher dose than suggested in guidelines [2]. For the whole duration of steroid treatment, the patient was subjected to a strict follow-up: therapy was well tolerated, with no adverse effects, as hypertension, weight gain, hyperglycemia or other blood test alterations. Prednisone was carefully tapered off over a 2-month period with no evidence of disease relapse and currently the patient is still in remission. Resumption of the vaccination schedule did not induce any recurrence of the disease.Fig. 1 Patient 1: widespread small blisters on erythematous skin of the trunk and abdomen\n\n\nFig. 2 Patient 1: large vesicles and tense bullae with surrounding erythema located in feet, with palm and sole involvement\n\n\nFig. 3 Patient 1: direct immunofluorescence showing linear deposition of IgG along the basement membrane zone\n\n\n\n\nA 17-month-old girl with a history of eczema and autoimmune enteropathy developed a blistering eruption on her hands and feet a few days after the second dose of hexavalent vaccination. Considering the autoimmune disorder affecting her gut, on the recommendation of gastroenterologists, she was treated with an immunosuppressive agent (tacrolimus) and corticosteroid; during a suspension of therapy for remission of gastrointestinal symptoms, she received the first dose of hexavalent vaccination at the age of 15 months with appearance of a single blister on the back of one hand 5 days later. At the age of 17 months 7 days after the second dose of vaccination, she developed a bullous rash on the limbs which subsequently spread to the whole body. Two punch biopsies were taken, one for the histologic examination and the other for DIF, and they led to the diagnosis of bullous pemphigoid. The girl was treated with oral prednisone 1 mg/kg/day; as the lesions did not improve the dose was increased to 2 mg/kg/day but still without benefit. Subsequently she received intravenous Ig and finally plasmapheresis (5 sessions) with full recovery within 6 months. The patient developed over the years an IPEX-like syndrome caused by deficiency of CD25 (IL2-RA), characterized by immunodeficiency and autoimmunity, which was genetically confirmed. She recently underwent a bone marrow transplant with success.\n\nA 2-month-old girl with unremarkable family history for bullous diseases, developed an eruption of bullous lesions, on an erythematous base, confluent, located in both hands and feet, with palm and sole involvement, together with multiple ovaloid erythematous plaques, some with vesicles, on the abdomen. Ten days before she had been diagnosed with acute gingivostomatitis subsequently confirmed by PCR detection of HSV-1 DNA as herpetic stomatitis. At the beginning, to avoid bullous impetigo, the infant was managed with intravenous co-amoxiclavulanate. IgM antibody titer against HSV-1 was positive and suggestive of recent infection. A skin biopsy subsequently confirmed BP, showing sub-epidermal blisters. A second biopsy for direct immunofluorescence DIF showed linear deposits of IgG and C3 at the epidermal BMZ, confirming the diagnosis of bullous pemphigoid. Immunoblot assay was positive for BP antigen 180. The infant was managed with oral prednisone 1 mg/kg/day with rapid improvement, and she became free of blisters after 3 weeks of treatment. Follow-up to 6 months was good.\n\nAll parents of the three reported cases provided written informed consent to the inclusion of data concerning their infants in the manuscript in compliance with the Helsinki Declaration.\n\nDiscussion\nThe reported cases are presentations of bullous pemphigoid, the most prevalent autoimmune blistering skin disease, presenting with tense blisters on erythematous skin, predominantly affecting elderly people and unusual in infancy. Bullous pemphigoid is usually a self-limiting disease with a clinical course that may last from months to years in adults. In childhood and infancy BP usually responds well to conventional treatments, with a good prognosis [8].\n\nThe etiopathogenesis of bullous pemphigoid is complex and during recent years much has been postulated regarding the trigger factors related to the development of this condition, as immunizations and viral infections [9–11]. None of our patients had a suggestive family history for blistering skin disease and specifically their mothers did not develop gestational pemphigoid during pregnancy.\n\nHere we report the case of two infants who developed an eruption of bullous lesions just a few days after vaccination against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B and Haemophilus influenzae B, while the third patient after a viral infection by HSV-1. The latency period ranged between 2 and 10 days. A too short interval from immunization to onset of skin lesions could be considered an argument against the existence of a true relationship: since IgG production begins 10–14 days post-immunization, a 2–3 day latency period would generally be considered too short a time-frame for autoimmune manifestations characterized by IgG deposition to develop. Some authors anyway have suggested that certain vaccines may unmask subclinical BP by inducing a nonspecific immune reactivation in genetically predisposed infants more sensitive to the stimulus [8]. Others hypothesized that intrauterine transmitted maternal IgG antibodies might play a role [4] but a vertical transference of antibodies seems unlikely since in all the cases of PB reported in the literature where tests on mother’s serum were performed, circulating anti-BMZ antibodies were not found [11]. Moreover, according to recent studies, the trauma caused by the vaccine injection may led to Th17 cell activation with increased of IL-17 which is able to release pro-inflammatory cytokines and proteolytic enzymes, which may result in blister formation [12]. Finally, CD25 deficiency may be related to BP, since the lack of CD25+ cells has been observed in bullous pemphigoid lesions [13].\n\nIn literature some tens of cases of childhood BP have been reported, of which about 20 have been related to vaccine administration, but only a few occurred in infants younger than 6 months of age [6, 10, 14]. Anyway, the association of BP and vaccination could be entirely coincidental, given that vaccination in infants is a usual and daily practice in developed countries while cases of BP reported in infants are really limited. The high rate of vaccinations in the first year of life in contrast with the low number of reported cases of BP after vaccination makes it difficult to explain a causal relationship, even if described cases of recurrence after a new dose of vaccination seem to reinforce the hypothesis of a causal association [8].\n\nAlthough the histopathological and immunological features of infantile BP are indistinguishable from those of childhood BP and adult BP, age-related differences in regional distribution of lesions were demonstrated. A recent study found that lesions are more likely located on the extremities during the first year of life [15]. For this reason, the clinical presentation of infantile BP seems to differ from that of childhood and adult BP, which are characterized by tense blisters predominantly appearing along folds in the skin on the lower abdomen, groin, upper thighs and arms. In our cases there was no correspondence between the location of the vaccine administration and the site of occurrence of the first lesions.\n\nThe diagnosis of BP in our three cases has been confirmed with DIF studies on perilesional skin, which showed linear deposits of IgG and/or C3 at the epidermal BMZ [16]. To perform the DIF, frozen sections fixed in acetone at a temperature of 4 °C were incubated with Ig fluorescein isothiocyanate in humid chamber (IgA,IgM,C3 diluite 1/10; IgG 1/20), then rinsed in PBS and covered with anti-fade mounting medium.\n\nLaboratory investigations are nonspecific, while histopathologic analysis shows sub-epidermal blisters. Diagnostic findings for BP are listed in Table 1. In our cases indirect immunofluorescence and detection of circulating autoantibodies against PB antigens were not performed.Table 1 Diagnostic findings for BP\n\nClinic\tBlistering lesions on erythematous skin, with a prevailing acral distribution\t\nHistology\tSubepidermal blister with a mixed perivascular infammatory infiltrate\t\nDirect immunofluorescence microscopy\tLinear deposits of IgG and C3 along the basement membrane\t\nIndirect immunofluorescence microscopy on salt-split-skin\tBP antibodies deposited primarily at the epidermal side of the induced blister\t\nELISA\tPresence of circulating antibodies against the 2 BP antigens (BP180 and BP230)\t\n\n\n\nRegarding differential diagnosis, BP should be differentiated from other subepidermal diseases: most of all DIF is useful in distinguishing BP from epidermolysis bullosa acquisita, mucous membrane pemphigoid and linear IgA disease. Bullous lesions may also be caused by insect bites, burns, cellulitis and contact dermatitis. Viral and bacterial skin infections should be recognized and treated before starting immunosuppressive therapy [7, 16].\n\nTreatment with oral prednisone was instituted and the lesions rapidly resolved in two out of three patients, with suppression of inflammation and blistering typically achieved in a period of a few weeks, after which the dose was gradually reduced; the third one was treated with an immunosuppressive agent (Tacrolimus) and corticosteroid and subsequently with intravenous immunoglobulin and plasmapheresis, due to a complex underlying autoimmune disease [7].\n\nAccording to a Cochrane review by Kirtschig et al. oral corticosteroid drugs are the most common treatment regimens and starting doses of prednisolone of 0.75 mg/kg/day or less seem to be adequate to control disease and reduce the incidence and severity of adverse reactions [17].\n\nOther treatments with reported benefit are potent topical steroids, azathioprine, mycophenolate mofetil, dapsone, methotrexate, cyclosporin, cyclophosphamide, plasma exchange, as well as erythromycin and tetracycline as monotherapy or with nicotinamide [7, 17]. There is a small number of case reports for the use of intravenous immunoglobulin (IVIg) [18]. Reports have also described successful therapy of BP patients with rituximab in treatment-refractory forms [19].\n\nSince up to 40% of patients with BP on systemic corticosteroids develop severe infectious complications resulting in hospitalization or death [20] we administered a broad-spectrum antibiotic therapy to our 3 patients.\n\nConclusion\nIn this article we reported two infants who developed an eruption of bullous lesions just a few days after vaccination against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B and Haemophilus influenzae B, while the third patient showed the same lesions after a viral infection by HSV-1. Although the mechanism of induction is unclear, the close relationship between trigger events and onset of the disease suggests that there may be an association. Treatment with oral prednisone was effective in achieving disease control in two out of three patients; the third one was treated with a combination of systemic corticosteroids and Tacrolimus and subsequently with intravenous immunoglobulin and plasmapheresis, due to a complex underlying autoimmune disease. BP is an uncommon autoimmune skin disorder in infancy, although recently some cases have been reported after vaccinations or viral infections [21, 22]. In most cases it shows prominent palmoplantar involvement and responds well to systemic steroid therapy, even if recognizing it promptly is important to establish appropriate treatment and prevent infectious complications which may be common and severe. More research will in fact be necessary to refine and further elaborate our knowledge on right trigger events of BP in infants.\n\nAbbreviations\nBMZBasement membrane zone\n\nBPBullous pemphigoid\n\nC3Complement component 3\n\nDIFDirect immunofluorescence\n\nHSV-1Herpes simplex virus type 1\n\nIgGImmunoglobulin G\n\nIgMImmunoglobulin M\n\nPCRPolymerase chain reaction\n\nAcknowledgements\nWe are grateful to parents of the three reported patients who made contributions to acquisition of data described in the manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nRaw data from the study are available upon request from the corresponding author.\n\nAuthors’ contributions\nL.B. conceptualized and designed the study, drafted the initial manuscript and references, revised and approved the final manuscript as submitted. P.C. carried out the initial analyses, drafted the initial manuscript, reviewed and revised the manuscript, and approved the final manuscript as submitted. L.B. performed the analyses with direct immunofluorescence, reviewed and revised the manuscript, and approved the final manuscript as submitted. S.M. critically reviewed the manuscript, edited the article and approved the final manuscript as submitted. F.S. designed and coordinated the data collection, wrote the initial manuscript, critically reviewed the manuscript, and approved the final manuscript as submitted.\n\nCompeting interests\nThe authors have no conflicts of interest relevant to this article to disclose. The authors have no financial relationships relevant to this article to disclose.\n\nConsent to publication\nWritten Informed consent for the publication of their details and clinical images was obtained from the parents of the patients.\n\nEthics approval and consent to participate\nThe study was approved by the local ethics committee (Comitato Interaziendale AA.SS.OO. O.I.R.M./S. Anna - Ordine Mauriziano di Torino prot. N 632/2015) before the start, and written informed consent was obtained from parents of infants before inclusion in the manuscript.\n==== Refs\nReferences\n1. Kuenzli S Grimaître M Krischer J Saurat J-H Calza A-M Borradori L Childhood bullous pemphigoid: report of a case with life-threatening course during homeopathy treatment Pediatr Dermatol 2004 21 2 160 3 10.1111/j.0736-8046.2004.21215.x 15078359 \n2. Fuertes De Vega I Iranzo-Fernández P Mascaró-Galy JM Bullous pemphigoid: clinical practice guidelines Actas Dermosifiliogr 2014 105 328 46 10.1016/j.ad.2012.10.022 23540594 \n3. Otten JV Hashimoto T Hertl M Payne AS Sitaru C Molecular diagnosis in autoimmune skin blistering conditions Curr Mol Med 2014 14 69 95 10.2174/15665240113136660079 24160488 \n4. Hafiji J Bhogal B Rytina E Burrows NP Bullous pemphigoid in infancy developing after the first vaccination Clin Exp Dermatol 2010 35 8 940 1 10.1111/j.1365-2230.2010.03839.x 21054491 \n5. Gurel MS Savas S Bilgin F Erdil D Leblebici C Sarikaya E Zosteriform pemphigoid after zoster: Wolf’s isotopic response Int Wound J 2016 13 1 141 2 10.1111/iwj.12423 25659195 \n6. De la Fuente S Hernández-Martín Á de Lucas R González-Enseñat MA Vicente A Colmenero I Postvaccination bullous pemphigoid in infancy: report of three new cases and literature review Pediatr Dermatol 2013 30 6 741 4 10.1111/pde.12231 24125034 \n7. Venning VA Taghipour K Mohd Mustapa MF Highet AS Kirtschig G British Association of Dermatologists’ guidelines for the management of bullous pemphigoid 2012 Br J Dermatol 2012 167 6 1200 14 10.1111/bjd.12072 23121204 \n8. Fisler RE Saeb M Liang MG Howard RM McKee PH Childhood bullous pemphigoid: a clinicopathologic study and review of the literature Am J Dermatopathol 2003 25 3 183 9 10.1097/00000372-200306000-00001 12775979 \n9. Erbagci Z Childhood bullous pemphigoid following hepatitis B immunization J Dermatol 2002 29 12 781 5 10.1111/j.1346-8138.2002.tb00223.x 12532044 \n10. Ister M Pouessel G Ythier H Catteau B Carpentier O Postvaccinal, corticosteroid-resistant bullous pemphigoid in infancy: treatment with intravenous immunoglobulin Pediatr Dermatol 2014 1 4 e94 5 10.1111/pde.12360 \n11. Neri I Greco A Bassi A Orgaz-Molina J Balestri R Oranges T Bullous pemphigoid in infant post vaccination: Myth or reality? Int J Immunopathol Pharmacol 2015 29 2 295 9 10.1177/0394632015603796 26684642 \n12. Lo Schiavo A Ruocco E Brancaccio G Bullous pemphigoid: Etiology, pathogenesis, and inducing factors: Facts and controversies Clin Dermatol 2013 31 391 9 10.1016/j.clindermatol.2013.01.006 23806156 \n13. Antiga E Quaglino P Volpi W Pierini I Del Bianco E Bianchi B Novelli M Savoia P Bernengo MG Fabbri P Caproni M Regulatory T cells in skin lesions and blood of patients with bullous pemphigoid J Eur Acad Dermatol Venereol 2014 28 222 30 10.1111/jdv.12091 23331964 \n14. Schwieger-Briel A Moellmann C Mattulat B Schauer F Kiritsi D Schmidt E Bullous pemphigoid in infants: characteristics, diagnosis and treatment Orphanet J Rare Dis 2014 9 1 185 10.1186/s13023-014-0185-6 25491396 \n15. Waisbourd-Zinman O Ben-Amitai D Cohen AD Feinmesser M Mimouni D Adir-Shani A Bullous pemphigoid in infancy: Clinical and epidemiologic characteristics J Am Acad Dermatol 2008 58 1 41 8 10.1016/j.jaad.2007.08.010 17945382 \n16. Kasperkiewicz M Zillikens D Schmidt E Pemphigoid diseases: pathogenesis, diagnosis, and treatment Autoimmunity 2012 45 1 55 70 10.3109/08916934.2011.606447 21923615 \n17. Kirtschig G Middleton P Bennett C Murrell DF Wojnarowska F Khumalo NP Interventions for bullous pemphigoid Cochrane Database Syst Rev 2010 20927731 \n18. Sugawara N Nagai Y Matsushima Y Aoyama K Ishikawa O Infantile bullous pemphigoid treated with intravenous immunoglobulin therapy J Am Acad Dermatol 2007 57 6 1084 9 10.1016/j.jaad.2007.08.005 17889964 \n19. Kasperkiewicz M Shimanovich I Ludwig RJ Rose C Zillikens D Schmidt E Rituximab for treatment-refractory pemphigus and pemphigoid: a case series of 17 patients J Am Acad Dermatol 2011 65 3 552 8 10.1016/j.jaad.2010.07.032 21641080 \n20. Phoon YW Fook-Chong SMC Koh HY Thirumoorthy T Pang SM Lee HY Infectious complications in bullous pemphigoid: An analysis of risk factors J Am Acad Dermatol 2015 72 5 834 9 10.1016/j.jaad.2015.01.029 25752714 \n21. Iyengar S Awasthi S Fazel N Okman J Kamangar F Sharon VR Acral bullae in an infant Arch Dis Child 2016 27150267 \n22. Taquin H Chiaverini C Lacour JP Spectrum of Clinical Responses to Therapies in Infantile Bullous Pemphigoid Pediatr Dermatol 2016 33 2 e77 81 10.1111/pde.12779 26764161\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2431", "issue": "17(1)", "journal": "BMC pediatrics", "keywords": "Bullous Pemphigoid; Case report; Drug therapy; Infant; Vaccination", "medline_ta": "BMC Pediatr", "mesh_terms": "D005260:Female; D006801:Humans; D007114:Immunization; D016756:Immunoglobulins, Intravenous; D007223:Infant; D008297:Male; D010391:Pemphigoid, Bullous; D012872:Skin Diseases, Vesiculobullous", "nlm_unique_id": "100967804", "other_id": null, "pages": "60", "pmc": null, "pmid": "28228112", "pubdate": "2017-02-23", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "15078359;24916151;25491396;17889964;26764161;17945382;24160488;23806156;12775979;21054491;25752714;27150267;25659195;21923615;23331964;12532044;23121204;20927731;26684642;21641080;23540594;24125034", "title": "Three case reports of post immunization and post viral Bullous Pemphigoid: looking for the right trigger.", "title_normalized": "three case reports of post immunization and post viral bullous pemphigoid looking for the right trigger" }
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{ "abstract": "Childhood urticaria is not rare, although its persistence is less frequent. In children, chronic spontaneous urticaria (CSU) is associated with comorbidities, including asthma, allergic rhinitis, or atopic dermatitis, and many children with CSU have a family history of atopy. The therapeutic approach to CSU in children is the same one recommended by international guidelines for treatment of chronic urticaria in adults. In the European Union, according to the European Medicine Agency, omalizumab is the add-on drug of choice for the management of CSU in adult and adolescent patients (from 12 years of age) with inadequate response to H1 antihistamine therapy. In addition, in children (6 to <12 years of age), it is the add-on therapy of choice to improve asthma control. The management of children with urticaria under 12 is a therapeutic area with few certainties, where omalizumab can be administered only \"off-label.\"", "affiliations": "Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.;Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.;Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.", "authors": "Sirufo|Maria Maddalena|MM|;Ginaldi|Lia|L|;De Martinis|Massimo|M|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3389/fped.2019.00213", "fulltext": "\n==== Front\nFront PediatrFront PediatrFront. Pediatr.Frontiers in Pediatrics2296-2360Frontiers Media S.A. 10.3389/fped.2019.00213PediatricsCase ReportSuccessful Treatment With Omalizumab in a Child With Asthma and Urticaria: A Clinical Case Report Sirufo Maria Maddalena 12Ginaldi Lia 12De Martinis Massimo 12*1Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy2Allergy and Clinical Immunology Unit, Department of Medicine, AUSL 04, Teramo, ItalyEdited by: Claudio Pignata, University of Naples Federico II, Italy\n\nReviewed by: Markus Weckmann, Universität zu Lübeck, Germany; Mario Sanchez-Borges, El Ávila Clinic, Venezuela\n\n*Correspondence: Massimo De Martinis demartinis@cc.univaq.itThis article was submitted to Pediatric Immunology, a section of the journal Frontiers in Pediatrics\n\n05 6 2019 2019 7 21327 11 2018 10 5 2019 Copyright © 2019 Sirufo, Ginaldi and De Martinis.2019Sirufo, Ginaldi and De MartinisThis 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.Childhood urticaria is not rare, although its persistence is less frequent. In children, chronic spontaneous urticaria (CSU) is associated with comorbidities, including asthma, allergic rhinitis, or atopic dermatitis, and many children with CSU have a family history of atopy. The therapeutic approach to CSU in children is the same one recommended by international guidelines for treatment of chronic urticaria in adults. In the European Union, according to the European Medicine Agency, omalizumab is the add-on drug of choice for the management of CSU in adult and adolescent patients (from 12 years of age) with inadequate response to H1 antihistamine therapy. In addition, in children (6 to <12 years of age), it is the add-on therapy of choice to improve asthma control. The management of children with urticaria under 12 is a therapeutic area with few certainties, where omalizumab can be administered only “off-label.”\n\nchronic spontaneous urticariaasthmachildomalizumabhypersensitivitytranslational medical researchprecision medicineallergy\n==== Body\nBackground\nChronic urticaria (CU) is a common skin disorder, characterized by the appearance of pruritic wheals or angioedema (and—in about 40% of cases—both manifestations), persisting for longer than 6 weeks. Due to its frequent and persevering itching attacks, it significantly impacts the quality of life of patients and their caregivers, with significant implications on their physical and psychological state; in children, it has been demonstrated that this condition is associated with a reduced school performance (1). CU can be differentiated into spontaneous or inducible urticaria, based on the trigger factor. Inducible urticaria is due to a particular stimulus, that can be mechanical (friction, pressure, vibration), thermal (hot, cold), or electromagnetic (solar radiation). It occurs after a short interval from the onset of the stimulus and regresses following the removal of the same. On the contrary, in chronic spontaneous urticaria (CSU), wheals are often associated with angioedema, are not predictable, and last from a few days to weeks (2). CSU originates from mast-cell activation, which releases histamine and other mediators (leukotrienes, prostaglandins, and platelet-activating factor) capable of inducing sensory nerve activation, vasodilatation, and plasma extravasation (3). Immediate hypersensitivity (type I) is the most common immunological disease and represents the most widely spread and the fastest-growing chronic human health condition in people from 15 years of age (4).\n\nEpidemiological data in children are scarce. Childhood urticaria is not rare (3.4–5.4%), although its persistence is less frequent (0.1–0.3%). According to recent data from Korea, the prevalence of CU is 1.8%. The trigger (or cause) of CU in children can be identified in 21–55% of cases. It can be associated with infections (viral, bacterial, parasitic, or helminthic), drugs, food or food additives, thyroid disease, or physical stimuli, but it is often an autoreactive/autoimmune/autoallergic process and, unlike in adults, identifying auto-antibodies in children does not affect the disease prognosis (1, 5).\n\nIn children, CSU is associated with comorbidities, 28.1% of which are represented by atopy (asthma, allergic rhinitis, or atopic dermatitis); in fact, 43.0% of children with CSU have a family history of atopy (6).\n\nAmong these comorbidities, asthma is the most common chronic lung disease in pediatric patients, and in 2–5% of cases, it remains symptomatic, despite the implementation of addressing modifiable risk factors and an adequate therapy (high-dose inhaled corticosteroids, long-acting β2-receptor agonists, leukotriene receptor antagonists, and occasionally, systemic steroids) (7).\n\nAccording to a consensus-based recommendation, the therapeutic approach to CSU in children should include the use—with caution—of the same algorithm of adults (1). The first-line treatment in the pediatric population is based on second-generation, non-sedating antihistamines; only medications with proven safety and efficacy should be administered, such as cetirizine, desloratadine, fexofenadine, levocetirizine, rupatadine, bilastine, and loratadine. All further steps should be taken carefully, and based on individual considerations, since up-dosing of antihistamines and further treatment options (omalizumab, ciclosporin) have not been studied adequately in children.\n\nOmalizumab is an immunoglobulin E specific IgG1 k antibody (recombinant DNA-derived humanized monoclonal antibody) that targets circulating free IgE. Omalizumab binds to IgE and lowers free IgE levels; consequently, IgE receptors (FcεRI) on cells down-regulate. How this produces an improvement of CSU symptoms is not entirely understood (8).\n\nIn the European Union—according to the European Medicine Agency—omalizumab in children (6 to <12 years of age) is indicated as add-on therapy to improve asthma control in patients with severe persistent allergic asthma, who present a positive skin test or in vitro reactivity to a perennial aero-allergen and frequent daytime symptoms or night-time awakenings, and who have suffered from multiple documented severe asthma exacerbations, despite the daily use of high-dose inhaled corticosteroids, plus a long-acting inhaled beta2-agonist. Omalizumab is also indicated as add-on therapy for the treatment of CSU in adult and adolescent patients (from 12 years of age) with inadequate response to H1 antihistamine treatment.\n\nGuidelines recommend the administration of omalizumab as a subcutaneous injection; the dosing and frequency of administration in asthma are guided by a nomogram derived from the total serum immunoglobulin E level and the body mass index, while in CU, a fixed 300-mg dose is administered every 4 weeks.\n\nThe treatment of children with urticaria under 12 is a therapeutic “limbo,” where omalizumab can be administered only “off-label.”\n\nCase Report\nWe report the case of an 8-year-old child (weight, 38 kg; height, 137 cm) with severe asthma sensitized to Dermatophagoides pteronyssinus and D. farinae. At age 6, he was started on budesonide/formoterol fumarate dihydrate 80 μg/4.5 μg (two inhalations twice a day), montelukast 5 mg once a day, and cetirizine 5 mg once a day, without any long-term or satisfactory relief from the symptoms. In addition, over the last year, despite a treatment with antihistamine and antileukotriene, there was no satisfactory improvement. The child also presented CU, which temporarily regressed with betamethasone 4 mg a day, discontinued due to poor tolerance and induction of psychomotor agitation.\n\nA complete medical history was obtained and a physical examination was performed at the time of diagnosis and upon each subsequent revaluation.\n\nThe physical examination showed evanescent coalescing wheals on the trunk and limbs.\n\nAt our first spirometric evaluation, the child had a FEV1 < 65%. The diagnosis of CSU is based on EAACI/GA2LEN/ EDF/WAO guidelines, and the evaluation of the clinical efficacy of omalizumab during therapy has been monitored with the Urticaria Activity Score (UAS 7) (2), which, before treatment, was 35.\n\nLaboratory investigations—including complete blood count with differential, standard biochemical profile, erythrocyte sedimentation rate, C-reactive protein, serum protein electrophoresis, d-dimer, thyroid function screening, serum protein electrophoresis, vitamin D, anti-nuclear antibodies, and stool examination for parasites—were performed, with negative results. Also negative was the autologous serum skin test performed. Total IgE was 82.8 kUA/l and serum-specific IgE positive to house dust mites was 6.63 KUA/l (D. pteronyssinus) and 4.03 KUA/l (D. farinae). Serum IgE reactivity was analyzed using the ISAC platform (Thermo Fisher Scientific, Uppsala, Sweden), by means of the latest commercially available ImmunoCAP-ISAC, as per manufacturer's instructions.\n\nInstrumental examinations (chest X-ray, electrocardiogram, abdominal ultrasound scan, and urea breath test) did not reveal any significant pathological finding.\n\nOmalizumab is now recommended—and widely used—as a first-line add-on treatment option in severe allergic asthma in children resistant to treatment (Global Initiative for Asthma—GINA), and is highly effective and safe (9).\n\nThe need for a more adequate asthma treatment associated with failed response to conventional treatment for CSU and intolerance to systemic corticosteroids in our patient and the good tolerance of omalizumab in asthmatic children older than 6 were the reasons for our choice of this drug. Therefore, an anti-IgE treatment was proposed to the child's parents and—after obtaining their informed consent, in compliance with the rules of our Institution—omalizumab was administered at room temperature (75 mg via subcutaneous injection per month). The dose of omalizumab we administered to our patient was that recommended in the treatment of asthma in children.\n\nCetirizine, montelukast, and budesonide/formoterol fumarate were gradually tapered down and stopped at week 24 of the omalizumab therapy. Table 1 reports the values of UAS7 and FEV1 for the observation period.\n\nTable 1 Clinical and therapeutic assessment of patient throughout omalizumab treatment.\n\nMonth\tUAS 7*\tFEV 1% Predicted\tFVC\tFEV1/FVC\tTotal IgE\tSpecific IgE\tWBC\tNeutrophils\tBasophils\tEosinophils\tCetirizine\tMontelukast\tBudesonide/formetherolfumaratedihydrate 80 μg/4.5 μg\tOmalizumab\t\n0\t35\t65\t5.26\t−0.9\t82,800 KUA/l\tDermatophagoides pteronyssinus 6.63 KUA/lDermatophagoides farinae 4.03 KUA/l\t7.60 × 103/μL\t48.1%−3.65 × 103/μL\t0.08%−0.06 × 103/μL\t5.3%−0.40 × 103/μL\t5 mg\t5 mg\tTwo inhalations twice a day\t75 mg\t\n1\t29\t\t\t\t\t\t\t\t\t\t5 mg\t5 mg\tTwo inhalations twice a day\t75 mg\t\n2\t20\t\t\t\t\t\t\t\t\t\t5mg\t5 mg\tTwo inhalations twice a day\t75 mg\t\n3\t14\t\t\t\t\t\t\t\t\t\t5 mg\t5 mg\tTwo inhalations twice a day\t75 mg\t\n4\t7\t\t\t\t\t\t\t\t\t\t0\t0\tTwo inhalations twice a day\t75 mg\t\n5\t0\t\t\t\t\t\t\t\t\t\t0\t0\tTwo inhalations once a day\t75 mg\t\n6\t0\t85\t4.20\t1.2\t\t\t\t\t\t\t0\t0\t0\t75 mg\t\n9\t0\t\t\t\t\t\t\t\t\t\t0\t0\t0\t75 mg\t\n12\t0\t95\t5.30\t5.9\t369 KUA/l\tDermatophagoides pteronyssinus >100 KUA/lDermatophagoides farinae 81.5 KUA/l\t10.83 × 103/μL\t53.7%−5.82 × 103/μL\t0.7%−0.07 × 103/μL\t4.1%−0.44 × 103/μL\t0\t0\t0\t75 mg\t\n18\t0\t95\t5.25\t5.6\t\t\t\t\t\t\t0\t0\t0\t75 mg\t\n* 7-day urticaria activity score (UAS7).\n\nAfter 3 months of therapy, UAS7 was reduced by 50% (UAS 14), and after 5 months, it was reduced by 100% (UAS 0). After 1 year, the remission of urticaria persists, confirming the resolution of the disease.\n\nAfter 6 months of therapy, the patient showed an improvement in his asthmatic symptoms, in agreement with the global spirometry values (FEV195%).\n\nMoreover, the patient did not manifest any adverse effects due to the omalizumab therapy. This work has been conducted in compliance with the relevant ethical standards and the norms established by the Internal Review Board of the University of L'Aquila (Comitato etico di Ateneo D.R.n.206/2013 and D.R.n.46/2017).\n\nThe patient's parents provided their written informed consent for the publication of this report.\n\nDiscussion\nWe have described the comorbidity of asthma and CSU and its treatment with omalizumab in an 8-year-old boy. CSU has a complex and multiform pathogenesis; therefore, its diagnosis and management, especially in children, is still uncertain.\n\nBeing clinically effective and safe, omalizumab now represents an obvious alternative treatment in subjects that are refractory to the antihistamine therapy. In adults treated with omalizumab, hives, itching, and angioedema are significantly reduced, while the patient's quality of life improves (10, 11).\n\nIn children, as in adults, the treatment of urticaria is essentially the same, with a preference for second-generation over first-generation antihistamine, in order to avoid the sedating effects typical of the latter. Corticosteroids should be avoided, due to their growth-related side effects, or at least they should be used for short periods <10–14 days (12, 13).\n\nBen-Shoshan and Grattan reviewed the diagnosis and management of CSU in children. Their findings supported the use of omalizumab for the most severe cases, while highlighting the effectiveness of second-generation antihistamines for the treatment of CSU (14).\n\nOmalizumab—an anti-IgE antibody—seems to be promising in a wide range of allergic diseases, and so far has shown a robust clinical efficacy in the treatment of moderate to severe persistent asthma and chronic idiopathic urticaria in adults (15, 16). Its primary action is neutralizing free serum IgE, thus reducing the amount that would normally be available to bind to FcεRI on mast cells and basophils and trigger the allergic cascade. Furthermore, in atopic subjects, treatment with omalizumab produces a marked down-regulation of FcεRI receptors on basophils.\n\nIndeed, the specific mechanism of action of omalizumab in the various diseases in which it has proven effective is still partly unknown. Several mediators orchestrate the allergic response, and omalizumab showed to act on both the early and the late phases of the allergic reaction, with a reduction of the proinflammatory cytokine levels and dendritic cells, lymphocyte, and eosinophil counts in tissues, eventually decreasing the inflammatory state of the whole immune system.\n\nComorbidity is quite frequent in the atopic disorders in children (17) but, in this case and in our opinion, the coexistence of both conditions at that age in relation to treatment is of particular significance. In fact, omalizumab is approved for the treatment of asthma in children from the age of 6 and for the treatment of CSU from the age of 12, and the posology of the drug is different in the treatment of the two diseases.\n\nThe need for a treatment with omalizumab in children under the age of 12 is rare, and few cases of children with CSU under 12 successfully treated with omalizumab are described in the literature (18, 19). The satisfactory response to omalizumab in our child, after the failure of previous standard therapeutic strategies, seems to confirm the effectiveness and the safety of this molecule in the treatment of urticaria as well as asthma, as already highlighted in other studies in adults (8). We also show that, in children with CU, omalizumab could be effective at a lower dose than in adults.\n\nAnother relevant learning of this case is the fact that it could be possible to prescribe the optimal treatment to the right patient, tailoring the most appropriate therapy to the individual patient, as suggested in children by recent guidelines (2). Precision medicine—that is, the choice of a personalized treatment based on the exact characteristics of the disease and the single patient—should be a requirement, especially in pediatrics.\n\nIn conclusion, controlled studies are needed on the use of omalizumab in children with CSU younger than 12. However, based on literature data and on our experience, it seems that an anti-IgE therapy could be a safe and effective alternative for the treatment of these young patients who have not responded to first-line treatment, possibly using a personalized approach.\n\nEthics Statement\nThe case described in compliance with the rules of our Institution not necessitate the approval of ethics committee.\n\nAuthor Contributions\nAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.\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\nThe authors would like to thank Novartis Farma Italia, which provided unconditional support for language revision and publishing expenses.\n==== Refs\nReferences\n1. Kudryavtseva AV Neskorodova KA Staubach P \nUrticaria in children and adolescent: an update review of the pathogenesis and management . Pediatr. Allergy Immunol. (2018 ) 30 :17 –24 . 10.1111/pai.12967 30076637 \n2. Zuberbier T Aberer W Asero R Abdul Latiff AH Baker D Ballmer-Weber B \nThe EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of Urticaria . The 2017 revision and update. Allergy . (2018 ) 73 :1393 –414 . 10.1111/all.13397 29336054 \n3. Kaplan AP . Chronic spontaneous urticaria: pathogenesis and treatment considerations . Allergy Asthma Immunol Res. (2017 ) 9 :477 –82 . 10.4168/aair.2017.9.6.477 28913986 \n4. De Martinis M Sirufo MM Ginaldi L \nAllergy and aging: an old/new emerging health issue . Aging Dis. (2017 ) 8 :162 –75 . 10.14336/AD.2016.0831 28400983 \n5. Caffarelli C Cuomo B Cardinale F Barberi S Dascola CP Agostinis F . Aetiological factors associated with chronic urticaria in children: a systematic review . Acta Derm. Venereol. (2013 ) 93 :268 –72 . 10.2340/00015555-1511 23224228 \n6. Cornillier H Giraudeau B Munck S Hacard F Jonville-Bera AP d'Acremont G . Chronic spontaneous urticaria in children—A systematic review on interventions and comorbidities . Pediatr Allergy Immunol. (2018 ) 29 :303 –10 . 10.1111/pai.12870 29392757 \n7. Bonner K Roberts G . Does allergy explain why some children have severe asthma? \nClin. Exp. Allergy . (2018 ) 48 :1594 –605 . 10.1111/cea.13234 30019503 \n8. De Martinis M Sirufo MM Ginaldi L \nA “stadium” urticaria . Cold urticaria is still a mostly unknown disease, with a wide spectrum of severity degrees and few therapeutic certainties: is omalizumab one of these? Reflections from a clinical case report. Iran Red Cresc. Med. J. (2019 ) 21 :e84250 \n10.5812/ircmj.84250 \n9. Just J Deschildre A Lejeune S Amat F . New perspectives of childhood asthma treatment with biologics . Pediatr Allergy Immunol. (2019 ) 30 :159 –71 . 10.1111/pai.13007 30444939 \n10. Vestergaard C Toubi E Maurer M Triggiani M Ballmer-Weber B Marsland A . Treatment of chronic spontaneous urticaria with an inadequate response to H1-antihistamines: an expert opinion . Eur J Dermatol. (2017 ) 27 :10 –9 . 10.1684/ejd.2016.2905 27882879 \n11. Giménez-Arnaud AM \nOmalizumab for treating chronic spontaneous urticaria: an expert review on efficacy and safety . Expert Opin Biol Ther. (2017 ) 17 :375 –85 . 10.1080/14712598.2017.1285903 28125304 \n12. Antia C Baquerizo K Korman A Alikhan A Bernstein JA . Urticaria: a comprehensive review: Treatment of chronic urticaria, special populations, and disease outcomes . J Am Acad Dermatol. (2018 ) 79 :617 –33 . 10.1016/j.jaad.2018.01.023 30241624 \n13. Uysal P Avcil S Erge D . High-dose anti-histamine use and risk factors in children with urticaria . Turk Pediatr Ars. (2016 ) 51 :198 –203 . 28123332 \n14. Ben-Shoshan M Grattan CE . Management of pediatric urticaria with review of the literature on chronic spontaneous urticaria in children . J Allergy Clin Immunol Pract. (2018 ) 6 :1152 –61 . 10.1016/j.jaip.2018.02.015 29550102 \n15. Sirufo MM De Martinis M Ginaldi L . Omalizumab an effective and safe alternative therapy in severe refractory atopic dermatitis: a case report . Medicine. (2018 ) 97 :e10897 . 10.1097/MD.0000000000010897 29901580 \n16. De Martinis M Sirufo MM Ginaldi L \nSolar urticaria, a disease with many dark sides: is omalizumab the right therapeutic response? Reflections from a clinical case report . Open Med. (in press) 14.\n17. Sesé L Schneider M Bourgoin M Saint-Pierre P Lambert N Guiddir T . Asthma with multiple allergic comorbidities is associated with complete response to omalizumab . Clin Exp Allergy. (2019 ) 49 :733 –5 . 10.1111/cea.13373 30779241 \n18. Ossorio-García L Jiménez-Gallo D Albarrán-Planelles C Arjona-Aguilera C Linares-Barrios M . Chronic spontaneous urticaria in an 8-year-old girl treated with omalizumab . Clin Exp Dermatol. (2016 ) 41 :929 –30 . 10.1111/ced.12922 27761937 \n19. Ulrich W . Anti-IgE for chronic urticaria—Are children little adults after all? \nPediatr Allergy Immunol. (2015 ) 26 :488 –9 . 10.1111/pai.12424 \n26358686\n\n", "fulltext_license": "CC BY", "issn_linking": "2296-2360", "issue": "7()", "journal": "Frontiers in pediatrics", "keywords": "allergy; asthma; child; chronic spontaneous urticaria; hypersensitivity; omalizumab; precision medicine; translational medical research", "medline_ta": "Front Pediatr", "mesh_terms": null, "nlm_unique_id": "101615492", "other_id": null, "pages": "213", "pmc": null, "pmid": "31275903", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "23224228;26358686;27761937;27882879;28123332;28125304;28400983;28913986;29336054;29392757;29550102;29901580;30019503;30076637;30241624;30444939;30779241;31231681", "title": "Successful Treatment With Omalizumab in a Child With Asthma and Urticaria: A Clinical Case Report.", "title_normalized": "successful treatment with omalizumab in a child with asthma and urticaria a clinical case report" }
[ { "companynumb": "IT-009507513-1907ITA015743", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "BETAMETHASONE DIPROPIONATE" }, "drugaddition...
{ "abstract": "The CYP24A1 gene encodes a mitochondrial 24-hydroxylase that inactivates 1,25(OH)2 D. Loss-of-function mutations in CYP24A1 cause hypercalcemia, nephrolithiasis and nephrocalcinosis. We describe a woman with CYP24A1 deficiency and recurrent gestational hypercalcemia. Her first pregnancy, at age 20, resulted with the intrauterine demise of twin fetuses. Postpartum, she developed severe hypercalcemia (14 mg/dL), altered mental status, and acute pancreatitis. Her PTH was suppressed (6 pg/mL) and her 1,25(OH)2 D was elevated (165 and 195 pg/mL on postpartum day 1 and 5, respectively). Between one and three months postpartum, her serum calcium decreased from 11.4 to 10.2 mg/dL while her 1,25(OH)2 D level decreased from 83 to 24 pg/mL. Her 24-hour urine calcium was 277 mg. Six months postpartum, she became pregnant again. At 14 weeks, her albumin-corrected calcium level was 10.4 mg/dL and her 1,25(OH)2 D level exceeded 200 pg/mL. To establish the diagnosis of CYP24A1 deficiency, we showed her 24,25(OH)2 D level to be undetectable (<2 ng/mL). Exon sequencing of the CYP24A1 gene revealed a homozygous, 8-nucleotide deletion in exon 8, causing an S334V substitution and premature termination due to a frame shift (c.999_1006del, p.Ser334Valfs*9). To prevent hypercalcemia, she was advised to discontinue prenatal vitamins, avoid sun exposure and calcium-rich foods, and start omeprazole and a calcium binder (250 mg K-Phos-neutral with meals). Despite these measures, both hypercalcemia (11.5 mg/dL) and acute pancreatitis recurred. Labor was induced and a healthy, normocalcemic boy was delivered. In the absence of lactation, maternal hypercalcemia resolved within 2 months. This report shows that CYP24A1-deficient subjects may be normocalcemic at baseline. Hypercalcemia may be unmasked by pregnancy through the routine use of calciferol-containing prenatal vitamins, increased 1-alpha hydroxylation of VitD by the placenta and maternal kidney, and production of PTHrP by the uteroplacental unit. CYP24A1 deficiency should be considered in patients with unexplained vitamin D-mediated hypercalcemia. © 2016 American Society for Bone and Mineral Research.", "affiliations": "Department of Medicine, University of California, San Diego, CA, USA. gwoods@ucsd.edu.;Department of Pathology, University of California, San Diego, CA, USA.;Fulgent Diagnostics, Temple City, CA, USA.;Mass Spectrometry R&D Department, Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA.;Department of Pathology, University of California, San Diego, CA, USA.;Department of Medicine, University of California, San Diego, CA, USA.", "authors": "Woods|Gina N|GN|;Saitman|Alec|A|;Gao|Hanlin|H|;Clarke|Nigel J|NJ|;Fitzgerald|Robert L|RL|;Chi|Nai-Wen|NW|", "chemical_list": "C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase", "country": "United States", "delete": false, "doi": "10.1002/jbmr.2859", "fulltext": null, "fulltext_license": null, "issn_linking": "0884-0431", "issue": "31(10)", "journal": "Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research", "keywords": "CYP24A1; HYPERCALCEMIA; PANCREATITIS; VITAMIN D", "medline_ta": "J Bone Miner Res", "mesh_terms": "D000208:Acute Disease; D000328:Adult; D001483:Base Sequence; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D010195:Pancreatitis; D011247:Pregnancy; D011644:Puerperal Disorders; D017384:Sequence Deletion; D065668:Vitamin D3 24-Hydroxylase", "nlm_unique_id": "8610640", "other_id": null, "pages": "1841-1844", "pmc": null, "pmid": "27105398", "pubdate": "2016-10", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": "25485595;23001465;25367603;24670084;13469755;6087399;9801466;9880118;8405421;13070618;9408745;26214117;22100522;19138316;23979953;3663537;21675912;22108281;26097993;6548698;24423361;25194629;24235083;18614854;18689395;15498883", "title": "A Young Woman With Recurrent Gestational Hypercalcemia and Acute Pancreatitis Caused by CYP24A1 Deficiency.", "title_normalized": "a young woman with recurrent gestational hypercalcemia and acute pancreatitis caused by cyp24a1 deficiency" }
[ { "companynumb": "US-MYLANLABS-2017M1000402", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": null, ...
{ "abstract": "OBJECTIVE\nTo estimate the frequency, distribution, and correlates of nonprescription use of pain relievers by middle-aged and elderly persons in the United States.\n\n\nMETHODS\nCross-sectional data analysis of a national community survey.\n\n\nMETHODS\nThe 2005 and 2006 National Surveys on Drug Use and Health.\n\n\nMETHODS\nTen thousand nine hundred fifty-three respondents aged 50 and older (6,717 aged 50-64 and 4,236 aged > or = 65).\n\n\nMETHODS\nSocial and demographic variables, detailed assessment of nonprescription use (and abuse) of prescription pain relievers (e.g., acetaminophen with codeine, morphine), substance use, major depression, self-reported medical illnesses, and self-rated health.\n\n\nRESULTS\nA small proportion of the sample (1.4%) reported nonprescription use of prescription pain relievers during the previous year. Combinations of acetaminophen and hydrocodone or propoxyphene were the most commonly used drugs. Use was associated with younger age (odds ratio (OR)=2.39, 95% confidence interval (CI)=1.31-4.36), American Indian and Alaska native (OR=8.78, 95% CI=2.50-30.85), and use of marijuana (OR=7.07, 95% CI=3.99-12.53). Fewer than 10% of nonprescription users were abusing these medications or dependent upon them.\n\n\nCONCLUSIONS\nIn a representative sample of middle-aged and older adults, nonprescription use of prescription pain relievers is relatively uncommon, but the much higher use by middle-aged adults suggests that, as this cohort ages, the problem may increase in elderly people.", "affiliations": "Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA. blaze001@mc.duke.edu", "authors": "Blazer|Dan G|DG|;Wu|Li-Tzy|LT|", "chemical_list": "D000700:Analgesics; D004366:Nonprescription Drugs", "country": "United States", "delete": false, "doi": "10.1111/j.1532-5415.2009.02306.x", "fulltext": null, "fulltext_license": null, "issn_linking": "0002-8614", "issue": "57(7)", "journal": "Journal of the American Geriatrics Society", "keywords": null, "medline_ta": "J Am Geriatr Soc", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000700:Analgesics; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007407:Interviews as Topic; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D004366:Nonprescription Drugs; D010146:Pain; D015995:Prevalence; D012307:Risk Factors; D019966:Substance-Related Disorders; D011795:Surveys and Questionnaires; D014481:United States", "nlm_unique_id": "7503062", "other_id": null, "pages": "1252-7", "pmc": null, "pmid": "19486199", "pubdate": "2009-07", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013487:Research Support, U.S. Gov't, P.H.S.", "references": "9243555;16858484;17227967;11166468;9572724;18443641;18042194;9243566;18664996;18291290;18054444;16157234;17296542;12609694", "title": "Nonprescription use of pain relievers by middle-aged and elderly community-living adults: National Survey on Drug Use and Health.", "title_normalized": "nonprescription use of pain relievers by middle aged and elderly community living adults national survey on drug use and health" }
[ { "companynumb": "US-JNJFOC-20130706819", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN\\CODEINE PHOSPHATE" }, "drugadditio...
{ "abstract": "In the last decade tyrosine kinase inhibitors (TKIs) have been employed for a wide range of hematological and solid tumors and today they represent a valid therapeutic option for different neoplasms. Among them, both sorafenib and lenvatinib were approved for the treatment of radioactive iodine (RAI) refractory differentiated thyroid carcinoma (DTC). Unfortunately, in some cases the efficacy of TKIs is limited by the onset of drug resistance after the initial response. Areas covered: We report the case of a patient with a RAI refractory advanced DTC, treated with lenvatinib after surgery, multiple RAI administrations, traditional chemotherapy, and sorafenib. During treatment with lenvatinib, a noticeable response was detected by sequential computed tomography scans but, after 27 months, tumor progression became evident and led to lenvatinib interruption. In absence of any active treatment, a further disease progression was documented, and lenvatinib was re-administered obtaining a new objective response. Starting from this case report, we review available reports about the rechallenge with TKIs in solid tumors, discussing the possible mechanisms underlying the efficacy of this approach. Expert commentary: Rechallenge with TKIs in solid tumors could be a therapeutic option in subjects with advanced and metastatic DTC who experience a progressive disease after initial response to lenvatinib.", "affiliations": "a Department of Medical Sciences , University of Turin , Turin , Italy.;a Department of Medical Sciences , University of Turin , Turin , Italy.;b Oncological Endocrinology Unit , Città della Salute e della Scienza Hospital , Turin , Italy.;b Oncological Endocrinology Unit , Città della Salute e della Scienza Hospital , Turin , Italy.;c Diagnostic and Interventional Radiology Unit , Città della Salute e della Scienza Hospital, University of Turin , Turin , Italy.;b Oncological Endocrinology Unit , Città della Salute e della Scienza Hospital , Turin , Italy.;a Department of Medical Sciences , University of Turin , Turin , Italy.", "authors": "Felicetti|Francesco|F|;Nervo|Alice|A|;Piovesan|Alessandro|A|;Berardelli|Rita|R|;Marchisio|Filippo|F|;Gallo|Marco|M|;Arvat|Emanuela|E|", "chemical_list": "D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D009536:Niacinamide; D000077157:Sorafenib; C531958:lenvatinib", "country": "England", "delete": false, "doi": "10.1080/14737140.2017.1390432", "fulltext": null, "fulltext_license": null, "issn_linking": "1473-7140", "issue": "17(12)", "journal": "Expert review of anticancer therapy", "keywords": "Differentiated thyroid carcinoma; drug-resistance; lenvatinib; rechallenge; tyrosine-kinase inhibitors", "medline_ta": "Expert Rev Anticancer Ther", "mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D018450:Disease Progression; D005260:Female; D006801:Humans; D009536:Niacinamide; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D000077157:Sorafenib; D013964:Thyroid Neoplasms; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "101123358", "other_id": null, "pages": "1093-1098", "pmc": null, "pmid": "28988510", "pubdate": "2017-12", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Tyrosine kinase inhibitors rechallenge in solid tumors: a review of literature and a case description with lenvatinib in thyroid cancer.", "title_normalized": "tyrosine kinase inhibitors rechallenge in solid tumors a review of literature and a case description with lenvatinib in thyroid cancer" }
[ { "companynumb": "IT-CIPLA LTD.-2017IT18968", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, ...
{ "abstract": "BACKGROUND\nIdiopathic pulmonary fibrosis (IPF) is a progressive and fibrosing lung disease with poor prognosis. Pirfenidone and nintedanib are anti-fibrotic drugs used for patients with IPF. These drugs reduce the rate of decline in forced vital capacity (FVC). Serum surfactant protein (SP)-A, SP-D, and Krebs von den Lungen-6 (KL-6) are monitoring and prognostic biomarkers in patients with IPF; however, their relationship with the therapeutic outcomes of anti-fibrotic drugs has not been investigated. We aim to clarify whether serum SP-A, SP-D, and KL-6 reflect therapeutic outcomes of pirfenidone and nintedanib administration in patients with IPF.\n\n\nMETHODS\nWe retrospectively investigated patients with IPF who were initiated on pirfenidone or nintedanib administration between January 2014 and June 2018 at our hospital. Changes in clinical parameters and serum SP-A, SP-D, and KL-6 levels were evaluated. Patients with ≥10% decline in FVC or ≥ 15% decline in diffusing capacity of the lung for carbon monoxide (DLco) from baseline to 6 months were classified as progression group, while the other patients were classified as stable group.\n\n\nRESULTS\nForty-nine patients were included (pirfenidone, 23; nintedanib, 26). Stable group comprised 32 patients, while progression group comprised 17 patients. In the stable group, changes in SP-A and KL-6 from baseline to 3 and 6 months significantly decreased compared with the progression group (SP-A: 3 months - 6.0% vs 16.7%, 6 months - 10.2% vs 20.2%, KL-6: 3 months - 9.2% vs 6.7%, 6 months - 15.0% vs 12.1%, p < 0.05). Changes in SP-A and SP-D levels showed significant negative correlations with the change in %FVC (r = - 0.46 and r = - 0.39, p < 0.01, respectively) and %DLco (r = - 0.67 and r = - 0.54, p < 0.01, respectively). Similar results were also seen in subgroup analysis for both pirfenidone and nintedanib groups. On logistic regression analysis, decrease in SP-A from baseline to 3 months and 6 months was found to predict the outcomes at 6 months (odds ratios: 0.89 and 0.88, respectively).\n\n\nCONCLUSIONS\nChanges in serum SP-A reflected the outcomes of anti-fibrotic drug therapy. Serum SP-A has a potential as a biomarker of therapeutic outcomes of anti-fibrotic drugs.", "affiliations": "Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.;Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan. ohtsukam@sapmed.ac.jp.;Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.;Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.;Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.;Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.;Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.;Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.;Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.", "authors": "Yoshikawa|Takumi|T|;Otsuka|Mitsuo|M|http://orcid.org/0000-0003-2324-2662;Chiba|Hirofumi|H|;Ikeda|Kimiyuki|K|;Mori|Yuki|Y|;Umeda|Yasuaki|Y|;Nishikiori|Hirotaka|H|;Kuronuma|Koji|K|;Takahashi|Hiroki|H|", "chemical_list": "D015415:Biomarkers; D007211:Indoles; C060192:MUC1 protein, human; D018396:Mucin-1; D037662:Pulmonary Surfactant-Associated Protein A; D037663:Pulmonary Surfactant-Associated Protein D; D011728:Pyridones; C445842:SFTPA1 protein, human; C093844:pirfenidone; C530716:nintedanib", "country": "England", "delete": false, "doi": "10.1186/s12890-020-1060-y", "fulltext": "\n==== Front\nBMC Pulm MedBMC Pulm MedBMC Pulmonary Medicine1471-2466BioMed Central London 106010.1186/s12890-020-1060-yResearch ArticleSurfactant protein A as a biomarker of outcomes of anti-fibrotic drug therapy in patients with idiopathic pulmonary fibrosis Yoshikawa Takumi http://orcid.org/0000-0003-2324-2662Otsuka Mitsuo ohtsukam@sapmed.ac.jp Chiba Hirofumi Ikeda Kimiyuki Mori Yuki Umeda Yasuaki Nishikiori Hirotaka Kuronuma Koji Takahashi Hiroki 0000 0001 0691 0855grid.263171.0Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido 060-8543 Japan 31 1 2020 31 1 2020 2020 20 2719 7 2019 23 1 2020 © The Author(s). 2020Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nIdiopathic pulmonary fibrosis (IPF) is a progressive and fibrosing lung disease with poor prognosis. Pirfenidone and nintedanib are anti-fibrotic drugs used for patients with IPF. These drugs reduce the rate of decline in forced vital capacity (FVC). Serum surfactant protein (SP)-A, SP-D, and Krebs von den Lungen-6 (KL-6) are monitoring and prognostic biomarkers in patients with IPF; however, their relationship with the therapeutic outcomes of anti-fibrotic drugs has not been investigated. We aim to clarify whether serum SP-A, SP-D, and KL-6 reflect therapeutic outcomes of pirfenidone and nintedanib administration in patients with IPF.\n\nMethods\nWe retrospectively investigated patients with IPF who were initiated on pirfenidone or nintedanib administration between January 2014 and June 2018 at our hospital. Changes in clinical parameters and serum SP-A, SP-D, and KL-6 levels were evaluated. Patients with ≥10% decline in FVC or ≥ 15% decline in diffusing capacity of the lung for carbon monoxide (DLco) from baseline to 6 months were classified as progression group, while the other patients were classified as stable group.\n\nResults\nForty-nine patients were included (pirfenidone, 23; nintedanib, 26). Stable group comprised 32 patients, while progression group comprised 17 patients. In the stable group, changes in SP-A and KL-6 from baseline to 3 and 6 months significantly decreased compared with the progression group (SP-A: 3 months − 6.0% vs 16.7%, 6 months − 10.2% vs 20.2%, KL-6: 3 months − 9.2% vs 6.7%, 6 months − 15.0% vs 12.1%, p < 0.05). Changes in SP-A and SP-D levels showed significant negative correlations with the change in %FVC (r = − 0.46 and r = − 0.39, p < 0.01, respectively) and %DLco (r = − 0.67 and r = − 0.54, p < 0.01, respectively). Similar results were also seen in subgroup analysis for both pirfenidone and nintedanib groups. On logistic regression analysis, decrease in SP-A from baseline to 3 months and 6 months was found to predict the outcomes at 6 months (odds ratios: 0.89 and 0.88, respectively).\n\nConclusions\nChanges in serum SP-A reflected the outcomes of anti-fibrotic drug therapy. Serum SP-A has a potential as a biomarker of therapeutic outcomes of anti-fibrotic drugs.\n\nKeywords\nSurfactant protein-A (SP-A)Surfactant protein-D (SP-D)Krebs von den Lungen-6 (KL-6)Idiopathic pulmonary fibrosis (IPF)PirfenidoneNintedanibhttp://dx.doi.org/10.13039/501100001691Japan Society for the Promotion of ScienceJP17K09619Otsuka Mitsuo issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial lung disease of unknown etiology [1]. Patients with IPF have a poor prognosis. The clinical course is typically characterized by acute exacerbations, progression to respiratory failure, and a high risk of lung cancer. The reported median survival of these patients is 3–5 years [2, 3]. Lung transplantation is the only curative treatment for IPF. However, notable advances have recently been made in pharmacological therapy (pirfenidone and nintedanib) for patients with IPF [4, 5].\n\nPirfenidone and nintedanib were shown to exhibit both anti-fibrotic and anti-inflammatory effects in patients with IPF; these were shown to reduce the rate of decline in forced vital capacity (FVC) and ameliorate disease progression [4, 5]. Pirfenidone has several anti-inflammatory and anti-fibrotic effects, including inhibition of collagen synthesis, down-regulation of transforming growth factor beta (TGF-β), and reduction in fibroblast proliferation [6]. Nintedanib is an intracellular inhibitor of tyrosine kinase that inhibits vascular endothelial growth factor (VEGF), fibroblast growth factors (FGFs), and platelet-derived growth factors (PDGFs) receptors [5]. Consequently, the ATS/ERS/JRS/ALAT statement conditionally recommends the use of pirfenidone and nintedanib in patients with IPF [7].\n\nProgression of IPF is monitored by respiratory symptoms, pulmonary function tests (PFTs), and high-resolution computed tomography (HRCT) [8]. Of these parameters, PFTs are the most important methods for objective monitoring and quantification of disease progression. In particular, decline in FVC and diffusion capacity of the lung for carbon monoxide (DLco) are surrogate markers for clinical monitoring and prognostic assessment of patients with IPF [9]. In ASCEND and INPULSIS-1/2 trials, the primary endpoint was the annual rate of decline in FVC [4, 5]. Amelioration of the decline in FVC and DLco over time is the only indicator for evaluation of therapeutic effect. Therefore, it is desirable to develop other biomarkers for assessment and prediction of therapeutic efficacy.\n\nSurfactant protein (SP)-A and SP-D are secretory proteins that belong to the collectin family, while Krebs von den Lungen (KL)-6 is a mucin-like high-molecular-weight glycoprotein classified as MUC-1 mucin. These are produced mainly by alveolar type II cells [10, 11]. These have been widely proved as serum biomarkers for the diagnosis of interstitial lung disease [10–12]; in addition, these were shown to be related to progression of IPF and the associated mortality [12–14]. However, the relationship between the changes in these serum biomarkers and the effects of pirfenidone and nintedanib in patients with IPF has not been reported. The purpose of this study was to assess whether these serum biomarkers reflect the changes in FVC and DLco, and could serve as biomarkers to monitor the therapeutic outcomes of pirfenidone and nintedanib in patients with IPF.\n\nMethods\nSubjects\nWe performed a retrospective cohort study of consecutive patients with IPF who were treated at Sapporo Medical University Hospital. This study was approved by the Institutional Review Board of Sapporo Medical University Hospital (#302–120, dated November 8, 2018). The requirement for written informed consent of patients was waived off because of the retrospective nature of the study. IPF was diagnosed according to the ATS/ERS/JRS/ALAT IPF statement 2018 [1]. Ninety-three patients with IPF were newly initiated on pirfenidone or nintedanib therapy between January 2014 and June 2018. We included patients with IPF who were treated with pirfenidone or nintedanib for ≥6 months. Pulmonary function tests (PFTs) were conducted after 6 months of initiation of treatment. We excluded patients with lung cancer, serious cardiovascular disease, serious infection, or collagen disease at the time of administration of pirfenidone or nintedanib. Also, we excluded patients using corticosteroids, immunosuppressants, or N-acetylcysteine during the observation period, because their therapies may affect the serum levels of the biomarkers.\n\nPirfenidone and nintedanib treatment\nThe daily dose of pirfenidone was increased in a stepwise manner from 600 mg to 1200–1800 mg every 2 weeks, as previously described [15]. The median maximum dose was 1500 mg (inter-quartile range [IQR], 1200–1800 mg), and the median final dose was 1200 mg (IQR, 1200–1800 mg). Nintedanib was initiated at a daily dose of 300 mg. The dose was decreased depending on the severity of adverse events. The median final dose was 250 mg (IQR, 200–300 mg).\n\nMeasurement of clinical parameters\nAll subjects were reviewed in terms of their clinical characteristics, PFT results (including FVC and DLco), arterial blood gas analysis, 6-min-walk test (6MWT), and serum SP-A, SP-D, and KL-6 levels at baseline (at the time of initiation of pirfenidone or nintedanib). The 6MWT was performed in accordance with the ATS guidelines [16]. Serum levels of SP-A, SP-D, and KL-6 were measured by enzyme-linked immunosorbent assays using commercial measurement kits as previously described [15]. We assessed the correlation between the parameters at baseline and those at 3 and 6 months, and the corresponding changes in FVC and DLco.\n\nChange in FVC and DLco, and definition of deterioration\nDisease progression during pirfenidone and nintedanib therapy was evaluated based on PFTs at 6 months (including up to 9 months) from baseline [17]. “Progression” was defined as a ≥ 10% relative decline in FVC from baseline and/or ≥ 15% relative decline in DLco from baseline. Patients with progression were classified into the “progression group,” whereas the others were classified into the “stable group.”\n\nChanges in SP-A, SP-D, and KL-6\nThe relative changes in serum SP-A, SP-D, and KL-6 at 3 months and 6 months from baseline were evaluated.\n\nStatistical analysis\nAll data are expressed as median (IQR). The Mann–Whitney U test or Wilcoxon signed-rank test was used to compare the differences between the stable group and the progression group. To compare the levels of SP-A, SP-D, and KL-6 at baseline, 3, and 6 months in each group, we performed the Friedman and Wilcoxon signed-rank tests with Bonferroni correction, which are non-parametric tests for comparing multiple groups of the paired sample. Spearman’s rank correlation coefficient was used to evaluate the correlation between the changes in serum biomarker levels and the change in FVC and DLco. Logistic regression analysis was performedto identify factors that predicted disease stability at 6 months from administration of anti-fibrotic drugs. Factors associated with p-values < 0.20 in the univariate analysis were included in the multivariate analysis. Receiver-operating characteristic (ROC) curves were constructed for distinguishing between the stable and progression for changes in serum SP-A, SP-D, and KL-6. Cut-off levels were determined using the Youden index. The use of these cut-off levels allowed the calculation of the sensitivity and specificity.\n\nAll tests were performed at a significance level of p < 0.05 or Bonferroni corrected p < 0.05. Statistical analysis was performed using JMP 13.0 (SAS institute, Cary, NC, USA).\n\nResults\nStudy population, patient characteristics, and clinical data\nOf the 93 patients with IPF who were initiated on pirfenidone or nintedanib therapy at our hospital, 49 patients were included in this analysis (pirfenidone, 23; nintedanib, 26) (Fig. 1). Twenty patients were excluded because the treatment was discontinued within 6 months. Reasons for discontinuation of pirfenidone treatment were disease progression (n = 3), nausea (n = 2), loss of appetite, liver function disorder, fever, xerophthalmia (n = 1, respectively). Reasons for discontinuation of nintedanib treatment were disease progression (n = 2), thrombocytopenia (n = 2), nausea (n = 2), diarrhea, liver function disorder, gastrointestinal bleeding, nasal bleeding, and rash (n = 1, respectively). Thirteen patients were lost to follow-up and were excluded. Eleven patients were excluded because they were treated with corticosteroids and immunosuppressant drugs during the observation period.\nFig. 1 Schematic illustration of the study design and patient-selection criteria\n\n\n\nOf the 49 patients included in this study, 32 patients were classified as the “stable group” (pirfenidone, 17; nintedanib, 15) and 17 patients were classified as the “progression group” (pirfenidone, 6; nintedanib, 11). The median observation period was 190.0 (169.8–263.2) days in the stable group and 183.0 (171.5–189.5) days in the progression group; there were no significant differences between the stable and the progression groups. Baseline characteristics were not significantly different between the stable and the progression groups (Table 1). Of the 26 patients treated with nintedanib, seven patients had past histories of treatment with pirfenidone (stable group, 4; progression group, 3). Two patients developed malignant tumor and were diagnosed with lung cancer. No patients developed acute exacerbations during the observation period. The changes in FVC and DLco from baseline to 6 months are shown in Fig. 2. The median change in FVC was 0.00 (− 0.08–0.09) L in the stable group and − 0.16 (− 0.29 to − 0.11) L in the progression group; the change in the stable group was significantly smaller than that in the progression group (p < 0.01). The median change in DLco was − 0.19 (− 1.00–0.42) mL/min/mmHg in the stable group and − 2.08 (− 3.13 to − 1.54) mL/min/mmHg in the progression group; the change in the stable group was significantly smaller than that in the progression group (p < 0.01).\nTable 1 Baseline characteristics and clinical data\n\nVariable\tAll subjects\tStable group\tProgression group\tP-value\t\n(n = 49)\t(n = 32)\t(n = 17)\t\nSex M/F (n)\t38/11\t24/8\t14/3\t0.56\t\nAge (yr)\t69 (65–75)\t70 (66–76)\t68 (64–75)\t0.38\t\nSmokers/never-smokers (n)\t36/13\t23/9\t13/4\t0.73\t\nPack-years smoking\t30 (0.8–51.5)\t34 (5–52.1)\t25 (0.8–49.5)\t0.61\t\nBMI\t23.8 (22.1–25.8)\t23.6 (22.1–25.5)\t25.0 (21.7–26.1)\t0.43\t\nGAP stage (n), I/II/III\t20/24/5\t14/15/3\t6/9/2\t0.84\t\nFVC (L)\t2.42 (2.08–2.86)\t2.40 (2.09–3.65)\t2.64 (2.02–2.78)\t0.83\t\n% FVC (%)\t76.6 (65.4–92.5)\t77.4 (65.1–94.4)\t76.6 (66.4–86.9)\t0.78\t\nDLco (mL/min/mmHg)\t10.7 (9.22–13.5)\t10.6 (9.25–13.5)\t10.7 (8.81–14.3)\t0.76\t\n% DLco (%)\t52.8 (44.3–59.8)\t52.8 (44.4–57.6)\t51.7 (43.6–70.3)\t0.97\t\nPaO2 at rest (Torr)\t82.7 (78.2–88.6)\t81.5 (77.2–91.6)\t83.8 (78.4–87.3)\t0.71\t\nMinimum SpO2 during 6MWT (%)\t91 (87.3–93)\t91 (88–93)\t90 (85.5–93)\t0.42\t\n6MWT Distance (meter)\t410 (380–480)\t420 (385–480)\t400 (360–490)\t0.94\t\nSP-A (ng/mL)\t57.8 (41.7–79.1)\t60.3 (42.6–76.1)\t56.6 (40.6–96.7)\t0.83\t\nSP-D (ng/mL)\t243 (181–352)\t241 (177–357)\t246 (166–350)\t0.97\t\nKL-6 (U/mL)\t901 (663–1494)\t885 (595.3–1618)\t901 (732–1336)\t0.44\t\npirfenidone/nintedanib\t23/26\t17/15\t6/11\t0.23\t\nTreatment history of anti-fibrotic drug (n), yes/no\t7/42\t4/28\t3/14\t0.66\t\nData are expressed as frequencies or medians (interquartile range). P-value: stable group vs. progression group.\n\nBMI body mass index; GAP (gender [G], age [A], and 2 lung physiology variables [P] [FVC and DLco]); FVC forced vital capacity; DLco diffusing capacity of the lung for carbon monoxide; PaO2 partial pressure of arterial oxygen; SpO2 arterial oxygen saturation measured by pulse oximetry; 6MWT 6 min-walk test; SP surfactant protein; KL-6 Krebs von den Lungen-6\n\n\nFig. 2 Rate of change in (a) FVC and (b) DLco in the initial 6 months. Changes in FVC and DLco in the stable group were significantly smaller than those in the progression group. Horizontal line indicates median concentration. The upper and lower limits of the line indicate the inter quartile range. Data were analyzed by Mann–Whitney U test. *p < 0.01 stable vs. progression group. FVC, forced vital capacity; DLco, diffusing capacity of the lung for carbon monoxide\n\n\n\nChanges in serum biomarkers at 3 and 6 months\nThe levels of SP-A, SP-D, and KL-6 at baseline, 3, and 6 months are shown in Table 2. In the stable group, SP-A and KL-6 levels significantly decreased from baseline to 3 months and 6 months. On the other hand, in the progression group, SP-A showed a significant increase from baseline to 3 and 6 months. KL-6 tended to increase at 3 and 6 months; however, the difference was not significant. At 6 months, KL-6 level in the stable group was significantly lower than that in the progression group.\nTable 2 Serum levels of SP-A, SP-D, and KL-6 at baseline, 3, and 6 months\n\n\tBaseline\t3 months\t6 months\t\nStable group\t\n SP-A (ng/mL)\t60.3 (42.6–76.1)\t53.1 (36.6–68.0) *\t49.2 (37.1–71.7) *\t\n SP-D (ng/mL)\t241 (177–357)\t194 (149–296)\t195 (128–263)\t\n KL-6 (U/mL)\t885 (595–1618)\t775 (581–1154) *\t738 (503–1213) *#\t\nProgression group\t\n SP-A (ng/mL)\t56.6 (40.6–96.7)\t67.0 (46.8–111.8) *\t69.3 (42.7–117.8) *\t\n SP-D (ng/mL)\t246 (166–350)\t261 (180–323)\t224 (192–353)\t\n KL-6 (U/mL)\t901 (732–1337)\t1195 (653–1821)\t1237 (748–1570) #\t\nData are expressed as medians (interquartile range).\n\n*: Bonferroni-corrected p < 0.05 baseline vs. 3 or 6 months. #: p < 0.05 stable group vs. progression group. SP surfactant protein; KL-6 Krebs von den Lungen-6\n\n\n\nThe relative changes in serum biomarker levels from baseline to 3 and 6 months are shown in Fig. 3. The median change in SP-A at 3 and 6 months was − 6.0 (− 20.1–3.6) % and − 10.2 (− 17.9 to − 3.85) % in the stable group, and 16.7 (6.5–30.7) % and 20.2 (3.0–27.9) % in the progression group; the changes at 3 and 6 months in the stable group were significantly smaller than those in the progression group. The median change in SP-D at 3 and 6 months was − 10.6 (− 30.3–1.0) % and − 13.7 (− 32.1–2.2) % in the stable group and − 0.4 (− 18.6–35.8) % and 0.5 (− 6.0–24.7) % in the progression group; the changes at 6 months in the stable group were significantly smaller than those in the progression group. The median changes in KL-6 at 3 and 6 months were − 9.2 (− 22.5–4.1) % and − 15.0 (− 30.6−− 2.8) % in the stable group and 6.7 (− 14.0–18.9) % and 12.1 (− 3.6–36.6) % in the progression group; the changes at 3 and 6 months in the stable group were significantly smaller than those in the progression group.\nFig. 3 Relative change in (a) SP-A, (b) SP-D, and (c) KL-6 levels in the initial 3 and 6 months. Changes in serum SP-A at 3 and 6 months, SP-D at 6 months, and KL-6 at 3 and 6 months were significantly smaller in the stable group than the progression group (*p < 0.05). Data were analyzed by Mann–Whitney U test. Horizontal line indicates median concentration. The upper and lower limits of the box indicate the inter quartile range\n\n\n\nPirfenidone and nintedanib subgroup evaluation\nWe performed subgroup analysis by disaggregating patients treated with pirfenidone and nintedanib. There was no significant difference between pirfenidone group and nintedanib group with respect to baseline characteristics (See Additional file 5: Table S1).\n\nIn the pirfenidone group, serum SP-A in the stable group was significantly lower than that in the progression group (p < 0.05); however, no significant difference was noted with respect to other baseline characteristics between the stable and progression subgroups of the pirfenidone and nintedanib groups. In both the pirfenidone and nintedanib groups, the changes in FVC and DLco from the baseline to 6 months in the stable group were significantly smaller than that in the progression group.\n\nIn patients treated with pirfenidone, the median change in SP-A at 3 and 6 months was − 6.0 (− 19.8–2.3) % and − 10.3 (− 20.1 to − 5.9) % in the stable group and 28.6 (− 3.8–41.1) % and 25.1 (0–33.9) % in the progression group; the changes at 3 and 6 months were significantly smaller in the stable group than in the progression group (p < 0.05) (See Additional file 1: Figure S1). The median change in SP-D at 6 months was − 12.7 (− 21.8–1.4) % in the stable group and 15.3 (− 5.8–26.7) % in the progression group; the change in the stable group was significantly smaller than that in the progression group (p < 0.05). The median change in KL-6 at 3 and 6 months was − 8.6 (− 16.9–7.4) % and − 8.5 (− 32.2–0.8) % in the stable group and 14.3 (− 0.5–86.1) % and 25.5 (7.5–44.3) % in the progression group; the changes at 3 and 6 months in the stable group were significantly smaller than those in the progression group (p < 0.05). In patients treated with nintedanib, the median change in SP-A at 3 and 6 months was − 5.0 (− 23.0–4.5) % and − 10.0 (− 18.5–5.6) % in the stable group and 14.7 (8.7–21.0) % and 18.7 (1.9–25.8) % in the progression group; the changes at 3 and 6 months in the stable group were significantly smaller than those in the progression group (p < 0.05). The median change in KL-6 at 6 months was − 16.6 (− 24.7 to − 4.7) % in the stable group and 6.8 (− 6.8–16.9) % in the progression group; the change was significantly smaller in the stable group than in the progression group (p < 0.05). The changes in SP-D were not significantly different between these groups.\n\nCorrelation between serum biomarkers and PFTs\nThe correlation between the changes in serum biomarker levels and the change in FVC and DLco are shown in Fig. 4. We observed a negative correlation between the change in FVC at 6 months and the changes in SP-A (correlation coefficient: − 0.46, p < 0.01) and SP-D (correlation coefficient: − 0.39, p < 0.01) at 6 months. We also observed a negative correlation between the change in DLco and the changes in SP-A (correlation coefficient: − 0.67, p < 0.01), SP-D (correlation coefficient: − 0.54, p < 0.01) and KL-6 (correlation coefficient: − 0.47, p < 0.01).\nFig. 4 Correlation between changes in (a) FVC and (b) DLco and changes in SP-A, SP-D, and KL-6. (a) Decline in FVC showed a correlation with decrease in serum SP-A and SP-D (r = − 0.46 and r = − 0.39, respectively, p < 0.01). (b) Decline in DLco showed a correlation with decrease in serum SP-A, SP-D, and KL-6 (r = − 0.67, r = − 0.54, and r = − 0.47 respectively, p < 0.01). Spearman’s correlation coefficients were used to analyze the linear relationship between the variables\n\n\n\nIn patients treated with pirfenidone, we observed a negative correlation between the change in FVC at 6 months and change in SP-A (correlation coefficient: − 0.60, p < 0.01) and SP-D (correlation coefficient: − 0.49, p < 0.05) at 6 months; similarly, we observed a negative correlation between the change in DLco and changes in SP-A (correlation coefficient: − 0.59, p < 0.05), SP-D (correlation coefficient: − 0.56, p < 0.05), and KL-6 (correlation coefficient: − 0.48, p < 0.05) (See Additional file 6: Table S2). In patients treated with nintedanib, we observed a negative correlation between the change in DLco and changes in SP-A (correlation coefficient: − 0.61, p < 0.01), SP-D (correlation coefficient: − 0.42, p < 0.05), and KL-6 (correlation coefficient: − 0.47, p < 0.05).\n\nPredictive factors of therapeutic effect of anti-fibrotic drugs\nWe performed logistic regression analysis to identify factors that predicted therapeutic outcome at 6 months (Table 3). On univariate analysis, the change in SP-A at 3 months (odd’s ratio [OR] 0.89, 95% CI 0.82–0.96, p < 0.01), KL-6 at 3 months (OR 0.96, 95% CI 0.92–0.99, p < 0.01), SP-A in 6 months (OR 0.89, 95% CI 0.84–0.95, p < 0.01), SP-D in 6 months (OR 0.95, 95% CI 0.92–0.99, p < 0.01), and KL-6 in 6 months (OR 0.93, 95% CI 0.89–0.97, p < 0.01) showed a significant association with outcomes. Three multivariate analysis models were constructed (Table 4). When the change in SP-A, SP-D, and KL-6 at 3 months were entered in the 3 months model (model 1), the change in SP-A at 3 months was a significant predictive factor (OR 0.88, 95% CI 0.80–0.97, p < 0.01). When the change in SP-A, SP-D, and KL-6 at 6 months were entered in the 6 months model (model 2), the change in SP-A at 6 months was a significant predictive factor (OR 0.90, 95% CI 0.84–0.97, p < 0.01). In the 3 months model and 6 months model (model 3), the changes in SP-A at 3 and 6 months were significant predictive factors (OR 0.89, 95% CI 0.76–0.98, p < 0.05; OR 0.88, 95% CI 0.76–0.96, p < 0.01; respectively).\nTable 3 Prediction of stability at 6 months from administration of anti-fibrotic drugs in univariate analysis\n\nVariable\tOR (95% CI)\tP-value\t\nSex, Male\t0.64 (0.15–2.83)\t0.55\t\nAge\t1.05 (0.96–1.14)\t0.24\t\nSmokers\t1.27 (0.33–4.96)\t0.72\t\nPack-years smoking\t1.01 (0.99–1.03)\t0.59\t\nBMI\t0.89 (0.74–1.08)\t0.22\t\n% FVC (%)\t1.01 (0.98–1.04)\t0.61\t\n% DLco (%)\t1.00 (0.95–1.04)\t0.83\t\nPaO2 at rest (Torr)\t1.01 (0.94–1.09)\t0.71\t\nMinimum SpO2 during 6MWT (%)\t1.06 (0.93–1.21)\t0.37\t\n6MWT Distance (m)\t1.00 (0.99–1.01)\t0.80\t\nSP-A (ng/mL)\t0.99 (0.98–1.01)\t0.30\t\nSP-D (ng/mL)\t1.00 (1.00–1.00)\t0.64\t\nKL-6 (U/mL)\t1.00 (1.00–1.00)\t0.65\t\nPirfenidone\t2.01 (0.62–6.99)\t0.23\t\nTreatment history of anti-fibrotic drugs (n)\t0.69 (0.14–3.53)\t0.66\t\nChange in SP-A in 3 months (%)\t0.89 (0.82–0.96)\t< 0.01\t\nChange in SP-D in 3 months (%)\t0.98 (0.96–1.00)\t0.12\t\nChange in KL-6 in 3 months (%)\t0.96 (0.92–0.99)\t< 0.01\t\nChange in SP-A in 6 months (%)\t0.89 (0.84–0.95)\t< 0.01\t\nChange in SP-D in 6 months (%)\t0.95 (0.92–0.99)\t< 0.01\t\nChange in KL-6 in 6 months (%)\t0.93 (0.89–0.97)\t< 0.01\t\nOR odd’s ratio; BMI body mass index; FVC forced vital capacity; DLco diffusing capacity of the lung for carbon monoxide; PaO2 partial pressure of arterial oxygen; SpO2 arterial oxygen saturation measured by pulse oximetry; 6MWT 6 min-walk test; SP surfactant protein; KL-6 Krebs von den Lungen-6\n\n\nTable 4 Prediction of stability at 6 months from administration of anti-fibrotic drugs in multivariate analysis\n\nvariable\tmodel 1\tmodel 2\tmodel 3 (model 1 + model 2)\t\nOR (95% CI)\tP-value\tOR (95% CI)\tP-value\tOR (95% CI)\tP-value\t\nChange in SP-A in 3 months (%)\t0.88 (0.80–0.97)\t< 0.01\t–\t–\t0.89 (0.76–0.98)\t< 0.05\t\nChange in SP-D in 3 months (%)\t1.10 (0.98–1.05)\t0.28\t–\t–\t1.04 (0.99–1.13)\t0.09\t\nChange in KL-6 in 3 months (%)\t0.99 (0.95–1.03)\t0.67\t–\t–\t0.99 (0.92–1.04)\t0.71\t\nChange in SP-A in 6 months (%)\t–\t–\t0.90 (0.84–0.97)\t< 0.01\t0.88 (0.76–0.96)\t< 0.01\t\nChange in SP-D in 6 months (%)\t–\t–\t0.98 (0.92–1.03)\t0.37\t0.98 (0.90–1.04)\t0.49\t\nChange in KL-6 in 6 months (%)\t–\t–\t0.95 (0.90–1.01)\t0.05\t0.96 (0.87–1.03)\t0.30\t\nOR odd’s ratio; SP surfactant protein; KL-6 Krebs von den Lungen-6\n\n\n\nWe analyzed the sensitivity and specificity to distinguish between the stable and the progressive patients for changes in SP-A, SP-D, and KL-6. The sensitivity and specificity estimated according to the ROC curve analyses are shown in Table S3 (See Additional file 7). The sensitivity, specificity and the AUC of change in SP-A in 3 months were 93, 75%, and 0.89, respectively. The sensitivity, specificity and AUC of change in SP-A in 6 months were 81, 81%, and 0.89, respectively.\n\nDiscussion\nWe report an association between changes in serum SP-A, SP-D, and KL-6 levels and change in FVC and DLco of patients with IPF treated with anti-fibrotic drugs. Patients with IPF who maintained their FVC and DLco showed a significant decrease in SP-A and KL-6 at 3 and 6 months. On the other hand, those who showed decline in FVC and DLco had increased SP-A levels at 3 and 6 months. The relative changes in serum biomarkers were significantly smaller in the stable group than in the progression group. The changes in serum biomarker levels showed a significant correlation with changes in FVC and DLco. In particular, changes in SP-A levels most closely reflected the outcomes of anti-fibrotic therapy. This study indicates that SP-A may be used as a biomarker to predict the outcomes of anti-fibrotic drug therapy.\n\nSerum levels of SP-A, SP-D, and KL-6 have been shown to be useful in predicting prognosis and monitoring disease activity in patients with IPF [12, 18, 19]. In previous studies, SP-A was found to be a predictor of early mortality in patients with IPF [19, 20]. In our previous studies, patients with high levels of SP-D tended to exhibit worsening restrictive impairment and poor prognosis [13, 21]. Serum KL-6 levels were shown to correlate with the severity and prognosis of patients with IPF [14, 22]; in addition, serial change in KL-6 levels was a prognostic factor for patients with IPF [23, 24]. However, the usefulness of these serum biomarkers in patients undergoing anti-fibrotic drug therapy is not well characterized. A few studies have investigated the clinical relevance of SP-D and KL-6 levels in the context of pirfenidone therapy. For example, SP-D was shown to be prognostic marker in patients with IPF treated with pirfenidone [15]. Similarly, in a study by Okuda, et al., levels of KL-6 and SP-D were decreased by pirfenidone therapy [25]. The present study showed that changes in serum biomarkers may serve as useful markers for clinical evaluation and monitoring of therapeutic efficacy in patients with IPF treated with anti-fibrotic drugs. Thus, our study provides novel insights for further investigations to verify the clinical relevance of these serum biomarkers in the context of anti-fibrotic therapy for IPF.\n\nIn the present study, serum biomarker levels at baseline did not show any significant differences between the stable group and the progression group. In our previous study, baseline level of SP-D was found to predict mortality of patients with IPF treated with pirfenidone [15]. This discrepancy may be partly explained by the shorter duration of follow-up and the difference in the definition of deterioration (including not only FVC but also DLCO) in the present study. In addition, previous study lacked longitudinal assessment to determine whether changes in serum biomarker levels reflect the therapeutic effect. In a study by Sokai, et al., serial changes in KL-6 in patients with IPF showed a significant correlation with changes in FVC and DLco; in addition, serial change in KL-6 level was a predictor of mortality; however, most of patients were not treated with anti-fibrotic drugs [24]. Our study is the first to demonstrate that serial changes in SP-A and KL-6 reflect the decline in pulmonary function of patients with IPF treated with anti-fibrotic drugs. These results suggest that serial measurement of serum biomarker levels is more useful for monitoring patients with IPF and their response to anti-fibrotic therapy.\n\nIPF is a progressive lung disease characterized by decline in FVC. In both ASCEND and INPULSIS-1/2 phase III trials, the primary endpoint was the annual rate of decline in FVC [4, 5]. Currently, alleviation of the rate of decline in FVC is the only criterion to ascertain the therapeutic efficacy of pirfenidone and nintedanib. No other biomarker of the therapeutic effect of anti-fibrotic therapy has been elucidated. It is difficult to evaluate the degree of efficacy of pirfenidone and nintedanib by pulmonary function tests alone. Furthermore, it is difficult to perform pulmonary function tests frequently in patients with severe IPF owing to the following reasons: 1) it imposes a physical burden on patients with serious disease; 2) the results depend on the patient’s efforts; 3) maximal effort may be difficult because of cough; 4) DLco cannot be measured in severe cases. Therefore, use of pulmonary function tests in conjunction with serum biomarkers will help reduce the burden on patients and allow for more frequent assessments. Moreover, this will facilitate more accurate assessment of the therapeutic outcomes of pirfenidone and nintedanib.\n\nIn IPF, serial changes in FVC and DLco at 6 or 12 months show greater prognostic value than baseline data [26, 27]. Even a decline in FVC by 5–10% at 6 months was associated with increased mortality [27]. In the study by Du Bois et al., change in percent-predicted FVC over 6 months was a strong predictor of death over 1-year period [28]. Risk of death was nearly five-fold higher for patients with > 10% decline in percent-predicted FVC, and two-fold higher for those with 5–10% decline [28]. The rate of decline in FVC at 6 months is associated with the subsequent prognosis. Although the evaluation period in this study was 6 months, it was considered to be an appropriate period for prognostic assessment. Furthermore, absence of signs of therapeutic effect at 6 months should prompt reconsideration of treatment such as a change to another anti-fibrotic drug.\n\nPatients with IPF show increased production of SP-A, SP-D, and KL-6 by alveolar type 2 epithelial cells in the lung tissues [11, 12, 29]. Levels of SP-A and SP-D in bronchoalveolar lavage (BAL) fluid in patients with IPF were shown to decrease as compared to healthy subjects, whereas levels of KL-6 were shown to increase [29–31]. It is considered that serum SP-A, SP-D, and KL-6 levels are elevated due to increased vascular leakage from the alveolar space, probably due to epithelial detachment, basement membrane injury, and capillary fragility [15, 29]. In this study, serum SP-A and KL-6 levels were found to decrease after treatment with anti-fibrotic drugs. These results may be explained by the following mechanisms of action of nintedanib: 1) suppression of vascular permeability and capillary angiogenesis via VEGF; 2) repair of lung tissue with reduction of fibroblast migration and cell proliferation with PDGF and FGF; 3) suppression of the production of SP-A in alveolar type 2 epithelial cells by FGF. Pirfenidone suppresses the production of TGF-β and inflammatory cytokines in addition to PDGF and FGF [32, 33]. It may also reduce the leakage by suppressing the production of SP-A and KL-6 by epithelial cells and by reducing abnormal tissue repair.\n\nIn the present study, in both pirfenidone and nintedanib groups, there was no difference in the reduction rate of pulmonary function between the stable group and the progression group; in addition, the number of patients in the stable group was also similar. Although the difference between the therapeutic effect of pirfenidone and nintedanib has not been clarified, the therapeutic effects may be comparable [34]. Moreover, it is not clear whether change from one anti-fibrotic drug to the other accrues any additional benefit. In the present study population, seven patients with IPF were shifted from pirfenidone to nintedanib; however, there was no difference between the stable and progression groups with respect to history of treatment with pirfenidone. Our results also showed additional therapeutic benefit in these patients, although the number of patients was small. A previous report also documented the therapeutic benefit of change in anti-fibrotic drug in a small number of cases; this phenomenon may be attributable to the different mechanisms of action of these drugs [35]. Further studies with larger sample are required to obtain more definitive evidence of the benefit of treatment with two anti-fibrotic drugs, and to determine the optimal sequence of use of anti-fibrotic drugs.\n\nThe present study has some limitations. First, this was a single-center retrospective study with a small sample size. Further, the number of subjects has decreased because 11 patients, including 3 cases where patients developed acute exacerbation before anti-fibrotic drug administration, were excluded because corticosteroid therapy was considered to affect serum biomarker expression. In the present study, we evaluated 60 people, including 11 patients who received treatment with corticosteroids and confirmed that the results were the same (see Additional files 2,3,4,8,9,10,11: Figure S2–S4, Table S4–S7). Therefore, treatment with steroids does not affect the results, and we thus believe that sampling errors will not occur in this study that has continued for more than 6 months. Second, nintedanib has been available in Japan since August 2015; therefore, only pirfenidone was available for use during the initial period of the study reference period. The nintedanib group included some patients who had a history of treatment with pirfenidone. However, there were no significant differences between the pirfenidone and nintedanib groups with respect to baseline characteristics, clinical data, and outcomes. Third, this study did not include a group that was not treated with anti-fibrotic drugs; thus, it may not be concluded that the amelioration of decline in FVC and DLco was attributable to anti-fibrotic drug therapy. However, it is difficult to plan comparative studies on the treatment of IPF in an era when anti-fibrotic drugs have become the standard therapy for treating IPF. Finally, the observation period was 6 months, and long-term efficacy and prognosis have not been investigated. It is necessary to clarify the relationship of serum biomarkers with therapeutic effect and prognosis over a longer term.\n\nConclusion\nChanges in serum SP-A levels reflected the outcomes of anti-fibrotic drug therapy. Serial measurements of SP-A may serve as a useful therapeutic biomarker and may help guide the management of IPF.\n\nSupplementary information\n\nAdditional file 1: Figure S1. Relative change in SP-A, SP-D, and KL-6 in patients treated with (A) pirfenidone and (B) nintedanib. (A) Change in SP-A at 3 and 6 months, SP-D at 6 months, and KL-6 at 3 and 6 months were significantly smaller in the stable group than the progression group (p < 0.05). (B) Change in SP-A at 3 and 6 months and KL-6 at 6 months were significantly smaller in the stable group than the progression group (p < 0.05)\n\n \nAdditional file 2: Figure S2. Rate of change in (A) FVC and (B) DLco in the initial 6 months of population which included patients who used corticosteroids. Changes in FVC and DLco in the stable group were significantly smaller than those in the progression group (p < 0.01)\n\n \nAdditional file 3: Figure S3. Relative change in (A) SP-A, (B) SP-D, and (C) KL-6 levels in the initial 3 and 6 months of population which included patients who used corticosteroids. Changes in SP-A, SP-D, and KL-6 at 3 and 6 months were significantly smaller in the stable group than the progression group (p < 0.05)\n\n \nAdditional file 4: Figure S4. Correlation between changes in (A) FVC and (B) DLco and changes in SP-A, SP-D, and KL-6 of population which included patients who used corticosteroids. (A) Change in FVC showed a negative correlation with changes in SP-A and SP-D (p < 0.01). (B) Change in DLco showed a negative correlation with changes in SP-A, SP-D, and KL-6 (p < 0.01)\n\n \nAdditional file 5: Table S1. Baseline characteristics and clinical data of the pirfenidone and nintedanib groups\n\n \nAdditional file 6: Table S2. Correlation between change in SP-A, SP-D, and KL-6 and change in pulmonary function in 6 months of the pirfenidone and nintedanib groups\n\n \nAdditional file 7: Table S3. Sensitivity and specificity for distinguish between the stable and the progressive patients for changes in SP-A, SP-D, and KL-6\n\n \nAdditional file 8: Table S4. Baseline characteristics and clinical data of population which included patients who used corticosteroids\n\n \nAdditional file 9: Table S5. Serum levels of SP-A, SP-D, and KL-6 at baseline, 3, and 6 months of population which included patients who used corticosteroids\n\n \nAdditional file 10: Table S6. Prediction of stability at 6 months from administration of anti-fibrotic drugs in univariate analysis of population which included patients who used corticosteroids\n\n \nAdditional file 11: Table S7. Prediction of stability at 6 months from administration of anti-fibrotic drugs in multivariate analysis of population which included patients who used corticosteroids\n\n \n\n\nAbbreviations\n6MWT6-min walk test\n\nALATLatin American Thoracic Association\n\nATSAmerican Thoracic Society\n\nAUCArea under the curve\n\nBALBronchoalveolar lavage\n\nDLcoDiffusing capacity of the lung for carbon monoxide\n\nERSEuropean Respiratory Society\n\nFGFsFibroblast growth factors\n\nFVCForced vital capacity\n\nHRCTHigh-resolution computed tomography\n\nIPFIdiopathic pulmonary fibrosis\n\nIQRInterquartile range\n\nJRSJapanese Respiratory Society\n\nKL-6Krebs von den Lungen-6\n\nOROdds ratio\n\nPaO2Partial pressure of oxygen in arterial blood\n\nPDGFsPlatelet-derived growth factors\n\nPFTPulmonary function test\n\nROCReceiver operating characteristic\n\nSP-ASurfactant protein-A\n\nSP-DSurfactant protein-D\n\nSpO2Peripheral capillary oxygen saturation\n\nTGF-βTransforming growth factor-beta\n\nVEGFVascular endothelial growth factor\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nTakumi Yoshikawa and Hirofumi Chiba contributed equally to this work.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1186/s12890-020-1060-y.\n\nAcknowledgements\nThe authors would like to thank Enago (www.enago.jp) for the English language review.\n\nAuthors’ contributions\nTY, MO and HC designed this study. TY, MO, and KI contributed to collection, analysis, and interpretation of data. YM, YU, HN, KK, HT also contributed to data interpretation. TY, MO, and KI wrote the initial draft of the manuscript. YM, YU, HN, KK, HT critically reviewed the manuscript. All authors have approved the final version of the manuscript.\n\nFunding\nThis work was supported in part by the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (C), Grant Number 17 K09619. The funder had no role in the design of the study, the collection, analysis, and interpretation of data, or writing the manuscript.\n\nAvailability of data and materials\nAll datasets are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThis study was conducted in accordance to the Declaration of Helsinki and was approved by the Institutional Review Board of Sapporo Medical University School of Medicine (approval number: 302–120, dated November 8, 2018). For this type of study, formal consent is not required.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nHC has served as a speaker for Boehringer Ingerheim; HT has received grants from Boehringer Ingerheim and Shionogi, and also has served as a speaker for Boehringer Ingerheim.\n==== Refs\nReferences\n1. Raghu G Remy-Jardin M Myers JL Richeldi L Ryerson CJ Lederer DJ Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline Am J Respir Crit Care Med 2018 198 e44 e68 10.1164/rccm.201807-1255ST 30168753 \n2. Nathan SD Shlobin OA Weir N Ahmad S Kaldjob JM Battle E Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium Chest 2011 140 221 229 10.1378/chest.10-2572 21729893 \n3. Natsuizaka M Chiba H Kuronuma K Otsuka M Kudo K Mori M Epidemiologic survey of Japanese patients with idiopathic pulmonary fibrosis and investigation of ethnic differences Am J Respir Crit Care Med 2014 190 773 779 10.1164/rccm.201403-0566OC 25162152 \n4. King TE Bradford WZ Castro-Bernardini S Fagan EA Glaspole I Glassberg MK A phase 3 trial of Pirfenidone in patients with idiopathic pulmonary fibrosis N Engl J Med 2014 370 2083 2092 10.1056/NEJMoa1402582 24836312 \n5. Richeldi L du Bois RM Raghu G Azuma A Brown KK Costabel U Efficacy and safety of nintedanib in advanced idiopathic pulmonary fibrosis N Engl J Med 2014 370 2071 2082 10.1056/NEJMoa1402584 24836310 \n6. Kolb M Bonella F Wollin L Therapeutic targets in idiopathic pulmonary fibrosis Respir Med 2017 131 49 57 10.1016/j.rmed.2017.07.062 28947042 \n7. Raghu G Rochwerg B Zhang Y Garcia CA Azuma A Behr J An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis: an update of the 2011 clinical practice guideline Am J Respir Crit Care Med 2015 192 e3 e19 10.1164/rccm.201506-1063ST 26177183 \n8. Raghu G Collard HR Egan JJ Martinez FJ Behr J Brown KK An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management Am J Respir Crit Care Med 2011 138 788 824 10.1164/rccm.2009-040GL \n9. Du Bois RM Weycker D Albera C Bradford WZ Costabel U Kartashov A Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference Am J Respir Crit Care Med 2011 184 1382 1389 10.1164/rccm.201105-0840OC 21940789 \n10. Takahashi H Sano H Chiba H Kuroki Y Pulmonary surfactant proteins a and D: innate immune functions and biomarkers for lung diseases Curr Pharm Des 2006 12 589 598 10.2174/138161206775474387 16472150 \n11. Kohno N Kyoizumi S Awaya Y Fukuhara H Yamakido M Akiyama M New serum Indicator of interstitial pneumonitis activity. Sialylated carbohydrate antigen KL-6 Chest 1989 96 68 73 10.1378/chest.96.1.68 2661160 \n12. Chiba H Otsuka M Takahashi H Significance of molecular biomarkers in idiopathic pulmonary fibrosis: a mini review Respir Investig 2018 56 384 391 10.1016/j.resinv.2018.06.001 30030108 \n13. Takahashi H Fujishima T Koba H Murakami S Kurokawa K Shibuya Y Serum surfactant proteins a and D as prognostic factors in idiopathic pulmonary fibrosis and their relationship to disease extent Am J Respir Crit Care Med 2000 162 1109 1114 10.1164/ajrccm.162.3.9910080 10988138 \n14. Yokoyama A Kondo K Nakajima M Matsushima T Takahashi T Nishimura M Prognostic value of circulating KL-6 in idiopathic pulmonary fibrosis Respirology 2006 11 164 168 10.1111/j.1440-1843.2006.00834.x 16548901 \n15. Ikeda K Shiratori M Chiba H Nishikiori H Yokoo K Saito A Serum surfactant protein D predicts the outcome of patients with idiopathic pulmonary fibrosis treated with pirfenidone Respir Med 2017 131 184 191 10.1016/j.rmed.2017.08.021 28947028 \n16. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories ATS statement: guidelines for the six-minute walk test Am J Respir Crit Care Med 2002 166 111 117 10.1164/ajrccm.166.1.at1102 12091180 \n17. Noble PW Albera C Bradford WZ Costabel U Glassberg MK Kardatzke D Articles Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomized trials Lancet 2011 377 1760 1769 10.1016/S0140-6736(11)60405-4 21571362 \n18. Travis WD Costabel U Hansell DM King TE Jr Lynch DA Nicholson AG An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias Am J Respir Crit Care Med 2013 188 733 748 10.1164/rccm.201308-1483ST 24032382 \n19. Zhang Y Kaminski N Biomarkers in idiopathic pulmonary fibrosis Curr Opin Pulm Med 2012 12 441 446 10.1097/MCP.0b013e328356d03c \n20. Kinder BW Brown KK McCormack FX Ix JH Kervitsky A Schwarz MI Serum surfactant protein-a is a strong predictor of early mortality in idiopathic pulmonary fibrosis Chest 2009 135 1557 1563 10.1378/chest.08-2209 19255294 \n21. Takahashi H Shiratori M Kanai A Chiba H Kuroki Y Abe S Monitoring markers of disease activity for interstitial lung diseases with serum surfactant proteins A and D Respirology 2006 11 Suppl S51 S54 10.1111/j.1440-1843.2006.00809.x 16423272 \n22. Satoh H Kurishima K Ishikawa H Ohtsuka M Increased levels of KL-6 and subsequent mortality in patients with interstitial lung diseases J Intern Med 2006 260 429 434 10.1111/j.1365-2796.2006.01704.x 17040248 \n23. Wakamatsu K Nagata N Kumazoe H Oda K Ishimoto H Yoshimi M Prognostic value of serial serum KL-6 measurements in patients with idiopathic pulmonary fibrosis Respir Investig 2017 55 16 23 10.1016/j.resinv.2016.09.003 28012488 \n24. Sokai A Tanizawa K Handa T Kanatani K Kubo T Ikezoe K Importance of serial changes in biomarkers in idiopathic pulmonary fibrosis ERJ Open Res 2017 3 00019 02016 10.1183/23120541.00019-2016 28875146 \n25. Okuda R Hagiwara E Baba T Kitamura H Kato T Ogura T Safety and efficacy of pirfenidone in idiopathic pulmonary fibrosis in clinical practice Respir Med 2013 107 1431 1437 10.1016/j.rmed.2013.06.011 23849626 \n26. Martinez FJ Flaherty K Pulmonary Function Testing in Idiopathic Interstitial Pneumonias Proc Am Thorac Soc 2006 3 315 321 10.1513/pats.200602-022TK 16738195 \n27. Zappala CJ Latsi PI Nicholson AG Colby TV Cramer D Renzoni EA Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis Eur Respir J 2010 35 830 835 10.1183/09031936.00155108 19840957 \n28. Du Bois RM Weycker D Albera C Bradford WZ Costabel U Kartashov A Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference Am J Respir Crit Care Med 2011 184 1382 1389 10.1164/rccm.201105-0840OC 21940789 \n29. Nishikiori H Chiba H Ariki S Kuronuma K Otsuka M Shiratori M Distinct compartmentalization of SP-A and SP-D in the vasculature and lungs of patients with idiopathic pulmonary fibrosis BMC Pulm Med 2014 14 196 10.1186/1471-2466-14-196 25488319 \n30. Günther A Schmidt R Nix F Yabut-Perez M Guth C Rosseau S Surfactant abnormalities in idiopathic pulmonary fibrosis, hypersensitivity pneumonitis and sarcoidosis Eur Respir J 1999 14 565 573 10.1034/j.1399-3003.1999.14c14.x 10543276 \n31. Kohno N Awaya Y Oyama T Yamakido M Akiyama M Inoue Y KL-6, a Mucin-like glycoprotein, in Bronchoalveolar lavage fluid from patients with interstitial lung disease Am Rev Respir Dis 2011 148 637 642 10.1164/ajrccm/148.3.637 \n32. Oku H Shimizu T Kawabata T Nagira M Hikita I Ueyama A Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis Eur J Pharmacol 2008 590 400 408 10.1016/j.ejphar.2008.06.046 18598692 \n33. Gurujeyalakshmi G Hollinger MA Giri SN Pirfenidone inhibits PDGF isoforms in bleomycin hamster model of lung fibrosis at the translational level Am J Phys 1999 276 L311 L318 10.1152/ajplung.1999.276.2.L311 \n34. Raghu G Selman M Nintedanib and Pirfenidone. New Antifibrotic treatments indicated for idiopathic pulmonary fibrosis offer hopes and raises questions Am J Respir Crit Care Med 2015 191 252 254 10.1164/rccm.201411-2044ED 25635489 \n35. Ikeda S Sekine A Baba T Katano T Tabata E Shintani R Negative impact of anorexia and weight loss during prior pirfenidone administration on subsequent nintedanib treatment in patients with idiopathic pulmonary fibrosis BMC Pulm Med 2019 19 78 10.1186/s12890-019-0841-7 30975118\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2466", "issue": "20(1)", "journal": "BMC pulmonary medicine", "keywords": "Idiopathic pulmonary fibrosis (IPF); Krebs von den Lungen-6 (KL-6); Nintedanib; Pirfenidone; Surfactant protein-A (SP-A); Surfactant protein-D (SP-D)", "medline_ta": "BMC Pulm Med", "mesh_terms": "D000368:Aged; D015415:Biomarkers; D018450:Disease Progression; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis; D007211:Indoles; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D018396:Mucin-1; D037662:Pulmonary Surfactant-Associated Protein A; D037663:Pulmonary Surfactant-Associated Protein D; D011728:Pyridones; D012189:Retrospective Studies; D016896:Treatment Outcome; D014797:Vital Capacity", "nlm_unique_id": "100968563", "other_id": null, "pages": "27", "pmc": null, "pmid": "32005219", "pubdate": "2020-01-31", "publication_types": "D016428:Journal Article", "references": "28947042;25488319;12091180;25635489;21729893;10543276;30168753;22847105;28875146;10988138;16423272;16548901;24836312;19255294;16738195;24836310;8368634;25162152;23849626;18598692;17040248;21571362;21471066;30975118;21940789;26177183;2661160;19840957;24032382;30030108;16472150;9950894;28947028;28012488", "title": "Surfactant protein A as a biomarker of outcomes of anti-fibrotic drug therapy in patients with idiopathic pulmonary fibrosis.", "title_normalized": "surfactant protein a as a biomarker of outcomes of anti fibrotic drug therapy in patients with idiopathic pulmonary fibrosis" }
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{ "abstract": "The safety of prasugrel in elderly and/or low body weight Japanese patients with ischemic stroke who have a relatively high bleeding risk with antiplatelet therapy remains unknown.\n\n\n\nWe aimed to investigate the safety and efficacy of long-term prasugrel monotherapy for stroke prevention compared with clopidogrel in elderly and/or low body weight Japanese patients with non-cardioembolic ischemic stroke.\n\n\n\nIn this randomized, double-blind, comparative, phase III study, elderly (age ≥75 years) and/or low body weight (≤50 kg) Japanese patients with a previous history of non-cardioembolic ischemic stroke were assigned to a prasugrel 3.75 mg (PRA3.75) group, a prasugrel 2.5 mg (PRA2.5) group, or a clopidogrel 50 mg (CLO50) group and followed up for 48 weeks. The primary safety endpoint was the combined incidence of primary safety events, defined as life-threatening, major, and other clinically relevant bleeding. The efficacy endpoint was a composite of ischemic stroke, myocardial infarction, and death from other vascular causes.\n\n\n\nA total of 654 patients (age 76.4 ± 7.3 years, body weight 55.6 ± 9.3 kg, women 43.9%) from 74 medical institutions within Japan were enrolled. The combined incidence (95% CI) of primary safety events was 4.2% (1.9-7.8%), 1.9% (0.5-4.7%), and 3.6% (1.6-6.9%) in the PRA3.75 group (n = 216), PRA2.5 group (n = 215), and CLO50 group (n = 223), respectively (hazard ratios [HR] PRA3.75/CLO50, 1.13 [0.44-2.93]; PRA2.5/CLO50, 0.51 [0.15-1.69]). The incidences of bleeding leading to treatment discontinuation (95% CI) were 2.3% (0.8-5.3%), 0.9% (0.1-3.3%), and 2.2% (0.7-5.2%) in the PRA3.75, PRA2.5, and CLO50 groups, respectively (HRs PRA3.75/CLO50, 1.01 [0.29-3.48]; PRA2.5/CLO50, 0.41 [0.08-2.12]). There was no significant difference in all bleeding events between groups. The incidence of ischemic stroke, myocardial infarction, and death from other vascular causes was lower, but not significantly so, in patients treated with prasugrel than in patients treated with clopidogrel: PRA3.75, 0.0% (0/216); PRA2.5, 3.3% (7/215); and CLO50, 3.6% (8/223; HRs PRA3.75/CLO50, 0.00 [0.00-0.00]; PRA2.5/CLO50, 0.90 [0.32-2.47]).\n\n\n\nElderly and/or low body weight -Japanese patients with previous non-cardioembolic ischemic stroke who received PRA3.75 showed similar results in terms of primary safety endpoint, and a numerically lower incidence of ischemic stroke, myocardial infarction, and death from other vascular causes, compared with those who received CLO50.", "affiliations": "Department of Neurology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan, kitagawa.kazuo@twmu.ac.jp.;Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.;Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Clinical Research Support Center, Mie University Hospital, Mie, Japan.;Department of Cardiology, Nishinomiya Municipal Central Hospital, Hyogo, Japan.;Waseda University Faculty of Science and Engineering, Tokyo, Japan.;Daiichi Sankyo Co., Ltd., Tokyo, Japan.;Department of Neurosurgery, Iwate Medical University, Iwate, Japan.", "authors": "Kitagawa|Kazuo|K|;Toyoda|Kazunori|K|;Kitazono|Takanari|T|;Nishikawa|Masakatsu|M|;Nanto|Shinsuke|S|;Ikeda|Yasuo|Y|;Abe|Kenji|K|;Ogawa|Akira|A|", "chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride", "country": "Switzerland", "delete": false, "doi": "10.1159/000506825", "fulltext": null, "fulltext_license": null, "issn_linking": "1015-9770", "issue": "49(2)", "journal": "Cerebrovascular diseases (Basel, Switzerland)", "keywords": "Body weight; Elderly; Prasugrel; Safety; Therapy", "medline_ta": "Cerebrovasc Dis", "mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D044466:Asians; D001835:Body Weight; D002545:Brain Ischemia; D000077144:Clopidogrel; D004311:Double-Blind Method; D005260:Female; D006304:Health Status; D006470:Hemorrhage; D006801:Humans; D015994:Incidence; D007564:Japan; D008297:Male; D010975:Platelet Aggregation Inhibitors; D000068799:Prasugrel Hydrochloride; D012008:Recurrence; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke; D013997:Time Factors; D016896:Treatment Outcome", "nlm_unique_id": "9100851", "other_id": null, "pages": "152-159", "pmc": null, "pmid": "32208397", "pubdate": "2020", "publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": "21160749;21168310;30074128;24759796;27133299;7678184;18202034;18223144;27222591;27260294;24788967;19451364;23610570;30784555;23553246", "title": "Safety and Efficacy of Prasugrel in Elderly/Low Body Weight Japanese Patients with Ischemic Stroke: Randomized PRASTRO-II.", "title_normalized": "safety and efficacy of prasugrel in elderly low body weight japanese patients with ischemic stroke randomized prastro ii" }
[ { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2020-01161", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PRASUGREL HYDROCHLORIDE" }, ...
{ "abstract": "A 42-year-old woman with juvenile idiopathic arthritis was treated with anakinra, corticosteroids, and hydroxychloroquine when she developed chronic hypoxic respiratory myopathy. She was admitted to the intensive care unit for acute hypercapnic respiratory failure and required prolonged intubation, subsequent tracheostomy, and long-term ventilatory support due to multiple failed spontaneous breathing trials after discontinuation of anakinra and steroids. Muscle biopsy revealed type II fiber atrophy with the accumulation of autophagosomes and vacuoles presenting as curvilinear bodies, elevated MHC class I antigen expression, and infiltration by CD68+ macrophages and CD8+ T cells. Type II fiber atrophy was attributed to corticosteroid use and curvilinear bodies due to blockade of autophagy by hydroxychloroquine. After hydroxychloroquine was discontinued, the patient recovered to her prehospitalization baseline.", "affiliations": "State University of New York, Upstate Medical University, Syracuse, NY, USA.;State University of New York, Upstate Medical University, Syracuse, NY, USA.;State University of New York, Upstate Medical University, Syracuse, NY, USA.;State University of New York, Upstate Medical University, Syracuse, NY, USA.", "authors": "Pillittere|Julie|J|;Mian|Sundus|S|;Richardson|Timothy E|TE|;Perl|Andras|A|", "chemical_list": "D000305:Adrenal Cortex Hormones; D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D006886:Hydroxychloroquine", "country": "United States", "delete": false, "doi": "10.1177/2324709620950113", "fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620950113\n10.1177_2324709620950113\nCase Report\nHydroxychloroquine-Induced Toxic Myopathy Causing Diaphragmatic Weakness and Lung Collapse Requiring Prolonged Mechanical Ventilation\nPillittere Julie MD1 Mian Sundus MD1 Richardson Timothy E. DO, PhD1 Perl Andras MD, PhD1 1 State University of New York, Upstate Medical University, Syracuse, NY, USA\nAndras Perl, MD, PhD, College of Medicine, State University of New York, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA. Email: perla@upstate.edu\n12 8 2020 \nJan-Dec 2020 \n8 23247096209501137 6 2020 1 7 2020 6 7 2020 © 2020 American Federation for Medical Research2020American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).A 42-year-old woman with juvenile idiopathic arthritis was treated with anakinra, corticosteroids, and hydroxychloroquine when she developed chronic hypoxic respiratory myopathy. She was admitted to the intensive care unit for acute hypercapnic respiratory failure and required prolonged intubation, subsequent tracheostomy, and long-term ventilatory support due to multiple failed spontaneous breathing trials after discontinuation of anakinra and steroids. Muscle biopsy revealed type II fiber atrophy with the accumulation of autophagosomes and vacuoles presenting as curvilinear bodies, elevated MHC class I antigen expression, and infiltration by CD68+ macrophages and CD8+ T cells. Type II fiber atrophy was attributed to corticosteroid use and curvilinear bodies due to blockade of autophagy by hydroxychloroquine. After hydroxychloroquine was discontinued, the patient recovered to her prehospitalization baseline.\n\nhydroxychloroquinecorticosteroidsmyopathyautophagycurvilinear bodytype II fiberatrophynecrosisjuvenile inflammatory arthritiscover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nHydroxychloroquine is widely utilized as a treatment for a variety of autoimmune rheumatic diseases. However, hydroxychloroquine can also lead to a number of side effects including bull’s eye maculopathy and less commonly toxic myopathy.1,2 Myopathy seen in hydroxychloroquine toxicity is thought to be due to the inhibition of lysosomal degradation of phospholipids and glycogen leading to the formation of curvilinear body seen on muscle biopsies.3 Hydroxychloroquine promotes the accumulation of autophagic vacuoles by inhibiting the lysosome acidification.4 Our case represents hydroxychloroquine-induced myopathy in a 42-year-old Caucasian female with prolonged use for treatment of JIA. The patient also suffered respiratory failure and required tracheostomy for long-term ventilatory support, which was only reversed on discontinuation of hydroxychloroquine.\n\nCase Presentation\nA 42-year-old woman with a past medical history significant for juvenile idiopathic arthritis (JIA) on anakinra 100 mg subcutaneous daily and hydroxychloroquine 200 mg twice daily, chronic adrenal insufficiency secondary to steroids, currently on hydrocortisone 20 mg every morning and 10 mg in the afternoon, seizure disorder, and a history of recent culture negative infective endocarditis with subsequent cardioembolic stroke presented from a nursing home after a mechanical fall. Imaging on arrival revealed an age indeterminate C7 vertebral fracture, which was treated with conservatively with a cervical collar and pain control. Shortly after admission, her hospital course was complicated by acute on chronic hypoxic and hypercapnic respiratory failure requiring rescue BiPAP (bilevel positive airway pressure) support and admission to the intensive care unit. The patient became encephalopathic, and arterial blood gas revealed respiratory acidosis with significant carbon dioxide retention of >105 mm Hg. The patient was intubated for impending respiratory failure.\n\nComputed tomography thorax was performed and showed a left-sided opacification initially treated as a left-sided pneumonia. However, her respiratory status failed to improve despite being on adequate antibiotic therapy, and she failed recurrent spontaneous breathing trials while off sedation. These findings lead to the discovery of significant neuromuscular weakness and the left-sided opacification. The opacification was suspected to be due to lung collapse secondary to left-sided diaphragmatic weakness (Figure 1). On day 13 of admission, the patient underwent tracheotomy for expected long-term ventilator support and percutaneous endoscopic gastrostomy.\n\nFigure 1. Computed tomography thorax revealing left lung opacity attributed to lung collapse due to diaphragmatic weakness.\n\nOf note, she had recurrent admissions including an admission for a mechanical fall from bed and was found to have a subarachnoid hemorrhage. She was hospitalized yet again after falling down the stairs and sustaining a comminuted fracture of the distal left tibia. Given her recurrent hospital admissions, prolonged hospital course, and diaphragmatic weakness, there was concern the patient had been exhibiting progressive weakness prior to admission. History taking was limited due to patient mechanical ventilation and nonverbal status. She had reportedly noticed progressive muscular weakness worsening over the past year, which was attributed to her recurrent hospitalizations leading to deconditioning. Prior to this year, the patient did not require supplemental oxygen.\n\nDuring admission, her serum aldolase initially was elevated at 11.8 (3.3-10.3 U/L normal), but 4 days later, it normalized to 4.6. Her creatine kinase was within normal limits at 70 U/L (normal = 20-180 U/L). Thyroid-stimulating hormone was elevated at 8.15 (normal = 0.27-4.2 IU/mL), but the free thyroxine was normal at 0.98 (normal = 0.93-1.7 ng/dL). Her alanine aminotransferase was mildly elevated at 36 U/L (her outpatient alanine aminotransferase from 3 months ago was also elevated at 58, with prior laboratory values within normal limits). Her aspartate aminotransferase was mildly elevated at 62 U/L (her outpatient aspartate aminotransferase from 3 months ago was also elevated at 46, with prior laboratory values within normal limits). Her bilirubin was within normal limits, and her creatinine has been chronically low ranging from 0.2 to 0.4mg/dL.\n\nRheumatology was consulted to evaluate the mechanism of her diaphragmatic weakness given her history of JIA. She was diagnosed with JIA at the age of 18 months. She resides in a nursing home and at baseline uses a wheelchair for mobility. According to her mother, she had been on various therapies for JIA. In the past, she developed complications from medications, including hematuria while on aspirin and gold salt therapy, and secondary systemic lupus erythematosus diagnosed after starting etanercept therapy at age 35 years. Based on history, it was estimated that she had been on hydroxychloroquine for about 10 years. She had a prolonged hiatus from hydroxychloroquine from her mid-20s to age 40 years, but was on a stable dose of 200 mg twice daily from age 40 to 42 years. The medication was stopped after concern for retinal maculopathy, a diagnosis that was later ruled out with ophthalmologic examination. The patient had significant synovitis in both hands and it was recommended to continue hydroxychloroquine. Anakinra was held this admission due to newly discovered Enterococcus faecalis urinary tract infection causing septic shock.\n\nNeurology was consulted to evaluate the patient’s progressive neuromuscular decline. Physical examination revealed muscle weakness in all extremities with proximal muscles affected more than distal muscles (⅗ strength in proximal muscles, ⅘ strength in distal muscles). She was hyporeflexic with 3 to 4 beats of clonus in both ankles. Brain magnetic resonance imaging was consistent with prior stroke and bilateral encephalomalacia, but no acute pathology was identified. Spinal magnetic resonance imaging returned unremarkable and no further neurologic imaging was recommended. Electromyogram (EMG) was performed and suggested myopathy with decreased motor unit recruitment of proximal upper and lower extremities without an inflammatory pattern. Needle EMG reported myopathic changes more significant in the proximal muscles compared with distal muscles. There was some irritability detected in proximal and distal arm muscles. There were no demyelinating features and no evidence of decrement on slow repetitive stimulation. Based on diagnostic testing and clinical presentation, demyelinating diseases and central nervous system insult were ruled out, a primary muscle pathology was suspected as the likely etiology for the patient’s weakness. A myositis panel was sent and returned negative. The myositis panel included anti-Jo1 Ab, PL-7, PL12, EJ, OJ, SRP, MI-2, Fibrillarin, MDA-5, NXP-2, TIF1 gamma, Anti-PM/Scl-100, U2 snRNP, anti-U1-RNP, Ku, and Anti-SSA. Muscle biopsy was performed on the right quadriceps muscle. Muscle biopsy light microscopy reported a granular myopathy with rimmed vacuoles and type II fiber atrophy with scattered inflammation (Figure 2A-C and G). The initial findings were relatively nonspecific but have been identified in critical illness myopathy and myopathy related to chronic corticosteroid or chronic chloroquine use.\n\nFigure 2. Histological analysis of right quadriceps muscle biopsy. Hematoxylin and eosin–stained images demonstrate (A) significant fiber size variation with increased granularity and vacuoles (arrow heads) and (B) perifascicular mononuclear inflammatory cells. Gomori trichrome sections demonstrate significant fiber size variation with increased granularity and vacuoles (arrow heads) (C). Perifascicular inflammatory cells highlighted by esterase (D), CD3, demonstrating infiltrating T-lymphocytes, primarily in the perifascicular compartment, with infiltration into the endomysium (E), and CD68, demonstrating histiocytes, also primarily in the perifascicular compartment (F). ATPase pH 9.4 demonstrating selective type II fiber atrophy (atrophy of darker stained fibers) (G). Electron microscopy images demonstrating abnormal autophagosomes (red arrow) (H) and curvilinear bodies corresponding to the vacuoles seen on light microscopy (arrowheads) (I).\n\nElectron microscopy (EM) as well as the addition of immunohistochemical stains; CD3, CD20, and CD68 were ordered to further evaluate the inflammatory cells found in the endomysial and perimysial regions on light microscopy (Figure 2D-F). Her serology was significant for normal JO-1 antibody at 4 [AU]/mL (normal = 0-99 [AU]/mL), borderline elevated ANA speckled pattern antibody at 80 1/dil (normal is <80 1/dil). At this time, her physical examination continued to reveal significant synovitis in the bilateral hand joints. Factoring in her uncontrolled inflammatory arthritis, her other rheumatological medications being held due to septic shock, and literature review highlighting the rarity of hydroxychloroquine toxicity, it was elected to continue the hydroxychloroquine inpatient, encourage inpatient physical therapy as tolerated, and closely await EM report. Rheumatology requested hydroxychloroquine levels to be drawn, which resulted as 763 ng/mL. The patient’s hydrocortisone was continued due to septic shock in the setting of chronic adrenal insufficiency, as she had been on chronic steroid therapy since the age 18 years.\n\nElectron microscopy showed granular material identified by the hematoxylin and eosin stains contained a number of abnormal autophagosomes (Figure 2H) and vacuoles contained characteristic curvilinear bodies (Figure 2), consistent with hydroxychloroquine-induced myopathy. There was no significant myosin loss identified. Immunohistochemical staining for CD3, CD20, and CD68 revealed the presence of frequent T lymphocytes and histiocytes in the perimysium and endomysium with less frequent B lymphocytes in the perimysium (Figure 2E and F). These findings were thought to be consistent with an inflammatory response to muscle injury. Gomori trichrome sections, similar to the hematoxylin and eosin stains, demonstrated fiber size variation and scattered vacuoles consistent with medication-induced myopathy such as hydroxychloroquine.5\n\nDiscussion\nOur patient’s profound respiratory failure became a diagnostic dilemma involving multiple subspecialists and diagnostic testing modalities. In addition to the confounding effect of the patient’s progressive JIA and recurrent hospitalizations causing deconditioning, the rarity of hydroxychloroquine-induced myopathy added to the diagnostic challenge in this case.\n\nHydroxychloroquine impairs acidity in lysosomes and therefore interferes with enzyme degradation of autophagic vacuoles leading to abnormal enlarged autophagosomes as seen in our patient’s muscle biopsy sample.4,6 Case series examining muscle biopsy from those with hydroxychloroquine toxicity highlight the pathologic changes to mitochondria, vacuoles, and the presence of curvilinear bodies.7 Patients being treated with antimalarials for rheumatologic diseases were followed over a 3-year period and microscopic changes consistent with chloroquine or hydroxychloroquine-induced myopathy were found in just over 12% with 6.7% experiencing clinical signs of toxicity.8\n\nThe condition is painless and predominantly affects the proximal muscles and is less severe than chloroquine myopathy.9 In 2007, Siddiqui et al described a case of respiratory failure requiring long-term mechanical ventilation.10 Existing literature identifies potential risk factors for toxicity including Caucasian race, renal failure, and the concomitant use of myotoxic medications.11 Our patient was Caucasian but did not have any evidence of renal failure during her hospital stay.11 Recovery time is not well understood and seems to vary considerably among patients and different forms of myopathy. In a retrospective review of 3 patients with antimalarial-induced myopathy, all 3 patients recovered completely within 8 weeks of discontinuing the medication.12 Khoo et al examined muscle biopsy of over 1400 patients being treated with hydroxychloroquine and of those 19 had curvilinear bodies on biopsy.13 More than 60% of these patients had muscle weakness. Additionally, there was no cumulative dose response relationship among those with curvilinear bodies on biopsy.13 Hydroxychloroquine-induced myopathy predominantly affects proximal muscles and spares sensory fibers.10 This pattern is consistent with our patient’s EMG findings of predominantly proximal muscle myopathy and lack of significant conclusive sensory deficit.\n\nTo our knowledge, this patient represents only the second case of hydroxychloroquine-induced myopathy necessitating mechanical ventilation. The 42-year-old patient in our case was considerably younger than the patient discussed in the prior case who was 88 years of age.10 This disparity is likely due to the patient’s extensive history of JIA, which was diagnosed at just 18 months old. Additionally, our case serves as an example of the diagnostic challenges of diagnosing hydroxychloroquine-induced myopathy. Patients with rheumatologic disorders are often on more than one immunosuppressive, including steroids, which are a well-known cause of myopathy.9\n\nIn our case, there were features of coexisting steroid-induced myopathy. Steroid-induced myopathy predominantly affects the proximal muscles and is dose-dependent unlike hydroxychloroquine toxicity.13 Furthermore, creatine kinase levels and EMG studies are within normal limits for the majority of cases as is the case for our patient.14,15 Occasionally, EMG studies show slow amplitude motor unit potentials.15,16 Although there is no definitive testing to diagnose steroid-induced myopathy features on muscle biopsy, such as atrophy of type II b fibers, help distinguish it from hydroxychloroquine-induced myopathy.16 Our patient did have evidence of type II fiber atrophy on biopsy in addition to curvilinear bodies, which further supports a combined process.\n\nOther differentials considered in our patient’s case include chronic inflammatory demyelinating polyneuropathy (CIDP), critical illness myopathy, and other inflammatory myopathy. CIDP is a progressive or relapsing disease affecting both motor and sensory fibers, particularly the large sensory fibers.16 CIDP typically affects both proximal and distal muscles, as well as sensory fibers leading to diminished deep tendon reflexes.17,18 EMG in CIDP typically shows evidence of demyelination predominantly in the distal muscles.19 In our patient, EMG lacked a demyelination pattern as well as significant sensory deficits. The patient’s EMG additionally demonstrated a proximal rather than distal muscle predominance of myopathy.\n\nFeatures of critical illness myopathy include elevated CK, lack of muscle excitability, motor amplitude <80% of the lower limit of normal in 2 or more nerves, and prolonged compound muscle action potential durations.20 Critical illness myopathy often leads to quadriparesis, especially in the proximal muscles and can even affect facial muscles.21 Critical illness myopathy is a term that covers a number of discrete entities. Among these is thick filament myopathy that is associated with nondepolarizing neuromuscular blocking agents, which are often used for paralysis during sedation, and glucocorticoids.22 Thick fiber myopathy leads to destruction of the muscle tissue and thus prolonged recovery time.22 Inability to wean mechanical ventilation is a common feature of critical illness myopathy and our patient failed multiple spontaneous breathing trials put this on the differential diagnosis.21 However, our patient’s lack of significant sensory involvement on EMG favors the predominant hydroxychloroquine-induced myopathy as the predominant etiology. Additionally, in critical illness myopathy, muscle biopsy pathology typically demonstrates myosin loss which was not found on EM of the muscle biopsy.21\n\nDiscontinuing hydroxychloroquine is the mainstay of treatment as demonstrated in a prospective longitudinal study, which showed improvement in muscle strength at 6-month intervals in those who initially exhibited moderate to severe clinical myopathy.8 The exact timeline and level of strength recovery the patients in the study experienced are unclear. Given pathologic findings consistent with steroid-induced myopathy, reducing the dose of steroids and potentially discontinue steroids entirely would be beneficial.23 However, this was not possible for our patient given her history of adrenal insufficiency and multiple failed attempts to wean dosages in the past. Overall, this case serves as an opportunity to highlight differential diagnoses related to myopathy in those with rheumatologic disorders. Many myopathic disorders discussed have overlapping features making isolating a diagnosis even more challenging. Additionally, it emphasizes the profound effect hydroxychloroquine-induced myopathy can have on patients, including respiratory failure necessitating mechanical ventilation.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Verbal informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article.\n==== Refs\nReferences\n1 \nChew AL Sampson DM Chelva E Khan JC Chen FK \nPerifoveal interdigitation zone loss in hydroxychloroquine toxicity leads to subclinical bull’s eye lesion appearance on near-infrared reflectance imaging\n. Doc Ophthalmol . 2018 ;136 :57 -68\n. doi:10.1007/s10633-017-9615-9 29124422 \n2 \nMarmor MF Melles RB \nDisparity between visual fields and optical coherence tomography in hydroxychloroquine retinopathy\n. Ophthalmology . 2014 ;121 :1257 -1262\n. doi:10.1016/j.ophtha.2013.12.002 24439759 \n3 \nStauber WT Hedge AM Trout JJ Schottelius BA \nInhibition of lysosomal function in red and white skeletal muscles by chloroquine\n. Exp Neurol . 1981 ;71 :295 -306\n. doi:10.1016/0014-4886(81)90090-x 7004885 \n4 \nTho JH Blumbergs P \nHydroxychloroquine induced vacuolar myopathy mimicking acid maltase\n. J Clin Neurosci . 2010 ;17 :1637 . doi:10.1016/S0022-510X(09)70541-6 \n5 \nCai C Anthony DC Pytel P \nA pattern-based approach to the interpretation of skeletal muscle biopsies\n. Mod Pathol . 2019 ;32 :462 -483\n. doi:10.1038/s41379-018-0164-x 30401945 \n6 \nShukla S Gultekin SH Saporta M \nPearls & Oy-sters: hydroxychloroquine-induced toxic myopathy mimics Pompe disease: critical role of genetic test\n. Neurology . 2019 ;92 :e742 -e745\n. doi:10.1212/WNL.0000000000006914 30745451 \n7 \nKhosa S Khanlou N Khosa GS Mishra SK \nHydroxychloroquine-induced autophagic vacuolar myopathy with mitochondrial abnormalities\n. Neuropathology . 2018 ;38 :646 -652\n. doi:10.1111/neup.12520 30411412 \n8 \nCasado E Gratacos J Tolosa C , et al\nAntimalarial myopathy: an underdiagnosed complication? Prospective longitudinal study of 119 patients\n. Ann Rheum Dis . 2006 ;65 :385 -390\n. doi:10.1136/ard.2004.023200 16096334 \n9 \nDoughty CT Amato AA \nToxic myopathies\n. Continuum (Minneap Minn) . 2019 ;25 :1712 -1731\n. doi:10.1212/CON.0000000000000806 31794468 \n10 \nSiddiqui AK Huberfeld SI Weidenheim KM Einberg KR Efferen LS \nHydroxychloroquine-induced toxic myopathy causing respiratory failure\n. Chest . 2007 ;131 :588 -590\n. doi:10.1378/chest.06-1146 17296665 \n11 \nStein M Bell MJ Ang LC \nHydroxychloroquine neuromyotoxicity\n. J Rheumatol . 2000 ;27 :2927 -2931\n.11128688 \n12 \nAvina-Zubieta JA Johnson ES Suarez-Almazor ME Russell AS \nIncidence of myopathy in patients treated with antimalarials. A report of three cases and a review of the literature\n. Br J Rheumatol . 1995 ;34 :166 -170\n. doi:10.1093/rheumatology/34.2.166 7704464 \n13 \nKhoo T Otto S Smith C , et al\nCurvilinear bodies are associated with adverse effects on muscle function but not with hydroxychloroquine dosing\n. Clin Rheumatol . 2017 ;36 :689 -693\n. doi:10.1007/s10067-016-3408-5 27629259 \n14 \nAskari A Vignos PJ JrMoskowitz RW \nSteroid myopathy in connective tissue disease\n. Am J Med . 1976 ;61 :485 -492\n. doi:10.1016/0002-9343(76)90327-2 973643 \n15 \nBowyer SL LaMothe MP Hollister JR \nSteroid myopathy: incidence and detection in a population with asthma\n. J Allergy Clin Immunol . 1985 ;76 :234 -242\n. doi:10.1016/0091-6749(85)90708-0 4019954 \n16 \nKhaleeli AA Edwards RH Gohil K , et al\nCorticosteroid myopathy: a clinical and pathological study\n. Clin Endocrinol (Oxf) . 1983 ;18 :155 -166\n. doi:10.1111/j.1365-2265.1983.tb03198.x 6851197 \n17 \nSaperstein DS Katz JS Amato AA Barohn RJ \nClinical spectrum of chronic acquired demyelinating polyneuropathies\n. Muscle Nerve . 2001 ;24 :311 -324\n. doi:10.1002/1097-4598(200103)24:3<311::aid-mus1001>3.0.co;2-a 11353415 \n18 \nDyck PJ Lais AC Ohta M , et al\nChronic inflammatory polyradiculoneuropathy\n. Mayo Clin Proc . 1975 ;50 :621 -637\n.1186294 \n19 \nChio A Cocito D Bottacchi E , et al\nIdiopathic chronic inflammatory demyelinating polyneuropathy: an epidemiological study in Italy\n. J Neurol Neurosurg Psychiatry . 2007 ;78 :1349 -1353\n. doi:10.1136/jnnp.2007.114868 17494979 \n20 \nLatronico N Friedrich O \nElectrophysiological investigations of peripheral nerves and muscles: a method for looking at cell dysfunction in the critically ill patients\n. Crit Care . 2019 ;23 :33 . doi:10.1186/s13054-019-2331-y 30696473 \n21 \nShepherd S Batra A Lerner DP \nReview of critical illness myopathy and neuropathy\n. Neurohospitalist . 2017 ;7 :41 -48\n. doi:10.1177/1941874416663279 28042370 \n22 \nKasper DM Fauci A Hauser SL Longo DLM Jameson JL Joseph L \nNeurologic critical care\n. In: Harrison’s Principles of Internal Medicine . 19th ed. \nMcGraw Hill Education ; 2015 .\n23 \nHaran M Schattner A Kozak N Mate A Berrebi A Shvidel L \nAcute steroid myopathy: a highly overlooked entity\n. QJM . 2018 ;111 :307 -311\n.29462474\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2324-7096", "issue": "8()", "journal": "Journal of investigative medicine high impact case reports", "keywords": "atrophy; autophagy; corticosteroids; curvilinear body; hydroxychloroquine; juvenile inflammatory arthritis; myopathy; necrosis; type II fiber", "medline_ta": "J Investig Med High Impact Case Rep", "mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D018501:Antirheumatic Agents; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D053590:Interleukin 1 Receptor Antagonist Protein; D018908:Muscle Weakness; D009135:Muscular Diseases; D052097:Quadriceps Muscle; D012121:Respiration, Artificial; D012131:Respiratory Insufficiency; D014057:Tomography, X-Ray Computed; D014139:Tracheostomy", "nlm_unique_id": "101624758", "other_id": null, "pages": "2324709620950113", "pmc": null, "pmid": "32787461", "pubdate": "2020", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "11128688;28042370;7704464;29124422;30401945;30411412;29462474;17494979;7004885;31794468;973643;6851197;24439759;30696473;17296665;16096334;1186294;4019954;11353415;27629259;30745451", "title": "Hydroxychloroquine-Induced Toxic Myopathy Causing Diaphragmatic Weakness and Lung Collapse Requiring Prolonged Mechanical Ventilation.", "title_normalized": "hydroxychloroquine induced toxic myopathy causing diaphragmatic weakness and lung collapse requiring prolonged mechanical ventilation" }
[ { "companynumb": "US-AMGEN-USASP2020144233", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETANERCEPT" }, "drugadditional": "3", ...
{ "abstract": "The most serious life-threatening warfarin-associated complications is hemorrhage in CNS structures. Reports of spontaneous spinal epidural hematomas in patients using warfarin, methods of diagnostics and treatment are but few. We describe the first case of warfarin-associated spontaneous spinal epidural hematoma in this country and a literature review of this issue.", "affiliations": null, "authors": "Byval'tsev|V A|VA|;Budaev|A E|AE|;Sorokovikov|V A|VA|;Belykh|E G|EG|;Kalinin|A A|AA|;Zhdanovich|G S|GS|;Asantsev|A O|AO|;Shepelev|V V|VV|", "chemical_list": "D000925:Anticoagulants; D014859:Warfarin", "country": "Russia (Federation)", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0023-2149", "issue": "93(12)", "journal": "Klinicheskaia meditsina", "keywords": null, "medline_ta": "Klin Med (Mosk)", "mesh_terms": "D000925:Anticoagulants; D006407:Hematoma, Epidural, Cranial; D006801:Humans; D008297:Male; D008875:Middle Aged; D013117:Spinal Cord Compression; D014859:Warfarin", "nlm_unique_id": "2985204R", "other_id": null, "pages": "44-52", "pmc": null, "pmid": "27149813", "pubdate": "2015", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review", "references": null, "title": "EPIDURAL HEMATOMA WITH SPINAL CHORD COMPRESSION ASSOCIATED WITH WARFARIN INTAKE.", "title_normalized": "epidural hematoma with spinal chord compression associated with warfarin intake" }
[ { "companynumb": "RU-MYLANLABS-2016M1027706", "fulfillexpeditecriteria": "1", "occurcountry": "RU", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "1", ...