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"abstract": "OBJECTIVE\nWe report a case of immune myopathy with perimysial pathology associated with anti-glycyl-transfer RNA synthetase (anti-EJ) antibody and an excellent treatment response.\n\n\nMETHODS\nChart review.\n\n\nRESULTS\nA 36-year-old woman presented with 3 months of fatigue, weight loss, progressive weakness in a scapuloperoneal distribution, and dysphagia. Nerve conduction studies, electromyography, and ultrasound suggested an irritable myopathy. She had marked elevations of creatine kinase and positive anti-glycyl-transfer RNA synthetase (anti-EJ) antibodies. A left biceps muscle biopsy revealed inflammation of the perimysium and surrounding perimysial blood vessels with focal fragmentation of the perimysium. Further evaluation revealed interstitial lung disease. Treatment with prednisone and mycophenolate mofetil led to marked clinical improvement of her symptoms.\n\n\nCONCLUSIONS\nOur case adds to the growing spectrum of inflammatory myopathies and highlights the importance of performing a comprehensive, multisystem workup.",
"affiliations": "*Neuromuscular Division, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY; and †Division of Rheumatology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.",
"authors": "Kwon|Patrick M|PM|;Zhou|Lan|L|;Motiwala|Rajeev|R|;Kerr|Leslie D|LD|;Shin|Susan C|SC|",
"chemical_list": "D001323:Autoantibodies; D006032:Glycine-tRNA Ligase",
"country": "United States",
"delete": false,
"doi": "10.1097/CND.0000000000000148",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1522-0443",
"issue": "18(4)",
"journal": "Journal of clinical neuromuscular disease",
"keywords": null,
"medline_ta": "J Clin Neuromuscul Dis",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D005260:Female; D006032:Glycine-tRNA Ligase; D006801:Humans; D017563:Lung Diseases, Interstitial; D018482:Muscle, Skeletal; D009220:Myositis; D015898:Tomography Scanners, X-Ray Computed; D014463:Ultrasonography",
"nlm_unique_id": "100887391",
"other_id": null,
"pages": "223-227",
"pmc": null,
"pmid": "28538253",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Immune Myopathy With Perimysial Pathology Associated With Interstitial Lung Disease and Anti-EJ Antibodies.",
"title_normalized": "immune myopathy with perimysial pathology associated with interstitial lung disease and anti ej antibodies"
} | [
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP010371",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
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"abstract": "BACKGROUND\nProteasome inhibitors are a relatively new class of chemotherapeutic agents. Bortezomib is the first agent of this class and is currently being used for the treatment of multiple myeloma. However, recent reports have linked exposure to bortezomib with the development of thrombotic microangiopathy. A new agent in this class, carfilzomib, has been recently introduced as alternative therapy for relapsing and refractory multiple myeloma. We report a case of renal thrombotic microangiopathy associated with the use of carfilzomib in a patient with refractory multiple myeloma.\n\n\nMETHODS\nA 62 year-old Caucasian man with hypertension and a 4-year history of multiple myeloma, had been previously treated with lenalidomide, bortezomib and two autologous hematopoietic stem cell transplants. After the second hematopoietic stem cell transplant, he developed acute kidney injury secondary to septic shock and required dialysis for 4 weeks. Subsequently, his serum creatinine stabilized at 2.1 mg/dL (185.64 μmol/L). Seventeen months after the second hematopoietic stem cell transplant, he was initiated on carfilzomib for relapse of multiple myeloma. Six weeks later, he developed abrupt worsening of lower extremity edema and hypertension, and new onset proteinuria. His kidney function remained stable. Kidney biopsy findings were consistent with thrombotic microangiopathy. Eight weeks after discontinuation of carfilzomib, proteinuria and hypertension improved. Due to progression of multiple myeloma, he died a few months later.\n\n\nCONCLUSIONS\nIn view of the previously reported association of bortezomib with thrombotic microangiopathy, the temporal association of the clinical picture with the initiation of carfilzomib, and the partial resolution of symptoms after discontinuation of the drug, we conclude that carfilzomib may have precipitated a case of clinically evident renal thrombotic microangiopathy in our patient.",
"affiliations": "Division of Nephrology and Hypertension, Department of Medicine, University of Louisville, 615 South Preston Street, Louisville, KY 40202, USA. liliane.hobeika@louisville.edu.",
"authors": "Hobeika|Liliane|L|;Self|Sally E|SE|;Velez|Juan Carlos Q|JC|",
"chemical_list": "D000970:Antineoplastic Agents; D001897:Boronic Acids; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D011719:Pyrazines; D013792:Thalidomide; D000069286:Bortezomib; C524865:carfilzomib; D003907:Dexamethasone; D003520:Cyclophosphamide; D013713:Teniposide; D000077269:Lenalidomide",
"country": "England",
"delete": false,
"doi": "10.1186/1471-2369-15-156",
"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 2526752484610.1186/1471-2369-15-156Case ReportRenal thrombotic microangiopathy and podocytopathy associated with the use of carfilzomib in a patient with multiple myeloma Hobeika Liliane liliane.hobeika@louisville.edu Self Sally E selfs@musc.edu Velez Juan Carlos Q velezj@musc.edu Division of Nephrology and Hypertension, Department of Medicine, University of Louisville, 615 South Preston Street, Louisville, KY 40202 USA Department of Pathology, Medical University of South Carolina, Charleston, SC USA Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, SC USA 30 9 2014 30 9 2014 2014 15 1568 4 2014 22 9 2014 © Hobeika et al.; licensee BioMed Central Ltd. 2014This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nProteasome inhibitors are a relatively new class of chemotherapeutic agents. Bortezomib is the first agent of this class and is currently being used for the treatment of multiple myeloma. However, recent reports have linked exposure to bortezomib with the development of thrombotic microangiopathy. A new agent in this class, carfilzomib, has been recently introduced as alternative therapy for relapsing and refractory multiple myeloma. We report a case of renal thrombotic microangiopathy associated with the use of carfilzomib in a patient with refractory multiple myeloma.\n\nCase presentation\nA 62 year-old Caucasian man with hypertension and a 4-year history of multiple myeloma, had been previously treated with lenalidomide, bortezomib and two autologous hematopoietic stem cell transplants. After the second hematopoietic stem cell transplant, he developed acute kidney injury secondary to septic shock and required dialysis for 4 weeks. Subsequently, his serum creatinine stabilized at 2.1 mg/dL (185.64 μmol/L). Seventeen months after the second hematopoietic stem cell transplant, he was initiated on carfilzomib for relapse of multiple myeloma. Six weeks later, he developed abrupt worsening of lower extremity edema and hypertension, and new onset proteinuria. His kidney function remained stable. Kidney biopsy findings were consistent with thrombotic microangiopathy. Eight weeks after discontinuation of carfilzomib, proteinuria and hypertension improved. Due to progression of multiple myeloma, he died a few months later.\n\nConclusion\nIn view of the previously reported association of bortezomib with thrombotic microangiopathy, the temporal association of the clinical picture with the initiation of carfilzomib, and the partial resolution of symptoms after discontinuation of the drug, we conclude that carfilzomib may have precipitated a case of clinically evident renal thrombotic microangiopathy in our patient.\n\nKeywords\nThrombotic microangiopathyMalignant hypertensionProteasome inhibitorProteinuriaissue-copyright-statement© The Author(s) 2014\n==== Body\nBackground\nBecause impairment of kidney function in patients with multiple myeloma (MM) can be caused by a variety of conditions, ascertaining the etiology of kidney dysfunction in patients with MM represents a challenging task for the practicing nephrologist. Patients with MM are at risk of acquiring acute kidney injury (AKI) as a result of light chain cast nephropathy [1], hypercalcemia [2], bisphosphonate-induced tubular injury [3] and lenalidomide nephrotoxicity [4]. Similarly, syndromes of glomerular involvement can also occur in MM as a result of light or heavy chain deposition disease, amyloidosis or bisphosphonate-induced podocytopathy. Furthermore, patients with MM who undergo hematopoietic stem cell transplantation (HSCT) are also at risk of acquiring renal syndromes inherent to HSCT, such as ischemic acute tubular necrosis and thrombotic microangiopathy (TMA) [5, 6]. The clinical features of TMA syndromes include microangiopathic hemolytic anemia, thrombocytopenia, and organ injury. The pathological features are vascular damage manifested by arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium and vessel wall. Renal pathology in TMA is characterized by thickened capillary walls, occlusion of vascular lumens, fibrin deposition and endothelial separation with expansion of subendothelial zone.\n\nOver the last few years, multiple reports have unveiled an association between anti-angiogenic therapy and TMA. Antineoplastic drugs designed to target vascular endothelial growth factor (VEGF) such as sunitinib, sorafenib, bevacizumab, and others, have been linked to the development of a syndrome characterized by severe hypertension and/or acute or chronic kidney injury, with or without proteinuria, and associated with histopathological evidence of TMA in the kidney [7, 8]. Bortezomib is a proteasome inhibitor that was approved by the Food and Drug Administration (FDA) in 2003 for the treatment of refractory MM and subsequently in 2008 as an initial treatment of patients with MM. Although it does not target VEGF directly, bortezomib has also been reported to be associated with TMA. In July 2012, a new member in its class, carfilzomib, was approved by the FDA for the treatment of relapsing or refractory MM.\n\nIn this report, we summarize the case of a patient with MM status post autologous HSCT and chronic kidney disease who experienced worsening hypertension along with a substantial increase in proteinuria shortly after the initiation of carfilzomib for the treatment of refractory disease. We propose carfilzomib as a possible trigger of malignant hypertension and renal TMA in this case.\n\nCase presentation\nThe patient was a 62 year-old Caucasian man with a long-standing history of essential hypertension and a 4-year history of MM (IgG kappa subtype). The latter was diagnosed after suffering a T7 compression fracture. At that time, his kidney function was normal (serum creatinine: 0.9 mg/dL (79.56 μmol/L)) and his blood pressure was fairly well controlled on four agents (carvedilol extended-release 80 mg daily, diltiazem 60 mg three times daily, valsartan 320 mg daily and hydralazine 25 mg three times daily). As initial therapy for MM, he received melphalan for conditioning, four cycles of lenalidomide and dexamethasone, followed by autologous HSCT. Three months later, his kidney function remained within normal limits. He subsequently developed a few episodes of volume depletion associated with transient increases in serum creatinine level, after which his serum creatinine stabilized at a level of 1.4 mg/dL (123.76 μmol/L). Ten months after HSCT, he was started on bortezomib, cyclophosphamide and dexamethasone (VCD) due to progression of MM. He received five cycles of VCD. His blood pressure remained fairly well controlled with no changes to his anti-hypertensive regimen. Fifteen months after the first HSCT and 1 month after completing VCD, he underwent a second autologous HSCT for relapse. This time, the hospital course was complicated with septic shock and a severe bout of AKI, with serum creatinine peaking at 7.4 mg/dL (654.16 μmol/L). After requiring four weeks of acute hemodialysis, he partially regained kidney function, ultimately being discharged from the hospital with a new baseline serum creatinine of 2.1 mg/dL (185.64 μmol/L). At the time of discharge, his antihypertensive regimen was modified to avoid blockade of the renin-angiotensin system in the setting of AKI. Accordingly, he was switched to hydralazine 50 mg three times daily, diltiazem extended-release 360 mg daily, metoprolol 200 mg twice daily and a clonidine patch 0.3 mg/24 h.\n\nSeventeen months after the second HSCT, a follow-up bone marrow biopsy specimen revealed persistent plasma cell infiltration. As a result, he was initiated on carfilzomib (20 mg/m2; followed by 27 mg/m2, four weeks apart), thalidomide 100 mg daily and dexamethasone 20 mg per week. Six weeks after the initiation of chemotherapy, the patient developed abrupt worsening of lower extremity edema and his hypertension became more difficult to control. After being stable with four agents (hydralazine, diltiazem, metoprolol and clonidine) averaging a blood pressure of 142/74 mmHg during previous office visits, he presented with a blood pressure of 206/100 mmHg (Figure 1). His physical examination also revealed pallor, but otherwise no additional abnormalities. Laboratory data showed: hemoglobin 8.2 g/dL (5.09 μmol/L), platelet count 53 K/cumm, serum creatinine 2.1 mg/dL (185.64 μmol/L), lactate dehydrogenase 183 IU/L, haptoglobin 23 mg/dL (0.23 g/L), total bilirubin 0.6 mg/dL (10.26 μmol/L), C3 112.3 mg/dL (1.123 g/L) (normal range: 88–201 mg/dL), C4 54.4 mg/dL (0.544 g/L) (normal range: 16–47 mg/dL), albumin 2.8 g/dL (28 g/L), serum kappa free light chain 82.4 mg/dL (normal range: 0.33-1.94), serum lambda free light chain 0.69 mg/dL (normal range: 0.57-2.63), serum free kappa/lambda ratio 119.42 (normal range: 0.26-1.65). Urinalysis showed 300 mg/dL protein on dipstick but no hematuria or pyuria. Urine protein electrophoresis showed elevated kappa light chain in the gamma zone at 11.9 mg/dL (232 mg per 24 hours) and a 24-hour urine collection revealed 2.6 grams of protein (53.3% albumin). Previous testing had shown presence of low-grade proteinuria (less than 0.5 grams per day) (Table 1). In addition to his antihypertensives, he was also taking acyclovir, citalopram, esomeprazole, zolpidem, tramadol and aspirin. He required the addition of eplerenone 25 mg daily, nifedipine extended-release 90 mg daily and benazepril 30 mg daily, for a total of 7 antihypertensives. Despite the 7-drug combination, he remained hypertensive averaging 190/95 mmHg.\n\nA renal sonogram revealed a right kidney of 10.8 and a left kidney of 10.6 cm of longitudinal diameter with moderately increased cortical echogenicity. Following acute reduction of blood pressure with intravenous labetalol, an ultrasound-guided percutaneous kidney biopsy was performed to evaluate the newly developed overt proteinuria. Histological examination of the biopsy specimen on light microscopy disclosed 8 out of 17 globally sclerotic glomeruli, some mesangiolysis (Figure 2a), moderate interstitial fibrosis and tubular atrophy, and severe arteriolar hyalinosis. There was no evidence of myeloma cast nephropathy. No thrombi were identified in the glomerular capillaries or arterioles. Congo red stain was negative. Immunofluorescence showed 4 out of 14 glomeruli with global sclerosis and one small artery that stained intensely for fibrin (Figure 2b), C1q, IgM and C3. The corresponding H&E-stained cryosection showed a thrombus in that artery. The specimen was negative for linear deposition of IgG or kappa along the glomerular and tubular basement membranes. Electron microscopy of one glomerulus showed diffuse foot process effacement, endothelial cell swelling and some loops with flocculent material between the endothelial cell and the glomerular basement membrane (Figure 2c). There was no immune complex deposition or finely granular electron dense deposits along the glomerular or tubular basement membranes. In summary, the findings were consistent with TMA, glomerular podocytopathy, hypertensive-related injury and chronic scarring.Figure 1 \nSchematic illustrating the clinical and laboratory presentation of our patient. Proteinuria in month 5 was measured on a spot urine sample. Proteinuria in months 6 and 8 was estimated from a 24-hour urine collection. Black arrows reflect carfilzomib administration (20 mg/m2 in month 4, and 27 mg/m2 in month 5).\n\n\n\nTable 1 \nLaboratory values\n\n\nVariable (normal range)\t2 months prior to biopsy\tAt time of biopsy\t2 months after biopsy\t\nHemoglobin (14–18 g/dL)\t8.8\t8.2\t8.0\t\nPlatelets (140–440 k/cumm)\t75\t53\t62\t\nSerum Creatinine (0.6-1.3 mg/dL)\t2.1\t2.1\t1.7\t\nLDH (100–240 IU/L)\tNA\t183\t174\t\nHaptoglobin (36–195 mg/dL)\tNA\t23\t5\t\nSerum M-spike (g/dL)\t1.06\t0.78\t1.18\t\nProteinuria (0–0.3 g/day)\t0.33\t2.6\t1.0\t\nalbumin on UPEP (%)\tNA\t53.3\t49.3\t\nM-spike on UPEP (%)\tNA\t8.8\t13.7\t\nAbbreviations: LDH, lactate dehydrogenase; NA, not available; UPEP, urine protein electrophoresis.\n\nFigure 2 \nRenal histologic findings in the patient. a. Light microscopy: mesangiolysis on Jones’ methenamine silver stain. b. Immunofluorescence: Small artery intensely stained for fibrin. c. Electron microscopy: Endothelial cell swelling and flocculent material between endothelial cell and glomerular basement membrane.\n\nAfter the results of the kidney biopsy were reviewed and discussed, carfilzomib was discontinued. Eight weeks later, proteinuria slightly improved to 1 gram on a 24 hour urine collection. His serum creatinine remained stable at 1.7 mg/dL (150.28 μmol/L) at that time. His arterial blood pressure improved significantly averaging 135/75 mmHg on 5 agents. Due to progression of MM and a joint decision of not pursuing further treatment, the patient died four months later.\n\nDiscussion\nWe present a case of an individual who experienced abrupt worsening of hypertension and proteinuria 6 weeks after receiving carfilzomib for the treatment of refractory MM. A kidney biopsy specimen revealed a TMA lesion along with podocytopathy and evidence of chronic scarring. No previous report of renal TMA associated with carfilzomib was found in published literature. Applying the Naranjo criteria for adverse drug reactions [9], the present case meets the criteria of ‘possible’ association with TMA. First, the timing of the administration of the drug and the subsequent clinical syndrome support our contention. The onset of worsening hypertension and proteinuria coincided with the initiation of carfilzomib, as depicted in Figure 1. Secondly, there is a precedent of reports of a drug of a similar class being associated with TMA. Thirdly, the patient partially recovered after the drug was discontinued.\n\nRenal TMA is a known complication of HSCT that typically occurs approximately 3 months post-transplantation (range 14 – 240 days) [10]. Notably, it is much more likely to occur after allogeneic compared to autologous HSCT, occurring in 8-12% following allogeneic HSCT. Although factors inherent to HSCT, such as graft-versus-host disease, high-dose chemotherapy, and total body irradiation have been implicated in the pathogenesis of allogeneic HSCT-associated renal TMA, it is generally thought that the use of calcineurin inhibitors (CI) may largely explain the increased incidence of renal TMA [5, 6] after allogeneic HSCT given the well-described association between CIs and TMA in solid organ transplantation [11]. On the other hand, TMA associated with autologous HSCT is extremely rare, only case reports were found in the literature [12–14]. In our case, the second autologous HSCT was performed more than a year prior to the onset of worsening proteinuria and malignant hypertension. Therefore, the type of HSCT, the absence of CI therapy and the timing of the clinical presentation do not favor autologous HSCT as the primary etiology of renal TMA in our patient. Radiation therapy was not given in this case.\n\nThe development of overt proteinuria along with uncontrolled hypertension stimulated the clinical decision to perform a kidney biopsy. In addition to the TMA lesion, the biopsy specimen revealed evidence of podocytopathy in the form of diffuse foot process effacement, thereby explaining the proteinuric nature of the renal syndrome. Various degrees of focal or diffuse foot process effacement were reported in all the patients included in a case series describing the association of TMA and chemotherapy with monoclonal antibodies against vascular endothelial growth factor (VEGF) [8].\n\nWe identified 4 cases of bortezomib-associated TMA in the medical literature. Two of those reports described cases of patients with MM who developed microangiopathic hemolytic anemia and thrombocytopenia during the course of the first cycle of bortezomib [15, 16]. ADAMTS13 activity was normal in both cases. The subjects improved after drug discontinuation. Two additional reports described cases of microangiopathic hemolytic anemia and thrombocytopenia complicated with AKI [17, 18]. Although kidney biopsy was not performed, a renal TMA lesion was suspected. In addition to drug discontinuation, those patients underwent plasmapheresis.\n\nBortezomib is a dipeptide boronate 20S proteasome inhibitor. It inhibits nuclear factor kappa B (NF-KB) translocation/transcription activity by blocking the degradation of its inhibitor iKB. Inhibition of NF-KB leads to a decrease in VEGF transcription [19]. Production of VEGF by podocytes is indispensable for maintenance of the adjacent glomerular endothelium. Anti-VEGF chemoagents, such as bevacizumab and sorafenib, can cause TMA by direct microvascular toxicity initiated by endothelial injury [8, 20, 21]. Bortezomib can also inhibit IL-6 induced proliferation and angiogenesis and enhance the release of pro-inflammatory cytokines (IL-6 and TNF-alpha) and generation of cell mediated immune response [22]. In addition, it has been shown that VEGF, acting through VEGFR-2, activates endothelial nitric oxide synthase (eNOS) activity, leading to increased vasodilatory nitric oxide production. Anti-VEGF therapies might cause systemic deficiency of nitric oxide with consequent hypertension [23, 24]. Therefore, it has been speculated that the mechanism by which proteasome inhibitors may induce TMA also involve modulation of VEGF. Notably, although bortezomib is being increasingly used to treat antibody-mediated rejection in organ transplantation, no reports of associated TMA have emerged to date [25–27]. Therefore, the strength of the association requires further validation.\n\nCarfilzomib is a tetrapeptide epoxyketone proteasome inhibitor. In preclinical studies, carfilzomib showed greater selectivity than bortezomib for the proteasome and had anti-proliferative activity in cells resistant to bortezomib [28]. In view of the previously reported association of bortezomib with TMA [15–18], we speculate that carfilzomib could have been involved in the pathogenesis of renal TMA in our case. In contrast to previous reports of proteasome inhibitor-associated TMA [15–18], our case describes a patient who presented with overt proteinuria and worsening hypertension but without extrarenal features of microangiopathic hemolytic anemia, i.e., renal-limited TMA. Undoubtedly, it could be argued that the long-standing history of essential hypertension could be responsible of some of the histological findings in the kidney biopsy specimen knowing that the renal TMA lesion in our patient is similar to that of malignant hypertension. Nonetheless, we hypothesize that the abruptness of the clinical presentation may reflect the onset of a mechanism of injury induced by carfilzomib, triggering malignant hypertension in a patient who was perhaps at high risk of developing it due to his underlying essential hypertension.\n\nConclusions\nIn summary, we suggest that clinicians should be aware of the possibility of an association between exposure to carfilzomib and the development of a clinical syndrome characterized by worsening proteinuria and uncontrolled HTN and pathological evidence of renal TMA. Discontinuation of the drug should be considered only after careful evaluation of risks and benefits of the chemotherapy and the prognosis of the existing malignancy.\n\nConsent\nInformed consent was obtained from the next of kin for publication of this case.\n\nAbbreviations\nAKIAcute kidney injury\n\neNOSEndothelial nitric oxide synthase\n\nFDAFood and drug administration\n\nHSCTHematopoietic stem cell transplantation\n\nMMMultiple myeloma\n\nNF-KBNuclear factor kappa B\n\nTMAThrombotic microangiopathy\n\nVCDBortezomib, cyclophosphamide and dexamethasone\n\nVEGFvascular endothelial growth factor.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nJCV and LH were the physicians who treated the patient in this report. SS was the pathologist who read the biopsy. The manuscript was prepared by LH under the direct supervision of JCV. All the authors participated in discussions about the manuscript and approved the final version.\n\n\nSupport\n\n\nJ.C.Q.V. is supported by a grant from Dialysis Clinics Incorporated.\n\n\nFinancial disclosure\n\n\nJ.C.Q.V. is a member of the Speaker Bureau for Otsuka Pharmaceuticals and Questcor Pharmaceuticals.\n==== Refs\nReferences\n1. Sanders PW Booker BB Pathobiology of cast nephropathy from human Bence Jones proteins J Clin Invest 1992 89 2 630 10.1172/JCI115629 1737851 \n2. Smolens P Barnes JL Kreisberg R Hypercalcemia can potentiate the nephrotoxicity of Bence Jones proteins J Lab Clin Med 1987 110 460 465 3655525 \n3. Markowitz GS Fine PL Stack JI Kunis CL Radhakrishnan J Palecki W Park J Nasr SH Hoh S Siegel DS D’Agati VD Toxic acute tubular necrosis following treatment with zoledronate Kidney Int 2003 64 1 281 289 10.1046/j.1523-1755.2003.00071.x 12787420 \n4. 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Usui J Glezerman IG Salvatore SP Chandran CB Flombaum CD Seshan SV Clinicopathological spectrum of kidney diseases in cancer patients treated with vascular endothelial growth factor inhibitors: a report of 5 cases and review of literature Hum Pathol 2014 45 9 1918 1927 10.1016/j.humpath.2014.05.015 25087655 \n21. Vigneau C Lorcy N Dolley-Hitze T Jouan F Arlot-Bonnemains Y Laguerre B Verhoest G Goujon JM Belaud-Rotureau MA Rioux-Leclercq N All anti-vascular endothelial growth factor drugs can induce ‘pre-eclampsia-like syndrome’: a RARe study Nephrol Dial Transplant 2014 29 2 325 332 10.1093/ndt/gft465 24302609 \n22. Mateos MV San Miguel JF Bortezomib in multiple myeloma Best Pract Res Clin Haematol 2007 20 4 701 715 10.1016/j.beha.2007.09.003 18070714 \n23. Horowitz JR Rivard A van der Zee R Hariawala M Sheriff DD Esakof DD Chaudhry GM Symes JF Isner JM Vascular endothelial growth factor/vascular permeability factor produces nitric oxide-dependent hypotension: evidence for a maintenance role in quiescent adult endothelium Arterioscler Thromb Vasc Biol 1997 17 11 2793 2800 10.1161/01.ATV.17.11.2793 9409257 \n24. Robinson ES Khankin EV Karumanchi SA Humphreys BD Hypertension induced by vascular endothelial growth factor signaling pathway inhibition: mechanisms and potential use as a biomarker Semin Nephrol 2010 30 6 591 601 10.1016/j.semnephrol.2010.09.007 21146124 \n25. Yang KS Jeon H Park Y Jo IH Kim JI Moon IS Choi BS Park CW Yang CW Kim YS Chung BH Use of bortezomib as anti-humoral therapy in kidney transplantation J Korean Med Sci 2014 29 5 648 651 10.3346/jkms.2014.29.5.648 24851019 \n26. Zinn MD L’Ecuyer TJ Fagoaga OR Aggarwal S Bortezomib use in a pediatric cardiac transplant center Pediatr Transplant 2014 18 5 469 476 10.1111/petr.12300 24931171 \n27. Eskandary F Bond G Schwaiger E Kikic Z Winzer C Wahrmann M Marinova L Haslacher H Regele H Oberbauer R Böhmig GA Bortezomib in late antibody-mediated kidney transplant rejection (BORTEJECT Study): study protocol for a randomized controlled trial Trials 2014 15 107 10.1186/1745-6215-15-107 24708575 \n28. Demo SD Kirk CJ Aujay MA Buchholz TJ Dajee M Ho MN Jiang J Laidig GJ Lewis ER Parlati F Shenk KD Smyth MS Sun CM Vallone MK Woo TM Molineaux CJ Bennett MK Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome Cancer Res 2007 67 13 6383 6391 10.1158/0008-5472.CAN-06-4086 17616698\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "15()",
"journal": "BMC nephrology",
"keywords": null,
"medline_ta": "BMC Nephrol",
"mesh_terms": "D058186:Acute Kidney Injury; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D003907:Dexamethasone; D018450:Disease Progression; D004487:Edema; D017809:Fatal Outcome; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D006977:Hypertension, Renal; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009842:Oligopeptides; D050199:Podocytes; D061988:Proteasome Inhibitors; D011507:Proteinuria; D011719:Pyrazines; D012008:Recurrence; D012772:Shock, Septic; D013713:Teniposide; D013792:Thalidomide; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "156",
"pmc": null,
"pmid": "25267524",
"pubdate": "2014-09-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24851019;24931171;17616698;22854237;24708575;11319595;24302609;12001991;18070714;22826795;9603418;21507163;3655525;8944231;1737851;19144762;9409257;10435734;7249508;18636313;18337603;25087655;9169652;19688133;18452093;21146124;16395267;12787420",
"title": "Renal thrombotic microangiopathy and podocytopathy associated with the use of carfilzomib in a patient with multiple myeloma.",
"title_normalized": "renal thrombotic microangiopathy and podocytopathy associated with the use of carfilzomib in a patient with multiple myeloma"
} | [
{
"companynumb": "PHHY2014US128968",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONIDINE"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nResults with docetaxel as single drug in squamous-cell head and neck cancer have been encouraging. The purpose of the present phase II study is to evaluate the antitumour efficacy and toxicity of the combination of docetaxel and cisplatin in patients with recurrent or disseminated squamous-cell carcinoma of the head and neck (SCCHN) for whom no curative therapy is available.\n\n\nMETHODS\nEligibility criteria included: written informed consent; WHO performance status < or = 2; age 18-70 years; adequate bone marrow, liver, and renal function; measurable or evaluable disease; no previous systemic chemotherapy (prior radiotherapy and/or surgery were allowed), no other previous or concurrent malignancy; no peripheral neuropathy. Treatment consisted of docetaxel 75 mg/m2 in a one-hour infusion after pre-treatment with prednisolone, followed by cisplatin 75 mg/m2 in a half-hour infusion preceded and followed by hydration. Treatment was repeated every three weeks for a maximum of eight cycles.\n\n\nRESULTS\nTwenty-five patients (median age 52 years, range 33-66) entered the trial, all were evaluable for survival, twenty-four for response and toxicity. Twenty-four patients had undergone prior radiotherapy and seventeen had also had surgery. Nineteen had local-regional recurrence only, three had local-regional disease and distant metastases, and three had distant metastases only. Patients received a median of 5 treatment cycles (range 2-8). Overall response rate was 33% (8 of 24) of patients; complete response rate was 8% (2 of 24) of patients, lasting 2.2 and 17.1 months, respectively; partial response rate was 25% (6 of 24) of patients, lasting for a median of 4.9 months (range 1.7-11.6 months). Median survival was 11 months. Toxicity was relatively well tolerated. However, one patient died of probable toxicity (neutropenia and infection) and three patients discontinued treatment because of toxicity (massive oedema, myocardial infarction, persistent thrombocytopenia). The most frequent moderate-to-severe toxicity (75% of patients) was grade 3-4 neutropenia, transient in all but one patient. Grade 3 neuropathy occurred in one patient, none had grade 4. Grade 3 oral mucositis occurred in three patients, none had grade 4. Grade 2-3 hypomagnesaemia occurred in 10 patients requiring magnesium infusion.\n\n\nCONCLUSIONS\nDocetaxel and cisplatin is an active combination in patients with recurrent or disseminated SCCHN. Remissions are however fairly short. Toxicity is significant, but generally manageable.",
"affiliations": "Department of Oncology, Herlev Hospital, University of Copenhagen, Denmark.",
"authors": "Specht|L|L|;Larsen|S K|SK|;Hansen|H S|HS|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1023/a:1008355315205",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "11(7)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": null,
"medline_ta": "Ann Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D000077143:Docetaxel; D005260:Female; D006258:Head and Neck Neoplasms; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009503:Neutropenia; D017239:Paclitaxel; D016019:Survival Analysis; D043823:Taxoids",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "845-9",
"pmc": null,
"pmid": "10997812",
"pubdate": "2000-07",
"publication_types": "D016430:Clinical Trial; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase II study of docetaxel and cisplatin in patients with recurrent or disseminated squamous-cell carcinoma of the head and neck.",
"title_normalized": "phase ii study of docetaxel and cisplatin in patients with recurrent or disseminated squamous cell carcinoma of the head and neck"
} | [
{
"companynumb": "DK-PFIZER INC-2020148928",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Levonorgestrel is used worldwide as an emergency oral contraceptive. There have been occasional reports of ectopic pregnancy after oral levonorgestrel use. We present a case of ectopic tubal pregnancy after the use of oral levonorgestrel as an emergency contraceptive in a 37-year-old woman with a history of treatment for Chlamydia trachomatis infection. She conceived after sexual intercourse on menstrual day 14 of the first menstrual cycle following a normal delivery. After salpingectomy for this right tubal pregnancy, her following pregnancy was an ectopic pregnancy in the contralateral tube, which was treated with laparoscopic salpingectomy. Histopathological examination revealed endometriosis. We should be aware of ectopic pregnancy even after emergency contraceptive use, especially in patients with risk factors, such as Chlamydia infection and endometriosis. Because the efficacy of levonorgestrel decreases after ovulation, we should check the stage of the cycle before prescription.",
"affiliations": "Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital, Niigata, Japan.;Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital, Niigata, Japan.;Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital, Niigata, Japan.;Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital, Niigata, Japan.;Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital, Niigata, Japan.;Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital, Niigata, Japan.;Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital, Niigata, Japan.;Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital, Niigata, Japan.;Department of Obstetrics and Gynecology, Niigata University Medical and Dental Hospital, Niigata, Japan.",
"authors": "Kitani|Yohei|Y|;Ishiguro|Tatsuya|T|https://orcid.org/0000-0002-6445-4066;Kobayashi|Akiko|A|;Tamura|Ryo|R|;Ueda|Haruka|H|;Adachi|Sosuke|S|;Nishikawa|Nobumichi|N|;Sekine|Masayuki|M|;Enomoto|Takayuki|T|",
"chemical_list": "D003271:Contraceptive Agents, Female; D016912:Levonorgestrel",
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.13815",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "45(2)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "ectopic pregnancy; emergency contraception; oral levonorgestrel; progesterone; risk factors",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000328:Adult; D044363:Contraception, Postcoital; D003271:Contraceptive Agents, Female; D004715:Endometriosis; D005260:Female; D006801:Humans; D016912:Levonorgestrel; D011247:Pregnancy; D011271:Pregnancy, Ectopic",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "473-476",
"pmc": null,
"pmid": "30246476",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Ectopic pregnancy following oral levonorgestrel emergency contraception use.",
"title_normalized": "ectopic pregnancy following oral levonorgestrel emergency contraception use"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2018R1-187215",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
},
"... |
{
"abstract": "BACKGROUND\nCardiovascular failure is the leading cause of death in severe acute drug intoxication. In this setting, we report the feasibility, complications, and outcome of emergency extracorporeal life support (ECLS) in refractory shock or cardiac arrest following a drug overdose.\n\n\nMETHODS\nThis is a retrospective cohort study of 17 patients admitted over a 10-year period for prolonged cardiac arrest or refractory shock following a drug overdose and not responding to optimal conventional treatment. Patients were evaluated in the medical ICU and cardiovascular surgery department of a university hospital. ECLS implantation used a centrifugal pump connected to a hollow-fiber membrane oxygenator and was performed in the operating room (n = 13), intensive care unit (n = 3), or emergency department (n = 1). ECLS was employed for refractory shock and prolonged cardiac arrest in 10 and 7 cases, respectively.\n\n\nRESULTS\nThe mean duration of external cardiac massage was 101 +/- 55 minutes. Fifteen patients had ingested cardiotoxic drugs, including 11 cases of drugs with membrane stabilizing activity. Time from hospital admission to initiation of ECLS was 6.4 +/- 7.0 hours. Time to ECLS implant was 58 +/- 11 minutes. The mean ECLS flow rate was 3.45 +/- 0.45 L/min. The average ECLS duration was 4.5 +/- 2.4 days. Early complications included limb ischemia (n = 6), femoral thrombus (n = 1), cava inferior thrombus (n = 1), and severe bleeding at the site of cannulation (n = 2). Fifteen patients were weaned off ECLS support and 13 (76%) were discharged to hospital without sequelae.\n\n\nCONCLUSIONS\nBased on our experience, we consider ECLS as a last resort, efficient, and relatively safe therapeutic option in this population. However, the uncontrolled nature of our data requires careful interpretation.",
"affiliations": "Department of Medical Intensive Care, Caen University Hospital, avenue Côte de Nacre, Caen Cedex 14033, France. daubin-c@chu-caen.fr",
"authors": "Daubin|Cédric|C|;Lehoux|Philippe|P|;Ivascau|Calin|C|;Tasle|Marine|M|;Bousta|Mehdi|M|;Lepage|Olivier|O|;Quentin|Charlotte|C|;Massetti|Massimo|M|;Charbonneau|Pierre|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/cc8017",
"fulltext": "\n==== Front\nCrit CareCritical Care1364-85351466-609XBioMed Central cc80171970616610.1186/cc8017ResearchExtracorporeal life support in severe drug intoxication: a retrospective cohort study of seventeen cases Daubin Cédric 1daubin-c@chu-caen.frLehoux Philippe 2lehoux-p@chu-caen.frIvascau Calin 3ivasvau-c@chu-caen.frTasle Marine 2tasle-m@chu-caen.frBousta Mehdi 1bousta-m@chu-caen.frLepage Olivier 3Lepage-o@chu-caen.frQuentin Charlotte 1quentin-c@chu-caen.frMassetti Massimo 3massetti-m@chu-caen.frCharbonneau Pierre 1charbonneau-p@chu-caen.fr1 Department of Medical Intensive Care, Caen University Hospital, avenue Côte de Nacre, Caen Cedex 14033, France2 Department of Anesthesiology, Caen University Hospital, avenue Côte de Nacre, Caen Cedex 14033, France3 Department of Thoracic and Cardiovascular Surgery, Caen University Hospital, avenue Côte de Nacre, Caen Cedex 14033, France2009 25 8 2009 13 4 R138 R138 27 4 2009 25 6 2009 22 7 2009 25 8 2009 Copyright ©2009 Daubin et al.; licensee BioMed Central Ltd.2009Daubin et al.; licensee BioMed Central Ltd.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction\nCardiovascular failure is the leading cause of death in severe acute drug intoxication. In this setting, we report the feasibility, complications, and outcome of emergency extracorporeal life support (ECLS) in refractory shock or cardiac arrest following a drug overdose.\n\nMethods\nThis is a retrospective cohort study of 17 patients admitted over a 10-year period for prolonged cardiac arrest or refractory shock following a drug overdose and not responding to optimal conventional treatment. Patients were evaluated in the medical ICU and cardiovascular surgery department of a university hospital. ECLS implantation used a centrifugal pump connected to a hollow-fiber membrane oxygenator and was performed in the operating room (n = 13), intensive care unit (n = 3), or emergency department (n = 1). ECLS was employed for refractory shock and prolonged cardiac arrest in 10 and 7 cases, respectively.\n\nResults\nThe mean duration of external cardiac massage was 101 ± 55 minutes. Fifteen patients had ingested cardiotoxic drugs, including 11 cases of drugs with membrane stabilizing activity. Time from hospital admission to initiation of ECLS was 6.4 ± 7.0 hours. Time to ECLS implant was 58 ± 11 minutes. The mean ECLS flow rate was 3.45 ± 0.45 L/min. The average ECLS duration was 4.5 ± 2.4 days. Early complications included limb ischemia (n = 6), femoral thrombus (n = 1), cava inferior thrombus (n = 1), and severe bleeding at the site of cannulation (n = 2). Fifteen patients were weaned off ECLS support and 13 (76%) were discharged to hospital without sequelae.\n\nConclusions\nBased on our experience, we consider ECLS as a last resort, efficient, and relatively safe therapeutic option in this population. However, the uncontrolled nature of our data requires careful interpretation.\n\nSee related commentary by Ashrafian and Athanasiou, http://ccforum.com/content/13/5/187\n==== Body\nIntroduction\nDrug-induced cardiovascular failure is the leading cause of death in severe acute drug intoxication [1,2]. In this setting, patients with refractory shock or cardiac arrest who do not respond to optimal conventional treatment may need special therapies, such as extracorporeal life support (ECLS). Although cardiovascular bypass is rarely used in the management of poisoning, it may have potential benefits for hemodynamic instability not responding to conventional measures. Promising results have been obtained using temporary circulatory support in several single-case reports [3-17] and short series [18,19]. However, the usefulness of cardiovascular bypass in drug-induced cardiac failure remains unclear [20]. The aim of the study was to describe our 10-year experience of ECLS as a last resort therapeutic option in acute poisoning. Seven of the cases included in this series were previously published [15,18].\n\nMaterials and methods\nWe reviewed the cases of all patients treated with emergency cardiopulmonary bypass for prolonged cardiac arrest or cardiogenic shock following drug intoxication at the University Hospital of Caen between 1997 and 2007. Our medical teams and nurses have a large amount of experience with emergency ECLS, specifically among critically ill patients [15,18,21,22].\n\nPatients\nDuring the study period, 721 patients were admitted for drug intoxication (Figure 1). One hundred and ten patients had hemodynamic failure responding to conventional treatment and 17 patients had refractory shock or cardiac arrest. In our practice, patients with refractory cardiac arrest, defined as an absence of return to spontaneous circulation after continuous cardio-pulmonary resuscitation over at least 45 minutes or refractory shock, defined as shock not responding to optimal conventional treatment, were candidates for ECLS support [23]. When the decision to implant ECLS was made by a senior intensivist, a senior cardiac surgeon and a perfusionist were immediately informed and ECLS performed.\n\nFigure 1 Flow chart indicating patient characteristics. CPC: cerebral performance class; ECLS: extra corporeal life support; ICU: intensive care unit.\n\nData collection\nAccording to French legislation at the time of the study and given the observational retrospective nature of the study, no ethical committee was requested and thus no informed consent was obtained from the patients. At the time of ECLS implantation the focus was specifically on hemodynamic (including electrocardiographic and echocardiographic), neurologic, respiratory, renal, liver, and hematologic data. Measured physiological variables were used to calculate the Simplified Acute Physiology Score (SAPS II) [24] and the Sequential Organ Failure Assessment (SOFA) score [25]. The toxicological screening was recorded and drugs classified as with or without cardiotoxic effect or membrane stabilizing activity (MSA). In addition, the clinical course of each patient during hospitalization was recorded. Vascular, neurologic, hemorrhagic, renal, and perfusion system complications were documented. The neurologic outcome at hospital discharge was assessed according to the cerebral performance class (CPC) categories [26]: CPC 1 = good cerebral performance, CPC 2 = moderate cerebral disability, CPC 3 = severe cerebral disability, CPC 4 = coma or vegetative state, and CPC 5 = brain death or death.\n\nCannulation technique\nDevice description, cannulation technique, management, and weaning from ECLS were previously reported in detail [22]. Briefly, the hardware for cardiopulmonary circulation consisted of a Biomedicus portable system (Medtronic, Inc, Minneapolis, MN, USA) incorporating a centrifugal pump console and a water pump system. The closed ECLS circuit consisted of pre-connected polyvinyl chloride tubing (Medtronic, Inc, Minneapolis, MN, USA) including a constrained vortex pump chamber, a hollow-fiber membrane oxygenator with an integral heat exchanger (Maxima PRF, Medtronic, Inc, Minneapolis, MN, USA), and a flow probe. All components were heparin-coated (Carmeda Bioactive Surface-coating). The cannulae were Biomedicus (17 F to 25 F), according to the size of patients.\n\nOnce the decision to implant ECLS support was made, the circuit was quickly primed with normal saline. Heparin was administered to the patient at 50 UI/kg immediately before cannulation of the vessels. The activated clotting time (ACT) was kept between 150 and 200 seconds at full-flow assistance. Peripheral femorofemoral cannulation was surgically set up using a modified Seldinger technique. Because cannulation-related limb ischemia was a major problem when we began this technique, additional distal limb perfusion was inserted to avoid severe leg ischemia. The distal tip of the arterial cannula was positioned in the common iliac artery or distal abdominal aorta, whereas the tip of the venous cannula was set in the right atrium under echocardiographic guidance and confirmed by chest radiograph.\n\nPatient management during ECLS\nPump flow was initially set at 2.5 L/m2 and vasopressor (norepinephrine and epinephrine) was used to maintain a mean blood pressure of at least 60 mmHg. An inotropic support was used even if systemic perfusion was adequately performed by ECLS to maintain a pulsatile flow through the native heart. The aim was to decompress the left heart and minimize stasis, therefore reducing the risk of intracardiac thrombosis. If necessary, to accomplish mechanical decompression of the left heart, an atrial balloon septostomy was performed. A femoral vein approach was used in which a transeptal puncture, followed by blade septostomy, was performed under combined radioscopy and echocardiographic guidance. Sequential balloon inflations were carried out to achieve left heart decompression, which was confirmed by echocardiography. The ECLS was monitored by trained ICU personnel. A perfusionist was also available for occasional monitoring visits and emergencies. Echocardiography was used serially to assess progressive myocardial recovery and exclude intracardiac thrombosis or other abnormalities. All patients were mechanically ventilated with 5 to 6 mL/kg tidal volume and 8 to 10 cmH2O positive end-expiratory pressure, and continuous venovenous hemofiltration was used to treat acute renal failure and regulate the intravascular volume and overall fluid balance, if necessary.\n\nWeaning\nThe decision to discontinue ECLS support was based on evidence of multiorgan failure, overwhelming sepsis, or severe neurological injury. Patients were weaned off ECLS if the left ventricular ejection fraction, assessed by echocardiography during a reduction of pump flow to 500 to 1000 mL/min, was stable (> 50%) without deterioration in hemodynamic status. During this period, anticoagulation was adapted to adequate values of ACT (250 to 300 seconds). If the patient's cardiovascular status remained stable, ECLS was withdrawn by cardiac surgeons.\n\nStatistical analysis\nQuantitative and qualitative data are expressed as mean (± standard deviation), or median (range) and percentage, respectively.\n\nResults\nPatients and drugs\nSeventeen patients (11 females, 6 males; mean age 39 ± 18 years) were treated with ECLS following drug intoxication. All patients, except two, had ingested cardiotoxic drugs, including 11 cases of drugs with MSA. The majority (12/17) of poisonings resulted from mixed poisonings involving a combination of cardiotoxic drugs, various psychotic drugs, and alcohol (Table 1).\n\nTable 1 Patients and drugs used\n\nPatients\tDrugs\t\n1\tSotalol 4.8 g, verapamil 7.2 g\t\n2\tDisopyramide* 10 g, alprazolam 10 mg\t\n3\tAcebutolol* 10 g, méprobamate 4 g, aspirin 15 g, alprazolam 10 mg\t\n4\tTianeptine, Bromazepam, fluoxetine, zolpidem 4 g\t\n5\tVerapamil 1.2 g, propanolol* 4 g, betaxolol 6.8 g\t\n6\tAcebutolol* 8 g, meprobamate 5 g\t\n7\tFlecaine*8 g, venlafaxine\t\n8\tVerapamil\t\n9\tDisopyramide* 3 g, lithium 7.5 g, citalopram 0.2 g\t\n10\tPropanolol* 2 g, meprobamate, paroxetine, paracetamol, dextropropoxyfene\t\n11\tMetoprolol, alcohol\t\n12\tVerapamil 3.6 g\t\n13\tPropanolol* 2 g, alcohol\t\n14\tCibenzoline*, benzodiazepines\t\n15\tTramadol 10 g, hydroxyzine 6 g, gabapertine 1 g, clonazepam 80 mg\t\n16\tPropafénone*, alcohol, oxilamine\t\n17\tPropanolol*\t\n* Drugs with membrane stabilizing activity (MSA).\n\nBaseline characteristics\nThe baseline characteristics of patients at the time of ECLS implantation are reported in Table 2. All patients, except two, were comatose. The patients' median SAPS II score was 69 (26 to 82) and median SOFA score was 13.5 (3 to 18). The ECLS setup was performed for 13 patients in the operating room, 3 in the intensive care unit, and 1 in the emergency department. Seven patients received ECLS during external cardiac massage for refractory cardiac arrest, which occurred in six cases at hospital admissions in the emergency room. Ten other patients also received ECLS, including two after the restoration of spontaneous circulation following a brief period of asystole, during refractory shock. The mean duration of external cardiac massage was 101 ± 55 minutes.\n\nTable 2 Baseline characteristics at the time of ECLS implantation*\n\nN°\tECM (min)\tGCS\tHR\tAP (mmHg)\tVasopressor\tECG\tLVEF\tLactate (mmol/L)\tBicarbonate (mmol/L)\t\n1§\t160\t3\t0\t0\tEpinephrine\tAsystole\tAkinesia\t-\t21.1\t\n2§¶\t150\t3\t0\t0\tEpinephrine\tAsystole\t-\t> 30\t17.8\t\n3§¶\t170\t3\t0\t0\tEpinephrine Isoproterenol\tAsystole\tAkinesia\t10.8\t19\t\n4\t60\t3\t40\t60/40\tEpinephrine\tBradycardia (QRS 183 ms)\tHypokinesia (LEVF 15%)\t5.85\t29.6\t\n5\t70\t3\t0\t0\tEpinephrine\tAsystole\t-\t7.3\t26.3\t\n6\t50\t3\t0\t0\t-\tAsystole\tAkinesia\t-\t-\t\n7\t60\t3\t30\t50/33\tEpinephrine Dobutamine\tBradycardia (QRS 214 ms)\tAkinesia\t-\t17.5\t\n8¶\tNo\t3\t60\t50/30\tEpinephrine Isoproterenol\tSinusal\t-\t10.5\t17.7\t\n9\tNo\t3\t40\t85/54\tEpinephrine Isoproterenol Dobutamine\tBradycardia (QRS 175 ms)\tHypokinesia\t9.65\t19.6\t\n10¶\tNo\t3\t68\t71/52\tEpinephrine Dobutamine\tSinusal\tHypokinesia (LVEF 20%)\t0.57\t17.2\t\n11\tNo\t3\t\t60/48\tEpinephrine Dobutamine\tSinusal\tHypokinesia (LVEF 20%)\t-\t-\t\n12\tNo\t8\t30\t70/40\tNorepinephrine Isoproterenol Dopamine\tAtrio-ventricular block\tHypokinesia (LVEF 25%)\t4.6\t17.9\t\n13**\tNo\t3\t55\t75/50\tEpinephrine\tSinusal\tHypokinesia (LVEF 30%)\t5.9\t11.7\t\n14§¶\tNo\t3\t140\t85/58\tEpinephrine\tVentricular tachycardia\tHypokinesia (LVEF 20%)\t8,8\t20.2\t\n15**¶\tNo\t3\t85\t82/56\tEpinephrine Norepinephrine\tRight bundle-branch block\tHypokinesia (LVEF 25%)\t1.7\t18\t\n16\tNo\t15\t60\t70/60\tEpinephrine\tBradycardia (QRS 203 ms)\tHypokinesia (LVEF 10%)\t3.7\t22.4\t\n17\tNo\t15\t36\t60/40\tEpinephrine Dobutamine\tSinusal\tHypokinesia (LVEF 10%)\t3.7\t19.9\t\n* For patients with cardiac arrest, we provided data recorded just before cardiac arrest if available\n\n** ECLS performed after restoration of spontaneous circulation following a brief period of asystole\n\n§ Patients with temporary external transthoracic electrostimulation before initiation of ECLS\n\n¶ Patients requiring continuous venovenous hemofiltration or conventional dialysis before or immediately following ECLS implantation\n\nAP: arterial pressure; ECG: echocardiogram; ECM: manual external cardiac massage; ECLS: extra corporeal life support; HR: heart rate; GCS: Glasgow coma score; LVEF: left ventricular ejection fraction; QRS: duration of the complex representing ventricular depolarization on electrocardiogram.\n\nBefore the initiation of ECLS support, a severe decrease in cardiac contractility was documented by echocardiography in 14 cases. All patients were mechanically ventilated and received vasopressor. Four patients needed temporary external transthoracic electrostimulation. Six patients required continuous venovenous hemofiltration or conventional dialysis for acute renal failure before or immediately after ECLS implantation. Before connection to ECLS, the median arterial pH was 7.37 (7.34 to 7.41), partial presure of arterial oxygen/fraction of inspired oxygen ratio was 239 (180 to 261), serum bicarbonate concentration was 19.0 mmol/L (17.7 to 20.6), plasma lactate concentration was 5.9 mmol/L (3.7 to 9.7), and serum creatinine concentration was 160 μmol/L (114 to 204).\n\nECLS feasibility\nECLS feasibility, assessed with respect to time from admission to ECLS initiation, and the percentage of successful procedures (i.e. flow rate > 2.5 L/m2 and mean blood pressure > 60 mmHg) is shown in Table 3. Time from hospital admission to initiation of ECLS was 6.4 ± 7.0 hours, and the time to ECLS implant was 58 ± 11 minutes. The mean ECLS flow rate was 3.45 ± 0.45 L/min. The average ECLS duration was 4.5 ± 2.4 days. In one patient (no. 17), an atrial balloon septostomy was performed to accomplish mechanical decompression of the left heart.\n\nTable 3 ECLS feasibility, duration and complications\n\nN°\tTime from admission to initiation ECLS (hours)\tTime to implant ECLS* (min)\tInitial ECLS flow rate (l/min)\tECLS duration (days)\tLVEF at ECLS discharge\tLong term surviving\t\n1**\t2.5\t60\t3.5\t2\t-\tNo\t\n2**\t1.5\t60\t3\t3\t-\tNo\t\n3\t2 hours 50 mins\t40\t3.5\t2.3\t62%\tYes\t\n4\t1\t60\t3.5\t2.5\t> 50%\tYes\t\n5\t1\t60\t-\t2.5\t76%\tYes\t\n6\t1\t60\t3.5\t2.3\t-\tYes\t\n7\t6\t60\t3.6\t3\t56%\tYes\t\n8\t5\t60\t3.7\t11\t-\tNo\t\n9\t6\t60\t3.4\t5\tnormal\tNo\t\n10\t24\t60\t4\t5\t42%\tYes\t\n11\t4\t60\t-\t4\t38%\tYes\t\n12\t2\t60\t4\t6\t> 50%\tYes\t\n13\t2.5\t45\t2.6\t7\t74%\tYes\t\n14\t15\t90\t4\t6\t45%\tYes\t\n15\t16\t60\t2.5\t8\t45%\tYes\t\n16\t3\t60\t3.5\t4\t50%\tYes\t\n17\t17\t40\t3.5\t3\t40%\tYes\t\n* Delay between ECLS decision and time at which ECLS flow was provided\n\n** Patients dead during ECLS assistance\n\nECLS: extra corporeal life support; LVEF: left ventricular ejection fraction.\n\nECLS complications\nSignificant cannulation-related injuries of femoral vessels were reported in 10 patients: six patients with limb ischemia requiring urgent revascularization in three cases, one femoral thrombus, one cava inferior thrombus, and two cases of severe bleeding at the site of cannulation requiring a surgical revision.\n\nClinical outcome\nFifteen patients were weaned off ECLS support and two patients withdrawn from support because of refractory multiorgan failure and cerebral death (Table 3). Thirteen patients survived and were discharged to hospital without significant cardiovascular or neurological sequelae (CPC 1 n = 9 and CPC 2 n = 4). Two patients died of septic shock and cerebral death during the hospital stay.\n\nDiscussion\nWe report one of the largest series of drug-induced cardiac arrest and refractory shock managed with ECLS. The high survival rate (76%) reported in this setting supports ECLS as an efficient rescue treatment in a subset of patients with drug-induced circulatory failure not responding to optimal conventional treatment.\n\nPatients and drugs\nClinical experience with emergency ECLS during poisoning leading to prolonged cardiac arrest or shock that does not respond to conventional treatment is limited [3-19]. Poly-intoxication including cardiotoxic drugs with MSA, which is known to be associated with a high mortality rate [27], was involved in a majority of cases, as previously reported [28]. All patients were in prolonged cardiac arrest or refractory shock according to the definitions proposed by Baud and colleagues [28].\n\nECLS feasibility and efficiency\nWe confirmed the feasibility of emergency ECLS in accordance with previous reports focusing on prolonged cardiac arrest regardless of the cause [19,22]. The physiologic objective was to provide temporal circulatory support to the vital organs and unload the failing heart as the injured myocardium attempts to recover. In previous cohort studies [19,22], survival rates were clearly higher in the toxic cardiac arrest group, as compared with other causes of cardiac arrest (3 of 12 vs 0 of 5 [19] and 4 of 6 vs 4 of 34 [22], respectively). The high survival rate (76%) reported in our cohort was in accordance with the general survival rate from 58% (15 of 26) in case reports of poisoned patients who benefited from ECLS [3-14,16,17,19]. The 5 of 7 (71%) survival rate we reported among patients with cardiac arrest was in contrast with the dramatically low survival rate of 7% and 4.5%, respectively, reported in overdoses involving cardiac arrest [29,30]. To our knowledge, no studies have reported the survival rate of patients with drug-induced cardiovascular shock apparently refractory to conventional treatment, limiting comparisons with our cohort. However, experimental studies with control groups demonstrated that ECLS improved survival in animal models of severe cardiotoxic drug-induced shock [31,32]. These results suggest that ECLS could be considered as a good emergency resuscitative tool in this setting.\n\nECLS complications\nSevere cannulation-related limb ischemia was the major problem when we first started the technique. Therefore, to accomplish a perfusion of the distal limb, surgeries performed an additional arterial shunt with a small 8 F catheter between the side port of arterial cannula and a point located some centimeters distally in the superficial femoral artery shunt. After this supplementary shunt was added, only distal embolic ischemia were reported. In contrast to Mégarbane and colleagues [19], the rate of cannulation-related complications, limb ischemia, and major bleeding was relatively high despite the modified Seldinger technique and additional distal limb perfusion. These differences could be explained by a higher ECLS duration in our study. However, our results were in accordance with reports of significant morbidity associated with emergency ECLS [33]. In addition, no death was induced by cannulation-related complications, and all survivors were discharged without significant cardiovascular or neurological sequelae.\n\nLimitations\nFirstly, because ECLS indication for drug overdose is rare, the sample size is small. Secondly, the uncontrolled retrospective observational design does not permit clarification of the role of ECLS therapy in drug-induced cardiac failure in a therapeutic algorithm. However, because usefulness of ECLS in this setting remains debatable [20], we believe this study adds important information about ECLS as a rescue therapy in patients with drug-induced cardiac arrest and refractory shock.\n\nConclusions\nBased on our experience, we consider ECLS as a last resort, efficient, and relatively safe therapeutic option in critically ill poisoned patients (i.e. cardiac arrest and refractory shock) who do not respond to conventional therapies, providing the cardiac surgeon with the means to rapidly intervene and control ECLS-related complications. However, because there is insufficient evidence concerning the use of ECLS as a treatment for severe cardiac impairment due to poisoning, further studies are needed to clarify criteria for unresponsiveness to conventional treatment and the indications of ECLS in this setting.\n\nKey messages\n• Cardiovascular failure is the leading cause of death following a cardiotoxic drug overdose.\n\n• This report supports the hypothesis that ECLS may be considered as a last resort, efficient, and relatively safe therapeutic option in critically ill poisoned patients (i.e. cardiac arrest and refractory shock) who do not respond to conventional therapies.\n\nAbbreviations\nACT: activated clotting time; CPC: cerebral performance class; ECLS: extra corporeal life support; MSA: membrane stabilizing activity; SAPS: Simplified Acute Physiology Score; SOFA: Sequential Organ Failure Assessment.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nCD and MB initiated the study, and the design. CD and PC were involved in the interpretation of the results. CD wrote the manuscript, and PC helped to draft the manuscript. PL, CI, MT, OL, MB, CQ, MM, and PC contributed to the conception of the study and revision of the manuscript. All authors read and approved the final manuscript.\n\nAuthors' information\nThe work has been presented in part at the annual congress of the Société de Réanimation de Langue Française (SRLF) held in January 2008, Paris, France.\n\nAcknowledgements\nWe are indebted to Dr Jean-Jacques Parienti from Department of Biostatistics and Clinical Research, Caen University Hospital, France, for his critical review of the manuscript. We thank Madame Valérie Valfong for her contribution to polishing the manuscript.\n==== Refs\nLai MW Klein-Schwartz W Rodgers GC Abrams JY Haber DA Bronstein AC Wruk KM 2005 Annual Report of the American Association of Poison Control Centers' national poisoning and exposure database Clin Toxicol (Phila) 2006 44 803 932 17015284 \nDeWitt CR Waksman JC Pharmacology, pathophysiology and management of calcium channel blocker and beta-blocker toxicity Toxicol Rev 2004 23 223 238 10.2165/00139709-200423040-00003 15898828 \nMégarbane B Leprince P Deye N Guerrier G Résière D Bloch V Baud FJ Extracorporeal life support in a case of acute carbamazepine poisoning with life-threatening refractory myocardial failure Intensive Care Med 2006 32 1409 1413 10.1007/s00134-006-0257-8 16835785 \nKamijo Y Soma K Uchimiya H Asari Y Ohwada T A case of serious organophosphate poisoning treated by percutaneus cardiopulmonary support Vet Hum Toxicol 1999 41 326 328 10509440 \nAuzinger GM Scheinkestel CD Successful extracorporeal life support in a case of severe flecainide intoxication Crit Care Med 2001 29 887 890 10.1097/00003246-200104000-00041 11373489 \nWilliams JM Hollingshed MJ Vasilakis A Morales M Prescott JE Graeber GM Extracorporeal circulation in the management of severe tricyclic antidepressantoverdose Am J Emerg Med 1994 12 456 458 10.1016/0735-6757(94)90062-0 8031434 \nGoodwin DA Lally KP Null DM JrExtracorporeal membrane oxygenation support for cardiac dysfunction from tricyclic antidepressant overdose Crit Care Med 1993 21 625 627 8472584 \nMcVey FK Corke CF Extracorporeal circulation in the management of massive propranolol overdose Anaesthesia 1991 46 744 746 10.1111/j.1365-2044.1991.tb09770.x 1928675 \nRooney M Massey KL Jamali F Rosin M Thomson D Johnson DH Acebutolol overdose treated with hemodialysis and extracorporeal membrane oxygenation J Clin Pharmacol 1996 36 760 763 8877682 \nYoshida K Kimura K Hibi K Nemoto T Iwasawa Y Hongo Y Sugiyama M Ishikawa T Kuji N Tochikubo O Ishii M A patient with disopyramide intoxication rescued by percutaneous cardiopulmonarysupport J Cardiol 1998 32 95 100 9752618 \nTecklenburg FW Thomas NJ Webb SA Case C Habib DM Pediatric ECMO for severe quinidine cardiotoxicity Pediatr Emerg Care 1997 13 111 113 10.1097/00006565-199704000-00007 9127419 \nYasui RK Culclasure TF Kaufman D Freed CR Flecainide overdose: is cardiopulmonary support the treatment? Ann Emerg Med 1997 29 680 682 10.1016/S0196-0644(97)70257-9 9140253 \nCorkeron MA van Heerden PV Newman SM Dusci L Extracorporeal circulatory support in near-fatal flecainide overdose Anaesth Intensive Care 1999 27 405 408 10470398 \nHolzer M Sterz F Schoerkhuber W Behringer W Domanovits H Weinmar D Weinstabl C Stimpfl T Successful resuscitation of a verapamil-intoxicated patient with percutaneous cardiopulmonary bypass Crit Care Med 1999 27 2818 2823 10.1097/00003246-199912000-00035 10628632 \nDaubin C Quentin C Goullé JP Guillotin D Lehoux P Lepage O Charbonneau P Refractory shock and asystole related to tramadol overdose Clin Toxicol (Phila) 2007 45 961 964 17852155 \nKolcz J Pietrzyk J Januszewska K Procelewska M Mroczek T Malec E Extracorporeal life support in severe propranolol and verapamil intoxication J Intensive Care Med 2007 22 381 385 10.1177/0885066607307528 18062140 \nBilbault P Pynn S Mathien C Mazzucotelli JP Schneider F Jaeger A Near-fatal betaxolol self-poisoning treated with percutaneous extracorporeal life support Eur J Emerg Med 2007 14 120 122 10.1097/MEJ.0b013e328013f87c 17496693 \nMassetti M Bruno P Babatasi G Neri E Khayat A Cardiopulmonary bypass and severe drug intoxication J Thorac Cardiovasc Surg 2000 120 424 425 10.1067/mtc.2000.109549 10917971 \nMégarbane B Leprince P Deye N Résière D Guerrier G Rettab S Théodore J Karyo S Gandjbakhch I Baud FJ Emergency feasibility in medical intensive care unit of extracorporeal life support for refractory cardiac arrest Intensive Care Med 2007 33 758 764 10.1007/s00134-007-0568-4 17342517 \nPurkayastha S Bhangoo P Athanasiou T Casula R Glenville B Darzi AW Henry JA Treatment of poisoning induced cardiac impairment using cardiopulmonary bypass: a review Emerg Med J 2006 23 246 250 10.1136/emj.2005.028605 16549566 \nBabatasi G Massetti M Verrier V Lehoux P Le Page O Bruno PG Khayat A Severe intoxication with cardiotoxic drugs: value of emergency percutaneous cardiocirculatory assistance Arch Mal Coeur Vaiss 2001 94 1386 1392 11828924 \nMassetti M Tasle M Le Page O Deredec R Babatasi G Buklas D Thuaudet S Charbonneau P Hamon M Grollier G Gerard JL Khayat A Back from irreversibility: extracorporeal life support for prolonged cardiac arrest Ann Thorac Surg 2005 79 178 183 10.1016/j.athoracsur.2004.06.095 15620939 \nConseil français de réanimation cardiopulmonaire; Société française d'anesthésie et de réanimation; Société française de cardiologie; Société française de chirurgie thoracique et cardiovasculaire; Société française de médecine d'urgence; Société française de pédiatrie; Groupe francophone de réanimation et d'urgence pédiatriques; Société française de perfusion; Société de réanimation de langue française Guidelines for indications for the use of extracorporeal life support in refractory cardiac arrest. French Ministry of Health Ann Fr Anesth Reanim 2009 28 182 190 19232884 \nLe Gall JR Lemeshow S Saulnier F A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study JAMA 1993 270 2957 2963 10.1001/jama.270.24.2957 8254858 \nVincent JL de Mendonça A Cantraine F Moreno R Takala J Suter PM Sprung CL Colardyn F Blecher S Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on \"sepsis-related problems\" of the European Society of Intensive Care Medicine Crit Care Med 1998 26 1793 1800 9824069 \nCummins RO Chamberlain DA Abramson NS Allen M Baskett P Becker L Bossaert L Delooz H Dick W Eisenberg M Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest: the Utstein Style. Task Force of the American Heart Association, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, and the Australian Resuscitation Council Ann Emerg Med 1991 20 861 874 10.1016/S0196-0644(05)81441-6 1854070 \nHenry JA Cassidy SL Membrane stabilising activity: a major cause of fatal poisoning Lancet 1986 1 1414 1417 10.1016/S0140-6736(86)91558-8 2872519 \nBaud FJ Megarbane B Deye N Leprince P Clinical review: aggressive management and extracorporeal support for drug-induced cardiotoxicity Crit Care 2007 11 207 10.1186/cc5700 17367544 \nKöppel C Oberdisse U Heinemeyer G Clinical course and outcome in class IC antiarrhythmic overdose J Toxicol Clin Toxicol 1990 28 433 444 10.3109/15563659009038586 2176700 \nParedes VL Rea TD Eisenberg MS Cobb LA Copass MK Cagle A Martin TG Out-of-hospital care of critical drug overdoses involving cardiac arrest Acad Emerg Med 2004 11 71 74 14709431 \nFreedman MD Gal J Freed CR Extracorporeal pump assistance--novel treatment for acute lidocaine poisoning Eur J Clin Pharmacol 1982 22 129 135 10.1007/BF00542457 7094983 \nLarkin GL Graeber GM Hollingsed MJ Experimental amitriptyline poisoning: treatment of severe cardiovascular toxicity with cardiopulmonary bypass Ann Emerg Med 1994 23 480 486 10.1016/S0196-0644(94)70066-4 8135422 \nMagovern GJ JrSimpson KA Extracorporeal membrane oxygenation for adult cardiac support: the Allegheny experience Ann Thorac Surg 1999 68 655 661 10.1016/S0003-4975(99)00581-0 10475466\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1364-8535",
"issue": "13(4)",
"journal": "Critical care (London, England)",
"keywords": null,
"medline_ta": "Crit Care",
"mesh_terms": "D002315:Cardiopulmonary Bypass; D015331:Cohort Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D005240:Feasibility Studies; D006801:Humans; D016896:Treatment Outcome",
"nlm_unique_id": "9801902",
"other_id": null,
"pages": "R138",
"pmc": null,
"pmid": "19706166",
"pubdate": "2009",
"publication_types": "D016428:Journal Article",
"references": "8877682;8031434;10509440;2872519;10475466;1928675;11373489;17852155;9824069;15898828;9140253;8254858;10917971;15620939;11828924;9752618;17342517;8472584;14709431;19232884;9127419;2176700;10628632;10470398;17015284;17496693;1854070;16549566;17367544;8135422;18062140;7094983;16835785",
"title": "Extracorporeal life support in severe drug intoxication: a retrospective cohort study of seventeen cases.",
"title_normalized": "extracorporeal life support in severe drug intoxication a retrospective cohort study of seventeen cases"
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"companynumb": "FR-MYLANLABS-2020M1078649",
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"abstract": "To provide new insights into toxic maculopathy secondary to pentosan polysulfate (PPS) utilizing multimodal testing.\n\n\n\nRetrospective case-series of four patients from two academic centers evaluated with multimodal imaging, electrophysiology, dark adaptometry (DA), and genetic testing.\n\n\n\nMedian age was 58 years, exposure to PPS was 18.5 years, and cumulative dose of was 2,025 grams. Seven of eight eyes had visual acuity of 20/40 or better. Optical coherence tomography (OCT) angiography demonstrated increased choriocapillaris flow voids (54.25%) in cases compared to controls (13.2%). Two subjects had abnormal foveal avascular zone configurations. Two subjects demonstrated collapse of the retinal pigment epithelium nodular excrescences and progressive retinal thinning over 4 to 5 years on OCT. Electrophysiology was normal (3/3 patients), but DA was delayed (2/2 patients).\n\n\n\nThe authors describe novel findings of PPS maculopathy, including flow voids in the choriocapillaris. Progressive retinal thinning may suggest a secondary retinal effect. These findings may improve understanding of the pathophysiology. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:13-22.].",
"affiliations": null,
"authors": "Abou-Jaoude|Michelle M|MM|;Davis|Alexander M|AM|;Fraser|Claire E|CE|;Leys|Monique|M|;Hinkle|David|D|;Odom|J Vernon|JV|;Maldonado|Ramiro S|RS|",
"chemical_list": "D010426:Pentosan Sulfuric Polyester",
"country": "United States",
"delete": false,
"doi": "10.3928/23258160-20201223-04",
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"issue": "52(1)",
"journal": "Ophthalmic surgery, lasers & imaging retina",
"keywords": null,
"medline_ta": "Ophthalmic Surg Lasers Imaging Retina",
"mesh_terms": "D006801:Humans; D008268:Macular Degeneration; D008875:Middle Aged; D010426:Pentosan Sulfuric Polyester; D012164:Retinal Diseases; D055213:Retinal Pigment Epithelium; D012189:Retrospective Studies",
"nlm_unique_id": "101599215",
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"pubdate": "2021-01-01",
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"references": null,
"title": "New Insights Into Pentosan Polysulfate Maculopathy.",
"title_normalized": "new insights into pentosan polysulfate maculopathy"
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"abstract": "We describe a case of intrathecal migration of a wire-reinforced epidural catheter in a parturient who received epidural labor analgesia. Epidural analgesia was initiated with a combined-spinal epidural technique and maintained by programmed intermittent epidural boluses. Epidural catheter aspiration after insertion was negative for cerebrospinal fluid. The patient's response to the first four doses of local anesthetic was consistent with epidural drug delivery. After the fifth dose, she developed a complete lower extremity motor block, hypotension, and high sensory blockade. Catheter aspiration was then positive for cerebrospinal fluid. After symptom resolution, labor pain was successfully managed with this inadvertent intrathecal catheter.",
"affiliations": "From the Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University School of Medicine, Stanford, California.",
"authors": "Betti|Francesca|F|;Carvalho|Brendan|B|;Riley|Edward T|ET|",
"chemical_list": null,
"country": "United States",
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"issue": "9(12)",
"journal": "A & A case reports",
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"medline_ta": "A A Case Rep",
"mesh_terms": "D000328:Adult; D015360:Analgesia, Epidural; D016362:Analgesia, Obstetrical; D057785:Catheters; D005260:Female; D006801:Humans; D011247:Pregnancy",
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "357-359",
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"pubdate": "2017-12-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intrathecal Migration of an Epidural Catheter While Using a Programmed Intermittent Epidural Bolus Technique for Labor Analgesia Maintenance: A Case Report.",
"title_normalized": "intrathecal migration of an epidural catheter while using a programmed intermittent epidural bolus technique for labor analgesia maintenance a case report"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-18-00435",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SUFENTANIL"
},
"d... |
{
"abstract": "METHODS\nA 62-year-old woman had been found unconscious on her bed. She had to be resuscitated several times in the ambulance on the way to hospital. On admission her pupils were dilated and fixed, the cardiovascular system was unstable. Her rectal temperature was 28 degrees C. She was a diabetic being treated with metformin and glimepiride and was in incipient renal failure (serum creatinine 1.5 mg/dl). She was also in heart failure due to coronary heart disease and was in a debilitated state.\n\n\nMETHODS\nShe had marked lactic acidosis (lactate 45.3 mmol/l; pH 6.6). Toxicological screening tests were negative.\n\n\nMETHODS\nIn the absence of a history she was at first treated symptomatically. Conventional management of the lactic acidosis neither corrected the acidosis nor stabilized the circulatory system. Continuous veno-venous haemodialysis with bicarbonate-buffered solutions succeeded in reducing the need for catecholamines. Neurological examination was supplemented by recording acoustic and sensory evoked potentials. Suspected metformin-induced lactic acidosis was confirmed by appropriate tests. Three weeks after admission she was well enough to be transferred to a normal medical ward and ultimately discharged without further complications.\n\n\nCONCLUSIONS\nMetformin should only be prescribed if the contraindications, in particular renal failure are carefully monitored. Severe lactic acidosis should be treated early with continuous veno-venous haemodialysis with bicarbonate-buffered substituting fluids. The good neurological results in this case are probably largely due to the marked hypothermia.",
"affiliations": "Klinik für Anaesthesiologie, Klinikum rechts der Isar, Technische Universität München. Wolfram.Reeker@lrz.tu-muenchen.de",
"authors": "Reeker|W|W|;Schneider|G|G|;Felgenhauer|N|N|;Tempel|G|G|;Kochs|E|E|",
"chemical_list": "D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C057619:glimepiride; D008687:Metformin",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-2007-1024085",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-0472",
"issue": "125(9)",
"journal": "Deutsche medizinische Wochenschrift (1946)",
"keywords": null,
"medline_ta": "Dtsch Med Wochenschr",
"mesh_terms": "D000140:Acidosis, Lactic; D000208:Acute Disease; D003128:Coma; D003131:Combined Modality Therapy; D000075202:Contraindications; D003924:Diabetes Mellitus, Type 2; D003937:Diagnosis, Differential; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D008687:Metformin; D008875:Middle Aged; D013453:Sulfonylurea Compounds",
"nlm_unique_id": "0006723",
"other_id": null,
"pages": "249-51",
"pmc": null,
"pmid": "10742816",
"pubdate": "2000-03-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Metformin-induced lactic acidosis.",
"title_normalized": "metformin induced lactic acidosis"
} | [
{
"companynumb": "DE-BAUSCH-BL-2018-001674",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GLIMEPIRIDE"
},
"drugadditional": null,
... |
{
"abstract": "Radiation recall dermatitis (RRD) refers to an acute inflammatory skin reaction appearing on a previously irradiated area following the systemic administration of a reaction-triggering agent. Despite various hypotheses, the pathomechanism of RRD appears complex and is still not fully understood. In addition, no clinical guidelines exist concerning whether drug treatment should be continued upon manifestation of an associated radiation recall phenomenon. We present the case of a patient with docetaxel-induced RRD, which was successfully treated with topical steroids and systemic antihistamines; re-challenge to docetaxel did result in very mild remanifestation of skin reactions.",
"affiliations": "Strahlenklinik, Sana Klinikum Offenbach, Starkenburgring 66, 63069, Offenbach, Germany. jstrouthos@gmail.com.;Strahlenklinik, Sana Klinikum Offenbach, Starkenburgring 66, 63069, Offenbach, Germany.;Strahlenklinik, Sana Klinikum Offenbach, Starkenburgring 66, 63069, Offenbach, Germany.",
"authors": "Strouthos|Iosif|I|;Tselis|Nikolaos|N|;Zamboglou|Nikolaos|N|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D006633:Histamine Antagonists; D043823:Taxoids; D000077143:Docetaxel",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00066-016-0984-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0179-7158",
"issue": "192(10)",
"journal": "Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al]",
"keywords": "Anti-inflammatory agents, non-steroidal; Antihistaminics; Corticosteriods; Irradiation; Radiation, sensitizing agents",
"medline_ta": "Strahlenther Onkol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D001859:Bone Neoplasms; D059248:Chemoradiotherapy; D000077143:Docetaxel; D006633:Histamine Antagonists; D006801:Humans; D008297:Male; D011836:Radiation Tolerance; D011855:Radiodermatitis; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "8603469",
"other_id": null,
"pages": "730-6",
"pmc": null,
"pmid": "27287082",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "25568855;8580062;10606426;11821473;17396045;16120169;9274459;12556327;16948841;16949767;9881712;24615187;11591023;7679610;15591727;13813586;14762890;11369064;11005698;25472806;849898;15662578;12415198;21045191;993094;19446501;12362258;628037",
"title": "Docetaxel-induced radiation recall dermatitis : A case report and literature review.",
"title_normalized": "docetaxel induced radiation recall dermatitis a case report and literature review"
} | [
{
"companynumb": "DE-ELI_LILLY_AND_COMPANY-DE201809009728",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional":... |
{
"abstract": "Overdosage of diphenhydramine may result in the development of anticholinergic symptoms, seizures, and coma. A fatal outcome following a diphenhydramine overdose does not commonly occur. This report describes the largest documented overdosage of diphenhydramine (7.5 g) which resulted in the death of a 14-year-old girl. The patient initially developed seizures following by cardiac conduction and hemodynamic compromise resulting in death despite life support measures.",
"affiliations": null,
"authors": "Krenzelok|E P|EP|;Anderson|G M|GM|;Mirick|M|M|",
"chemical_list": "D004155:Diphenhydramine",
"country": "United States",
"delete": false,
"doi": "10.1016/s0196-0644(82)80501-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-0644",
"issue": "11(4)",
"journal": "Annals of emergency medicine",
"keywords": null,
"medline_ta": "Ann Emerg Med",
"mesh_terms": "D000293:Adolescent; D001145:Arrhythmias, Cardiac; D004155:Diphenhydramine; D005260:Female; D005751:Gastric Lavage; D006323:Heart Arrest; D006801:Humans; D012151:Resuscitation; D012640:Seizures; D013405:Suicide",
"nlm_unique_id": "8002646",
"other_id": null,
"pages": "212-3",
"pmc": null,
"pmid": "7073039",
"pubdate": "1982-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Massive diphenhydramine overdose resulting in death.",
"title_normalized": "massive diphenhydramine overdose resulting in death"
} | [
{
"companynumb": "US-SA-2020SA362147",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nChemoradiotherapy (CRT) is an effective modality for stage I esophageal squamous cell carcinoma (ESCC). However, salvage treatments are often required even if complete response (CR) has been achieved. To this end, it is important to accurately diagnose lymph node or other organ metastatic recurrences. Note that lymph node enlargements (except metastatic recurrence) are often detected during the follow-up period after CRT. The purpose of this study was to elucidate the clinical characteristics of lymph node enlargement after CRT.\n\n\nMETHODS\nIn this retrospective cohort study, patients diagnosed with stage I (T1 [submucosal invasion] N0M0) ESCC were treated with cisplatin and 5-fluorouracil concurrently with radiotherapy. A total of 55 patients were enrolled in the study from February 2006 to August 2011.\n\n\nRESULTS\nThe median follow-up period was 46 months. The 3-year overall and progression-free survival rates were 90.7% and 71.2%, respectively, and the CR rate was 87.2% (48/55). Nine of the 48 CR patients were finally diagnosed with recurrences, including 7 lymph node metastases and 2 local recurrences. Lymph node enlargement was initially identified in 20 of the total 55 patients during the follow-up; 9 patients were finally diagnosed with lymph node recurrence, whereas 11 patients had benign reactive lymph node enlargement.\n\n\nCONCLUSIONS\nThe present study demonstrated the high incidence of enlarged lymph nodes after CRT for stage I ESCC. It is important to accurately distinguish between benign lymph node enlargement and recurrent lymph nodes to avoid unnecessary salvage treatments.",
"affiliations": "Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. takehara@gh.med.osaka-u.ac.jp.",
"authors": "Hayashi|Yoshito|Y|;Nishida|Tsutomu|T|;Tsujii|Masahiko|M|;Tsutsui|Shusaku|S|;Yamamoto|Katsumi|K|;Isohashi|Fumiaki|F|;Yamasaki|Makoto|M|;Miyata|Hiroshi|H|;Kato|Motohiko|M|;Yamada|Takuya|T|;Shinzaki|Shinichiro|S|;Iijima|Hideki|H|;Ogawa|Kazuhiko|K|;Doki|Yuichiro|Y|;Takehara|Tetsuo|T|",
"chemical_list": "D000970:Antineoplastic Agents; D002945:Cisplatin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1186/1471-2407-14-706",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 25253238491710.1186/1471-2407-14-706Research ArticleLymph node enlargement after definitive chemoradiotherapy for clinical stage I esophageal squamous cell carcinoma Hayashi Yoshito y.hayashi@gh.med.osaka-u.ac.jp Nishida Tsutomu tnishida@gh.med.osaka-u.ac.jp Tsujii Masahiko mt@gh.med.osaka-u.ac.jp Tsutsui Shusaku stsutsui@hosp.itami.hyogo.jp Yamamoto Katsumi katsumiy770@yahoo.co.jp Isohashi Fumiaki isohashi@radonc.med.osaka-u.ac.jp Yamasaki Makoto myamasaki@gesurg.med.osaka-u.ac.jp Miyata Hiroshi hmiyata@gesurg.med.osaka-u.ac.jp Kato Motohiko motohiko@gh.med.osaka-u.ac.jp Yamada Takuya yamtak@gh.med.osaka-u.ac.jp Shinzaki Shinichiro shinzaki@gh.med.osaka-u.ac.jp Iijima Hideki hiijima@gh.med.osaka-u.ac.jp Ogawa Kazuhiko kogawa@radonc.med.osaka-u.ac.jp Doki Yuichiro ydoki@gesurg.med.osaka-u.ac.jp Takehara Tetsuo takehara@gh.med.osaka-u.ac.jp Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan Department of Radiation Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan 24 9 2014 24 9 2014 2014 14 7062 9 2013 20 9 2014 © Hayashi et al.; licensee BioMed Central Ltd. 2014This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Background\nChemoradiotherapy (CRT) is an effective modality for stage I esophageal squamous cell carcinoma (ESCC). However, salvage treatments are often required even if complete response (CR) has been achieved. To this end, it is important to accurately diagnose lymph node or other organ metastatic recurrences. Note that lymph node enlargements (except metastatic recurrence) are often detected during the follow-up period after CRT. The purpose of this study was to elucidate the clinical characteristics of lymph node enlargement after CRT.\n\nMethods\nIn this retrospective cohort study, patients diagnosed with stage I (T1 [submucosal invasion] N0M0) ESCC were treated with cisplatin and 5-fluorouracil concurrently with radiotherapy. A total of 55 patients were enrolled in the study from February 2006 to August 2011.\n\nResults\nThe median follow-up period was 46 months. The 3-year overall and progression-free survival rates were 90.7% and 71.2%, respectively, and the CR rate was 87.2% (48/55). Nine of the 48 CR patients were finally diagnosed with recurrences, including 7 lymph node metastases and 2 local recurrences. Lymph node enlargement was initially identified in 20 of the total 55 patients during the follow-up; 9 patients were finally diagnosed with lymph node recurrence, whereas 11 patients had benign reactive lymph node enlargement.\n\nConclusion\nThe present study demonstrated the high incidence of enlarged lymph nodes after CRT for stage I ESCC. It is important to accurately distinguish between benign lymph node enlargement and recurrent lymph nodes to avoid unnecessary salvage treatments.\n\nKeywords\nEsophageal carcinomaChemoradiotherapyLymph node enlargementissue-copyright-statement© The Author(s) 2014\n==== Body\nBackground\nEsophageal carcinoma is the major cause of cancer-related mortality in the world and also in Japan\n[1]. Surgical esophagectomy with lymphadenectomy is considered to be the standard treatment for patients in clinical stages I to III ESCC\n[2, 3]. Recent improvements of endoscopic techniques (non-surgical treatments) have allowed organ preservation in patients with mucosal ESCC. However, endoscopic resection (ER) is not indicated for ESCC with submucosal invasion. Moreover, there is a high incidence of lymph node occult metastasis in 10% to 30% of the patients with submucosal cancer. Today, these patients are usually treated surgically. The survival rate of patients with submucosal tumors treated surgically at 3 years is > 80%, but esophagectomy is an invasive procedure and has the risk of postoperative morbidity. For the patients in stages II and III ESCC, postoperative chemotherapy is superior to surgery alone in disease free survival and preoperative chemotherapy leads to the superiority to postoperative chemotherapy in overall survival\n[4, 5], which suggests that chemotherapy is efficacious in suppressing lymph node recurrences. Several reports have recently confirmed that concurrent chemoradiotherapy (CRT) is a more effective treatment in patients with advanced ESCC, compared to radiotherapy alone\n[6–8]. CRT is considered to be less invasive because of the better quality of life after the treatment compared to esophagectomy. Definitive CRT is considered to have an indication not only for the advanced stage but for the early stage as well\n[9–11]. A phase II study has demonstrated that definitive CRT is a favorable alternative to esophagectomy in patients with clinical stage I ESCC\n[10, 12].\n\nCRT seems to be an effective modality, particularly for submucosal ESCC without lymph node metastasis. However, it is known that patients with submucosal invasion have invisible lymph node metastases at the time of diagnosis. Accordingly, they are considered to be at high risk for lymph node recurrence after CRT, and salvage treatments are often required to improve their survival, although they had achieved complete response (CR). To detect metastatic or recurrent lesions as soon as possible, endoscopy and thoraco-abdominal computed tomography (CT) are regularly performed for monitoring after CRT. If a recurrence occurred locally in the mucosal layer, it is easy to diagnose with endoscopic biopsy and ER is a useful salvage modality to control in such cases. On the contrary, it is difficult to accurately diagnose lymph node recurrence after CRT because little is known about the recurrence pattern after CRT for patients with clinical stage I ESCC. We experienced several cases in which lymph node enlargements were detected after CRT. Although surgical esophagectomy was performed in the early period, we observed that a few cases were pathologically benign, which suggested that benign lymph node enlargement that was reactive to the treatment might mimic metastasis in certain cases. The aim of this study was to elucidate the clinical characteristics of lymph node enlargement after CRT.\n\nMethods\nPatient population\nThis retrospective study used the database at the Department of Gastroenterology and Hepatology of Osaka University Hospital. From February 2006 to August 2011, 55 consecutive patients with stage I (T1 [submucosal cancer] N0 M0) ESCC who were treated with CRT were analysed. TNM staging was determined according to the Union for International Cancer Control criteria. None of the patients chose the surgical treatment. The median patient age was 66 years (range, 49–82 years). The clinical stage was diagnosed by endoscopy, endoscopic ultrasonography, cervical and thoraco-abdominal CT. Tumor localization was identified by combining chromoendoscopy with Lugol staining. Tumor invasion depth was evaluated using magnification endoscopy with narrow band imaging (NBI) and endoscopic ultrasonography in addition to conventional CT. The CRT was performed as following criteria: 1) Eastern Cooperative Oncology Group performance status of 0–2; 2) leucocyte count >3,000/m3, platelet count >100,000/m3; 3) aspartate aminotransferase or alanine transferase level within 3 times the normal upper limit; 4) creatinine level <1.5 mg/dl and creatinine clearance >50 ml/min; and 5) no other serious complications. All patients had adequate hepatic and renal functions and performance status scores of 0. The tumor histological type was diagnosed as squamous cell carcinoma based on an endoscopic biopsy. This study was approved by the Institutional Review Board of Osaka University.\n\nChemoradiotherapy\nAll patients were treated with cisplatin and 5-FU chemotherapy. Cisplatin was administered at a dose of 70 mg/m2 body surface area on Day 1 and Day 29, and 5-FU was administered at a dose of 700 mg/m2 per day by continuous infusion for 24 hours on Days 1–5 and Days 29–33. Nedaplatin was administered instead of cisplatin to 3 patients on Day 29 because of renal dysfunction induced by cisplatin. The concurrent radiotherapy consisted of external administrations of 2 Gy daily to a total dose of 60 Gy without a planned break. The gross tumor volume was limited to the primary tumor. The planning target volume was defined by adding 2- to 3-cm margins above and below the tumor without prophylactic lymph node coverage according to the clips marked during the endoscopic procedure. The lateral, anterior, and posterior margins were limited to 1–2 cm. The radiation therapy field comprised the planning target volume for up to 40 Gy with anterior/posterior opposed portals and exposed to an additional 20 Gy with bilateral oblique portals excluding the spinal cord.\n\nAssessments of response, recurrence and toxicity after CRT\nAfter CRT, the clinical response was assessed with endoscopic observation accompanied by biopsy specimens and a thoraco-abdominal multidetector CT scan. CR was defined when a tumor was not detected by endoscopic observation and CT scan for >4 weeks. First, the initial evaluation was performed 1 month after CRT and subsequently followed up at 3-month intervals up to 1 year and subsequently at 6 months and up to 5 years by endoscopy and thoraco-abdominal CT scan or until recurrence was diagnosed. Metachronous esophageal recurrence out of the radiation field was not included in the present study. A lymph node enlargement was defined when the size of a lymph node was larger than the initial size before CRT or newly detected by CT scan. The early cases were diagnosed as a recurrence or a benign enlargement pathologically by surgical resection. In the later cases, the lymph node enlargement was followed by CT scan with closed interval. During the closed follow-up, the enlarged lymph nodes were diagnosed as a recurrence when they increased in size and number in the CT scan. When the exacerbation was not detected for more than 6 months, lymph node enlargement was defined as “benign”.\n\nAdverse events were retrospectively evaluated using the Common Terminology Criteria version 4.0. We evaluated therapeutic late toxicity according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring schema (available at http://www.rtog.org/).\n\nStatistical analysis\nIf there were missing cases, the date of the last observation was defined as the censor date. The overall survival was calculated using the Kaplan-Meier method from the date of CRT initiation to death from any cause. Cumulative progression-free survival was calculated using the Kaplan-Meier method from the date of CRT initiation to the recurrence or death from any cause. A Wilcoxon test was performed to compare diameters and intervals until lymph node enlargement between benign enlargement and recurrence. All analyses were performed using JMP software (V.10.0.2, SAS Institute Inc., Cary, NC, USA).\n\nResults\nPatient characteristics\nThe median follow-up period after initiating CRT was 46 months (range, 2–83 months). The main clinical characteristics of the patients are presented in Table \n1. Before the treatment, 5 patients had been treated for malignancies in other organs, which were inactive when CRT was performed for ESCC. During the follow-up period, the second primary cancers in the other organs were observed in 10 patients: pancreas, skin, and prostate, 1; biliary duct, 1; urinary tract, 1; pharynx, 1; colon, 1; lung and stomach, 1; vocal cord and stomach, 1; valve, 1; thyroid, 1; and stomach, 1. Esophageal intraepithelial neoplasia, which occurred metachronously out of the radiation therapy field, was detected in 3 patients after CRT; all of whom were treated with ER.Table 1 \nPatient characteristics\n\n\nNumber of patients\t55\t\nGender male/female\t49/6\t\nAge, median [range] (yrs)\t66 [49–82]\t\nPerformance status, 0/1/2\t55/0/0\t\nTumor main location\t\t\nUpper thoracic\t7\t\nMiddle thoracic\t34\t\nLower thoracic\t14\t\nInactive multiple cancers in other organ\t\t\nno/yes\t50/5\t\nMedian follow-up period [range] (months)\t46 [2–83]\t\n\n\nAdherence and adverse events\nAll but 2 patients successfully underwent total treatment, and the treatment completion rate was 96%. One of the 2 patients received only 52 Gy irradiation because he withdrew further treatment, and the other patient received an 80% dose of chemotherapy on Days 29–33 because of digestive toxicity. One patient died 2 weeks after CRT completion. The causal correlation with the treatment was not confirmed; however, treatment-related death was suspected.\n\nWith regard to hematologic adverse events, grade 3 or 4 leukocytopenia was observed in 8 patients, and grade 3 anaemia was observed in 1 patient. Grade 3 appetite loss and nausea were seen in 3 patients, and grade 3 mucositis was observed in 3 patients. Late toxicity events were observed 3 to 24 months after the treatment. Grade 3 interstitial lung disease was observed in 1 patient (1.8%). Grade 3 pericardial effusions were observed in 3 patients (5.5%). Two of these patients had been treated for cardiac disease before CRT.\n\nTreatment efficacy\nThe 3-year overall survival rate in all patients was 90.7% (Figure \n1a). The CR rate was 87.2% (48/55). Although 6 non-CR patients, except for 1 patient who was suspected of treatment-related death, underwent salvage treatment, including surgery and chemotherapy, 2 died because of lymph node recurrence and liver metastasis (Table \n2). Of the 48 CR patients, 5 died from lymph node recurrences, and 4 patients died without ESCC recurrences during the follow-up period: urinary tract cancer, 1; biliary tract cancer, 1; sudden death of unknown cause, 1; and acute heart failure, 1.The 3-year progression-free survival rate was 71.2% (Figure \n1b). Of the 48 CR patients, recurrences were detected in 9 patients from 8 to 41 months after CRT initiation. The local recurrences of 2 patients were treated completely with ER. Lymph node recurrences were found in 7 patients who underwent salvage surgery or chemotherapy. Of the limited 48 CR patients, the 3-year progression-free survival rate was 81.5%.Figure 1 \nTreatment Efficacy of CRT. a. Cumulative overall survival curve. The 3-year overall survival rate was 90.7%. b. Cumulative progression-free survival curve. The 3-year progression-free survival rate was 71.2%.\n\n\n\nTable 2 \nCharacteristics patients experiencing treatment failure after CRT\n\n\nNo.\tTumor location\tResponse\tTime to failure\tSurvival\tRecurrent location\tTreatment after failure\t\n1\tLt\tCR\t41\tDeceased\tLN\tChemotherapy\t\n2\tMt\tCR\t30\tDeceased\tLN\tSurgery\t\n3\tLt\tCR\t30\tSurvive\tLocal\tESD\t\n4\tMt\tCR\t28\tDeceased\tLN\tChemotherapy\t\n5\tLt\tCR\t20\tSurvive\tLN\tSurgery\t\n6\tMt\tCR\t20\tSurvive\tLN\tSurgery\t\n7\tMt\tCR\t10\tDeceased\tLN\tChemotherapy\t\n8\tMt\tCR\t8\tSurvive\tLocal\tESD\t\n9\tUt\tCR\t8\tDeceased\tLN\tSurgery\t\n10\tMt\tNo CR\t8\tDeceased\tLiver\tChemotherapy\t\n11\tMt\tNo CR\t5\tSurvive\tLN\tSurgery\t\n12\tMt\tNo CR\t4\tSurvive\tLocal\tSurgery\t\n13\tMt\tNo CR\t4\tSurvive\tLocal\tSurgery\t\n14\tMt\tNo CR\t4\tDeceased\tLN\tSurgery\t\n15\tMt\tNo CR\t3\tUnknown\tLung\tChemotherapy\t\nUT, upper thoracic; MT, middle thoracic; LT, lower thoracic; LN, lymph node; ESD, endoscopic submucosal dissection.\n\nLymph node enlargement\nWe performed a scheduled thoraco-abdominal CT before and after the treatment according to the protocol for detecting metastatic recurrence. Although no enlarged lymph node was detected by CT before CRT, the enlarged lymph nodes were detected in 20 (36.3%) of the 55 patients during the scheduled follow-up (Table \n3). Initially, the salvage surgery including lymphadenectomy for lymph node enlargements were performed in 4 patients. Two patients who underwent surgery were pathologically diagnosed with benign enlarged lymph nodes. Then, we monitored patients with newly enlarged lymph nodes using CT to determine whether the nodes were metastatic recurrences. Among the 20 patients in whom enlarged lymph nodes were detected after CRT, 7 patients were diagnosed with lymph node recurrences because of the additional growth of lymph nodes within 6 months or surgical pathological examinations. The size of the lymph nodes of 13 patients did not change within 6 months, and they satisfied the “benign” definition. However, in 2 patients, the lymph nodes (patients 3 and 6) grew slowly and were finally diagnosed as metastatic recurrences more than 1 year after their initial detections. Consequently, 9 of these 20 patients (45%) were diagnosed with metastasis, and 11 patients (55%) were considered to have reactive enlargement of lymph nodes. The average interval from initiating CRT to the point of lymph node enlargement was 14.1 months in the patients with recurrent metastasis and 12.0 months in the patients with benign lymph node enlargement. The average lymph node diameters were 9.3 mm in the patients with recurrent metastasis and 8.3 mm in the patients with benign lymph node enlargement. We did not find significant differences between the recurrence and the benign enlargements in the interval after CRT or lymph node size. The benign lymph node enlargements that were diagnosed were followed for >19 months, except for 1 patient who was followed for 8 months, which suggests that these patients had benign lymph node enlargements. Regarding the benign lymph node enlargements, FDG accumulation on PET-CT was positive in one patient and negative in 5 patients, and 5 patients did not undergo PET-CT. All of enlarged lymph nodes diagnosed as metastatic recurrence finally showed FDG accumulation. Regarding the alteration of lymph node diameter after detecting lymph node enlargement, we observed that several nodes shrank promptly, whereas others maintained the same size during the follow-up period. Half of the lymph node enlargements that occurred after CRT were eventually diagnosed as false-positive, which means that they could avoid unnecessary treatment.Table 3 \nCharacteristics of lymph node enlargement\n\n\nMetastasis\t\nNo.\tTumor location\tEfficacy\tLN location\tLN size\tTime to LN enlargement\tLN size after follow-up\tFollow-up until final diagnosis\tFDG accumulation\tPathology\tSalvage treatment\t\n1\tMt\tCR\tMediastinum\t21 mm\t17 months\t35 mm\t3 months\tPositive\tSCC\tSurgery\t\n2\tMt\tCR\tSupraclavicular\t12 mm\t19 months\t20 mm\t1 month\tPositive\tSCC\tSurgery\t\n3\tLt\tCR\tRecurrent nerve/supraclavicular\t8 mm\t27 months\t12 mm\t14 months\tPositive\t-\tChemotherapy\t\n4\tMt\tCR\tCardia\t8 mm\t5 months\t11 mm\t5 months\tPositive\t-\tChemotherapy\t\n5\tMt\tCR\tCervical paraesophageal\t7 mm\t30 months\t7 mm\t-\tPositive\tSCC\tSurgery\t\n6\tMt\tCR\tMediastinum/supraclavicular\t6 mm\t14 months\t12 mm\t14 months\tPositive\t-\tChemotherapy\t\n7\tUt\tCR\tRecurrent nerve\t6 mm\t8 months\t10 mm\t2 months\tPositive\tSCC\tSurgery\t\n8\tMt\tNo CR\tLeft gastric artery\t10 mm\t5 months\t10 mm\t-\tPositive\tSCC\tSurgery\t\n9\tMt\tNo CR\tSupraclavicular\t6 mm\t2 months\t10 mm\t2 months\tPositive\tSCC\tSurgery\t\n\nBenign enlargement\n\t\n\nNo.\n\t\nTumor location\n\t\nEfficacy\n\t\nLN location\n\t\nLN size\n\t\nFDG accumulation\n\t\nTime to LN enlargement\n\t\nDuration until LN shrinkage\n\t\nPathology\n\t\nFollow-up after LN enlargement\n\t\n1\tLt\tCR\tInfradiaphragmatic\t19 mm\tNegative\t2 months\t-\t-\t59 months\t\n2\tLt\tCR\tMain bronchus\t17 mm\tNegative\t9 months\t3 months\t-\t64 months\t\n3\tMt\tCR\tMediastinum\t10 mm\tNegative\t19 months\t-\t-\t22 months\t\n4\tMt\tCR\tRecurrent nerve\t10 mm\tPositive\t16 months\tUp to surgery\tBenign\t46 months\t\n5\tMt\tCR\tSubcarinal\t10 mm\tN.A.\t29 months\t-\t-\t19 months\t\n6\tMt\tCR\tSupraclavicular\t10 mm\tNegative\t2 months\t12 months\t-\t60 months\t\n7\tMt\tCR\tSuperficial cervical\t9 mm\tN.A.\t39 months\t-\t-\t8 months\t\n8\tMt\tCR\tRecurrent nerve\t9 mm\tN.A.\t5 months\tUp to surgery\tBenign\t78 months\t\n9\tUt\tCR\tMain bronchus\t8 mm\tN.A.\t2 months\t29 months\t-\t68 months\t\n10\tUt\tCR\tCardia\t6 mm\tNegative\t4 months\t7 months\t-\t51 months\t\n11\tMt\tCR\tMain bronchus\t6 mm\tN.A.\t3 months\t-\t-\t33 months\t\nUT, upper thoracic; MT, middle thoracic; LT, lower thoracic; LN, lymph node; SCC, squamous cell carcinoma; N.A., not assessed.\n\n\n\nDiscussion\nThe current study demonstrated favourable therapeutic outcomes, including CR rate, overall survival, and progression-free survival, as previously reported, for the ESCC patients treated with CRT\n[10]. More importantly, the present study clearly demonstrated the high incidence of lymph node enlargements found during the follow-up after CRT.\n\nSalvage surgery was performed in the early cases as soon as we detected an enlarged lymph node by CT during the follow-up after CRT. However, we noticed that in the pathological examination after surgery, benign lymph node enlargements occasionally occurred early in several cases. For the later cases, we closely followed lymph node enlargement after CRT to determine the likelihood of a recurrence or of a benign enlargement clinically. The present study indicated that the benign enlargements accounted for >50% of all enlarged lymph nodes detected by CT scan. Based on the premise that benign lymph node enlargements are frequently detected after CRT, we must distinguish recurrences from simple enlargements using non-invasive modality. In the present study, we defined the lymph node enlargement as “benign” when the exacerbation was not detected for >6 months. However, 2 patients finally suffered from metastatic lymph nodes, although their enlarged lymph nodes were not exacerbated within 6 months after initiating CRT. Presently, to avoid unnecessary salvage esophagectomy and lymphadenectomy, we must closely monitor patients with enlarged lymph nodes. Additional studies regarding modalities, biomarkers, or clinicopathological characteristics that discriminated between lymph node enlargement and recurrence should be performed.\n\nWith regard to feasibility, adverse events were tolerable compared to the previous study\n[10]. However, we must recognise the treatment risk after CRT, particularly cardiac toxicity. One patient died within 3 months of initiating treatment. Three patients suffered from cardiac disease accompanied by pericardial effusion as adverse events. We are uncertain whether CRT was directly related to the cardiac disease observed in these cases, because 2 of the 3 patients had been previously treated for myocardial infarction or angina. Moreover, although pericardial effusion was not induced, acute heart failure occurred in 1 patient who had been previously treated for angina, and 2 patients died suddenly from unknown causes. In all cases, the primary tumors were located in the inferior esophagus. The pericardial exposure with radiation might have caused the cardiovascular events, such as heart failure or arrhythmia. These results suggest that we must pay particular attention to those patients who have previous histories of cardiac diseases and inferior esophageal tumors.\n\nThe present study has several limitations. First, this is a retrospective study in a single hospital, and the total patient population is small. Second, the mechanism of benign enlargements of lymph nodes is uncertain. It is possible that the decrease of radiation dose contributes the suppression of lymph node enlargements. However, in the present study, lymph node enlargements did not depend on whether they included within or out of radiation field. Third, the histological type of all patients enrolled in this study was squamous cell carcinoma. It is uncertain whether these findings shown in this manuscript are applicable to esophageal adenocarcinoma which is common in Western countries.\n\nConclusion\nIn conclusion, our study reveals that CRT is effective and feasible for patients with clinical stage I ESCC and that lymph node enlargements are often detected during follow-up after CRT. Note that benign lymph node enlargements comprise >50% of the enlarged lymph nodes after CRT.\n\nAbbreviations\nCRComplete response\n\nCRTChemoradiotherapy\n\nCTComputed tomography\n\nEREndoscopic resection\n\nESCCEsophageal squamous cell carcinoma\n\nNBINarrow band imaging.\n\nCompeting interests\n\nThe authors declare that they have no competing interest.\n\nAuthors’ contributions\n\nYH collected data and prepared manuscript. TN, ST, MY, HM, KY, and YD planned and designed the study. YH, TN, MT, ST, SS, KY, TY, MK and HI performed chemoradiotherapy. MY, KY and YD performed salvage surgery. FI performed radiotherapy. KO, YD and TT supervised the project. TT edited the manuscript. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1. Parkin DM Bray F Ferlay J Pisani P Global cancer statistics, 2002 CA Cancer J Clin 2005 55 74 108 10.3322/canjclin.55.2.74 15761078 \n2. Muro K A phase II study of chemoradiotherapy in patients with stage II, III esophageal squamous cell carcinoma (ESCC): (JCOG 9906) J Clin Oncol 2008 25 supple 644s \n3. Kato H Tachimori Y Mizobuchi S Igaki H Ochiai A Cervical, mediastinal, and abdominal lymph node dissection (three-field dissection) for superficial carcinoma of the thoracic esophagus Cancer 1993 72 10 2879 2882 10.1002/1097-0142(19931115)72:10<2879::AID-CNCR2820721004>3.0.CO;2-Q 8221552 \n4. Ando N Iizuka T Ide H Ishida K Shinoda M Nishimaki T Takiyama W Watanabe H Isono K Aoyama N Makuuchi H Tanaka O Yamana H Ikeuchi S Kabuto T Nagai K Shimada Y Kinjo Y Fukuda H Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study–JCOG9204 J Clin Oncol 2003 21 24 4592 4596 10.1200/JCO.2003.12.095 14673047 \n5. Ando N Kato H Igaki H Shinoda M Ozawa S Shimizu H Nakamura T Yabusaki H Aoyama N Kurita A Ikeda K Kanda T Tsujinaka T Nakamura K Fukuda H A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907) Ann Surg Oncol 2012 19 1 68 74 10.1245/s10434-011-2049-9 21879261 \n6. Herskovic A Martz K al-Sarraf M Leichman L Brindle J Vaitkevicius V Cooper J Byhardt R Davis L Emami B Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus N Engl J Med 1992 326 24 1593 1598 10.1056/NEJM199206113262403 1584260 \n7. Cooper JS Guo MD Herskovic A Macdonald JS Martenson JA Jr Al-Sarraf M Byhardt R Russell AH Beitler JJ Spencer S Asbell SO Graham MV Leichman LL Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85–01). Radiation Therapy Oncology Group JAMA 1999 281 17 1623 1627 10.1001/jama.281.17.1623 10235156 \n8. Coia LR Engstrom PF Paul AR Stafford PM Hanks GE Long-term results of infusional 5-FU, mitomycin-C and radiation as primary management of esophageal carcinoma Int J Radiat Oncol Biol Phys 1991 20 1 29 36 10.1016/0360-3016(91)90134-P 1704362 \n9. Ohtsu A Boku N Muro K Chin K Muto M Yoshida S Satake M Ishikura S Ogino T Miyata Y Seki S Kaneko K Nakamura A Definitive chemoradiotherapy for T4 and/or M1 lymph node squamous cell carcinoma of the esophagus J Clin Oncol 1999 17 9 2915 2921 10561371 \n10. Kato H Sato A Fukuda H Kagami Y Udagawa H Togo A Ando N Tanaka O Shinoda M Yamana H Ishikura S A phase II trial of chemoradiotherapy for stage I esophageal squamous cell carcinoma: Japan clinical oncology group study (JCOG9708) Jpn J Clin Oncol 2009 39 10 638 643 10.1093/jjco/hyp069 19549720 \n11. Smith TJ Ryan LM Douglass HO Jr Haller DG Dayal Y Kirkwood J Tormey DC Schutt AJ Hinson J Sischy B Combined chemoradiotherapy vs. radiotherapy alone for early stage squamous cell carcinoma of the esophagus: a study of the Eastern Cooperative Oncology Group Int J Radiat Oncol Biol Phys 1998 42 2 269 276 10.1016/S0360-3016(98)00232-6 9788404 \n12. Yamamoto S Ishihara R Motoori M Kawaguchi Y Uedo N Takeuchi Y Higashino K Yano M Nakamura S Iishi H Comparison between definitive chemoradiotherapy and esophagectomy in patients with clinical stage I esophageal squamous cell carcinoma Am J Gastroenterol 2011 106 6 1048 1054 10.1038/ajg.2011.42 21343920\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
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"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D002945:Cisplatin; D004938:Esophageal Neoplasms; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008198:Lymph Nodes; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome",
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"pubdate": "2014-09-24",
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"title": "Lymph node enlargement after definitive chemoradiotherapy for clinical stage I esophageal squamous cell carcinoma.",
"title_normalized": "lymph node enlargement after definitive chemoradiotherapy for clinical stage i esophageal squamous cell carcinoma"
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"abstract": "The same mechanisms that mediate antitumor immunity from checkpoint inhibitors (CPIs) can also lead to unintended targeting of normal tissues, characterized as immune-related adverse events (irAEs). Those with pre-existing autoimmune disease are believed to be particularly vulnerable for exacerbating underlying autoimmunity or inducing severe irAEs. We report the first case of CPI-associated reactivation of primary membranous nephropathy (MN) in a patient with pleural mesothelioma responding to immunotherapy. Due to its specificity in targeting B-lymphocytes, rituximab was used to treat primary MN with the expectation that this would not interfere with the benefits gained from T cell-mediated antitumor immunity. Rituximab was effective in treating CPI-associated reactivation of MN, and the patient was successfully rechallenged with nivolumab and maintained stable kidney function and sustained clinical antitumor effect. While exacerbation of pre-existing autoimmune diseases from CPIs is common, therapy for autoimmune reactivation can be rationally directed by an understanding of the immunosuppressive mechanism with goals of cancer treatment.",
"affiliations": "Section of Nephrology, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Section of Hematology-Oncology, Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA.;Section of Nephrology, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Pathology and Laboratory Medicine, University of Texas Health Science Center McGovern Medical School, Houston, Texas, USA.;Department of Medical Oncology, Institute of Academic Medicine and Weill Cornell Medical College, Houston Methodist Cancer Center, Houston, Texas, USA.;Department of Melanoma Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Section of Nephrology, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA aabudayyeh@mdanderson.org.",
"authors": "Lin|Jamie S|JS|0000-0002-7073-9658;Wang|Daniel Y|DY|;Mamlouk|Omar|O|0000-0002-1242-2740;Glass|William F|WF|;Abdelrahim|Maen|M|;Yee|Cassian|C|;Abudayyeh|Ala|A|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000082082:Immune Checkpoint Inhibitors; D000069283:Rituximab",
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"doi": "10.1136/jitc-2020-001287",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\njitc-2020-001287\n10.1136/jitc-2020-001287\nCase Report\n1506\n2518 1619\nImmune checkpoint inhibitor associated reactivation of primary membranous nephropathy responsive to rituximab\nhttp://orcid.org/0000-0002-7073-9658Lin Jamie S 1 Wang Daniel Y 2 http://orcid.org/0000-0002-1242-2740Mamlouk Omar 1 Glass William F 3 Abdelrahim Maen 4 Yee Cassian 56 Abudayyeh Ala 1 1 Section of Nephrology, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA\n2 Section of Hematology-Oncology, Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA\n3 Department of Pathology and Laboratory Medicine, University of Texas Health Science Center McGovern Medical School, Houston, Texas, USA\n4 Department of Medical Oncology, Institute of Academic Medicine and Weill Cornell Medical College, Houston Methodist Cancer Center, Houston, Texas, USA\n5 Department of Melanoma Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA\n6 Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA\nCorrespondence to Dr Ala Abudayyeh; aabudayyeh@mdanderson.org\n2020 \n5 10 2020 \n8 2 e00128727 8 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.The same mechanisms that mediate antitumor immunity from checkpoint inhibitors (CPIs) can also lead to unintended targeting of normal tissues, characterized as immune-related adverse events (irAEs). Those with pre-existing autoimmune disease are believed to be particularly vulnerable for exacerbating underlying autoimmunity or inducing severe irAEs. We report the first case of CPI-associated reactivation of primary membranous nephropathy (MN) in a patient with pleural mesothelioma responding to immunotherapy. Due to its specificity in targeting B-lymphocytes, rituximab was used to treat primary MN with the expectation that this would not interfere with the benefits gained from T cell-mediated antitumor immunity. Rituximab was effective in treating CPI-associated reactivation of MN, and the patient was successfully rechallenged with nivolumab and maintained stable kidney function and sustained clinical antitumor effect. While exacerbation of pre-existing autoimmune diseases from CPIs is common, therapy for autoimmune reactivation can be rationally directed by an understanding of the immunosuppressive mechanism with goals of cancer treatment.\n\ncase reportsimmunotherapyautoimmunityhttp://dx.doi.org/10.13039/100000062National Institute of Diabetes and Digestive and Kidney DiseasesK08 DK119466special-featureunlocked\n==== Body\nBackground\nImmune checkpoint therapy has dramatically altered the treatment landscape of patients with cancer. However, the same mechanisms that mediate antitumor immunity can also lead to unintended targeting of normal tissues, characterized as immune-related adverse events (irAEs). Those with pre-existing autoimmune disease are believed to be particularly vulnerable for exacerbating underlying autoimmunity or inducing severe irAEs. Primary membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. It is an antibody-mediated autoimmune glomerular disease, where approximately 70% of patients will produce autoantibodies to the M-type phospholipase A2 receptor (PLA2R) on glomerular podocytes.1 Fortunately, only approximately 30% of untreated patients with MN will progress to end-stage kidney failure. Immunosuppressive treatment is recommended for those at risk for progressive disease. MN can also be associated with malignancies, infections, and certain medications including checkpoint inhibitors (CPIs).2 The strong association between malignancy and MN3 4 can make it difficult to distinguish from CPI-associated MN. Furthermore, treatment of paraneoplastic glomerular diseases is achieved with treatment of the underlying cancer. Here we present a patient with history of primary MN (>10 years) and malignant pleural mesothelioma. We report the first case of immune checkpoint inhibitor (CPI)-associated reactivation of primary MN responsive to rituximab in a patient with pleural mesothelioma on immune checkpoint therapy with durable complete remission.\n\nCase presentation\nA 60-year-old man with clinical stage IA malignant pleural mesothelioma receiving off-label nivolumab, anti-programmed cell death-1 (PD-1) therapy, was referred to the University of Texas MD Anderson Cancer Center (MDACC) nephrology clinic for concern of reactivation of primary MN.\n\nThe patient has had a history of primary MN for approximately 14 years. He was found to have nephrotic range proteinuria (3–4 g/day) on an annual physical examination and referred to a local nephrologist. Per the patient, initial workup was unrevealing and his proteinuria spontaneously improved to <1.0 g/day. In 2011, he had recurrence of proteinuria and underwent kidney biopsy. At the time, PLA2R testing was unavailable; however, his biopsy findings in 2011 were suggestive of primary MN including thickened glomerular capillaries, glomerular basement membrane (GBM) pits and spikes, subepithelial intramembranous deposits (figure 1A–C), and absence of subendothelial and mesangial deposits. Screening for secondary causes of MN including: hepatitis B and C serologies, anti-nuclear antibody (ANA) titer, prostate-specific antigen (PSA) level, chest x-ray, and colonoscopy were unrevealing. Non-immunosuppressive therapy, including lisinopril and simvastatin, was initiated. While he was ultimately unable to tolerate lisinopril due to hyperkalemia, he went into spontaneous remission. Since 2011, he has only had one additional relapse in 2017 that also spontaneously remitted without use of steroids or immunosuppressive treatment.\n\nFigure 1 Renal biopsy 2011. (A) Periodic acid–Schiff (PAS) stain of glomerulus with thick capillary walls. (B) Jones methenamine silver (silver): basement membrane pits and spikes. (C) Electronic micrograph (EM): thickened glomerular basement membrane (GBM) ~1000 nm, subepithelial, intramembranous deposits (green arrows) and electron-lucent intramembranous spaces (purple arrows). Renal biopsy 2019. (D) Hematoxylin\nand eosin (H&E) stain thick glomerular capillaries with patchy mild to focally moderate infiltration by lymphocytes. (E) Phospholipase A2 receptor (PLA2R) stain is diffuse and granular with capillary distribution. (F) EM thickened GBM measuring >3000 nm (normal 230–430 nm). Electron-dense subepithelial deposits (green arrow). Diffuse podocyte effacement. Scale bar: 50 μm (A–E) and 1 μm (C, F).\n\nIn September 2018, he was diagnosed with malignant pleural mesothelioma (MPM) of the right hemithorax, biphasic with predominant sarcomatoid type. He was deemed not to be a candidate for surgery or combination chemotherapy due to poor performance status. Benefits of single-agent chemotherapy versus off-label use of nivolumab were discussed. After careful consideration, he proceeded with off-label nivolumab infusions (240 mg intravenous every 2 weeks), along with careful monitoring of his kidney function by his local nephrologist. Interval improvement in his cancer was seen on positron emission tomography/computed tomography (PET/CT) imaging. Shortly after starting nivolumab, his proteinuria began to increase. Additionally, he developed diabetic ketoacidosis and checkpoint inhibitor-induced type 1 diabetes with positive glutamic acid decarboxylase 65 (GAD65) antibody within 1 month of therapy (figure 2).\n\nFigure 2 Timeline of events: (A) 24-hour urine protein was <1 g/24 hours prior to during time of diagnosis and prior to nivolumab therapy. In November 2019, proteinuria peaked at 13.4 g/24 hours. (B) Serum albumin level nadired at 1.9 g/dL. (C) Serum creatinine peaked at 1.26 mg/dL. *Nivolumab 480 mg intravenous every month. †Rituximab 1 g intravenous administered on days 1 and 15. MDACC, University of Texas MD Anderson Cancer Center (MDACC); T1DM, type 1 diabetes mellitus.\n\nIn November 2019, the patient came to nephrology clinic at MDACC for a second opinion. Notable labs included a serum albumin of 1.9 g/dL, an elevated serum creatinine (Cr) 1.25 mg/dL (baseline Cr 0.82–0.91 mg/dL), urinalysis with trace glucose 150; protein>=500, negative bilirubin, ketones, blood, urobilinogen, nitrate, leucocyte esterase; white blood cells/high power field (HPF) : 1; red blood cells/HPF : 2; hyaline casts: 4 (high), and a 24-hour urine protein 13.4 g/day which had previously been <1.0 g/day prior to therapy with nivolumab (figure 2). Hepatitis serologies and review of secondary causes of MN were again unremarkable.\n\nDue to concern for reactivation of primary MN versus other CPI-nephritis etiologies, he underwent a kidney biopsy. Biopsy results suggested chronic reactivated primary MN. Light microscopy revealed thick glomerular capillaries (figure 1D) and immunofluorescence demonstrated capillary granular IgG and C3 deposits (not shown) and strongly positive PLA2R stain (figure 1E). Electron microscopy showed electron-lucent intramembranous spaces, subepithelial electron dense deposits, thickened GBM measuring >3000 nm (average adult 230–430 nm) and extensive podocyte foot process effacement (figure 1F). Due to concern for progressive decline in his kidney function, consideration of immunosuppressive treatment options was discussed with his primary oncologist. The patient was subsequently initiated on rituximab, a monoclonal chimeric antibody binding specifically to CD20 on B lymphocytes with hope that this would not affect any antitumor benefits attributable to T cell immunity. Nivolumab was held while two infusions of rituximab at 1 g were administered 14 days apart. Lab results 1 month after rituximab treatment showed an improved serum creatinine of 1.01 mg/dL, decrease in proteinuria by over 50% (4.6 g/day), and albumin level of 2.9 g/dL. Flow cytometry analysis of CD19+ B cell counts confirmed complete depletion and undetectable serum PLA2R level (baseline level unavailable). The patient continued to receive nivolumab and has since received five cycles of nivolumab following rituximab therapy with stable to improved kidney function (figure 2). PET/CT imaging continues to show complete metabolic response and no new sites of increased fluorodeoxyglucose activity suspicious for neoplasia (figure 3).\n\nFigure 3 (A) Positron emission tomography/computed tomography (PET/CT) (left) demonstrates hypermetabolic lesion in the pleura of the right anterior rib space (red arrow). Maximum intensity projection (MIP, right) with multifocal lesions (blue arrow). (B) Follow-up PET/CT (left) and MIP (right) with complete metabolic response.\n\nDiscussion\nAs the clinical indications for immune checkpoint inhibitors has increased in recent years, a greater understanding of the pathogenesis and treatment of those with pre-existing autoimmune disease and cancer represents a major challenge. We report the first case of CPI-associated reactivation of primary MN in a patient receiving anti-PD1 therapy responsive to rituximab.\n\nThe pathophysiology of CPI-associated irAEs is not completely understood. CPI increases antitumor immunity by blocking intrinsic down-regulators of immunity. This can lead to the activation of autoreactive T cells, subsequent production of proinflammatory cytokines, and an autoimmune humoral response.5 Current literature suggests that over one-third of patients with pre-existing rheumatic or autoimmune disease have experienced flares of their prior disorder in association with treatment using immune CPIs for malignancy.6 7 Disease flares were more commonly reported with anti–PD-1/PD-L1 agents than with CTLA-4 blockade (62% vs 36%), whereas de novo irAEs were more common among patients treated with CTLA-4 blockade (42% vs 26%).6 Those with adverse events were more likely to have a partial or complete tumorous response, compared with those who did not have adverse events.6 While there appears to be a correlative relationship between development of irAEs and efficacy of treatment, further prospective studies are needed to define the causal relationship and how it will impact clinical decision-making.\n\nMost reports of CPI-associated reactivation of autoimmune disease describe patients with rheumatological features. To our knowledge, this is the first case of reactivated autoimmune MN following CPI therapy responsive to rituximab. MN is the most common cause of non-diabetic nephrotic syndrome in adults. The term membranous nephropathy reflects the histologic changes noted on light microscopy, specifically GBM thickening. Primary or idiopathic MN account for most MN cases and are accompanied by the appearance of autoantibodies to PLA2R (70%–80% of primary MN), and a much smaller fraction (3%–5%) with autoantibodies to thrombospondin type 1 domain containing 7A protein (THSD7A). PLA2R and THSD7A are expressed on glomerular podocytes.1 8 While secondary MN is associated with hepatitis B or C, malignancy, and certain drugs (eg, non-steroidal anti-inflammatory, gold, captopril, penicillamine) accounts for 20%–25% of adult cases. Current research suggests that anti-PLA2R can be used to differentiate primary MN from secondary or paraneoplastic associated MN,9 but cases of malignancies have been reported in those with positive PLA2R status.10 11 To date, all reported cases of malignant pleural mesothelioma and MN have been PLA2R negative or unknown.12–14 In general, positive immunohistochemical stain for PLA2R confirms the diagnosis of primary MN; in lieu of biopsy positive serological PLA2R levels can also be used, and if detectable, serve as a surrogate to monitor immunologic activity and disease course.15 Serologic response frequently precedes the decline in proteinuria due to delay in functional recovery of the glomerular filtration barrier and podocyte remodeling from the immunologic damage.\n\nNivolumab-associated reactivation of primary MN was strongly suspected in our patient, but usage of CPIs can also be associated with other immune-mediated kidney diseases. These renal pathologies are varied. In addition to acute tubulointerstitial nephritis, other manifestations include lupus nephropathy, thrombotic microangiopathy, focal segmental glomerulosclerosis, minimal-change disease, secondary or PLA2R negative MN, pauci-immune glomerulonephritis, IgA nephropathy, C3 glomerulopathy, and AA amyloidosis.2\n16 Thus, renal biopsy for definitive diagnosis was imperative to determine etiology and treatment for our patient.\n\nMPM is a rare and often fatal cancer. Those with the sarcomatoid and biphasic histologic subtypes have more aggressive disease.17 Our patient experienced a durable response with nivolumab therapy suggesting that activated T lymphocytes were successfully targeting cancer cells. Unfortunately, this treatment led to the development of Type 1 diabetes and likely reactivated his underlying autoimmune disease. Based on his clinical and immunologic profile including: worsening performance status, severe lower extremity edema, progressive decline in kidney function from active MN, severe nephrotic syndrome (total urine protein >13 g/day and serum albumin <1.9 g/dL), positive PLA2R status, and continued immune activation from CPI therapy, our patient was considered high to very high risk for progressive functional kidney decline.\n\nCurrent treatment guidelines for MN recommend immunosuppressive therapy with cyclophosphamide and steroids, rituximab, or cyclosporine. Of these options, all except for rituximab directly or indirectly suppress T cell function potentially impacting the antitumor effectiveness of CPI therapy. Cyclophosphamide, an alkylating agent, non-discriminatorily crosslinks DNA resulting in absolute lymphopenia in both T and B cells and is associated with increase cancer risk. Cyclosporine, a calcineurin inhibitor, blocks transcription of interleukin 2, suppressing T cell activation and, while it is effective in treating proteinuria, has a high rate of relapse following discontinuation of therapy.18 Due to its specificity in targeting B-lymphocytes, rituximab seemingly provided the best option to treat our patient’s antibody-mediated glomerular disease without directly affecting his cancer therapy. In situations where T cell sparing agents may not be an option, then competing risks must be considered in managing patients with declining kidney function and treatment of cancer. Fortunately, our patient responded to rituximab with improved kidney function and has continued to receive nivolumab with stable kidney function.\n\nSince B cells likely contribute to CPI-induced reactivation or de novo autoimmune irAEs,19 treatment with rituximab has been successful in several cases of CPI-induced irAEs. Majority of these diseases had pre-existing indications or off-label use for rituximab such as bullous pemphigold,20 idiopathic thrombocytopenic purpura,21 Sjogren’s syndrome,22 pauci-immune glomerulonephritis,2 and granulomatous necrotizing vasculitis.2 Use of rituximab for CPI-related renal vasculitis was further demonstrated by Mamlouk et al. – all cases achieved partial or complete renal recovery following rituximab treatment.23 This could suggest that while CPIs may trigger the irAE(s), the underlying B cell pathophysiology of the disease remains unchanged.\n\nFinally, the role of B cells in cancer prognosis and immune checkpoint therapy is unknown in MPM. In other cancers such as melanoma, the role of B cells in melanoma progression is controversial, as both protumor and antitumor B cell functions have been reported.24 Studies of other solid tumors have identified various B cell subsets as critical protumorous mediators of malignancy,25 if so, these findings would support B cell depletion or Bruton’s tyrosine kinase inhibition along with checkpoint inhibition as an appealing strategy.26 In general, B cell infiltration in mesothelioma is sparse, although a subgroup with higher numbers of B cells is described.27 In mesothelioma epithelioid type, B cell infiltration has been associated with better patient survival,28 but this association is not known in the biphasic sarcomatoid type. Understanding the role of B cells in specific cancer progression could be beneficial for those with pre-existing autoimmune disease and cancer diagnosis, allowing for either complementary or split treatment should irAEs occur. The clinical application of B cell monitoring could lead to earlier irAE intervention, reduced irAE severity, and direct treatment strategy and/or predict clinical outcomes. More research is needed for determining these clinical applications.\n\nIn conclusion, we have shown that rituximab was effective in treating CPI-associated reactivation of primary MN. The patient was successfully re-challenged with nivolumab and maintained stable kidney function and sustained clinical anti-tumor effect. Exacerbation of pre-existing autoimmune diseases from immune checkpoint blockade is common, and therapy for autoimmune reactivation should be rationally directed by an understanding of the immunosuppressive mechanism in concert with goals of cancer treatment.\n\nWe thank the patient and his family for providing permission to report adverse events and for their participation and contribution to research.\n\nTwitter: @JamieLinMD, @tcellsrus\n\nContributors: Data acquisition was performed by JSL, DYW, and AA. WFG performed the histological examination of the kidney biopsies and contributed in writing the pathology section of the manuscript. The manuscript was prepared by JSL and edited by DYW, OM, WFG, MA, CY, and AA. All the authors contributed to the quality control data, analysis, interpretation of data and writing and final proof of paper. All authors read and approved the final manuscript.\n\nFunding: The University of Texas MD Anderson Cancer Center is supported in part by the National Institutes of Health through Cancer Center Support Grant P30CA016672. JSL is supported by National Institutes of Health (K08 DK119466). CY is member of Parker Institute of Cancer Immunotherapy.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Obtained.\n\nEthics approval: This study was approved by the institutional review board in accordance with the principles of the Declaration of Helsinki.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Beck LH , Bonegio RGB , Lambeau G , et al \nM-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy\n. N Engl J Med \n2009 ;361 :11 –21\n. 10.1056/NEJMoa0810457 19571279 \n2 Mamlouk O , Selamet U , Machado S , et al \nNephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience\n. j. immunotherapy cancer \n2019 ;7 :2 .\n3 Lefaucheur C , Stengel B , Nochy D , et al \nMembranous nephropathy and cancer: epidemiologic evidence and determinants of high-risk cancer association\n. Kidney Int \n2006 ;70 :1510 –7\n.16941021 \n4 Plaisier E , Ronco P \nScreening for cancer in patients with glomerular diseases\n. Clin J Am Soc Nephrol \n2020 ;15 :886 –8\n.32019761 \n5 Tahir SA , Gao J , Miura Y , et al \nAutoimmune antibodies correlate with immune checkpoint therapy-induced toxicities\n. Proc Natl Acad Sci U S A \n2019 ;116 :22246 –51\n. 10.1073/pnas.1908079116 31611368 \n6 Abdel-Wahab N , Shah M , Lopez-Olivo MA , et al \nUse of immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoimmune disease: a systematic review\n. Ann Intern Med \n2018 ;168 :121 –30\n. 10.7326/M17-2073 29297009 \n7 Johnson DB , Beckermann KE , Wang DY \nImmune checkpoint inhibitor therapy in patients with autoimmune disease\n. Oncology \n2018 ;32 :190 –4\n.29684232 \n8 Tomas NM , Beck LH , Meyer-Schwesinger C , et al \nThrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy\n. N Engl J Med \n2014 ;371 :2277 –87\n. 10.1056/NEJMoa1409354 25394321 \n9 Timmermans SAMEG , Ayalon R , van Paassen P , et al \nAnti-phospholipase A2 receptor antibodies and malignancy in membranous nephropathy\n. Am J Kidney Dis \n2013 ;62 :1223 –5\n. 10.1053/j.ajkd.2013.07.019 24021909 \n10 Bjørneklett R , Vikse BE , Svarstad E , et al \nLong-term risk of cancer in membranous nephropathy patients\n. Am J Kidney Dis \n2007 ;50 :396 –403\n. 10.1053/j.ajkd.2007.06.003 17720518 \n11 Kim Y \nRelapse of membranous nephropathy with cancer immunotherapy\n. Clin Kidney J \n2019 ;33 \n10.1093/ckj/sfz074 \n12 Sakamoto K , Suzuki H , Jojima T \nMembranous glomerulonephritis associated with diffuse malignant pleural mesothelioma: report of a case\n. Surg Today \n2000 ;30 :1124 –6\n. 10.1007/s005950070014 11193748 \n13 Pu X , Dou Y , Liu D , et al \nMembranous nephropathy associated with malignant pleural mesothelioma in an adult patient: a case report\n. Mol Clin Oncol \n2016 ;5 :407 –10\n. 10.3892/mco.2016.976 27699035 \n14 Galesic K , Bozic B , Heinzl R , et al \nPleural mesothelioma and membranous nephropathy\n. Nephron \n2000 ;84 :71 –4\n. 10.1159/000045541 10644911 \n15 Hofstra JM , Beck LH , Beck DM , et al \nAnti-phospholipase A₂ receptor antibodies correlate with clinical status in idiopathic membranous nephropathy\n. Clin J Am Soc Nephrol \n2011 ;6 :1286 –91\n. 10.2215/CJN.07210810 21474589 \n16 Cortazar FB , Marrone KA , Troxell ML , et al \nClinicopathological features of acute kidney injury associated with immune checkpoint inhibitors\n. Kidney Int \n2016 ;90 :638 –47\n. 10.1016/j.kint.2016.04.008 27282937 \n17 Tsao AS , Wistuba I , Roth JA , et al \nMalignant pleural mesothelioma\n. J Clin Oncol \n2009 ;27 :2081 –90\n. 10.1200/JCO.2008.19.8523 19255316 \n18 Fervenza FC , Appel GB , Barbour SJ , et al \nRituximab or cyclosporine in the treatment of membranous nephropathy\n. N Engl J Med \n2019 ;381 :36 –46\n. 10.1056/NEJMoa1814427 31269364 \n19 Das R , Bar N , Ferreira M , et al \nEarly B cell changes predict autoimmunity following combination immune checkpoint blockade\n. J Clin Invest \n2018 ;128 :715 –20\n. 10.1172/JCI96798 29309048 \n20 Sowerby L , Dewan AK , Granter S , et al \nRituximab treatment of Nivolumab-Induced bullous pemphigoid\n. JAMA Dermatol \n2017 ;153 :603 –5\n. 10.1001/jamadermatol.2017.0091 28355425 \n21 Shiuan E , Beckermann KE , Ozgun A , et al \nThrombocytopenia in patients with melanoma receiving immune checkpoint inhibitor therapy\n. J Immunother Cancer \n2017 ;5 :8 . 10.1186/s40425-017-0210-0 28239462 \n22 Ghosn J , Vicino A , Michielin O , et al \nA severe case of neuro-Sjögren's syndrome induced by pembrolizumab\n. J Immunother Cancer \n2018 ;6 :110 . 10.1186/s40425-018-0429-4 30348223 \n23 Mamlouk O , Lin JS , Abdelrahim M , et al \nCheckpoint inhibitor-related renal vasculitis and use of rituximab\n. Journal for ImmunoTherapy of Cancer \n2020 ;8 :e000750 .32718987 \n24 Griss J , Bauer W , Wagner C , et al \nB cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma\n. Nat Commun \n2019 ;10 :4186. 10.1038/s41467-019-12160-2 31519915 \n25 Petitprez F , de Reyniès A , Keung EZ , et al \nB cells are associated with survival and immunotherapy response in sarcoma\n. Nature \n2020 ;577 :556 –60\n. 10.1038/s41586-019-1906-8 31942077 \n26 Somasundaram R , Zhang G , Fukunaga-Kalabis M , et al \nTumor-associated B-cells induce tumor heterogeneity and therapy resistance\n. Nat Commun \n2017 ;8 :607. 10.1038/s41467-017-00452-4 28928360 \n27 Minnema-Luiting J , Vroman H , Aerts J , et al \nHeterogeneity in immune cell content in malignant pleural mesothelioma\n. Int J Mol Sci \n2018 ;19 . 10.3390/ijms19041041 . [Epub ahead of print: 30 Mar 2018].\n28 Chee SJ , Lopez M , Mellows T , et al \nEvaluating the effect of immune cells on the outcome of patients with mesothelioma\n. Br J Cancer \n2017 ;117 :1341 –8\n. 10.1038/bjc.2017.269 28817839\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2051-1426",
"issue": "8(2)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "autoimmunity; case reports; immunotherapy",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D015433:Glomerulonephritis, Membranous; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D000069283:Rituximab",
"nlm_unique_id": "101620585",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33020246",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "28817839;16941021;31611368;17720518;29297009;28928360;27282937;30612580;21474589;25394321;19255316;19571279;31519915;30348223;31942077;29601534;29684232;31269364;27699035;24021909;32019761;10644911;32718987;29309048;28239462;11193748;28355425",
"title": "Immune checkpoint inhibitor associated reactivation of primary membranous nephropathy responsive to rituximab.",
"title_normalized": "immune checkpoint inhibitor associated reactivation of primary membranous nephropathy responsive to rituximab"
} | [
{
"companynumb": "US-TEVA-2020-US-1851342",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nTo compare zofenopril + hydrochlorothiazide (Z + H) vs. irbesartan + hydrochlorothiazide (I + H) efficacy on daytime SBP in elderly (>65 years) patients with isolated systolic hypertension (ISH), untreated or uncontrolled by a previous monotherapy.\n\n\nMETHODS\nAfter a 1-week run-in, 230 ISH patients (office SBP ≥ 140 mmHg and DBP < 90 mmHg + daytime SBP ≥ 135 mmHg and daytime DBP < 85 mmHg) were randomized double-blind to 18-week treatment with Z + H (30 + 12.5 mg) or I + H (150 + 12.5 mg) once daily, in an international, multicenter study. Z and I doses could be doubled after 6 and 12 weeks, and nitrendipine 20 mg added at 12 weeks in nonnormalized patients.\n\n\nRESULTS\nIn the full analysis set (n = 216) baseline-adjusted average (95% confidence interval) daytime SBP reductions after 6 weeks (primary study end point) were similar (P = 0.888) with Z + H [7.7 (10.7, 4.6) mmHg, n = 107] and I + H [7.9 (10.7, 5.0) mmHg, n = 109]. Daytime SBP reductions were sustained during the study, and larger (P = 0.028) with low-dose Z + H at study end [16.2 (20.0, 12.5) mmHg vs. 11.2 (14.4, 7.9) mmHg I + H]. Daytime SBP normalization (<135 mmHg) rate was similar under Z + H and I + H at 6 and 12 weeks, but more common under Z + H at 18 weeks (68.2 vs. 56.0%, P = 0.031). Both drugs equally reduced SBP in the last 6 h of the dosing interval and homogeneously reduced SBP throughout the 24 h. The proportion of patients reporting drug-related adverse events was low (Z + H: 4.4% vs. I + H: 6.0%; P = 0.574).\n\n\nCONCLUSIONS\nElderly patients with ISH respond well to both low and high-dose Z or I combined with H.",
"affiliations": "aDepartment of Clinical and Experimental Medicine, Careggi Hospital, University of Florence, Florence bItalian Institute of Telemedicine, Varese cThe ZEUS Study Group, Italy dThe ZEUS Study Group, Romania.",
"authors": "Modesti|Pietro A|PA|;Omboni|Stefano|S|;Taddei|Stefano|S|;Ghione|Sergio|S|;Portaluppi|Francesco|F|;Pozzilli|Paolo|P|;Volpe|Massimo|M|;Arca|Marcello|M|;Calabrò|Paolo|P|;Fulgheri|Paolo L Dessì|PL|;Bucci|Marco|M|;Berra|Sergio|S|;Villani|Giovanni Q|GQ|;Vladoianu|Mircea|M|;Popescu|Elena|E|;Velican|Valerica G|VG|;Pirvu|Octavian|O|",
"chemical_list": "D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D013777:Tetrazoles; D006852:Hydrochlorothiazide; C044958:zofenopril; D002216:Captopril; D000077405:Irbesartan",
"country": "England",
"delete": false,
"doi": "10.1097/HJH.0000000000000805",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0263-6352",
"issue": "34(3)",
"journal": "Journal of hypertension",
"keywords": null,
"medline_ta": "J Hypertens",
"mesh_terms": "D000368:Aged; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D001794:Blood Pressure; D018660:Blood Pressure Monitoring, Ambulatory; D002216:Captopril; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide; D006973:Hypertension; D000077405:Irbesartan; D008297:Male; D013599:Systole; D013777:Tetrazoles; D016896:Treatment Outcome; D059289:Vascular Stiffness",
"nlm_unique_id": "8306882",
"other_id": null,
"pages": "576-87; discussion 587",
"pmc": null,
"pmid": "26703917",
"pubdate": "2016-03",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Zofenopril or irbesartan plus hydrochlorothiazide in elderly patients with isolated systolic hypertension untreated or uncontrolled by previous treatment: a double-blind, randomized study.",
"title_normalized": "zofenopril or irbesartan plus hydrochlorothiazide in elderly patients with isolated systolic hypertension untreated or uncontrolled by previous treatment a double blind randomized study"
} | [
{
"companynumb": "IT-CIPLA LTD.-2016IT00033",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE\\IRBESARTAN"
},
"drugaddi... |
{
"abstract": "In this phase I/II study, we explored the combination of Temsirolimus with Bendamustine and Rituximab (BeRT) in patients with r/r follicular lymphoma (FL) or mantle cell lymphoma (MCL). Patients with 1-3 prior therapies received Bendamustine (90 mg/m(2), day 1+2) and Rituximab (375 mg/m(2), day 1) with Temsirolimus in doses from 25 to 75 mg added on day 1, 8, 15 of a 28-day cycle. Fifteen (11 MCL, 4 FL) patients were included in the phase I. Median age was 73 years and median pretreatment number was 2. No formal dose-limiting toxicity was observed. Dominant non-hematological side effects were fatigue in 11 (73%), nausea in 9 (60%), mucositis in 7 (47%) and vomiting in 6 patients (40%). Cough, diarrhea, pyrexia and rash were observed in five patients (33%) each. Grade 3/4 events included leukopenia in 6 (40%), neutropenia in 4 (27%) and thrombocytopenia in 2 patients (13%). An objective response was observed in 14/15 patients (93%), including 5 complete response (33%; all MCL). After a median follow-up of 19 months, 67% of patients are without signs of progression. Temsirolimus can be safely added to BR with promising preliminary activity. Recruitment in phase II is ongoing.",
"affiliations": "Department of Internal Medicine III (Hematology, Oncology, Pneumology), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.;III. Medical Department, Technical University Munich, Munich, Germany.;Department of Hematology, Oncology, Charité - University Medical School Berlin, Berlin, Germany.;Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.;Department of Internal Medicine II, Center of Internal Medicine, Johann Wolfgang Goethe-University, Frankfurt, Germany.;Institute of Experimental Cancer Research and Department of Internal Medicine III, University Hospital, Ulm, Germany.;Department of Internal Medicine III (Hematology, Oncology, Pneumology), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.;Interdisciplinary Centre for Clinical Trials (IZKS), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.;Interdisciplinary Centre for Clinical Trials (IZKS), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.;Department of Internal Medicine III (Hematology, Oncology, Pneumology), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.;Division of Hematophathology, Christian-Albrechts-University, Kiel, Germany.;Department of Internal Medicine III (Hematology, Oncology, Pneumology), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.;Department of Internal Medicine III, Ludwig-Maximilians-University, Munich, Germany.",
"authors": "Hess|G|G|0000000292825688;Keller|U|U|;Scholz|C W|CW|;Witzens-Harig|M|M|;Atta|J|J|;Buske|C|C|;Kirschey|S|S|;Ruckes|C|C|;Medler|C|C|;van Oordt|C|C|;Klapper|W|W|;Theobald|M|M|;Dreyling|M|M|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D009588:Nitrogen Mustard Compounds; D000069283:Rituximab; C401859:temsirolimus; D000069461:Bendamustine Hydrochloride; D020123:Sirolimus",
"country": "England",
"delete": false,
"doi": "10.1038/leu.2015.60",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "29(8)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069461:Bendamustine Hydrochloride; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008224:Lymphoma, Follicular; D020522:Lymphoma, Mantle-Cell; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009588:Nitrogen Mustard Compounds; D011379:Prognosis; D011446:Prospective Studies; D012074:Remission Induction; D000069283:Rituximab; D012449:Safety; D020123:Sirolimus; D015996:Survival Rate",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "1695-701",
"pmc": null,
"pmid": "25765545",
"pubdate": "2015-08",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "18241520;23782157;19581539;23401442;17242396;21239695;24450858;22873532;21486866;22058200;20828385;18543327;18626004;21082954;19261329;21804550;15668467;15983389;24615778;23045577;21440503;22677155;17148679;16019483;15908650;20387065;21228334;23545991;20837940;24122387;22349722;17020981;25057177;23433739;11807147;17001068;22315486;17613757",
"title": "Safety and efficacy of Temsirolimus in combination with Bendamustine and Rituximab in relapsed mantle cell and follicular lymphoma.",
"title_normalized": "safety and efficacy of temsirolimus in combination with bendamustine and rituximab in relapsed mantle cell and follicular lymphoma"
} | [
{
"companynumb": "DE-PFIZER INC-DE-WYE-G06596510",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BISOPROLOL FUMARATE"
},
"drugadditional... |
{
"abstract": "Magnusiomyces capitatus (previously known as Geotrichum capitatum or Blastoschizomyces capitatus or Trichosporon capitatum) is a rare cause of fungal infection in immunocompromised patients. Most of these cases (87%) have been reported from the Mediterranean region, as it is extremely rare to recognize it in other regions. Here we report a first case of disseminated M. capitatus infection in Slovakia. The patient - 19 year old woman with myelodysplastic syndrome was diagnosed with M. capitatus fungemia after allogeneic stem cell transplantation. The infection occurred despite antifungal prophylaxis with micafungin, which was in vitro sensitive to the yeast. The treatment according to minimal inhibitory concentrations (micafungin, voriconazol) and granulocyte transfusions were administered. M. capitatus was cleared out from the bloodstream. However, patient died of multiple organ failure. Autopsy showed multiple lesions in organs, but did not prove presence of yeast by histopathology. M. capitatus was confirmed by polymerase chain reaction from all tested organs: heart, brain, lungs, spleen, liver and kidneys. We present the post mortem pictures showing the yeast lesions in affected organs. 2012 Elsevier Ltd. All rights reserved.",
"affiliations": "Department of Paediatric Haematology and Oncology, Comenius University Children's Hospital, Bratislava, Slovakia.;Department of Paediatric Haematology and Oncology, Comenius University Children's Hospital, Bratislava, Slovakia.;Department of Paediatric Haematology and Oncology, Comenius University Children's Hospital, Bratislava, Slovakia.;Department of Paediatric Haematology and Oncology, Comenius University Children's Hospital, Bratislava, Slovakia.;Department of Internal Medicine - Hematology and Oncology, University Hospital Brno, Brno, Czechia.;Department of Internal Medicine - Hematology and Oncology, University Hospital Brno, Brno, Czechia.;Department of Mycology, HPL Ltd. a Member of Medirex Group, Bratislava, Slovakia.;Department of Paediatric Anesthesiology, Comenius University Children's Hospital, Bratislava, Slovakia.;Department of Paediatric Haematology and Oncology, Comenius University Children's Hospital, Bratislava, Slovakia.",
"authors": "Tanuskova|Dominika|D|;Horakova|Julia|J|;Svec|Peter|P|;Bodova|Ivana|I|;Lengerova|Martina|M|;Bezdicek|Matej|M|;Poczova|Miroslava|M|;Koppl|Jozef|J|;Kolenova|Alexandra|A|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.mmcr.2017.03.004",
"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(17)30011-810.1016/j.mmcr.2017.03.004Case ReportFirst case of invasive Magnusiomyces capitatus infection in Slovakia Tanuskova Dominika donissima@gmail.coma⁎Horakova Julia aSvec Peter aBodova Ivana aLengerova Martina bBezdicek Matej bPoczova Miroslava cKoppl Jozef dKolenova Alexandra aa Department of Paediatric Haematology and Oncology, Comenius University Children's Hospital, Bratislava, Slovakiab Department of Internal Medicine – Hematology and Oncology, University Hospital Brno, Brno, Czechiac Department of Mycology, HPL Ltd. a Member of Medirex Group, Bratislava, Slovakiad Department of Paediatric Anesthesiology, Comenius University Children's Hospital, Bratislava, Slovakia⁎ Corresponding author. donissima@gmail.com31 3 2017 6 2017 31 3 2017 16 12 15 18 1 2017 22 3 2017 28 3 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Magnusiomyces capitatus (previously known as Geotrichum capitatum or Blastoschizomyces capitatus or Trichosporon capitatum) is a rare cause of fungal infection in immunocompromised patients. Most of these cases (87%) have been reported from the Mediterranean region, as it is extremely rare to recognize it in other regions. Here we report a first case of disseminated M. capitatus infection in Slovakia. The patient – 19 year old woman with myelodysplastic syndrome was diagnosed with M. capitatus fungemia after allogeneic stem cell transplantation. The infection occurred despite antifungal prophylaxis with micafungin, which was in vitro sensitive to the yeast. The treatment according to minimal inhibitory concentrations (micafungin, voriconazol) and granulocyte transfusions were administered. M. capitatus was cleared out from the bloodstream. However, patient died of multiple organ failure. Autopsy showed multiple lesions in organs, but did not prove presence of yeast by histopathology. M. capitatus was confirmed by polymerase chain reaction from all tested organs: heart, brain, lungs, spleen, liver and kidneys. We present the post mortem pictures showing the yeast lesions in affected organs. 2012 Elsevier Ltd. All rights reserved.\n\nKeywords\nBlastoschizomycesGeotrichumMagnusiomycesStem cell transplantation\n==== Body\n1 Introduction\nMagnusiomyces capitatus is a rare cause of fungal infection in immunocompromised patients, occurring almost exclusively in the Mediterranean region, with only a few case reports from outside this region. This paper presents the first case of disseminated M. capitatus infection in Slovakia. We present the post mortem pictures showing the lesions in affected organ, in which M. capitatus was confirmed by polymerase chain reaction (PCR).\n\n2 Case\nA 19-year old woman with refractory cytopenia type of myelodysplastic syndrome (RCC/MDS) was admitted to our unit for planned allogeneic stem cell transplantation. Multiresistant Pseudomonas aeruginosa from stool and rectum and Candida glabrata from vulva were found in routinely performed pretransplant swabs, however the patient had no signs of infection. Peripheral blood stem cell transplantation from a 9/10 HLA- matched unrelated donor was performed (D 0) following the conditioning consisting of Fludarabine (4×40 mg/m2) and Thiotepa (3×5 mg/kg). Anti-thymocyte globulin (3×15 mg/kg), cyclosporine A and methotrexate (10 mg/m2) were used for T cell depletion and graft-versus-host disease (GvHD) prophylaxis. Micafungin (1 mg/kg/daily) was used for antifungal prophylaxis. On D −2 the patient became febrile and on D +3 a yeast - M. capitatus was identified in blood cultures from central venous catheter (CVC). This yeast was found in several consecutive blood cultures. From D+8 multiresistant, yet sensitive to colimycine P. aeruginosa was identified in blood cultures from CVC and from peripheral blood as well (being colonized with the bacteria – the swab from rectum and stool). At this point the patient had suffered from agranulosis for 4 months for what we know. In-vitro susceptibility testing of M. capitatus showed sensitivity to azoles, amphotericin B and micafungin (Table 1) and combined micafungin (2 mg/kg) and voriconazole (1.day 6 mg/kg, then 4 mg/kg) treatment began. The sensitivity was valued according to CLSI breakpoints for Candida spp., there are none specifically set for this pathogen. Lung high resolution computed tomography (HRCT) showed inflammatory infiltrates in the both lungs with fluidothorax. Treatment with granulocytes infusions began on D+10. Patient's condition started to deteriorate, respiratory failure occurred and she was febrile despite the targeted antifungal and antibacterial treatment. On D+12 the patient was transferred to paediatric intensive care unit (PICU) due to required mechanical ventilation (MV). The deteriorating condition continued with renal failure, and the patient received haemodialysis starting on D+14. Leukocytes engraftment occurred on D+17, with complete donor chimerism in peripheral blood. The molecular adsorbents recirculating system (MARS) was required for liver failure from D+19. The first negative blood culture for P. aeuroginosa was recorded on D+18, for M. capitatus the first negative blood culture was found on D+19. Nevertheless, P. aeruginosa was still found in swabs from rectum and throat and M. capitatus in the urine and in the swabs from nose and from tongue (D+26). On D+38 computed tomography of brain, lungs and abdomen showed multiple areas of hypodensity in following organs: brain, liver, spleen, kidneys, and lungs (Picture 1). These were the assumed infectious emboli of the yeast, however the unstable and critical condition of the patient made it impossible to perform biopsy. The patient suffered another complications – left thoracoscopic revision due to fluidothorax and haemothorax (D+33), which was complicated with haemorrhagic shock after the thoracoscopy, left thoracotomy with haematoma evacuation and drainage (D+40), diffuse bleeding from the gastrointestinal tract. Cultivations of pleural effusions (D+33) and from bronchoalveolar lavage specimen (D+53) were both tested negative for bacterial and mycotic agents as well. The patient died D+71 of multiple organ failure. The autopsy showed multiple lesions in heart, brain, lungs, spleen, liver and kidneys (Picture 2, Picture 3, Picture 4, Picture 5, Picture 6, Picture 7), but did not prove any mycotic infection in the morphological picture. Autopsy samples were tested with two different panfungal PCR methods [1], [2].Picture 1 Lungs CT scan with multiple areas of hypodensities.\n\nPicture 1Picture 2 Lungs.\n\nPicture 2Picture 3 Heart.\n\nPicture 3Picture 4 Heart.\n\nPicture 4Picture 5 Kidneys.\n\nPicture 5Picture 6 Liver.\n\nPicture 6Picture 7 Brain.\n\nPicture 7Table 1 Minimum inhibitory concentrations (MIC) of the Magnusiomyces capitatum isolate as reported by Department of mycology, HPL Ltd. a Member of Medirex Group, Bratislava, Slovakia Bratislava, Slovakia.\n\nTable 1.Antifungal agent\tMIC (μg/mL)\t\nFluconazole\tC 6.0\t\nItraconazole\tC 0.125\t\nVoriconazole\tC 0.094\t\nPosaconazole\tC 0.75\t\nAmphotericin\tC 0.38\t\nCaspofungin\tR 32\t\nAnidulafungin\tR 32\t\nMicafungin\tC 0.003\t\n\n\nRegarding the tissue samples neither of our methods was positive despite our expectations. Consequently, we designed a novel specific PCR (Table 2) for detection of Saprochaete capitata and S. clavata followed by species identification based on sequencing. After PCR products sequencing we confirmed M. capitatus (Anamorph S. capitata) as an aetiological agent of disseminated invasive fungal infections in all affected tissues. On the contrary, culture samples (cultivated from blood) were positive by all used methods. In our opinion this was caused by significantly different loads of fungal DNA in tissue samples and culture samples. High amount of DNA in a sample can lead to a positive amplification despite a few mismatches between primers and targeted DNA sequences.Table 2 Primers for Saprochaete specific PCR.\n\nTable 2.Primer\tSequence (5´→ 3´)\t\nSCMC-1\tCAATTCTTGAACGCACATGG\t\nSCMC-R\tGCGGGTAGTCTTGCTTGATA\t\n\n\n3 Discussion\nMagnusiomyces capitatus (previously known as Geotrichum capitatum or Blastoschizomyces capitatus or Trichosporon capitatum) and its anamorph Saprochaete capitata\n[3], is a rare cause of disseminated disease [4]. M. capitatus can be isolated from the environment and may be a constituent of the microflora of the skin and the mucosa of the respiratory and digestive tracts [5]. It is an opportunistic mycotic pathogen and can cause an infection, especially in neutropenic haemato-oncology patients, typically in the Mediterranean region- Italy, Spain, and France report 87% of the cases in Europe [4], [6]. However, the case reports have been recently published from other countries, that are not typical for this infection - Kuwait, Switzerland, Nepal [7], [8], [9]. To our knowledge, this is the first case of M. capitatus infection in Slovakia. The reason why this infection has been found in such atypical regions has not been recognised [10], [11].\n\nThe clinical presentation is similar to the other fungi, usually persistent fever despite antibacterial treatment. The yeast causes fungemia, but deep organs can be involved as well - the lungs, kidneys, liver, spleen, brain and endocardium [4], which was proved in our case as well.\n\nTreatment should be started as soon as possible. There are not enough clinical data to assess the optimal treatment for M. capitatus in haematology patients. However, based on in vitro susceptibility and the limited clinical data available, any amphotericin B formulation with or without flucytosine can be recommended [12], [13]. Similarly, voriconazole can be used as well, alone or in combination [8]. M. capitatus is considered intrinsically resistant to echinocandins [14], in our case the yeast was resistent to anidalufungin and caspofungin, however sensitive to micafungin that had been administered to the patient at the time of the appearance of infection. This finding suggests that in vitro and in vivo activity of antifungals may differ. There are several publications on cases of infections in patients receiving echinocandins (caspofungin and micafungin) [7], [15], [16]. The removal of central venous catheter also seems to be an important aspect of treatment, as removal was shown as a prognostic indicator for success in one study [6]. Other adjuvant therapies to improve the phagocytic activity such as colony-stimulating factors, granulocyte transfusions and interferon-γ have been combined with antifungal drugs with some success [17], [18], [19].\n\nThe outcome of invasive disease caused by M. capitatus depends mainly on patient immunity. In patients with profound neutropenia, mortality is greater than 90% and survival has largely coincided with the recovery of the neutrophil count [5]. Despite the targeted combined antimycotic treatment and administration of granulocyte transfusions until the engraftment, the infection disseminated and was fatal in our case.\n\nConflict of interest\nThere are none.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 Bezdicek M. Lengerova M. Ricna D. Weinbergerova B. Kocmanova I. Volfova P. Drgona L. Poczova M. Mayer J. Racil Z. Rapid detection of fungal pathogens in bronchoalveolar lavage samples using panfungal PCR combined with high resolution melting analysis Med. Mycol. 54 2016 714 724 27161789 \n2 Ferrer C. Colom F. Frasés S. Mulet E. Abad J.L. Alió J.L. Detection and identification of fungal pathogens by PCR and by ITS2 and 5.8S ribosomal DNA typing in ocular infections J. Clin. Microbiol. 39 2001 2873 2879 11474006 \n3 Sybren De Hoog G. Smith M.T. Ribosomal gene phylogeny and species delimitation in Geotrichum and its teleomorphs Stud. Mycol. 50 2004 489 515 \n4 Girmenia C. Pagano L. Martino B. D’Antonio D. Fanci R. Specchia G. Melillo L. Buelli M. Pizzarelli G. Venditti M. Martino P. GIMEMA infection program, invasive infections caused by trichosporon species and geotrichum capitatum in patients with hematological malignancies: a retrospective multicenter study from Italy and review of the literature J. Clin. Microbiol. 43 2005 1818 1828 15815003 \n5 Bouza E. Muñoz P. Invasive infections caused by Blastoschizomyces capitatus and Scedosporium spp Clin. Microbiol. Infect. 10 2004 76 85 14748804 \n6 Martino R. Salavert M. Parody R. Tomas J.F. de la Camara R. Vazquez L. Jarque I. Prieto E. Sastre J.L. Gadea I. Peman J. Sierra J. Blastoschizomyces capitatus infection in patients with leukemia: report of 26 cases Clin. Infect. Dis. 38 2004 335 341 14727202 \n7 P. Purohit, I. Al-Obaid, E. Al-Oneizi, O. Al-Hindi, L. Joseph, S. Ahmad, Z. Khan, C.Z. Khan, Breakthrough disseminated Saprochaete capitata infection in a child with acute myeloid leukaemia receiving caspofungin therapy, (n.d.). 〈http://dx.doi.org/10.1099/jmmcr.0.001750〉.\n8 Birrenbach T. Bertschy S. Aebersold F. Mueller N.J. Achermann Y. Muehlethaler K. Zimmerli S. Emergence of Blastoschizomyces capitatus yeast infections, Central Europe Emerg. Infect. Dis. 18 2012 98 101 22261201 \n9 Subramanya Supram H. Gokhale S. Chakrabarti A. Rudramurthy S.M. Gupta S. Honnavar P. Emergence of Magnusiomyces capitatus infections in Western Nepal Med. Mycol. 54 2016 103 110 26483432 \n10 Robert V.A. Casadevall A. Vertebrate endothermy restricts most fungi as potential pathogens J. Infect. Dis. 200 2009 1623 1626 19827944 \n11 Garcia-Solache M.A. Casadevall A. Global warming will bring new fungal diseases for mammals MBio 1 2010 \n12 Gadea I. Cuenca-Estrella M. Prieto E. Diaz-Guerra T.M. Garcia-Cia J.I. Mellado E. Tomas J.F. Rodriguez-Tudela J.L. Genotyping and antifungal susceptibility profile of Dipodascus capitatus isolates causing disseminated infection in seven hematological patients of a tertiary hospital J. Clin. Microbiol. 42 2004 1832 1836 15071063 \n13 Cofrancesco E. Viviani M.A. Boschetti C. Tortorano A.M. Balzani A. Castagnone D. Treatment of chronic disseminated Geotrichum capitatum infection with high cumulative dose of colloidal amphotericin B and itraconazole in a leukaemia patient Mycoses 38 2016 377 384 〈http://www.ncbi.nlm.nih.gov/pubmed/8569813〉 (accessed 16 December 2016) \n14 Arendrup M.C. Boekhout T. Akova M. Meis J.F. Cornely O.A. Lortholary O. European Society of Clinical Microbiology and Infectious Diseases Fungal Infection Study Group, European Confederation of Medical Mycology, ESCMID† and ECMM‡ joint clinical guidelines for the diagnosis and management of rare invasive yeast infections Clin. Microbiol. Infect. 20 2014 76 98 \n15 Yilmaz Karapinar D. Karadaş N. Önder Siviş Z. Yazici P. Duyu M. Metin D. Karapinar B. Aydinok Y. Karapinar D.Y. Karadas N. Sivis Z.Ö. Yazici P. Duyu M. Metin D. Karapinar B. Aydinok Y. Rare severe mycotic infections in children receiving empirical caspofungin treatment for febrile neutropenia Braz. J. Infect. Dis. 19 2015 549 552 26275731 \n16 Chittick P. Palavecino E.L. Delashmitt B. Evans J. Peacock J.E. Case of fatal blastoschizomyces capitatus infection occurring in a patient receiving empiric micafungin therapy Antimicrob. Agents Chemother. 53 2009 5306 5307 19738005 \n17 DeMaio J. Colman L. The use of adjuvant interferon- therapy for Hepatosplenic Blastoschizomyces capitatus infection in a patient with leukemia Clin. Infect. Dis. 31 2000 822 824 11017841 \n18 Pagano L. Morace G. Ortu-La Barbera E. Sanguinetti M. Leone G. Adjuvant therapy with rhGM-CSF for the treatment of Blastoschizomyces capitatus systemic infection in a patient with acute myeloid leukemia Ann. Hematol. 73 1996 33 34 〈http://www.ncbi.nlm.nih.gov/pubmed/8695721〉 (accessed 16 December 2016) 8695721 \n19 Pérez-Sanchez I. Anguita J. Rabadan P.M. Muñoz P. Serrano D. Escudero A. Pintado T. Blastoschizomyces capitatus infection in acute leukemia patients Leuk. Lymphoma 39 2000 209 212 10975401\n\n",
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"title": "First case of invasive Magnusiomyces capitatus infection in Slovakia.",
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"abstract": "This paper describes a case of cardiac arrest during femtosecond laser enabled penetrating keratoplasty (FLEK) in a young, healthy patient with no known cardiac risk factors and discusses the risk of cardiac arrest during intraocular surgery. A healthy 22-year-old man who underwent repeat FLEK under general anaesthesia developed bradycardia and subsequent cardiac arrest while open sky during surgery. After resuscitation and completion of the transplant surgery, the patient recovered and the graft has survived with excellent uncorrected visual acuity over 1 year after surgery. Understanding the risks of cardiac arrest and death during intraocular surgery is imperative to discussing the systemic risks of surgery during the preoperative informed consent.",
"affiliations": "SoCal Eye Physicians in Long Beach, Long Beach, California, USA.;Anesthesiology and Perioperative Care, University of California Irvine School of Medicine, Orange, California, USA.;Ophthalmology, University of California Irvine School of Medicine, Irvine, California, USA gargs@hs.uci.edu.",
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"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\nbcr-2020-235272\n10.1136/bcr-2020-235272\nUnexpected Outcome (Positive or Negative) Including Adverse Drug Reactions\n1506\n1525\n1302\n309\nCase reportCardiac arrest during cornea transplant surgery\nJarstad Allison 1 Chou Jody 2 Garg Sumit 3 1 SoCal Eye Physicians in Long Beach, Long Beach, California, USA\n2 Anesthesiology and Perioperative Care, University of California Irvine School of Medicine, Orange, California, USA\n3 Ophthalmology, University of California Irvine School of Medicine, Irvine, California, USA\nCorrespondence to Dr Sumit Garg; gargs@hs.uci.edu\n2020 \n26 8 2020 \n26 8 2020 \n13 8 e23527231 7 2020 © BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.This paper describes a case of cardiac arrest during femtosecond laser enabled penetrating keratoplasty (FLEK) in a young, healthy patient with no known cardiac risk factors and discusses the risk of cardiac arrest during intraocular surgery. A healthy 22-year-old man who underwent repeat FLEK under general anaesthesia developed bradycardia and subsequent cardiac arrest while open sky during surgery. After resuscitation and completion of the transplant surgery, the patient recovered and the graft has survived with excellent uncorrected visual acuity over 1 year after surgery. Understanding the risks of cardiac arrest and death during intraocular surgery is imperative to discussing the systemic risks of surgery during the preoperative informed consent.\n\ncardiovascular medicineophthalmologyspecial-featureunlocked\n==== Body\nBackground\nIntraoperative cardiac arrest is a dreaded complication of any surgery. In ophthalmology, the risk of cardiac arrest is extremely low, but is still a possibility. In this paper, we discuss a case of cardiac arrest during femtosecond laser enabled keratoplasty (FLEK) under general anaesthesia after the central cornea button had been removed, often referred to as ‘open-sky’. It is imperative for ophthalmologists to be aware of the risks of general anaesthesia and to counsel patients of the rare but real risk of cardiac arrest and even death during eye surgery.\n\nCase presentation\nThe patient is a healthy 23-year-old man who underwent FLEK at the age of 17 in the left eye and at the age of 22 in the right eye for keratoconus (figure 1). Both surgeries were performed under general anaesthesia. The postoperative course in the left eye was uncomplicated; however, at 4 months following keratoplasty in the right eye, the patient experienced a rejection episode, treated with topical Pred Forte (Allergan, Irvine, California, USA) hourly for 1 week, which was then switched to topical Durezol (Alcon Laboratories, Fort Worth, Texas, USA) hourly for 2 weeks. The rejection episode resolved, but because of endothelial cell decompensation resulting in graft failure and visually significant corneal oedema, the decision was made to taper the Durezol and repeat right FLEK at postoperative month 6.\n\nFigure 1 Oculus Pentacam topography for the right eye prior to the first femtosecond laser enabled keratoplasty revealing keratoconus with a central cone.\n\nFor the first FLEK surgery on the right eye, the patient underwent an IntraLase iFS (Johnson and Johnson Vision, Santa Ana, California, USA) cut of his cornea in a zigzag-C pattern in the laser suite under topical anaesthesia without complication and was transferred to the operating room where general anaesthesia was initiated (table 1) and a laryngeal mask airway (LMA) was placed. A retrobulbar block was not given. After the surgical time out, the surgery lasted 51 min and the patient was extubated without complication.\n\nTable 1 Anaesthesia agents administered by anaesthesia episode\n\nMedication\tFirst anaesthesia episode:\nLeft eye FLEK #1*\tSecond anaesthesia episode:\nRight eye FLEK#1\tThird anaesthesia episode:\nRight eye FLEK #2\t\nMidazolam\t2 mg\t2 mg\t2 mg\t\nFentanyl\t25 µg\t100 µg\t25 µg\t\nPropofol\t200 mg\t200 mg\t150 mg\t\nLidocaine\t50 mg\t100 mg\t100 mg, 100 mg †\t\nDexamethasone\t \t4 mg\t4 mg\t\nOndansetron\t4 mg\t4 mg\t4 mg\t\nPhenylephrine\t300 mg\t \t \t\nEpinephrine\t20 mg\t \t \t\nGlycopyrrolate\t \t \t1 mg\t\nEpinephrine\t \t \t1 mg\t\nAmiodarone\t \t \t150 mg\t\nCalcium chloride\t \t \t1000 mg\t\nLactated ringer’s solution\t800 mL\t800 mL\t800 mL\t\n*The first anaesthesia episode is not described in detail in this paper.\n\n†The first bolus of lidocaine was given on initiation of anaesthesia and a second bolus of lidocaine was given during cardiac arrest.\n\nFLEK, femtosecond laser enabled keratoplasty.\n\nThe patient underwent his first keratoplasty at age 17 under general anaesthesia, so the surgeon decided to perform repeat FLEK in the right eye under general anaesthesia since this was the patient’s third keratoplasty and the previous two surgeries proceeded without complication under general anaesthesia. Prior to surgery, the ECG revealed a normal sinus rhythm, the patient was pre-retreated with 2 mg of midazolam and was taken to the operating theatre. After applying American Society of Anesthesia (ASA) standard monitors, general anaesthesia using an LMA was induced with 25 mcg of fentanyl, 150 mg of propofol and 100 mg of lidocaine. The operating table was then turned 90 degrees counterclockwise, the patient was prepped and draped, a time out was performed and the surgery began. Again, a retrobulbar block was not given.\n\nDuring the procedure, the previously placed donor corneal button was removed, and the fresh donor cornea was brought to the field. Three minutes into the surgery the first cardinal suture had been passed through the donor button but had not yet passed through the host cornea in the 12 o’clock meridian when the patient’s heart rate became bradycardic, dropping from the 110’s to the 20’s. The surgeon was told to cease manipulation of the eye immediately. At that time there was no torquing of the eye away from primary position, but forceps had grasped the host cornea at the 12 o’clock position in preparation to pass the suture.\n\nInvestigations\nThe surgery was paused, 1 mg of glycopyrrolate was given without any response of the heart rate, and the patient subsequently became asystolic without a pulse. Acute cardiac life support was initiated. Chest compressions were started immediately, a code was called and a crash cart was brought to the bedside. The surgeon took care to plug the open sky with a finger during chest compressions to prevent expulsion of intraocular contents. Defibrillator pads were placed, but no shock was given as the patient was still in asystole, so chest compressions were resumed. Epinephrine 1 mg was given. Approximately 1 min after bradycardia was noted, the patient had return of a spontaneous heart rate with sinus tachycardia and a pulse was palpable. End tidal carbon dioxide was in the 50’s at this time. Three minutes later, the ECG showed a wide complex rhythm in the rate of 80’s. A 100 mg bolus of lidocaine was given without a response, followed by 150 mg of amiodarone, which resulted in resolution of the wide complex rhythm and return of sinus tachycardia. Next an arterial line was placed, and a point of care arterial blood gas (ABG) was drawn showing electrolyte abnormalities and an elevated glucose and creatinine (table 2). Systolic blood pressure was in the 70’s after the arterial line was placed. Phenylephrine was given with improvement in blood pressure. The entire code lasted 5 min, after which the surgical team proceeded with the remainder of the case.\n\nTable 2 Intraoperative point of care limited arterial blood gas\n\n\tPatient’s reading\tNormal\t\nSodium\t136 mmol/L\t138–146 mEq/L\t\nPotassium\t4.00 mmol/L\t3.7–5.5 mmol/L\t\nChloride\t99 mmol/L\t99–111 mmol/L\t\nTotal CO2\t21 mmol/L\t23–29 mmol/L\t\nAnion gap\t21 mmol/L\t10–20 mmol/L\t\nGlucose\t147 mg/dL\t70–110 mg/dL\t\nBlood urea nitrogen\t12 mg/dL\t7–25 mg/dL\t\nCreatinine\t2.5 mg/dL\t0.6–1.3 mg/dL\t\nCalcium ionised\t0.96 mmol/L\t1.13–1.32 mmol/L\t\nOutcome and follow-up\nThe new donor button had remained on the field during chest compressions and was found in the superior fornix under the eyelid. The donor button was sutured to the host quickly with 16 interrupted 10-0 nylon sutures. The knots were buried, and the graft host junction was confirmed to be Seidel negative prior to injecting subconjunctival cefazolin and methylprednisolone. The surgery lasted 43 min from initial incision to close, and paramedics were waiting outside the operating theatre when the surgery was complete. The patient was extubated and found to be awake, alert and following commands. A sign-out was given to the paramedics, who accompanied the patient to the recovery area, where the patient’s heart rate was sinus tachycardia in the 120’s and blood pressure was 170/70 mm Hg.\n\nThe paramedics transferred the patient to a nearby hospital where he was admitted for cardiac testing. He was discharged 5 days later after his cardiac work-up was negative and electrolyte abnormalities resolved. The patient is currently doing well without systemic ramifications of the cardiac arrest episode. He experienced a second rejection episode of the right cornea while on topical prednisolone four times daily, which was treated with topical Durezol (Alcon Laboratories) every 2 hours and Combigan (Allergan, Madison, New Jersey, USA) twice daily to prevent intraocular pressure elevation. The keratoplasty graft is currently clear and the most recent uncorrected visual acuity over 1 year following repeat FLEK was 20/30. Vision in the left eye (which also underwent FLEK) remains 20/20 on Lotemax (Basuch and Lomb, Rochester, New York, USA) once daily. He has established care with cardiology and a repeat cardiac stress test was normal.\n\nDiscussion\nTo the best of our knowledge this is the first reported case of intraoperative cardiac arrest during FLEK. Despite eye surgery being relatively ‘safe’ with low systemic risk, any surgery that involves anaesthesia carries the additional risks of cardiac arrest and death. Even if the risk is minimal, as surgeons, we are obligated to inform patients of the potential systemic adverse effects of surgery, not just those limited to the eye.\n\nCardiac arrest is a rare complication of surgery and anaesthesia. A Japanese study from 2004 reported the rate of cardiac arrest as 6.34 per 10 000 anaesthesia cases. In the same study, the incidence of cardiac arrest totally attributed to anaesthetic mismanagement was only 0.47 per 10 000 cases.1 More commonly, cardiac arrest is due to preoperative health complications and intraoperative events such as surgical blood loss leading to haemorrhagic shock. The American College of Surgeons National Surgical Quality Improvement Database from 2005 to 2007 reports the incidence of cardiac arrest during non-cardiac surgery as 7.22 per 10 000 cases. In these cases, intraoperative blood loss was the most important risk factor for cardiac arrest.2 The risk increases with age as well as ASA physical status ranking, with the majority of arrests occurring in patients with an ASA physical status of 3, 4 or 5 (on a scale of 1–5).3 Special situations that carry an increased risk of cardiac arrest include emergency surgery (163 per 10 000 cases) and surgeries in children less than 1 year of age (22.9 per 10 000 cases).4 5 Given the low levels of blood loss and that most intraocular surgeries are planned, the risks of cardiac arrest during intraocular surgery are extremely rare.\n\nRates of cardiac arrest during intraocular surgery are not well published. In the 1960’s Petrusack, Smith and Breslin reviewed thousands of cases over a 10-year period at the Eye and Ear Hospital in Pittsburgh. After reviewing over 30 000 anaesthesia cases, the study found only two deaths that occurred intraoperatively, both under local anaesthesia, not general. The death rate following general anaesthesia was 6.9 per 10 000 cases and 3.5 per 10 000 cases following local anaesthetic.6 The fact that no deaths occurred intraoperatively during eye surgery is especially remarkable, considering a 2013 study that analysed when perioperative cardiac arrest takes place. In this study of 2524 perioperative deaths from cardiac arrest within 24 hours of surgery, a stunning 1458 occurred intraoperatively.7\n\nThe oculocardiac reflex leading to bradycardia has been well established and is associated with manipulation of the globe, pressure on the orbital contents, a pulling force on the intraocular muscles and intravitreal injections.8 9 In this case, the patient’s eye was in primary position when he became bradycardic and later asystolic, so it is possible, but unlikely, that this arrhythmia was a reflexive response to globe manipulation. In both surgeries on the right eye, a retrobulbar block was not performed. It is unclear if the presence of retrobulbar anaesthetic would have altered the outcome of the surgery, but this is an area in need of further investigation. Though some surgeons perform a retrobulbar, peribulbar or sub-Tenon’s injection of anaesthetic at the time of keratoplasty surgery, we generally prefer to avoid injections into the orbital septum to minimise posterior pressure during open sky procedures to avoid expulsion of the intraocular contents while the cornea button is removed. Cornea transplant surgery does not involve the uvea which tends to be more painful, as such the authors do not routinely perform retrobulbar blocks in the setting of keratoplasty when general anaesthesia is used, however, this should be considered on a case-by-case basis.\n\nIn predisposed patients, slight changes in pressure on the globe and even changes in temperature of the eye can induce bradycardia. This is known as the diving reflex, which manifests as bradycardia when irrigation fluid of 20°C or cooler is applied along the ophthalmic division of the fifth cranial nerve.10 The bradycardia occurs without hypotension and can be more profound than that seen from the oculocardiac reflex.11 In the presented case, room temperature balanced salt solution was used to irrigate the ocular surface, but the eye was not irrigated at the time of the onset of the patient’s bradycardia and is unlikely to have triggered the oculocardiac reflex in this case.\n\nIt is not clear why the patient experienced cardiac arrest. He may be vagotonic at baseline and susceptible, but his postoperative cardiac work-up has been negative. He had no known preoperative risk factors, and he had undergone uncomplicated general anaesthesia on two previous occasions for similar eye surgeries. Despite no comorbidities, his ASA score was 2 due to the previous two keratoplasties, and he had the same anaesthesiologist for both surgeries on the right eye (initial FLEK and repeat FLEK). The medications administered during anaesthesia induction were similar between cases on the right eye, with the exception of less fentanyl and propofol given in the third anaesthesia event (repeat FLEK of the right eye).\n\nThe limited point of care ABG (table 2) shows a sodium level of 136, which does not meet the criteria for hyponatraemia and is clinically inconsequential. A mildly low bicarbonate level suggests mild metabolic acidosis which is common during cardiac arrest due to the increase of lactic acid. Unfortunately, a pH is not included in the point of care ABG that was done. Elevated glucose is likely a stress response related to the cardiac arrest or due to the bolus of epinephrine given during the resuscitation process. The patient’s ionised calcium level was 0.96, which was borderline low (normal range 1.13–1.32). This cause of mild hypocalcaemia is unclear although the patient did have an abnormal elevation of creatinine demonstrating possible chronic renal pathology. Chronic kidney disease can affect calcium levels through impaired vitamin D metabolism. Calcium is known to increase cardiac contractility, and when administered at a fast rate, a transient increase in heart rate can also be observed. However, calcium is not part of the recommended medications for symptomatic bradycardia, and this would not have been the initial drug of choice when the patient was first noted to have severe bradycardia. After the patient had return of spontaneous rhythm and regained a pulse, the point of care ABG was drawn showing mildly low calcium. At this time calcium was not given because the patient had adequate blood pressure and heart rate; however, if the patient had been hypotensive with a mildly low calcium, administration of calcium could have been considered.\n\nAlthough the final outcome was positive and the patient did not suffer from permanent systemic effects, not all surgical teams are as fortunate when faced with this devastating intraoperative event.\n\nOne may easily overlook mentioning the risk of intraoperative cardiac arrest and death during the preoperative informed consent, given that the rate is low. However, we urge ophthalmologists to include this in preoperative discussion, given that the risk exists and the outcomes of cardiac arrest can be devastating and significant.\n\nLearning points\nCardiac arrest, though rare, is a well-document risk of any ocular surgery.\n\nIt is imperative for ophthalmologists to counsel their patients on this risk during preoperative discussions prior to surgery.\n\nWhen cardiac arrest occurs, prompt implementation of advanced cardiac life support with a cohesive team approach can lead to successful resuscitation.\n\nDuring open sky procedures, it is imperative to plug the wound during chest compressions to prevent expulsion of intraocular contents.\n\nContributors: AJ, JC and SG contributed equally to this case report.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Irita K , Kawashima Y , Iwao Y , et al \n[Annual mortality and morbidity in operating rooms during 2002 and summary of morbidity and mortality between 1999 and 2002 in Japan: a brief review]\n. Masui \n2004 ;53 :320 –35\n.15071889 \n2 Goswami S , Brady JE , Jordan DA , et al \nIntraoperative cardiac arrests in adults undergoing noncardiac surgery: incidence, risk factors, and survival outcome\n. Anesthesiology \n2012 ;117 :1018 –26\n. 10.1097/ALN.0b013e31827005e9 23042223 \n3 Nunnally ME , O'Connor MF , Kordylewski H , et al \nThe incidence and risk factors for perioperative cardiac arrest observed in the National anesthesia clinical outcomes registry\n. Anesth Analg \n2015 ;120 :364 –70\n. 10.1213/ANE.0000000000000527 25390278 \n4 Siriphuwanun V , Punjasawadwong Y , Lapisatepun W , et al \nIncidence of and factors associated with perioperative cardiac arrest within 24 hours of anesthesia for emergency surgery\n. Risk Manag Healthc Policy \n2014 ;7 :155 –62\n. 10.2147/RMHP.S67935 25214804 \n5 Gobbo Braz L et al \nPerioperative cardiac arrest and its mortality in children. A 9-year survey in a Brazilian tertiary teaching hospital\n. Paediatr Anaesth \n2006 ;8 :860 –6\n.\n6 Petruscak J , Smith RB , Breslin P \nMortality related to Ophthalmological surgery\n. Arch Ophthalmol \n1973 ;89 :106 –9\n. 10.1001/archopht.1973.01000040108008 4683601 \n7 Ramachandran SK , Mhyre J , Kheterpal S , et al \nAmerican Heart Association’s Get With The Guidelines-Resuscitation Investigators. Predictors of survival from perioperative cardiopulmonary arrests: a retrospective analysis of 2,524 events from the Get With The Guidelines-Resuscitation registry\n. Anesthesiology \n2013 ;12 :1322 –39\n.\n8 Van Brocklin MD , Hirons RR , Yolton RL \nThe oculocardiac reflex: a review\n. J Am Optom Assoc \n1982 ;53 :407 –13\n.7047626 \n9 Paciuc-Beja M , Meizner-Grezemkovsky D , Paciuc M , et al \nOculocardiac reflex during intravitreal injection\n. Med Hypothesis Discov Innov Ophthalmol \n2020 ;9 :111 –7\n.32490017 \n10 Arndt GA , Stock MC \nBradycardia during cold ocular irrigation under general anaesthesia: an example of the diving reflex\n. Can J Anaesth \n1993 ;40 :511 –4\n. 10.1007/BF03009732 8403114 \n11 Berk WA , Shea MJ , Crevey BJ \nBradycardic responses to vagally mediated bedside maneuvers in healthy volunteers\n. Am J Med \n1991 ;90 :725 –9\n.2042688\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1757-790X",
"issue": "13(8)",
"journal": "BMJ case reports",
"keywords": "cardiovascular medicine; ophthalmology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D006323:Heart Arrest; D006801:Humans; D007431:Intraoperative Complications; D015948:Keratoplasty, Penetrating; D008297:Male; D055815:Young Adult",
"nlm_unique_id": "101526291",
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"pmid": "32847878",
"pubdate": "2020-08-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "2042688;7047626;4683601;23838723;15071889;8403114;23042223;32490017;16884469;25214804;25390278",
"title": "Cardiac arrest during cornea transplant surgery.",
"title_normalized": "cardiac arrest during cornea transplant surgery"
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"abstract": "Tumor-induced osteomalacia (TIO) is a rare disease in which patients suffer from fractures and progressive disabling bone pain and muscle weakness. TIO is caused by the hypersecretion of Fibroblast Growth Factor 23 (FGF23) from rare neoplasms of mesenchymal origin. This case report describes a 29-year-old male with 2 years of low back/hip pain, gait changes, proximal muscle weakness, and multiple stress fractures. Bone densitometry was remarkable for severe osteoporosis, hypophosphatemia was seen on routine labs, and advanced labs demonstrated an \"inappropriately normal\" FGF23 level. A 68Ga-DOTATATE scan and MRI showed a 1.3 × 1.1 × 1.0 cm intracranial mass. The patient underwent tumor resection by Neurosurgery. Shortly after, laboratory levels normalized, and the patient's symptoms improved drastically. This case exemplifies the notion that TIO can be caused by FGF23 levels within normal limits, the role of 68-Ga DOTATATE imaging for establishing a diagnosis, and that these tumors can arise anywhere-even intracranially. We also review current surgical and nonsurgical treatment options, as well as emerging novel therapeutics.",
"affiliations": "Medical Scientist Training Program, Vanderbilt University Medical Center, 2nd Floor Eskind Biomedical Library and Learning Center, Vanderbilt University School of Medicine, 2209 Garland Avenue, Nashville, TN 37240, USA.;Department of Neurological Surgery, Vanderbilt University Medical Center, T-4224F Medical Center North, 1161 21st Avenue South, Nashville, TN 37232, USA.;Hearing and Speech Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.;Vanderbilt University Medical Center, Program for Metabolic Bone Disorders at Vanderbilt, Endocrinology and Diabetes, 8210 Medical Center East, 1215 21st Avenue South, Nashville, TN 37232, USA.",
"authors": "Colazo|Juan M|JM|;Thompson|Reid C|RC|;Covington|Natalie V|NV|;Dahir|Kathryn M|KM|",
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"doi": "10.1016/j.radcr.2020.01.039",
"fulltext": "\n==== Front\nRadiol Case Rep\nRadiol Case Rep\nRadiology Case Reports\n1930-0433 Elsevier \n\nS1930-0433(20)30039-X\n10.1016/j.radcr.2020.01.039\nMusculoskeletal\nAn intracranial mass causing tumor-induced osteomalacia (TIO): Rapid and complete resolution of severe osteoporosis after surgical resection\nColazo Juan M. BScjuan.m.colazo@vanderbilt.eduab⁎ Thompson Reid C. MDreid.thompson@vumc.orgc Covington Natalie V. PhDnatalie.covington@vumc.orgd Dahir Kathryn M. MDkathryn.dahir@vumc.orge⁎1 a Medical Scientist Training Program, Vanderbilt University Medical Center, 2nd Floor Eskind Biomedical Library and Learning Center, Vanderbilt University School of Medicine, 2209 Garland Avenue, Nashville, TN 37240, USA\nb Department of Biomedical Engineering, Vanderbilt University, 2301 Vanderbilt Place, PMB351826, Nashville, TN 37235, USA\nc Department of Neurological Surgery, Vanderbilt University Medical Center, T-4224F Medical Center North, 1161 21st Avenue South, Nashville, TN 37232, USA\nd Hearing and Speech Sciences, Vanderbilt University Medical Center, Nashville, TN, USA\ne Vanderbilt University Medical Center, Program for Metabolic Bone Disorders at Vanderbilt, Endocrinology and Diabetes, 8210 Medical Center East, 1215 21st Avenue South, Nashville, TN 37232, USA\n⁎ Corresponding authors. juan.m.colazo@vanderbilt.edukathryn.dahir@vumc.org1 buildingbones.org.\n\n\n25 2 2020 \n5 2020 \n25 2 2020 \n15 5 492 497\n14 12 2019 25 1 2020 25 1 2020 © 2020 The Authors. Published by Elsevier Inc. on behalf of University of Washington.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Tumor-induced osteomalacia (TIO) is a rare disease in which patients suffer from fractures and progressive disabling bone pain and muscle weakness. TIO is caused by the hypersecretion of Fibroblast Growth Factor 23 (FGF23) from rare neoplasms of mesenchymal origin. This case report describes a 29-year-old male with 2 years of low back/hip pain, gait changes, proximal muscle weakness, and multiple stress fractures. Bone densitometry was remarkable for severe osteoporosis, hypophosphatemia was seen on routine labs, and advanced labs demonstrated an “inappropriately normal” FGF23 level. A 68Ga-DOTATATE scan and MRI showed a 1.3 × 1.1 × 1.0 cm intracranial mass. The patient underwent tumor resection by Neurosurgery. Shortly after, laboratory levels normalized, and the patient's symptoms improved drastically. This case exemplifies the notion that TIO can be caused by FGF23 levels within normal limits, the role of 68-Ga DOTATATE imaging for establishing a diagnosis, and that these tumors can arise anywhere—even intracranially. We also review current surgical and nonsurgical treatment options, as well as emerging novel therapeutics.\n\nKeywords\nTIOParaneoplastic syndromeTumor-induced osteomalaciaFibroblast growth factor 2368Ga-DOTATATEMRIDXABurosumab\n==== Body\nIntroduction\nOsteomalacia is the softening of bones caused by impaired bone mineralization at sites of bone remodeling and during bone formation primarily due to inadequate levels of available phosphate, calcium, and vitamin D or because of calcium resorption. Only recently, a novel paraneoplastic disease termed tumor-induced osteomalacia (TIO) has been described [1,2]. TIO is caused by an overproduction and secretion of FGF23 from a phosphaturic mesenchymal tumor. Normally, FGF23 is secreted by osteocytes in response to hyperphosphatemia and exogenous calcitriol. FGF23 then acts on the kidneys by decreasing the expression of NPT2, a sodium-phosphate cotransporter in the proximal tubule [3]. Due to its relative overexpression and secretion in this disease, FGF23 in excess decreases phosphate reabsorption while increasing its excretion, causing renal phosphate wasting as well as impairing intestinal phosphate absorption through suppression of renal calcitriol production. Over time, hypophosphatemia will arise and cause osteomalacia due to the inadequate availability of phosphate in the blood for active bone mineralization.\n\nCase report\nA 29-year-old male presented with 2 years of low back and hip pain, gait changes, proximal muscle weakness, and multiple stress fractures. There was no personal or family history of metabolic bone disorders, rickets, or cancer. He was initially evaluated by rheumatology and diagnosed with psoriatic arthritis, though treatment with steroids and etanercept did not improve his symptoms. An elevated alkaline phosphatase level prompted his referral to endocrinology clinic. In our clinic, a bone scan (Fig. 1) was performed that showed multiple foci of uptake mostly representing fractures. Pertinent laboratory values include a low serum phosphorus (1.3 mg/dL; 2.3-4.7 mg/dL), serum calcium (9.8 mg/dL, 8.4-10.5 mg/dL), low total Vitamin D (15 ng/mL; 25-80 ng/mL), low 1, 25 Dihydroxyvitamin D (10.0 pg/mL; 19.9-79.3 pg/mL), elevated total alkaline phosphatase (354 U/L; 40-150 U/L) elevated bone specific alkaline phosphatase (110.0 mcg/L; 6.5-20.1 mcg/L), parathyroid hormone (79 pg/mL; 16-77 pg/mL). A 24-hour urine phosphorous was performed (1, 160 mg/24hr; 400-1300 mg/24hr). Areal bone density was assessed by dual-energy X-ray absorptiometry (DXA) using a GE Lunar Prodigy Advanced densitometer and revealed a spine BMD of 0.789 g/cm2 (Z score of −4.3) (Fig. 3A), and a total left femur BMD of 0.599 gm/cm2 (Z score of −3.9) (Fig. 3C).Figure 1 Nuclear medicine scan prior to diagnosis. Whole body bone scan performed prior to diagnosis and 3 months before surgical resection, findings include: (1) Focal uptake at the left femoral neck which may represent a site of insufficiency fracture (black arrow). (2) Multiple foci of uptake involving ribs (dark blue stars) and spinous process of T1 (orange arrow), likely representing fractures. (3) Uptake at the superior aspect of the right acetabulum which is likely related to an insufficiency fracture seen on a prior MRI (yellow arrows). (4) Foci of prominent uptake in the bilateral feet are suggestive of reactive/arthritic changes and/or fractures (light blue double arrow). (5) Focal uptake in the bilateral knees (red arrows) likely representing arthritis changes. (6) Diffuse uptake in the sacroiliac (SI) joints bilaterally (green arrows).\n\nFigure 1\n\nDue to suspected TIO, a FGF23 level was obtained which was in the upper range of normal (179 RU/mL; ≤ 180 RU/mL). The patient was started on phosphorous and calcitriol. A 68Ga-DOTATATE scan showed an intracranial focal area of uptake near the region of the right temporal lobe of the brain (Fig. 2A). A homogenously enhancing 1.3 × 1.1 × 1.0 cm intracranial lesion, appearing strikingly like a meningioma, arising from the right middle cranial fossa was redemonstrated on MRI (Fig. 2B). The patient was referred to Neurosurgery and underwent a craniotomy to resect the tumor. Pathology showed areas of well-circumscribed proliferation with variable cellularity, prominent hyalinization of blood vessels, and a chondromyxoid matrix [4] (Fig. 2C). These findings are consistent with a final pathologic diagnosis of a benign mesenchymal tumor.Figure 2 Characteristics of the intracranial mass. (A) 68Ga-DOTATATE Scan. An intracranial focal area of uptake near the region of the right temporal lobe of the brain (Black Arrow). (B) Fast spoiled gradient-recalled-echo (FSPGR) MRI scan. There is an extra-axial homogenously enhancing mass (White Arrow), arising from the anterior floor of the right middle cranial fossa along the posterior margin of the greater wing of the right sphenoid bone measuring 1.3 × 1.1 × 1.0 cm in AP, transverse, and craniocaudal dimension. (C) Histological Images with Hematoxylin and Eosin (H&E) Staining. Successive H&E histological sections (A–D) show a tumor composed of a mixture of bland spindle cells, adipose tissue, abundant blood vessels, and areas of extracellular chodromyxoid matrix with focal calcifications. The spindle cell component has oval nuclei with eosinophilic cytoplasm and indistinct cell borders. Mitotic figures are not identified. The vessels are ectatic with perivascular hyalinization, with some hemangiopericytoma-like morphology. No giant cells are observed. (A) No magnification. (B–D) Magnified at 20×.\n\nFigure 2\n\nShortly after surgery, the patient's serum phosphorus normalized. FGF23 was initially undetectable postoperatively and then normalized to the midnormal range where it has remained. Within 3 months postresection, his pain and his ability to stand (Supplementary Video 1) and walk (Supplementary Video 2) improved significantly and he was able to resume swing dancing, which he had not been able to do for nearly a year.\n\nA follow-up 9-month DXA scan showed a remarkable improvement in BMD to the normal range. Total spine BMD at 9 months postresection was 1.294 gm/cm2 (Z score of +0.5), which was an improvement of 64% (Fig. 3A and B), and his left total femur was 1.156 gm/cm2 (Z score of +0.5), which was an improvement of 93% (Fig. 3C and D). A more recent 1-year postresection interval history shows that the patient is doing well—recently joining a gym and working out weekly. All his fractures have healed, and he has some residual arthritis in his knees and ankles but no bone pain, fractures, or gait abnormalities (Fig. 4).Figure 3 DXA scans with estimated BMD before and after surgical resection. (A) Preoperative AP Spine DXA Scan calculated an estimated average BMD of 0.789 g/cm2 in regions L1-L4. (B) 9-month postresection AP Spine DXA scan calculated an estimated average BMD of 1.294 g/cm2 in regions L1-L4. (C) Preoperative dual femur DXA scan calculated an estimated average BMD of 0.599 g/cm2 (left total femur) and 0.606 g/cm2 (right total femur). (D) 9-months postresection dual femur DXA scan calculated an estimated average BMD of 1.156 g/cm2 (left total femur) and 1.217 g/cm2 (right total femur).\n\nFigure 3Figure 4 Nuclear medicine scans 10 months postsurgical resection. (A) Whole body bone scan showing multiple foci of moderately increased radiotracer uptake in the bilateral shoulders, knees, ankles, and feet, albeit much less than preresection. This uptake is consistent with degenerative changes. There is no evidence of acute fracture. (B) Bone scan of bilateral feet shows uptake that is nonspecific and may represent old fractures on a background of degenerative changes. No acute fractures seen.\n\nFigure 4\n\nDiscussion\nOsteomalacia is the softening of bones caused by impaired bone mineralization at sites of bone remodeling and during bone formation primarily due to inadequate levels of available phosphate, calcium, and vitamin D or because of calcium resorption [5]. Typical signs and symptoms of osteomalacia include diffuse body pains, muscle weakness, fragility/fractures of the bones, and severely low bone mass. Since these symptoms are very generalizable and can range from mild to severe, these patients are often misdiagnosed and/or undiagnosed for many years. Additionally, young men are less likely to be evaluated for osteoporosis and fractures [6].\n\nThe most common cause of osteomalacia is vitamin D deficiency, therefore a serum total vitamin D level is a good primary screening test. Less common causes include hereditary disorders of vitamin D or phosphorous [7] which are typically identified in childhood. After a total vitamin D test, a serum phosphorous test should be performed. Hypophosphatemia should prompt 24-hour urine phosphorous and calcium levels to differentiate between malabsorption and phosphate wasting [8].\n\nIn our patient, vitamin D was low and additional lab tests showed hypophosphatemia with an increased 24-hour urine phosphorus (100 mg/day or a FEPO4 above 5% is indicative of renal phosphate wasting in patients with hypophosphatemia). Overall, these results suggested a phosphate wasting disorder [9].\n\nUltimately, differentiating between different phosphate wasting disorders is dependent on FGF23 (Table 1), which was only recently discovered in 2000 [10]. The normal physiological function of FGF23 is to regulate phosphate concentration in the blood. Normally, FGF23 is secreted by osteocytes in response to hyperphosphatemia or exogenous calcitriol. FGF23 then acts on the kidneys by decreasing the expression of NPT2, a sodium-phosphate cotransporter, in the proximal tubule [3]. Due to this, FGF23 decreases the reabsorption of phosphate while increasing its excretion. In addition, recent studies have shown that FGF23 may also suppress 1-alpha-hydroxylase, reducing its ability to activate vitamin D and therefore impairing both intestinal phosphorous and calcium absorption and homeostasis [11].Table 1 Phosphate wasting disorder differential diagnosis.\n\nA differential diagnosis table for phosphate wasting disorders, including TIO, distinguished by serum FGF23 level [12].\n\nTable 1Phosphate wasting disorders with low FGF23\tPhosphate wasting disorders with high or “inappropriately normal” FGF23\t\nAlcohol consumption\tX-linked hypophosphatemia (XLH)\t\nProton pump inhibitor\n (PPI) Use\tEpidermal nevus syndromes (ENS)\t\nFanconi syndrome\tAutosomal dominant/autosomal recessive rickets\t\nMyeloma\tMcCune Albright syndrome\t\nIron use\tCutaneous-skeletal hypophosphatemia syndrome (CSHS)\t\nCopper disorders\tTumor-induced osteomalacia (TIO)\t\n\n\nA pertinent distinction between other diagnoses with high or “inappropriately normal” FGF23 (Table 1) and TIO is time of presentation. While most of these diseases present early in life, TIO tends to present later in life with an abrupt time course and a negative family history [1].\n\nIn our patient, FGF23 was in the upper range of normal, but not elevated, otherwise known as “inappropriately normal.” The determination of an “inappropriately normal” FGF23 value is dependent on serum phosphorous and calcitriol levels [12]. Compared to previously published cases, a nonelevated FGF23 level was unique to our patient. For example, Chong et al (2013) presents 31 TIO cases; all 31 having elevated FGF23 levels [13]. Therefore, FGF23 levels on the higher end of normal should, in some instances, be pursued [12].\n\nLocating the active tumor in TIO can be difficult since they are usually small and can be located anywhere, but most commonly in the hands, feet, and nasal cavities with intracranial/brain lesions being rare. In recent literature, a full body 68Ga-DOTATATE scan has been shown to be the most specific imaging test [14]. The 68Ga-DOTATATE scan works by utilizing 68Gallium (68Ga)-conjugated somatostatin peptide analogues, such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)TATE, which enables somatostatin receptor imaging with positron emission tomography. This type of scan is most often used for somatostatin receptor positive neuroendocrine tumors and was only recently approved by the US Food and Drug Administration in 2016. Since phosphaturic mesenchymal tumors often express somatostatin receptors, this technique allows for “targeted” imaging of TIO-causing lesions. That being said, false positivity can still be caused by hypersplenism, fractures, sarcoidosis, or even vertebral hemangiomas [15]. If multiple tumors are present, selective FGF23 venous sampling has shown promise in deciphering the FGF23-producing tumor. Complete resection of the tumor is currently the only definitive cure. If the tumor cannot be located, is determined unresectable, or the patient is not a surgical candidate, phosphate and calcitriol should be given. A promising emerging treatment option currently under investigation is Burosumab, an anti-FGF23 IgG1 monoclonal antibody [16].\n\nFinally, osteoporosis has been traditionally considered a postmenopausal disorder of women and DXA scans have been underutilized in men [17]. Phosphate wasting disorders, including TIO, should be considered in the differential diagnosis of unexplained osteoporosis and fractures and a serum phosphorus level should be evaluated as part of a routine metabolic workup. This case demonstrates the utility of DXA to establish severity of disease as well as to monitor our patient's rapid and remarkable response to intervention [18].\n\nConclusion\nTIO is a paraneoplastic syndrome of Fibroblast Growth Factor 23 (FGF23) that causes renal phosphate wasting, ultimately leading to the development of osteomalacia [1]. In patients with TIO, biochemical studies show hypophosphatemia, hyperphosphaturia, and excessive or “inappropriately normal” FGC23 levels. DXA scans should be used to establish disease severity and to monitor recovery post-treatment. A detailed history is important in the final diagnosis of TIO as it is an acquired disorder and thus patients often have an unremarkable childhood history and family history of rickets and/or other bone diseases [10]. Full body imaging should be pursued if there is a high clinical suspicion for TIO [14]. A 68Ga-DOTATAE scan has been shown to be the most specific due to somatostatin-targeting but can have some false positives [15]. With resection, TIO is curable and laboratory values usually normalize shortly after surgery. In this case report, biochemical correction of FGF23 levels after surgical resection led to a remarkable and rapid correction of disability, fractures, and mineralization of bone mass from severely low to normal in a young male in just 9 months. If a mass is not found, is determined to be unresectable, or the patient is not a surgical candidate, phosphorous and calcitriol should be started and taken long-term. Burosumab (an anti-FGF23 monoclonal antibody approved for XLH) is currently under study and may be a potential therapeutic option for these patients [15].\n\nAppendix Supplementary materials\nImage, video 1 Image, video 2 \n\nAcknowledgments\nOne of the authors (JMC) is supported by NIGMS of the National Institutes of Health under award number T32GM007347. The content in this report is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.\n\nCompliance with Ethical Standards\nInformed consent was obtained from the participant of this case study.\n\nCompeting interest: Juan M Colazo, Reid C Thompson, Natalie V Covington, and Kathryn M Dahir declare that they have no conflict of interest.\n\nSupplementary material associated with this article can be found, in the online version, at doi:10.1016/j.radcr.2020.01.039.\n==== Refs\nReferences\n1 McCrance RA. Osteomalacia with Looser's nodes (Milkman's syndrome) due to a raised resistance to vitamin D acquired about the age of 15 years Q J Med 16 1947 33 46 20296654 \n2 Jan de Beur SM Tumor-induced osteomalacia JAMA 294 2005 1260 1267 16160135 \n3 Phosphate Jüppner H. FGF‐23 Kidney Int Suppl 79 121 2011 S24 S27 \n4 Agaimy A. Michal M. Chiosea S. Petersson F. Hadravsky L. Kristiansen G. Phosphaturic mesenchymal tumors: clinicopathologic, immunohistochemical and molecular analysis of 22 cases expanding their morphologic and Immunophenotypic spectrum Am J Surg Pathol 41 2017 1371 1380 28614212 \n5 Francis RM Selby PL Osteomalacia Baillieres Clin Endocrinol Metab. 11 1997 145 163 9222490 \n6 Harper CM Fitzpatrick SK Zurakowski D Rozental TD Distal radial fractures in older men. A missed opportunity? J. Bone Joint Surg. Am. 96 21 2014 1820 1827 25378510 \n7 Bhan A Rao AD Rao DS Osteomalacia as a result of vitamin D deficiency Rheum Dis Clin North Am 38 2012 81 91 22525844 \n8 Payne RB. Renal tubular reabsorption of phosphate (TmP/GFR): indications and interpretation Ann Clin Biochem 35 Pt 2 1998 201 206 Review 9547891 \n9 Day A.L. Morgan S.L. Saag K.G Hypophosphatemia in the setting of metabolic bone disease: case reports and diagnostic algorithm Ther Adv Musculoskelet Dis 10 2018 151 156 30023010 \n10 Econs MJ Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23 Nat Genet 26 3 2000 345 348 PMID 11062477 11062477 \n11 Perwad F. Zhang M.Y. Tenenhouse H.S. Portale A.A. Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1α-hydroxylase expression in vitro Am J Physiol 293 5 2007 F1577 F1583 \n12 Huang X Jiang Y Xia W FGF23 and phosphate wasting disorders Bone Res 1 2013 120 132 26273497 \n13 Chong WH Andreopoulou P Chen CC Reynolds J Guthrie L Kelly M Tumor localization and biochemical response to cure in tumor-induced osteomalacia J Bone Miner Res 28 2013 1386 1398 23362135 \n14 Zhang J Zhu Z Zhong D Dang Y Xing H Du Y 68Ga DOTATATE PET/CT is an accurate imaging modality in the detection of culprit tumors causing osteomalacia Clin Nucl Med 40 2015 642 646 26053726 \n15 Hofman M.S. Eddie Lau W.F. Hicks R.J. Somatostatin receptor imaging with 68 Ga DOTATATE PET/CT: clinical utility, normal patterns, pearls, and pitfalls in interpretation1 Radiographics 35 2015 500 516 25763733 \n16 Beur Suzanne Jan De Miller Paul Weber Thomas Peacock Munro Insogna Karl Kumar Rajiv OR13-1 Burosumab Improves the Biochemical, Skeletal, and Clinical Symptoms of Tumor-Induced Osteomalacia Syndrome J Endocr Soc 3 2019 13 21 Issue Supplement_1, AprilOR 30560225 \n17 Management of osteoporosis in postmenopausal women: 2010position statement of The North American Menopause Society Menopause 2010170125–54., quiz 55–56\n18 Blake G.M. Fogelman I. The role of DXA bone density scans in the diagnosis and treatment of osteoporosis Postgrad Med 83 982 2007 509 517\n\n",
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"title": "An intracranial mass causing tumor-induced osteomalacia (TIO): Rapid and complete resolution of severe osteoporosis after surgical resection.",
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"abstract": "OBJECTIVE\nTo emphasize the application prospects of in vivo confocal microscopy (IVCM) in distinguishing intraocular lesions from inflammatory and neoplastic diseases.\n\n\nMETHODS\nRetrospective case report.\n\n\nRESULTS\nA patient with neoplastic masquerade syndrome initially underwent IVCM examination. After six separate intravitreal injections of 400 mg/0.1 ml methotrexate, IVCM revealed a complete remission of intraocular lymphoma.\n\n\nCONCLUSIONS\nAlthough IVCM findings alone are not enough to diagnose intraocular neoplasm with absolute certainty, they can provide useful indication for distinguishing between intraocular inflammatory diseases and neoplasms.",
"affiliations": "a Department of Ophthalmology, The Second Xiangya Hospital , Central South University , Changsha , Hunan , P.R. China.;a Department of Ophthalmology, The Second Xiangya Hospital , Central South University , Changsha , Hunan , P.R. China.;a Department of Ophthalmology, The Second Xiangya Hospital , Central South University , Changsha , Hunan , P.R. China.",
"authors": "Zhang|Pu|P|;Tian|Jiao|J|;Gao|Ling|L|http://orcid.org/0000-0002-9850-2038",
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"keywords": "Intraocular inflammation; in vivo confocal microscopy; intraocular lymphoma; neoplastic masquerade syndrome; uveitis",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D000869:Anterior Eye Segment; D000964:Antimetabolites, Antineoplastic; D001082:Aqueous Humor; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D064090:Intraocular Lymphoma; D058449:Intravitreal Injections; D015863:Iridocyclitis; D016403:Lymphoma, Large B-Cell, Diffuse; D008727:Methotrexate; D018613:Microscopy, Confocal; D008875:Middle Aged; D012008:Recurrence; D012189:Retrospective Studies",
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"title": "Intraocular Lymphoma Masquerading as Recurrent Iridocyclitis: Findings Based on in vivo Confocal Microscopy.",
"title_normalized": "intraocular lymphoma masquerading as recurrent iridocyclitis findings based on in vivo confocal microscopy"
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"abstract": "The COVID-19 pandemic challenges neurologists in counselling patients with multiple sclerosis (pwMS) regarding their risk by SARS-CoV-2 and in guiding disease-modifying treatment (DMT).\n\n\n\nTo characterize the prevalence and outcome of COVID-19 in pwMS specifically associated with different DMT in a nationwide population-based study.\n\n\n\nWe included patients aged ≥18 years with a confirmed diagnosis of MS and a diagnosis of COVID-19 established between January 1, 2020 and December 31, 2020. We classified COVID-19 course as either mild, severe or fatal. Impact of DMT and specifically immunosuppressants (alemtuzumab, cladribine, fingolimod, ocrelizumab or rituximab) on COVID-19 outcome was determined by multivariable models, adjusted for a-priori-risk.\n\n\n\nOf 126 MS patients with COVID-19 (mean age 43.2 years [SD 13.4], 71% female), 86.5% had a mild course, 9.5% a severe course and 3.2% died from COVID-19. A-priori-risk significantly predicted COVID-19 severity (R2 0.814; p<0.001) and mortality (R2 0.664; p<0.001). Adjusting for this a-priori-risk, neither exposure to any DMT nor exposure to specific immunosuppressive DMT were significantly associated with COVID-19 severity (odds ratio [OR] 1.6; p = 0.667 and OR 1.9; p = 0.426) or mortality (OR 0.5; p = 0.711 and 2.1; 0.233) when compared to no DMT.\n\n\n\nIn a population-based MS cohort, COVID-19 outcome was not associated with exposure to DMT and immunosuppressive DMT when accounting for other already known risk factors. This provides reassuring evidence that COVID-19 risk can be individually anticipated in MS and-except for a very small proportion of high-risk patients-treatment decisions should be primarily focused on treating MS rather than the pandemic.",
"affiliations": "Department of Neurology, Medical University of Vienna, Vienna, Austria.;Department of Neurology, Kepler University Hospital, Linz, Austria.;Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.;Department of Neurology, Medical University of Graz, Graz, Austria.;Department of Neurology, Medical University of Vienna, Vienna, Austria.;Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.;Department of Neurology, Medical University of St. Pölten, St. Pölten, Austria.;Department of Neurology 2, Med Campus III, Kepler University Hospital GmbH, Linz, Austria.;Department of Neurology, Medical University of Vienna, Vienna, Austria.;Department of Neurology, Medical University of Vienna, Vienna, Austria.;Department of Neurology, Paracelsus Medical University of Salzburg, Salzburg, Austria.;Department of Neurology 2, Med Campus III, Kepler University Hospital GmbH, Linz, Austria.;Department of Neurology, Medical University of Graz, Graz, Austria.;Department of Neurology, Medical University of Vienna, Vienna, Austria.",
"authors": "Bsteh|Gabriel|G|0000-0002-0825-0851;Assar|Hamid|H|;Hegen|Harald|H|;Heschl|Bettina|B|;Leutmezer|Fritz|F|;Di Pauli|Franziska|F|;Gradl|Christiane|C|;Traxler|Gerhard|G|;Zulehner|Gudrun|G|;Rommer|Paulus|P|;Wipfler|Peter|P|;Guger|Michael|M|;Enzinger|Christian|C|;Berger|Thomas|T|;|||",
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"fulltext": "\n==== Front\nPLoS One\nPLoS One\nplos\nPLoS ONE\n1932-6203\nPublic Library of Science San Francisco, CA USA\n\n10.1371/journal.pone.0255316\nPONE-D-21-12442\nResearch Article\nMedicine and Health Sciences\nMedical Conditions\nInfectious Diseases\nViral Diseases\nCovid 19\nMedicine and Health Sciences\nEpidemiology\nMedical Risk Factors\nMedicine and Health Sciences\nEpidemiology\nMedical Risk Factors\nCancer Risk Factors\nMedicine and Health Sciences\nOncology\nCancer Risk Factors\nMedicine and Health Sciences\nClinical Medicine\nClinical Immunology\nAutoimmune Diseases\nMultiple Sclerosis\nBiology and Life Sciences\nImmunology\nClinical Immunology\nAutoimmune Diseases\nMultiple Sclerosis\nMedicine and Health Sciences\nImmunology\nClinical Immunology\nAutoimmune Diseases\nMultiple Sclerosis\nMedicine and Health Sciences\nMedical Conditions\nDemyelinating Disorders\nMultiple Sclerosis\nMedicine and Health Sciences\nNeurology\nDemyelinating Disorders\nMultiple Sclerosis\nMedicine and Health Sciences\nMedical Conditions\nNeurodegenerative Diseases\nMultiple Sclerosis\nMedicine and Health Sciences\nNeurology\nNeurodegenerative Diseases\nMultiple Sclerosis\nBiology and life sciences\nOrganisms\nViruses\nRNA viruses\nCoronaviruses\nSARS coronavirus\nSARS CoV 2\nBiology and life sciences\nMicrobiology\nMedical microbiology\nMicrobial pathogens\nViral pathogens\nCoronaviruses\nSARS coronavirus\nSARS CoV 2\nMedicine and health sciences\nPathology and laboratory medicine\nPathogens\nMicrobial pathogens\nViral pathogens\nCoronaviruses\nSARS coronavirus\nSARS CoV 2\nBiology and life sciences\nOrganisms\nViruses\nViral pathogens\nCoronaviruses\nSARS coronavirus\nSARS CoV 2\nMedicine and Health Sciences\nPharmacology\nDrugs\nImmunosuppressives\nMedicine and Health Sciences\nMedical Conditions\nCardiovascular Diseases\nCardiovascular Disease Risk\nMedicine and Health Sciences\nCardiology\nCardiovascular Medicine\nCardiovascular Diseases\nCardiovascular Disease Risk\nMedicine and Health Sciences\nClinical Medicine\nSigns and Symptoms\nLymphopenia\nCOVID-19 severity and mortality in multiple sclerosis are not associated with immunotherapy: Insights from a nation-wide Austrian registry\nCOVID-19 severity and mortality in multiple sclerosis do not depend on immunotherapy\nhttps://orcid.org/0000-0002-0825-0851\nBsteh Gabriel Conceptualization Data curation Formal analysis Writing – original draft 1*\nAssar Hamid Data curation Methodology Writing – review & editing 2\nHegen Harald Data curation Methodology Writing – review & editing 3\nHeschl Bettina Data curation Methodology Writing – review & editing 4\nLeutmezer Fritz Data curation Methodology Writing – review & editing 1\nDi Pauli Franziska Data curation Methodology Writing – review & editing 3\nGradl Christiane Data curation Methodology Writing – review & editing 5\nTraxler Gerhard Data curation Methodology Writing – review & editing 6\nZulehner Gudrun Data curation Methodology Writing – review & editing 1\nRommer Paulus Data curation Methodology Writing – review & editing 1\nWipfler Peter Data curation Methodology Writing – review & editing 7\nGuger Michael Data curation Methodology Writing – review & editing 6\nEnzinger Christian Data curation Methodology Writing – review & editing 4\nBerger Thomas Conceptualization Supervision Writing – review & editing 1\nfor the AUT-MuSC investigators1¶\n1 Department of Neurology, Medical University of Vienna, Vienna, Austria\n2 Department of Neurology, Kepler University Hospital, Linz, Austria\n3 Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria\n4 Department of Neurology, Medical University of Graz, Graz, Austria\n5 Department of Neurology, Medical University of St. Pölten, St. Pölten, Austria\n6 Department of Neurology 2, Med Campus III, Kepler University Hospital GmbH, Linz, Austria\n7 Department of Neurology, Paracelsus Medical University of Salzburg, Salzburg, Austria\nAktas Orhan Editor\nHeinrich-Heine-Universitat Dusseldorf, GERMANY\nCompeting Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Gabriel Bsteh: has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, and received honoraria for consulting Biogen, Roche and Teva. Hamid Assar: has participated in meetings sponsored by, received honoraria (advisory boards, consultations) or travel funding from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. Harald Hegen: has participated in meetings sponsored by, received speaker honoraria or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Siemens and Teva, and received honoraria for consulting Biogen, Novartis and Teva. Bettina Heschl: has nothing to disclose. Fritz Leutmezer: has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Bayer, Biogen, Celgene, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. Franziska Di Pauli: has participated in meetings sponsored by, received honoraria (lectures, advisory boards, consultations) or travel funding from Bayer, Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, Roche and Teva. Christiane Gradl: has participated in meetings sponsored by, received honoraria (lectures, consultations) and/or travel funding from Biogen, D-Pharma, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. Gerhard Traxler: has participated in meetings sponsored by, received honoraria (lectures, advisory boards, consultations) or travel funding from Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. Gudrun Zulehner: has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. Paulus Rommer: has received honoraria for consultancy/speaking from AbbVie, Allmiral, Alexion, Biogen, Merck, Novartis, Roche, Sandoz, Sanofi Genzyme, has received research grants from Amicus, Biogen, Merck, Roche. Peter Wipfler: has received funding for travel and honoraria (lectures, advisory boards) from Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. Michael Guger: has received support and honoraria for research, consultation, lectures and education from Almirall, Bayer, Biogen, Celgene, Genzyme, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Shire and Teva. Christian Enzinger: has received funding for travel and speaker honoraria from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Shire and Teva. has received research support from Biogen, Celgene, Merck, and Teva; is serving on scientific advisory boards for Bayer, Biogen, Celgene, Merck, Novartis, Roche and Teva. Thomas Berger: has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for MS: Allergan, Bayer, Biogen, Bionorica, Celgene, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Teva. His institution has received financial support in the past 12 months by unrestricted research grants (Bayer, Biogen, Merck, Novartis, Sanofi Aventis, Teva) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Teva. This does not alter our adherence to PLOS ONE policies on sharing data and materials.\n\n¶ Membership of AUT-MuSC investigators is provided in the Acknowledgments.\n\n* E-mail: gabriel.bsteh@meduniwien.ac.at\n27 7 2021\n2021\n27 7 2021\n16 7 e025531614 4 2021\n13 7 2021\n© 2021 Bsteh et al\n2021\nBsteh et al\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\n\nBackground\n\nThe COVID-19 pandemic challenges neurologists in counselling patients with multiple sclerosis (pwMS) regarding their risk by SARS-CoV-2 and in guiding disease-modifying treatment (DMT).\n\nObjective\n\nTo characterize the prevalence and outcome of COVID-19 in pwMS specifically associated with different DMT in a nationwide population-based study.\n\nMethods\n\nWe included patients aged ≥18 years with a confirmed diagnosis of MS and a diagnosis of COVID-19 established between January 1, 2020 and December 31, 2020. We classified COVID-19 course as either mild, severe or fatal. Impact of DMT and specifically immunosuppressants (alemtuzumab, cladribine, fingolimod, ocrelizumab or rituximab) on COVID-19 outcome was determined by multivariable models, adjusted for a-priori-risk.\n\nResults\n\nOf 126 MS patients with COVID-19 (mean age 43.2 years [SD 13.4], 71% female), 86.5% had a mild course, 9.5% a severe course and 3.2% died from COVID-19. A-priori-risk significantly predicted COVID-19 severity (R2 0.814; p<0.001) and mortality (R2 0.664; p<0.001). Adjusting for this a-priori-risk, neither exposure to any DMT nor exposure to specific immunosuppressive DMT were significantly associated with COVID-19 severity (odds ratio [OR] 1.6; p = 0.667 and OR 1.9; p = 0.426) or mortality (OR 0.5; p = 0.711 and 2.1; 0.233) when compared to no DMT.\n\nConclusions\n\nIn a population-based MS cohort, COVID-19 outcome was not associated with exposure to DMT and immunosuppressive DMT when accounting for other already known risk factors. This provides reassuring evidence that COVID-19 risk can be individually anticipated in MS and–except for a very small proportion of high-risk patients–treatment decisions should be primarily focused on treating MS rather than the pandemic.\n\nThe author(s) received no specific funding for this work. Data AvailabilityData supporting the findings of this study are available from the corresponding author upon reasonable request by a qualified researcher and can be accessed from and upon approval by the ethics committee of the Medical University Vienna (contact via letter to Borschkegasse 9, 1090 Vienna, Austria) since data contain potentially sensitive information.\nOutbreaksCOVID-19\nData Availability\n\nData supporting the findings of this study are available from the corresponding author upon reasonable request by a qualified researcher and can be accessed from and upon approval by the ethics committee of the Medical University Vienna (contact via letter to Borschkegasse 9, 1090 Vienna, Austria) since data contain potentially sensitive information.\n==== Body\nIntroduction\n\nThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused more than 83 million confirmed infections worldwide and approximately 1.8 million have died from the consequences of the virus-associated respiratory disease (CoronaVirus-Disease 2019, COVID-19) as by December 31st, 2020. Mortality and clinical severity of COVID-19 are strongly dependent of age and preexisting comorbidities [1, 2].\n\nMultiple sclerosis (MS) is often considered as a disease affecting young adults, but a substantial number of patients with MS (pwMS) are older than 60 years and might thus be at an increased risk of severe morbidity and mortality from COVID-19 [2–4].\n\nFurther, there is particular concern whether immunomodulatory or immunosuppressive disease-modifying treatments (DMT), which are to some extent associated with a greater risk of infection, also increase the risk for COVID-19 severity and mortality [5, 6]. Although initial reports indicated a low proportion of pwMS at high risk of COVID-19 mortality, evidence regarding the effect of DMT on the course of COVID-19 is as scarce as direly needed for guiding pwMS through the pandemic [5, 7, 8].\n\nThe objective of this study was to characterize the prevalence, severity and overall mortality of SARS-CoV-2 infections in pwMS specifically associated with different DMT in a nationwide population-based study.\n\nMethods\n\nPatients and data collection\n\nIn this nationwide multicenter observational study, we included patients with a confirmed diagnosis of MS aged ≥18 years and with a diagnosis of COVID-19 (defined by either a positive SARS-CoV-2 polymerase chain reaction [PCR] or clinical diagnosis supported by i) a subsequent positive SARS-CoV-2 antibody test or b) a positive SARS-CoV-2 PCR in a close contact person of the patient) established between January 1, 2020 and December 31, 2020 into the Austrian MS-COVID-19 registry (AUT-MuSC) [9].\n\nPatients were recruited through the Austrian MS network, which is a collaboration of MS centers certified by the Austrian Neurological Society adhering to a common and controlled high-quality standard of managing and documenting about 13.500 patients with MS in Austria [10]. The study was designed and conducted in accordance with the Declaration of Helsinki, the General Data Protection Regulation and the Strengthening Reporting of Observational Studies in Epidemiology (STROBE) guidelines and was approved by the ethics committee of the Medical University Vienna (ethical approval number: EK 1338–2020).\n\nWhen the treating neurologist was informed about a diagnosis of COVID-19 or a confirmed SARS-CoV-2 infection in an MS patient either at an on-site visit or remotely, data were collected retrospectively by fulfilling a pseudonymized case report form from a review of medical records, which was then sent to the coordinating study center at the Department of Neurology, Medical University of Vienna. Patients included were informed about the objective of the study and written informed consent was obtained.\n\nData collected included demographic data, details of MS course, DMT history, a detailed documentation of prior and current comorbidities and a detailed description of source, course, available laboratory and radiographic diagnostics, treatment and outcome of COVID-19.\n\nDefinitions and endpoints\n\nPatients were classified regarding their a-priori risk of COVID-19 severity and mortality according to a recently developed risk score (MS-COV-risk, see Table 1), categorizing MS patients based on age, physical disability (Expanded Disability Status Scale [EDSS] score), smoking status, obesity (body-mass-index ≥30), and presence of cardiovascular disease (coronary heart disease and/or ischemic heart failure and/or cardiac valve disease), chronic pulmonary disease (asthma, obstructive pulmonary disease [COPD] or pulmonary fibrosis), diabetes mellitus, chronic kidney disease and current malignancy as having either low (<1%), mild (<5%), moderate (~15%), high (~30%) or very high risk (~50%) of COVID-19 mortality [7].\n\n10.1371/journal.pone.0255316.t001 Table 1 MS-COV-risk score.\n\nFactor\tScore\t\nDiabetes AND age <40 years\t5\t\nAge ≥65 years\t3\t\nChronic kidney disease\t3\t\nChronic obstructive pulmonary disease\t1\t\nCardiovascular disease\t1\t\nCurrent Malignancy\t1\t\nObesity (BMI ≥30)\t1\t\nDiabetes\t1\t\nSmoking\t1\t\nSevere physical disability (EDSS >6)\t1\t\nAge <40\t-6\t\nRisk category\tScore Interval\t\nLow risk\t≤0\t\nMild risk\t1–3\t\nModerate risk\t4–7\t\nHigh risk\t8–11\t\nVery high risk\t≥12\t\nBMI: body mass index. EDSS: expanded disability status scale. See reference [7].\n\nPatients were grouped according to their DMT status at the time of SARS-CoV-2 infection as either receiving no DMT (N-DMT); immunomodulating DMT (IM-DMT) comprising dimethyl fumarate, glatiramer acetate, interferon-beta preparations, natalizumab, and teriflunomide; or immunosuppressive DMT (IS-DMT) comprising alemtuzumab, cladribine, fingolimod, ocrelizumab or rituximab [8, 11].\n\nThe primary endpoint was COVID-19 severity defined as the clinical status at the most severe point of COVID-19 course on a 4-point ordinal scale, where 0 indicates an asymptomatic course; 1 a mild course (no pneumonia or mild pneumonia without hospitalization); 2 a severe course requiring hospitalization and fulfilling at least one of five criteria (breathing rate >30/minute, SpO2 ≤93%, PaO2/FiO2-Ratio <300, Pulmonary infiltrate >50% within 24-48h, requirement of noninvasive ventilation, high-flow oxygen, mechanical ventilation or extracorporeal membrane oxygenation), and 3 death. The secondary endpoint was defined as mortality from COVID-19.\n\nStatistical analysis\n\nStatistical analysis was performed using SPSS 26.0 (SPSS Inc, Chicago, IL). Categorical variables were expressed in frequencies and percentages. Continuous variables were tested for normal distribution by Shapiro-Wilk test and expressed as mean and standard deviation (SD) or median and range as appropriate. Univariate group comparisons were conducted by t-test, ANOVA, Mann-Whitney-U test, Kruskal-Wallis test or chi-square test as appropriate.\n\nFirst, we investigated the strength of association between a-priori risk scoring and COVID-19 outcome (severity and mortality) by performing univariable correlation analyses (Spearman-rho) and multivariable logistic regression models with COVID-19 severity/mortality as the dependent variable and MS-COV-risk score (absolute score and risk categories) as the independent variable adjusting for sex (age is already included in the MS-COV-risk score) and lymphopenia before COVID-19 as a possible risk factor not included in the MS-COV-risk score [8]. Then, we tested the independent impact of overall DMT as well as IM-DMT and IS-DMT on COVID-19 outcome by calculating multivariate logistic regression models with COVID-19 severity/mortality as the dependent variable and DMT categories (reference category: N-DMT) as the independent variable adjusted for a-priori-risk as expressed by MS-COV-risk score adjusting for sex and lymphopenia before COVID-19. Finally, we conducted sensitivity analyses evaluating the robustness of results to the impact of any single DMT substance by stepwise removal from analyses. Robustness of the statistically significant differences to unidentified confounders not accounted for by MS-COV-risk score was quantified with Rosenbaum sensitivity test for Hodges–Lehmann Γ [12]. Missing values were handled by multiple (20 times) imputation using the missing not at random (MNAR) approach with pooling of estimates according to Rubin’s rules [13]. A two-sided p-value <0.05 was considered statistically significant.\n\nResults\n\nWe included 126 patients with a mean age of 43.2 years [SD 13.4] and a female predominance of 71%. Overall characteristics of the study cohort are given in Table 2. A detailed description of every patient included is presented in (S1 Table).\n\n10.1371/journal.pone.0255316.t002 Table 2 Characteristics of the AUT-MuSC-19 cohort.\n\n\tn = 126\t\nFemalea\t90 (71.4)\t\nAge (years)b,c\t43.2 (13.4; 21–79)\t\nBMI c\t24.1 (17.4–41.0)\t\nSmokersa\t17 (3.5)\t\nEthnicitya\t\t\n Caucasiana\t123 (97.6)\t\n Othera\t3 (2.4)\t\nNo of comorbidities associated with increased COVID-19 morbidityc*\t0 (0–5)\t\nDisease duration (years) b\t12.0 (9.3)\t\nDisease coursea\t\t\n RRMSa\t98 (77.8)\t\n SPMSa\t19 (15.1)\t\n PPMSa\t9 (7.1)\t\nEDSSc\t2.0 (0–8.5)\t\nOn DMTa\t90 (71.4)\t\n IM-DMT\t48 (38.1)\t\n Interferon-betaa\t6 (4.8)\t\n Glatiramer acetatea\t11 (8.7)\t\n Dimethyl fumaratea\t19 (15.1)\t\n Teriflunomidea\t2 (1.6)\t\n Natalizumaba\t10 (7.9)\t\n IS-DMT\t41 (32.5)\t\n Fingolimoda\t16 (12.7)\t\n Ocrelizumab/Rituximaba\t12 (9.5)\t\n Alemtuzumaba\t2 (1.6)\t\n Cladribine\t2 (1.6)\t\n Azathioprina\t1 (0.8)\t\nLymphopenia at last lab before SARS-CoV2 infectiona**\t19 (18.4)\t\n Grade 3 or lowera\t7 (6.8)\t\nBMI: body mass index. DMT: disease modifying treatment. EDSS: Expanded Disability Status Scale. IM-DMT: Immunomodulating DMT = dimethyl fumarate, glatiramer acetate, interferon beta preparations, natalizumab, and teriflunomide. IS-DMT: Immunosuppressive DMT = alemtuzumab, cladribine, fingolimod, ocrelizumab or rituximab. MS: multiple sclerosis. PPMS: primary progressive MS. RRMS: relapsing-remitting MS. SPMS: secondary progressive MS.\n\naabsolute number and percentage.\n\nbmean and standard deviation.\n\ncmedian and minimum-maximum range.\n\n*defined as cardiovascular diseases, chronic obstructive pulmonary disease, chronic kidney disease, diabetes and concurrent malignancy.\n\n**available from 103 patients.\n\nThe number of comorbidities associated with increased COVID-19 morbidity (cardiovascular disease, chronic obstructive pulmonary disease, chronic kidney disease, diabetes and concurrent malignancy) as well as MS-associated physical disability (EDSS) significantly increased with age (rho = 0.176, p = 0.049 and rho = 0.576, p<0.001, respectively). Frequency of obesity and smoking was not associated with age, but pwMS receiving DMT were significantly younger than those without DMT (mean age 39.0 vs. 53.6; p<0.001). Of the 103 patients with available differential blood count before COVID-19 onset, 19 (18.4%) had lymphopenia, with 7 (6.8%) grade 3 or lower.\n\nOverall, 5 (4.0%) were asymptomatically infected with SARS-CoV-2, 109 (86.5%) had mild COVID-19 and 12 (9.5%) had a severe course, of whom 4 (3.2%) died from COVID-19.\n\nA-priori-risk and COVID-19 outcome\n\nOverall, a-priori risk categories were distributed as follows: 75 (59.5%) low risk, 39 (3.0%) mild risk, 8 (6.3%) moderate risk and 4 (3.2%) high risk of COVID-19 mortality. We therefore condensed patients with moderate and high risk into one group to facilitate further categorical analyses.\n\nMS-COV-risk score was strongly correlated with COVID-19 outcome (rho = -0.426, p<0.001). Among the 103 patients for whom lymphocyte counts were available before COVID-19 onset, we did not find an association between lymphopenia and COVID-19 severity or mortality.\n\nIn the multivariable models adjusting for sex and lymphopenia, MS-COV-risk score significantly predicted COVID-19 severity (odds ratio [OR]: 1.4 per 1 point increase; 95% confidence interval [CI]: 1.2–3.7; p = 0.001; R2 0.814; p<0.001) and mortality (OR: 2.4; CI: 1.2–5.4; p = 0.007; R2 0.664; p<0.001).\n\nThe impact of DMT on COVID-19 outcome\n\nCOVID-19 outcome according to DMT categories and single DMT substances is shown in Fig 1. We did not find any significant association between DMT and COVID-19 morbidity, neither overall, nor when stratifying according to a-priori risk categories (Table 3).\n\n10.1371/journal.pone.0255316.g001 Fig 1 COVID-19 outcome according to DMT classes (A) and single substances (B). DMT: disease modifying treatment. IM-DMT: Immunomodulating DMT = dimethyl fumarate, glatiramer acetate, interferon beta preparations, natalizumab, and teriflunomide. IS-DMT: Immunosuppressive DMT = alemtuzumab, cladribine, fingolimod, ocrelizumab or rituximab. p-values calculated by chi-square test. N-DMT: no DMT.\n\n10.1371/journal.pone.0255316.t003 Table 3 COVID-19 severity and mortality according to a-priori risk and DMT class.\n\nRisk category\t\tAt risk\tSevere COVID-19\tp-value\tFatal COVID-19\tp-value\t\nLow risk (Score ≤0) N = 75\tN-DMT\t17\t0\t0.4551\t0 (0)\tNA\t\nIM-DMT\t31\t1\t0 (0)\t\nIS-DMT\t27\t2\t0 (0)\t\nMild risk (Score 1–3) N = 39\tN-DMT\t11\t0\t0.3151\t0 (0)\tNA\t\nIM-DMT\t16\t0\t0 (0)\t\nIS-DMT\t12\t1\t0 (0)\t\nModerate/high risk (Score ≥4) N = 12\tN-DMT\t9\t6\t0.6871\t3\t0.6771\t\nIM-DMT\t1\t1\t0\t\nIS-DMT\t2\t1\t1\t\nDMT: disease modifying treatment. IM-DMT: Immunomodulating DMT = dimethyl fumarate, glatiramer acetate, interferon beta preparations, natalizumab, and teriflunomide. IS-DMT: Immunosuppressive DMT = alemtuzumab, cladribine, fingolimod, ocrelizumab or rituximab.\n\n1calculated by chi-square test. N-DMT: no DMT.\n\nAdjusting for MS-COV-risk score, sex and lymphopenia before SARS-CoV-2 infection, exposure to any DMT was neither associated with COVID-19 severity (OR: 1.6; CI: 0.2–11.9; p = 0.667) nor with mortality (OR: 0.5; CI: 0.2–19.6; p = 0.711, Table 4) when compared to no DMT. Similarly, exposure to IS-DMT was not associated with COVID-19 severity (OR: 1.9; CI: 0.5–9.4; p = 0.426) and mortality (OR 2.1; CI: 0.8–12.3; p = 0.233).\n\n10.1371/journal.pone.0255316.t004 Table 4 COVID-19 severity and mortality depend on a priori risk but not DMT class.\n\nCOVID-19 severity\tCOVID-19 mortality\t\n\tOR\t95% CI\tp value\t\tOR\t95% CI\tp value\t\nMS-COV-risk score (per point)\t1.5\t1.2–3.7\t0.005\tMS-COV-risk score (per point)\t2.4\t1.2–7.3\t0.021\t\nDMT1\t1.6\t0.2–11.9\t0.667\tDMT1\t0.5\t0.2–19.6\t0.711\t\n IM-DMT\t1.1\t0.2–7.3\t0.943\t IM-DMT\t0.2\t0.0–3.4\t0.122\t\n IS-DMT\t1.9\t0.5–9.4\t0.426\t IS-DMT\t2.1\t0.8–12.3\t0.233\t\n\tR square 0.832; p<0.001\t\tR square 0.683; p<0.001\t\n1reference category: no DMT.\n\nIM-DMT: Immunomodulating DMT = dimethyl fumarate, glatiramer acetate, interferon beta preparations, natalizumab, and teriflunomide. IS-DMT: Immunosuppressive DMT = alemtuzumab, cladribine, fingolimod, ocrelizumab or rituximab. OR: odds ratio. 95% CI: confidence interval. Calculated by binary linear regression models with severe COVID-19 and fatal COVID-19 adjusted for sex and lymphopenia before COVID-19.\n\nDiscussion\n\nIn this nationwide population-based study of SARS-CoV-2 infections in pwMS, we report several key findings: 1) prevalence, severity and mortality in pwMS in Austria are comparable to the general population, 2) COVID-19 severity and mortality can be predicted by applying a score of known a-priori risk factors and 3) COVID-19 severity and mortality are not associated with exposure to DMT and specifically immunosuppressive DMT when accounting for a-priori risk.\n\nPrevalence\n\nGiven a population of approximately 13,500 MS patients in Austria, the 126 pwMS included in this population-based study would translate to a prevalence of 0.93% at the end of 2020.[10] This would seem well below the prevalence of 4.2% of COVID-19 in the general population (360,815 confirmed cases in 8.5 million people) during the same period [14, 15]. However, the prevalence in the general population is based on the number of positive SARS-CoV-2 tests rather than symptomatic COVID-19. Considering that only about 20% of seropositive MS patients appear to have symptomatic COVID-19 and that only 5/126 (3.9%) patients were asymptomatic in our cohort, the true prevalence of SARS-CoV-2 infection in the Austrian MS population can be estimated at 4.1% and, thus, lies well within the range of the general population [16]. This is in line with previous studies applying various definitions of SARS-CoV-2 infection/COVID-19 and pharmacoepidemiological techniques adding to the mounting evidence that pwMS are neither more nor less likely to contract SARS-CoV-2 [17–19]. Thus, it can be inferred that the AUT-MuSC-19 registry is likely to include most of pwMS with a symptomatic SARS-CoV-2 infections in Austria and is likely representative of a central European, primarily Caucasian MS population.\n\nCOVID severity and mortality\n\nEvidence regarding the specific morbidity and mortality from COVID-19 in pwMS is still scarce. In our population-based cohort, we found 9.5% with severe COVID-19 course and 3.2% mortality. Encouragingly, this is within the range of mortality reports both in Austria (1.7%; 6,222 of 360,815 confirmed cases) and globally (2.2%) in the general population and in line with previous studies suggesting that MS patients do not have an increased risk of COVID-19 fatality compared with the population at large [8, 14, 20–22].\n\nIt is well established that in the general population COVID-19 severity and mortality increases with older age and in the presence of comorbidities, i.e. cardiovascular disease, pulmonary disease, chronic kidney disease, malignancy, obesity and smoking [1, 2, 23, 24]. In MS patients, advanced physical disability represents an additional factor associated with poor COVID-19 outcome [8, 22]. We have recently introduced a score (MS-COV-risk) to cumulatively quantify these a-priori risk factors in order to predict COVID-19 severity and mortality in pwMS [7]. Here, we found that by applying the MS-COV-risk score, 81% of the variation in COVID-19 severity (R2 0.862; p<0.001) and 66% of mortality (R2 0.663; p<0.001) could be predicted. This both validates the predictive ability of the MS-COV-risk score and confirms that COVID morbidity in pwMS is largely determined by factors independent of MS and, thus, can be anticipated.\n\nThe role of DMT\n\nOne of the most pressing questions in managing pwMS during the pandemic is whether immunomodulatory or immunosuppressive DMT increase the risk for COVID-19 severity and mortality. While MS is generally not associated with increased morbidity from viral pathogens, some DMTs are to some extent associated with a greater risk of infection [21]. Therefore, initial recommendations of various expert committees at the beginning of the pandemic in early 2020 have offered very conservative advice with some even suggesting discontinuation of DMT. As the number of cases grew over the subsequent months, evidence is reassuringly growing that poor outcome in pwMS contracting COVID-19 is primarily dependent on age, obesity, comorbidities and degree of physical disability rather than DMT use in general [5, 8, 22, 25–28]. Our data confirm and extend these findings showing that when accounting for a-priori risk, COVID-19 severity and mortality are independent of both overall exposure to DMT as well immunosuppressive DMT. This has also been recently shown in a large pharmacoepidemiological study [18]. However, there is some concern regarding a possibly increased risk under treatment with anti-CD20 B cell depleting agents as indicated by a recent large observational study [28]. Also, there have been reports of a decreased serologic response in pwMS after SARS-CoV-2 infection [29, 30]. Our study is not sufficiently powered to determine the effect of single DMT substances on COVID outcome. However, sensitivity analyses did not indicate a significant change of results when removing single DMT substances. Similar to other studies, we also did not find an association between lymphopenia and COVID-19 morbidity, neither in univariable analyses nor when accounting for a-priori risk and DMT [8, 26].\n\nTherefore, in pwMS with low to moderate risk of COVID-19 mortality, the benefit-risk ratio is clearly in favor of both continuing and initiating DMT when indicated by the MS course in the respective individual patient. The majority of the small group of pwMS displaying a high a-priori risk of having severe COVID-19 does not even receive DMT (in our cohort 0 of 4 patients) and is unlikely to display significant disease activity, hence, the question of stopping or delaying DMT hardly arises [7]. Consequently, most expert committees have now adopted less cautious guidelines emphasizing the paramount need for ensuring optimal treatment of MS individually integrating MS specific parameters as well as comorbidities, social circumstances, personal risk perception etc., especially during the pandemic [31, 32]. In this light, reports of significant drops in patient rate and changed/deferred DMT regimens are particularly concerning as quality of life of pwMS greatly depends on prompt access to a broad range of health and care service [33, 34]. It is essential for MS caregivers to uphold the standard of care for pwMS, including continuation of safety monitoring procedures as far as possible depending on local circumstances [21, 32].\n\nStrengths and limitations\n\nThe main strengths of this study are its population-based approach and the detailed characterization of the study cohort provided by the high-quality data from certified specialized MS centers. We have to acknowledge some potential limitations inherent to the study design.\n\nMS patients with asymptomatic SARS-CoV-2 infection may have been systematically missed due to the study design. As already noted earlier, our study is not sufficiently powered to determine the effect of single DMT substances on COVID outcome. Thus, we had to use a categorization in immunomodulating and immunosuppressive DMTs in the primary analyses, resulting in an estimated power of 73% for detecting an increased risk of COVID severity by an odds ratio of 2. However, we conducted sensitivity analyses evaluating the robustness of results to the impact of any single DMT substance by stepwise removal, which did not indicate a significant change of results. In addition, there may be a referral bias as severe COVID-19 courses may be more likely to be reported. On the other hand, patients with advanced and progressive MS or patients not receiving DMT are less frequently seeing a neurologist regularly and, thus, this cohort might be underrepresented in this study. There may also be confounders influencing COVID severity/mortality in pwMS unaccounted for by MS-COV-risk score and DMT. However, Rosenbaum bounds did indicate only a small potential impact of hidden bias not accounted for in the multivariable models [12].\n\nConclusion\n\nWe showed in a population-based MS cohort that COVID-19 severity and mortality are not associated with exposure to DMT and immunosuppressive DMT when accounting for unmodifiable risk factors. This provides reassuring evidence that the COVID-19 risk can be anticipated in MS and–except for a very small proportion of high-risk patients–treatment decisions should be primarily focused on treating MS rather than the pandemic.\n\nSupporting information\n\nS1 Table Characteristics of all 126 patients included.\n\nATZ: alemtuzumab, CHD: coronary heart disease., CKD: Chronic kidney disease, CLA: cladribine, COPD: chronic obstructive pulmonary disease, DMF: dimethyl fumarate, DMT: disease modifying treatment, EDSS: Expanded disability status scale, FTY: fingolimod, F: female, GLA: glatiramer acetate, IFN: interferon beta, M: male, NTZ: natalizumab, OCR: ocrelizumab, PCR: SARS-CoV-2-polymerase-chain-reaction, RTX: rituximab, TERI: teriflunomide.\n\n(DOCX)\n\nClick here for additional data file.\n\nWe thank all the AUT-MuSC-19 investigators, clinical research staff, and especially the patients for helping to collect these data. The named individuals were not compensated for their help. Lead AUT-MuSC investigator: Gabriel Bsteh, MD, PhD; Email: gabriel.bsteh@meduniwien.ac.at.\n\nAUT-MuSC investigators in alphabetical order: Assar, Hamid (Kepler University Hospital, Linz, Austria); Berger, Thomas (Medical University of Vienna, Vienna, Austria); Böck, Klaus (Kepler University Hospital, Linz, Austria); Bsteh, Christian (Private practice neurologist, Salzburg, Austria); Bsteh, Gabriel (Medical University of Vienna, Vienna, Austria); Di Pauli, Franziska (Medical University of Innsbruck, Innsbruck, Austria); Enzinger, Christian (Medical University of Graz, Graz, Austria); Gradl, Christiane (Medical University of St. Pölten, St. Pölten, Austria); Guger, Michael (Med Campus III, Kepler University Hospital GmbH, Linz, Austria); Hegen, Harald (Medical University of Innsbruck, Innsbruck, Austria); Heschl, Bettina (Medical University of Graz, Graz, Austria); Hiller, Marie-Sophie (Barmherzige Brüder Hospital, Eisenstadt, Austria); Kornek, Barbara (Medical University of Vienna, Vienna, Austria); Leutmezer, Fritz (Medical University of Vienna, Vienna, Austria); Mayr, Markus (District Hospital Kufstein, Kufstein, Austria); Morgenstern, Gabriele (Private practice neurologist, Lienz, Austria); Rommer, Paulus (Medical University of Vienna, Vienna, Austria); Schnabl, Peter (Private practice neurologist, Velden, Austria); Schneider-Koch, Gabriela (Ottakring Hospital, Vienna, Austria); Schrotter, Gabriele (LKH West Graz, Graz, Austria); Traxler, Gerhard (Clinic for Neurology 2, Med Campus III, Kepler University Hospital GmbH, Linz, Austria); Wipfler, Peter (Paracelsus Medical University of Salzburg, Salzburg, Austria); Zulehner, Gudrun (Medical University of Vienna, Vienna, Austria); Zrzavy, Tobias (Medical University of Vienna, Vienna, Austria).\n\n10.1371/journal.pone.0255316.r001\nDecision Letter 0\nAktas Orhan Academic Editor\n© 2021 Orhan Aktas\n2021\nOrhan Aktas\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nSubmission Version0\n25 May 2021\n\nPONE-D-21-12442\n\nCOVID-19 severity and mortality in multiple sclerosis do not depend on immunotherapy: insights from a nation-wide Austrian registry\n\nPLOS ONE\n\nDear Dr. Bsteh,\n\nThank you for submitting your manuscript to PLOS ONE. 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Thank you for stating the following in the Competing Interests section:\n\n\"I have read the journal's policy and the authors of this manuscript have the following competing interests:\n\nGabriel Bsteh: has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, and received honoraria for consulting Biogen, Roche and Teva.\n\nHamid Assar: has participated in meetings sponsored by, received honoraria (advisory boards, consultations) or travel funding from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva.\n\nHarald Hegen: has participated in meetings sponsored by, received speaker honoraria or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Siemens and Teva, and received honoraria for consulting Biogen, Novartis and Teva.\n\nBettina Heschl: has nothing to disclose.\n\nFritz Leutmezer: has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Bayer, Biogen, Celgene, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme and Teva.\n\nFranziska Di Pauli: has participated in meetings sponsored by, received honoraria (lectures, advisory boards, consultations) or travel funding from Bayer, Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, Roche and Teva.\n\nChristiane Gradl: has participated in meetings sponsored by, received honoraria (lectures, consultations) and/or travel funding from Biogen, D-Pharma, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva.\n\nGerhard Traxler: has participated in meetings sponsored by, received honoraria (lectures, advisory boards, consultations) or travel funding from Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and Teva.\n\nGudrun Zulehner: has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva.\n\nPaulus Rommer: has received honoraria for consultancy/speaking from AbbVie, Allmiral, Alexion, Biogen, Merck, Novartis, Roche, Sandoz, Sanofi Genzyme, has received research grants from Amicus, Biogen, Merck, Roche.\n\nPeter Wipfler: has received funding for travel and honoraria (lectures, advisory boards) from Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and Teva.\n\nMichael Guger: has received support and honoraria for research, consultation, lectures and education from Almirall, Bayer, Biogen, Celgene, Genzyme, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Shire and Teva.\n\nChristian Enzinger: has received funding for travel and speaker honoraria from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Shire and Teva. has received research support from Biogen, Celgene, Merck, and Teva; is serving on scientific advisory boards for Bayer, Biogen, Celgene, Merck, Novartis, Roche and Teva.\n\nThomas Berger: has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for MS: Allergan, Bayer, Biogen, Bionorica, Celgene, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Teva. His institution has received financial support in the past 12 months by unrestricted research grants (Bayer, Biogen, Merck, Novartis, Sanofi Aventis, Teva) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Teva.\"\n\nPlease confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: \"This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. 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Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests\n\n[Note: HTML markup is below. Please do not edit.]\n\nReviewers' comments:\n\nReviewer's Responses to Questions\n\nComments to the Author\n\n1. Is the manuscript technically sound, and do the data support the conclusions?\n\nThe manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.\n\nReviewer #1: Partly\n\nReviewer #2: Yes\n\n**********\n\n2. Has the statistical analysis been performed appropriately and rigorously?\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n3. Have the authors made all data underlying the findings in their manuscript fully available?\n\nThe PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n4. Is the manuscript presented in an intelligible fashion and written in standard English?\n\nPLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.\n\nReviewer #1: Yes\n\nReviewer #2: Yes\n\n**********\n\n5. Review Comments to the Author\n\nPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)\n\nReviewer #1: Bsteh et al present a timely, population-based study regarding COVID-19 severity and mortality in multiple sclerosis patients in Austria. The authors included 129 multiple sclerosis patients with COVID-19, 86.5% had a mild course, 9.5% a severe course and 3.2% died. According to the authors, COVID-19 prevalence of the study cohort lies well within the general population. Neither exposure to any diseases-modifying treatment nor exposure to specific immunosuppressive DMT were significantly associated with COVID-19 severity. The mansucript is well-written and the results are of interest. However, the manuscript would improve when addressing a few minor issues.\n\n1. Methods/results and abstract/conclusions are slightly imbalanced. Correlation does not imply causation, and both the manuscript title and the conclusion \"treatment decisions should be focused on treating MS rather than the pandemic\" are rather strong for a population-based study (with power issues) including 'only' 129 multiple sclerosis patients. Furthermore, the authors should clearly state that (asymptomatic) COVID-19 patients with multiple sclerosis may have been systematically missed due to the study design. Please adapt accordingly.\n\n2. In the methods section, the authors wrote that the reference category is \"multiple sclerosis patients without disease-modifying treatment exposure\". In order to increase readability, please mention the reference category also in the abstract, results and discussion when appropriate.\n\n3. The authors state that any disease-modifying treatment exposure was not associated with COVID-19 severity. However, a recently published study suggests that interferon antibodies are present in COVID-19 patients with a life-threatening course, especially in men and older patients (DOI: 10.1126/science.abd4585). Therefore, substituting interferon(-beta) may be beneficial regarding COVID-19 severitiy. If feasible, the authors could carefully comment on the 6 (4.8%) multiple sclerosis patients receiving interferon-beta having mild (and not life-threatening) COVID-19 (according to Suppl Table 1).\n\nI thank the authors for their relevant scientific work.\n\nReviewer #2: The authors report the findings on COVID-19 severity and mortality in MS patients investigated in a nation-wide Austrian registry. According to their results, outcome of COVID-19 is not modified by disease-modifying immunotherapy for MS.\n\nThe methods are sound, the results are clearly presented, and the conclusions are justified. I have only a few suggestions:\n\n1) Methods. Please explain how diagnosis of COVID-19 was performed for the Austrian MS-COVID-19 registry.\n\n2) Methods. Please insert a table outlining the MS-COV-risk score recently developed by the authors. This would help a lot to better understand the findings.\n\n3) Table 1. please also show range for age\n\n4) Page 6, punctuation after reference [12]\n\n**********\n\n6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.\n\nIf you choose “no”, your identity will remain anonymous but your review may still be made public.\n\nDo you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.\n\nReviewer #1: No\n\nReviewer #2: No\n\n[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link \"View Attachments\". If this link does not appear, there are no attachment files.]\n\nWhile revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.\n\n10.1371/journal.pone.0255316.r002\nAuthor response to Decision Letter 0\nSubmission Version1\n23 Jun 2021\n\nRebuttal to comments of reviewers and editor from initial submission (PONE-D-21-12442: COVID-19 severity and mortality in multiple sclerosis do not depend on immunotherapy: insights from a nation-wide Austrian registry)\n\nJournal Requirements\n\n1. When submitting your revision, we need you to address these additional requirements.Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.\n\nResponse: Done.\n\n2. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.\n\nResponse: Done.\n\n3. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager.\n\nResponse: Done.\n\n4. One of the noted authors is a group or consortium [AUT-MuSC investigators]. In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address.\n\nResponse: Done.\n\n5. Thank you for stating the following in the Competing Interests section: \"I have read the journal's policy and the authors of this manuscript have the following competing interests. Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: \"This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.\n\nResponse: Done.\n\nReviewers' comments\n\nReviewer: 1\n\nComment: Bsteh et al present a timely, population-based study regarding COVID-19 severity and mortality in multiple sclerosis patients in Austria. The authors included 129 multiple sclerosis patients with COVID-19, 86.5% had a mild course, 9.5% a severe course and 3.2% died. According to the authors, COVID-19 prevalence of the study cohort lies well within the general population. Neither exposure to any diseases-modifying treatment nor exposure to specific immunosuppressive DMT were significantly associated with COVID-19 severity. The mansucript is well-written and the results are of interest. However, the manuscript would improve when addressing a few minor issues.\n\nResponse: Thank you for this positive assessment of our study.\n\nComment: 1. Methods/results and abstract/conclusions are slightly imbalanced. Correlation does not imply causation, and both the manuscript title and the conclusion \"treatment decisions should be focused on treating MS rather than the pandemic\" are rather strong for a population-based study (with power issues) including 'only' 129 multiple sclerosis patients. Furthermore, the authors should clearly state that (asymptomatic) COVID-19 patients with multiple sclerosis may have been systematically missed due to the study design. Please adapt accordingly.\n\nResponse: Thank you for this comment. We agree and have made an effort to improve the balance of the manuscript (see title, abstract and discussion section)\n\nComment: 2. In the methods section, the authors wrote that the reference category is \"multiple sclerosis patients without disease-modifying treatment exposure\". In order to increase readability, please mention the reference category also in the abstract, results and discussion when appropriate.\n\nResponse: Thank you for this comment. We have mentioned the reference category as requested (see abstract, results and discussion section)\n\nComment: 3. The authors state that any disease-modifying treatment exposure was not associated with COVID-19 severity. However, a recently published study suggests that interferon antibodies are present in COVID-19 patients with a life-threatening course, especially in men and older patients (DOI: 10.1126/science.abd4585). Therefore, substituting interferon(-beta) may be beneficial regarding COVID-19 severitiy. If feasible, the authors could carefully comment on the 6 (4.8%) multiple sclerosis patients receiving interferon-beta having mild (and not life-threatening) COVID-19 (according to Suppl Table 1).\n\nResponse: Thank you again for this comment. While this is certainly an interesting aspect, we do not think that our data stemming from 6 patients treated with interferon beta preparations allows for an evidence-based or sufficiently informed comment on the potential role of autoantibodies against IFN-alpha2 and IFN-ω.\n\nComment: I thank the authors for their relevant scientific work.\n\nResponse: We thank the reviewer for the diligent work and constructive criticism.\n\nReviewer: 2\n\nComment: The authors report the findings on COVID-19 severity and mortality in MS patients investigated in a nation-wide Austrian registry. According to their results, outcome of COVID-19 is not modified by disease-modifying immunotherapy for MS. The methods are sound, the results are clearly presented, and the conclusions are justified.\n\nResponse: Thank you for your positive assessment.\n\nComment: 1) Methods. Please explain how diagnosis of COVID-19 was performed for the Austrian MS-COVID-19 registry.\n\nResponse: Thank you for this comment. Diagnosis of was defined either by a positive SARS-CoV-2 polymerase chain reaction [PCR] or a clinical diagnosis supported by i) a subsequent positive SARS-CoV-2 antibody test or b) a positive SARS-CoV-2 PCR in a close contact person). This was clarified in the methods section (p4).\n\nComment: 2) Methods. Please insert a table outlining the MS-COV-risk score recently developed by the authors. This would help a lot to better understand the findings.\n\nResponse: Thank you for this suggestion. We have now included a table outlining the MS-COV-risk score as requested.\n\nComment: 3) Table 1. please also show range for age\n\nResponse: We have added range for age as requested.\n\nComment: 4) Page 6, punctuation after reference [12]\n\nResponse: Thank you for spotting this error. We have corrected the punctuation accordingly.\n\nAttachment Submitted filename: Rebutal_Letter_AutMuSC19_PlosOne.docx\n\nClick here for additional data file.\n\n10.1371/journal.pone.0255316.r003\nDecision Letter 1\nAktas Orhan Academic Editor\n© 2021 Orhan Aktas\n2021\nOrhan Aktas\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nSubmission Version1\n14 Jul 2021\n\nCOVID-19 severity and mortality in multiple sclerosis are not associated with immunotherapy: insights from a nation-wide Austrian registry\n\nPONE-D-21-12442R1\n\nDear Dr. Bsteh,\n\nWe’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.\n\nWithin one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.\n\nAn invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.\n\nIf your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.\n\nKind regards,\n\nOrhan Aktas, M.D.\n\nAcademic Editor\n\nPLOS ONE\n\nAdditional Editor Comments (optional):\n\nReviewers' comments:\n\nReviewer's Responses to Questions\n\nComments to the Author\n\n1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your \"Accept\" recommendation.\n\nReviewer #2: All comments have been addressed\n\n**********\n\n2. Is the manuscript technically sound, and do the data support the conclusions?\n\nThe manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.\n\nReviewer #2: Yes\n\n**********\n\n3. Has the statistical analysis been performed appropriately and rigorously?\n\nReviewer #2: Yes\n\n**********\n\n4. Have the authors made all data underlying the findings in their manuscript fully available?\n\nThe PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.\n\nReviewer #2: Yes\n\n**********\n\n5. Is the manuscript presented in an intelligible fashion and written in standard English?\n\nPLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.\n\nReviewer #2: Yes\n\n**********\n\n6. Review Comments to the Author\n\nPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)\n\nReviewer #2: All my comments have been addressed. The study adds important aspects to our understanding of the possible impact of immunotherapies on the outcome of MS patients in the pandemic era.\n\n**********\n\n7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.\n\nIf you choose “no”, your identity will remain anonymous but your review may still be made public.\n\nDo you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.\n\nReviewer #2: No\n\n10.1371/journal.pone.0255316.r004\nAcceptance letter\nAktas Orhan Academic Editor\n© 2021 Orhan Aktas\n2021\nOrhan Aktas\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\n19 Jul 2021\n\nPONE-D-21-12442R1\n\nCOVID-19 severity and mortality in multiple sclerosis are not associated with immunotherapy: insights from a nation-wide Austrian registry\n\nDear Dr. Bsteh:\n\nI'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.\n\nIf your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.\n\nIf we can help with anything else, please email us at plosone@plos.org.\n\nThank you for submitting your work to PLOS ONE and supporting open access.\n\nKind regards,\n\nPLOS ONE Editorial Office Staff\n\non behalf of\n\nDr. Orhan Aktas\n\nAcademic Editor\n\nPLOS ONE\n==== Refs\nReferences\n\n1 Guan W , Ni Z , Hu Y , et al . Clinical Characteristics of Coronavirus Disease 2019 in China. New Engl J Med. 2020;382 (18 ):1708–1720. doi: 10.1056/NEJMoa2002032 32109013\n2 Zhou F , Yu T , Du R , et al . Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395 (10229 ):1054–1062. doi: 10.1016/S0140-6736(20)30566-3 32171076\n3 Wang Z , Yang B , Li Q , Wen L , Zhang R . Clinical Features of 69 Cases with Coronavirus Disease 2019 in Wuhan, China. Clin Infect Dis. Published online 2020. doi: 10.1093/cid/ciaa272 32176772\n4 Minden SL , Frankel D , Hadden LS , Srinath KP , Perloff JN . Disability in elderly people with multiple sclerosis: An analysis of baseline data from the Sonya Slifka Longitudinal Multiple Sclerosis Study. Neurorehab. 2004;19 :55–67. doi: 10.3233/nre-2004-19107 14988588\n5 Möhn N , Konen FF , Pul R , et al . Experience in Multiple Sclerosis Patients with COVID-19 and Disease-Modifying Therapies: A Review of 873 Published Cases. J Clin Med. 2020;9 (12 ):4067. doi: 10.3390/jcm9124067 33339436\n6 Grebenciucova E , Pruitt A . Infections in Patients Receiving Multiple Sclerosis Disease-Modifying Therapies. Curr Neurol Neurosci. 2017;17 (11 ):88. doi: 10.1007/s11910-017-0800-8 28940162\n7 Bsteh G , Bitschnau C , Hegen H , et al . Multiple sclerosis and COVID-19: how many are at risk? Eur J Neurol. Published online 2020. doi: 10.1111/ene.14555 32978860\n8 Louapre C , Collongues N , Stankoff B , et al . Clinical Characteristics and Outcomes in Patients With Coronavirus Disease 2019 and Multiple Sclerosis. JAMA Neurol. 2020;77 (9 ). doi: 10.1001/jamaneurol.2020.2581 32589189\n9 Thompson AJ , Banwell BL , Barkhof F , et al . Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17 (2 ):162–173. doi: 10.1016/S1474-4422(17)30470-2 29275977\n10 Salhofer-Polanyi S , Cetin H , Leutmezer F , et al . Epidemiology of Multiple Sclerosis in Austria. Neuroepidemiol. 2017;49 (1–2 ):40–44. doi: 10.1159/000479696 28848208\n11 Brownlee W , Bourdette D , Broadley S , Killestein J , Ciccarelli O . Treating multiple sclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pandemic. Neurology. 2020;94 (22 ):10.1212/WNL.0000000000009507. doi: 10.1212/WNL.0000000000009507 32241953\n12 Rosenbaum PR , Rubin DB . Reducing Bias in Observational Studies Using Subclassification on the Propensity Score. J Am Stat Assoc. 1984;79 (387 ):516–524. doi: 10.2307/2288398\n13 Council National Research (CNR). The Prevention and Treatment of Missing Data in Clinical Trials. National Academies Press (US); 2010. doi: 10.17226/12955\n14 Agentur für Gesundheit und Ernährungssicherheit (AGES). AGES Dashboard COVID19. Published December 31, 2020. Accessed December 31, 2020. https://covid19-dashboard.ages.at\n15 Asamer E-M , Astleithner F , Cetkovic P , et al . Quality assessment for register-based statistics—Results for the Austrian census 2011. Blauensteiner S , ed. Austrian J Stat. 2014;45 (2 ):3–14. doi: 10.17713/ajs.v45i2.97\n16 Capasso N , Palladino R , Montella E , et al . Prevalence of SARS-CoV-2 Antibodies in Multiple Sclerosis: The Hidden Part of the Iceberg. J Clin Med. 2020;9 (12 ):4066. doi: 10.3390/jcm9124066 33339402\n17 Evangelou N , Garjani A , dasNair R , et al . Self-diagnosed COVID-19 in people with multiple sclerosis: a community-based cohort of the UK MS Register. J Neurology Neurosurg Psych. 2021;92 (1 ):107–109. doi: 10.1136/jnnp-2020-324449 32855290\n18 Kovvuru S , Nalleballe K , Onteddu SR , et al . Immunosuppression in chronic autoimmune neurological disorders during the COVID-19 pandemic. J Neurol Sci. Published online 2020:117230. doi: 10.1016/j.jns.2020.117230 33256952\n19 Talaat F , Ramadan I , Aly S , Hamdy E . Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic? Mult Scler Relat Dis. 2020;46 :102580. doi: 10.1016/j.msard.2020.102580 33296977\n20 WHO. WHO Coronavirus Disease (COVID-19) Dashboard. Published December 31, 2020. Accessed December 31, 2020. https://covid19.who.int\n21 Berger JR , Brandstadter R , Bar-Or A . COVID-19 and MS disease-modifying therapies. Neurol Neuroimmunol Neuroinflamm. 2020;7 (4 ):e761. doi: 10.1212/NXI.0000000000000761 32414755\n22 Sormani MP , sclerosis ISG on C-19 infection in multiple. An Italian programme for COVID-19 infection in multiple sclerosis. Lancet Neurol. 2020;19 (6 ):481–482. doi: 10.1016/S1474-4422(20)30147-2 32359409\n23 Tian J , Yuan X , Xiao J , et al . Clinical characteristics and risk factors associated with COVID-19 disease severity in patients with cancer in Wuhan, China: a multicentre, retrospective, cohort study. Lancet Oncol. Published online 2020. doi: 10.1016/S1470-2045(20)30309-0 32479790\n24 Hamer M , Kivimäki M , Gale CR , Batty GD . Lifestyle Risk Factors, Inflammatory Mechanisms, and COVID-19 Hospitalization: A Community-Based Cohort Study of 387,109 Adults in UK. Brain Behav Immun. Published online 2020. doi: 10.1016/j.bbi.2020.05.059 32454138\n25 Parrotta E , Kister I , Charvet L , et al . COVID-19 outcomes in MS: Observational study of early experience from NYU Multiple Sclerosis Comprehensive Care Center. Neurol- Neuroimmunol Neuroinflamm. 2020;7 (5 ):e835. doi: 10.1212/NXI.0000000000000835 32646885\n26 Loonstra FC , Hoitsma E , Kempen ZL van , Killestein J , Mostert JP . COVID-19 in multiple sclerosis: The Dutch experience. Mult Scler J. 2020;26 (10 ):1256–1260. doi: 10.1177/1352458520942198 32662742\n27 Sharifian-Dorche M , Sahraian MA , Fadda G , et al . COVID-19 and Disease-Modifying Therapies in Patients with Demyelinating Diseases of the Central Nervous System: A Systematic Review. Mult Scler Relat Dis. 2021;50 :102800. doi: 10.1016/j.msard.2021.102800 33578206\n28 Sormani MP , Rossi ND , Schiavetti I , et al . Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis. Ann Neurol. Published online 2021. doi: 10.1097/WCO.0000000000000697 30950845\n29 Maillart E , Papeix C , Lubetzki C , Roux T , Pourcher V , Louapre C . Beyond COVID-19: do MS/NMO-SD patients treated with anti-CD20 therapies develop SARS-CoV2 antibodies? Mult Scler Relat Dis. 2020;46 :102482. doi: 10.1016/j.msard.2020.102482 32916509\n30 Baker D , Roberts CAK , Pryce G , et al . COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases. Clin Exp Immunol. 2020;202 (2 ):149–161. doi: 10.1111/cei.13495 32671831\n31 Bsteh G , Monz E , Zamarian L , et al . Combined evaluation of personality, risk and coping in MS patients: A step towards individualized treatment choice–The PeRiCoMS-Study I. J Neurol Sci. Published online March 3, 2017:1–22. doi: 10.1016/j.jns.2017.03.002 28431632\n32 Amor S , Baker D , Khoury SJ , Schmierer K , Giovanonni G . SARS-CoV-2 and Multiple Sclerosis: Not All Immune Depleting DMTs are Equal or Bad. Ann Neurol. 2020;87 (6 ):794–797. doi: 10.1002/ana.25770 32383812\n33 Manacorda T , Bandiera P , Terzuoli F , et al . Impact of the COVID-19 pandemic on persons with multiple sclerosis: Early findings from a survey on disruptions in care and self-reported outcomes. J Health Serv Res Po. Published online 2020:135581962097506. doi: 10.1177/1355819620975069 33337256\n34 Mateen FJ , Rezaei S , Alakel N , Gazdag B , Kumar AR , Vogel A . Impact of COVID-19 on U.S. and Canadian neurologists’ therapeutic approach to multiple sclerosis: a survey of knowledge, attitudes, and practices. J Neurol. 2020;267 (12 ):3467–3475. doi: 10.1007/s00415-020-10045-9 32638107\n\n",
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"title": "COVID-19 severity and mortality in multiple sclerosis are not associated with immunotherapy: Insights from a nation-wide Austrian registry.",
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"abstract": "How efficacious is transplantation of ovarian cortex previously exposed to chemotherapy?\n\n\n\nPrior exposure to chemotherapy did not disrupt the function of cryopreserved ovarian tissue after transplantation.\n\n\n\nOvarian tissue cryopreservation (OTC) followed by ovarian tissue transplantation (OTT) is an efficacious technique for restoration of female fertility. At least 130 children have been born following this procedure. To date, little is known about the efficacy of OTT in patients exposed to cancer chemotherapy prior to OTC.\n\n\n\nThis study evaluates the recovery of ovarian function and fertility in 31 consecutive patients who had received OTT, between 2005 and 2015.\n\n\n\nThirty one patients, wanting children, were transplanted with autologous ovarian cortex, among which 22 patients (71%) had been exposed to chemotherapy before OTC. Recovery of ovarian function was considered total once menstruation occurred. Ovarian function recovery (OFR), ovarian graft survival, and incidence of pregnancy were related to previous chemotherapy exposure, type of chemotherapy and graft characteristics (number of grafted fragments and follicular density).\n\n\n\nThe amount of ovarian tissue collected was the only parameter to show any significant change between patients with versus without previous chemotherapy. At 1 year after OTT, the cumulative incidence of OFR was 83% (93% in patients exposed to chemotherapy and 67% in others (P = 0.14)). A low follicular density (<0.3 foll/mm2) in the transplant and a low number of grafted fragments (<16) were significantly associated with a delayed OFR. Graft survival at 2 years after OTT was 77%. It was significantly lower in patients exposed to bifunctional alkylating agents before ovarian cryopreservation and in patients with a low follicular density. The proportion of women who succeeded in having at least one live birth was 23% in the total population, 0% (0/9) in the group 'no previous chemotherapy', and 32% (7/22) in the group 'previous chemotherapy'. The cumulative incidence of pregnancy (Kaplan-Meier) at 3 years after OTT was 36% overall and 49% in case of previous chemotherapy, with no difference related to previous chemotherapy exposure. In total there were 13 pregnancies and 8 births in 7 patients.\n\n\n\nThe pathology in the two groups of patients was not comparable. In the group of patients who had chemotherapy before OTC, there were 95% of hematological malignancies. In the group of patients who did not have chemotherapy before OTC only 1 out of 9 patients had a malignant hematological disease while 44% had some pathology affecting the ovaries. Few women are available for study and only large changes are likely to have statistical significance.\n\n\n\nThese results suggest that prior cancer chemotherapy should no longer be considered a limitation to cryopreservation of ovarian tissue and current recommendations in this regard should be revised.\n\n\n\nThis study was supported by the Agence de la Biomédecine (France's biomedical office). There are no competing interests to report.\n\n\n\nNCT02184806.",
"affiliations": "Department of Hematology, Adolescents and Young Adults Unit, Fertility Preservation, Assistance Publique-Hôpitaux de Paris (AP-HP) Saint Louis Hospital, Paris, France.;Department of Obstetrics Gynecology, AP-HP Pitié-Salpêtrière-Charles Foix University Hospital, Paris, France.;Médecine Sorbonne Université, Paris, France.;Department of Radiology, AP-HP Pitié-Salpêtrière-Charles Foix University Hospital, Paris, France.;Department of Pathology, Gustave Roussy Institute, Villejuif, France.;Médecine Sorbonne Université, Paris, France.;Department of Hematology/Oncology, AP-HP Saint Louis Hospital, Paris, France.;Department of Oncological Surgery, Gustave Roussy Institute, Villejuif, France.;Department of Pediatric Hematology, AP-HP Robert Debré University Hospital, Paris, France.;Department of Hematology, AP-HP Pitié-Salpêtrière-Charles Foix University Hospital, Paris, France.;Department of Clinical Hematology, Robert Debré Hospital, Reims, France.;Department of Radiology, AP-HP Pitié-Salpêtrière-Charles Foix University Hospital, Paris, France.;Department of Reproductive Biology, AP-HP Cochin Hospital, Paris, France.;Department of Oncological Surgery, Gustave Roussy Institute, Villejuif, France.;Department of Reproductive Biology, AP-HP Cochin Hospital, Paris, France.;Department of Radiology, AP-HP Pitié-Salpêtrière-Charles Foix University Hospital, Paris, France.;Department of Hematology, Adolescents and Young Adults Unit, Fertility Preservation, Assistance Publique-Hôpitaux de Paris (AP-HP) Saint Louis Hospital, Paris, France.;Médecine Sorbonne Université, Paris, France.;Médecine Sorbonne Université, Paris, France.;Department of Obstetrics Gynecology, AP-HP Pitié-Salpêtrière-Charles Foix University Hospital, Paris, France.;Department of Reproductive Biology, AP-HP Cochin Hospital, Paris, France.;Médecine Sorbonne Université, Paris, France.;Department of Obstetrics Gynecology, AP-HP Pitié-Salpêtrière-Charles Foix University Hospital, Paris, France.;Department of Hematology, Adolescents and Young Adults Unit, Fertility Preservation, Assistance Publique-Hôpitaux de Paris (AP-HP) Saint Louis Hospital, Paris, France.",
"authors": "Poirot|C|C|;Fortin|A|A|;Lacorte|J M|JM|;Akakpo|J P|JP|;Genestie|C|C|;Vernant|J P|JP|;Brice|P|P|;Morice|P|P|;Leblanc|T|T|;Gabarre|J|J|;Delmer|A|A|;Badachi|Y|Y|;Drouineaud|V|V|;Gouy|S|S|;Chalas|C|C|;Egels|S|S|;Dhédin|N|N|;Touraine|P|P|;Dommergues|M|M|;Lebègue|G|G|;Wolf|J P|JP|;Capron|F|F|;Lefebvre|G|G|;Boissel|N|N|;|||",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating",
"country": "England",
"delete": false,
"doi": "10.1093/humrep/dez047",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-1161",
"issue": "34(6)",
"journal": "Human reproduction (Oxford, England)",
"keywords": "alkylating agents; chemotherapy; follicular density; live birth; ovarian tissue cryopreservation; ovarian tissue transplantation; pregnancy",
"medline_ta": "Hum Reprod",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating; D064592:Autografts; D001723:Birth Rate; D000073116:Cancer Survivors; D015925:Cryopreservation; D005260:Female; D059247:Fertility Preservation; D006085:Graft Survival; D006801:Humans; D050498:Live Birth; D008598:Menstruation; D009369:Neoplasms; D010053:Ovary; D011247:Pregnancy; D020127:Recovery of Function; D013997:Time Factors; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8701199",
"other_id": null,
"pages": "1083-1094",
"pmc": null,
"pmid": "31116405",
"pubdate": "2019-06-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Impact of cancer chemotherapy before ovarian cortex cryopreservation on ovarian tissue transplantation.",
"title_normalized": "impact of cancer chemotherapy before ovarian cortex cryopreservation on ovarian tissue transplantation"
} | [
{
"companynumb": "FR-BAXTER-2022BAX010064",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "4",
... |
{
"abstract": "Hyperammonemia is a rare and important complication post-liver transplantation. We review a case of a 5-month-old boy with biliary atresia who received a split liver transplant following a variceal bleed. The transplant was complicated by recurrent portal vein thrombosis. Colonized with Serratia marcescens pretransplant, he developed disseminated infection associated with very high levels of ammonia that led to his death. It is important to be aware of serum ammonia levels in patients with portal vein thrombosis, particularly in the setting of gastrointestinal bleeding and sepsis.",
"affiliations": "Department of Paediatric Gastroenterology, Starship Children's Health, Auckland, New Zealand.;Department of Paediatric Gastroenterology, Starship Children's Health, Auckland, New Zealand.;Starship Children's Health, Adult and Paediatric National Metabolic Service, Auckland, New Zealand.;Department of Paediatric Gastroenterology, Starship Children's Health, Auckland, New Zealand.;Starship Children's Health, Infectious Diseases, Auckland, New Zealand.;Department of Paediatric Gastroenterology, Starship Children's Health, Auckland, New Zealand.",
"authors": "Mouat|Stephen|S|0000-0002-2526-3726;Bishop|Jonathan|J|;Glamuzina|Emma|E|;Chin|Simon|S|;Best|Emma J|EJ|;Evans|Helen M|HM|0000-0002-8860-2705",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13180",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "22(4)",
"journal": "Pediatric transplantation",
"keywords": "hyperammonaemia; pediatric liver transplant",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D017809:Fatal Outcome; D006801:Humans; D022124:Hyperammonemia; D007223:Infant; D016031:Liver Transplantation; D008297:Male; D011183:Postoperative Complications; D016868:Serratia Infections; D012706:Serratia marcescens",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13180",
"pmc": null,
"pmid": "29624817",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Fatal hyperammonemia associated with disseminated Serratia marcescens infection in a pediatric liver transplant recipient.",
"title_normalized": "fatal hyperammonemia associated with disseminated serratia marcescens infection in a pediatric liver transplant recipient"
} | [
{
"companynumb": "NZ-VALIDUS PHARMACEUTICALS LLC-NZ-2021VAL000575",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFOTAXIME SODIUM"
},
"... |
{
"abstract": "BACKGROUND\nStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are mucocutaneous reactions, typically to medications, that are associated with a high patient mortality. Controversy exists over which systemic treatments decrease mortality associated with SJS/TEN.\n\n\nOBJECTIVE\nIn this study we sought to determine whether intravenous immunoglobulin (IVIg) or cyclosporine use for SJS/TEN results in better patient outcomes.\n\n\nMETHODS\nWe undertook a retrospective chart review of 71 patients admitted between 2001 and 2011 for SJS/TEN at a tertiary care center of which 64 cases were included in the data analysis. Predicted severity-of-illness score for TEN mortality was compared with actual mortality for patients treated with either cyclosporine or IVIg.\n\n\nRESULTS\nOur cohort demonstrated a relative mortality benefit to the use of cyclosporine in the treatment of SJS/TEN with a standardized mortality ratio of 0.43, over the use of IVIg with a standardized mortality ratio of 1.43.\n\n\nCONCLUSIONS\nThis is single-center retrospective study.\n\n\nCONCLUSIONS\nThe use of cyclosporine over IVIg may offer a greater mortality benefit in the treatment of SJS/TEN.",
"affiliations": "Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: kirchhof.mark@gmail.com.;Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada.;Division of Plastic Surgery, Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.;Division of Plastic Surgery, Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.;Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.",
"authors": "Kirchhof|Mark G|MG|;Miliszewski|Monica A|MA|;Sikora|Sheena|S|;Papp|Anthony|A|;Dutz|Jan P|JP|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D016572:Cyclosporine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-9622",
"issue": "71(5)",
"journal": "Journal of the American Academy of Dermatology",
"keywords": "Stevens-Johnson syndrome; cyclosporine; intravenous immunoglobulin; toxic epidermal necrolysis",
"medline_ta": "J Am Acad Dermatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D016572:Cyclosporine; D018450:Disease Progression; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013262:Stevens-Johnson Syndrome; D015996:Survival Rate",
"nlm_unique_id": "7907132",
"other_id": null,
"pages": "941-7",
"pmc": null,
"pmid": "25087214",
"pubdate": "2014-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Retrospective review of Stevens-Johnson syndrome/toxic epidermal necrolysis treatment comparing intravenous immunoglobulin with cyclosporine.",
"title_normalized": "retrospective review of stevens johnson syndrome toxic epidermal necrolysis treatment comparing intravenous immunoglobulin with cyclosporine"
} | [
{
"companynumb": "PHHY2015CA145159",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nDiabetic ketoacidosis (DKA) is a serious complication of diabetes seen commonly in autoimmune Type 1 diabetes mellitus (DM), however patients with Type 2 diabetes are also at risk. Diabetic ketoacidosis may be precipitated by the catabolic stress of acute illness such as trauma, surgery, or infections. Recent studies have suggested that sodium-glucose cotransporter-2 (SGLT-2) inhibitors precipitate DKA in Type 2 diabetes. We present a case series of four patients on SGLT-2 inhibitors who presented with DKA.\n\n\nMETHODS\nMedical records were reviewed and patients who were admitted with diabetic ketoacidosis in the last one year at our institute were identified. The charts of such patients were reviewed and we were able to identify 4 patients who were admitted with DKA and were on SGLT-2 inhibitors at the time of admission for the management of their diabetes.\n\n\nRESULTS\nThe age group of the four patients was between 45-65 years. Interestingly, all four patients were female. The admission blood glucose levels of these patients ranged from 203 to 400(mg/dl). The pH at the time of admission was in the acidotic range with anion gap ranging from 19 to 24. Two of these four patients had symptoms of a localized infection at the time of admission, which was confirmed by laboratory and radiological evaluation. Three of these patients required management in the intensive care unit.\n\n\nCONCLUSIONS\nKetoacidosis is a rare but serious side effect of SGLT2 inhibitors. It is being increasingly reported as these drugs are now commonly being prescribed in the primary care setting. Awareness that DKA can occur in the setting of relative euglycemia is critical to recognize this life-threatening complication of diabetes. More research is needed to better understand the underlying pathophysiology and precipitating factors leading to ketoacidosis in SGLT-2 inhibitor treated patients.",
"affiliations": "Department of Internal Medicine, University of Miami Palm Beach Regional Consortium, Atlantis, FL, United States.;Department of Internal Medicine, University of Miami Palm Beach Regional Consortium, Atlantis, FL, United States.;JFK Medical Center, Atlantis, FL, United States.;Department of Internal Medicine, University of Miami Palm Beach Regional Consortium, Atlantis, FL, United States.;Department of Internal Medicine, University of Miami Palm Beach Regional Consortium, Atlantis, FL, United States.",
"authors": "Sharma|Purva V|PV|;Jobanputra|Yash B|YB|;Lewin|Karen|K|;Bagatell|Stuart|S|;Lichtstein|Daniel M|DM|",
"chemical_list": "D001559:Benzhydryl Compounds; D005960:Glucosides; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000068896:Canagliflozin; C570240:empagliflozin",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574887113666180314101436",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8871",
"issue": "13(2)",
"journal": "Reviews on recent clinical trials",
"keywords": "Canagliflozin; SGLT-2 inhibitors; diabetes mellitus; diabetic ketoacidosis; empagliflozin; type 2 diabetes.",
"medline_ta": "Rev Recent Clin Trials",
"mesh_terms": "D000368:Aged; D001559:Benzhydryl Compounds; D000068896:Canagliflozin; D003924:Diabetes Mellitus, Type 2; D016883:Diabetic Ketoacidosis; D005260:Female; D005960:Glucosides; D006801:Humans; D008875:Middle Aged; D012189:Retrospective Studies; D000077203:Sodium-Glucose Transporter 2 Inhibitors",
"nlm_unique_id": "101270873",
"other_id": null,
"pages": "156-160",
"pmc": null,
"pmid": "29542418",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diabetic Ketoacidosis in Patients with Type 2 Diabetes on Sodium-Glucose Cotransporter-2 Inhibitors - A Case Series.",
"title_normalized": "diabetic ketoacidosis in patients with type 2 diabetes on sodium glucose cotransporter 2 inhibitors a case series"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-016547",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DULAGLUTIDE"
},
... |
{
"abstract": "A 69-year-old man was diagnosed with IgG λ-type multiple myeloma (MM), Stage II in October 2010. He was treated with one cycle of high-dose dexamethasone. After three cycles of bortezomib, the patient exhibited slow elevations in the free light-chain levels and developed a significant new increase of serum M protein. Bone marrow cytogenetic analysis revealed a complex karyotype characteristic of malignant plasma cells. To better understand the molecular pathogenesis of this patient, we sequenced for mutations in the entire coding regions of 409 cancer-related genes using a semiconductor-based sequencing platform. Sequencing analysis revealed eight nonsynonymous somatic mutations in addition to several copy number variants, including CCND1 and RB1. These alterations may play roles in the pathobiology of this disease. This targeted next-generation sequencing can allow for the prediction of drug resistance and facilitate improvements in the treatment of MM patients.",
"affiliations": "Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan.;Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan.;Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan.;Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan.;Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan.;Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan.;Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan ; Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan.;Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan.;Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan.",
"authors": "Ikeda|Hiroshi|H|;Ishiguro|Kazuya|K|;Igarashi|Tetsuyuki|T|;Aoki|Yuka|Y|;Hayashi|Toshiaki|T|;Ishida|Tadao|T|;Sasaki|Yasushi|Y|;Tokino|Takashi|T|;Shinomura|Yasuhisa|Y|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OTT.S86515",
"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S86515ott-8-2805Case ReportMolecular diagnostics of a single drug-resistant multiple myeloma case using targeted next-generation sequencing Ikeda Hiroshi 1Ishiguro Kazuya 1Igarashi Tetsuyuki 1Aoki Yuka 1Hayashi Toshiaki 1Ishida Tadao 1Sasaki Yasushi 12Tokino Takashi 2Shinomura Yasuhisa 11 Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan2 Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, JapanCorrespondence: Hiroshi Ikeda; Yasushi Sasaki, Department of Gastroenterology, Rheumatology and Clinical Immunology, Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo 060 8543, Japan, Email hiikeda@sapmed.ac.jp; yasushi@sapmed.ac.jp2015 05 10 2015 8 2805 2815 © 2015 Ikeda et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2015The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.A 69-year-old man was diagnosed with IgG λ-type multiple myeloma (MM), Stage II in October 2010. He was treated with one cycle of high-dose dexamethasone. After three cycles of bortezomib, the patient exhibited slow elevations in the free light-chain levels and developed a significant new increase of serum M protein. Bone marrow cytogenetic analysis revealed a complex karyotype characteristic of malignant plasma cells. To better understand the molecular pathogenesis of this patient, we sequenced for mutations in the entire coding regions of 409 cancer-related genes using a semiconductor-based sequencing platform. Sequencing analysis revealed eight nonsynonymous somatic mutations in addition to several copy number variants, including CCND1 and RB1. These alterations may play roles in the pathobiology of this disease. This targeted next-generation sequencing can allow for the prediction of drug resistance and facilitate improvements in the treatment of MM patients.\n\nKeywords\nmultiple myelomadrug resistancegenome-wide sequencingsemiconductor sequencertarget therapy\n==== Body\nIntroduction\nMultiple myeloma (MM) is characterized by malignant plasma cell proliferation in the bone marrow (BM) associated with monoclonal protein in the serum and/or urine.1,2 Hematopoietic stem cell transplantation and novel agents such as bortezomib, thalidomide, and lenalidomide have improved the survival of MM patients.3,4 However, most patients eventually relapse even after the achievement of a complete therapeutic response. Improvements in molecular profiling technologies have provided new insight into the basic molecular events underlying the development of MM as well as the mechanisms of anticancer drug resistance. The transition from the long-established one-size-fits-all approach to new strategies based on individual genetic profiles provides an opportunity to transform current diagnostics into individual prognostic and even predictive classifications.\n\nIn MM, there are two distinct genetic subtypes based on copy number alterations and translocations. Approximately half of all MM cases are hyperdiploid, which is characterized by multiple trisomies of chromosomes 3, 5, 7, 9 11, 15, 19, and 21 and a lower prevalence of primary translocations involving the immunoglobulin heavy chain (IgH) locus at 14q32.5,6 The remaining cases form the nonhyperdiploid group, and chromosomes 8, 13, 14, and 16 are frequently lost. Nonhyperdiploid myeloma is strongly associated with translocations of IgH alleles with various partner chromosomes. Copy number alterations in chromosomal regions, such as 1q, 6q, 8p, and 16q, occur in both subtypes. Overall, nonhyperdiploid MM is associated with worse survival compared with hyperdiploid MM.\n\nMethods for determining DNA content and, ultimately, ploidy in MM include conventional cytogenetics, fluorescence in situ hybridization (FISH), comparative genomic hybridization, and, recently, massively parallel whole genome sequencing. Because unique mutations have been observed in individual human cancer samples, the identification and characterization of the molecular alterations of individual cancer patients is a critical step toward the development of more effective personalized therapies. For example, next-generation sequencing (NGS) technologies have revolutionized cancer genomics research by providing a comprehensive method of detecting genomic alterations associated with somatic cancer.7–9 In this study, we sequenced all exons of 409 cancer-related genes in matched tumor and normal DNA samples from a multidrug-resistant myeloma patient using a next-generation semiconductor sequencing protocol.\n\nCase report\nA 69-year-old male presented in October 2010 with back pain. Physical examination and magnetic resonance imaging revealed large focal lesions in the fourth thoracic vertebra (Figure 1A) and first lumbar vertebra (Figure 1B). Laboratory evaluation revealed a white blood cell count of 2.5×103/μL with no atypical cells, a red blood cell count of 3.67×106/μL, a hemoglobin level of 11.6 g/dL, and a platelet count of 122×106/μL. The serum total protein level was 10.7 g/dL, the albumin level was 3.4 g/dL, the serum β2 microglobulin level was 4.2 mg/dL, and the serum calcium level was 8.9 mg/dL. The concentrations of IgG, IgA, and IgM were 6,284, 34, and 25 mg/dL, respectively. The monoclonal protein IgG was increased, and serum immunofixation revealed the production of IgG with λ light-chain restriction (data not shown). The proliferation of plasma cells (more than 10% among all nucleated cells) was also detected in BM aspirates. When BM biopsy was performed, the infiltration of plasma cells expressing IgG λ monoclonal protein was identified by pathological investigation, and the patient was diagnosed with MM (Stage II according to the International Staging System). Chromosome analysis at this time using conventional Giemsa banding of BM-derived metaphase spreads revealed a normal karyotype (46, XX) in all analyzed cells. The patient was then treated with one cycle of high-dose dexamethasone, followed by three cycles of bortezomib plus dexamethasone. He achieved complete response according to the International Myeloma Working Group uniform response criteria. His symptoms were also significantly improved.\n\nIn August 2012, the serum concentrations of IgG and free light chain (FLC) gradually increased, suggesting the worsening of his MM. His complete blood count was as follows: 1.8×103/μL white blood cells, 3.61×106/μL red blood cells, 11.6 g/dL hemoglobin, and 55×106/μL platelets. BM analysis showed complex aberrations often observed in this patient (Figures 2A and 2B) and an elevated plasma cell percentage (59.8%). His karyotype was 39, XY, del(1)(p22p36), −3, −6, der(8)t(6:8)(p11.1:p23), −10, t(11:14)(q13:q32), −12, add(13) (q22), add(16)(q22), −17, add(18)(p11), −19, −20, +mar [4]/46, XY [20]. The chromosomal translocation t(11:14) (q13:q32), which generates the IgH/CCND1 fusion gene, was also identified in our case by FISH (Figure 2C).\n\nThe patient was started on a bortezomib, cyclophosphamide, and dexamethasone regimen. No serious complications occurred during the course of the treatment, and a partial response was observed with a decrease in the serum FLC value. After seven cycles of this regimen, however, his condition progressively deteriorated, with increases in serum lambda immunoglobulin light chain and LDH, a deterioration of renal function, and the appearance of circulating plasma cells in the peripheral blood (up to 5% of the total peripheral leukocyte population). He was admitted for combination chemotherapy with combination chemotherapy with bortezomib, cyclophosphamide, lenalidomide, and dexamethasone, but his response was poor (Figure 3), and an increase in myeloma cells was detected by BM biopsy. Unfortunately, the patient has since passed away, and his family did not choose to perform postmortem examination.\n\nThe patient provided consent for use of his medical record and samples for clinical and research purposes, and the examination was performed in accordance with the Declaration of Helsinki. The sequence study was approved by the Institutional Review Boards of Sapporo Medical University. Retrospectively, to better understand the molecular pathogenesis in this patient, we sequenced 409 cancer-related genes in matched tumor and nontumor DNA samples at relapse in August 2012 using an Ion Torrent PGM (Life Technologies, Carlsbad, CA, USA). DNA was extracted from magnetic bead–enriched BM CD138 positive tumor cells from the patient, and CD138 negative cells were used as matched nontumor cells. DNA (40 ng) was used for multiplex polymerase chain reaction (PCR) amplification with an Ion Ampliseq Comprehensive Cancer Panel (Life Technologies), enabling the targeted coverage of all exons of 409 cancer-related genes frequently cited and mutated (covered regions =95.4% of total). The 15,992 amplicons obtained represented more than 1.2 Mb of target sequence. Library preparation and sequencing with an Ion Torrent PGM was performed as previously described.9 The mean read depths were 125× (tumor) and 152× (normal). Alignment to the human genome build 19 and variant calling were performed by Ion Reporter Software 4.0. Mutations were also validated by conventional Sanger sequencing. We identified eight nonsynonymous somatic mutations (6.49 mutations/Mb; Table 1). We included missense mutations in seven genes (SYNE1, IKBKB, ERBB3, MYH11, CYLD, TP53, and CDH2) and a frameshift mutation in EGFR. Changes in relative copy number were also assessed from the sequencing data, and we identified 133 copy number variant (CNV) regions, including 87 gain and 46 loss regions (Figure 2B and Table S1). Importantly, we found a gain in the copy number of CCND1, a gene encoding cyclin D1. To check the contamination of tumor cells in the CD138 negative subset, we compared CD138 negative DNA of this patient and peripheral blood DNA from two healthy donors. We found single nucleotide variants in the CD138 negative DNA of this patient; however, all variants had previously been reported in the NCBI dbSNP database (http://www.ncbi.nlm.nih.gov/SNP/) (Tables 2 and 3). Therefore, we can rule out tumor cell contamination in the CD138 negative subset.\n\nDiscussion\nMM is a plasma cell malignancy characterized by a heterogeneous clinical course. Treatments for MM have remarkably improved in recent years, due in part to the introduction of novel therapies such as bortezomib, thalidomide, and lenalidomide. Despite these advancements, the prognosis of patients with relapse and refractory MM remains poor, and novel therapies are needed. Alternatively, the identification of novel targets or signaling pathways regulating myeloma cell proliferation would improve the clinical outcome and survival of refractory MM patients. Several pathways related to drug resistance and cell survival, such as Notch1, Akt, and NF-κB, are activated to protect MM cells from death.10–12 Here, we describe the characterization of genetic abnormalities found in myeloma cells in a patient with refractory MM.\n\nIn nonhyperdiploid MM, the IgH gene (14q32) commonly fuses with FGFR3 (4p16), MMSET (4p16.3), CCND3 (6p21), CCND1 (11q13), and MAF (16q23), resulting in the direct or indirect dysregulation of cyclin D.13 Among the nonhyperdiploid myelomas, the hypodiploid subtype (≦44 chromosomes) has the most aggressive clinical phenotype, but the genetic differences between the groups have not been completely defined. Cytogenetic analysis revealed that this patient had a hypodiploid karyotype with 39 chromosomes and complex chromosomal abnormalities, including t(11:14) (q13:q32). CCND1 expression is generally related to copy number aberrations. Although we did not analyze CCND1 mRNA expression, CNV analysis revealed a gain of 11q13–q21, suggesting the presence of cyclin D1 dysregulation.\n\nSeveral NGS platforms are available for the sequencing of targeted genomic regions to analyze a variety of disease-associated changes, such as point mutations, insertions, deletions, and CNVs. CNV analysis of the sequencing data revealed that this patient had diverse DNA copy number alterations, including large and regional gains and losses (Figure 2B and Table S1). Additionally, we detected eight somatic mutations among 409 cancer-related genes (Table 1). We considered gene sets based on existing insights into the biology of this MM patient. It has been proposed that activation of the NF-kB pathway is important in the pathogenesis of MM, as well as in resistance to chemotherapy. We observed two point mutations and three CNVs affecting NF-κB pathway genes, including IKBKB, CYLD, IKBKE, CD79B, and SYK (Tables 1 and S1). Although additional experiments are required to establish the functional significance of genetic alterations of these genes in MM cells, NF-κB pathway activation may be involved in the molecular pathogenesis of this patient’s disease.\n\nAlterations in the tumor suppressor retinoblastoma (RB) and p53 or their respective pathways are frequently observed in human cancers.14 In MM, a deletion or mutation of p53 (17p13) or RB1 (13q14.2) is considered to be predictive of poor prognosis. We found a monoallelic chromosome 17 deletion and a missense mutation in the DNA-binding domain of p53 (Arg158Gly), suggesting the abrogation of p53 transcription. Moreover, the deletion of the CNV in 13q14.2 was detected in this patient, resulting in the inactivation of two key regulators of the cell cycle, RB1 and p53.\n\nA recent study has described an increased rate of mutations in receptor tyrosine kinases (RTKs) and their associated signaling effectors, pointing to a more potent role of this pathway in MM than was previously appreciated.15 We found two mutations in RTKs, including a missense mutation in ERBB3 and a truncating mutation in EGFR, and have suggested a role of aberrant RTK signaling in the development or progression of MM in this patient. In addition, few studies have addressed the functional roles of the remaining three mutated genes (SYNE1, MYH11, and CDH2) in myeloma, and further investigations are required. SYNE1 is frequently silenced by DNA methylation in primary cancers of the colon and lung,16,17 suggesting that a loss of SYNE1 function may be a genetic event that promotes tumor progression. MYH11 is a member of the myosin family, and inversion at the MYH11 locus is found in acute myeloid leukemia.18 Additionally, MYH11 mutations have been shown to occur in human colorectal cancers with microsatellite instability.19 N-cadherin, encoded by the CDH2 gene, is a transmembrane protein and plays an important role in cell adhesion. Recently, circulating N-cadherin levels was reported to be a negative prognostic factor in patients with MM.20 In this study, we performed comprehensive genomic analyses using PCR target enrichment and semiconductor-based sequencing of matched tumor and normal DNA samples obtained from an individual with refractory MM. We detected several genetic alterations that may have been associated with the poor prognosis and poor response to chemotherapy of this patient. Although its value should be further confirmed in larger samples, targeted NGS is considered a valuable tool for high-throughput genetic testing in clinical research.\n\nSupplementary material\nTable S1 Locus\tPloidy\tLength (bp)\tGene\t\n1p36.31(6531783–6532696)\t9\t913\tPLEKHG5\t\n1p36.31(6534071–6534252)\t9\t181\tPLEKHG5\t\n1p36.22(11204731–11317231)\t3\t112,500\tMTOR:MTOR–AS1\t\n1p33(47685376–47838806)\t4\t153,430\tTAL1:CMPK1\t\n1p33p13.2(47840544–114940663)\t1\t67,100,119\tCMPK1:CDKN2C:JUN:JAK1:BCL10:LOC646626:DPYD:DPYD–AS1:TRIM33\t\n1p13.2p12(115006125–120491804)\t1\t5,485,679\tTRIM33:NRAS:NOTCH2\t\n1q21.1(144882848–144922543)\t3\t39,695\tPDE4DIP\t\n1q21.1(144922543–144946743)\t1\t24,200\tPDE4DIP\t\n1q25.3q31.1(185069308–186287597)\t1\t1,218,289\tRNF2:MIR548F1:PRG4:TPR\t\n1q31.1(186287597–186315401)\t3\t27,804\tMIR548F1:TPR\t\n1q31.1(186340019–186645716)\t6\t305,697\tMIR548F1:TPR:PTGS2\t\n1q32.1(204396791–204438963)\t3\t42,172\tPIK3C2B\t\n1q32.1(204494558–204518660)\t1\t24,102\tMDM4\t\n1q32.1(204518660–206652476)\t4\t2,133,816\tMDM4:IKBKE\t\n1q43(237037987–237060883)\t5\t22,896\tMTR\t\n1q44(243776889–243809266)\t0\t32,377\tAKT3\t\n2p25.2(5832763–5833155)\t10\t392\tSOX11\t\n2p25.2p23.3(5833155–24951356)\t3\t19,118,201\tSOX11:MYCN:NCOA1\t\n2p23.3(24952332–24952686)\t0\t354\tNCOA1\t\n2p23.3(24962207–25462090)\t4\t499,883\tNCOA1:DNMT3A\t\n2p21(42509881–47672730)\t3\t5,162,849\tEML4:MSH2\t\n2p21(47672761–47693939)\t0\t21,178\tMSH2\t\n2p21(47698056–47705686)\t5\t7,630\tMSH2\t\n2p16.1p15(61145266–61715462)\t1\t570,196\tREL:XPO1\t\n2q22.1q22.2(141031958–142888394)\t3\t1,856,436\tLRP1B\t\n2q22.3(148657078–148657416)\t6\t338\tACVR2A\t\n2q31.2q32.2(178096331–190719874)\t4\t12,623,543\tNFE2L2:PMS1\t\n2q33.1(198263157–198266593)\t1\t3,436\tSF3B1\t\n2q33.1(198266665–198274567)\t5\t7,902\tSF3B1\t\n2q33.1q34(198285075–209101941)\t4\t10,816,866\tSF3B1:CREB1:IDH1\t\n2q35q36.1(216288165–223066804)\t3\t6,778,639\tFN1:STK36:PAX3\t\n3p26.2p25.2(3192502–12458385)\t1\t9,265,883\tCRBN:FANCD2:C3orf24:VHL:PPARG RAF1:XPC:TGFBR2:MLH1:ITGA9:MYD88:CTNNB1:LTF:SETD2:BAP1: PBRM1:M\t\n3p25.2p13(12641643–70014401)\t1\t57,372,758\tAGI1:MITF\t\n3p13(71008300–71015133)\t0\t6,833\tFOXP1\t\n3p13(71015133–71247590)\t1\t232,457\tFOXP1\t\n3q22.3q23(138425984–142178221)\t4\t3,752,237\tPIK3CB:FOXL2:ATR\t\n3q23(142180753–142185454)\t10\t4,701\tATR\t\n3q23(142186790–142226819)\t4\t40,029\tATR\t\n3q23(142279172–142285045)\t4\t5,873\tATR\t\n3q26.32q27.3(178916622–187442712)\t3\t8,526,090\tPIK3CA:SOX2–OT:SOX2:LOC100131635:BCL6\t\n3q29(195590930–195622288)\t3\t31,358\tTNK2\t\n4p16.3(1800963–1809006)\t3\t8,043\tFGFR3\t\n4q12q13.1(55987269–62801812)\t4\t6,814,543\tKDR:LPHN3\t\n4q13.1(62863973–62935895)\t10\t71,922\tLPHN3\t\n5q11.2(55259956–55272179)\t1\t12,223\tIL6ST\t\n5q13.1(67522495–67589174)\t4\t66,679\tPIK3R1\t\n5q13.1q22.2(67589211–112111335)\t1\t44,522,124\tPIK3R1:APC\t\n5q22.2(112111335–112176325)\t3\t64,990\tAPC\t\n5q31.1q32(131972888–149514586)\t3\t17,541,698\tRAD50:CTNNA1:CSF1R:PDGFRB\t\n5q35.3(176683949–180058790)\t3\t3,374,841\tNSD1:FLT4\t\n6p25.3p22.3(393089–18264237)\t5\t17,871,148\tIRF4:DEK\t\n6p21.32p21.1(32169809–44219786)\t4\t12,049,977\tNOTCH4:DAXX:PIM1:FOXP4:MIR4641:HSP90AB1\t\n6p21.1p12.3(44219786–51720789)\t3\t7,501,003\tHSP90AB1:PKHD1\t\n6p12.3(51720789–51732717)\t0\t11,928\tPKHD1\t\n6p12.3(51732717–51774287)\t5\t41,570\tPKHD1\t\n6p12.2(51882320–51909967)\t4\t27,647\tPKHD1\t\n6p12.2p12.1(52880891–52906053)\t7\t25,162\tICK\t\n6p12.1(56371186–56373367)\t10\t2,181\tRNU6–71:DST\t\n6p12.1(56373367–56418558)\t3\t45,191\tRNU6–71:DST\t\n6p12.1(56420267–56479190)\t4\t58,923\tRNU6–71:DST\t\n6p12.1(56489295–56505172)\t7\t15,877\tRNU6–71:DST\t\n6q12q252(69348493–152749529)\t1\t83,401,036\tBAI3:MAP3K7:EPHA7:PRDM1:FOXO3:ROS1:SGK1:MYB:TNFAIP3:ESR1: SYNE1\t\n6q25.2(152755037–152762469)\t0\t7,432\tSYNE1\t\n6q25.2q27(152763208–167275671)\t1\t14,512,463\tSYNE1:IGF2R:RPS6KA2\t\n7p22.1(6038830–6048682)\t6\t9,852\tPMS2\t\n7p21.2p112(13978822–55211092)\t1\t41,232,270\tETV1:IKZF1:EGFR\t\n7p11.2q212(55211092–91632356)\t3\t36,421,264\tEGFR:LOC100507500:SBDS:AKAP9\t\n7q22.1(98478735–98491481)\t1\t12,746\tTRRAP\t\n7q22.1(98491496–98503897)\t4\t12,401\tTRRAP\t\n7q31.2(116398533–116409750)\t1\t11,217\tMET\t\n7q31.2q31.33(116409750–126882846)\t3\t10,473,096\tMET:POT1:GRM8\t\n7q36.1(151873440–151884429)\t3\t10,989\tMLL3\t\n7q36.1(151884429–151896501)\t6\t12,072\tMLL3\t\n8p12(30915961–31015061)\t1\t99,100\tWRN\t\n8p11.21(41801269–41838483)\t4\t37,214\tKAT6A\t\n8q11.21(48761708–48842433)\t3\t80,725\tPRKDC\t\n8q11.21(48848199–48848467)\t9\t268\tPRKDC\t\n8q13.3(71056866–71068855)\t4\t11,989\tNCOA2\t\n8q22.3(103271231–103284984)\t4\t13,753\tUBR5\t\n8q22.3(103287769–103288057)\t0\t288\tUBR5\t\n8q22.3q23.3(103301703–113267690)\t3\t9,965,987\tUBR5:CSMD3\t\n8q23.3(113275800–113326867)\t5\t51,067\tCSMD3\t\n8q23.3(113353734–113697671)\t4\t343,937\tCSMD3\t\n9p24.1(5021975–5055745)\t1\t33,770\tJAK2\t\n9p24.1(5069115–5080629)\t0\t11,514\tJAK2\t\n9p24.1p13.2(5080644–37034041)\t1\t31,953,397\tJAK2:PTPRD:PSIP1:CDKN2A:CDKN2B–AS1:CDKN2B:TAF1L:FANCG:PAX5\t\n9q21.2q22.2(80336237–93607934)\t3\t13,271,697\tGNAQ SYK\t\n10p12.31(21971114–22019887)\t4\t48,773\tMLLT10\t\n10p12.31q24.32(22030804–104155714)\t1\t82,124,910\tMLLT10:RET:MAPK8:NCOA4:TET1:KAT6B:BMPR1A:PTEN:ACTA2:FAS:CY P2C19:BLNK:TLX1\t\n1 0q24.32q26.13(104157967–123353360)\t1\t19,195,393\tNFKB2:SUFU:TCF7L2:FGFR2\t\n11p15.5p15.4(532629–3714618)\t3\t3,181,989\tHRAS:INS–IGF2:IGF2:NUP98\t\n11p15.4(3794886–4144704)\t1\t349,818\tNUP98:RRM1\t\n11p15.4(4147854–4159656)\t4\t11,802\tRRM1\t\n11q13.1q21(64577195–95712842)\t3\t31,135,647\tMEN1:CCND1:NUMA1:MRE11A:MAML2\t\n11q21(95826628–96075072)\t6\t248,444\tMAML2:MIR1260B\t\n11q22.2(102195186–102221298)\t3\t26,112\tBIRC3:BIRC2\t\n11q22.3(108126821–108202634)\t3\t75,813\tATM\t\n11q22.3(108202640–108205758)\t8\t3,118\tATM\t\n12p13.32q12(4383139–43825146)\t1\t39,442,007\tCCND2:ING4:ZNF384:KRAS:ADAMTS20\t\n12q12q24.33(43845982–132562299)\t1\t88,716,317\tADAMTS20:ARID2:MLL2:ATF1:SMUG1:ERBB3:DDIT3:CDK4:MDM2: PTPN11:HNF1A:HCAR1:EP400\t\n13q12.13q14.2(26828777–48881526)\t1\t22,052,749\tCDK8:FLT3:FLT1:FOXO1:RB1\t\n13q14.2(48916694–48955639)\t0\t38,945\tRB1\t\n13q14.2q34(49027105–113976789)\t1\t64,949,684\tRB1:BIVM–ERCC5:ERCC5:IRS2:LAMP1\t\n14q32.12(92435944–92470292)\t1\t34,348\tTRIP11\t\n14q32.2q32.31(99697796–102549592)\t4\t2,851,796\tBCL11B:HSP90AA1\t\n14q32.31q32.33(102568334–105259056)\t4\t2,690,722\tHSP90AA1:AKT1\t\n15q14q15.1(39881158–40914530)\t3\t1,033,372\tTHBS1:BUB1B:PAK6:CASC5\t\n15q15.1(40914530–40914946)\t8\t416\tCASC5\t\n15q15.1q21.3(40915027–57574785)\t3\t16,659,758\tCASC5:LTK:TGM7:TCF12\t\n15q26.1(91293154–91304549)\t4\t11,395\tBLM\t\n15q26.1(91306116–91358510)\t1\t52,394\tBLM\t\n16p13.3(2110598–2110873)\t7\t275\tTSC2\t\n16p13.3(2126481–2129066)\t8\t2,585\tTSC2\t\n16p13.3(2129066–3824694)\t3\t1,695,628\tTSC2:CREBBP\t\n16p12.2(23614957–23646619)\t1\t31,662\tPALB2\t\n16p12.2p12.1(23646619–27460675)\t3\t3,814,056\tPALB2:IL21R:LOC283888\t\n16q12.1(50825401–50827575)\t0\t2,174\tCYLD\t\n16q12.1q24.3(50828113–89882998)\t1\t39,054,885\tCYLD:MMP2:CDH1:CDH5:CDH1:MAF:ZNF276:FANCA\t\n17p13.2(5405081–5442941)\t4\t37,860\tNLRP1\t\n17p13.1(8046119–8053735)\t5\t7,616\tPER1\t\n17p13.1(8108179–8111176)\t4\t2,997\tAURKB\t\n17p12q11.2(12016465–29663487)\t3\t17,647,022\tMAP2K4:FLCN:NF1\t\n17q11.2(29663487–29663721)\t0\t234\tNF1\t\n17q11.2(29663721–29684308)\t4\t20,587\tNF1\t\n17q23.3q25.3(62008693–75398324)\t4\t13,389,631\tCD79B:PRKAR1A:SEPT9\t\n17q25.3(78346858–78363051)\t3\t16,193\tRNF213:LOC100294362\t\n19q13.2(42788861–42799411)\t0\t10,550\tCIC\t\n19q13.32q13.43(45252220–57746806)\t1\t12,494,586\tBCL3:MARK4:ERCC2:CD3EAP:ERCC1:PPP2R1A:AURKC\t\n20q12(39708708–40730948)\t3\t1,022,240\tTOP1:PLCG1:PTPRT\t\n21q22.2q22.3(39947501–46330714)\t3\t6,383,213\tERG:ITGB2\t\n22q11.21(22127160–22153507)\t1\t26,347\tMAPK1\t\n22q11.23(23523722–23524530)\t1\t808\tBCR\t\n22q13.2(41574270–42526792)\t4\t952,522\tEP300:CYP2D6\t\n Acknowledgments\nThis work was supported in part by the Scientific Support Programs for Cancer Research Grant-in-Aid Scientific Research on Innovative Areas Ministry of Education, Culture, Sports, Science, and Technology. This is the same research abstract number 4424 AACR Annual Meeting Philadelphia 2015.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Sagittal T1-weighted magnetic resonance images depict focuses of plasma cell infiltration and pathologic fractures in the T4 (A) and L1 (B) vertebrae.\n\nNote: Red arrows indicate large focal lesions in the vertebrae.\n\nFigure 2 Evaluation of a bone marrow aspirate.\n\nNotes: (A) Conventional karyotyping of metaphase cells from BM aspirate was performed using the G-banding technique. Complex cytogenetic aberrancies including loss of chromosomes, and additional uncharacterized materials at chromosome 8 (1) and 13 (2) are shown here. In addition, a dicentric translocation involving chromosome 11 and 14 (3) were also observed. (B) Visualization of CNVs over the entire genome in the karyotype view. The decreased copy number is indicated in red with increased copy number indicated in blue. (C) Interphase FISH studies were performed on BM aspirates using IgH/CCND1 dual color dual fusion probe (Vysis Inc., Des Plaines, IL, USA). The cell showed one orange (normal CCND1), one green (normal IgH), and two yellow signals (arrows), indicating typical t(11;14) rearrangement.\n\nAbbreviations: CNV, copy number variant; FISH, fluorescence in situ hybridization; BM, bone marrow.\n\nFigure 3 Clinical course of the patient.\n\nAbbreviations: HD, high dose; DEX, dexamethsone; Cy, cyclophosphamide; FLC, free light chain; IgG, Immunoglobulin G.\n\nTable 1 Somatic mutations identified in our case\n\nGene\tFunction\tExon\tProtein\tCoding\tTotal coverage\tVariant coverage\tVariant frequency (%)\t\nSYNE1\tMissense\t60\tp.Val3187Gly\tc.9560T>G\t68\t11\t16.2\t\nEGFR\tFrameshift deletion\t13\tp.Glu513Gly\tc.1538_1539delG\t235\t218\t92.8\t\nIKBKB\tMissense\t9\tp.Val241Glu\tc.722T>A\t125\t20\t16.0\t\nERBB3\tMissense\t25\tp.Thr1024Asn\tc.3071C>A\t158\t47\t29.7\t\nMYH11\tMissense\t8\tp.Ala275Gly\tc.824C>G\t70\t15\t21.4\t\nCYLD\tMissense\t18\tp.Cys791Arg\tc.2371T>C\t25\t15\t60.0\t\nTP53\tMissense\t5\tp.Arg158Gly\tc.472C>G\t79\t71\t89.9\t\nCDH2\tMissense\t16\tp.Asp906Glu\tc.2718C>G\t86\t16\t18.6\t\nNotes: List of total coverage, variant read coverage, and variant frequencies of somatic mutations identified in DNA isolated from BM aspirates of this case. BM mononuclear cells were separated using Ficoll–Paque density sedimentation, and plasma cells were purified by positive selection with anti-CD138 magnetic-activated cell separation microbeads (Miltenyi Biotec, Bergisch Gladbach, Germany). Somatic mutations were detected using statistical approaches in tumor (CD138 positive) and normal (CD138 negative) samples from the Ion Reporter software 4.0 tumor-normal workflow. A sequencing coverage of 25× and a minimum variant frequency of 15% of the total number of distinct tags were used as cutoffs. Mutations were called if they occurred in <1% of reads in the normal control, and were absent from dbSNP and the 1,000 Genomes Project database.\n\nAbbreviation: BM, bone marrow.\n\nTable 2 Nucleotide variants identified in CD138-negative bone marrow aspirates from our case-1\n\nLocus number\tCoverage\tVariant coverage\tFrequency (%)\tGene\tFunction\tExon\tProtein\tCoding\tdbsnpa\t\nchr2:219543924\t155\t67\t43.2\tSTK36\tMissense\t7\tp.Arg240Trp\tc.718C>T\trs35038757\t\nchr3:14199887\t189\t101\t53.4\tXPC\tMissense\t9\tp.Ala499Val\tc.1496C>T\trs2228000\t\nchr4:106155185\t127\t127\t100.0\tTET2\tMissense\t3\tp.Pro29Arg\tc.86C>G\trs12498609\t\nchr4:1801064\t158\t60\t38.0\tFGFR3\tMissense\t3\tp.Gly65Arg\tc.193G>A\trs2305178\t\nchr4:1807488\t100\t48\t48.0\tFGFR3\tMissense\t13\tp.Val555Leu\tc.1663G>T\trs199544087\t\nchr4:55139771\t328\t155\t47.3\tPDGFRA\tMissense\t10\tp.Ser478Pro\tc.1432T>C\trs35597368\t\nchr4:55981531\t153\t59\t38.6\tKDR\tMissense\t4\tp.Val136Met\tc.406G>A\trs35636987\t\nchr5:176637576\t102\t102\t100.0\tNSD1\tMissense\t5\tp.Ser726Pro\tc.2176T>C\trs28932178\t\nchr5:256509\t134\t61\t45.5\tSDHA\tMissense\t15\tp.Val657Ile\tc.1969G>A\trs6962\t\nchr5:7878179\t139\t79\t56.8\tMTRR\tMissense\t5\tp.Ser202Leu\tc.605C>T\trs1532268\t\nchr6:152443756\t115\t60\t52.2\tSYNE1\tMissense\t146\tp.Gly8737Ser\tc.26209G>A\trs2295191\t\nchr6:32190390\t150\t148\t98.7\tNOTCH4\tMissense\t3\tp.Lys117Gln\tc.349A>C\trs915894\t\nchr6:56351972\t143\t74\t51.7\tDST\tMissense\t81\tp.Leu4874Val\tc.14620C>G\trs80260070\t\nchr6:56417545\t104\t103\t99.0\tDST\tMissense\t55\tp.Thr3230Ala\tc.9688A>G\trs4715631\t\nchr6:56463410\t144\t72\t50.0\tDST\tMissense\t40\tp.Gln1812Arg\tc.5435A>G\trs4712138\t\nchr7:6026988\t140\t67\t47.9\tPMS2\tMissense\t11\tp.Pro470Ser\tc.1408C>T\trs1805321\t\nchr7:91712698\t220\t101\t45.9\tAKAP9\tMissense\t33\tp.Asn2792Ser\tc.8375A>G\trs6960867\t\nchr8:145741439\t180\t105\t58.3\tRECQL4\tMissense\t5\tp.Arg355Gln\tc.1064G>A\trs374743591\t\nchr10:43610119\t230\t111\t48.3\tRET\tMissense\t11\tp.Gly691Ser\tc.2071G>A\trs1799939\t\nchr10:70332672\t226\t117\t51.8\tTET1\tMissense\t2\tp.Ser193Thr\tc.577T>A\trs12773594\t\nchr12:49431094\t189\t94\t49.7\tKMT2D\tMissense\t34\tp.Met3349Val\tc.10045A>G\trs80149580\t\nchr14:51224417\t141\t74\t52.5\tNIN\tMissense\t18\tp.Pro1111Ala\tc.3331C>G\trs2236316\t\nchr14:92460227\t200\t98\t49.0\tTRIP11\tMissense\t15\tp.Glu1696Lys\tc.5086G>A\trs80200454\t\nchr14:92472416\t87\t48\t55.2\tTRIP11\tMissense\t11\tp.Ser635Cys\tc.1904C>G\trs59635749\t\nchr15:40898643\t173\t77\t44.5\tCASC5\tMissense\t4\tp.Arg43Thr\tc.128G>C\trs7177192\t\nchr15:40913840\t208\t92\t44.2\tCASC5\tMissense\t10\tp.Ala460Ser\tc.1378G>T\trs2412541\t\nchr15:40914177\t114\t54\t47.4\tCASC5\tMissense\t10\tp.Met572Thr\tc.1715T>C\trs11858113\t\nchr15:40915190\t148\t78\t52.7\tCASC5\tMissense\t10\tp.Arg910Gly\tc.2728A>G\trs8040502\t\nchr15:40916632\t173\t78\t45.1\tCASC5\tMissense\t10\tp.Asp1390Glu\tc.4170T>A\trs141726041\t\nchr15:41805237\t149\t72\t48.3\tLTK\tMissense\t2\tp.Arg42Gln\tc.125G>A\trs2305030\t\nchr17:5462805\t136\t67\t49.3\tNLRP1\tMissense\t4\tp.Arg404Gln\tc.1211G>A\trs3744718\t\nchr18:47800179\t147\t61\t41.5\tMBD1\tMissense\t12\tp.Pro401Ala\tc.1201C>G\trs125555\t\nchr18:50832072\t125\t73\t58.4\tDCC\tMissense\t13\tp.Leu679Arg\tc.2036T>G\trs2271042\t\nchr19:18876309\t106\t52\t49.1\tCRTC1\tMissense\t10\tp.Thr344Ala\tc.1030A>G\trs3746266\t\nNotes: DNA was extracted from CD138-negative BM aspirates of this case and peripheral blood of healthy donor-1 (TT) using the QIAamp DNA Mini kit (Qiagen GmbH, Hilden, Germany) following manufacturer’s instructions. DNA (40 ng) was used for multiplex PCR amplification with an Ion Ampliseq Comprehensive Cancer Panel (Life Technologies, Carlsbad, CA,USA), enabling the targeted coverage of all exons of 409 cancer-related genes in a 4-tube reaction (covered regions =95.4% of total). Nucleotide variants on the CD138-negative BM aspirates of this case were detected using the peripheral blood of healthy donor-1 as a normal control. A sequencing coverage of 25× and a minimum variant frequency of 15% of the total number of distinct tags were used as cutoffs.\n\na dbSNP ID number.\n\nAbbreviations: BM, bone marrow; PCR, polymerase chain reaction.\n\nTable 3 Nucleotide variants identified in CD138 negative bone marrow aspirates from our case-2\n\nLocus number\tCoverage\tVariant coverage\tFrequency (%)\tGene\tCodon\tExon\tProtein\tCoding\tdbsnpa\t\nchr1:114948281\t64\t63\t98.4\tTRIM33\tMissense\t15\tp.Ile840Thr\tc.2519T>C\trs6537825\t\nchr1:144879485\t120\t28\t23.3\tPDE4DIP\tMissense\t27\tp.Thr1322Arg\tc.3965C>G\trs113467089\t\nchr1:206665052\t136\t68\t50.0\tIKBKE\tMissense\t18\tp.Ala602Val\tc.1805C>T\trs12059562\t\nchr1:226555302\t223\t119\t53.4\tPARP1\tMissense\t17\tp.Val762Ala\tc.2285T>C\trs1136410\t\nchr2:219543924\t155\t67\t43.2\tSTK36\tMissense\t7\tp.Arg240Trp\tc.718C>T\trs35038757\t\nchr4:1801064\t158\t60\t38.0\tFGFR3\tMissense\t3\tp.Gly65Arg\tc.193G>A\trs2305178\t\nchr4:1807488\t100\t48\t48.0\tFGFR3\tMissense\t13\tp.Val555Leu\tc.1663G>T\trs199544087\t\nchr4:55139771\t328\t155\t47.3\tPDGFRA\tMissense\t10\tp.Ser478Pro\tc.1432T>C\trs35597368\t\nchr4:55981531\t153\t59\t38.6\tKDR\tMissense\t4\tp.Val136Met\tc.406G>A\trs35636987\t\nchr5:256509\t134\t61\t45.5\tSDHA\tMissense\t15\tp.Val657Ile\tc.1969G>A\trs6962\t\nchr5:38496637\t214\t94\t43.9\tLIFR\tMissense\t13\tp.Asp578Asn\tc.1732G>A\trs3729740\t\nchr5:7878179\t139\t79\t56.8\tMTRR\tMissense\t5\tp.Ser202Leu\tc.605C>T\trs1532268\t\nchr6:152443756\t115\t60\t52.2\tSYNE1\tMissense\t146\tp.Gly8737Ser\tc.26209G>A\trs2295191\t\nchr6:51890823\t157\t87\t55.4\tPKHD1\tMissense\t32\tp.Ala1262Val\tc.3785C>T\trs9296669\t\nchr6:51914956\t104\t52\t50.0\tPKHD1\tMissense\t22\tp.Arg760Cys\tc.2278C>T\trs9370096\t\nchr6:56351972\t143\t74\t51.7\tDST\tMissense\t81\tp.Leu4874Val\tc.14620C>G\trs80260070\t\nchr6:56417282\t157\t157\t100.0\tDST\tMissense\t55\tp.Met3317Ile\tc.9951G>A\trs4715630\t\nchr6:56417545\t104\t103\t99.0\tDST\tMissense\t55\tp.Thr3230Ala\tc.9688A>G\trs4715631\t\nchr7:106509331\t138\t63\t45.7\tPIK3CG\tMissense\t2\tp.Ser442Tyr\tc.1325C>A\trs17847825\t\nchr8:145741439\t180\t105\t58.3\tRECQL4\tMissense\t5\tp.Arg355Gln\tc.1064G>A\trs374743591\t\nchr9:8518052\t124\t67\t54.0\tPTPRD\tMissense\t21\tp.Gln447Glu\tc.1339C>G\trs10977171\t\nchr10:43610119\t230\t111\t48.3\tRET\tMissense\t11\tp.Gly691Ser\tc.2071G>A\trs1799939\t\nchr12:49431094\t189\t94\t49.7\tKMT2D\tMissense\t34\tp.Met3349Val\tc.10045A>G\trs80149580\t\nchr14:51202311\t140\t69\t49.3\tNIN\tMissense\t28\tp.Gln1934Glu\tc.5800C>G\trs2295847\t\nchr14:92460227\t200\t98\t49.0\tTRIP11\tMissense\t15\tp.Glu1696Lys\tc.5086G>A\trs80200454\t\nchr14:92472416\t87\t48\t55.2\tTRIP11\tMissense\t11\tp.Ser635Cys\tc.1904C>G\trs59635749\t\nchr15:39880822\t330\t157\t47.6\tTHBS1\tMissense\t10\tp.Thr523Ala\tc.1567A>G\trs2292305\t\nchr15:40914177\t114\t54\t47.4\tCASC5\tMissense\t10\tp.Met572Thr\tc.1715T>C\trs11858113\t\nchr15:40916632\t173\t78\t45.1\tCASC5\tMissense\t10\tp.Asp1390Glu\tc.4170T>A\trs141726041\t\nchr15:41805237\t149\t72\t48.3\tLTK\tMissense\t2\tp.Arg42Gln\tc.125G>A\trs2305030\t\nchr16:15820863\t305\t305\t100.0\tMYH11\tMissense\t29\tp.Ala1241Thr\tc.3721G>A\trs16967494\t\nchr18:47800179\t147\t61\t41.5\tMBD1\tMissense\t12\tp.Pro401Ala\tc.1201C>G\trs125555\t\nchr18:50832072\t125\t73\t58.4\tDCC\tMissense\t13\tp.Leu679Arg\tc.2036T>G\trs2271042\t\nchr22:42526694\t112\t76\t67.9\tCYP2D6\tMissense\t1\tp.Pro34Ser\tc.100C>T\trs1065852\t\nNotes: DNA was extracted from CD138 negative BM aspirates of this case and peripheral blood of healthy donor 2 (Y.S.) using the QIAamp DNA Mini kit (Qiagen GmbH, Hilden, Germany) following manufacturer’s instructions. DNA (40 ng) was used for multiplex PCR amplification with an Ion Ampliseq Comprehensive Cancer Panel (Life Technologies, Carlsbad, CA, USA), enabling the targeted coverage of all exons of 409 cancer-related genes in a four tube reaction (covered regions =95.4% of total). Nucleotide variants on the CD138-negative BM aspirates of this case were detected using the peripheral blood of healthy donor-2 as a normal control. A sequencing coverage of 25× and a minimum variant frequency of 15% of the total number of distinct tags were used as cutoffs.\n\na dbSNP ID number.\n\nAbbreviations: BM, bone marrow; PCR, polymerase chain reaction.\n==== Refs\nReferences\n1 Ikeda H Hideshima T Fulciniti M The monoclonal antibody nBT062 conjugated to cytotoxic Maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo Clin Cancer Res 2009 15 4028 4037 19509164 \n2 Görgün G Calabrese E Hideshima T A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma Blood 2010 115 5202 5213 20382844 \n3 Anderson KC Therapeutic advances in relapsed or refractory multiple myeloma J Natl Compr Canc Netw 2013 11 676 679 23704241 \n4 Röllig C Knop S Bornhäuser M Multiple myeloma Lancet 2015 385 9983 2197 2208 25540889 \n5 Chinen Y Phosphoinositide protein kinase PDPK1 is a crucial cell signaling mediator in multiple myeloma Cancer Res 2014 74 7418 7429 25269480 \n6 Görgün G Calabrese E Soydan E Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma Blood 2010 116 3227 3237 20651070 \n7 Damerla RR Chatterjee B Li Y Francis RJ Fatakia SN Lo CW Ion Torrent sequencing for conducting genome-wide scans for mutation mapping analysis Mamm Genome 2014 3–4 120 128 \n8 Singh RR Patel KP Routbort MJ Clinical validation of a next-generation sequencing screen for mutational hotspots in 46 cancer-related genes J Mol Diagn 2013 5 607 622 23810757 \n9 Chapman MA Initial genome sequencing and analysis of multiple myeloma Nature 2011 471 467 472 21430775 \n10 Nefedova Y Cheng P Alsina M Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines Blood 2004 103 3503 3510 14670925 \n11 Hideshima T Catley L Raje N Inhibition of Akt induces significant downregulation of survivin and cytotoxicity in human multiple myeloma cells Br J Haematol 2007 138 783 791 17760810 \n12 Markovina S Callander NS Bortezomib-resistant nuclear factor-kappa B activity in multiple myeloma cells Mol Cancer Res 2008 6 1356 1364 18708367 \n13 Jimenez-Zepeda VH Braggio E Fonseca R Dissecting karyotypic patterns in non-hyperdiploid multiple myeloma: an overview on the karyotypic evolution Clin Lymphoma Myeloma Leuk 2013 13 552 558 23856591 \n14 Fonseca R Blood E Rue M Harrington D Clinical and biologic implications of recurrent genomic aberrations in myeloma Blood 2003 101 4569 4575 12576322 \n15 Leich E Weißbach S Klein HU Multiple myeloma is affected by multiple and heterogeneous somatic mutations in adhesion- and receptor tyrosine kinase signaling molecules Blood Cancer J 2013 3 102 \n16 Tessema M Willink R Do K Promoter methylation of genes in and around the candidate lung cancer susceptibility locus 6q23–25 Cancer Res 2008 68 1707 1714 18339850 \n17 Schuebel KE Chen W Cope L Glöckner SC Comparing the DNA hypermethylome with gene mutations in human colorectal cancer PLoS Genet 2007 3 9 1709 1723 17892325 \n18 Castilla LH Garrett L Adya N The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelo-monocytic leukaemia Nat Genet 1999 23 2 144 146 10508507 \n19 Alhopuro P Phichith D Tuupanen S Unregulated smooth-muscle myosin in human intestinal neoplasia Proc Natl Acad Sci U S A 2008 105 14 5513 5518 18391202 \n20 Vandyke K Chow AW Williams SA Circulating N-cadherin levels are a negative prognostic indicator in patients with multiple myeloma Br J Haematol 2013 161 4 499 507 23438504\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6930",
"issue": "8()",
"journal": "OncoTargets and therapy",
"keywords": "drug resistance; genome-wide sequencing; multiple myeloma; semiconductor sequencer; target therapy",
"medline_ta": "Onco Targets Ther",
"mesh_terms": null,
"nlm_unique_id": "101514322",
"other_id": null,
"pages": "2805-15",
"pmc": null,
"pmid": "26491355",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "18391202;20382844;19509164;24306492;18339850;17892325;12576322;21430775;20651070;18708367;25540889;23856591;23438504;23396385;25269480;23810757;17760810;10508507;14670925;23704241",
"title": "Molecular diagnostics of a single drug-resistant multiple myeloma case using targeted next-generation sequencing.",
"title_normalized": "molecular diagnostics of a single drug resistant multiple myeloma case using targeted next generation sequencing"
} | [
{
"companynumb": "JP-CELGENE-JPN-2015110927",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND\nIbrutinib is a small molecule tyrosine kinase inhibitor that blocks the activity of B cells and other immune effectors and is used in a variety of hematologic malignancies. There have been numerous reports of increased frequency of serious infections including invasive fungal infections (IFI) in patients on ibrutinib.\n\n\nMETHODS\nDemographic and clinical features of all patients receiving ibrutinib at a single tertiary care center were collected from electronic medical records. Univariate and multivariate statistical analyses were performed to find out the factors associated with infection.\n\n\nRESULTS\nA total of 244 patients received ibrutinib for hematologic malignancies, of which 44 (18.0%) experienced ≥ 1 serious infection including 5 (2.0%) with IFI (1 pulmonary cryptococcosis, 4 pulmonary aspergillosis), 39 (16.0%) with bacterial infections and 8 (3.3%) with viral infections. Ten patients (4.1%) experienced multiple infections or co-infections while on ibrutinib and 10 (4.1%) expired or were transferred to hospice as a result of infection. In multivariate analysis risk factors that were less common in uninfected versus infected patients included advanced age (73 years vs. 77 years), Eastern Cooperative Oncologic Grade (ECOG) performance score ≥ 2 (6.5% vs. 31.8%) and concurrent use of steroids (4.5% vs. 20.5%) or other cytotoxic agents (0% vs. 4.6%).\n\n\nCONCLUSIONS\nThere was a high rate of serious infection but relatively few IFI in patients receiving ibrutinib. Most patients who developed serious infections while on ibrutinib had additional predisposing risk factors including concurrent use of steroids or other cytotoxic agents, advanced age and frailty.",
"affiliations": "Department of Internal Medicine, Yale School of Medicine, 333 Cedar St, New Haven, CT, 06510, USA. Electronic address: thomas.holowka@unchealth.unc.edu.;Yale School of Medicine, 367 Cedar St, New Haven, CT, 06510, USA. Electronic address: harry.cheung@yale.edu.;Section of Infectious Disease, Department of Internal Medicine, Yale School of Medicine, USA. Electronic address: maricar.malinis@yale.edu.;Yale Center for Analytical Science, Yale School of Public Health, PO Box 208034, New Haven, CT, 06520, USA. Electronic address: geliang.gan@yale.edu.;Yale Center for Analytical Science, Yale School of Public Health, PO Box 208034, New Haven, CT, 06520, USA. Electronic address: yanhong.deng@yale.edu.;Department of Pharmacy, Yale New Haven Health, 20 York St, New Haven, CT, 06510, USA. Electronic address: sarah.perreault@ynhh.org.;Section of Hematology, Department of Internal Medicine, Yale School of Medicine, 333 Cedar St, New Haven, CT, 06510, USA. Electronic address: iris.isufi@yale.edu.;Section of Infectious Disease, Department of Internal Medicine, Yale School of Medicine, 333 Cedar St, New Haven, CT, 06510, USA. Electronic address: marwan.azar@yale.edu.",
"authors": "Holowka|Thomas|T|;Cheung|Harry|H|;Malinis|Maricar|M|;Gan|Geliang|G|;Deng|Yanhong|Y|;Perreault|Sarah|S|;Isufi|Iris|I|;Azar|Marwan M|MM|",
"chemical_list": "D010880:Piperidines; C551803:ibrutinib; D000225:Adenine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2021.08.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "27(12)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Chronic lymphocytic leukemia; Ibrutinib; Immunocompromised; Infection; Invasive fungal infection; Lymphoma",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000225:Adenine; D000368:Aged; D006801:Humans; D015994:Incidence; D000072742:Invasive Fungal Infections; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D010880:Piperidines; D012307:Risk Factors",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "1700-1705",
"pmc": null,
"pmid": "34389223",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Incidence and associated risk factors for invasive fungal infections and other serious infections in patients on ibrutinib.",
"title_normalized": "incidence and associated risk factors for invasive fungal infections and other serious infections in patients on ibrutinib"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP031175",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditiona... |
{
"abstract": "A high proportion of patients with relapsed classical Hodgkin's lymphoma achieve a response with the antibody-drug conjugate brentuximab vedotin, and the drug is well tolerated. We modified the escalated BEACOPP regimen (eBEACOPP; bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and implemented brentuximab vedotin with the aim to reduce toxic effects while maintaining the protocol's efficacy.\n\n\n\nWe did an open-label, multicentre, randomised phase 2 study at 20 study sites in Germany. Adult patients (aged 18-60 years) with newly diagnosed, advanced, classical Hodgkin's lymphoma were randomly assigned (1:1) to treatment with six cycles of either BrECAPP (brentuximab vedotin 1·8 mg/kg on day 1, etoposide 200 mg/m2 on days 2-4, doxorubicin 35 mg/m2 on day 2, cyclophosphamide 1250 mg/m2 on day 2, procarbazine 100 mg/m2 on days 2-8, and prednisone 40 mg/m2 on days 2-15) or BrECADD (brentuximab vedotin 1·8 mg/kg on day 1, etoposide 150 mg/m2 on days 2-4, doxorubicin 40 mg/m2 on day 2, cyclophosphamide 1250 mg/m2 on day 2, dacarbazine 250 mg/m2 on days 3-4, and dexamethasone 40 mg on days 2-5). Randomisation was done centrally by stratified minimisation, with study site and sex as stratification factors. The co-primary endpoints were complete response to chemotherapy and complete remission at the end of treatment, which were assessed by intention to treat. Patients who were found not to meet inclusion criteria after randomisation or without restaging data after two cycles of study treatment were excluded from the primary endpoint analysis. All patients who started study treatment were assessable for safety. This report presents the final analysis at a median follow-up of 17 months (IQR 13·2-21·5). The preplanned 2-year follow-up analysis is yet to be reported. This trial is registered with ClinicalTrials.gov, number NCT01569204.\n\n\n\nBetween Oct 26, 2012, and May 15, 2014, 104 patients were enrolled to the study (52 were assigned to each study arm). Two patients dropped out before the start of study treatment because of acute infection (n=1) and withdrawal of consent (n=1) and one patient was excluded because of intermediate-stage disease (all were assigned BrECAPP). 42 (86%, 95% CI 73-94) of 49 patients assigned BrECAPP achieved a complete response after chemotherapy and 46 (94%, 95% CI 83-99) had complete remission as their final treatment outcome. In the BrECADD group, 46 (88%, 95% CI 77-96) of 52 patients achieved both a complete response after chemotherapy and complete remission as their final treatment outcome. 58 serious adverse events were reported, 32 events in 21 of 50 patients who received BrECAPP and 26 events in 18 of 52 patients who received BrECADD. The most common grade 3-4 toxic effects were haematological adverse events (91 [89%] of 102 patients). Grade 3-4 organ toxic effects were reported in seven (17%) of 42 patients assigned BrECAPP and two (4%) of 46 allocated BrECADD. 16 (32%) of 50 patients assigned BrECAPP and 18 (35%) of 52 allocated BrECADD had grade 1-2 peripheral neuropathy, and one (2%) patient assigned BrECAPP developed grade 3 peripheral neuropathy; all but one case (allocated BrECAPP) resolved. No deaths were reported during the follow-up period.\n\n\n\nBoth eBEACOPP variants met the co-primary efficacy endpoints. Particularly, the BrECADD regimen was associated with a more favourable toxicity profile and was, therefore, selected to challenge standard eBEACOPP for the treatment of advanced classical Hodgkin's lymphoma in the phase 3 HD21 study by the German Hodgkin Study Group (NCT02661503), which aims to further reduce treatment-related morbidity.\n\n\n\nTakeda Pharmaceuticals.",
"affiliations": "First Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany; German Hodgkin Study Group (GHSG), University Hospital of Cologne, Cologne, Germany.;First Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany; German Hodgkin Study Group (GHSG), University Hospital of Cologne, Cologne, Germany.;First Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany; German Hodgkin Study Group (GHSG), University Hospital of Cologne, Cologne, Germany.;Second Department of Internal Medicine, University Hospital of Tübingen, Tübingen, Germany.;Department of Internal Medicine III, University Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany.;Fifth Department of Internal Medicine, University Hospital of Heidelberg, Heidelberg, Germany.;Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.;Second Department of Internal Medicine, University Hospital of Würzburg, Würzburg, Germany.;First Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany; German Hodgkin Study Group (GHSG), University Hospital of Cologne, Cologne, Germany.;Department of Pathology, Hematopathology Section, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.;German Hodgkin Study Group (GHSG), University Hospital of Cologne, Cologne, Germany.;Department of Nuclear Medicine, University Hospital of Cologne, Cologne, Germany; German Hodgkin Study Group (GHSG), University Hospital of Cologne, Cologne, Germany.;Department of Nuclear Medicine, University Hospital of Cologne, Cologne, Germany; German Hodgkin Study Group (GHSG), University Hospital of Cologne, Cologne, Germany.;First Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany; German Hodgkin Study Group (GHSG), University Hospital of Cologne, Cologne, Germany.;German Hodgkin Study Group (GHSG), University Hospital of Cologne, Cologne, Germany.;First Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany; German Hodgkin Study Group (GHSG), University Hospital of Cologne, Cologne, Germany.;First Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany; German Hodgkin Study Group (GHSG), University Hospital of Cologne, Cologne, Germany. Electronic address: peter.borchmann@uni-koeln.de.",
"authors": "Eichenauer|Dennis A|DA|;Plütschow|Annette|A|;Kreissl|Stefanie|S|;Sökler|Martin|M|;Hellmuth|Johannes C|JC|;Meissner|Julia|J|;Mathas|Stephan|S|;Topp|Max S|MS|;Behringer|Karolin|K|;Klapper|Wolfram|W|;Kuhnert|Georg|G|;Dietlein|Markus|M|;Kobe|Carsten|C|;Fuchs|Michael|M|;Diehl|Volker|V|;Engert|Andreas|A|;Borchmann|Peter|P|",
"chemical_list": "D018796:Immunoconjugates; D001761:Bleomycin; D011344:Procarbazine; D014750:Vincristine; D005047:Etoposide; D000079963:Brentuximab Vedotin; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(17)30696-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "18(12)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D000079963:Brentuximab Vedotin; D016001:Confidence Intervals; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005047:Etoposide; D005260:Female; D005858:Germany; D006689:Hodgkin Disease; D006801:Humans; D018796:Immunoconjugates; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011241:Prednisone; D011344:Procarbazine; D011379:Prognosis; D011446:Prospective Studies; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "1680-1687",
"pmc": null,
"pmid": "29133014",
"pubdate": "2017-12",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Incorporation of brentuximab vedotin into first-line treatment of advanced classical Hodgkin's lymphoma: final analysis of a phase 2 randomised trial by the German Hodgkin Study Group.",
"title_normalized": "incorporation of brentuximab vedotin into first line treatment of advanced classical hodgkin s lymphoma final analysis of a phase 2 randomised trial by the german hodgkin study group"
} | [
{
"companynumb": "DE-ACCORD-093539",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
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"drugadditional": "3",
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"abstract": "OBJECTIVE\nTo assess the effectiveness and safety of antiretrovirals (ARVs) used for treatment or prophylaxis in a breastfeeding population of HIV-1-infected women (Burkina-Faso, Kenya, South Africa).\n\n\nMETHODS\nHIV-1-infected pregnant women with <200 CD4 cells per cubic millimeter or with World Health Organization stage 4 disease (cohort A) and asymptomatic women with >500 CD4 cells per cubic millimeter (cohort B) were enrolled into 2 prospective cohorts. Women with 200-500 CD4 cells per cubic millimeter were enrolled in a parallel randomized trial. Women in cohort A initiated antiretroviral therapy. Women in cohort B received zidovudine from 34 to 36 weeks gestation until delivery, with single-dose nevirapine in labor (cohort B). All children received single-dose nevirapine.\n\n\nRESULTS\nOf 248 women enrolled, 111 (cohort A) and 125 (cohort B) infants alive at 24 hours after birth were analyzed. Sixty-nine percent and 42% of women had undetectable viral load at delivery, respectively. Ten children in each cohort died. The 18-month cumulative incidences of HIV-1 infection were 7.5% (95% confidence interval: 3.8% to 14.5%) (cohort A) and 5.8% (2.8% to 11.8%) (cohort B). Sixty-one percent (cohort A) and 78% (cohort B) were breastfed for a median duration of 20 weeks. Four children in cohort A and only 1 in cohort B became HIV-1 infected after 6 weeks of age.\n\n\nCONCLUSIONS\nAntiretroviral therapy initiated a median of 7 weeks before delivery in women with advanced HIV-1 disease was associated with a significant residual risk of HIV-1 transmission due to insufficient decrease in viral load by the time of delivery. Among women with >500 CD4 cells per cubic millimeter, the risk of breast-milk transmission was very low despite lack of postnatal prophylaxis.",
"affiliations": null,
"authors": "|||",
"chemical_list": "D019380:Anti-HIV Agents; D015215:Zidovudine; D019829:Nevirapine",
"country": "United States",
"delete": false,
"doi": "10.1097/QAI.0b013e3181e36634",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-4135",
"issue": "54(5)",
"journal": "Journal of acquired immune deficiency syndromes (1999)",
"keywords": null,
"medline_ta": "J Acquir Immune Defic Syndr",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D001942:Breast Feeding; D002050:Burkina Faso; D018791:CD4 Lymphocyte Count; D018890:Chemoprevention; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D007630:Kenya; D008297:Male; D009035:Mothers; D019829:Nevirapine; D011446:Prospective Studies; D013019:South Africa; D019562:Viral Load; D015215:Zidovudine",
"nlm_unique_id": "100892005",
"other_id": null,
"pages": "533-41",
"pmc": null,
"pmid": "20543706",
"pubdate": "2010-08",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Eighteen-month follow-up of HIV-1-infected mothers and their children enrolled in the Kesho Bora study observational cohorts.",
"title_normalized": "eighteen month follow up of hiv 1 infected mothers and their children enrolled in the kesho bora study observational cohorts"
} | [
{
"companynumb": "CH-MICRO LABS LIMITED-ML2019-02025",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
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"drugadditional": nu... |
{
"abstract": "Nivolumab (PD-1 inhibitor) and other immune checkpoint inhibitors are used primarily to promote reactivation of anti-tumor immunity. However, due to their generalized immunorestorative properties, these agents may also trigger an unusual spectrum of side-effects termed immune-related adverse events. In the case of the lung, pulmonary infiltrates in patients treated with the anti-PD-1 inhibitors, nivolumab, or pembrolizumab, especially patients with non-small cell lung cancer, can result from immune-related pneumonitis, which, until fairly recently was believed to be of non-infective origin. This, in turn, may result in progression and pseudo-progression of disease. An increasing body of evidence has, however, identified pulmonary tuberculosis as an additional type of anti-PD-1 therapy-associated, immune-related adverse event, seemingly as a consequence of excessive reactivation of immune responsiveness to latent Mycobacterium tuberculosis infection. The current case report describes a 56-year old Caucasian female who presented with microbiologically-confirmed tuberculosis infection while on nivolumab therapy for non-small cell lung cancer. Notably, the patient, seemingly the first described from the African Continent, had not received immunosuppressive therapy prior to the diagnosis of tuberculosis.",
"affiliations": "The Medical Oncology Centre of Rosebank, Johannesburg, South Africa.;The Medical Oncology Centre of Rosebank, Johannesburg, South Africa.;The Medical Oncology Centre of Rosebank, Johannesburg, South Africa.;Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.",
"authors": "van Eeden|Ronwyn|R|;Rapoport|Bernardo L|BL|;Smit|Teresa|T|;Anderson|Ronald|R|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2019.00659",
"fulltext": "\n==== Front\nFront OncolFront OncolFront. Oncol.Frontiers in Oncology2234-943XFrontiers Media S.A. 10.3389/fonc.2019.00659OncologyCase ReportTuberculosis Infection in a Patient Treated With Nivolumab for Non-small Cell Lung Cancer: Case Report and Literature Review van Eeden Ronwyn 1*Rapoport Bernardo L. 12Smit Teresa 1Anderson Ronald 21The Medical Oncology Centre of Rosebank, Johannesburg, South Africa2Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South AfricaEdited by: Alfredo Addeo, Geneva University Hospitals (HUG), Switzerland\n\nReviewed by: Matteo Giaj Levra, Centre Hospitalier Universitaire de Grenoble, France; Giulio Metro, Hospital of Santa Maria della Misericordia in Perugia, Italy\n\n*Correspondence: Ronwyn van Eeden dr.rvaneeden@rosebankoncology.co.zaThis article was submitted to Thoracic Oncology, a section of the journal Frontiers in Oncology\n\n24 7 2019 2019 9 65914 4 2019 05 7 2019 Copyright © 2019 van Eeden, Rapoport, Smit and Anderson.2019van Eeden, Rapoport, Smit and AndersonThis 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.Nivolumab (PD-1 inhibitor) and other immune checkpoint inhibitors are used primarily to promote reactivation of anti-tumor immunity. However, due to their generalized immunorestorative properties, these agents may also trigger an unusual spectrum of side-effects termed immune-related adverse events. In the case of the lung, pulmonary infiltrates in patients treated with the anti-PD-1 inhibitors, nivolumab, or pembrolizumab, especially patients with non-small cell lung cancer, can result from immune-related pneumonitis, which, until fairly recently was believed to be of non-infective origin. This, in turn, may result in progression and pseudo-progression of disease. An increasing body of evidence has, however, identified pulmonary tuberculosis as an additional type of anti-PD-1 therapy-associated, immune-related adverse event, seemingly as a consequence of excessive reactivation of immune responsiveness to latent Mycobacterium tuberculosis infection. The current case report describes a 56-year old Caucasian female who presented with microbiologically-confirmed tuberculosis infection while on nivolumab therapy for non-small cell lung cancer. Notably, the patient, seemingly the first described from the African Continent, had not received immunosuppressive therapy prior to the diagnosis of tuberculosis.\n\ncheckpoint inhibitorsimmune reconstitutionnon-small cell lung cancerpulmonary infiltratestuberculosis\n==== Body\nBackground\nNivolumab, the focus of this case report, has been shown to have a significant overall survival benefit compared to docetaxel in the setting of second-line treatment of non-small cell lung cancer (NSCLC). The toxicity profile of nivolumab is also better than that of docetaxel, although the spectrum of side-effects varies greatly (1). Nivolumab is an immune checkpoint inhibitor, which is a fully humanized IgG4 monoclonal antibody that blocks programmed death cell protein-1 (PD-1), an inhibitory receptor that down-regulates the anti-tumor effector functions of T cells, while also interfering with the generation of immunological memory (2).\n\nThe side-effects of checkpoint inhibitors are referred to as immune-related adverse events (IrAEs) and are apparently related to over-activity of the immune system (3). One of these side-effects is pneumonitis, which has an incidence of <1%. Pneumonitis is more commonly seen with PD-1 and PD-L1 inhibitors than with CTLA-4 inhibitors (4). It presents clinically as shortness of breath and cough, while radiological examination reveals infiltrates, which typically resemble interstitial pneumonia, manifesting as reticular nodular infiltrates and ground glass opacities (4, 5). These non-specific features are, however, shared by a broad range of pulmonary disorders of both infective and non-infective origin, complicating differential diagnosis, often necessitating analysis of sputum, bronchoscopy with washings, or even biopsy (4–6). Thereafter, treatment of pneumonitis should be initiated without delay to lessen morbidity and mortality (4–6).\n\nA small number (n = 9) of recent studies, spanning the period 2016–2019 and encompassing only 11 patients, has alerted oncologists practicing immune checkpoint inhibitor-based immunotherapy to the emerging threat of pulmonary tuberculosis (PTB) as a cause of pulmonary infiltrates, possibly mimicking pneumonitis as an IrAE (7–15). All of these reports, which are summarized in Table 1, involve administration of the PD-1-targeted monoclonal antibodies nivolumab (7 patients) or pembrolizumab (4 patients) to patients suffering from lung cancer (n = 5), malignancies of the upper respiratory tract (n = 2), advanced melanoma (n = 2), Hodgkin's lymphoma (n = 1) and Merkel cell carcinoma (n = 1) (7–15). With respect to demographics, the patients were either of Asian (n = 6) or Caucasian (n = 5) origin, aged 49–87 years and predominantly male (n = 10) (7–15). To our knowledge, there are no reports of similar cases associated with the use of CTLA-4 and PD-L1 inhibitors.\n\nTable 1 Summary of case reports documenting development of acute pulmonary tuberculosis in cancer patients treated with PD-1 inhibitors.\n\nPatient(s)\tCountry of origin of report\tType of malignancy\tPD-1 inhibitor\tOutcome\tReferences\t\nAge\tGender\t\t\t\t\t\t\n87\tM\tSingapore\tHodgkin's lymphoma\tPembrolizumab\tSurvived\t(7)\t\n72\tM\tJapan\tNSCLC*\tNivolumab\tNot reported\t(8)\t\n59\tM\tChina\tStage 4 pulmonary adenocarcinoma\tNivolumab\tSurvived\t(10)+\t\n50\tM\tFrance\tMetastatic melanoma\tPembrolizumab\tSurvived\t(9)\t\n64\tM\tFrance\tNSCLC\tNivolumab\tDied\t(9)\t\n65\tF\tChina\tAdvanced melanoma\tPembrolizumab\tSurvived\t(11)\t\n56\tM\tDenmark\tNSCLC\tNivolumab\tNot reported\t(12)\t\n49\tM\tTaiwan\tStage 4 squamous cell carcinoma of hard palate\tNivolumab\tDied\t(13)\t\n59\tM\tUSA\tNasopharyngeal carcinoma\tNivolumab\tDied\t(14)\t\n83\tM\tUSA\tMerkel cell carcinoma\tPembrolizumab\tSurvived\t(14)\t\n75\tM\tJapan\tLung adenocarcinoma\tNivolumab\tSruvived\t(15)\t\n* Non-small cell lung carcinoma;\n\n+ patient with pericardial tamponade.\n\nWith the exception of the patient with Hodgkin's lymphoma, who had received two cycles of chlorambucil and prednisolone several months prior to administration of pembrolizumab (7), none of the other patients had received prior treatment with corticosteroids or other anti-inflammatory/immunosuppressive agents, specifically tumor necrosis factor-α-targeted monoclonal antibodies, which may predispose for active opportunistic infection with M. tuberculosis (8–15). Likewise, anti-PD-1 therapy-associated lymphopenia was excluded as a possible cause of acute PTB. This led the authors of these studies, as well as other commentators (16), to propose reactivation of immune responsiveness to latent M. tuberculosis bacilli and an accompanying severe inflammatory response as the probable cause of PD-1-related disease. This scenario is similar to TB-associated immune reconstitution syndrome (IRIS) associated with initiation of antiretroviral therapy of HIV-infected patients (17).\n\nThe current case report represents a meaningful addition to the current literature on the association of anti-PD-1 based monoclonal antibody therapy of advanced cancer with subsequent development of acute PTB, as it may be the first description of this type of IrAE originating from sub-Saharan Africa, a region with a particularly high prevalence of TB.\n\nCase Presentation\nWritten informed consent was obtained for the publication of this “Case Report.” The patient was a 56-year-old Caucasian female accountant who was initially diagnosed with NSCLC in 2013. She presented with coughing, weight loss and progressive shortness of breath. The patient had severe chronic obstructive airway disease as a result of a 30-pack year history.\n\nThe diagnosis was made on the basis of the findings of fine needle aspiration cytology and a confirmatory biopsy of a right-sided cervical lymph node. Histology showed a moderately differentiated adenocarcinoma with an immunohistochemical profile, which was consistent with that of lung cancer (CK7 Positive, CK 20 Negative, and TTF1 Positive). Her initial staging CT showed a large right-sided perihilar mass with significant left and right hilar nodes, sub-carinal and para-tracheal lymphadenopathy, as well as multiple satellite nodules in both lungs.\n\nA metastatic work-up was requested. An abdominal CT scan and a bone scan showed no evidence of metastatic disease. At diagnosis, the patient had stage IV disease (T4N3M1a). The patient was given first line treatment of carboplatin and gemcitabine. She had a partial response to treatment with a 60% reduction in the size of tumor bulk according to RECIST (18). In early 2014, the patient presented with progressive dyspnoea and radiological evidence of cut-off obstruction of the bronchus. This event was assessed as disease progression. Treatment consisted of palliative radiation to the hilar mass.\n\nShe subsequently received 6 cycles of single-agent pemetrexed when her symptoms became significantly worse (Figure 1A) up to mid-2015. Later in the year the patient's disease progressed and she received treatment with nivolumab as part of a South African expanded access program (EAP). This program was available for patients with NSCLC failing platinum-based chemotherapy in the first-line metastatic setting.\n\nFigure 1 Images showing no evidence of PTB pre-treatment (A), while (B,C) show development of PTB during administration of nivolumab. (D) shows a follow-up radiological investigation demonstrating cancer progression. (A) Initial disease progression (2 Apr 2014). (B,C) PTB infection during nivolumab treatment (22 Apr 2016). (D) Progression of disease (9 May 2016).\n\nThe patient experienced clinical improvement on nivolumab. However, in early 2016 she developed new symptoms of shortness of breath, cough and weight loss. A CT scan of the chest showed evidence of progressive disease, with new nodules bilaterally as well as new features of lymphangitis carcinomatosis. (Figures 1B,C). The new infiltrate was evident on the two different scans. An increasing right lung infiltration was noted, which was radiologically reported as either a secondary infection or disease progression. Pneumonitis was a differential diagnosis at the time.\n\nThe patient was hospitalized as her symptoms were severe. She was treated with intravenous corticosteroids and broad-spectrum antibiotics for possible bacterial infection. The infiltrate was atypical and sputum was tested for acid-fast bacilli (AFB) to check for PTB. It is relevant to note that this patient came from a good socioeconomic area with no known exposure to TB. Her HIV status was negative. Sputum test was positive for AFB with numerous organisms observed microscopically (>10 per field in 20 fields). The patient was referred to an infectious diseases specialist for PTB management (isoniazid, ethambutol, rifampicin and pyrazinamide). She improved clinically and was discharged on anti-TB medication and steroids tapered.\n\nAn attempt was made to restart nivolumab therapy, but the patient developed grade 2 diarrhea. After infectious causes were excluded, the diarrhea resolved with low dose oral corticosteroids. Shortly after that, the patient was readmitted for shortness of breath and respiratory symptoms and died in May 2016. Follow-up radiological investigation demonstrated cancer progression (Figure 1D).\n\nDiscussion\nThe current case report, apparently the first originating from the African Continent, adds to the somewhat limited literature identifying PD-1-targeted immunotherapy of advanced cancer as a possible cause of apparent reactivation of latent M. tuberculosis infection, unrelated to prior administration of corticosteroids (19), possibly mimicking pneumonitis, a recognized IrAE.\n\nVarious causes of immunosuppression may predispose cancer patients to develop active or latent TB infection. Notwithstanding primary and secondary iatrogenic immunosuppression associated with stem cell transplantation for corrective therapy of hematological malignancies and that resulting from treatment with certain types of cytotoxic, anti-cancer chemotherapeutic agents, cancer per se may also result in secondary immunosuppression. This is certainly the case for those hematological malignancies which cause leukopenia, as well as for many types of solid tumor, which, due to their anatomic location cause obstruction and disruption of mechanical barriers (20). Cancer-associated immunosuppression may also be exacerbated by other factors such as immunosenescence, malnourishment and cigarette smoking (20, 21). With respect to development of PTB, the association of this infection with lung cancer and smoking is well-recognized (22), while associations of PTB with non-pulmonary malignancies, including Hodgkin's lymphoma, malignant melanoma (in males), as well as several other types of cancer have also been described (23, 24).\n\nIn the setting of anti-PD-1 therapy-associated pulmonary IrAEs, development of PTB, as well as some other types of microbial and viral infection, has, until recently, been attributed to opportunistic infection due to prolonged administration of corticosteroids to suppress pneumonitis (19). However, a report by Lee et al. in 2016 (7), subsequently confirmed by others (8–15), alerted clinical oncologists to the existence of alternative mechanisms of anti-PD-1-therapy-related development of acute PTB. In contrast to opportunistic infection with M. tuberculosis, these alternative mechanisms appear to involve triggering of exuberant, harmful pulmonary inflammatory responses due to reactivation of immune responsiveness to latent M. tuberculosis bacilli.\n\nWith respect to immunopathogenesis, Barber et al. in their recent description of two cases of PD-1 blockade-associated PTB, also reported that administration of the immune checkpoint inhibitor resulted in an increased prevalence of circulating M. tuberculosis-specific, interferon-γ (IFN-γ)-producing CD4 Th1 cells, but not Th17 cells, CD8 cells, regulatory T cells, or specific antibodies (14). These findings in humans are in agreement with several earlier studies in which CD4 T cell PD-1 gene knockout mice were used to investigate the role of this immune checkpoint inhibitor in the immunopathogenesis of acute, pulmonary M. tuberculosis infection (25–27). In these experimental animal studies, deficiency of PD-1 was found to result in excessive production of IFN-γ in the lungs of M. tuberculosis-infected mice, which, as opposed to controlling the infection, resulted in increased pulmonary bacterial loads, lung pathology and mortality, clearly underscoring a role for PD-1 in regulating harmful IFN-γ-mediated lung inflammation and dysfunction (25–27). However, as noted by Barber et al., further studies in the clinical setting are necessary to establish the exact mechanisms involved in PD-1-targeted therapy-related development of acute PTB (14).\n\nNevertheless, it is noteworthy in this context, that IFN-γ has been reported to suppress expression of the macrophage class-A scavenger receptor known as macrophage receptor with collagenous structure (MARCO), which promotes interaction of these cells with non-opsonized M. tuberculosis via binding to the bacterial cell wall glycolipid, trehalose 6, 6′-dimycolate (28–31). This type of interaction of the pathogen with MARCO promotes both phagocytosis and macrophage activation and is considered to be a major component of the host response to mycobacterial infection (29).\n\nIn conclusion, it is clear from the current and earlier reports that apparent reactivation of latent M. tuberculosis infection in many, but possibly not all cases (14), is a potential complication of PD-1-targeted immunotherapy of patients with advanced cancer. Where the index of suspicion may be high, this raises the issues of advance testing for latent TB and initiation of TB prophylaxis. In addition, as immune-based anti-cancer therapies become more affordable, these issues may become of particular relevance to developing countries where the prevalence of TB is high.\n\nData Availability\nNo datasets were generated or analyzed for this study.\n\nAuthor Contributions\nRvE, TS, and BR conceptualized the original case report. RA has critically reviewed the original manuscript and has contributed significantly to its restructuring and reviewing the literature.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1. Borghaei H Paz-Ares L Horn L Spigel DR Steins M Ready NE . Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer . N Engl J Med. (2015 ) 373 :1627 –39 . 10.1056/NEJMoa1507643 26412456 \n2. Guo L Zhang H Chen B \nNivolumab as programmed death-1 (PD-1) inhibitor for targeted immunotherapy in tumor . J Cancer . (2017 ) 3 :410 –6 . 10.7150/jca.17144 \n3. Chen TW Razak AR Bedard PL Siu LL Hansen AR \nA systematic review of immune-related adverse event reporting in clinical trials of immune checkpoint inhibitors . Ann Oncol. (2015 ) 9 :1824 –9 . 10.1093/annonc/mdv182 \n4. Postow M . Managing immune checkpoint-blocking antibody side effects . Am Soc Clin Oncol Educ Book. (2015 ) 76 –83 . 10.14694/EdBook_AM.2015.35.76 25993145 \n5. Villadolid J Amin A \nImmune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities . Transl Lung Cancer Res . (2015 ) 5 :560 –75 . 10.3978/j.issn.2218-6751.2015.06.06 \n6. Rapoport BL van Eeden R Sibaud V Epstein JB Klastersky J Aapro M \nSupportive care for patients undergoing immunotherapy . Support Care Cancer . (2017 ) 10 :3017 –30 . 10.1007/s00520-017-3802-9 \n7. Lee JJ Chan A Tang T . Tuberculosis reactivation in a patient receiving anti-programmed death-1 (PD-1) inhibitor for relapsed Hodgkin's lymphoma . Acta Oncol. (2016 ) 55 :519 –20 . 10.3109/0284186X.2015.1125017 26754959 \n8. Fujita K Terashima T Mio T \nAnti-PD1 antibody treatment and the development of acute pulmonary tuberculosis . J Thorac Oncol. (2016 ) 12 :2238 –40 . 10.1016/j.jtho.2016.07.006 \n9. Picchi H Mateus C Chouaid C Besse B Marabelle A Michot JM . Infectious complications associated with the use of immune checkpoint inhibitors in oncology: reactivation of tuberculosis after anti PD-1 treatment . Clin Microbiol Infect . (2018 ) 24 :216 –8 . 10.1016/j.cmi.2017.12.003 29269089 \n10. Chu YC Fang KC Chen HC Yeh YC Tseng CE Chou TY . Pericardial tamponade caused by a hypersensitivity response to tuberculosis reactivation after anti-PD-1 treatment in a patient with advanced pulmonary adenocarcinoma . J Thorac Oncol. (2017 ) 12 :e111 –4 . 10.1016/j.jtho.2017.03.012 28748816 \n11. He W Zhang X Li W Kong C Wang Y Zhu L . Activated pulmonary tuberculosis in a patient with melanoma during PD-1 inhibition: a case report . Onco Targets Ther . (2018 ) 11 :7423 –7 . 10.2147/OTT.S178246 30425530 \n12. Jensen KH Persson G Bondgaard AL Pøhl M . Development of pulmonary tuberculosis following treatment with anti-PD-1 for non-small cell lung cancer . Acta Oncol. (2018 ) 57 :1127 –8 . 10.1080/0284186X.2018.1433877 29384034 \n13. Tsai CC Chen JH Wang YC Chang FY . Re-activation of pulmonary tuberculosis during anti-programmed death-1 (PD-1) treatment . Q J Med . (2019 ) 112 :41 –2 . 10.1093/qjmed/hcy243 30351391 \n14. Barber DL Sakai S Kudchadkar RR Fling SP Day TA Vergara JA . Tuberculosis following PD-1 blockade for cancer immunotherapy . Sci Transl Med. (2019 ) 11 :eaat2702 . 10.1126/scitranslmed.aat2702 30651320 \n15. Takata S Koh G Han Y Yoshida H Shiroyama T Takada H . Paradoxical response in a patient with non-small cell lung cancer who received nivolumab followed by anti-Mycobacterium tuberculosis agents . J Infect Chemother. (2019 ) 25 :54 –8 . 10.1016/j.jiac.2018.06.016 30055859 \n16. Reungwetwattana T Adjei AA . Anti-PD-1 antibody treatment and the development of acute pulmonary tuberculosis . J Thorac Oncol. (2016 ) 11 :2048 –50 . 10.1016/j.jtho.2016.10.008 27866633 \n17. Walker NF Stek C Wasserman S Wilkinson RJ Meintjes G . The tuberculosis-associated immune reconstitution inflammatory syndrome: recent advances in clinical and pathogenesis research . Curr Opin HIV AIDS . (2018 ) 13 :512 –21 . 10.1097/COH.0000000000000502 30124473 \n18. Therasse P Arbuck SG Eisenhauer EA Wanders J Kaplan RS Rubinstein L \nNew guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada . J Natl Cancer Inst . (2000 ) 3 :205 –16 . 10.1093/jnci/92.3.205 \n19. Kyi C Hellmann MD Wolchok J Chapman P Postow M . Opportunistic infections in patients treated with immunotherapy for cancer . J Immunother Cancer. (2014 ) 2 :19 . 10.1186/2051-1426-2-19 24991413 \n20. Baden LR Swaminathan S Angarone M Blouin G Camins BC Casper C . Prevention and Treatment of Cancer-Related Infections, version 2.2016, NCCN Clinical Practice Guidelines in Oncology . J Natl Compr Canc Netw . (2016 ) 14 :882 –913 . 10.6004/jnccn.2016.0093 27407129 \n21. Carter BD Abnet CC Feskanich D Freedman ND Hartge P Lewis CE \nSmoking and mortality – beyond established causes . N Engl J Med. (2015 ) 372 :631 –40 . 10.1056/NEJMsa1407211 25671255 \n22. Harikrishna J Sukaveni V Prabath Kumar D Mohan A \nCancer and tuberculosis . JIACM . (2012 ) 13 :142 –4 . Available online at: http://medind.nic.in/jac/t12/i2/jact12i2p142.pdf\n23. Falagas ME Kouranos VD Athanassa Z Kopterides P . Tuberculosis and malignancy . Q J Med . (2010 ) 103 :461 –87 . 10.1093/qjmed/hcq068 20504861 \n24. Kuo SC Hu YW Liu CJ Lee YT Chen YT Chen TL . Association between tuberculosis infections and non-pulmonary malignancies: a nationwide population-based study . Br J Cancer. (2013 ) 109 :229 –34 . 10.1038/bjc.2013.220 23652313 \n25. Barber DL Mayer-Barber KD Feng CG Sharpe AH Sher A . CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition . J Immunol. (2011 ) 186 :1598 –607 . 10.4049/jimmunol.1003304 21172867 \n26. Tousif S Singh Y Prasad DV Sharma P Van Kaer L Das G . T cells from programmed death-1 deficient mice respond poorly to Mycobacterium tuberculosis infection . PLoS ONE . (2011 ) 6 :e19864 . 10.1371/journal.pone.0019864 21589883 \n27. Sakai S Kauffman KD Sallin MA Sharpe AH Young HA Ganusov VV . CD4 T cell-derived IFN-γ plays a minimal role in control of pulmonary Mycobacterium tuberculosis infection and must be actively repressed by PD-1 to prevent lethal disease . PLoS Pathog. (2016 ) 12 :e1005667 . 10.1371/journal.ppat.1005667 27244558 \n28. Sun K Metzger DW . Inhibition of pulmonary antibacterial defense by interferon-γ during recovery from influenza infection . Nat Med . (2008 ) 14 :558 –64 . 10.1038/nm1765 18438414 \n29. Bowdish DM Sakamoto K Kim MJ Kroos M Mukhopadhyay S Leifer CA . MARCO, TLR2, and CD14 are required for macrophage cytokine responses to mycobacterial trehalose dimycolate and Mycobacterium tuberculosis . PLoS Pathog. (2009 ) 5 :e1000474 . 10.1371/journal.ppat.1000474 19521507 \n30. Wang Z Zhou S Sun C Lei T Peng J Li W . Interferon-γ inhibits nonopsonized phagocytosis of macrophages via an mTORC1-c/EBPβ pathway . J Innate Immun . (2015 ) 7 :165 –76 . 10.1159/000366421 25277143 \n31. Thuong NT Tram TT Dinh TD Thai PV Heemskerk D Bang ND . MARCO variants are associated with phagocytosis, pulmonary tuberculosis susceptibility and Beijing lineage . Genes Immun. (2016 ) 17 :419 –25 . 10.1038/gene.2016.43 27853145\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "9()",
"journal": "Frontiers in oncology",
"keywords": "checkpoint inhibitors; immune reconstitution; non-small cell lung cancer; pulmonary infiltrates; tuberculosis",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "659",
"pmc": null,
"pmid": "31396484",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10655437;18438414;19521507;20504861;21172867;21589883;23652313;24991413;25277143;25671255;25888611;25993145;26412456;26629425;26754959;27244558;27407129;27423391;27853145;27866633;28261342;28707167;28748816;29269089;29384034;30055859;30124473;30351391;30425530;30651320",
"title": "Tuberculosis Infection in a Patient Treated With Nivolumab for Non-small Cell Lung Cancer: Case Report and Literature Review.",
"title_normalized": "tuberculosis infection in a patient treated with nivolumab for non small cell lung cancer case report and literature review"
} | [
{
"companynumb": "ZA-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-225429",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"dru... |
{
"abstract": "Objectives The aim of this report is to describe a case of GAD-65 autoantibody associated epilepcy, diagnosed long before the onset of autoimmune diabetes. Case presentation This report presents a 36-year-old female with type 1 diabetes, diagnosed at the age of 26, and a cryptogenic focal epilepsy with complex partial seizures, with duration of 2-3 min and frequency of 5-6 per month, diagnosed at 16 years of age. Electroencephalography revealed epileptiform abnormalities temporally and centro-parietally on the left and temporally on the right with forward propagation on both sides. Due to the drug refractory seizures, titers of GAD-65 autoantibodies were examined (19 years after the diagnosis of epilepsy and 9 years after the diagnosis of diabetes) and were found to be elevated in serum and cerebrospinal fluid, strongly supporting its autoimmune genesis. Insulin pump therapy was used in this patient with a beneficial effect on glycemia. Conclusions Autoimmune epilepsy is a clinical entity and should be taken into consideration in patients with other autoimmune diseases, especially diabetes, and with drug refractory seizures, even preceding the onset of diabetes. Achieving stable glycemic control, including the usage of the new technologies in type 1 diabetes treatment, is vital in these cases.",
"affiliations": "Department of Endocrinology, Division of Diabetology, Medical University Sofia, 2, Zdrave str., 1431, Sofia, Bulgaria.;Department of Endocrinology, Division of Diabetology, Medical University Sofia, Sofia, Bulgaria.;Department of Endocrinology, Division of Diabetology, Medical University Sofia, Sofia, Bulgaria.;Department of Endocrinology, Division of Diabetology, Medical University Sofia, Sofia, Bulgaria.;Department of Endocrinology, Division of Diabetology, Medical University Sofia, Sofia, Bulgaria.",
"authors": "Dimova|Rumyana|R|;Grozeva|Greta|G|;Chakarova|Nevena|N|;Tsarkova|Polina|P|;Tankova|Tsvetalina|T|",
"chemical_list": "D001323:Autoantibodies; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2",
"country": "Germany",
"delete": false,
"doi": "10.1515/jpem-2019-0395",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0334-018X",
"issue": "33(6)",
"journal": "Journal of pediatric endocrinology & metabolism : JPEM",
"keywords": "GAD-65 autoantibodies; autoimmune epilepsy; type 1 diabetes",
"medline_ta": "J Pediatr Endocrinol Metab",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D001327:Autoimmune Diseases; D003922:Diabetes Mellitus, Type 1; D004827:Epilepsy; D005260:Female; D005968:Glutamate Decarboxylase; D006801:Humans; D012640:Seizures",
"nlm_unique_id": "9508900",
"other_id": null,
"pages": "817-820",
"pmc": null,
"pmid": "32436860",
"pubdate": "2020-05-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "GAD-65 autoantibody associated epilepsy.",
"title_normalized": "gad 65 autoantibody associated epilepsy"
} | [
{
"companynumb": "BG-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-256223",
"fulfillexpeditecriteria": "1",
"occurcountry": "BG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drug... |
{
"abstract": "Infections caused by the Scedosporium genus have become recognized as a fatal complication after lung transplantation in Europe and Australia, but the reports have been rare from Asian countries including Japan. We present a case of pneumonia caused by a mixed infection of Scedosporium apiospermum (SA) and Lomentospora prolificans (LP) that developed after augmentation of immunosuppression for chronic lung allograft dysfunction (CLAD) after lung transplantation. A 13-year-old man underwent bilateral lung transplantation for pulmonary hypertension. One year after surgery, he was treated with a series of augmented immunosuppressive therapy for severe acute rejection and subsequent CLAD. Three months following the first steroid pulse therapy, his serum β-D-glucan elevated without any sign of fungal infection by other tests. The serum β-D-glucan once returned to a normal level by empirical administration of micafungin; however, the patient's condition worsened again by discontinuation of it. He did not recover by restarting micafungin, and computed tomography (CT) scans eventually demonstrated new infiltrates in his lung field 6 weeks after the elevation of serum β-D-glucan. Microscopic findings of transbronchial lung biopsy specimens showed filamentous fungi, and the culture of bronchoalveolar lavage fluid revealed the growth of SA and LP. Despite subsequent voriconazole administration, he died 14 days after the start of voriconazole. Early and aggressive inspection including bronchoscopy should be performed for the diagnosis of Scedosporium infection in immunocompromised patients, even if CT scans and sputum culture show no evidence of infection.",
"affiliations": "Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.;Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan. Electronic address: hisashi.oishi.c7@tohoku.ac.jp.;Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan; Department of Thoracic Surgery, Fujita Health University School of Medicine, Toyoake, Japan.;Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.;Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.;Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.;Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.",
"authors": "Suzuki|Yamato|Y|;Oishi|Hisashi|H|;Matsuda|Yasushi|Y|;Noda|Masafumi|M|;Kumata|Sakiko|S|;Hayasaka|Kazuki|K|;Okada|Yoshinori|Y|",
"chemical_list": "D047071:beta-Glucans",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2021.02.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "53(4)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000293:Adolescent; D001992:Bronchoalveolar Lavage Fluid; D005541:Forced Expiratory Volume; D006801:Humans; D006976:Hypertension, Pulmonary; D016867:Immunocompromised Host; D000072742:Invasive Fungal Infections; D016040:Lung Transplantation; D008297:Male; D011014:Pneumonia; D021681:Scedosporium; D013909:Thorax; D014057:Tomography, X-Ray Computed; D047071:beta-Glucans",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1375-1378",
"pmc": null,
"pmid": "33707042",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pneumonia With Scedosporium apiospermum and Lomentospora prolificans in a Patient After Bilateral Lung Transplantation for Pulmonary Hypertension: A Case Report.",
"title_normalized": "pneumonia with scedosporium apiospermum and lomentospora prolificans in a patient after bilateral lung transplantation for pulmonary hypertension a case report"
} | [
{
"companynumb": "JP-PFIZER INC-2021300753",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nSingle-ventricle congenital heart disease (CHD) in pediatric patients with Glenn and Fontan physiology represents a unique physiology requiring the surgical diversion of the systemic venous return from the superior vena cava (Glenn) and then the inferior vena cava (Fontan) directly to the pulmonary arteries. Because many of these patients are on chronic anticoagulation therapy and may have right-to-left shunts, arrhythmias, or lymphatic disorders that predispose them to bleeding and/or clotting, they are at risk of experiencing neurological injury requiring intubation and positive pressure ventilation, which can significantly hamper pulmonary blood flow and cardiac output. The aim of this study was to describe the complex neurological and cardiopulmonary interactions of these pediatric patients after acute central nervous system (CNS) injury.\n\n\nMETHODS\nThe authors retrospectively analyzed the records of pediatric patients who had been admitted to a quaternary children's hospital with CHD palliated to bidirectional Glenn (BDG) or Fontan circulation and acute CNS injury and who had undergone intubation and mechanical ventilation. Patients who had been admitted from 2005 to 2019 were included in the study. Clinical characteristics, surgical outcomes, cardiovascular and pulmonary data, and intracranial pressure data were collected and analyzed.\n\n\nRESULTS\nNine pediatric single-ventricle patients met the study inclusion criteria. All had undergone the BDG procedure, and the majority (78%) were status post Fontan palliation. The mean age was 7.4 years (range 1.3-17.3 years). At the time of acute CNS injury, which included traumatic brain injury, intracranial hemorrhage, and cerebral infarct, the median time interval from the most recent cardiac surgical procedure was 3 years (range 2 weeks-11 years). Maintaining normocarbia to mild hypercarbia for most patients during intubation periods did not cause neurological deterioration, and hemodynamic profiles were more favorable as compared to periods of hypocarbia. Hypocarbia was associated with unfavorable hemodynamics but was necessary to decrease intracranial hypertension. Most patients were managed using low mean airway pressure (MAWP) in order to minimize the impact on preload and cardiac output.\n\n\nCONCLUSIONS\nThe authors highlight the complex neurological and cardiopulmonary interactions with respect to partial pressure of arterial CO2 (PaCO2) and MAWP when pediatric CHD patients with single-ventricle physiology require mechanical ventilation. The study data demonstrated that tight control of PaCO2 and minimizing MAWP with the goal of early extubation may be beneficial in this population. A multidisciplinary team of pediatric critical care intensivists, cardiac intensivists and anesthesiologists, and pediatric neurosurgeons and neurologists are recommended to ensure the best possible outcomes.",
"affiliations": "1Division of Neurosurgery, Children's Hospital of Philadelphia, Department of Neurosurgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia.;3Department of Neurosurgery, Philadelphia College of Osteopathic Medicine, Philadelphia.;1Division of Neurosurgery, Children's Hospital of Philadelphia, Department of Neurosurgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia.;1Division of Neurosurgery, Children's Hospital of Philadelphia, Department of Neurosurgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia.;1Division of Neurosurgery, Children's Hospital of Philadelphia, Department of Neurosurgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia.;1Division of Neurosurgery, Children's Hospital of Philadelphia, Department of Neurosurgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia.;4Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Perelman School of Medicine, Philadelphia.;4Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Perelman School of Medicine, Philadelphia.;4Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Perelman School of Medicine, Philadelphia.;4Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Perelman School of Medicine, Philadelphia.",
"authors": "Lang|Shih-Shan|SS|;Valeri|Amber|A|;Storm|Phillip B|PB|;Heuer|Gregory G|GG|;Tucker|Alexander M|AM|;Kennedy|Benjamin C|BC|;Kozyak|Benjamin W|BW|;Sinha|Anjuli|A|;Kilbaugh|Todd J|TJ|;Huh|Jimmy W|JW|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1933-0707",
"issue": null,
"journal": "Journal of neurosurgery. Pediatrics",
"keywords": "Fontan physiology; Glenn physiology; carbon dioxide; cerebral ischemia; congenital heart disease; intracranial hemorrhage; intracranial hypertension; mean airway pressure; pediatric; trauma; traumatic brain injury; vascular disorders",
"medline_ta": "J Neurosurg Pediatr",
"mesh_terms": null,
"nlm_unique_id": "101463759",
"other_id": null,
"pages": "1-9",
"pmc": null,
"pmid": "34243155",
"pubdate": "2021-07-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Acute neurological injury in pediatric patients with single-ventricle congenital heart disease.",
"title_normalized": "acute neurological injury in pediatric patients with single ventricle congenital heart disease"
} | [
{
"companynumb": "US-BAYER-2021A247674",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Bleeding is one of the serious adverse events of bevacizumab (BV). In our report, two patients had locally advanced breast cancer with bleeding. They received BV plus weekly paclitaxel (PTX), and good local control was observed. Case 1: The patient was a 50-year-old postmenopausal woman. She had left-sided breast cancer (T4cN2cM1 [bone]-stageIV) that was negative for estrogen receptor (ER), negative for progesterone receptor(PgR), and 1+for human epidermal growth factor receptor 2 (HER2). The patient began receiving different regimens of chemotherapy: 5-fluorouracil (5-FU), epirubicin (EPI), and cyclophosphamide(CPA), (FEC); PTX; docetaxel (DTX); and gemcitabine (GEM) plus PTX. Subsequently, she received BV plus PTX. The tumor was markedly reduced in size at the completion of 2 cycles. Bleeding and exudate were also reduced. The patient had a partial response until the sixth cycle, and good local control was obtained. However, the patient had progressive disease at the completion of 8 cycles. Therefore, therapy was changed to capecitabine(CAP)plus CPA, but the patient died one year after she began treatment with BV plus PTX. Case 2: The patient was a 76-year-old postmenopausal woman. She had right-sided breast cancer (T4bN3bM1[lung]-stageIV) that was negative for ER, negative for PgR, and 0 for HER2. The patient began receiving different regimens of chemotherapy: EPI and CPA (EC); and PTX. Subsequently, she received BV plus PTX. The tumor was markedly reduced in size at the completion of 2 cycles. Bleeding and exudate were also reduced. The patient had a partial response until the third cycle, and good local control was obtained. However, the patient had progressive disease at the completion of 4 cycles. Therefore, therapy was changed to CAP and DTX, but the patient died six months after she began treatment with BV plus PTX.",
"affiliations": "Breast Center, Dokkyo Medical University Koshigaya Hospital.",
"authors": "Ishizuna|Kazuo|K|;Ninomiya|Jun|J|;Ogawa|Toshihisa|T|;Kojima|Makoto|M|;Kawashima|Miho|M|;Nozaki|Miwako|M|;Yamagishi|Hidetsugu|H|;Ueda|Yoshihiko|Y|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "41(5)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001943:Breast Neoplasms; D017809:Fatal Outcome; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008875:Middle Aged; D017239:Paclitaxel; D017698:Postmenopause",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "637-40",
"pmc": null,
"pmid": "24917012",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Locally advanced breast cancer with bleeding - two cases effectively treated with bevacizumab plus weekly paclitaxel.",
"title_normalized": "locally advanced breast cancer with bleeding two cases effectively treated with bevacizumab plus weekly paclitaxel"
} | [
{
"companynumb": "JP-CIPLA LTD.-2018JP10008",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Dobutamine stress echocardiography (DSE) is a commonly utilized method for coronary artery disease (CAD) diagnosis, and it provides important long-term prognostic information. We report a case of a 53-year-old female with multiple cardiovascular risk factors who underwent DSE for evaluation of underlying CAD. The examination was complicated by wide complex tachycardia and promoted administration of esmolol, which shortly led to ST-segment elevation myocardial infarction (STEMI). Coronary angiography showed complete absence of CAD. Coronary vasospasm was a possible suggested mechanism due to the pharmacologic interaction between beta-blockers and dobutamine on alpha- and beta-adrenergic receptors.",
"affiliations": "Internal Medicine, Detroit Medical Center/Sinai Grace Hospital, Detroit, USA.;Cardiology, University of Connecticut Health, Farmington, USA.;Internal Medicine, Detroit Medical Center/Sinai Grace Hospital, Detroit, USA.;Medicine, Wayne State University, Detroit, USA.",
"authors": "Manasrah|Nouraldeen|N|;Naik|Rohan|R|;Al Sbihi|Ali F|AF|;Afonso|Luis C|LC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.10015",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.10015\nCardiology\nInternal Medicine\nMedical Education\nCoronary Vasospasm After Dobutamine Stress Echocardiogram Triggered by Esmolol\nMuacevic Alexander Adler John R Manasrah Nouraldeen 1 Naik Rohan 2 Al Sbihi Ali F 1 Afonso Luis C 3 \n1 \nInternal Medicine, Detroit Medical Center/Sinai Grace Hospital, Detroit, USA \n\n2 \nCardiology, University of Connecticut Health, Farmington, USA \n\n3 \nMedicine, Wayne State University, Detroit, USA \n\nNouraldeen Manasrah nouraldeen_adnan@yahoo.com\n25 8 2020 \n8 2020 \n12 8 e1001520 7 2020 25 8 2020 Copyright © 2020, Manasrah et al.2020Manasrah et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/37879-coronary-vasospasm-after-dobutamine-stress-echocardiogram-triggered-by-esmololDobutamine stress echocardiography (DSE) is a commonly utilized method for coronary artery disease (CAD) diagnosis, and it provides important long-term prognostic information. We report a case of a 53-year-old female with multiple cardiovascular risk factors who underwent DSE for evaluation of underlying CAD. The examination was complicated by wide complex tachycardia and promoted administration of esmolol, which shortly led to ST-segment elevation myocardial infarction (STEMI). Coronary angiography showed complete absence of CAD. Coronary vasospasm was a possible suggested mechanism due to the pharmacologic interaction between beta-blockers and dobutamine on alpha- and beta-adrenergic receptors.\n\nmyocardial infarction with no obstructive coronary atherosclerosisdobutamine stress echocardiographycoronary vasospasmThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nDobutamine stress echocardiography (DSE) is a commonly utilized non-invasive diagnostic modality in patients with suspected coronary heart disease. Indications of DSE have increased significantly in recent years, leading to more tests and consequently more complications. Although traditionally very safe, several complications of DSE have been reported such as coronary spasm, hypotension, supraventricular or ventricular arrhythmias, and myocardial infarction [1]. We present a patient who developed ST-elevation myocardial infarction (STEMI) during dobutamine stress testing due to coronary vasospasm that was possibly triggered by esmolol. \n\nCase presentation\nA 53-year-old female smoker with a medical history of hypertension and hyperlipidemia presented to our hospital with atypical chest pain of six-hour duration. The pain was insidious in onset, gradually progressive, and was located under her left breast, with radiation to her left arm and back. It was described as burning in quality, reproducible, and non-exertional and improved with ibuprofen. The patient denied any symptoms of shortness of breath, dizziness, diaphoresis, palpitations, nausea, or vomiting. She was able to perform her daily activities without limitations. Physical exam revealed stable vital signs: blood pressure: 123/78 mmHg, heart rate: 73 beats/minute, respiratory rate: 18 breaths/minute, temperature: 36.5 degrees Celsius, SpO2: 97% on room air. Cardiovascular examination revealed a pulse with regular rate and rhythm, normal S1 and S2, with no murmurs or added sounds. Respiratory examination was normal with normal vesicular breath sounds heard bilaterally with no adventitious sounds. The rest of physical examination was unremarkable. Electrocardiogram (EKG) on admission was significant for T-wave inversions in leads V4-V6 and inferior leads II, III, and aVF (Figure 1). Serial cardiac troponin-I was negative. All other laboratory evaluation was within normal limits. \n\nFigure 1 Electrocardiogram (EKG): T-wave inversions in leads V4-V6 and inferior leads II, III, and aVF \nWe used TIMI (Thrombolysis in Myocardial Infarction) risk score [2] and HEART (History, ECG, Age, Risk factors and Troponin) score [3], which are useful tools for early risk stratification; they help in making decisions about patient's management and predict the likelihood of adverse cardiac events. The calculated scores were 2 and 5, respectively, so our patient underwent DSE to evaluate for inducible ischemia and underlying coronary artery disease (CAD). Intravenous dobutamine infusion was started at 10 mcg/kg/min, increasing to 50 mcg/kg/min in three-minute stages. Intravenous atropine (0.75 mg) was also administered, so 85% of maximum predicted heart rate could be achieved. Subsequently, continuous EKG showed significant tachycardia 170 beats/minute, along with QRS widening (Figure 2).\n\nFigure 2 Electrocardiogram (ECG): wide complex tachycardia\nECG shows wide complex tachycardia, extreme left axis deviation, R waves in aVR and VI, findings consistent with ventricular tachycardia likely originating in the left ventricle\n\nThis prompted administration of intravenous esmolol 15 mg and dobutamine infusion was stopped, and QRS duration reverted back to the baseline. Shortly thereafter, the patient complained of substernal chest pain that was different from the chest pain that brought her to the hospital. It was sudden, rapidly progressive, substernal in location, and described as tightness and heaviness. Continuous EKG showed ST-segment elevations in inferior and anterolateral leads II, III, aVF, and V3-V6 (Figure 3).\n\nFigure 3 Electrocardiogram (ECG): ST-segment elevations in inferior and anterolateral leads II, III, aVF, and V3-V6\nContinuous EKG showed ischemic ST changes with J-point elevation, PR depression, and 3 mm ST-segment elevations in inferior and anterolateral leads II, III, aVF, and V3-V6\n\nSublingual nitroglycerin was given immediately in an attempt to relieve the substernal chest pain. Loading doses of aspirin and ticagrelor were administered. Cardiac troponins were drawn, and the patient was taken for emergency left heart catheterization (LHC). Contrary to our expectation, LHC showed complete absence of CAD. Cardiac troponin-I was elevated at 1.29 ng/ml. Subsequent troponin drawn three hours later showed a drop down to 0.41 ng/ml. The chest pain and ST-segment elevations persisted for about 20 minutes with gradual resolution following administration of sublingual nitroglycerin. Subsequent 12-lead EKG was normal. Resting echocardiogram showed left ventricular ejection fraction of 67%, no new regional wall motion abnormalities, and no valvular abnormalities. Echocardiographic response to stress did not reveal any new regional wall motion abnormalities, but it did show dilation of the left ventricular cavity in recovery.\n\nThe patient was monitored in cardiac telemetry unit for two days, counseled on smoking cessation, and discharged on her home medications of amlodipine, hydralazine, and atorvastatin. In aggregate, findings were deemed secondary to coronary vasospasm in the mid-left anterior descending (wrap around) distribution and possibly also in the right coronary artery distribution.\n\nDiscussion\nDobutamine is a synthetic catecholamine with a relatively short plasma half-life; it has strong β1-receptor, moderate β2-receptor, and mild α1-receptor agonist activity (5+, 3+, and 1+ potency, respectively). In DSE, it is used at high doses (20-40 mg/kg/min) which induce an increase in myocardial oxygen demand and in the setting of flow limiting stenosis; it reveals wall motion abnormalities indicating the presence of underlying CAD. Data from 26 studies in a meta-analysis reported the incidence of potentially life-threatening complications associated with DSE is <0.01% [4]. Despite this relatively good safety profile, approximately half of patients experience some reaction to the dobutamine infusion, including nausea, flushing, headache, neck/chest pounding, paresthesia, urinary urgency, palpitations, or dyspnea. Other less frequent complications may occur such as myocardial infarction, hypotension, and coronary artery spasm. The estimated prevalence of coronary artery spasm during DSE is 0.4% [5]. The conspicuous absence of CAD in this female patient with cardiovascular risk factors who developed typical chest pain and diffuse ST elevations during DSE presented a diagnostic dilemma.\n\nOur differential diagnosis at that time included coronary artery vasospasm, Takotsubo cardiomyopathy, and spontaneous coronary artery dissection (SCAD), among others. The absence of typical echocardiographic findings associated with Takotsubo cardiomyopathy and the lack of typical emotional stressor made this diagnosis less likely. However, there have been reports of dobutamine itself being responsible for Takotsubo cardiomyopathy [6]. Another consideration was an SCAD, and our patient was relatively young female with risk factors for coronary dissection. SCAD, especially type 2 and type 3, can be a challenging diagnosis to make purely angiographically without intracoronary imaging, and requires a high index of suspicion to diagnose accurately. However, the complete resolution of angina symptoms and electrocardiographic abnormalities following administration of sublingual nitroglycerin clearly supports a diagnosis of dobutamine-esmolol-induced coronary vasospasm. Female sex, smoking, dyslipidemia, and hypertension are all risk factors for coronary spasm.\n\nAlthough the exact etiology of the vasospasm is unclear, one possible mechanism is the pharmacologic interaction between beta-blockers and dobutamine on alpha- and beta-adrenergic receptors. There is significant overlap in receptor activity, with a possible imbalance created by the mild alpha-1 vasoconstrictor effect of dobutamine and its moderate beta-2 receptor vasodilator effect. Administration of a beta-blocker can cause further imbalance. The resulting vasospasm was significant enough to cause a rise in cardiac troponin which had been undetectable prior to stress testing. Esmolol is effective and well tolerated for the management of dobutamine-related tachycardia, but in our case, it induced coronary vasospasm. A careful review of literature identified two similar case reports of vasospasm during DSE induced by esmolol [7,8].\n\nEndothelial dysfunction could also be a key factor in the pathogenesis of the dobutamine-induced vasospasm [9]. In the presence of endothelial dysfunction, it seems that the vasodilator predominance of dobutamine on β2 receptor is lost in favor of a vasoconstrictor response on ά1 receptor. Moreover, in patients with endothelial dysfunction, endothelium-derived nitric oxide activity is deficient, making them hyper-responsive to precipitating factors for coronary spasm, including dobutamine that is not known to do so in normal endothelium [10].\n\nConclusions\nOur illustrative case highlights a rare complication of DSE and serves to alert the clinicians on the differential, mechanisms, and clinical approach to managing ST-elevation during the course of pharmacologic stress echocardiography. Coronary vasodilators like nitroglycerin are usually effective in treating coronary vasospasm. This case also highlights the fact that dobutamine-induced vasospasm may mimic acute coronary syndrome and often requires cardiac catheterization to exclude thrombosis as a pathological cause of STEMI. In the future, if stress testing is needed in such patients, vasodilator stress testing should be preferred because this patient has displayed sensitivity to catecholamines and will likely remain at increased risk for coronary spasm. Among young individuals presenting with a STEMI, non-atherosclerotic causes of MI like spasm, embolism, dissection, and vasculitis must be considered.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Incidence, pathophysiology, and treatment of complications during dobutamine-atropine stress echocardiography Circulation Geleijnse ML Krenning BJ Nemes A 1756 1767 121 2010 20404267 \n2 The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making JAMA Antman EM Cohen M Bernink PJLM 835 842 284 2000 10938172 \n3 Chest pain in the emergency room: value of the HEART score Neth Heart J Six AJ Backus BE Kelder JC 191 196 16 2008 18665203 \n4 Dobutamine stress echocardiography: a review and update Res Rep Clin Cardiol Gilstrap L Bhatia RS Weiner R Dudzinski D 69 81 2014 2014 \n5 Prevalence of coronary artery spasm during dobutamine stress echocardiography Am J Cardiol Mansencal N El Hajjaji I El Mahmoud R Digne F Dubourg O 800 804 109 2012 22189013 \n6 Dobutamine-induced takotsubo cardiomyopathy: a systematic review of the literature and case report Anatol J Cardiol Hajsadeghi S Rahbar MH Iranpour A Salehi A Asadi O Jafarian SR 412 416 19 2018 29848925 \n7 Coronary vasospasm after dobutamine stress echocardiogram triggered by esmolol Int J Cardiol 5 2015 Martínez AM Del Riquelme MM Ayala JM Espín DS 17 19 193 2015 26005167 \n8 Coronary artery spasm during dobutamine stress echocardiography in a patient with angiographically normal coronary arteries (Article in En, Portuguese) Rev Port Cardiol Ferreira LD Gil MA Monaco CG Silva CE Peixoto LB Ortiz J 389 395 23 2004 https://pubmed.ncbi.nlm.nih.gov/15185564/ 15185564 \n9 Dobutamine: development of a new catecholamine to selectively increase cardiac contractility Circ Res Tuttle RR Mills J 185 196 36 1975 234805 \n10 Endothelial function and coronary spastic angina Intern Med Kawano H Ogawa H 91 99 44 2005 15750267\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(8)",
"journal": "Cureus",
"keywords": "coronary vasospasm; dobutamine stress echocardiography; myocardial infarction with no obstructive coronary atherosclerosis",
"medline_ta": "Cureus",
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"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e10015",
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"pubdate": "2020-08-25",
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"references": "15750267;10938172;20404267;18665203;29848925;234805;15185564;26005167;22189013",
"title": "Coronary Vasospasm After Dobutamine Stress Echocardiogram Triggered by Esmolol.",
"title_normalized": "coronary vasospasm after dobutamine stress echocardiogram triggered by esmolol"
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"abstract": "OBJECTIVE\nTo compare the perioperative outcomes between patients with narcolepsy and matched controls undergoing anesthetic management.\n\n\nMETHODS\nRetrospective 2:1 matched study design.\n\n\nMETHODS\nLarge tertiary medical center.\n\n\nMETHODS\nNarcoleptic patients who underwent general anesthesia from January 1, 2011, through September 30, 2015, were matched with controls by age, sex, and type and year of surgery.\n\n\nMETHODS\nMedical records were reviewed for episodes of respiratory depression during phase I recovery and for other meaningful perioperative outcomes.\n\n\nRESULTS\nThe perioperative courses of 76 narcoleptic patients and their controls were examined. Compared to controls, narcoleptic patients were more often prescribed central nervous system stimulants (73.7% vs 4.0%, P<0.001) and antidepressants (46.1% vs 27.6%, P=0.007) and more often had obstructive sleep apnea (40.8% vs 19.1%, P<0.001). The intraoperative course was similar. The number of episodes of respiratory depression was not different between patients and controls (5 [6.6%] vs 12 [7.9%], respectively; P=0.80). Narcoleptic patients had a higher frequency of emergency response team activations (5 of 76 [6.6%]; 95% CI, 2.2%-14.7%) compared to controls (2 of 152 [1.3%]; 95% CI, 0.2%-4.7%) (P=0.04). Hemodynamic instability was the indication for all emergency response team activations except 1, which was for a narcoleptic patient who had excessive postoperative sedation and respiratory depression.\n\n\nCONCLUSIONS\nNarcoleptic patients had similar intraoperative courses as the matched controls, including phase I anesthetic recovery. However, they had a higher rate of emergency response team activations than the controls, which suggests that patients with narcolepsy may be at increased perioperative risk.",
"affiliations": "Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, United States; Multidisciplinary Epidemiology and Translational Research in Intensive Care (METRIC), Mayo Clinic, Rochester, MN, United States.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, United States.;Department of Neurology, Mayo Clinic, Rochester, MN, United States.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, United States.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, United States. Electronic address: weingarten.toby@mayo.edu.",
"authors": "Cavalcante|Alexandre N|AN|;Hofer|Ryan E|RE|;Tippmann-Peikert|Maja|M|;Sprung|Juraj|J|;Weingarten|Toby N|TN|",
"chemical_list": "D000928:Antidepressive Agents; D000697:Central Nervous System Stimulants",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jclinane.2017.04.008",
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"issn_linking": "0952-8180",
"issue": "41()",
"journal": "Journal of clinical anesthesia",
"keywords": "Emergency response teams; General anesthesia; Hemodynamic instability; Narcolepsy; Respiratory depression",
"medline_ta": "J Clin Anesth",
"mesh_terms": "D000328:Adult; D000368:Aged; D000762:Anesthesia Recovery Period; D000768:Anesthesia, General; D000928:Antidepressive Agents; D016022:Case-Control Studies; D000697:Central Nervous System Stimulants; D005260:Female; D057209:Hospital Rapid Response Team; D006801:Humans; D008297:Male; D008875:Middle Aged; D009290:Narcolepsy; D059035:Perioperative Period; D012131:Respiratory Insufficiency; D012189:Retrospective Studies; D012307:Risk Factors; D020181:Sleep Apnea, Obstructive; D013514:Surgical Procedures, Operative; D062606:Tertiary Care Centers",
"nlm_unique_id": "8812166",
"other_id": null,
"pages": "120-125",
"pmc": null,
"pmid": "28433385",
"pubdate": "2017-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Perioperative risks of narcolepsy in patients undergoing general anesthesia: A case-control study.",
"title_normalized": "perioperative risks of narcolepsy in patients undergoing general anesthesia a case control study"
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"companynumb": "US-TEVA-2018-US-910449",
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"activesubstancename": "CLONAZEPAM"
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"abstract": "OBJECTIVE\nBisphosphonates are the most common class of medications used to treat osteoporosis. Their widespread use has uncovered rare complications, including atypical femoral fractures (AFF). The pathogenesis of AFF is incompletely understood; however, if oversuppression of bone remodeling contributes to AFF, it is plausible that other potent antiresorptive agents, such as denosumab, could be associated with AFF as well.\n\n\nMETHODS\nWe report a case of an 81-year-old woman with densitometric osteopenia, chronic kidney disease, and hyperparathyroidism, who was initiated on denosumab for elevated fracture risk. Approximately 6 months after her initial denosumab injection, she developed severe right groin and thigh pain without prior trauma.\n\n\nRESULTS\nA femoral radiograph was normal, without cortical thickening, but a magnetic resonance imaging revealed a transverse subtrochanteric insufficiency fracture with a medial defect involving 25% of the femoral cortex. She did not receive any further doses of denosumab. Bone turnover markers did not suggest oversuppression. Her fracture was treated conservatively with nonweight bearing status with resultant full recovery.\n\n\nCONCLUSIONS\nThis fracture does not meet the current definition of an AFF as, for that definition, a lateral femoral location is required. This case does not provide conclusive evidence for a causal relationship between treatment with denosumab and this unusual fracture. It clearly illustrates, however, the occurrence of an unusual, nontraumatic subtrochanteric fracture in a patient treated with the potent antiresorptive agent denosumab with many features in common with bisphosphonate-associated AFF.",
"affiliations": "Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.",
"authors": "Paparodis|Rodis|R|;Buehring|Bjoern|B|;Pelley|Elaine M|EM|;Binkley|Neil|N|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D004164:Diphosphonates; D000069448:Denosumab",
"country": "United States",
"delete": false,
"doi": "10.4158/EP12367.CR",
"fulltext": null,
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"issn_linking": "1530-891X",
"issue": "19(3)",
"journal": "Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists",
"keywords": null,
"medline_ta": "Endocr Pract",
"mesh_terms": "D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000069448:Denosumab; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D006620:Hip Fractures; D006801:Humans; D010024:Osteoporosis",
"nlm_unique_id": "9607439",
"other_id": null,
"pages": "e64-8",
"pmc": null,
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"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of an unusual subtrochanteric fracture in a patient receiving denosumab.",
"title_normalized": "a case of an unusual subtrochanteric fracture in a patient receiving denosumab"
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"companynumb": "US-AMGEN-USASP2012007615",
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"activesubstancename": "DENOSUMAB"
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{
"abstract": "Hepatitis-associated aplastic anemia is a rare syndrome in which bone marrow failure occurs within weeks to 1 year after attack of acute hepatitis. Studies suggest that cytotoxic T lymphocytes play a central role in bone marrow destruction, but the exact etiology remains unknown. Bone marrow transplantation or immunosuppressive therapy are primary curative options. We present a case of a young male who was admitted to the Department of Gastroenterology and Hepatology for acute hepatitis of an unknown cause. Liver biopsy revealed extensive inflammatory process with hepatocyte necrosis. Forty days later, new onset pancytopenia was identified. Bone marrow biopsy showed severe hypocellularity, and he was diagnosed with severe hepatitis-associated aplastic anemia. Treatment with cyclosporine was initiated, but with inadequate response, and pretransplant evaluation was started. Due to severe neutropenia, following alveotomy procedure, the patient developed deep neck infection with consequent airway obstruction. Despite urgent treatment, his condition deteriorated to sepsis with lethal outcome.",
"affiliations": "Department of Gastroenterology and Hepatology, University Hospital of Split, Split, Croatia.;Department of Gastroenterology and Hepatology, University Hospital of Split, Split, Croatia.;Department of Gastroenterology and Hepatology, University Hospital of Split, Split, Croatia.;Department of Haematology, University Hospital of Split, Split, Croatia.;Department of Gastroenterology and Hepatology, University Hospital of Split, Split, Croatia.;Department of Gastroenterology and Hepatology, University Hospital of Split, Split, Croatia.",
"authors": "Božić Ozretić|Dorotea|D|;Piplović Vuković|Tonka|T|;Vuković|Jonatan|J|;Madunić|Sanja|S|;Podrug|Kristian|K|;Puljiz|Željko|Ž|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000508438",
"fulltext": "\n==== Front\nCase Rep Gastroenterol\nCase Rep Gastroenterol\nCRG\nCase Reports in Gastroenterology\n1662-0631 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000508438\ncrg-0014-0383\nSingle Case\nFatal Hepatitis-Associated Aplastic Anemia in a Young Male\nBožić Ozretić Dorotea a* Piplović Vuković Tonka a Vuković Jonatan ab Madunić Sanja c Podrug Kristian a Puljiz Željko ab aDepartment of Gastroenterology and Hepatology, University Hospital of Split, Split, Croatia\nbUniversity of Split, School of Medicine, Split, Croatia\ncDepartment of Haematology, University Hospital of Split, Split, Croatia\n*Dorotea Božić Ozretić, Department of Gastroenterology and Hepatology, Clinical Hospital of Split, Spinčićeva 1, HR–21 000 Split (Croatia), dora.bozic@hotmail.com\nMay-Aug 2020 \n28 7 2020 \n28 7 2020 \n14 2 383 390\n21 4 2020 1 5 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Hepatitis-associated aplastic anemia is a rare syndrome in which bone marrow failure occurs within weeks to 1 year after attack of acute hepatitis. Studies suggest that cytotoxic T lymphocytes play a central role in bone marrow destruction, but the exact etiology remains unknown. Bone marrow transplantation or immunosuppressive therapy are primary curative options. We present a case of a young male who was admitted to the Department of Gastroenterology and Hepatology for acute hepatitis of an unknown cause. Liver biopsy revealed extensive inflammatory process with hepatocyte necrosis. Forty days later, new onset pancytopenia was identified. Bone marrow biopsy showed severe hypocellularity, and he was diagnosed with severe hepatitis-associated aplastic anemia. Treatment with cyclosporine was initiated, but with inadequate response, and pretransplant evaluation was started. Due to severe neutropenia, following alveotomy procedure, the patient developed deep neck infection with consequent airway obstruction. Despite urgent treatment, his condition deteriorated to sepsis with lethal outcome.\n\nKeywords\nHepatitisAplastic anemiaHepatitis-associated aplastic anemiaBone marrow transplantationDeep neck infection\n==== Body\nBackground\nHepatitis-associated aplastic anemia (HAAA) is a rare syndrome in which bone marrow (BM) failure occurs after an episode of acute hepatitis (AH). Hepatitis may be self-limiting, mild or severe, sometimes even fulminant, leading to urgent liver transplantation. HAAA accounts for 5% of acquired aplastic anemias (AA), whose incidence in Europe is estimated to be 2–3 cases per million inhabitants per year [1, 2, 3, 4]. It usually affects children and young males within weeks to one year after attack of AH, frequently in the phase of liver function improvement [5]. The presumed cause of hepatitis is still unknown. HAAA is fatal if untreated, mostly due to serious bacterial infections, catalyzed by severe neutropenia.\n\nCase Presentation\nA 29-year-old male was admitted to the Department of Gastroenterology and Hepatology for acute liver injury. He was previously healthy, except for treatment for megaloblastic anemia for 2 years. Patient presented with malaise, headache, and muscle pain, with high transaminase and bilirubin levels (TBIL 324, AST 2,086, ALT 3,382), and coagulopathy (INR 1.42). He showed no signs of encephalopathy.\n\nA wide spectrum of diagnostic procedures was conducted with exclusion of viral, autoimmune, and metabolic liver diseases. He reported drinking alcohol only on occasions and denied any illicit drug usage or exposure to any medications or toxins. Liver biopsy revealed an extensive inflammatory process involving both lobules and portal spaces with lytic and confluent hepatocyte necrosis, with no signs of fibrosis (Fig. 1). Corticosteroid treatment was initiated.\n\nOn day 41, new onset pancytopenia was identified (RBC 4.23 × 1012/L, WBC 2.99 × 109/L, PLT 20 × 109/L). At that time, his liver biochemical parameters showed persistent decrease and the corticosteroid treatment was continued (Fig. 2). On day 85, BM biopsy was performed and showed mild hypocellularity.\n\nSince the pancytopenia progressed, BM biopsy was repeated on day 115 and revealed severe hypocellularity of 10%, with no megakaryopoiesis (Fig. 3). BM immunophenotyping revealed dominance of T lymphocytes (77%) with a high proportion of CD4 (31%) and CD8 cells (41%). Peripheral blood immunophenotyping also confirmed a high proportion of T cells (94%), with the CD4/CD8 ratio on the lower limit (1.2). The cytogenetic study showed normal karyotype. Paroxysmal nocturnal hemoglobinuria clone was excluded. He met all criteria for the diagnosis of severe HAAA (BM cellularity 10%, WBC 2.5 × 109/L, Ne 0.40 × 109/L, PLT 18 × 109/L, reticulocytes 16.7 × 109/L). On the same day, treatment with cyclosporine (Cys) (2.5–3 mg/kg twice daily, adjusting trough levels to 200–400 ng/mL) was initiated. He was immediately sent to the Bone Marrow Transplant Center, where it was decided to continue Cys treatment with regular assessment of the therapy response. He was further treated as an outpatient of both our Clinical Center and the Transplant Center, dependent on platelet transfusions two times a week. In that period, he was hospitalized several times for ulcerative gingivostomatitis, severe thrombocytopenia, febrile neutropenia, polyarthralgias, and maculopapular rash. Response on Cys treatment was inadequate, with persistent pancytopenia. Pretransplant evaluation for bone marrow transplantation (BMT) from a HLA-matched sibling (sister) was initiated.\n\nThree months after initiation of Cys, he was admitted for febrile granulocytopenia and pain in the oral cavity due to gingival ulcerations. Microbiological analysis of throat swab revealed Enterococcus faecalis in low number of copies. He was treated with antibiotics, antifungal and antiviral prophylaxis, and adequate oral hygiene. Oral surgeon was consulted and alveotomy of the 8th teeth of mandible on the right side was performed because of impacted teeth with pericoronitis. The procedure went without complications. His condition began to improve, the inflammatory parameters decreased, and oral nutrition was introduced. Two weeks later, his clinical condition began to deteriorate again, with swelling and pain on the right side of the face. The suspicion on the peritonsillar abscess was raised, and the otorhinolaryngologist performed surgical incision and evacuation. Three days later, there was evident progression in the swelling of the face and neck, the patient was highly febrile, with swallowing and breathing difficulties.\n\nEmergency MSCT revealed an abscess collection 4.2 cm × 2.3 cm in the area of the retromolar trigone, with edema of oropharyngeal, parapharyngeal, and retropharyngeal soft tissues. Comprehensive edema of subcutaneous soft tissues of neck with the thickening of platysma was also described (Fig. 4). Urgent tracheotomy with neck incision and evacuation was performed. His treatment with wide spectrum antibiotics, antifungals, granulocyte stimulating factors, and transfusions of platelets and erythrocytes was continued. Despite all measures he died due to sepsis with development of disseminated intravascular coagulation, 4 months after the diagnosis of HAAA.\n\nDiscussion\nSevere AA is defined according to the Camitta criteria: BM cellularity <25% together with two of the following criteria: neutrophils <0.5 × 109/L, platelets <20 × 109/L, and reticulocytes <20 × 109/L [6].\n\nHAAA is a rare form of AA, occurring after attack of AH. Although it may follow viral infections such as HIV, hepatitis A, B, C, G, EBV, CMV, parvo B19, echovirus, and transfusion transmitted virus, the majority of cases are seronegative for hepatotropic viruses [1, 5, 7, 8]. Studies report a viral etiology in only 6% of cases [1]. HAAA was also described in connection with toxic liver injury [9] and is reported in patients who underwent orthotopic liver transplantation for nonviral hepatitis [10]. Our patient developed severe AA after an episode of seronegative AH, in the phase of liver function improvement.\n\nAccording to the immunopathogenesis of HAAA, studies suggest an antigen-driven T cell expansion, with the initial target organ being the liver [11]. Infiltration of clonal and nonclonal T cells, presenting as skewed T cell repertoire, occurs both in liver and in the blood at the time of BM failure [11]. Common cytotoxic T lymphocytes (CTL) recognize similar target antigens in BM cells as in liver in the early period, and then selective clonal expansion of CTL that are highly tropic to BM occurs, with subsequent destruction of BM cells at later stages [12]. CTL produce IFN-γ, which itself and by activation of cytokine cascade leads to cell apoptosis and necrosis, ultimately inhibiting hematopoiesis [7]. This is confirmed by immunohistochemical staining of liver specimens, revealing accumulation of CTL in HAAA patients, as well as increased proportion of HLA DR-positive CD8 cells (which are considered to be activated CTL) and decreased CD4/CD8 ratio in their peripheral blood [5, 7, 13]. CD8-expressing Kupffer cells may be important mediators of HAAA [14]. Response to immunosuppressive therapy (IST) has been proven by replacement of broad skewing pattern of T cell distribution to normal [11, 12]. Our patient had plentiful T lymphocyte infiltrate both in liver and BM specimen, as well as in peripheral blood, with low normal CD4/CD8 ratio.\n\nHAAA is always fatal without treatment. The first-line therapy is allogenic BMT from an HLA-matched sibling [7]. According to studies, the mean survival after BMT is 82–86% at 5 years and 70% at 10 years [1, 7, 15]. IST is reserved for patients without an HLA-matched sibling donor and includes antithymocyte globulin (ATG), antilymphocyte globulin, Cys, and cyclophosphamide [5, 16−18]. Combination of Cys and ATG together with growth factors is the treatment of choice. The mean response rate with intensive combined IST is 70–80% [5, 17, 18], with predicted 10-year survival of 69–88% [1, 18]. According to Locasciulli et al. [1], the strongest negative predictors of survival are age over 20 years and delayed treatment. Patients with very severe HAAA (<0.2 × 109/L) take longer to respond to therapy [18]. It is recommended not to delay IST despite potential hepatotoxic effects of Cys and ATG, which may even improve liver function by suppression of T lymphocytes [7, 18]. For patients not responding on IST, BMT from HLA-matched unrelated donor is an option [1, 7]. Prophylactic therapy for CMV is recommended due to risk of interstitial pneumonitis [18]. In HBsAg- or anti-HBc-positive patients, antiviral prophylaxis with lamivudine, telbivudine, or entecavir is advocated [7]. The most common causes of death are severe infections and intracranial hemorrhage [13, 15, 18].\n\nThe treatment of our patient was started with Cys due to severe HAAA at the time of diagnosis. He was immediately sent to the Bone Marrow Transplant Center, where it was decided to continue Cys and to consider other treatment options depending on the response. Three months later, at the time when the pretransplant evaluation of our patient and the donor was ongoing, he was admitted for febrile neutropenia. He developed retromolar trigone abscess with the infection spreading to deep neck tissues, leading to airway obstruction. Deep neck infections (DNI) are defined as infections in the potential spaces and the fascial planes of the neck [19]. Odontogenic infections are the most common cause of DNI, responsible for 70% of cases in adults, and it is assumed that the port of entry in our patient was the dental procedure performed 2 weeks earlier [20]. Risk factors for DNI development are immunosuppression, low socioeconomic status, and comorbidities, while the main isolated pathogens are Staphylococci, Streptococci, and Enterococci species [20]. Most frequent complications are airway obstruction, descending necrotizing mediastinitis, Lemierre's syndrome, necrotizing cervical fasciitis, pneumonia, and sepsis [19, 20]. Treatment with broad-spectrum antibiotics is obligatory, usually in combination with surgical treatment [19, 20]. Despite both surgical and antibiotic treatment with supportive measures that were taken in our patient, his condition deteriorated and led to lethal outcome.\n\nIn conclusion, when treating patients with AH, one must always consider the possibility of HAAA development, usually in the phase of liver function improvement. Delayed diagnosis and treatment are significant negative predictors of survival. BMT, or IST in patients without HLA-matched sibling donor, are the cornerstones of treatment. Since patients with AA are highly susceptible to infections, special caution is recommended regarding odontogenic infections that may lead to DNI and cause life-threatening complications such as airway obstruction, necrotizing mediastinitis, or sepsis. Thorough dental and periodontal care with antibiotic and antiviral prophylaxis in patients with AA is of great importance.\n\nStatement of Ethics\nThe research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. We obtained approval and written informed consent for participation and publication from the family member. The consent form is available if requested from the Editor.\n\nConflict of Interest Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nThe authors have funded all research personally.\n\nAuthor Contributions\nD.B.O., T.P.V., and Ž.P. designed the report; K.P., T.P.V., and S.M. treated the patient; D.B.O. collected the patient's data; D.B.O., K.P., S.M., and T.P.V. analyzed the data, D.B.O. and J.V. wrote the paper. All the authors gave their approval for the final version of the article to be published and all the authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nFig. 1 Liver biopsy specimen (HSA immunohistochemical staining): acute lobular and portal T lymphocyte infiltrate with lytic and confluent hepatocyte necrosis.\n\nFig. 2 Graphical trends of the laboratory parameters in the first 5 months after admission. AST, aspartate transaminase; ALT, alanine transaminase; TBIL, total bilirubin; CYS, cyclosporine introduction; WBC, white blood cell count; PLT, platelets.\n\nFig. 3 Bone marrow specimen: very low cellularity with partial acellularity.\n\nFig. 4 MSCT of the neck: an abscess collection in the area of the retromolar trigone, with edema of deep neck tissues.\n==== Refs\nReferences\n1 Locasciulli A Bacigalupo A Bruno B Montante B Marsh J Tichelli A Severe Aplastic Anemia Working Party of the European Blood and Marrow Transplant Group (SAA-WP, EBMT) Hepatitis-associated aplastic anaemia: epidemiology and treatment results obtained in Europe. A report of The EBMT aplastic anaemia working party Br J Haematol 2010 6 149 (6) 890 5 20456352 \n2 Vaht K Göransson M Carlson K Isaksson C Lenhoff S Sandstedt A Incidence and outcome of acquired aplastic anemia: real-world data from patients diagnosed in Sweden from 2000-2011 Haematologica 2017 10 102 (10) 1683 90 28751565 \n3 International Agranulocytosis and Aplastic Anemia Study. Incidence of aplastic anemia: the relevance of diagnostic criteria Blood 1987 70 (6) 1718 21 3676511 \n4 Montané E Ibáñez L Vidal X Ballarín E Puig R García N Catalan Group for Study of Agranulocytosis and Aplastic Anemia Epidemiology of aplastic anemia: a prospective multicenter study Haematologica 2008 4 93 (4) 518 23 18322256 \n5 Brown KE Tisdale J Barrett AJ Dunbar CE Young NS Hepatitis-associated aplastic anemia N Engl J Med 1997 4 336 (15) 1059 64 9091802 \n6 Camitta BM Rappeport JM Parkman R Nathan DG Selection of patients for bone marrow transplantation in severe aplastic anemia Blood 1975 3 45 (3) 355 63 1090310 \n7 Gonzalez-Casas R Garcia-Buey L Jones EA Gisbert JP Moreno-Otero R Systematic review: hepatitis-associated aplastic anaemia—a syndrome associated with abnormal immunological function Aliment Pharmacol Ther 2009 9 30 (5) 436 43 19508613 \n8 Rauff B Idrees M Shah SA Butt S Butt AM Ali L Hepatitis associated aplastic anemia: a review Virol J 2011 2 8 (1) 87 21352606 \n9 Qureshi K Sarwar U Khallafi H Severe Aplastic Anemia following Acute Hepatitis from Toxic Liver Injury: Literature Review and Case Report of a Successful Outcome Case Reports Hepatol 2014 2014 216570 25587471 \n10 Delehaye F Habes D Dourthe ME Bertrand Y Michel G Gaudichon J Management of childhood aplastic anemia following liver transplantation for nonviral hepatitis: A French survey Pediatr Blood Cancer 2020 4 67 (4) e28177 31925926 \n11 Lu J Basu A Melenhorst JJ Young NS Brown KE Analysis of T-cell repertoire in hepatitis-associated aplastic anemia Blood 2004 6 103 (12) 4588 93 14988156 \n12 Ikawa Y Nishimura R Kuroda R Mase S Araki R Maeba H Expansion of a liver-infiltrating cytotoxic T-lymphocyte clone in concert with the development of HAAA Br J Haematol 2013 161 (4) 599 602 23419100 \n13 Wang H Tu M Fu R Wu Y Liu H Xing L The clinical and immune characteristics of patients with hepatitis-associated aplastic anemia in China PLoS One 2014 5 9 (5) e98142 7 24845454 \n14 Cengiz C Turhan N Yolcu OF Yilmaz S Hepatitis associated with aplastic anemia: do CD8(+) kupffer cells have a role in the pathogenesis? Dig Dis Sci 2007 9 52 (9) 2438 43 17443406 \n15 Mori T Onishi Y Ozawa Y Kato C Kai T Kanda Y Outcome of allogeneic hematopoietic stem cell transplantation in adult patients with hepatitis-associated aplastic anemia Int J Hematol 2019 6 109 (6) 711 7 30963471 \n16 Savage WJ DeRusso PA Resar LM Chen AR Higman MA Loeb DM Treatment of hepatitis-associated aplastic anemia with high-dose cyclophosphamide Pediatr Blood Cancer 2007 12 49 (7) 947 51 17252566 \n17 Chen HF Xu BX Shen HS Li ZY Jin LJ Tang JQ Efficacy and safety of immunosuppressive therapy in the treatment of seronegative hepatitis associated aplastic anemia Drug Des Devel Ther 2014 9 8 1299 305 \n18 Osugi Y Yagasaki H Sako M Kosaka Y Taga T Ito T Japan Childhood Aplastic Anemia Study Group Antithymocyte globulin and cyclosporine for treatment of 44 children with hepatitis associated aplastic anemia Haematologica 2007 12 92 (12) 1687 90 18055993 \n19 Kauffmann P Cordesmeyer R Tröltzsch M Sömmer C Laskawi R Deep neck infections: A single-center analysis of 63 cases Med Oral Patol Oral Cir Bucal 2017 9 22 (5) e536 41 28809368 \n20 Adoviča A Veidere L Ronis M Sumeraga G Deep neck infections: review of 263 cases Otolaryngol Pol 2017 10 71 (5) 37 42\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "14(2)",
"journal": "Case reports in gastroenterology",
"keywords": "Aplastic anemia; Bone marrow transplantation; Deep neck infection; Hepatitis; Hepatitis-associated aplastic anemia",
"medline_ta": "Case Rep Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101474819",
"other_id": null,
"pages": "383-390",
"pmc": null,
"pmid": "32884515",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "29154249;28751565;17252566;24845454;31925926;1090310;18322256;3676511;25587471;17443406;20456352;21352606;25246771;18055993;23419100;14988156;28809368;30963471;9091802;19508613",
"title": "Fatal Hepatitis-Associated Aplastic Anemia in a Young Male.",
"title_normalized": "fatal hepatitis associated aplastic anemia in a young male"
} | [
{
"companynumb": "NVSC2020HR293721",
"fulfillexpeditecriteria": "1",
"occurcountry": "HR",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
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{
"abstract": "OBJECTIVE\nBleeding events related to endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) are rare. However, for patients treated with antithrombotic agents, the bleeding risk of EUS-FNA is uncertain. Hence, the aim of this study was to assess the bleeding event rate associated with EUS-FNA in patients receiving antithrombotic treatment.\n\n\nMETHODS\nA retrospective study was conducted in 742 consecutive patients who underwent EUS-FNA for solid lesions between 2008 and 2015. We compared the bleeding event rates among patients who were not administered antithrombotic agents, those whose agent use was discontinued, those who continued treatment with aspirin or cilostazol, and those who were administered heparin as a replacement.\n\n\nRESULTS\nThere were 131 patients (17.7 %) treated with antithrombotic agents. Seven experienced bleeding events, and the overall bleeding event rate was 0.9 % (7/742). All bleeding events were intraoperative; there were no postoperative bleeding episodes. Subgroup analysis by antithrombotic agent revealed bleeding event rates of 1.0 % (6/611), 0 % (0/62), 1.6 % (1/61), and 0 % (0/8) for the non-administration, discontinuation of agents, continuation of aspirin or cilostazol, and heparin replacement groups, respectively. Only one severe bleeding event necessitated hemostatic treatment (1/742; 0.1 %); this occurred in a patient in the non-administration group, and there were no severe bleeding events in patients receiving antithrombotic treatment.\n\n\nCONCLUSIONS\nThe present study found a low incidence of EUS-FNA-related bleeding in patients receiving antithrombotic treatment. The bleeding event rate was low even in patients who underwent EUS-FNA while continuing aspirin or cilostazol.",
"affiliations": "Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan.;Department of Gastroenterology, Gifu Prefectural Tajimi Hospital, Tajimi, Japan.;Department of Gastroenterology, Gifu Prefectural Tajimi Hospital, Tajimi, Japan.;Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan.;Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan.;Department of Gastroenterology, Gifu Prefectural Tajimi Hospital, Tajimi, Japan.;Department of Gastroenterology, Gifu Prefectural Tajimi Hospital, Tajimi, Japan.;Department of Gastroenterology, Gifu Prefectural Tajimi Hospital, Tajimi, Japan.;Department of Gastroenterology, Gifu Prefectural Tajimi Hospital, Tajimi, Japan.;Department of Gastroenterology, Gifu Prefectural Tajimi Hospital, Tajimi, Japan.;Department of Gastroenterology, Gifu Prefectural Tajimi Hospital, Tajimi, Japan.;Department of Gastroenterology, Gifu Prefectural Tajimi Hospital, Tajimi, Japan.;Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan.;Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan.",
"authors": "Inoue|Tadahisa|T|;Okumura|Fumihiro|F|;Sano|Hitoshi|H|;Kobayashi|Yuji|Y|;Ishii|Norimitsu|N|;Suzuki|Yuta|Y|;Fukusada|Shigeki|S|;Kachi|Kenta|K|;Ozeki|Takanori|T|;Anbe|Kaiki|K|;Iwasaki|Hiroyasu|H|;Mizushima|Takashi|T|;Ito|Kiyoaki|K|;Yoneda|Masashi|M|",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "Australia",
"delete": false,
"doi": "10.1111/den.12687",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0915-5635",
"issue": "29(1)",
"journal": "Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society",
"keywords": "Anticoagulant agents; antiplatelet agents; antithrombotic agents; bleeding; endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA)",
"medline_ta": "Dig Endosc",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016063:Blood Loss, Surgical; D004066:Digestive System Diseases; D061765:Endoscopic Ultrasound-Guided Fine Needle Aspiration; D016099:Endoscopy, Gastrointestinal; D005260:Female; D005343:Fibrinolytic Agents; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007564:Japan; D008297:Male; D008875:Middle Aged; D019106:Postoperative Hemorrhage; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate; D013923:Thromboembolism; D018608:Ultrasonography, Doppler; D055815:Young Adult",
"nlm_unique_id": "9101419",
"other_id": null,
"pages": "91-96",
"pmc": null,
"pmid": "27305322",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Bleeding risk of endoscopic ultrasound-guided fine-needle aspiration in patients undergoing antithrombotic therapy.",
"title_normalized": "bleeding risk of endoscopic ultrasound guided fine needle aspiration in patients undergoing antithrombotic therapy"
} | [
{
"companynumb": "JP-OTSUKA-2016_016257",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Chemoradiotherapy before surgical treatment of locally advanced lower rectal cancer is currently uncommon in Japan. We have treated 5 patients with T3 and/or N1 and 2 patients with rectal cancer using chemoradiotherapy including capecitabine and oxaliplatin( XELOX). The treatment consisted of concomitant administration of radiotherapy( 45 Gy/25 Fr), capecitabine (2,000 mg/m2/day; 2 weeks followed by 1 week off), and XELOX (2 courses). Surgery was performed 1 month after the final dose of chemotherapy was administered. The adverse events of Grade greater than 2 observed were radiation dermatitis (n=3), peripheral neuropathy (n=1), and rash (n=1). Either laparoscopic abdominoperineal resection( n=4) or open low anterior resection( n=1) was performed for surgical treatment. Histopathological regression grading revealed Grade 1a (n=1) and Grade 2 (n=4). The combined therapy resulted in downstaging in all patients. Preoperative chemoradiotherapy followed by XELOX might be effective for the treatment of locally advanced lower rectal cancer.",
"affiliations": "Dept. of Surgery, Suita Municipal Hospital.",
"authors": "Murata|Kohei|K|;Okamura|Shu|S|;Okubo|Hirofumi|H|;Owada|Yoshiyuki|Y|;Nishigaki|Takahiko|T|;Wada|Yuma|Y|;Kato|Ryo|R|;Makino|Shunichiro|S|;Takeoka|Tomohira|T|;Okada|Kazuyuki|K|;Fukuchi|Nariaki|N|;Ebisui|Chikara|C|;Kinuta|Masakatsu|M|",
"chemical_list": "D010071:Oxaloacetates; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "40(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D059248:Chemoradiotherapy; D003841:Deoxycytidine; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010071:Oxaloacetates; D012004:Rectal Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2020-2",
"pmc": null,
"pmid": "24393999",
"pubdate": "2013-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Neoadjuvant chemoradiotherapy with capecitabine and oxaliplatin for the treatment of locally advanced lower rectal cancer.",
"title_normalized": "neoadjuvant chemoradiotherapy with capecitabine and oxaliplatin for the treatment of locally advanced lower rectal cancer"
} | [
{
"companynumb": "JP-ROCHE-1187254",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nCisplatin with pemetrexed (CP) and carboplatin with paclitaxel and bevacizumab (CbTB) are standard first-line treatments for patients with advanced nonsquamous (NS) non-small-cell lung cancer (NSCLC). Quality of life (QoL) is a key objective in the management of advanced NSCLC. Thus, effect on QoL could be an additional factor in the choice of treatment.\n\n\nMETHODS\nPatients with untreated stage IIIB/IV NS-NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 were randomized to receive first-line chemotherapy with cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2), every 3 weeks, for 6 cycles followed by maintenance pemetrexed; or carboplatin area under the curve 6, paclitaxel 200 mg/m(2), and bevacizumab 15 mg/kg, every 3 weeks, for 6 cycles followed by maintenance bevacizumab. The primary end point was the difference in QoL between the 2 treatment arms after 12 weeks of maintenance, measured using the EuroQoL 5 Dimensions-Index (EQ5D-I) and EQ5D-visual analogue scale (EQ5D-VAS).\n\n\nRESULTS\nOne hundred eighteen patients were randomized to CP (n = 60) or CbTB (n = 58). Baseline characteristics were well balanced. The proportion of patients evaluable for the primary end point was lower than planned. After 12 weeks of maintenance, the difference between mean changes in EQ5D-I was 0.137, favoring CP (95% confidence interval [CI], -0.02 to 0.29, Wilcoxon P = .078), although not statistically significant; and the difference between mean changes in EQ5D-VAS was 0.97 (95% CI, -9.37 to 11.31, Wilcoxon P = .41).\n\n\nCONCLUSIONS\nAlthough the study was underpowered because of a small number of patients evaluable for the primary end point, QoL did not differ between treatment arms. Other factors such as comorbidities and schedule should be used when deciding on first-line treatment.",
"affiliations": "Medical Oncology Unit, National Cancer Research Center \"Giovanni Paolo II\", Bari, Italy. Electronic address: galetta@teseo.it.;Medical Oncology Department and Breast Unit - \"Sen. Perrino\" Hospital Strada Statale 7 per Mesagne, Brindisi, Italy.;Medical Oncology Division, \"S.G. Moscati\" Hospital, Taranto, Italy.;Medical Oncology Division, \"La Maddalena\" Hospital, Palermo, Italy.;Thoraco-Pulmonary Medical Oncology, National Cancer Institute \"Fondazione G. Pascale\" - IRCCS, Napoli, Italy.;Medical Oncology Unit, \"Buccheri-La Ferla\" Hospital, Palermo, Italy.;Medical Oncology Division, \"Casa Sollievo della Sofferenza\" Hospital, Foggia, Italy.;Medical Oncology Division, \"Fatebenefratelli\" Hospital, Benevento, Italy.;Medical Oncology Unit, National Cancer Research Center \"Giovanni Paolo II\", Bari, Italy.;Medical Oncology Department and Breast Unit - \"Sen. Perrino\" Hospital Strada Statale 7 per Mesagne, Brindisi, Italy.;Medical Oncology Division, \"S.G. Moscati\" Hospital, Taranto, Italy.;Medical Oncology Unit, National Cancer Research Center \"Giovanni Paolo II\", Bari, Italy.;Medical Oncology Unit, National Cancer Research Center \"Giovanni Paolo II\", Bari, Italy.;Gruppo Oncologico Italia Meridionale (GOIM), Bari, Italy.;Clinical Trials Unit, National Cancer Institute \"Fondazione G. Pascale\" - IRCCS, Napoli, Italy.;Gruppo Oncologico Italia Meridionale (GOIM), Bari, Italy.",
"authors": "Galetta|Domenico|D|;Cinieri|Saverio|S|;Pisconti|Salvatore|S|;Gebbia|Vittorio|V|;Morabito|Alessandro|A|;Borsellino|Nicola|N|;Maiello|Evaristo|E|;Febbraro|Antonio|A|;Catino|Annamaria|A|;Rizzo|Pietro|P|;Montrone|Michele|M|;Misino|Andrea|A|;Logroscino|Antonio|A|;Rizzi|Daniele|D|;Di Maio|Massimo|M|;Colucci|Giuseppe|G|",
"chemical_list": "D000068437:Pemetrexed; D000068258:Bevacizumab; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-7304",
"issue": "16(4)",
"journal": "Clinical lung cancer",
"keywords": "Advanced NSCLC; EQ5D; Quality of life; Symptom palliation; Treatment choice",
"medline_ta": "Clin Lung Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D002945:Cisplatin; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel; D000068437:Pemetrexed; D011788:Quality of Life; D016896:Treatment Outcome",
"nlm_unique_id": "100893225",
"other_id": null,
"pages": "262-73",
"pmc": null,
"pmid": "25582493",
"pubdate": "2015-07",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Cisplatin/Pemetrexed Followed by Maintenance Pemetrexed Versus Carboplatin/Paclitaxel/Bevacizumab Followed by Maintenance Bevacizumab in Advanced Nonsquamous Lung Cancer: The GOIM (Gruppo Oncologico Italia Meridionale) ERACLE Phase III Randomized Trial.",
"title_normalized": "cisplatin pemetrexed followed by maintenance pemetrexed versus carboplatin paclitaxel bevacizumab followed by maintenance bevacizumab in advanced nonsquamous lung cancer the goim gruppo oncologico italia meridionale eracle phase iii randomized trial"
} | [
{
"companynumb": "IT-CIPLA LTD.-2015IT05699",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Epilepsy affects 3.5 million people in the United States (US). Rural-dwelling individuals have less access to healthcare and consequently poorer health outcomes. This study describes the outcomes of an interprofessional telehealth program for rural-dwelling individuals with epilepsy in one US state.\n\n\n\nAn academic medication therapy management pharmacist provided clinical services to rural-dwelling individuals with epilepsy between November 2015 and June 2018, using video-conferencing technology and follow-up telephonic consultation. Data collected included: demographics, prescribed seizure medications, comorbidities, drug-drug and drug-disease interactions, adverse drug reactions, therapeutic duplications, dose-related safety concerns, adherence concerns, and recommendations to resolve identified issues. Data were summarized using appropriate descriptive statistics.\n\n\n\nA total of 168 patients (51% male, mean age 28 ± 15 years), participated in this pilot study. Most participants (94%) were prescribed at least one seizure medication including: benzodiazepines (n = 89), lamotrigine (n = 58), and levetiracetam (n = 56). The majority (55%) had at least one comorbidity including: mood disorders (n = 49) and psychiatric disorders (n = 26). Common medications with reported precautions for people with a seizure history were: selective serotonin reuptake inhibitors (n = 18), second-generation atypical antipsychotics (n = 17) and benzodiazepines (n = 16). Participants had at least one: drug-disease interaction (33%), drug-drug interaction (54%), adverse drug reaction (37%), therapeutic duplication (13%); dose-related safety concerns (35%); and medication utilization concerns (13%).\n\n\n\nThis pharmacist-delivered pilot program was effective in: reaching underserved patients with epilepsy, identifying and recommending resolutions to medication-related problems, and demonstrating the value of pharmacists in an interprofessional team. Further work is warranted to identify telehealth strategies to reduce medication associated problems.",
"affiliations": "University of Arizona College of Pharmacy, 1295 N Martin Ave, PO Box 210202, Tucson, Arizona, 85721, United States. Electronic address: axon@pharmacy.arizona.edu.;University of Arizona College of Pharmacy, 1295 N Martin Ave, PO Box 210202, Tucson, Arizona, 85721, United States. Electronic address: taylor@pharmacy.arizona.edu.;University of Arizona College of Pharmacy, 1295 N Martin Ave, PO Box 210202, Tucson, Arizona, 85721, United States. Electronic address: dylanvo@pharmacy.arizona.edu.;SinfoniaRx, 100 N Stone Ave, Tucson, Arizona, 85701, United States. Electronic address: jmbingham@sinfoniarx.com.",
"authors": "Axon|David Rhys|DR|;Taylor|Ann M|AM|;Vo|Dylan|D|;Bingham|Jennifer|J|",
"chemical_list": "D000927:Anticonvulsants",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.eplepsyres.2019.106235",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-1211",
"issue": "158()",
"journal": "Epilepsy research",
"keywords": "Epilepsy; Interprofessional; Medication-related problems; Rural health; Telehealth; Underserved populations",
"medline_ta": "Epilepsy Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D054539:Medication Therapy Management; D008875:Middle Aged; D010595:Pharmacists; D012017:Referral and Consultation; D012640:Seizures",
"nlm_unique_id": "8703089",
"other_id": null,
"pages": "106235",
"pmc": null,
"pmid": "31726287",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Initial assessment of an interprofessional team-delivered telehealth program for patients with epilepsy.",
"title_normalized": "initial assessment of an interprofessional team delivered telehealth program for patients with epilepsy"
} | [
{
"companynumb": "US-OTSUKA-2019_040284",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nSildenafil is indicated for the treatment of male erectile dysfunction. It has been used successfully in males to remediate problems associated with impaired neural and/or hemodynamic response to sexual stimulation. Sildenafil is a cyclic guanosine-specific phosphodiesterase type 5 inhibitor that prevents the metabolism of cyclic guanosine which produces arterial smooth muscle relaxation within the corpora cavernosa of the penis and ultimately enhances penile tumescence. Inherent to its pharmacology, sildenafil produces mild decreases in systolic and diastolic blood pressure and an array of minimal side effects due to the inhibition of other types of phosphodiesterase. Drug interactions involving the concurrent use of sildenafil with nitrates and nitrites are well-documented and can produce profound hypotension leading to decreased coronary perfusion and myocardial infarction. Sildenafil is metabolized primarily by cytochrome P450 3A4, and inhibitors of this enzyme (e.g., macrolide antibiotics, antifungals, cimetidine) may increase sildenafil serum concentrations and lead to enhanced pharmacological and toxicological effects. The antiviral protease inhibitors have been demonstrated to inhibit first-pass metabolism and increase serum concentrations and half-life of sildenafil.\n\n\nCONCLUSIONS\nPreviously unpublished data from the American Association of Poison Control Centers Toxic Exposure Surveillance System indicate that unintentional pediatric exposures to sildenafil are unlikely to be associated with adverse effects. Adults may experience effects similar to those identified in the preclinical trials. This may be due to larger doses in this population, preexisting cardiovascular pathology, or the concomitant use of contraindicated medications.",
"affiliations": "Children's Hospital of Pittsburgh, Department of Pharmacy, University of Pittsburgh, Pennsylvania, USA. krenzee@chplink.chp.edu",
"authors": "Krenzelok|E P|EP|",
"chemical_list": "D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate",
"country": "United States",
"delete": false,
"doi": "10.1081/clt-100102015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0731-3810",
"issue": "38(6)",
"journal": "Journal of toxicology. Clinical toxicology",
"keywords": null,
"medline_ta": "J Toxicol Clin Toxicol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D062787:Drug Overdose; D006801:Humans; D008297:Male; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011039:Poison Control Centers; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones",
"nlm_unique_id": "8213460",
"other_id": null,
"pages": "645-51",
"pmc": null,
"pmid": "11185972",
"pubdate": "2000",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Sildenafil: clinical toxicology profile.",
"title_normalized": "sildenafil clinical toxicology profile"
} | [
{
"companynumb": "US-PFIZER INC-2018303737",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SILDENAFIL CITRATE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo determine the outcomes of alternating doses of ibuprofen and acetaminophen in the treatment of post-tonsillectomy pain in children and to identify characteristics of children who had inadequate pain control.\n\n\nMETHODS\nThe medical records of children who received alternating doses of ibuprofen and acetaminophen for post-tonsillectomy pain between August 2012 and November 2013 at a tertiary care children's hospital were reviewed. Incidences of postoperative bleeding and unresolved pain were determined.\n\n\nRESULTS\nA total of 583 patients (304 males, 279 females, age range=1-18 years) had received alternating doses of ibuprofen and acetaminophen after tonsillectomy and adenoidectomy. Of the 583 patients, 56 (9.6%) reported inadequate pain control. Age, sex, obesity, presence of comorbid conditions, indications for surgery, and concurrent surgical procedures were not different between children who had adequate analgesia and children who had unresolved pain. Twenty-four patients (4.1%) had postoperative bleeding. Nine patients (1.5%) required surgical intervention for bleeding.\n\n\nCONCLUSIONS\nAlternating doses of ibuprofen and acetaminophen provided an effective treatment for post-tonsillectomy pain in the majority of children and did not increase rate of bleeding. Means of improving response rate to alternating doses of ibuprofen and acetaminophen merit further investigation.",
"affiliations": "Department of Otolaryngology-Head and Neck Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.;Department of Otolaryngology-Head and Neck Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA Division of Pediatric Otolaryngology, Children's Medical Center, Dallas, TX, USA seckin.ulualp@utsouthwestern.edu.",
"authors": "Liu|Christopher|C|;Ulualp|Seckin O|SO|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D007052:Ibuprofen",
"country": "United States",
"delete": false,
"doi": "10.1177/0003489415583685",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4894",
"issue": "124(10)",
"journal": "The Annals of otology, rhinology, and laryngology",
"keywords": "acetaminophen; ibuprofen; pain; tonsillectomy",
"medline_ta": "Ann Otol Rhinol Laryngol",
"mesh_terms": "D000082:Acetaminophen; D000233:Adenoidectomy; D000293:Adolescent; D018712:Analgesics, Non-Narcotic; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007052:Ibuprofen; D015994:Incidence; D007223:Infant; D008297:Male; D059408:Pain Management; D010147:Pain Measurement; D010149:Pain, Postoperative; D019106:Postoperative Hemorrhage; D012189:Retrospective Studies; D013781:Texas; D014068:Tonsillectomy; D016896:Treatment Outcome",
"nlm_unique_id": "0407300",
"other_id": null,
"pages": "777-81",
"pmc": null,
"pmid": "25902839",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcomes of an Alternating Ibuprofen and Acetaminophen Regimen for Pain Relief After Tonsillectomy in Children.",
"title_normalized": "outcomes of an alternating ibuprofen and acetaminophen regimen for pain relief after tonsillectomy in children"
} | [
{
"companynumb": "US-JNJFOC-20151111293",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
"... |
{
"abstract": "Mesalamine suppositories have been used widely for the treatment of distal ulcerative colitis and considered to be safer than systemic administration for its limited systemic absorption. However, previous studies have shown that mesalamine suppository occasionally causes severe hypersensitivity reactions including fever, rashes, colitis exacerbation and acute eosinophilic pneumonia. Here we present a 25-year-old woman with ulcerative colitis with bloody diarrhea accompanied by abdominal pain and fever which were aggravated after introduction of mesalamine suppositories. In light of symptom exacerbation of ulcerative colitis, increased inflammatory injury of colon mucosa shown by colonoscopy and elevated peripheral eosinophil count after mesalamine suppositories administration, and the Naranjo algorithm score of 10, the possibility of hypersensitivity reaction to mesalamine suppositories should be considered, warning us to be aware of this potential reaction after administration of mesalamine formulations even if it is the suppositories.",
"affiliations": "Hao Ding, Xiao-Chang Liu, Qiao Mei, Jian-Ming Xu, Jing Hu, Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China.;Hao Ding, Xiao-Chang Liu, Qiao Mei, Jian-Ming Xu, Jing Hu, Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China.;Hao Ding, Xiao-Chang Liu, Qiao Mei, Jian-Ming Xu, Jing Hu, Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China.;Hao Ding, Xiao-Chang Liu, Qiao Mei, Jian-Ming Xu, Jing Hu, Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China.;Hao Ding, Xiao-Chang Liu, Qiao Mei, Jian-Ming Xu, Jing Hu, Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China.;Hao Ding, Xiao-Chang Liu, Qiao Mei, Jian-Ming Xu, Jing Hu, Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China.",
"authors": "Ding|Hao|H|;Liu|Xiao-Chang|XC|;Mei|Qiao|Q|;Xu|Jian-Ming|JM|;Hu|Xiang-Yang|XY|;Hu|Jing|J|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D013488:Suppositories; D012460:Sulfasalazine; D019804:Mesalamine",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v20.i13.3716",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "20(13)",
"journal": "World journal of gastroenterology",
"keywords": "Hypersensitivity; Mesalamine suppositories; Sulfasalazine; Surgery; Ulcerative colitis",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D015746:Abdominal Pain; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003093:Colitis, Ulcerative; D003113:Colonoscopy; D003967:Diarrhea; D005260:Female; D006801:Humans; D006967:Hypersensitivity; D007249:Inflammation; D019804:Mesalamine; D012720:Severity of Illness Index; D012460:Sulfasalazine; D013488:Suppositories",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "3716-8",
"pmc": null,
"pmid": "24707159",
"pubdate": "2014-04-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "4146729;10630512;7768395;20441247;21960801;3979912;8537058;14218553;19444457;9518293;1827746;15555743;23667838;4150435;8386034",
"title": "Ulcerative colitis flair induced by mesalamine suppositories hypersensitivity.",
"title_normalized": "ulcerative colitis flair induced by mesalamine suppositories hypersensitivity"
} | [
{
"companynumb": "CN-ACTAVIS-2015-10738",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPatients aged 60 years and older stand for the fastest growing group of patients with end-stage renal disease worldwide, and the need for kidney transplants among this population is rising. In Japan, living donor kidney transplantation is mainly performed to deal with the severe shortage of deceased donors, and the number of spousal transplants is currently increasing.\n\n\nMETHODS\nA total of 164 patients with ESRD underwent living donor kidney transplantation at our institution, of whom 21 patients aged 60 years and older had spousal kidney transplantation. ABO-incompatible kidney transplantation was performed in 5 of the 21 cases. We analyzed these recipients.\n\n\nRESULTS\nPatient and graft survival rates were 100%. The incidence of acute rejection was 23.8%. Eight patients experienced cytomegalovirus viremia, two patients experienced Pneumocystis jiroveci infection, and one experienced bacterial pneumonia. Two patients developed cancers and underwent curative operation after transplantation.\n\n\nCONCLUSIONS\nElderly kidney transplantation from spousal donors is associated with age-related immune dysfunction, which may develop infections and malignancies and could be immunologically high risk due to the high rate of ABO-incompatibility and poor histocompatibility. An effort to minimize the adverse effect of immunosuppression and to reduce the risk of acute rejection may be needed for an excellent long-term outcome.",
"affiliations": "Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.",
"authors": "Iwai|Tomoaki|T|;Uchida|Junji|J|;Kuwabara|Nobuyuki|N|;Kabei|Kazuya|K|;Yukimatsu|Nao|N|;Okamura|Motohiro|M|;Yamasaki|Takeshi|T|;Naganuma|Toshihide|T|;Kumada|Norihiko|N|;Nakatani|Tatsuya|T|",
"chemical_list": "D000017:ABO Blood-Group System; D007166:Immunosuppressive Agents",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000368324",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0042-1138",
"issue": "95(1)",
"journal": "Urologia internationalis",
"keywords": null,
"medline_ta": "Urol Int",
"mesh_terms": "D000017:ABO Blood-Group System; D000368:Aged; D001787:Blood Group Incompatibility; D003586:Cytomegalovirus Infections; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006085:Graft Survival; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007564:Japan; D007668:Kidney; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D018454:Spouses; D016896:Treatment Outcome",
"nlm_unique_id": "0417373",
"other_id": null,
"pages": "99-105",
"pmc": null,
"pmid": "25633349",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Outcome of Elderly Kidney Transplant Recipients from Spousal Donors.",
"title_normalized": "clinical outcome of elderly kidney transplant recipients from spousal donors"
} | [
{
"companynumb": "PHHY2015JP108615",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "Combined small cell carcinoma (SCC) and squamous cell carcinoma (SqCC) of the oropharynx is extremely rare and shows an aggressive clinical course. There are only 5 reported cases of combined SCC and SqCC in the English language literature. Here, we report a 59-year-old male presenting with a right tonsillar mass. The mass was biopsied, and the histological findings showed a proliferation of small-sized tumor cells with scant cytoplasm. Immunohistochemically, the tumor cells were positive for neuroendocrine markers (synaptophysin, chromogranin A, and CD56). Our first diagnosis was tonsillar small cell carcinoma. We treated the patient with concurrent chemoradiotherapy together with cisplatin followed by surgery. The resected tonsillar specimen showed a residual tumor composed of SCC and SqCC, and lymph nodes showed metastatic tumor cells of the SCC component. Immunohistochemically, the SCC component was positive for all neuroendocrine markers and p16; on the other hand, the SqCC component was positive for p40, p63, p16, and EGFR. Fluorescence in situ hybridization revealed that neither component showed any EGFR gene copy number gain. The patient was treated with adjuvant chemotherapy consisting of irinotecan and cisplatin. Liver and bone metastases developed, resulting in the death of the patient. We discuss the present case and review similar cases. Most cases of combined SCC and SqCC occur regardless of p16 status, and a therapeutic strategy has yet to be determined. Further examination of this kind of combined tumor is necessary.",
"affiliations": "Department of Otolaryngology, Hamanomachi Hospital, Nagahama 3-3-1, Chuo-ku, Fukuoka 810-8539, Japan; Department of Otolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. Electronic address: tn01061@surgpath.med.kyushu-u.ac.jp.;Department of Pathology, Hamanomachi Hospital, Nagahama 3-3-1, Chuo-ku, Fukuoka 810-8539, Japan.;Department of Internal Medicine, Hamanomachi Hospital, Nagahama 3-3-1, Chuo-ku, Fukuoka 810-8539, Japan.;Department of Otolaryngology, Hamanomachi Hospital, Nagahama 3-3-1, Chuo-ku, Fukuoka 810-8539, Japan.;Department of Otolaryngology, Hamanomachi Hospital, Nagahama 3-3-1, Chuo-ku, Fukuoka 810-8539, Japan.;Department of Otolaryngology, Hamanomachi Hospital, Nagahama 3-3-1, Chuo-ku, Fukuoka 810-8539, Japan.;Department of Otolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.;Department of Otolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.;Department of Otolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.",
"authors": "Nakano|Takafumi|T|;Motoshita|Junichi|J|;Tanaka|Risa|R|;Okabe|Midori|M|;Tamae|Akihiro|A|;Shiratsuchi|Hideki|H|;Yasumatsu|Ryuji|R|;Nakashima|Torahiko|T|;Nakagawa|Takashi|T|",
"chemical_list": "D000077146:Irinotecan; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin; D002166:Camptothecin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.anl.2016.07.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-8146",
"issue": "44(4)",
"journal": "Auris, nasus, larynx",
"keywords": "EGFR; Oropharynx; Small cell carcinoma; p16",
"medline_ta": "Auris Nasus Larynx",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D002166:Camptothecin; D018288:Carcinoma, Small Cell; D002294:Carcinoma, Squamous Cell; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D066246:ErbB Receptors; D017809:Fatal Outcome; D006801:Humans; D000077146:Irinotecan; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D018193:Neoplasms, Complex and Mixed; D009959:Oropharyngeal Neoplasms; D013517:Otorhinolaryngologic Surgical Procedures",
"nlm_unique_id": "7708170",
"other_id": null,
"pages": "472-478",
"pmc": null,
"pmid": "27496009",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Primary combined small cell carcinoma and squamous cell carcinoma of the oropharynx with special reference to EGFR status of small cell carcinoma component: Case report and review of the literature.",
"title_normalized": "primary combined small cell carcinoma and squamous cell carcinoma of the oropharynx with special reference to egfr status of small cell carcinoma component case report and review of the literature"
} | [
{
"companynumb": "JP-CIPLA LTD.-2017JP13682",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThis study aimed to identify the natural course of cytomegalovirus (CMV)/Epstein-Barr virus (EBV) after rabbit antithymocyte globulin and cyclosporine (rATG-CsA) for aplastic anemia (AA).\n\n\nMETHODS\nIn 113 prospectively observed AA patients treated with rATG-CsA, the CMV/EBV cohort was classified into two groups by baseline viremic status: no viremia (CMV-G1, n = 112; EBV-G1, n = 98) and the presence of viremia (CMV-G2, n = 1; EBV-G2, n = 13).\n\n\nRESULTS\nIn CMV-G1, the mean CMV load increased up to 3 months but was completely resolved from 6 months. The mean EBV load of EBV-G1 showed a peak at 1 month and then gradually decreased over time but remained detectable throughout the observation period. EBV-G2 showed fluctuating EBV dynamics. With reactivation rates of 38.4% in CMV-G1 and 62.2% in EBV-G1, a longer time to rATG-CsA from diagnosis and a lower absolute lymphocyte count at 1 month from rATG-CsA were significantly associated with CMV and EBV reactivation, respectively. The mean peak CMV and EBV loads of patients with CMV-related (3.5%) and EBV-related (0.9%) diseases were evidently higher than those of the remaining patients without CMV and EBV diseases in the respective cohort.\n\n\nCONCLUSIONS\nConsidering frequent reactivation and distinct courses of CMV/EBV, virologic surveillance is recommended after rATG-CsA for AA.",
"affiliations": "Division of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Infectious Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Division of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.",
"authors": "Park|Sung-Soo|SS|https://orcid.org/0000-0002-8826-4136;Cho|Sung-Yeon|SY|;Han|Eunhee|E|;Min|Gi June|GJ|;Park|Silvia|S|;Yoon|Jae-Ho|JH|https://orcid.org/0000-0002-2145-9131;Lee|Sung-Eun|SE|https://orcid.org/0000-0002-9810-2050;Cho|Byung-Sik|BS|;Eom|Ki-Seong|KS|;Kim|Yoo-Jin|YJ|;Lee|Seok|S|;Kim|Hee-Je|HJ|;Min|Chang-Ki|CK|;Cho|Seok-Goo|SG|;Lee|Jong Wook|JW|https://orcid.org/0000-0003-2949-4166",
"chemical_list": "D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D016572:Cyclosporine; C512542:thymoglobulin",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13308",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "103(4)",
"journal": "European journal of haematology",
"keywords": "Epstein-Barr virus; aplastic anemia; cytomegalovirus; immunosuppressive therapy; thymoglobulin",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic; D000961:Antilymphocyte Serum; D016572:Cyclosporine; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D020031:Epstein-Barr Virus Infections; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D019562:Viral Load; D014775:Virus Activation; D055815:Young Adult",
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"title": "Reactivation and dynamics of cytomegalovirus and Epstein-Barr virus after rabbit antithymocyte globulin and cyclosporine for aplastic anemia.",
"title_normalized": "reactivation and dynamics of cytomegalovirus and epstein barr virus after rabbit antithymocyte globulin and cyclosporine for aplastic anemia"
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"abstract": "BACKGROUND\nHereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue that resolves in approximately 3 days. It can be presented with peripheral edema, abdominal and life-threatening laryngeal angioedema. A variety of triggers are known to cause episodes of angioedema including estrogen exposure. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a recognized triggering factor.\n\n\nMETHODS\nWe present a female Caucasian patient with pre-existing HAE and disease exacerbations during pregnancy, requiring prophylactic use of plasma-derived C1 inhibitor concentrate. She was treated with Cinryze® replacement therapy throughout the pregnancy 1000 IU i.v. 48 times. She gave birth to a healthy male infant, via C-section. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE.\n\n\nCONCLUSIONS\nIn the case presented, the angioedema attacks worsened as the pregnancy progressed. The treatment with Cinryze® replacement therapy was effective and safe during pregnancy, with no adverse effects on the infant.",
"affiliations": "Department of Rheumatology, Clinical Immunology and Allergology, University Hospital Osijek, J. Huttlera 4, 31000, Osijek, Croatia. zeljkakardum@gmail.com.;Department of Rheumatology, Clinical Immunology and Allergology, University Hospital Osijek, J. Huttlera 4, 31000, Osijek, Croatia.;Department of Rheumatology, Clinical Immunology and Allergology, University Hospital Osijek, J. Huttlera 4, 31000, Osijek, Croatia.;School of Medicine, Josip Juraj Strossmayer University of Osijek J, Huttlera 4, 31000, Osijek, Croatia.",
"authors": "Kardum|Željka|Ž|;Prus|Višnja|V|;Milas Ahić|Jasminka|J|;Kardum|Darjan|D|",
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"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947 BioMed Central London \n\n2622\n10.1186/s13256-020-02622-3\nCase Report\nSuccessful treatment with Cinryze® replacement therapy of a pregnant patient with hereditary angioedema: a case report\nKardum Željka zeljkakardum@gmail.com 12 Prus Višnja 12 Milas Ahić Jasminka 12 Kardum Darjan 23 1 grid.412412.00000 0004 0621 3082Department of Rheumatology, Clinical Immunology and Allergology, University Hospital Osijek, J. Huttlera 4, 31000 Osijek, Croatia \n2 grid.412680.90000 0001 1015 399XSchool of Medicine, Josip Juraj Strossmayer University of Osijek J, Huttlera 4, 31000 Osijek, Croatia \n3 grid.412412.00000 0004 0621 3082Neonatal Intensive Care Unit, Department of Pediatrics, University Hospital Osijek, J. Huttlera 4, 31000 Osijek, Croatia \n24 1 2021 \n24 1 2021 \n2021 \n15 2027 2 2020 8 12 2020 © The Author(s) 2021Open 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\nHereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue that resolves in approximately 3 days. It can be presented with peripheral edema, abdominal and life-threatening laryngeal angioedema. A variety of triggers are known to cause episodes of angioedema including estrogen exposure. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a recognized triggering factor.\n\nCase presentation\nWe present a female Caucasian patient with pre-existing HAE and disease exacerbations during pregnancy, requiring prophylactic use of plasma-derived C1 inhibitor concentrate. She was treated with Cinryze® replacement therapy throughout the pregnancy 1000 IU i.v. 48 times. She gave birth to a healthy male infant, via C-section. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE.\n\nConclusions\nIn the case presented, the angioedema attacks worsened as the pregnancy progressed. The treatment with Cinryze® replacement therapy was effective and safe during pregnancy, with no adverse effects on the infant.\n\nKeywords\nHereditary angioedemaPregnancyC1 replacement therapyCinryze®Case reportissue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\nHereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue, without pruritus or urticaria, that resolves in approximately 3 days. The disease can be presented with peripheral edema, abdominal, but also with life-threatening laryngeal angioedema [1].\n\nSeveral types of HAE are described; the most explored one is due to C1 inhibitor deficiency, known as type I. It is caused by SERPING 1 mutation, on the long arm of chromosome 11, leading to C1 inhibitor deficiency which subsequently results in low C1 inhibitor and C4 protein levels in blood serum [2].\n\nA variety of triggers, such as stress, surgical procedures, some medications (ACE inhibitors, estrogen-containing medication) are identified to cause episodes of angioedema [3, 4]. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a known triggering factor.\n\nWe present a female patient with HAE and frequent disease exacerbations during pregnancy, that required prophylactic use of plasma-derived C1 inhibitor concentrate (pdC1) throughout the pregnancy.\n\nCase presentation\nWe present a female Caucasian patient with HAE type I, diagnosed at the age of 26, with SERPING 1 mutation (confirmed by molecular testing), with very low C1inhibitor and C4 levels. Molecular testing was also positive for her father and brother. They also had low C1 inhibitor and C4 levels, but they never had any HAE symptoms.\n\nHer symptoms of HAE first appeared when she was 15 years old, as swelling of her hand, without pain or urticaria. She was misdiagnosed with allergy-induced angioedema in the emergency department and was treated with glucocorticoids and antihistamines, without improvement. Edema subsided 3 days later. After that attack, peripheral angioedema appeared approximately once a year and lasted for a few days.\n\nSince the age of 20 until the age of 26, she had several times very intense abdominal pain, with swelling, that required a visit to the emergency room (ER), where she would receive analgetic and proton -pump inhibitor (PPI) i.v., Gastroenterologist examined her, and after gastroscopy, the diagnosis of chronic erosive gastritis was established. Finally, at the age of 25, due to recurrent peripheral oedema, she was referred to clinical immunologist and allergist. After an extensive workup, at the age of 26, HAE type I was diagnosed.\n\nOnce HAE was diagnosed, she was treated with tranexamic acid (1000 mg daily orally) and icatibant 30 mg subcutaneously as on-demand therapy, which she had to use approximately once a year, due to abdominal angioedema.\n\nIn her medical history, at the age of 28, she had one spontaneous abortion at 8 weeks of pregnancy. Since the patient planned pregnancy, tranexamic acid was excluded, and recombinant C1 inhibitor, conestat alpha, was provided as on-demand therapy.\n\nAt the age of 29, in July 2018. patient came to the emergency room (ER) because of the swelling of her eyelids and lips, and she was treated with a total of 160 mg of methylprednisolone and chloropyramine 20 mg i.v. As she reported difficulty swallowing, an examination by ear, nose and throat (ENT) specialist was performed, and the edema of the epiglottis and sinus piriformis was established. Since there was no improvement after the anti-allergic therapy, recombinant C1 inhibitor was applied, (conestat alpha 2100 IU i.v.) and total regression of edema ensued a few hours later. She was admitted to the Department of Rheumatology, Clinical Immunology and Allergology for further observation.\n\nHer social history revealed that she is a tradeswoman by profession, but is currently unemployed, married, living in a family house with her husband in a rural area, without any domestic animals in her household. The patient is a nonsmoker; she denied using alcohol, drugs or other medications. On admission, her temperature was 36.8°C, heart rate 76 beats/min, blood pressure 120/75 mmHg. There was no swelling of her face, neck or uvula. Her chest was clear to auscultation bilaterally, no wheezing. S1S2 were heard, no murmur, rubs or gallops. The abdomen was not distended; there was no tenderness on palpation and no organomegaly. There was no swelling or edema of her extremities. Neurological examination was unremarkable, with no nuchal rigidity, ophthalmic abnormalities, or cranial nerve signs.\n\nDuring hospitalization, pregnancy was confirmed (8 weeks gestation). According to HAE guidelines, a pdC1 inhibitor is recommended in pregnancy, and Cinryze® was advised as only available pd1C1 inhibitor in our country at that time. In July 2018, she received the first application of Cinryze® 1000 IU i.v. and it was prescribed as on-demand therapy.\n\nTwo weeks later, she returned to the ER because of nausea and intense abdominal pain. Examination by obstetrics and gynaecology (OBGYN) specialist was performed, and complications related to pregnancy were excluded. The ultrasound of the abdomen displayed a small amount of fluid around the liver, spleen and intestines, and her blood workup was unremarkable.\n\nAfter surgical and gastroenterologist (GE) examination she was referred to clinical immunologist and abdominal angioedema attack was diagnosed. She received Cinryze® 1000 iu i.v. and afterwards admitted to the Department for further evaluation. Blood workup revealed mild leukocytosis 14 ×109/L (ref. 3.4–9.7 × 109/L), normal C-reactive protein levels (5 mg/L; ref. <5) and elevated D-dimer levels >35000 Ug/L FEU (ref. 0–500) and low C4 0.04 g/L (ref. 0.1–0.4). Other blood workup was unremarkable: serum amylase 52U/L (ref. 30–110), lipase 9 U/L (0–160), LDH (s) 128 U/L (130–241), AST 24U/L (11–38), ALT 39 U/L (12–48), ALP 52 U/L (20–140), urea 1.6 mmol/L (2.8–8.3), creatinine (s) 49 umol/L (64–104), total bilirubin 11 umol/L (3-20), erythrocytes 4.31 × 1012/L (4.35–5.72), haemoglobin 131 g/L (138-175), thromocytes 189 × 109/L (158–424). Urine culture was sterile, EBV, CMV, Toxoplasma gondii serology revealed past contact.\n\nTwo hours after Cinryze® treatment, her symptoms resolved. On the next day, leukocyte levels were normal, and D-dimer values were significantly lower (4992 ug/L).\n\nShe was discharged from the hospital with Cinryze® i.v. as on-demand therapy and application of low weight molecular heparin s.c. (dalteparin 7500 IU s.c. once daily) was recommended through the entire pregnancy due to history of previous spontaneous abortion and elevated D-dimers.\n\nAfter that episode, the attacks were more frequent, with abdominal angioedema attacks every 3 days, and peripheral edema with the swelling of hands almost every other day. At 17 weeks gestation, the patient was started on Cinryze® prophylactic therapy 1000 IU i.v., two times a week. As the pregnancy progressed, her attacks became more frequent despite prophylactic treatment, so during the final month of the pregnancy, she received Cinryze® every two to three days.\n\nIn January 2019, she gave birth to a male term infant (gestational age 38 weeks), via C-section. The newborn infant was eutrophic (birth weight 3370 g), and had an average head circumference (33 cm). Upon birth, the infant was mildly dyspneic, had regular heart rate (>120/min), pink skin colour, was mildly hypotonic and had normal reflexes. Apgar scores were 8 at 1ʹ and 8 at 5ʹ. Due to transitory tachypnea of the newborn, he required non-invasive respiratory support with heated and humidified high flow nasal cannula (HFNC) for six hours. The hospitalization was otherwise uneventful, and he was discharged after 8 days. Head ultrasound was normal; there were no signs of perinatal infection.\n\nBefore the C-section, the patient received Cinryze® 1000 IU iv. For the next two weeks after the delivery, prophylactic therapy was continued, and subsequently, icatibant as on-demand therapy was recommended. The patient chose not to breastfeed. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE. Her first abdominal attack after the symptom-free period was less intensive than during pregnancy. Overall, during the pregnancy, the patient in total received Cinryze® (1000 IU i.v.) 48 times.\n\nDiscussion\nIn the report we presented a female patient with HAE type I, with pregnancy as an exact trigger for HAE attacks, leading to the progression of the number of attacks as the pregnancy advanced, and the patient required prophylactic treatment. Interestingly, attacks started in the early pregnancy with a severe presentation of the disease that was not previously present, and resolved immediately after the delivery, leaving the patient symptom free for several months. There are only a few case reports and studies available, which give a detailed description of HAE worsening during the pregnancy, but to our knowledge, non showed such progression despite prophylactic therapy [5-9].\n\nHereditary angioedema is a rare disease that affects both male and female patients, but the attacks are more frequent in female patients [10]. The likely explanation is the possible effect of estrogen on the kallikrein-kinin system and subsequently on the disease course. [11]. Furthermore, it is known that HAE attacks can be precipitated by estrogen replacement therapy and contraceptive hormones [4, 10].\n\nIn our patient, the first symptom appeared during puberty onset. Although the SERPING 1 mutation and low levels of C1 inhibitor and C4 complement were found in her father and brother, she was the only member of the family with HAE symptoms.\n\nThe impact of pregnancy on HAE symptoms in patients is still unclear. Martinez-Saguer et al. showed that in 83% of pregnancies, attack rates increased during pregnancy with the highest rates in the second and third trimesters [12]. Czaller et al. in their study reported that attack frequency increases in 48% of pregnancies, most of them experienced worsening in the third trimester. Still, in 19% of the pregnancies, there was no influence on the course of HAE [9]. In contrast to these findings, Chinniah showed that women with HAE have significantly reduced or absent attacks in the last two trimesters of pregnancy [13].\n\nIn our patient, the first HAE symptom, when the pregnancy was revealed, was life-threatening laryngeal edema, whereas, before pregnancy, HAE symptoms were always presented as peripheral or abdominal edema. As the pregnancy progressed, her attacks became more frequent, especially in the last trimester, and were presented as abdominal and peripheral edema. Following the international WAO/EAACI guideline for the management of hereditary angioedema, the patient was treated with C1 inhibitor concentrate as prophylactic therapy during the pregnancy [1, 14].\n\nSome authors suggest an increased number of attacks following frequent treatments with C1 concentrate [15]. This was not confirmed in our case, since our patient received 48 times pdC1 inhibitor concentrate and the attacks stopped after the delivery, and afterwards, she was a symptom-free for 6 months.\n\nThe patient was treated with pdC1 inhibitor concentrate Cinryze®, although there is no relevant epidemiological data regarding its safety during pregnancy. Until now, there are only a few case reports of its safety during pregnancy [16].\n\nConclusion\nIn the case presented, the angioedema attacks worsened as the pregnancy progressed. After delivery, the patient was symptom-free for six months. During the pregnancy, she was treated with pdC1 inhibitor concentrate Cinryze®, which showed to be a safe choice, although there is no relevant epidemiological data regarding its safety during pregnancy. Our report further confirms that Cinryze® therapy is effective and safe treatment during pregnancy, with no adverse effects on the infant.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors acknowledge and thank the patient for her consent and insight, and also the staff and educators of the University Hospital Osijek, Croatia\n\nAuthors' contributions\nŽK and DK acquired, analyzed, and interpreted data and drafted the article and revised it critically for important intellectual content. VP and JMA revised the article critically for important intellectual content. All authors participated in writing the final manuscript. All authors read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nThe study was approved by University Hospital Osijek Ethics committee No R2-1060/2020 and informed written consent was obtained.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nŽK and VP has received speaker honorariums from Takeda Pharmaceuticals. DK owns stock in Takeda Pharmaceuticals. JMA declares that she has no conflict of interest.\n==== Refs\nReferences\n1. Banerji A Riedl M Managing the female patient with hereditary angioedema Women's Health. 2016 12 3 351 361 10.2217/whe.16.6 \n2. Nedelea I Deleanu D Isolated angioedema: an overview of clinical features and etiology (Review) Exp Ther Med. 2018 10.3892/etm.2018.6982 30679975 \n3. Ricketti A Cleri D Ramos-Bonner L Vernaleo J Hereditary angioedema presenting in late middle age after angiotensin-converting enzyme inhibitor treatment Ann Allergy Asthma Immunol. 2007 98 4 397 401 10.1016/S1081-1206(10)60889-7 17458439 \n4. Bouillet L Longhurst H Boccon-Gibod I Bork K Bucher C Bygum A Disease expression in women with hereditary angioedema Am J Obstet Gynecol. 2008 199 5 484.e1 484.e4 10.1016/j.ajog.2008.04.034 18554570 \n5. Gorman PJ Hereditary angioedema and pregnancy: a successful outcome using C1 esterase inhibitor concentrate Can Fam Phys. 2008 54 3 365 366 \n6. Lovsin B Guzej Z Vok M Kramar I Ravnikar J C-1 esterase inhibitor prophylaxis for delivery in hereditary angioedema J Obstet Gynaecol. 1999 19 5 537 538 10.1080/01443619964427 15512387 \n7. Hermans C Successful management with C1-inhibitor concentrate of hereditary angioedema attacks during two successive pregnancies: a case report Arch Gynecol Obstet. 2007 276 3 271 276 10.1007/s00404-007-0329-1 17653743 \n8. Sankrithi P Shah K Bernabe CC Pregnancy-induced exacerbation of hereditary angioedema in a multiparous Caucasian female Cureus. 2020 12 5 e8006 32528748 \n9. Czaller I Visy B Csuka D Füst G Tóth F Farkas H The natural history of hereditary angioedema and the impact of treatment with human C1-inhibitor concentrate during pregnancy: a long-term survey Eur J Obstet Gynecol Reprod Biol. 2010 152 1 44 49 10.1016/j.ejogrb.2010.05.008 20541309 \n10. Bork K Fischer B Dewald G Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy Am J Med. 2003 114 4 294 298 10.1016/S0002-9343(02)01526-7 12681457 \n11. Madeddu P Emanueli C Varoni M Demontis M Anania V Gorioso N Regulation of bradykinin B2-receptor expression by oestrogen Br J Pharmacol. 1997 121 8 1763 1769 10.1038/sj.bjp.0701255 9283715 \n12. Martinez-Saguer I Rusicke E Aygören-Pürsün E Heller C Klingebiel T Kreuz W Characterization of acute hereditary angioedema attacks during pregnancy and breast-feeding and their treatment with C1 inhibitor concentrate Am J Obstet Gynecol. 2010 203 2 131.e1 131.e7 10.1016/j.ajog.2010.03.003 20471627 \n13. Chinniah N Katelaris C Hereditary angioedema and pregnancy Aust N Z J Obstet Gynaecol. 2009 49 1 2 5 10.1111/j.1479-828X.2008.00945.x 19281571 \n14. Maurer M Magerl M Ansotegui I Aygören-Pürsün E Betschel S Bork K The international WAO/EAACI guideline for the management of hereditary angioedema—the 2017 revision and update World Allergy Organ J. 2018 11 5 10.1186/s40413-017-0180-1 \n15. Bork K Hardt J Hereditary angioedema: increased number of attacks after frequent treatments with C1 inhibitor concentrate Am J Med. 2009 122 8 780 783 10.1016/j.amjmed.2009.02.024 19635282 \n16. Baker J Sheffer A Christensen J Hurewitz D Lazar R Kalfus I CinryzeTM replacement therapy in hereditary angioedema and pregnancy J Allergy Clin Immunol Pract. 2009 123 2 S106 S106 10.1016/j.jaci.2008.12.385\n\n",
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"journal": "Journal of medical case reports",
"keywords": "C1 replacement therapy; Case report; Cinryze®; Hereditary angioedema; Pregnancy",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000799:Angioedema; D054179:Angioedemas, Hereditary; D050718:Complement C1 Inhibitor Protein; D004487:Edema; D005260:Female; D006801:Humans; D008297:Male; D011247:Pregnancy",
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"title": "Successful treatment with Cinryze® replacement therapy of a pregnant patient with hereditary angioedema: a case report.",
"title_normalized": "successful treatment with cinryze replacement therapy of a pregnant patient with hereditary angioedema a case report"
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"abstract": "BACKGROUND\nBK virus-associated nephropathy (BKVAN) is a relatively common cause of renal dysfunction in the first six months after renal transplantation. It arises from reactivation of the latent and usually harmless BK virus (BK virus) due to immunosuppression and other factors including some that are unique to renal transplantation such as allograft injury. BKVAN is much rarer in non-renal solid organ transplantation, where data regarding diagnosis and management are extremely limited.\n\n\nMETHODS\nWe report a case of a 58-year-old man found to have worsening renal dysfunction nine months after bilateral sequential lung transplantation for chronic obstructive pulmonary disease (COPD). He had required methylprednisolone for acute allograft rejection but achieved good graft function. Urine microscopy and culture and renal ultrasound were normal. BK virus PCR was positive at high levels in urine and blood. Renal biopsy subsequently confirmed BKVAN. The patient progressed to end-stage renal failure requiring haemodialysis despite reduction in immunosuppression, including switching mycophenolate for everolimus, and the administration of intravenous immunoglobulin (IVIG).\n\n\nCONCLUSIONS\nThis very rare case highlights the challenges presented by BK virus in the non-renal solid organ transplant population. Diagnosis can be difficult, especially given the heterogeneity with which BKV disease has been reported to present in such patients, and the optimal approach to management is unknown. Balancing reduction in immunosuppression against prevention of allograft rejection is delicate. Improved therapeutic options are clearly required.",
"affiliations": "Discipline of Medicine, University of Adelaide, Adelaide, SA, 5000, Australia. thomas.crowhurst@gmail.com.;SA Pathology, Royal Adelaide Hospital, Central Adelaide Local Health Network, 1 Port Road, Adelaide, SA, 5000, Australia.;Discipline of Medicine, University of Adelaide, Adelaide, SA, 5000, Australia.;Discipline of Medicine, University of Adelaide, Adelaide, SA, 5000, Australia.;Discipline of Medicine, University of Adelaide, Adelaide, SA, 5000, Australia.",
"authors": "Crowhurst|Thomas|T|http://orcid.org/0000-0003-4873-5439;Nolan|James|J|;Faull|Randall|R|;Holmes|Mark|M|;Holmes-Liew|Chien-Li|CL|",
"chemical_list": "D004279:DNA, Viral; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D008775:Methylprednisolone",
"country": "England",
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"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect. Dis\nBMC Infectious Diseases\n1471-2334 BioMed Central London \n\n5292\n10.1186/s12879-020-05292-0\nCase Report\nBK virus-associated nephropathy in a lung transplant patient: case report and literature review\nhttp://orcid.org/0000-0003-4873-5439Crowhurst Thomas thomas.crowhurst@gmail.com 12 Nolan James 3 Faull Randall 14 Holmes Mark 12 Holmes-Liew Chien-Li 12 1 grid.1010.00000 0004 1936 7304Discipline of Medicine, University of Adelaide, Adelaide, SA 5000 Australia \n2 grid.416075.10000 0004 0367 1221SA Lung Transplant Service, Royal Adelaide Hospital, Central Adelaide Local Health Network, 1 Port Road, Adelaide, SA 5000 Australia \n3 grid.416075.10000 0004 0367 1221SA Pathology, Royal Adelaide Hospital, Central Adelaide Local Health Network, 1 Port Road, Adelaide, SA 5000 Australia \n4 grid.416075.10000 0004 0367 1221Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Central Adelaide Local Health Network, 1 Port Road, Adelaide, SA 5000 Australia \n14 8 2020 \n14 8 2020 \n2020 \n20 6001 4 2020 26 7 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\nBK virus-associated nephropathy (BKVAN) is a relatively common cause of renal dysfunction in the first six months after renal transplantation. It arises from reactivation of the latent and usually harmless BK virus (BK virus) due to immunosuppression and other factors including some that are unique to renal transplantation such as allograft injury. BKVAN is much rarer in non-renal solid organ transplantation, where data regarding diagnosis and management are extremely limited.\n\nCase presentation\nWe report a case of a 58-year-old man found to have worsening renal dysfunction nine months after bilateral sequential lung transplantation for chronic obstructive pulmonary disease (COPD). He had required methylprednisolone for acute allograft rejection but achieved good graft function. Urine microscopy and culture and renal ultrasound were normal. BK virus PCR was positive at high levels in urine and blood. Renal biopsy subsequently confirmed BKVAN. The patient progressed to end-stage renal failure requiring haemodialysis despite reduction in immunosuppression, including switching mycophenolate for everolimus, and the administration of intravenous immunoglobulin (IVIG).\n\nConclusions\nThis very rare case highlights the challenges presented by BK virus in the non-renal solid organ transplant population. Diagnosis can be difficult, especially given the heterogeneity with which BKV disease has been reported to present in such patients, and the optimal approach to management is unknown. Balancing reduction in immunosuppression against prevention of allograft rejection is delicate. Improved therapeutic options are clearly required.\n\nKeywords\nBK virusNephropathyEnd-stage renal failureLung transplantationCase reportissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nBK virus (BKV) is a non-enveloped double-stranded DNA polyomavirus. It resides in renal tubular and uroepithelial cells, causing no sequelae in immunocompetent individuals [1]. Primary infection occurs in childhood and as many as 80% of adults demonstrate serological evidence of exposure [2]. Intermittent viral replication manifests as asymptomatic viruria in 7–15% of healthy people [3]. Immunocompromise can enable significant reactivation whereby BKV can progress from viruria to viraemia and cause end-organ disease, usually BKV-associated nephropathy (BKVAN) in renal transplant recipients and haemorrhagic cystitis in haematopoietic stem cell transplant recipients. Reports of BKVAN in other states of immunocompromise, especially after lung transplantation, are rare.\n\nBKV viruria occurs in 25–30% of renal transplant recipients and 11–13% develop viraemia, with 1–10% progressing to BKVAN usually by 6 months post-transplant [4, 5]. The key risk for BKVAN is degree of immunosuppression; other factors include ABO incompatibility, tacrolimus-containing regimen, donor-positive to recipient-negative serostatus, extremes of age and male sex [6–9]. Higher pre-transplant levels of neutralising anti-BKV antibodies may reduce the risk of BKVAN [10]. The rarity with which the disease affects native kidneys highlights unique characteristics of renal transplantation that engender a more permissible environment for reactivation; these include allograft injury from surgery and ischaemia, rejection, HLA mismatch impacting host immune activity in the allograft, and others [11, 12].\n\nScreening for BKVAN is recommended after renal transplantation and involves monitoring for BKV viraemia via quantitative polymerase chain reaction (PCR), given viraemia is a reliable precursor to BKVAN [13]. Persistent or significant viraemia is pre-emptively managed with reduction of immunosuppression before allograft dysfunction arises [5]. Screening is not recommended in other solid organ transplantation. Electron microscopy for cast-like urinary polyomavirus aggregates (‘Haufen’) is highly sensitive and specific for BKVAN, and may be particularly useful in paediatric patients where biopsy is difficult [14, 15]. In renal transplantation, biopsy is reserved for when there is diagnostic uncertainty or when reduction of immunosuppression has not led to improvement in renal dysfunction or viraemia. Histological findings in BKVAN share similarities with other viral nephropathies and include intranuclear viral inclusions, tubular damage, and mononuclear or polymorphonuclear infiltrates in affected areas; confirmation occurs via positive immunohistochemistry (IHC) for simian virus 40 (SV40) large T antigen, which cross-reacts with BKV and other polyomaviruses like JC virus (JCV) [16]. The Banff Working Group Classification of Definitive Polyomavirus Nephropathy was published in 2018 on the basis of a large retrospective analysis of proven polyomavirus nephropathy cases; it seeks to provide a consensus morphologic grading scheme that reflects important clinical parameters including presentation at diagnosis, renal function after index biopsy, and future graft failure [6].\n\nReduction in immunosuppression is the only proven strategy for management of BKVAN, however there is no universally agreed approach. There is some evidence mTOR inhibitors, compared with calcineurin inhibitors and mycophenolate, could enable superior control of BKVAN without increasing risk of rejection [17, 18]. Other therapies such as intravenous immunoglobulin (IVIG), leflunomide and cidofovir are unproven but occasionally employed. Quinolone antibiotics have been shown to provide no benefit while increasing antimicrobial resistance [19]. Future treatments may include brincidofovir and allogeneic polyomavirus-specific T cell therapy [20, 21].\n\nCase presentation\nA 58-year-old man was noted to have 3 months of progressive renal dysfunction at routine outpatient follow-up for his bilateral sequential lung transplant, which was performed 9 months earlier for severe chronic obstructive pulmonary disease (COPD). Methylprednisolone alone was used for induction. He was found to have acute rejection (A1B0) on surveillance bronchoscopy at 2 months post-transplant and was managed with pulse methylprednisolone with good results. His immunosuppressive regimen consisted of prednisolone, tacrolimus and mycophenolate. Before the onset of renal dysfunction, his prednisolone dose was 10 mg daily and mycophenolate dose was 500 mg twice daily. Median tacrolimus trough level from months three to six post-transplant was 11.2 μg/L (interquartile range [IQR]: 8.6–13.7 μg/L). He had not experienced further rejection and his graft function was good with a forced expiratory volume in 1 s (FEV1) of 2.44 l (82% predicted and 91% of post-transplant baseline).\n\nOther post-transplant issues included (a) positive galactomannan on three-month surveillance bronchoscopy without invasion which was managed with itraconazole, (b) respiratory syncytial virus and rotavirus at 3 months post-transplant, (c) steroid-induced diabetes mellitus which settled with reduction in prednisolone, (d) hypertension controlled with angiotensin receptor blockade, (e) persistent small left effusion drained at 10 months post-transplant, (f) asymptomatic cytolomegalovirus (CMV) viraemia detected at 10 months post-transplant and treated with valganciclovir, (g) iron deficiency anaemia due to dysplastic colonic polyps which were removed, (h) cataracts and (i) benign squamous papilloma affecting the right main bronchus anastomosis which was detected at 15 months post-transplant due to declining allograft function and which improved with balloon dilatation. Histological assessment did not demonstrate a viral aetiology for the bronchial squamous papilloma, however specific testing for human papilloma virus was not performed.\n\nBackground medical problems prior to transplant included coeliac disease, central sleep apnoea managed with oxygen, osteoporosis and hypercholesterolaemia. Pharmacological therapy at the time of detection of renal dysfunction, in addition to his immunosuppression, included: azithromycin, pantoprazole, candesartan, atorvastatin, calcium citrate, vitamin D, annual zoledronic acid, magnesium supplementation plus prophylactic itraconazole, trimethoprim/sulfamethoxazole and valganciclovir.\n\nThe patient had a pre-transplant glomerular filtration rate (GFR) of 85 ml/min/1.73m2 and a stable baseline of 70 ml/min/1.73m2 at 6 months post-transplant; this relatively mild stepwise decline in renal function was attributed to multifactorial peri-operative renal injury, as is seen very often after lung transplantation. His renal function then progressively deteriorated over 3 months to reach a GFR of 35 ml/min/1.73m2 at 9 months post-transplant despite reduced tacrolimus trough levels over this period (median: 5.2 μg/L | IQR: 4.5–5.9 μg/L). Urinary microscopy and culture analyses were bland on two separate occasions over 3 days with no haematuria, pyuria, decoy cells or casts. Ultrasound of the renal tract performed at the same time was normal with no evidence of obstruction and normal renal size. Given the absence of another identifiable cause and the immunosuppression, PCR for BKV was performed on samples collected at the same time as those for urinary microscopy and culture; the PCR was positive at > 10 million copies/ml in urine and 358,000 copies/ml in blood. Nephrology input was sought. Mycophenolate was ceased, target tacrolimus level was reduced to 5 μg/L, everolimus was commenced with a target level of 2.5 to 3 μg/L and a biopsy was planned.\n\nA renal biopsy was performed 3 weeks after the positive BKV PCR result (Figs. 1, 2, 3 and 4). The biopsy comprised a formalin fixed 9 mm core of renal tissue including 50% each of cortex and medulla. Routine renal biopsy haematoxylin and eosin histology sections were produced and routine histochemical stains performed. There were up to 7 viable glomeruli per section and no obsolescent forms. The glomeruli showed no morphologic abnormality. There was mild cortical fibrosis, less than 10% of cortical area, with Banff ci1 assigned. There was no cortical inflammation. The biopsy included a portion of an arterial vessel with mild to moderate arteriosclerosis. Arterioles were normal. In medullary tubules adjacent to the cortico-medullary junction were cells with abnormal nuclei consistent with viral cytopathic effect; nuclear inclusions were seen along with lymphocytic tubulitis and sloughed epithelial cells. In this region, IHC with antibody to SV40 was positive in the nuclei of epithelial cells. The involved tubules were quantified according to the method described by Nickeleit et al. [6]. This rendered a count of 2.5% and a pvl score of 2 (1 to 10%). The combination of Banff ci1 and pvl 2 produced an overall classification of polyomavirus nephropathy class 2. Tissue was not submitted by the clinician for immunofluorescence. Electron microscopy of tissue received in glutaraldehyde showed glomeruli with ischaemic alterations only; no viral particles were seen in the tissue.\nFig. 1 Histological section of renal biopsy at 100 times magnification with trichrome stain showing no significant chronic damage to the renal cortical parenchyma.\n\nFig. 2 Histological section of renal biopsy at 600 times magnification showing viral cytopathic effect\n\nFig. 3 Immunohistochemical stain with antibody to SV40 at 600 times magnification showing positively staining nuclei of tubular epithelial cells\n\nFig. 4 Histological section of renal biopsy at 400 times magnification showing interstitial oedema, tubulitis and viral cytopathic effect\n\n\n\nThe combination of the clinical, virological and histological findings allowed a definitive diagnosis of polyomavirus nephropathy due to BKV. Decline in renal function continued despite reduction in immunosuppression. The quantitative BKV PCR in blood climbed over the ensuing 8 months to reach and remain > 10,000,000 copies/ml. Three doses of IVIG were given over 2 months but this was then ceased due to an absence of effect. Patient progress is summarised in Fig. 5. He was regularly reviewed by nephrology and, at 20 months post-diagnosis of BKVAN and 29 months post-transplant, he had an arteriovenous fistula formed for planned commencement of haemodialysis.\nFig. 5 Graphic depiction of patient progress with time on the X-axis and viral load in blood (green line) on the left Y-axis, with creatinine (blue line) and glomerular filtration rate on the right Y-axis (red line). BKV: BK virus. IVIG: intravenous immunoglobulin. BKVAN: BK virus-associated nephropathy. GFR: glomerular filtration rate\n\n\n\nDiscussion and conclusions\nThis case is the eighth reported instance of BKVAN after lung transplantation, the seventh where a confirmatory biopsy has been performed and the first in which the Banff classification for polyomavirus nephropathy has been applied [22–28]. Reported cases are summarised in Table 1. Our case is worthy of discussion because of its rarity and because it highlights the dilemmas associated with organ-threatening infections in immunosuppressed transplant recipients.\nTable 1 Summary of all reported cases of BK virus-associated nephropathy in lung transplant recipients including the present case\n\nAuthor and year\tAge at transplant\nGender\tIndication for transplant\tOnset of renal dysfunction (months post-transplant)\nCreatinine at disease onset (μmol/l)\tBKV PCR in urine and blood at diagnosis\tBiopsy\tManagement\tOutcome\t\nSchwarz et al. 2005 [15]\t38 years\n\nMale\n\n\tPulmonary fibrosis due to chemotherapy for seminoma\t15 months\n\n227 μmol/l\n\n\tUrine: +\n\n> 100,000,000 Geq/ml\n\nBlood: +\n\n117,500 Geq/ml\n\n\tPositive\tImmunosuppression not reduced due to recent rejection, hence cidofovir used, then leflunomide in place of cidofovir due to improved biopsy results\tRepeat renal biopsy performed three months after original diagnostic biopsy and one month after a course of cidofovir showed absence of BKVAN changes (with BKV PCR in blood also showing significant reduction) with further subsequent improvement on leflunomide, however renal function nonetheless deteriorated and RRT was required\t\nEgli et al. 2010 [16]\t67 years\n\nFemale\n\n\tCOPD\t63 months\n\n183 μmol/l\n\n\tUrine: +\n\n> 100,000,000 Geq/ml\n\nBlood: +\n\n71,000 Geq/ml\n\n\tPositive\t↓ immunosuppression, leflunomide (but was ceased at 3 months for diarrhoea / anaemia)\tStabilisation of creatinine (peak was at 237 μmol/l improving to 190 μmol/l) and undetectable BKV PCR in blood (still positive in urine) at 1 year post-diagnosis\t\nDufek et al. 2013 [17]\t8 years\n\nMale\n\n\tBronchiolitis obliterans\t12 months\n\nN/A\n\n\tUrine:\n\n> 100,000,000 Geq/ml\n\nBlood: +\n\n> 100,000,000 Geq/ml\n\n\tPositive\tHaemodialysis, switch of mycophenolate for everolimus, ↓ tacrolimus and prednisolone, intravenous cidofovir\tDevelopment of rapidly progressive, ultimately fatal, collecting duct carcinoma with strong positivity for SV40 antibody staining in the nuclei of tumour cells\t\nSharma et al. 2013 [18]\t30 years\n\nMale\n\n\tCystic fibrosis\t24 months\n\n195 μmol/l\n\n\tUrine: N/A\n\nBlood: +\n\n3,500,000 Geq/ml\n\n\tPositive\tLeflunomide commenced and mycophenolate ceased\tIncrease then stabilisation of creatinine at 274 μmol/l at 20 months post-diagnosis\t\nVigil et al. 2016 [19]\t70 years\n\nMale\n\n\tIPF\t24 months\n\n265 μmol/l\n\n\tUrine: N/A\n\nBlood: +\n\n10,000,000 Geq/ml\n\n\tPositive\tMycophenolate was ceased, tacrolimus and prednisolone continued, leflunomide started and three doses of IVIG given\tImprovement in BKV PCR in blood and stabilisation of creatinine at 250 μmol/l\t\nKuppachi et al. 2017 [20]\t63 years\n\nMale\n\n\tCOPD\t24 months\n\n230 μmol/l\n\n\tUrine: N/A\n\nBlood: +\n\n87,900 Geq/ml\n\n\tPositive\tAzathioprine ceased, ↓ tacrolimus, leflunomide commenced\tInitial good response with reduction in BKV PCR in blood and stabilisation of renal function at 265 μmol/l, but then was found to have locally-advanced prostate carcinoma and separate metastatic urothelial carcinoma (two separate primary malignancies) which rapidly advanced in parallel with drastic increases in BKV PCR counts\t\nOkumura et al. 2019 [21]\t30 years /\n\n44 years\n\nFemale\n\n\tLAM/relapsed LAM\t3 months\n\n66 μmol/l\n\n\tUrine: +\n\n> 100,000,000 Geq/ml\n\nBlood: +\n\n800 Geq/ml\n\n\tN/A\t↓ immunosuppression to standard maintenance levels post-transplant, and addition of sirolimus at six months post-transplant\tGradual improvement in renal function and reduction in BKV PCR in blood, with levels falling to undetectable levels at 5 months post-diagnosis\t\nPresent case\n\n2020\n\n\t57 years\n\nMale\n\n\tCOPD\t9 months\n\n184 μmol/l\n\n\tUrine: +\n\n> 10,000,000 Geq/ml\n\nBlood: +\n\n358,000 Geq/ml\n\n\tPositive\t↓ immunosuppression, change of mycophenolate to everolimus, and then IVIG when renal function deteriorated further\tGradual deterioration in renal function despite these measures, requiring fistula formation for the planned commencement of haemodialysis\t\nLegend for Table 1: table summarising the eight reported cases of BKVAN in lung transplant recipients. BKVAN BK virus-associated nephropathy. BKV BK virus. PCR Polymerase chain reaction. Geq/ml Genome equivalents per millilitre. RRT Renal replacement therapy. COPD Chronic obstructive pulmonary disease. N/A Information not available from publication. SV40 Simian virus 40. IPF Idiopathic pulmonary fibrosis. IVIG Intravenous immunoglobulin. LAM Lymphangioleiomyomatosis\n\n\n\nOur case shares some similarities with those previously reported. Unlike renal transplant where BKVAN usually arises within 6 months, our case replicates the pattern of somewhat later presentation observed in earlier reports of BKVAN after lung transplant; median time to presentation across the eight reported cases is 19.5 months with IQR of 11–24 months. As with three of the other seven cases, our patient was more immunosuppressed than would be usual following lung transplantation due to the additional methylprednisolone for his acute rejection; in two of the three other cases the reason was also treatment for acute rejection whereas in the third it was neutropenia due to trimethoprim/sulfamethoxazole [22–24]. Higher levels of immunosuppression may have led to BKVAN in these patients, but this leaves the question as to what caused disease in the other four cases where immunosuppression was at routine levels. Urinary microscopy was bland in our patient, as it was in two of the other three cases for which results have been reported; only Okumura et al. have demonstrated decoy cells associated with BKVAN in a lung transplant patient [25, 26, 28].\n\nOur case is only the second reported instance where BKVAN has progressed to end-stage renal failure despite reduction in immunosuppression. This occurred in parallel with persistent extremely high BKV PCR levels measured in blood. There are no obvious factors that explain the poor outcome of our patient compared with the previously reported cases, however analysis is challenging given the paucity of data. BKV appears to have heterogenous manifestations in lung transplant recipients, noting the development of aggressive urothelial carcinoma in two of the reported cases almost certainly due to viral oncogenic effect, and with another report by Elidemir and colleagues describing haemorrhagic cystitis from BKV in a paediatric lung transplant recipient [24, 27, 29].\n\nSome studies have attempted to determine whether non-renal solid organ transplant recipients should undergo to a similar screening regime to detect BK viraemia and prevent BKVAN. Barton and colleagues performed a prospective cross-sectional study of consecutive non-renal solid organ transplant recipients with unexplained chronic renal dysfunction of at least 3 months duration, with 65% of their 34 subjects being lung transplant recipients [30]. None of the patients had viraemia and only 15% had viruria; they associated viruria with mycophenolate use and a history of CMV disease, but GFR was similar in those with and without viruria. Thomas et al. undertook a prospective study of 50 lung transplant recipients, analysing urine and blood samples over a 17-month period for BKV but also JCV and SV40 [31]. All blood samples were negative. Urine was positive for BKV on at least one occasion in 32% of patients, while JCV and SV40 were detected at least once in 24 and 12% of subjects respectively. Doucette et al. performed a 9-month study of BKV in 60 patients with non-renal solid organ transplants, with 47% being lung transplant recipients; viruria was found in 15% but viraemia was not detected and there was no significant difference in GFR between those with and without viruria [32]. These studies seem to suggest that although polyomavirus viruria is common and harmless in lung transplant recipients, viraemia and BKVAN appear to be rare events.\n\nThe apparent clinical insignificance of BKV viruria has, however, been questioned by another more recent study by Thomas and colleagues [33]. They followed 99 lung transplant patients for 4.5 years with urine samples tested for BKV, JCV and SV40. Polyomavirus viruria occurred at least once in 66% of cases (BKV 42% | JCV 28% | SV40 7%) and was positively associated with COPD but, surprisingly, negatively associated with acute rejection. Patients with viruria did not have significantly different renal function overall, however transient dysfunction was temporally associated with viruria episodes. Importantly, BKV viruria was associated with reduced survival however the magnitude of this effect was not reported; viruria was associated with chronic lung allograft dysfunction (CLAD) as a cause of death, with 26% of those with viruria dying of CLAD versus 10% of those without (p = 0.047). Causation is unproven and multiple other factors may explain these findings, but this study raises questions.\n\nThere are no data beyond case reports to indicate the reliability of BKV viraemia as a surrogate marker for risk of BKVAN in lung transplant recipients. The evidence in renal transplant recipients is strong [13]. Razonable and colleagues conducted a retrospective analysis of samples collected during a longitudinal study of CMV in solid organ transplant recipients including renal transplants but not including lung transplants [34]. BKV viraemia was found in 26% of renal, 6.7% of heart and 4.1% of liver transplants in the first year post-transplant, at a median of 100 days. All three positive cardiac transplant cases and one of five positive liver cases developed BKV viraemia after treatment for acute allograft rejection. None of the non-renal solid organ transplant patients with BKV viraemia developed renal dysfunction. Salama et al. found no BKV viraemia and no association between BKV viruria and renal function in 41 liver transplant recipients [35]. Louches et al. conducted a prospective longitudinal study of a consecutive sample of 28 heart transplant patients, finding 21% developed viraemia and 43% developed viruria; two of the five viraemic patients developed renal impairment [36]. Application of these data to lung transplant recipients is difficult. We believe that the optimal approach at this time is to monitor renal function in lung transplant recipients regularly and to test for BKV when there is persistent renal dysfunction of uncertain cause; however, we feel there is insufficient evidence to support routine surveillance for BKV viraemia in all lung transplant recipients. BKV viruria is relatively common in this patient population and does not appear to be sufficiently correlated with end-organ disease to warrant its use as a surveillance measure. Biopsy remains important for many reasons including rare cases of nephropathy from other polyomaviruses [37].\n\nBKV is a rare but important cause of disease in lung transplant recipients with manifestations including BKVAN, haemorrhagic cystitis and urothelial carcinoma. Research could examine factors causing BKV reactivation and disease in these patients; it is interesting to consider whether donor-positive to recipient-negative serostatus might be a risk factor and, if so, whether this would imply BKV transmission via lung transplantation. The optimal approach to diagnosis is unclear and the role of screening requires further investigation. Improved treatments are required and may include allogeneic polyomavirus-specific T cell therapy.\n\nAbbreviations\nBKVBK virus\n\nBKVANBK virus-associated nephropathy\n\nPCRPolymerase chain reaction\n\nIHCImmunohistochemistry\n\nSV40Simian virus 40\n\nJCVJC virus\n\nIVIGIntravenous immunoglobulin\n\nIQRInterquartile range\n\nCOPDChronic obstructive pulmonary disease\n\nFEV1Forced expiratory volume in 1 s\n\nCMVCytolomegalovirus\n\nGFRGlomerular filtration rate\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNone.\n\nAuthors’ contributions\nTC collected the data and drafted the manuscript. JN extensively reviewed the manuscript, provided histology slides for inclusion and provided expert pathologist input. RF extensively reviewed the manuscript and provided input from a nephrology perspective. MH and CLHL both extensively reviewed the manuscript and provided input from a lung transplantation perspective. All authors have read and approved the manuscript.\n\nFunding\nNo external funding was obtained for the preparation of this case report.\n\nAvailability of data and materials\nAll relevant data for this case are shared in this manuscript. Further provision of data will not be contemplated due to the priority of patient confidentiality.\n\nEthics approval and consent to participate\nWritten patient consent has been obtained for the publication of this manuscript and associated images. Given that the preparation of this case report only required retrospective review of existing clinical data, ethics approval from an ethics committee was not required.\n\nConsent for publication\nWritten patient consent has been obtained for the publication of this manuscript and associated images.\n\nCompeting interests\nThe authors declare that they have no completing interests.\n==== Refs\nReferences\n1. Viswesh V, Yost SE, Kaplan B. The prevalence and implications of BK virus replication in non-renal solid organ transplant recipients: A systematic review. Transplant Rev (Orlando). 2015;29(3):175–180. doi: 110.1016/j.trre.2015.1002.1004. Epub 2015 Feb 1024.\n2. Knowles WA, Pipkin P, Andrews N, et al. Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol. 2003;71(1):115–123. doi: 110.1002/jmv.10450.\n3. Polo C, Perez JL, Mielnichuck A, Fedele CG, Niubo J, Tenorio A. 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Polyomavirus nephropathy: quantitative urinary polyomavirus-Haufen testing accurately predicts the degree of intrarenal viral disease. Transplantation. 2015;99(3):609–615. doi: 610.1097/TP.0000000000000367.\n16. Wiseman AC. Polyomavirus nephropathy: a current perspective and clinical considerations. Am J Kidney Dis. 2009;54(1):131–142. doi: 110.1053/j.ajkd.2009.1001.1271. Epub 2009 Apr 1025.\n17. Moscarelli L, Caroti L, Antognoli G, et al. Everolimus leads to a lower risk of BKV viremia than mycophenolic acid in de novo renal transplantation patients: a single-center experience. Clin Transplant. 2013;27(4):546–554. doi: 510.1111/ctr.12151. Epub 12013 Jun 12113.\n18. Wojciechowski D, Chandran S, Webber A, Hirose R, Vincenti F. Mycophenolate mofetil withdrawal with conversion to everolimus to treat BK virus infection in kidney transplant recipients. Transplant Proc. 2017;49(8):1773–1778. doi: 1710.1016/j.transproceed.2017.1706.1030.\n19. Knoll GA, Humar A, Fergusson D, et al. Levofloxacin for BK virus prophylaxis following kidney transplantation: a randomized clinical trial. JAMA. 2014;312(20):2106–2114. doi: 2110.1001/jama.2014.14721.\n20. Papanicolaou GA, Lee YJ, Young JW, et al. Brincidofovir for polyomavirus-associated nephropathy after allogeneic hematopoietic stem cell transplantation. Am J Kidney Dis. 2015;65(5):780–784. doi: 710.1053/j.ajkd.2014.1011.1020. Epub 2015 Jan 1017.\n21. Tzannou I, Papadopoulou A, Naik S, et al. Off-the-shelf virus-specific T cells to treat BK Virus, Human herpesvirus 6, cytomegalovirus, epstein-barr virus, and adenovirus infections after allogeneic hematopoietic stem-cell transplantation. J Clin Oncol. 2017;35(31):3547–3557. doi: 3510.1200/JCO.2017.3573.0655. Epub 2017 Aug 3547.\n22. Schwarz A, Mengel M, Haller H, Niedermeyer J. Polyoma virus nephropathy in native kidneys after lung transplantation. Am J Transplant. 2005;5(10):2582–2585. doi: 2510.1111/j.1600–6143.2005.01043.x.\n23. Egli A, Helmersen DS, Taub K, Hirsch HH, Johnson A. Renal failure five years after lung transplantation due to polyomavirus BK-associated nephropathy. Am J Transplant. 2010;10(10):2324–2330. doi: 2310.1111/j.1600–6143.2010.03265.x. Epub 02010 Sep 03214.\n24. Dufek S, Haitel A, Muller-Sacherer T, Aufricht C. Duct Bellini carcinoma in association with BK virus nephropathy after lung transplantation. J Heart Lung Transplant. 2013;32(3):378–379. doi: 310.1016/j.healun.2012.1011.1033. Epub 2013 Jan 1012.\n25. Sharma SG, Nickeleit V, Herlitz LC, et al. BK polyoma virus nephropathy in the native kidney. Nephrol Dial Transplant. 2013;28(3):620–631. doi: 610.1093/ndt/gfs1537. Epub 2012 Dec 1018.\n26. Vigil D, Konstantinov NK, Barry M, et al. BK nephropathy in the native kidneys of patients with organ transplants: clinical spectrum of BK infection. World J Transplant. 2016;6(3):472–504. doi: 410.5500/wjt.v5506.i5503.5472.\n27. Kuppachi S, Holanda D, Eberlein M, et al. An unexpected surge in plasma BKPyV viral load heralds the development of BKPyV-Associated metastatic bladder cancer in a lung transplant recipient with BKPyV nephropathy. Am J Transplant. 2017;17(3):813–818. doi: 810.1111/ajt.14057. Epub 12016 Oct 14021.\n28. Okumura J, Nakahara Y, Nakaguro M, et al. BK virus-associated viruria and viremia in a patient with lymphangioleiomyomatosis after lung re-transplantation: A case report and review of the literature on BK virus infection post-lung transplantation. J Infect Chemother. 2019;25(10):820–824. doi: 810.1016/j.jiac.2019.1004.1002. Epub 2019 Apr 1023.\n29. Elidemir O, Chang IF, Schecter MG, Mallory GB. BK virus-associated hemorrhagic cystitis in a pediatric lung transplant recipient. Pediatr Transplant. 2007;11(7):807–810. doi: 810.1111/j.1399–3046.2007.00778.x.\n30. Barton TD, Blumberg EA, Doyle A, et al. A prospective cross-sectional study of BK virus infection in non-renal solid organ transplant recipients with chronic renal dysfunction. Transpl Infect Dis. 2006;8(2):102–107. doi: 110.1111/j.1399–3062.2006.00155.x.\n31. Thomas LD, Vilchez RA, White ZS, et al. A prospective longitudinal study of polyomavirus shedding in lung-transplant recipients. J Infect Dis. 2007;195(3):442–449. doi: 410.1086/510625. Epub 512006 Dec 510622.\n32. Doucette KE, Pang XL, Jackson K, et al. Prospective monitoring of BK polyomavirus infection early posttransplantation in nonrenal solid organ transplant recipients. Transplantation. 2008;85(12):1733–1736. doi: 1710.1097/TP.1730b1013e3181722ead.\n33. Thomas LD, Milstone AP, Vilchez RA, Zanwar P, Butel JS, Dummer JS. Polyomavirus infection and its impact on renal function and long-term outcomes after lung transplantation. Transplantation. 2009;88(3):360–366. doi: 310.1097/TP.1090b1013e3181ae1095ff1099.\n34. Razonable RR, Brown RA, Humar A, Covington E, Alecock E, Paya CV. A longitudinal molecular surveillance study of human polyomavirus viremia in heart, kidney, liver, and pancreas transplant patients. J Infect Dis. 2005;192(8):1349–1354. doi: 1310.1086/466532. Epub 462005 Sep 466514.\n35. Salama M, Boudville N, Speers D, Jeffrey GP, Ferrari P. Decline in native kidney function in liver transplant recipients is not associated with BK virus infection. Liver Transpl. 2008;14(12):1787–1792. doi: 1710.1002/lt.21627.\n36. Loeches B, Valerio M, Palomo J, Bouza E, Munoz P. BK virus in heart transplant recipients: a prospective study. J Heart Lung Transplant. 2011;30(1):109–111. doi: 110.1016/j.healun.2010.1008.1028. Epub 2010 Oct 1016.\n37. Milstone A, Vilchez RA, Geiger X, Fogo AB, Butel JS, Dummer S. Polyomavirus simian virus 40 infection associated with nephropathy in a lung-transplant recipient. Transplantation. 2004;77(7):1019–1024. doi: 1010.1097/1001.tp.0000119156.0000152197.ca.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "20(1)",
"journal": "BMC infectious diseases",
"keywords": "BK virus; Case report; End-stage renal failure; Lung transplantation; Nephropathy",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D001739:BK Virus; D004279:DNA, Viral; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D016040:Lung Transplantation; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D009173:Mycophenolic Acid; D027601:Polyomavirus Infections; D029424:Pulmonary Disease, Chronic Obstructive; D014412:Tumor Virus Infections",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "600",
"pmc": null,
"pmid": "32795251",
"pubdate": "2020-08-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23758330;20952211;29279304;17205484;16162212;19025923;15214877;25399012;16734633;30859620;30343190;19394729;19667938;15707414;12858417;25136849;19158358;27683628;29748530;28783452;16170751;15087764;31027885;22511874;25736693;28923623;26474168;20840474;17910663;19352121;27647675;25600489;23249622;23137180;18580464;23321158",
"title": "BK virus-associated nephropathy in a lung transplant patient: case report and literature review.",
"title_normalized": "bk virus associated nephropathy in a lung transplant patient case report and literature review"
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"abstract": "Benzodiazepines (BZDs) are central nervous system (CNS) depressants which are widely used to treat insomnia and anxiety, despite having long-term adverse side effects. (Fortea González, Oriolo, Balcells Oliveró, Sánchez Del Valle & Castellvi, 2017). As with alcohol, continued use can lead to tolerance and dependence phenomena. Discontinuation in such cases can produce abstinence symptoms such as tremors, anxiety, seizures and, occasionally, death (Brett y Murnion, 2015).",
"affiliations": "Hospital Clínic i Universitari de Barcelona. coliveras@clinic.cat.",
"authors": "Oliveras|Clara|C|;Fortea|Adriana|A|;Espinosa|Laura|L|;Barrio|Pablo|P|;Lligoña|Anna|A|;Balcells-Olivero|Mercè|M|",
"chemical_list": "D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; D003975:Diazepam",
"country": "Spain",
"delete": false,
"doi": "10.20882/adicciones.1058",
"fulltext": null,
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"issn_linking": "0214-4840",
"issue": "30(2)",
"journal": "Adicciones",
"keywords": null,
"medline_ta": "Adicciones",
"mesh_terms": "D000437:Alcoholism; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; D003975:Diazepam; D005260:Female; D006801:Humans; D008875:Middle Aged; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "9605506",
"other_id": null,
"pages": "155-157",
"pmc": null,
"pmid": "29353302",
"pubdate": "2018-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "\"Diazepam loading\": ¿Can a strategy for preventing alcohol withdrawal be used to treat benzodiazepine use disorder?",
"title_normalized": "diazepam loading can a strategy for preventing alcohol withdrawal be used to treat benzodiazepine use disorder"
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"abstract": "BACKGROUND\nAntimicrobial susceptibility of Helicobacter (H.) pylori is usually determined by phenotypic methods. When H. pylori cannot be grown owing to contaminations or delay in transport of gastric tissue samples to the microbiological laboratory, molecular genetic testing is a reasonable alternative. The aim of this retrospective study was to assess the outcome of salvage eradication treatments based on molecular genetic susceptibility testing.\n\n\nMETHODS\nData on 144 H. pylori PCR-positive gastric tissue samples of patients primarily with prior unsuccessful eradication treatments were retrospectively analyzed. Eradication treatments were recommended based on genotypic clarithromycin and/or levofloxacin susceptibility as tested by real-time PCR or reverse hybridization. Treatment success was assessed by attending physicians using urea breath test; stool-antigen ELISA; and microbiology/histopathology.\n\n\nRESULTS\nOverall success rate of molecular genetic testing-guided salvage treatments was low (68%); none of the regimens chosen was significantly better than another. Multivariable logistic regression analysis did not reveal any factors that may predict treatment failure.\n\n\nCONCLUSIONS\nEradication success was poor despite susceptibility testing. Gastroenterologists are advised to prescribe recommended salvage treatments, considering recommended dosages and prolonged treatment duration.",
"affiliations": "Faculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center-University of Freiburg, Freiburg, Germany.;Faculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center-University of Freiburg, Freiburg, Germany.;Faculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center-University of Freiburg, Freiburg, Germany.;Faculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center-University of Freiburg, Freiburg, Germany.",
"authors": "Blümel|Benjamin|B|;Goelz|Hanna|H|;Kist|Manfred|M|;Glocker|Erik-Oliver|EO|http://orcid.org/0000-0002-7829-6281",
"chemical_list": "D000900:Anti-Bacterial Agents; D064704:Levofloxacin; D017291:Clarithromycin",
"country": "England",
"delete": false,
"doi": "10.1111/hel.12494",
"fulltext": null,
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"issn_linking": "1083-4389",
"issue": "23(4)",
"journal": "Helicobacter",
"keywords": "\nPCR\n; Helicobacter pylori infection; eradication therapy; genotyping; resistance",
"medline_ta": "Helicobacter",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D017291:Clarithromycin; D024881:Drug Resistance, Bacterial; D005260:Female; D016481:Helicobacter Infections; D016480:Helicobacter pylori; D006801:Humans; D064704:Levofloxacin; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009154:Mutation; D012189:Retrospective Studies; D016879:Salvage Therapy; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9605411",
"other_id": null,
"pages": "e12494",
"pmc": null,
"pmid": "29873430",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Retrospective study on outcome of salvage Helicobacter pylori eradication therapies based on molecular genetic susceptibility testing.",
"title_normalized": "retrospective study on outcome of salvage helicobacter pylori eradication therapies based on molecular genetic susceptibility testing"
} | [
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"companynumb": "DE-MYLANLABS-2018M1084695",
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"activesubstancename": "CLARITHROMYCIN"
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"abstract": "A 75-year-old man presented with shortness of breath and somnolence and was found to have urosepsis. Blood and urine cultures subsequently grew multidrug-resistant (MDR) Klebsiella pneumoniae (Kp) with the New Delhi metallo-β-lactamase gene. The patient was treated successfully with plazomicin and meropenem/vaborbactam combination therapy. The course was complicated by acute kidney injury temporarily requiring haemodialysis, gastrointestinal bleed requiring multiple transfusions and hospital readmission with blood cultures again positive with MDR Kp. Plazomicin drug levels were persistently high during treatment, suggesting that therapeutic drug monitoring may be needed to safely use this drug in patients with severe renal dysfunction. This case marks the first use of plazomicin for bacteraemia in the literature outside of a clinical trial and demonstrates its safe and effective use in a patient with advanced renal disease, and provides important insights about dosing and therapeutic drug monitoring considerations in this patient population.",
"affiliations": "Department of Medicine, VA Boston Healthcare System, West Roxbury, Massachusetts, USA wearle@bidmc.harvard.edu.;Department of Medicine, VA Boston Healthcare System, West Roxbury, Massachusetts, USA.;Department of Pharmacy, VA Boston Healthcare System, West Roxbury, Massachusetts, USA.;Department of Medicine, Section of Infectious Diseases, VA Boston Healthcare System, West Roxbury, Massachusetts, USA.",
"authors": "Earle|William|W|;Bonegio|Ramón G B|RGB|;Smith|Donald B|DB|;Branch-Elliman|Westyn|W|",
"chemical_list": "D000900:Anti-Bacterial Agents; C550938:plazomicin; D012853:Sisomicin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-243609",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(8)",
"journal": "BMJ case reports",
"keywords": "acute renal failure; infections; safety; urinary tract infections",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D007709:Klebsiella; D008297:Male; D051436:Renal Insufficiency, Chronic; D017582:Renal Replacement Therapy; D012853:Sisomicin",
"nlm_unique_id": "101526291",
"other_id": null,
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"pmid": "34413038",
"pubdate": "2021-08-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Plazomicin for the treatment of multidrug-resistant Klebsiella bacteraemia in a patient with underlying chronic kidney disease and acute renal failure requiring renal replacement therapy.",
"title_normalized": "plazomicin for the treatment of multidrug resistant klebsiella bacteraemia in a patient with underlying chronic kidney disease and acute renal failure requiring renal replacement therapy"
} | [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PLAZOMICIN"
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... |
{
"abstract": "This study aimed to compare the analgesic effect, patients' satisfaction, tolerance and hip-joint function recovery by preoperative meloxicam versus postoperative meloxicam in treating hip osteoarthritis (OA) patients receiving total hip arthroplasty (THA). 132 hip OA patients who underwent THA surgery were allocated into postoperative analgesia (POST) and preoperative analgesia (PRE) groups at a 1:1 ratio. In the PRE group, patients took meloxicam 15 mg at 24 h pre-operation, 7.5 mg at 4 h, 24 h, 48 h and 72 h post-operation; in the POST group, patients received meloxicam 15 mg at 4 h post-operation, then 7.5 mg at 24 h, 48 h and 72 h post-operation. Furthermore, postoperative pain, consumption of patient-controlled analgesia (PCA), overall satisfaction and adverse events were evaluated within 96 h post-operation; meanwhile, Harris hip score was assessed within 6 months post-operation. Pain VAS at rest at 6 h, 12 h, 24 h, and pain VAS at passive movement at 6 h, 12 h were decreased in PRE group compared to POST group. In addition, additional consumption of PCA and the total consumption of PCA were both reduced in PRE group compared to POST group. Additionally, overall satisfaction in PRE group was higher at 24 h, 48 h and 72 h compared to POST group. While Harris hip score was of no difference between POST group and PRE group at M3 or M6. Besides, no difference in adverse events incidence was found between the two groups. In conclusion, preoperative meloxicam achieves better efficacy and similar tolerance compared to postoperative meloxicam in hip OA patients post THA.",
"affiliations": "Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 26, Shengli Street, Wuhan, 430014, People's Republic of China.;Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 26, Shengli Street, Wuhan, 430014, People's Republic of China.;Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 26, Shengli Street, Wuhan, 430014, People's Republic of China. haodunye9398649@163.com.;Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 26, Shengli Street, Wuhan, 430014, People's Republic of China.;Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 26, Shengli Street, Wuhan, 430014, People's Republic of China.",
"authors": "Ren|Lingyun|L|;Meng|Li|L|;Yan|Hong|H|http://orcid.org/0000-0003-1885-3872;Sun|Wei|W|;Yao|Dan|D|",
"chemical_list": "D000077239:Meloxicam",
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s10787-020-00718-2",
"fulltext": "\n==== Front\nInflammopharmacology\nInflammopharmacology\nInflammopharmacology\n0925-4692 1568-5608 Springer International Publishing Cham \n\n718\n10.1007/s10787-020-00718-2\nOriginal Article\nPreoperative meloxicam versus postoperative meloxicam for pain control, patients’ satisfaction and function recovery in hip osteoarthritis patients who receive total hip arthroplasty: a randomized, controlled study\nRen Lingyun Meng Li http://orcid.org/0000-0003-1885-3872Yan Hong haodunye9398649@163.com Sun Wei Yao Dan grid.33199.310000 0004 0368 7223Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 26, Shengli Street, Wuhan, 430014 People’s Republic of China \n6 6 2020 \n6 6 2020 \n2020 \n28 4 831 838\n6 3 2020 29 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/.This study aimed to compare the analgesic effect, patients’ satisfaction, tolerance and hip-joint function recovery by preoperative meloxicam versus postoperative meloxicam in treating hip osteoarthritis (OA) patients receiving total hip arthroplasty (THA). 132 hip OA patients who underwent THA surgery were allocated into postoperative analgesia (POST) and preoperative analgesia (PRE) groups at a 1:1 ratio. In the PRE group, patients took meloxicam 15 mg at 24 h pre-operation, 7.5 mg at 4 h, 24 h, 48 h and 72 h post-operation; in the POST group, patients received meloxicam 15 mg at 4 h post-operation, then 7.5 mg at 24 h, 48 h and 72 h post-operation. Furthermore, postoperative pain, consumption of patient-controlled analgesia (PCA), overall satisfaction and adverse events were evaluated within 96 h post-operation; meanwhile, Harris hip score was assessed within 6 months post-operation. Pain VAS at rest at 6 h, 12 h, 24 h, and pain VAS at passive movement at 6 h, 12 h were decreased in PRE group compared to POST group. In addition, additional consumption of PCA and the total consumption of PCA were both reduced in PRE group compared to POST group. Additionally, overall satisfaction in PRE group was higher at 24 h, 48 h and 72 h compared to POST group. While Harris hip score was of no difference between POST group and PRE group at M3 or M6. Besides, no difference in adverse events incidence was found between the two groups. In conclusion, preoperative meloxicam achieves better efficacy and similar tolerance compared to postoperative meloxicam in hip OA patients post THA.\n\nKeywords\nHip osteoarthritisTotal hip arthroplastyPreoperativeMeloxicamPain controlissue-copyright-statement© Springer Nature Switzerland AG 2020\n==== Body\nIntroduction\nOsteoarthritis (OA) is a common degenerative joint disease and is one of the most predominant causes of pain and physical inactivity in the worldwide population (Aresti et al. 2016; Skou et al. 2019). Among the total OA cases, articulatio coxae, also named as hip joint, is the second most frequently involved joint, resulting in chronic pain in patients’ outer hip, groin, and sometimes extends to the knee, and the pain often aggravates as the disease progresses (Aresti et al. 2016). Therapeutic modalities for hip OA patients include physical exercise, weight management, non-steroidal anti-inflammatory drugs (NSAIDs) or other analgesics, sodium hyaluronate injection and surgery (Migliore and Anichini 2017; Murphy et al. 2016; Skou and Roos 2019). Among all the treatment options mentioned above, total hip arthroplasty (THA) surgery is the gold standard for hip OA patients with severe disease conditions with satisfactory efficacy in improving the function of hip joint (Shon et al. 2019).\n\nReducing pain after THA surgery and maintaining the function recovery have always been the cornerstones of hip OA management in the clinical setting, as most of the patients would experience pain after receiving THA, and normally the pain could be moderate or even severe that notably harms the patients’ quality of life (Gan et al. 2003; Myles et al. 2000). Intravenous patient-controlled analgesia (PCA) is commonly applied for postoperative pain control in hip OA patients who receive THA, and several analgesics are frequently applied in PCA, such as the opioid drugs (Fan et al. 2018). However, excessive use of PCA may contribute to opioid drug overuse, which subsequently results in several adverse events, for instance, nausea and vomiting. Thereby, in hip OA patients who undergo THA, it is of note to explore a treatment strategy to achieve sufficient pain control and reduced adverse events at the same time. Meloxicam, a kind of NSAIDs, contributes a lot to the pain control in many diseases related to arthritis with good efficacy and tolerance (Park et al. 2014; Ruperto et al. 2005). In recent years, there have been accumulating studies revealing favorable efficiency of preoperative meloxicam in relieving pain post orthopedic surgeries (Hou et al. 2019; Shantiaee et al. 2017). Nevertheless, the efficacy of preoperative meloxicam for relieving pain in hip OA patients receiving THA is still unclear.\n\nThus, this randomized, controlled study aimed to compare the efficacy and safety of preoperative meloxicam versus postoperative meloxicam in treating hip OA patients who received THA.\n\nMaterials and methods\nPatients\nA total of 132 hip OA who scheduled to receive THA surgery, between Jan. 2017 and Dec. 2018 were consecutively enrolled in this randomized, controlled study. The inclusion criteria were: (1) diagnosed as hip OA by clinical and imaging findings; (2) age above 18 years; (3) appropriate and scheduled to receive THA surgery; (4) American Society of Anesthesiology (ASA) physical status I–II. Meanwhile, the exclusion criteria were: (1) hypersensitivity to NSAIDs; (2) usage of corticosteroid medication or chronic opioids within 3 months; (3) usage of analgesic drugs within 7 days; (4) uncontrolled hypertension during rest at two repeated measurements; (5) severe heart, kidney or liver dysfunction (6) recent major trauma or systemic infection within 3 months; (7) history of hip surgery; (8) history of bleeding or coagulation disorders; (9) history of gastrointestinal ulceration or dyspepsia.\n\nEthics approval\nThis study was approved by the Ethics Committee of our hospital, and was conducted in line with the Declaration of Helsinki. Meanwhile, all patients provided written informed consents before enrollment.\n\nSample size calculation\nBased on the primary outcome of pain visual analogue scale score (VAS) at rest, we assumed that pain VAS at rest was 2.0 ± 0.5 and 2.3 ± 0.5 in the preoperative analgesia group (PRE group) and postoperative analgesia group (POST group), respectively. Subsequently, according to a power of 90% (β), a 5% level of significance (α) with double side and a sample size ratio of 1:1, the smallest sample size was required to be 60 in each group. Meanwhile, considering a 10% drop-out rate, the smallest sample size was set to 66 in each group with a total of 132 in the study.\n\nRandomization\nAfter enrollment, 132 hip OA patients were randomly allocated to PRE group (N = 66) and POST group (N = 66) as a 1:1 ratio based on blocked randomization method with block length of 6. The randomized code was generated by SAS 9.0 software (Statistical Analysis System, USA), and the execution of randomization was conducted by a third company (H&J CRO International, Inc., Shanghai, China).\n\nTreatment\nAfter randomization, in PRE group, patients received meloxicam (Boehringer Ingelheim, German) as follows (Shao et al. 2019): 15 mg (oral) at 24 h pre-operation, 7.5 mg (oral) at 4 h, 24 h, 48 h and 72 h post-operation, respectively; while in POST group, patients received meloxicam (Boehringer Ingelheim, German) as follows (Shao et al. 2019): 15 mg (oral) at 4 h post-operation, then 7.5 mg (oral) at 24 h, 48 h and 72 h post-operation, respectively. Besides, as a routine, all patients in both two groups received 0.1 mg fentanyl (Yichang Humanwell Pharmaceutical Co., LTD, China) and 6 mg tropisetron mesylate (Qilu Pharmaceutical Co., LTD, China) by intravenous injection as a loading dose of analgesia, followed by the application of intravenous PCA for 48 h post-operation. The PCA contained 100 mL solution complemented with 1 mg fentanyl (Yichang Humanwell Pharmaceutical Co., LTD, China), 50 mg tramadol (Qianjiang Pharmaceutical Co., LTD, China) and 6 mg tropisetron mesylate (Qilu Pharmaceutical Co., LTD, China), with a basal rate of 1.0 mL/h, a lock-out time of 15 min and a bolus dose of 0.5 mL.\n\nAssessments\nPain VAS at rest (0–10 point, 0 no pain, 10 worst pain) and pain VAS at passive movement (0–10 point, 0 no pain, 10 worst pain) were evaluated at the enrollment (Pre), 6 h (h), 12 h, 24 h, 48 h, 72 h, and 96 h post-operation. Meanwhile, the consumption of PCA was recorded during 96 h post-operation. Overall satisfaction (0–10 point, 0 worst satisfaction, 10 best satisfaction) was evaluated at 24 h, 48 h, 72 h, and 96 h post-operation. Besides, the adverse events (AEs) during 96 h intervention period were recorded. After the 96 h intervention period, patients were further followed up for 6 months (M), and Harris hip score was evaluated at the enrollment (Pre), M3 and M6.\n\nStatistics\nStatistical analysis was performed using SPSS Software Version 22.0 (IBM, USA), figures were made using GraphPad Software Version 7.00 (GraphPad, USA). Data were mainly exhibited as mean ± standard deviation or count (%). Comparisons between two groups were detected by the t test or Chi-square test. P < 0.05 was considered as significant.\n\nResults\nStudy flow\nA hundred and seventy-eight hip OA patients who planned to undergo THA surgery were screened, then 46 of them were excluded because of being incompatible with inclusions or meeting the exclusions (n = 29) and disagreement to sign the informed consents (n = 17) (Fig. 1). The remaining eligible 132 patients were enrolled and randomized as a 1:1 ratio into POST group (n = 66) and PRE group (n = 66), respectively. The study was separated into two stages: 96-h intervention stage and the non-intervention follow-up stage. In the 96-h intervention stage, no one dropped out from POST group or PRE group; all 66 patients in POST group and all 66 patients in PRE group were included in the analyses of pain, consumption of PCA, overall satisfaction and AEs. Subsequently, in the non-intervention follow-up stage, all patients were followed up for 6 months post THA; in POST group, there were three patients who lost follow-up; in PRE group, there were two patients who lost follow up and one patient who died by accident. Finally, there were 63 patients who were included in the analysis of Harris hip score in each group.Fig. 1 Study flow chart\n\n\n\nThe characteristics of patients\nNo difference in patients’ characteristics was found between POST group and PRE group (all P > 0.05) (Table 1). The patients in our study had a mean age of 64.7 ± 7.9 years in POST group and 63.1 ± 8.4 years in PRE group. There were 29 (44.0%) males and 37 (56.0%) females in POST group, and 24 (36.4%) males as well as 42 (63.6%) females in PRE group, respectively. In addition, the mean BMI was 23.6 ± 2.2 kg/m2 in POST group and was 23.1 ± 2.4 kg/m2 in PRE group. Besides, pain VAS at rest and pain VAS at passive movement were 4.9 ± 1.2 and 6.2 ± 1.4 in POST group, and were 4.8 ± 1.3 as well as 6.3 ± 1.3 in PRE group, respectively. Moreover, the Harris hip score in average was 6.2 ± 1.4 in POST group and was 6.3 ± 1.3 in PRE group.Table 1 Patients’ characteristics\n\nParameters\tPOST group (N = 66)\tPRE group (N = 66)\tP value\t\nAge (years), mean ± SD\t64.7 ± 7.9\t63.1 ± 8.4\t0.310\t\nGender, No. (%)\t\t\t0.375\t\n Male\t29 (44.0)\t24 (36.4)\t\t\n Female\t37 (56.0)\t42 (63.6)\t\t\nBMI (kg/m2), mean ± SD\t23.6 ± 2.2\t23.1 ± 2.4\t0.253\t\nPain VAS at rest, mean ± SD\t4.9 ± 1.2\t4.8 ± 1.3\t0.647\t\nPain VAS at passive movement, mean ± SD\t6.2 ± 1.4\t6.3 ± 1.3\t0.672\t\nHarris hip score, mean ± SD\t42.6 ± 11.5\t41.3 ± 10.7\t0.502\t\nComparison was determined by t test or Chi-square test\n\nPOST group postoperative analgesia group, PRE group preoperative analgesia group, SD standard deviation, BMI body mass index, VAS visual analogue scale\n\n\n\nComparison of postoperative pain control\nIn the 96-h intervention stage, pain VAS at rest and pain VAS at passive movement gradually decreased over time in both POST group and PRE group. The pain VAS at rest in PRE group was decreased at 6 h (P < 0.001), 12 h (P = 0.005) and 24 h (P = 0.012), while was of no difference at 48 h (P = 0.058), 72 h (P = 0.207) or 96 h (P = 0.262) compared to the POST group (Fig. 2a). As for pain VAS at passive movement, it was declined in PRE group at 6 h (P = 0.017) and 12 h (P = 0.009), but did not vary at 24 h (P = 0.088), 48 h (P = 0.207), 72 h (P = 0.300) or 96 h (P = 0.613) compared to POST group (Fig. 2b). Moreover, the additional consumption of PCA was decreased in PRE group than that in POST group (P = 0.041), and the total consumption of PCA was also reduced in PRE group compared to POST group (P = 0.041) (Fig. 3).Fig. 2 Pain VAS at rest and pain VAS at passive movement. The comparison of pain VAS at rest (a) and pain VAS at passive movement (b) at Pre, 6 h, 12 h, 24 h, 48 h, 72 h and 96 h between the POST group and the PRE group. VAS visual analogue scale score, Pre enrollment, POST postoperative analgesia group, PRE preoperative analgesia group\n\nFig. 3 Consumption of PCA. The comparison of additional consumption of PCA and total consumption of PCA between the POST group and the PRE group. PCA patient-controlled analgesia, POST postoperative analgesia group, PRE preoperative analgesia group\n\n\n\nComparison of patients’ satisfaction\nIn the 96-h intervention stage, the patients’ satisfaction post-operation constantly increased along with time in both POST group and PRE group. More importantly, the overall satisfaction in the PRE group was elevated at 24 h (P = 0.006), 48 h (P = 0.028), and 72 h (P = 0.041) but was of no difference at 96 h (P = 0.097) compared to the POST group (Fig. 4).Fig. 4 Patients’ overall satisfaction. The comparison of overall satisfaction at 24 h, 48 h, 72 h and 96 h between the POST group and the PRE group. POST postoperative analgesia group, PRE preoperative analgesia group\n\n\n\nComparison of adverse events\nIn the 96-h intervention stage, no difference in the adverse events incidences was found between the PRE group and the POST group, which included nausea (P = 0.333), vomiting (P = 0.572), constipation (P = 0.730), urinary retention (P = 0.310), drowsiness (P = 0.541), dizziness (P = 0.541) and others (P = 1.000) (Table 2).Table 2 Adverse events\n\nParameters\tPOST group (N = 66)\tPRE group (N = 66)\tP value\t\nNausea, No. (%)\t21 (31.8)\t16 (26.6)\t0.333\t\nVomiting, No. (%)\t8 (12.1)\t6 (9.1)\t0.572\t\nConstipation, No. (%)\t4 (6.1)\t5 (7.6)\t0.730\t\nUrinary retention, No. (%)\t3 (4.5)\t1 (1.5)\t0.310\t\nDrowsiness, No. (%)\t2 (3.0)\t1 (1.5)\t0.541\t\nDizziness, No. (%)\t1 (1.5)\t2 (3.0)\t0.541\t\nOthers, No. (%)\t3 (4.5)\t3 (4.5)\t1.000\t\nComparison was determined by Chi-square test\n\nPOST group postoperative analgesia group, PRE group preoperative analgesia group\n\n\n\nComparison of hip joint function recovery\nIn the non-intervention stage, the Harris hip score was elevated deliberately over time within 6 months in both POST group and PRE group. Then the results displayed that the score at M3 (P = 0.175) and M6 (P = 0.376) was similar between PRE group and POST group (Fig. 5).Fig. 5 Harris hip score. The comparison of Harris hip score at Pre, M3 and M6 between the POST group and the PRE group. Pre enrollment, M3 3 months, M6 6 months, POST postoperative analgesia group, PRE preoperative analgesia group\n\n\n\nDiscussion\nIn the present study, the effect of preoperative meloxicam versus postoperative meloxicam regarding postoperative pain control, patients’ satisfaction, adverse events and recovery of hip joint in hip OA patients who received THA were assessed. Then the findings illustrated that in hip OA patients who received THA, compared to postoperative meloxicam: (a) preoperative meloxicam was superior at reducing pain VAS at rest and pain VAS at passive movement; in addition, it also decreased additional and total consumption of PCA; (b) preoperative meloxicam elevated overall satisfaction; (c) preoperative meloxicam did not increase the incidence of adverse events; (d) preoperative meloxicam had no effect on improving the Harris hip score.\n\nMeloxicam has been used for postoperative pain control for a long time, mostly in patients with arthritis, moreover, the preoperative use of meloxicam has been elucidated by several studies as a non-inferior modality compared to postoperative meloxicam for controlling the pain in patients with osteoarthritis post-surgery. A recent phase III randomized, multicenter, double-blind, placebo-controlled trial elucidates that meloxicam decreases the opioid use and does not increase the adverse events compared to placebo in patients with moderate-to-severe pain after major orthopedic surgeries (Sharpe et al. 2020). Another phase III, randomized, placebo-controlled study also reveals that meloxicam reduces opioid use and is evenly tolerable compared to placebo in patients with mild to severe pain after major orthopedic surgeries (Bergese et al. 2019). These studies uncover a good efficacy of meloxicam in controlling postoperative pain and its satisfactory tolerance in patients after various orthopedic surgeries. More importantly, in regard with the preoperative use of meloxicam, a previous study illuminates that preoperative meloxicam reduces pain VAS at rest, pain VAS at flexion, Physician's Global Assessment (PGA) score in knee OA patients who receive total knee arthroplasty (TKA) compared to postoperative use of meloxicam (Shao et al. 2019). In addition, another study reveals that early preoperative use of meloxicam diminishes pain VAS, PGA score, consumption of pethidine use compared with postoperative use of meloxicam in knee OA patients after arthroscopic knee surgery (AKS) (Hou et al. 2019). Furthermore, a prior study illustrates that very early preemptive meloxicam is more effective regarding reducing pain VAS at rest, pain VAS at flexion, and improving PGA score compared to early preemptive meloxicam as well as postoperative meloxicam in knee OA patients who receive AKS (Yuan et al. 2019). These findings all indicate a favorable efficiency and non-inferior tolerance of preoperative meloxicam in relieving postoperative pain in OA patients who receive orthopedic surgeries.\n\nAs for hip OA patients undergoing THA, the existed studies are very limited, and they all focus on researching the effect of preoperative meloxicam on preventing blood loss and heterotopic ossification in patients with hip OA after THA (Legenstein et al. 2003; van der Heide et al. 2004; Weber et al. 2003). To the best knowledge of ours, no study has been done to assess the effect of preoperative meloxicam on postoperative pain relieving in hip OA patients who receive THA. In the present study, we found that preoperative meloxicam reduced pain VAS at rest, pain VAS at passive movement and consumption of PCA compared to postoperative meloxicam in hip OA patients receiving THA. The possible explanations might include: patients in PRE group were treated with preoperative oral meloxicam and postoperative oral meloxicam, while patients in POST group were treated with only postoperative oral meloxicam. Therefore, in patients treated with preoperative meloxicam, the drug probably reached the concentration of stable state more quickly than patients treated with postoperative meloxicam; consequently, meloxicam could diminish painful stimulus and prevent the transmission of nerve impulse to the central nervous system more rapidly, which to some extend enabled a more favorable analgesic effect (Gates et al. 2005; Goncalves de Freitas et al. 2016). Besides, we also observed that the overall satisfaction was superior in patients receiving preoperative meloxicam compared to patients treated with postoperative meloxicam. And this result might derive from that the effect of pain control was more favorable in patients treated with preoperative meloxicam, which subsequently resulted in better patients’ satisfaction.\n\nMeloxicam has always been a tolerable NASIDs for pain and postoperative pain control in OA patients. For example, a previous randomized controlled study reveals that meloxicam achieves similar adverse events incidence compared to placebo in patients with moderate to severe pain after major orthopedic surgeries, which consist of injection-site reactions, bleeding, cardiovascular, hepatic, renal, thrombotic, and wound-healing events (Bergese et al. 2019). As for the pre-operation use of meloxicam in OA patients after surgery, a study reports that early preoperative meloxicam injection achieves evenly adverse events incidence compared to postoperative meloxicam injection in knee OA patients post-AKS, including nausea, constipation, vomiting, dizziness and drowsiness (Hou et al. 2019). Another study also illuminates similar results, which discloses that no difference is found regarding adverse events proportions between knee OA patients receiving TKA treated with preoperative meloxicam administration and patients treated with postoperative meloxicam administration (Shao et al. 2019). In this study, we found that the adverse events were mostly nausea, vomiting, constipation, urinary retention, drowsiness, dizziness, and the incidence of these adverse events post-THA were similar between patients treated with preoperative meloxicam and patients treated with postoperative meloxicam. These results indicated that preoperative meloxicam was as tolerable as postoperative meloxicam in hip OA patients who received THA.\n\nWith reference to the improvement of hip joint function recovery, there is still no study reporting the effect of preoperative meloxicam on it in hip OA patients after THA. In this study, we discovered that the hip joint function assessed by Harris hip score was of no difference between hip OA patients receiving THA treated with preoperative meloxicam and hip OA patients receiving THA treated with postoperative meloxicam. This result might derive from that there were other factors affecting the recovery of hip joint function, for instance, the physical exercise. Moreover, this insignificance might also result from the relatively small sample size and short observational period in our study.\n\nIn this study, the limitations might include: (a) the sample size of 132 patients was relatively small, which possibly contributed to a less strong statistical power in the analyses; (b) in the 96-h intervention stage, the patients, clinicians or researchers were not blinded, thus, there might be bias in our study; (c) the follow-up period was 6 months in the non-interventional follow-up stage, which was a little short for assessing the long-term recovery of hip joint function.\n\nCollectively, preoperative meloxicam is superior regarding postoperative pain control, patients’ satisfaction, and non-inferior in terms of safety as well as hip joint function recovery compared to postoperative meloxicam in treating hip OA patients who underwent THA.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nLingyun Ren and Li Meng contributed equally to this work.\n\nCompliance with ethical standards\nConflict of interest\nThe authors declare that they have no conflict of interest.\n==== Refs\nReferences\nAresti N Kassam J Nicholas N Achan P Hip osteoarthritis BMJ 2016 354 i3405 10.1136/bmj.i3405 27383835 \nBergese SD A Phase 3, randomized, placebo-controlled evaluation of the safety of intravenous meloxicam following major surgery Clin Pharmacol Drug Dev 2019 8 1062 1072 10.1002/cpdd.666 30786162 \nde Freitas AT Lemonica L De Faveri J Pereira S Bedoya Henao MD Preemptive analgesia with acupuncture monitored by c-Fos expression in rats J Acupunct Meridian Stud 2016 9 16 21 10.1016/j.jams.2015.08.002 26896072 \nFan ZR Ma J Ma XL Wang Y Sun L Wang Y Dong BC The efficacy of dexamethasone on pain and recovery after total hip arthroplasty: a systematic review and meta-analysis of randomized controlled trials Medicine (Baltimore) 2018 97 e0100 10.1097/MD.0000000000010100 29595631 \nGan TJ Consensus guidelines for managing postoperative nausea and vomiting Anesth Analg 2003 97 62 71 10.1213/01.ane.0000068580.00245.95 12818945 \nGates BJ Nguyen TT Setter SM Davies NM Meloxicam: a reappraisal of pharmacokinetics, efficacy and safety Expert Opin Pharmacother 2005 6 2117 2140 10.1517/14656566.6.12.2117 16197363 \nHou J Li W Chen Y Yang L Li L Zhao L Early preoperative versus postoperative administration of meloxicam in pain control, patient global status improvement, knee function recovery of arthroscopic knee surgery Medicine (Baltimore) 2019 98 e17133 10.1097/MD.0000000000017133 31577705 \nLegenstein R Bosch P Ungersbock A Indomethacin versus meloxicam for prevention of heterotopic ossification after total hip arthroplasty Arch Orthop Trauma Surg 2003 123 91 94 10.1007/s00402-003-0487-y 12664317 \nMigliore A Anichini S Intra-articular therapy in hip osteoarthritis Clin Cases Miner Bone Metab 2017 14 179 181 10.11138/ccmbm/2017.14.1.179 29263729 \nMurphy NJ Eyles JP Hunter DJ Hip osteoarthritis: etiopathogenesis and implications for management Adv Ther 2016 33 1921 1946 10.1007/s12325-016-0409-3 27671326 \nMyles PS Williams DL Hendrata M Anderson H Weeks AM Patient satisfaction after anaesthesia and surgery: results of a prospective survey of 10,811 patients Br J Anaesth 2000 84 6 10 10.1093/oxfordjournals.bja.a013383 10740539 \nPark HJ Park MC Park YB Lee SK Lee SW The concomitant use of meloxicam and methotrexate does not clearly increase the risk of silent kidney and liver damages in patients with rheumatoid arthritis Rheumatol Int 2014 34 833 840 10.1007/s00296-013-2920-z 24362788 \nRuperto N A randomized, double-blind clinical trial of two doses of meloxicam compared with naproxen in children with juvenile idiopathic arthritis: short- and long-term efficacy and safety results Arthritis Rheum 2005 52 563 572 10.1002/art.20860 15692986 \nShantiaee Y Javaheri S Movahhedian A Eslami S Dianat O Efficacy of preoperative ibuprofen and meloxicam on the success rate of inferior alveolar nerve block for teeth with irreversible pulpitis Int Dent J 2017 67 85 90 10.1111/idj.12272 27933616 \nShao Y Zhao X Zhai Y Yang J Wang S Liu L Wang J Comparison of analgesic effect, knee joint function recovery, and safety profiles between pre-operative and post-operative administrations of meloxicam in knee osteoarthritis patients who underwent total knee arthroplasty Ir J Med Sci 2019 10.1007/s11845-019-02128-y 31732867 \nSharpe KP Berkowitz R Tyndall WA Boyer D McCallum SW Mack RJ Du W Safety, tolerability, and effect on opioid use of meloxicam IV following orthopedic surgery J Pain Res 2020 13 221 229 10.2147/JPR.S216219 32021411 \nShon WY Park BY Park PS Im JT Yun HH Total hip arthroplasty: past, present, and future. What has been achieved? Hip Pelvis 2019 31 179 189 10.5371/hp.2019.31.4.179 31824872 \nSkou ST Roos EM Physical therapy for patients with knee and hip osteoarthritis: supervised, active treatment is current best practice Clin Exp Rheumatol 2019 120 112 117 \nSkou ST Gronne DT Roos EM Prevalence, severity, and correlates of pain flares in response to a repeated sit to stand activity: a cross-sectional study of 14,902 patients with knee and hip osteoarthritis in primary care J Orthop Sports Phys Ther 2019 10.2519/jospt.2019.9125 31492080 \nvan der Heide HJ Spruit M Slappendel R Klooster N van Limbeek J Prophylaxis for heterotopic ossification after primary total hip arthroplasty. A cohort study between indomethacin and meloxicam Acta Orthop Belg 2004 70 240 246 15287403 \nWeber EW Slappendel R Durieux ME Dirksen R van der Heide H Spruit M COX 2 selectivity of non-steroidal anti-inflammatory drugs and perioperative blood loss in hip surgery. A randomized comparison of indomethacin and meloxicam Eur J Anaesthesiol 2003 20 963 966 10.1017/s0265021503001558 14690098 \nYuan Y Cui D Zhang Y Preemptive meloxicam achieves a better effect on postoperative pain control and similar tolerance compared with postoperative meloxicam in patients receiving arthroscopic knee surgery Inflammopharmacology 2019 27 1091 1100 10.1007/s10787-019-00614-4 31254137\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0925-4692",
"issue": "28(4)",
"journal": "Inflammopharmacology",
"keywords": "Hip osteoarthritis; Meloxicam; Pain control; Preoperative; Total hip arthroplasty",
"medline_ta": "Inflammopharmacology",
"mesh_terms": "D019644:Arthroplasty, Replacement, Hip; D005260:Female; D006801:Humans; D008297:Male; D000077239:Meloxicam; D008875:Middle Aged; D015207:Osteoarthritis, Hip; D010146:Pain; D059408:Pain Management; D010147:Pain Measurement; D010149:Pain, Postoperative; D017060:Patient Satisfaction; D020127:Recovery of Function",
"nlm_unique_id": "9112626",
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"pages": "831-838",
"pmc": null,
"pmid": "32506275",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "31254137;29263729;31824872;30786162;12664317;29595631;31577705;32021411;15692986;31492080;15287403;31732867;27933616;26896072;24362788;31621559;12818945;14690098;10740539;27671326;27383835;16197363",
"title": "Preoperative meloxicam versus postoperative meloxicam for pain control, patients' satisfaction and function recovery in hip osteoarthritis patients who receive total hip arthroplasty: a randomized, controlled study.",
"title_normalized": "preoperative meloxicam versus postoperative meloxicam for pain control patients satisfaction and function recovery in hip osteoarthritis patients who receive total hip arthroplasty a randomized controlled study"
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"abstract": "Organ donor criteria continue to be extended in an attempt to meet growing demands. Patients with continuous-flow left ventricular assist devices are one group of potential donors being considered. One concern with this group is the effect of continuous flow for a prolonged duration, as opposed to normal pulsatile flow, on end-organ function. We report the 1st case of a liver transplantation from a donor who had a continuous-flow left ventricular assist device for 9 months. The recipient was a 69-year-old woman with a history of cryptogenic cirrhosis and hepatocellular carcinoma. The transplantation was complicated by moderate acute cellular rejection as well as biliary obstruction requiring sphincterotomy and stent placement. After management of those complications, the patient's liver function tests returned to normal values and remained stable at her 6-month post-transplantation follow-up. This case shows that organ transplantation from a donor with a continuous-flow left ventricular assist device for a prolonged period can be performed successfully.",
"affiliations": "Gill Heart Institute, University of Kentucky, Lexington, Kentucky. Electronic address: khalid.munawar@umm.edu.;Gill Heart Institute, University of Kentucky, Lexington, Kentucky.;Division of Digestive Health and Nutrition, University of Kentucky, Lexington, Kentucky.;Gill Heart Institute, University of Kentucky, Lexington, Kentucky.;Gill Heart Institute, University of Kentucky, Lexington, Kentucky.",
"authors": "Munawar|K|K|;Rajagopalan|N|N|;Grigorian|A|A|;Dennis|D|D|;Guglin|M|M|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.transproceed.2017.09.039",
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"issn_linking": "0041-1345",
"issue": "49(10)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000368:Aged; D006528:Carcinoma, Hepatocellular; D005260:Female; D006353:Heart-Assist Devices; D006801:Humans; D008103:Liver Cirrhosis; D017093:Liver Failure; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D014019:Tissue Donors; D016896:Treatment Outcome",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2406-2408",
"pmc": null,
"pmid": "29198691",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Liver Transplantation From a Donor With a Continuous-Flow Left Ventricular Assist Device for 9 Months.",
"title_normalized": "successful liver transplantation from a donor with a continuous flow left ventricular assist device for 9 months"
} | [
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"abstract": "We describe five cases of acneiform eruption caused by vitamin B12 in five females aged 37, 32, 62, 29, and 21 years, respectively. The eruption appeared from 1 week to 5 months after the beginning of the therapy with i.m. or oral vitamin B12. Clinical picture was characterized by papules and pustules located on the face. In three patients, similar lesions were also present on the neck, shoulders, chest, and upper portion of the back. Comedones and cysts were absent. In two patients, serum vitamin B12 levels were very high. Histopathologic examination in one patient revealed an eosinophilic folliculitis. Spontaneous and complete remission was observed in all patients 3-6 weeks after vitamin B12 discontinuation.",
"affiliations": "Department of Pathophysiology and Transplantation, Università degli Studi di Milano, I.R.C.C.S. Foundation, 'Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.;Department of Pathophysiology and Transplantation, Università degli Studi di Milano, I.R.C.C.S. Foundation, 'Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.;Department of Pathophysiology and Transplantation, Università degli Studi di Milano, I.R.C.C.S. Foundation, 'Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.;Department of Pathophysiology and Transplantation, Università degli Studi di Milano, I.R.C.C.S. Foundation, 'Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.",
"authors": "Veraldi|Stefano|S|;Benardon|Susanna|S|;Diani|Marco|M|;Barbareschi|Mauro|M|",
"chemical_list": "D014805:Vitamin B 12",
"country": "England",
"delete": false,
"doi": "10.1111/jocd.12360",
"fulltext": null,
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"issn_linking": "1473-2130",
"issue": "17(1)",
"journal": "Journal of cosmetic dermatology",
"keywords": "acne; acneiform eruptions; vitamin B12",
"medline_ta": "J Cosmet Dermatol",
"mesh_terms": "D017486:Acneiform Eruptions; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D008875:Middle Aged; D011379:Prognosis; D012075:Remission, Spontaneous; D018570:Risk Assessment; D014805:Vitamin B 12; D028761:Withholding Treatment; D055815:Young Adult",
"nlm_unique_id": "101130964",
"other_id": null,
"pages": "112-115",
"pmc": null,
"pmid": "28594082",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Acneiform eruptions caused by vitamin B12: A report of five cases and review of the literature.",
"title_normalized": "acneiform eruptions caused by vitamin b12 a report of five cases and review of the literature"
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"companynumb": "IT-ACCORD-068161",
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"d... |
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"abstract": "Subretinal fluid accumulation in a patient with systemic lupus erythematosus (SLE) may represent a diagnostic challenge. We present a case of a 43-year-old man with baseline diagnosis of SLE and hydroxychloroquine-associated maculopathy who reported progressive vision loss on the right eye, associated with corticosteroids use for an arthritic crisis. Ophthalmological examination did not reveal any acute finding. On optical coherence tomography, subretinal fluid in the perifoveal area was visible on the right eye, with corresponding enlargement of the visual field defect. An increased choroidal thickness was also visible. Fluorescein angiography revealed, on the right eye, two pinpoint areas of leakage and indocyanine green angiography signs of choroidal vascular hyperpermeability. Considering a diagnosis of a non-central central serous chorioretinopathy, corticosteroids use was interrupted, with resolution of the subretinal fluid. This case illustrates the relevance of a multimodal imaging approach to guide the diagnosis of patient with an SLE with subretinal fluid.",
"affiliations": "Ophthalmology, Centro Hospitalar de Lisboa Central EPE, Lisboa, Portugal cdiogo777@gmail.com.;Ophthalmology, Centro Hospitalar de Lisboa Central EPE, Lisboa, Portugal.;Ophthalmology, Centro Hospitalar de Lisboa Central EPE, Lisboa, Portugal.;Ophthalmology, Centro Hospitalar de Lisboa Central EPE, Lisboa, Portugal.",
"authors": "Hipolito-Fernandes|Diogo|D|http://orcid.org/0000-0002-5972-4068;Luís|Maria Elisa|ME|http://orcid.org/0000-0002-9361-089X;Flores|Rita|R|;Anjos|Rita|R|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; D006886:Hydroxychloroquine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-237243",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(1)",
"journal": "BMJ case reports",
"keywords": "macula; ophthalmology; retina",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D018501:Antirheumatic Agents; D018450:Disease Progression; D004359:Drug Therapy, Combination; D006801:Humans; D006886:Hydroxychloroquine; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D008297:Male; D012164:Retinal Diseases",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33462009",
"pubdate": "2021-01-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Non-central serous chorioretinopathy in a patient with systemic lupus erythematosus and hydroxychloroquine retinopathy.",
"title_normalized": "non central serous chorioretinopathy in a patient with systemic lupus erythematosus and hydroxychloroquine retinopathy"
} | [
{
"companynumb": "PT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-284064",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
... |
{
"abstract": "Peripheral neuropathy is the most common dose-limiting toxicity associated with oxaliplatin. We report on a 61-year-old female patient with advanced primary ampullary adenocarcinoma who received 35 cycles of FOLFIRINOX (5-fluorouracil, irinotecan, and oxaliplatin) chemotherapy. The patient has tolerated this treatment without developing significant peripheral neuropathy.",
"affiliations": "Division of Medical Oncology, Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.;Division of Medical Oncology, Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.",
"authors": "Bukhari|Nedal|N|;Winquist|Eric|E|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000477841",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000477841cro-0010-0577Case ReportChronic Oxaliplatin-Based Chemotherapy in a Primary Ampullary Adenocarcinoma Patient without Significant Peripheral Neuropathy: Case Report and Literature Review Bukhari Nedal ab*Winquist Eric aaDivision of Medical Oncology, Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, CanadabDepartment of Medical Oncology, King Fahad Specialist Hospital, Dammam, Saudi Arabia*Nedal Bukhari, MBBS, FRCPC, FACP, Division of Medical Oncology, Department of Oncology, Schulich School of Medicine and Dentistry, Western University, 790 Commissioners Road East, London, ON N6A 4L6 (Canada), E-Mail nedal.bukhari36@gmail.comMay-Aug 2017 29 6 2017 29 6 2017 10 2 577 581 29 5 2017 29 5 2017 Copyright © 2017 by S. Karger AG, Basel2017This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Peripheral neuropathy is the most common dose-limiting toxicity associated with oxaliplatin. We report on a 61-year-old female patient with advanced primary ampullary adenocarcinoma who received 35 cycles of FOLFIRINOX (5-fluorouracil, irinotecan, and oxaliplatin) chemotherapy. The patient has tolerated this treatment without developing significant peripheral neuropathy.\n\nKeywords\nOxaliplatinAmpullary adenocarcinomaPeripheral neuropathyFOLFIRINOXCarbohydrate antigen 19-9\n==== Body\nBackground\nOxaliplatin is a third-generation platinum agent that has been an integral part of the treatment of colorectal and certain pancreatobiliary malignancies. Oxaliplatin is given in combination with fluoropyrimidines such as 5-fluorouracil or capecitabine in the setting of colorectal cancer as adjuvant or palliative treatment [1, 2]. Oxaliplatin is widely used in combination with a 5-fluorouracil and irinotecan (FOLFIRINOX) regimen in advanced pancreatic cancer based on results from the ACCORD trial by Conroy et al. [3].\n\nOxaliplatin is also active in other pancreatobiliary malignancies such as cholangiocarcinomas and periampullary adenocarcinomas when given in combination with either fluoropyrimidines or gemcitabine [4, 5, 6].\n\nOxaliplatin is associated with mild hematological toxicities and gastrointestinal side effects are not uncommon, including nausea, vomiting, diarrhea, and abdominal pain. Drug-induced fever and hypersensitivity have been reported [6]. However, oxaliplatin-related neurotoxicity is by far the most common side effect and dose-limiting toxicity.\n\nCase Presentation\nA previously healthy 61-year-old Caucasian female presented with jaundice preceded by vague abdominal pain, anorexia, and weight loss for 3 weeks. Initial CT scans revealed findings highly suggestive of periampullary malignancy with dilated pancreatic and biliary ducts. Biopsy was consistent with primary ampullary adenocarcinoma. Staging revealed pulmonary metastases. Palliative biliary decompression was performed and resulted in significant symptomatic improvement. Baseline carbohydrate antigen 19-9 (CA 19-9) was 835 kU/L (normal <37 U/L); complete blood counts were within normal ranges. The AST level was 286 U/L (normal range 10–40 U/L), ALT 291 U/L (normal range 7–56 U/L), alkaline phosphatase 1,283 U/L (normal range 44–147 U/L), and total bilirubin 347 µmol/L (normal range 3–25 µmol/L). Palliative FOLFIRINOX chemotherapy started, with oxaliplatin dosed at 85 mg/m2. The patient had a significant clinical improvement after a few cycles of chemotherapy with a gradual decrease in her bilirubin, liver enzymes, and CA 19-9 level.\n\nObjective response to chemotherapy was noted after 12 cycles with significant shrinkage of the primary lesion and pulmonary metastases. She then took a break from chemotherapy and was monitored with clinical assessments, blood tests, and CT scans that continued to show stable disease for 9 months. Eventually, her cancer progressed and she restarted FOLFIRINOX. She again responded to treatment, confirmed by restaging a CT scan which showed an interval decrease in her primary lesion and metastases, and she subsequently took a second break from treatment.\n\nThe patient remained stable for almost 1 year until CT scans revealed disease progression with a significant raise in her CA 19-9. The decision was made to restart FOLFIRINOX treatment. She has now had 12 cycles, has shown further response to treatment supported by CT findings and declining CA 19-9 levels, and is currently on her third break from chemotherapy. The last treatment course was complicated by myelosuppression on a few occasions, causing a delay in treatment of no more than a week. This prompted dose reduction of FOLFIRINOX by 15–20%. Grade 1–2 acute sensory peripheral neuropathy lasting for 2–3 days was the only neurological side effect reported by the patient, with complete resolution prior to each cycle. This patient has had 35 cycles of FOLFIRINOX to date and she is likely to be rechallenged with the same regimen when her disease progresses. Tolerance of this amount of FOLFIRINOX without neuropathy is extremely rare.\n\nDiscussion\nOxaliplatin is associated with acute and chronic neurotoxicity. The acute form occurs in more than 85% of patients. Acute neurotoxicity usually develops rapidly within 24–72 h and may include sensory and motor findings like perioral paresthesia, pharyngolaryngeal dysesthesia, cold sensitivity, paresthesia and dysesthesia of the hands and feet, and muscle cramps. Patients may also experience jaw stiffness, dyspnea, dysphagia, and ocular changes [7, 8].\n\nOxaliplatin-induced acute neurotoxicity is thought to be secondary to chelation of calcium by oxalate (a metabolite of oxaliplatin), with transient activation of disinhibited peripheral nerve voltage-gated calcium-dependent sodium channels leading to hyperexcitability of peripheral nerves [9, 10, 11, 12, 13].\n\nAcute changes in axonal excitability are less noticeable with later treatment cycles, probably due to chronic nerve dysfunction and sensory loss, masking acute side effects at a higher cumulative dose.\n\nWith chronic neurotoxicity, cumulative sensory neurotoxicity is the dose-limiting toxicity of oxaliplatin. Typical symptoms are dysesthesia and paresthesia of the extremities of gradually prolonged duration, which eventually persist between treatment cycles and increase in intensity with the cumulative dose. This chronic neurotoxicity can severely affect activities of daily living. In an analysis of Alliance N08CB trial patients treated with oxaliplatin, tingling was the most severe symptom, followed by numbness and then pain [8].\n\nThe incidence and severity are predominantly related to cumulative dose, although other factors like preexisting diabetes and severity of acute neuropathy may contribute. Patients with more severe acute neurotoxicity during the first cycle of therapy may experience more chronic sensory toxicity [8].\n\nOxaliplatin-induced neurotoxicity improves after discontinuation of therapy in the majority of cases. However, it may continue to worsen for a few months after treatment is discontinued (coasting phenomenon). Neuropathy is at least partially reversible in approximately 80% of patients; half of these patients report complete resolution within 8 months after treatment discontinuation.\n\nCoasting phenomenon is when symptoms of peripheral sensory neurotoxicity start or worsen after oxaliplatin is discontinued. This phenomenon occurs in approximately 10–15% of patients completing oxaliplatin-based chemotherapy and is not well understood [7].\n\nThere are no agents recommended for the prevention of chemotherapy-induced peripheral neuropathy. For the treatment of symptomatic peripheral neuropathy, the best available data support a moderate recommendation for treatment with duloxetine. Other agents under investigation include tricyclic antidepressants (such as nortriptyline), gabapentin, and a compounded topical gel containing baclofen, amitriptyline HCL, and ketamine [14].\n\nThere are reports suggesting increased susceptibility to oxaliplatin-induced peripheral neuropathy with pharmacogenetic variations in genes encoding for drug transporters (ABCC1, ABCG1, and SLC22A2), detoxification enzymes (MPO, GSTA1, GSTM1/3, GSTP1, and GSTT1), DNA repair mechanisms (ERCC2, XPA, XRCC1, and ERCC1) and integrin β3 (an integral cell-surface protein known to participate in cell adhesion and in cell surface-mediated signaling) Leu33Pro polymorphism. Available data remain controversial and further research is required.\n\nConclusion\nThis case suggests that some patients with platinum-sensitive disease can tolerate prolonged courses of treatment with FOLFIRINOX without significant peripheral neuropathy. It also confirms that FOLFIRINOX is an active, safe, and well-tolerated option for patients with ampullary adenocarcinoma.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n==== Refs\nReferences\n1 Van Cutsem E Cervantes A Adam R Sobrero A Van Krieken JH Aderka D ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016 27 1386 27380959 \n2 André T Boni C Mounedji-Boudiaf L Navarro M Tabernero J Hickish T Topham C Zaninelli M Clingan P Bridgewater J Tabah-Fisch I de Gramont A Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004 350 23 \n3 Andre T Tournigand C Rosmorduc O Provent S Maindrault-Goebel F Avenin D Selle F Paye F Hannoun L Houry S Gayet B Lotz JP de Gramont A Louvet C GERCOR Group Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol 2004 15 1339 1343 15319238 \n4 Knox JJ Hedley D Oza A Feld R Siu LL Chen E Nematollahi M Pond GR Zhang J Moore MJ Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial. J Clin Oncol 2005 23 2332 2338 15800324 \n5 Conroy T Desseigne F Ychou M Bouché O Guimbaud R Bécouarn Y Adenis A Raoul J-L Gourgou-Bourgade S de la Fouchardière C Bennouna J Bachet J-B Khemissa-Akouz F Péré-Vergé D Delbaldo C Assenat E Chauffert B Michel P Montoto-Grillot C Chem M Ducreux M FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011 364 19 \n6 Ghosn M Kourie HR El Rassy E Haddad FG Hanna C El Karak F Nasr D Where does chemotherapy stands in the treatment of ampullary carcinoma? A review of literature. World J Gastrointest Oncol 2016 8 745 750 27795814 \n7 Grothey A Clinical management of oxaliplatin-associated neurotoxicity. Clin Colorectal Cancer 2005 5 (suppl 1) S38 S46 15871765 \n8 Argyriou AA Cavaletti G Briani C Velasco R Bruna J Campagnolo M Alberti P Bergamo F Cortinovis D Cazzaniga M Santos C Papadimitriou K Kalofonos HP Clinical pattern and associations of oxaliplatin acute neurotoxicity: a prospective study in 170 patients with colorectal cancer. Cancer 2013 119 438 22786764 \n9 Pachman DR Qin R Seisler DK Smith EM Beutler AS Ta LE Lafky JM Wagner-Johnston ND Ruddy KJ Dakhil S Staff NP Grothey A Loprinzi CL Clinical course of oxaliplatin-induced neuropathy: results from the randomized phase III trial N08CB (Alliance). J Clin Oncol 2015 33 3416 26282635 \n10 Park SB Lin CS Krishnan AV Goldstein D Friedlander ML Kiernan MC Oxaliplatin-induced neurotoxicity: changes in axonal excitability precede development of neuropathy. Brain 2009 132 (Pt 10) 2712 19745023 \n11 Grolleau F Gamelin L Boisdron-Celle M Lapied B Pelhate M Gamelin E A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels. J Neurophysiol 2001 85 2293 2297 11353042 \n12 Wilson RH Lehky T Thomas RR Quinn MG Floeter MK Grem JL Acute oxaliplatin-induced peripheral nerve hyperexcitability. J Clin Oncol 2002 20 1767 11919233 \n13 Park SB Lin CS Krishnan AV Goldstein D Friedlander ML Kiernan MC Dose effects of oxaliplatin on persistent and transient Na+ conductances and the development of neurotoxicity. PLoS One 2011 6 e18469 \n14 Hershman DL Lacchetti C Dworkin RH Lavoie Smith EM Bleeker J Cavaletti G Chauhan C Gavin P Lavino A Lustberg MB Paice J Schneider B Smith ML Smith T Terstriep S Wagner-Johnston N Bak K Loprinzi CL Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2014 32 1941 1967 24733808\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "10(2)",
"journal": "Case reports in oncology",
"keywords": "Ampullary adenocarcinoma; Carbohydrate antigen 19-9; FOLFIRINOX; Oxaliplatin; Peripheral neuropathy",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "577-581",
"pmc": null,
"pmid": "28868015",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "11353042;11919233;15175436;15319238;15800324;15871765;19745023;21494615;21561347;22786764;24733808;26282635;27380959;27795814",
"title": "Chronic Oxaliplatin-Based Chemotherapy in a Primary Ampullary Adenocarcinoma Patient without Significant Peripheral Neuropathy: Case Report and Literature Review.",
"title_normalized": "chronic oxaliplatin based chemotherapy in a primary ampullary adenocarcinoma patient without significant peripheral neuropathy case report and literature review"
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"companynumb": "CA-TEVA-815593USA",
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"occurcountry": "CA",
"patient": {
"drug": [
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"actiondrug": "2",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
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{
"abstract": "Stevens-Johnsons Syndrome (SJS) is an immune-complex-mediated hypersensitivity reaction and has been linked as an adverse side effects to many drugs. Lamotrigine, an anticonvulsive medication and also a commonly used mood stabiliser, can be associated with this adverse reaction. Although this has not been reported very commonly , SJS has high mortality and morbidity and requires careful attention as the use of Lamotrigine is increasing in clinical practice. We present a case where the patient developed Stevens - Johnson Syndrome three weeks after being started on Lamotrigine. The case is discussed for its relevance to the use of Lamotrigine which is currently prescribed very commonly in psychiatric practices.",
"affiliations": "Dr. Shama Parveen, The Medical Centre, Manor Court Avenue, Nuneaton, CV11 5HX, UK.;Dr. M. Afzal Javed, The Medical Centre, Manor Court Avenue, Nuneaton, CV11 5HX, UK.",
"authors": "Parveen|Shama|S|;Javed|M Afzal|MA|",
"chemical_list": null,
"country": "Pakistan",
"delete": false,
"doi": "10.12669/pjms.296.4385",
"fulltext": "\n==== Front\nPak J Med SciPak J Med SciPJMSPakistan Journal of Medical Sciences1682-024X1681-715XProfessional Medical Publicaitons Karachi, Pakistan pjms-29-1450Case ReportStevens Johnson Syndrome associated with Lamotrigine Parveen Shama 1Javed M. Afzal 21 Dr. Shama Parveen, The Medical Centre, Manor Court Avenue, Nuneaton, CV11 5HX, UK.2 Dr. M. Afzal Javed, The Medical Centre, Manor Court Avenue, Nuneaton, CV11 5HX, UK.Correspondence: Dr. M. Afzal Javed, The Medical Centre, Manor Court Avenue, Nuneaton, CV11 5HX, UK. E-mail: afzal@afzaljaved.co.ukNov-Dec 2013 29 6 1450 1452 15 8 2013 25 9 2013 26 9 2013 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Stevens-Johnsons Syndrome (SJS) is an immune-complex-mediated hypersensitivity reaction and has been linked as an adverse side effects to many drugs. Lamotrigine, an anticonvulsive medication and also a commonly used mood stabiliser, can be associated with this adverse reaction. Although this has not been reported very commonly , SJS has high mortality and morbidity and requires careful attention as the use of Lamotrigine is increasing in clinical practice. We present a case where the patient developed Stevens - Johnson Syndrome three weeks after being started on Lamotrigine. The case is discussed for its relevance to the use of Lamotrigine which is currently prescribed very commonly in psychiatric practices.\n\nKey Words\nStevens-Johnsons syndromeHypersensitivity reactionLamotrigine\n==== Body\nINTRODUCTION\nStevens–Johnson Syndrome (SJS), a dermatological emergency is a rare condition; with a reported incidence of around 2.6 to 6.1 cases per million people per year with a mortality rate of around 5%.1 SJS is named after two American pediatricians, Albert Mason Stevens and Frank Chambliss Johnson, who jointly published the first description of the disorder in the American Journal of Diseases of Children in 1922.2 Stevens-Johnson Syndrome (SJS) is an immune-complex-mediated hypersensitivity reaction that characteristically involves skin and mucous membrane. The main known cause is hypersensitivity to certain drugs, followed by infections and, rarely, cancers.3,4\n\nAlthough reported as a rare event Stevens–Johnson Syndrome (SJS) has been found to be more common in adults than in children. Women are affected more often than men, with cases occurring at a two to one (2:1) ratio. SJS is linked to a number of drugs, infections & carcinomas; people with AIDS are also at an increased risk of developing this disorder.1\n\n\nSJS and toxic epidermal necrolysis (TEN) are two forms of this life-threatening skin condition, in which cell death causes the epidermis to separate from the dermis. Toxic Epidermal Necrolysis (TEN) is a more severe form of SJS and may be associated with high morbidity and mortality. Toxic Epidermal Necrolysis (TEN) can be classified by the extent of body surface area detachment as SJS - A \"minor form of TEN,\" with less than 10% body surface area (BSA) detachment, Overlapping SJS/TEN - Detachment of 10-30% BSA and TEN - Detachment of more than 30% BSA.5\n\nClinical features of SJS include significant involvement of skin and oral, nasal, eye, vaginal, urethral, GI, and lower respiratory tract mucous membranes. Lesions may continue to erupt in crops for as long as 2-3 weeks. Skin rash can begin as macules that develop into papules, vesicles, bullae, urticarial plaques or confluent erythema. Bullous lesion can rupture and may lead to further complications. Mucosal involvement includes erythema, oedema, sloughing, blistering, ulceration and necrosis. GI and respiratory involvement may progress to necrosis. SJS is a serious systemic disorder with the potential for severe morbidity and even death. Whereas Toxic Epidermal Necrolysis has a higher mortality (30-35%); Stevens-Johnson Syndrome and transitional forms correspond to the same syndrome, but with less extensive skin detachment and a lower mortality (5-15%).6\n\nSJS has been commonly reported as an adverse reaction to a number of drugs, and carcinomas & infections have also been linked to its occurrence. Drug aetiologies include reaction to drugs including Penicillin, Sulphonamide, Phenytoin, Valproate, Carbamazepine, non-steroidal anti-inflammatory drugs, anti-malarial and allopurinol.7,8 Coxsackievirus, Echovirus, Herpes Simplex viruses and Mycoplasma infections have also been linked to this syndrome in some cases. Similarly SJS has also been associated with immunisation, e.g. measles and hepatitis B.9 However, in approximately 25 to 50 percent of cases no cause can be identified.\n\nAnti-epileptics as a group have been shown to cause SJS with variation in its association with individual anti epileptic medications.8 Although present data supports an association of SJS with combined use of all antiepileptic drugs, the data for individual drugs are not convincing because of small numbers of exposed patients and an inability to adjust for possible confounding variables.10 Among antiepileptic drugs, SJS has been generally reported with the use of Carbamazepine, Phenobarbital and Phenytoin especially during the early period or start of these medications (usually the first few days or few weeks). Lamotrigine, another commonly used antiepileptic drug and also an emerging treatment for Depression has not been well reported to be associated with SJS in medical literature although there have been some reports linking Lamotrigine with this syndrome. We are presenting a case where a patient developed SJS after 3-4 weeks of use of Lamotrigine. Although she showed significant improvement in her mental state after the addition of Lamotrigine, her initial response during the first 2-3 weeks did not show any signs of this syndrome.\n\nCASE REPORT\nThis 56 years old lady who has been known to the local mental health services for the past 20 years with symptoms of depression and anxiety was attending follow up appointments on and off. For her current episode she was in contact with the local team for the last few years and had presented with moderate to severe depression that needed regular follow up and review of her medication. She also had two inpatient hospital admissions to the psychiatric unit after attempting suicide on two occasions during this episode. During her latest admission, she was treated with different antidepressants and anxiolytics but without any major benefit. Because of the poor control of symptoms of depression, Lamotrigine was added to her other medications (Sertaline and Buspirone which she had been taking for many months). She was started on lamotrigine 25 mg daily which was gradually increased to 50 mg twice daily over the next 2 weeks. Her anxiety and depressive symptoms showed significant improvement on this combination and she started feeling almost back to her normal self. She was continued on this treatment & was discharged from the psychiatric inpatient unit on a combination of Lamotrigine 50mg twice a day, Sertaline 150 mg daily and Buspirone 5mg twice daily. At her weekly follow up, she continued showing improvement in her mental state and the treating team was very satisfied with her response to treatment.\n\nAbout 16 days following hospital discharge she developed conjunctivitis and over the next 3-4 days, developed swelling of the face and lips. She also developed erosion of the mucous membrane inside her mouth & erythematous papules and bullous eruptions over her body that were particularly bad on the palms of her hands and soles of her feet where she developed detachment of the epidermis. In view of her increasing symptoms, she had to be referred to the general hospital on the 4th day after developing these side effects. She was admitted for further treatment. She had to be treated in the Intensive Care Unit as her physical symptoms deteriorated over the next few days. All her routine blood tests were normal except C-Reactive Protein which was high. She was kept under the care of a medical specialist, ophthalmologist and dermatologist who agreed with the clinical diagnosis of Stevens - Johnson Syndrome. Lamotrigine, along with her other antidepressant medications was stopped. After a few days she started feeling better, made a full recovery in 2 weeks time and was discharged home. Her ophthalmic symptoms needed a few more weeks for full recovery.\n\nDISCUSSION\nLamotrigine is an anti epileptic medication which is also used as a mood stabilizer.11 Side effects of Lamotrigine generally include CNS symptoms like headache, fatigue, dizziness, sleep disturbance, tremor, movement disorder, agitation, confusion, hallucinations, Gastrointestinal symptoms like diarrhoea, nausea, vomiting, hepatic dysfunction and skin & cutaneous side effects like rash. Stevens-Johnson syndrome has also been mentioned as a rare hypersensitivity reaction/ side effect in the drug information pack of Lamotrigine characterised by severe rash, fever, lymphadenopathy, hepatic dysfunction, blood disorder, and Disseminated Intravascular Coagulation with multi organ dysfunction. \n\nHypersensitivity reactions can happen with almost all antiepileptic drugs with cutaneous side effects occurring in 3 to 10% patients and rash usually developing in the first few weeks in a small number of patients.8,12 It has also been mentioned that SJS can turn into more severe Toxic Epidermal Necrolysis (TEN).1,6 However not many reports have been published suggesting SJS as a common side effect of the use of Lamotrigene. SJS, on the other hand, has been reported from concomitant use of Valproic Acid and Lamotrigine13,14 and it is thought that Valproic Acid interferes with the metabolism of Lamotrigine by inhibiting glucuronide causing increased Lamotrigine blood levels.15,16 It has also been suggested that rapid dose escalation of Lamotrigine increases the risk of cutaneous rash.14,17,18\n\nIn our case, the patient was on Sertraline and Buspirone for many months and did not show any side effects suggestive of a drug reaction. There is also no evidence in the literature that either Sertraline or Buspirone can cause SJS or concomitant use of these medications with Lamotrigine increases the risk of SJS.\n\nRapid dose escalation is usually linked to the increased the risk of coetaneous side & dose escalation in our case was done as 25mg once daily for a week, followed by 50mg once daily for a week and then it was increased to 50mg twice daily. All her symptoms developed after about two week of being on Lamotrigine (50 mg twice daily dose).\n\nWe are reporting this case, since there is increasing use of Lamotrigine in psychiatry (especially as a mood stabilizer) and because of the rarity of Stevens–Johnson Syndrome (SJS) as an adverse effect of Lamotrigine. Mechanisms for Lamotrigine-induced SJS are less well understood but recent evidence suggests that antiepileptic drug-related hypersensitivity may be a consequence of chemotoxic and immunologically mediated injury; however, the pathogenesis of this reaction may vary somewhat among different antiepileptic drugs.19 It is very easy to forget about this important side effect which can have very high mortality and morbidity.\n\nThe risk of developing SJS with Lamotrigine is rare and relatively predictable during the first few weeks of its use; clinicians prescribing this medication should however be aware of this high risk condition. Current evidence indicates that although Lamotrigine may cause a serious rash for which clinicians must continue to observe standard new dosing paradigms & practice precautions, in the case of non-serious rash, a re-challenge with Lamotrigine can also be considered20 in many cases.\n==== Refs\nReferences\n1 Mockenhaupt M The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis Expert Rev Clin Immunol 2011 7 6 803 813 22014021 \n2 Stevens AM Johnson FC A new eruptive fever associated with stomatitis and ophthalmia; report of two cases in children Am J Dis Child 1922 24 526 533 \n3 Mockenhaupt M Schopf E Epidemiology of drug-induced severe skin reactions Semion Cutan Med Surg 1996 15 4 236 243 \n4 Ward KE Archambault R Mersfelder TL Severe adverse skin reactions to nonsteroidal anti inflammatory drugs: A review of the literature Am J Health Syst Pharm 2010 67 3 206 213 20101062 \n5 French LE Toxic epidermal necrolysis and Stevens Johnson syndrome: our current understanding Allergol Int 2006 55 1 9 16 17075281 \n6 Ghislain PD Roujeau JC Treatment of severe drug reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity syndrome Dermatol Online J 2002 8 1 5 12165215 \n7 Frittsch PO Sidoroff A Drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis Am J Clin Dermatol 2000 1 6 349 360 11702611 \n8 Mockenhaupt M Messenheimer J Tennis P Schlingmann J Risk of Stevens–Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics Neurology 2005 64 7 1134 1138 15824335 \n9 Leaute-Labreze C Lamireau T Chawki D Maleville J Tareb A Diagnosis, classification, and management of erythema multiforme and Stevens-Johnson syndrome Arch Dis Child 2000 83 4 347 352 10999875 \n10 Dunn N Wilton L Shakir S Stevens-Johnson syndrome and antiepileptics Lancet 1999 354 1033 1034 10501393 \n11 Keck PE Jr Mc Elroy SL Anticonvulsants and antiepileptics in the treatment of bipolar disease J Clin Psychiatr 1998 59 Suppl 6 74 81 \n12 Rzany B Correia O Kelly JP Naldi L Ariane A Stern R Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study Lancet 1999 353 2190 2194 10392983 \n13 Messenhaimer J Mullens EL Giorgy L Young F Safety review of adult clinical trial experience with lamotrigine Drug Saf 1998 18 281 296 9565739 \n14 Yalcin B Karaduman A Stevens Johnson Syndrome associated with concomitant use of lamotrigine and valproic acid J Am Acad Dermatol 2000 43 898 899 11044815 \n15 Gilman JT Lamotrigine: an antiepileptic agent for the treatment of partial seizures Ann Pharmacother 1995 29 144 151 7756713 \n16 Chaffin JJ Davis SM Suspected Lamotrigine induced toxic epidermal necrolysis Ann Pharmacotherapy 1997 31 720 723 \n17 Tavernok SJ Newton ER Brown SW Rechallenge with lamotrigine after initial rash Epilepsia 1994 35 Suppl 7 72 \n18 Jones D Chhiap V Resor S Appel G Grossman ME Phenytoin like hypersensitivity associated with lamotrigine J Am Acad Dermatol 1997 36 1016 1018 9204073 \n19 Naisbitt DJ Farrell J Wong G Depta JP Dodd CC Hopkins JE Characterization of drug-specific T cells in lamotrigine hypersensitivity J Allergy Clin Immunol 2003 111 1393 1403 12789244 \n20 P-Codrea Tigaran S Sidenius P Dam M Lamotrigine-induced Rash: Worth a Rechallenge Acta Neurol Scand 2005 111 191 194 15736314\n\n",
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"issue": "29(6)",
"journal": "Pakistan journal of medical sciences",
"keywords": "Hypersensitivity reaction; Lamotrigine; Stevens-Johnsons syndrome",
"medline_ta": "Pak J Med Sci",
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"title": "Stevens Johnson Syndrome associated with Lamotrigine.",
"title_normalized": "stevens johnson syndrome associated with lamotrigine"
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"abstract": "Pulmonary alveolar proteinosis (PAP) is an uncommon lung disorder characterized by the excessive accumulation of surfactant-derived lipoproteins in the pulmonary alveoli and terminal bronchiole. Secondary PAP associated with primary myelofibrosis (PMF) is extremely rare, and to our knowledge, no autopsy case has been reported. We herein report an autopsy case of secondary PAP occurring in a patient with PMF who was treated with the Janus kinase 1/2 inhibitor ruxolitinib. We confirmed a diagnosis of PAP with complications based on the pathological findings at the autopsy. Notably, this case might suggest an association between ruxolitinib treatment and PAP occurrence.",
"affiliations": "Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Pathology, Okayama University Hospital, Japan.;Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Bioscience Medical Research Center, Niigata University Medical & Dental Hospital, Japan.;Department of Allergy and Respiratory Medicine, Okayama University Hospital, Japan.;Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.",
"authors": "Sugiura|Hiroyuki|H|;Nishimori|Hisakazu|H|;Nishii|Kazuya|K|;Toji|Tomohiro|T|;Fujii|Keiko|K|;Fujii|Nobuharu|N|;Matsuoka|Ken-Ichi|KI|;Nakata|Koh|K|;Kiura|Katsuyuki|K|;Maeda|Yoshinobu|Y|",
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"fulltext": "\n==== Front\nIntern Med\nIntern. Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n32448830\n10.2169/internalmedicine.4082-19\nCase Report\nSecondary Pulmonary Alveolar Proteinosis Associated with Primary Myelofibrosis and Ruxolitinib Treatment: An Autopsy Case\nSugiura Hiroyuki 1 Nishimori Hisakazu 1 Nishii Kazuya 1 Toji Tomohiro 2 Fujii Keiko 1 Fujii Nobuharu 1 Matsuoka Ken-ichi 1 Nakata Koh 3 Kiura Katsuyuki 4 Maeda Yoshinobu 1 \n1 Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan\n\n2 Department of Pathology, Okayama University Hospital, Japan\n\n3 Department of Bioscience Medical Research Center, Niigata University Medical & Dental Hospital, Japan\n\n4 Department of Allergy and Respiratory Medicine, Okayama University Hospital, Japan\nCorrespondence to Dr. Hisakazu Nishimori, n-mori@md.okayama-u.ac.jp\n\n\n23 5 2020 \n15 8 2020 \n59 16 2023 2028\n20 10 2019 17 3 2020 Copyright © 2020 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Pulmonary alveolar proteinosis (PAP) is an uncommon lung disorder characterized by the excessive accumulation of surfactant-derived lipoproteins in the pulmonary alveoli and terminal bronchiole. Secondary PAP associated with primary myelofibrosis (PMF) is extremely rare, and to our knowledge, no autopsy case has been reported. We herein report an autopsy case of secondary PAP occurring in a patient with PMF who was treated with the Janus kinase 1/2 inhibitor ruxolitinib. We confirmed a diagnosis of PAP with complications based on the pathological findings at the autopsy. Notably, this case might suggest an association between ruxolitinib treatment and PAP occurrence. \n\npulmonary alveolar proteinosisprimary myelofibrosisautopsyruxolitinib\n==== Body\nIntroduction\nPulmonary alveolar proteinosis (PAP) is an uncommon lung disorder characterized by the excessive accumulation of surfactant-derived lipoproteins in the pulmonary alveoli and terminal bronchiole (1). PAP can be classified into three clinically distinct forms: autoimmune, hereditary, and secondary (2). Secondary PAP results from conditions involving functional impairment or reduced numbers of alveolar macrophages; the most frequent underlying disease is hematological malignancy (2).\n\nPrimary myelofibrosis (PMF) is a myeloproliferative neoplasm associated with bone marrow fibrosis, pancytopenia, constitutional symptoms (e.g., night sweats, pruritus, weight loss, and a fever), hepatosplenomegaly, and extramedullary hematopoiesis (3). Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, is generally administered to relieve PMF-related symptoms (4), and it is also approved for the treatment of polycythemia vera (PV). Because thrombocytopenia is a dose-limiting toxicity, the initial dose of myelofibrosis is based on the platelet count, as follows: platelet count >200,000/μL: 20 mg twice daily and platelet count 100,000-200,000/μL: 15 mg twice daily. Common adverse events of ruxolitinib include hematological toxicity, diarrhea, and fatigue (4).\n\nWe herein report an autopsy case of secondary PAP occurring in a patient with PMF who had been treated with ruxolitinib. The patient also experienced complications of pneumocystis pneumonia (PCP) and Mycobacterium Avium Complex (MAC) infection. Secondary PAP associated with PMF is extremely rare, and to our knowledge, no autopsy case has been reported. In this case, the autopsy was diagnostically important because PAP and the underlying disease were confirmed by definitive pathological findings, which helped exclude other pulmonary diseases. Notably, there has been only one case report describing the onset of PAP during the administration of ruxolitinib, which occurred in a patient after hematopoietic stem cell transplantation administered for myelodysplastic syndrome (MDS) (5). Our case suggests an association between ruxolitinib and the occurrence of PAP.\n\nCase Report\nA 70-year-old man was referred to our hospital with appetite loss and general malaise. He had severe anemia and splenomegaly. A bone marrow biopsy showed bone marrow fibrosis, and he was diagnosed with PMF. A mutation analysis of JAK2V617F for this patient was negative. The JAK2V617F mutation is often found in patients with myeloproliferative disease, including 60-65% of patients with PMF, 95-97% with PV, and 60-65% with essential thrombocythemia (6). The efficacy of ruxolitinib is independent of this mutation (7). Seven years after he was diagnosed with PMF, he began outpatient treatment with ruxolitinib to ameliorate anemia and splenomegaly. Since starting ruxolitinib administration, he had not shown any respiratory symptoms. Two years later, he developed respiratory failure and a high fever that did not respond to oral antibiotics, and he was admitted to our hospital.\n\nComputed tomography showed diffuse ground grass opacity in the bilateral lungs (crazy-paving pattern) (Fig. 1A). Laboratory data at the time of admission are shown in Table. In summary, C-reactive protein (CRP), lactate dehydrogenase, Krebs von den Lungen-6, and β-D-glucan levels were increased (shown in Bolｄ). Hemoglobin, hematocrit, and platelet counts were decreased (shown in Italic). His white blood cell count and surfactant protein-D levels were within the normal range.\n\nFigure 1. (A) Chest computed tomography on the day of admission showed bilateral ground glass opacities and intralobular and interlobular septal thickening (crazy-paving appearance). (B) The bronchoalveolar lavage fluid (BALF) showed a light milky appearance. (C) A Papanicolaou-stained cytologic smear of the BALF showed foamy macrophages (arrowhead) with a background of amorphous materials (magnification ×600).\n\nTable. Laboratory Data at Admission.\n\n\tPatient'sdata\tCutoff value\t\nC-reactive protein (CRP)\t2.21\tmg/dL\t<0.15\tmg/dL\t\nLactate dehydrogenase (LDH)\t785\tU/L\t<222\tU/L\t\nKrebs von den Lungen-6 (KL-6)\t1,835\tU/mL\t<500\tU/mL\t\nSurfactant protein–D (SP-D)\t<17.2\tng/mL\t<110\tng/mL\t\nβ-D-glucan (β-DG)\t66.1\tpg/mL\t<11\tpg/mL\t\nWhite blood cell (WBC)\t6.68×103\t/μL\t<8.6×103\t/μL\t\nHemoglobin (Hb)\t6.1\tg/dL\t>13.7\tg/dL\t\nHematocrit (Ht)\t\n16.7\n\t%\t>40.7\t%\t\nPlatelet (Plt)\t14.9×104\n\t/μL\t>15.8×104\t/μL\t\nBronchoscopy revealed milky bronchoalveolar lavage fluid (BALF), which showed foamy macrophages with a background of amorphous materials by Papanicolaou stain (Fig. 1B, C). The total cell number in the BALF was 1.2×106/mL. The proportions of macrophages, lymphocytes, neutrophils, eosinophils, and basophils were 11%, 9%, 21%, 59%, and 0%, respectively, indicating an elevation in the eosinophil proportion. The CD4/CD8 T lymphocyte ratio was 0.5. Polymerase chain reaction for Pneumocystis jirovecii in the BALF was positive. An enzyme-linked immunosorbent assay of the patient's serum was performed by the Department of Bioscience Medical Research Center, Niigata University Medical & Dental Hospital (Niigata, Japan), and it was found to be negative for anti-granulocyte macrophage colony-stimulating factor (GM-CSF) antibody (0.23 μg/mL, cut-off value >1.0 μg/mL).\n\nHe was diagnosed with secondary PAP based on the milky appearance of the BALF, which showed characteristics findings for a smear by Papanicolau stain, his history of PMF, and anti-GM-CSF antibody negativity. He was also diagnosed with complication of PCP because of the high levels of β-D-glucan and P. jirovecii positivity.\n\nHe was treated by sulfamethoxazole and trimethoprim for PCP and cefepime for the bacterial infection, which may have caused complications. Ruxolitinib was discontinued because of active infection. During antibiotic treatment, the patient's temperature returned to normal, and the CRP and β-D-glucan levels decreased. However, antibiotics seemed to be ineffective, as the patient developed a second fever, and his CRP level increased three weeks after admission. Because of the increased eosinophil proportion in the BALF, we considered the possibility of complication of eosinophilic pneumonia and started methylprednisolone at 1 mg/kg. His temperature decreased again, and the CRP levels seemed to recover, but they became exacerbated again four weeks after admission. Mycobacterium intracellulae was then detect in the sputum and BALF collected at the admission, and the serum samples were positive for MAC antibody. He was diagnosed with complications of pulmonary MAC infection and started clarithromycin and ethambutol. However, his respiratory failure progressed, and he died 65 days after admission. The clinical course is shown in Fig. 2. With the patient's family's consent, we performed an autopsy.\n\nFigure 2. Clinical course shown by CRP, WBC and the SpO2 to FiO2 ratio. CRP: C-reactive protein, WBC: white blood cell, SpO2: saturation of percutaneous oxygen, FiO2: fraction of inspiratory oxygen, CFPM: cefepime, S/T: sulfamethoxazole and trimethoprim, CAM: clarithromycin, EB: ethambutol, mPSL: methylprednisolone\n\nThe autopsy showed that both lungs were filled with eosinophilic material. This eosinophilic material in the alveoli was positive for Periodic acid-Schiff and surfactant A stains. Ziehl-Neelsen stain indicated invasion of inflammatory cells and acid-fast bacteria in the lung, which suggested persistent MAC infection (Fig. 3). There was no abnormal invasion of eosinophils in the autopsied lung. There was also no increase in myeloblasts in the bone marrow. Based on these findings, the major cause of death was deemed to be progression of PAP and pulmonary MAC infection.\n\nFigure 3. Histopathological sections from the lung autopsy showed filling of the alveolar spaces with eosinophilic granular substances on Hematoxylin and Eosin staining (A); the cells were Periodic acid-Schiff (PAS) stain-positive (B) and surfactant A stain-positive (C) (magnification ×200). Ziehl-Neelsen staining indicated acid-fast bacteria and invasion of inflammatory cells (D) (magnification ×400). These findings were consistent with PAP compromised with MAC infection. PAP: pulmonary alveolar proteinosis, PAS: periodic acid-Schiff, MAC: mycobacterium avium complex\n\nDiscussion\nTo our knowledge, this is the first autopsy case of secondary PAP associated with PMF. Although there have been many case reports of PAP associated with MDS, there has been only one other case report of PAP secondary to PMF, and an autopsy was not performed in that report (8). In the present case, the autopsy was diagnostically important because PAP and the complicated disease were confirmed by definitive pathological findings, which helped exclude other pulmonary diseases. We confirmed complications of pulmonary MAC infection and excluded complications of eosinophilic pneumonia based on the pathological findings obtained at the autopsy.\n\nNotably, in the present case, PAP occurred during administration of the JAK1/2 inhibitor ruxolitinib, which might suggest an association between ruxolitinib and PAP occurrence. Ruxolitinib is a generally effective treatment option for relieving PMF-related symptoms, such as appetite loss, dyspnea, fatigue, insomnia, and pain (4). There is only one other case report describing the onset of PAP during ruxolitinib administration in a patient after hematopoietic stem cell transplantation for MDS (5). The authors suggest that ruxolitinib may lead to the development of PAP by disrupting intracellular GM-CSF signaling, as the GM-CSF receptor is coupled with a JAK, and the first step of intracellular signaling in macrophages depends on JAK2 activation and STAT3 phosphorylation. However, to our knowledge, there are no reports showing a direct association between STAT3 inhibition and the occurrence of PAP. Hildebrandt et al. reported that reduced STAT5 phosphorylation in peripheral blood mononuclear cells and granulocytes was seen in six cases of juvenile PAP caused by CSF2RA mutations (9). In their report, the median age at the symptom onset was 3.5 years (9). In another report, mononuclear cells of mice treated with ruxolitinib showed a trend toward a reduced phosphor-STAT5 induction in response to in vitro GM-CSF stimulation, although this trend was not statistically significant (10). In the present case, an onset of two years from the start of ruxolitinib treatment seems to be reasonable based on the immunological abnormality of PMF. Given these present and previous findings, we consider the mechanism of PAP development to be as follows: 1) PMF with a background of immunological abnormality tends to induce PAP, and 2) ruxolitinib administration affects the JAK/STAT pathway.\n\nIn addition, the etiology of secondary PAP has not been completely elucidated, a mouse study demonstrated that macrophage dysfunction had a pivotal role in the development of PAP (11), and ruxolitinib can inhibit macrophage activity and hemophagocytic lymphohistiocytosis in a mouse model (12, 13). In these reports, ruxolitinib inhibited STAT5 phosphorylation of macrophages and macrophage-stimulating cytokines, such as interferon-γ and tumor necrosis factor-α (12, 13). Theoretically, it is possible that ruxolitinib affects the alveolar macrophage function and results in the development of PAP.\n\nIn the present case, the patient developed two opportunistic infections in the lung: PCP and pulmonary MAC infection. PAP patients are likely to develop opportunistic infections in the lung because of the dysfunction of lung macrophages. Furthermore, the underlying disease of this patient was myelofibrosis, and he was extremely immunocompromised and therefore prone to suffer from opportunistic infections. The major causes of death in secondary PAP patients complicated with MDS, which is a disease similar to PMF, are progression of PAP and infectious disease (14). The administration of ruxolitinib might also be related to opportunistic infections of the lung, as ruxolitinib has been reported to have an immunosuppressive effect, which can increase the risk of infection (15). Ruxolitinib is especially known to be a risk factor of pneumonia (16) and mycobacterial infection (17). Interestingly, a previously reported case of PAP associated with ruxolitinib was complicated with M. abcessus lung infection (5). To our knowledge, the accurate incidence of PCP and mycobacterial infection during ruxolitinib treatment has not been reported, but ruxolitinib suppresses the JAK1/2 signaling pathway, thereby affecting many cytokines and growth factors that are important for the immune function. Therefore, ruxolitinib may theoretically affect the development of these infections. Conversely, prednisolone was reported as a risk factor for infection in patients with autoimmune PAP (18). We started prednisolone because of the possibility of complication of eosinophilic pneumonia, and this may have worsened the pulmonary MAC infection.\n\nIn conclusion, we experienced a case of secondary PAP occurring in a patient with PMF who was being treated with ruxolitinib. The patient also developed PCP and pulmonary MAC infection. We confirmed the diagnosis of PAP and the complicated disease based on the pathological findings obtained at the autopsy. The JAK1/2 inhibitor ruxolitinib might be related to the development of PAP and subsequent opportunistic infection.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nWe thank all of the staff at Okayama University Hospital.\n==== Refs\n1. \nTrapnell BC , Whitsett JA , Nakata K \nPulmonary alveolar proteinosis\n. N Engl J Med \n349 : 2527 -2539\n, 2003 .14695413 \n2. \nTrapnell BC , Nakata K , Bonella F , et al \nPulmonary alveolar proteinosis\n. Nat Rev Dis Primers \n5 : 16 , 2019 .30846703 \n3. \nVerstovsek S , Mughal T , Vaddi K , Sarlis N \nMyelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes\n. Int J Gen Med \n7 : 89 -101\n, 2014 .24501543 \n4. \nCervantes F \nHow I treat myelofibrosis\n. Blood \n124 : 2635 -2642\n, 2014 .25232060 \n5. \nSalvator H , Berti E , Catherinot E , et al \nPulmonary alveolar proteinosis and Mycobacterium abscessus lung infection related to ruxolitinib after allogeneic stem cell transplantation\n. Eur Respir J \n51 : 1701960 , 2018 .29650554 \n6. \nCazzola M , Kralovics R \nFrom Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms\n. Blood \n123 : 3714 -3719\n, 2017 .\n7. \nGuglielmelli P , Biamonte F , Rotunno G , et al \nImpact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study\n. Blood \n123 : 2157 -2160\n, 2014 .24458439 \n8. \nTsutsumi Y , Tanaka J , Saito S , et al \nMyelofibrosis after essential thrombocytopenia complicated by alveolar proteinosis\n. Leuk Lymphoma \n44 : 1049 -1052\n, 2003 .12854908 \n9. \nHildebrandt J , Yalcin E , Bresser HG , et al \nCharacterization CSF2RA mutation related juvenile pulmonary alveolar proteinosis\n. Orphanet J Rare Dis \n9 : 171 , 2014 .25425184 \n10. \nSachs Z , Been RA , DeCoursin KJ , et al \nStat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by NF1 deficiencey\n. Hematologica \n101 : 1190 -1199\n, 2016 .\n11. \nForbes A , Pickell M , Foroughian M , Yao LJ , Lewis J , Veldhuizen R \nAlveolar macrophage depletion is associated with increased surfactant pool sizes in adult rats\n. J Appl Physiol (1985) \n103 : 637 -645\n, 2007 .17446406 \n12. \nMaschalidi S , Sepulveda FE , Garrigue A , Fischer A , de Saint , Basile G \nTherapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice\n. Blood \n128 : 60 -72\n, 2016 .27222478 \n13. \nAlbeituni S , Verbist KC , Tedrick PE , et al \nMechanisms of action of ruxolitinib in murine models of hemophagocytic lymphohistiocytosis\n. Blood \n134 : 147 -159\n, 2019 .31015190 \n14. \nIshii H , Seymour JF , Tazawa R , et al \nSecondary pulmonary alveolar proteinosis complicating myelodysplastic syndrome results in worsening of prognosis: a retrospective cohort study in Japan\n. BMC Pulm Med \n14 : 1 -10\n, 2014 .24387157 \n15. \nLussana F , Cattaneo M , Rambaldi A , Squizzato A \nRuxolitinib-associated infections: a systematic review and meta-analysis\n. Am J Hematol \n93 : 339 -347\n, 2018 .29150886 \n16. \nVerstovsek S , Mesa RA , Gotlib J , et al \nLong-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial\n. J Hematol Oncol \n10 : 55 , 2017 .28228106 \n17. \nAnand K , Burns EA , Ensor J , Rice L , Pingali SR \nMycobacterial infections with ruxolitinib: a retrospective pharmacovigilance review\n. Clin Lymphoma Myeloma Leuk \n20 : 18 -23\n, 2020 .31699655 \n18. \nAkasaka K , Tanaka T , Kitamura N , et al \nOutcome of corticosteroid administration in autoimmune pulmonary alveolar proteinosis: a retrospective cohort study\n. BMC Pulm Med \n15 : 88 , 2015 .26264717\n\n",
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"issue": "59(16)",
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"keywords": "autopsy; primary myelofibrosis; pulmonary alveolar proteinosis; ruxolitinib",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D001344:Autopsy; D006801:Humans; D008297:Male; D009570:Nitriles; D055728:Primary Myelofibrosis; D047428:Protein Kinase Inhibitors; D011649:Pulmonary Alveolar Proteinosis; D011720:Pyrazoles; D011743:Pyrimidines",
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"title": "Secondary Pulmonary Alveolar Proteinosis Associated with Primary Myelofibrosis and Ruxolitinib Treatment: An Autopsy Case.",
"title_normalized": "secondary pulmonary alveolar proteinosis associated with primary myelofibrosis and ruxolitinib treatment an autopsy case"
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"abstract": "Four infants who were exposed to sodium valproate or valproic acid during pregnancy are described. Common facial features in the three surviving infants include epicanthic folds, a flat nasal bridge, a broad nasal base, anteverted nostrils, a shallow philtrum, and a thin upper lip with a thick lower lip. Ridging of the metopic suture, congenital heart defect, postaxial polydactyly, and hypospadias were additional features in individual cases. In agreement with previous authors, we feel that there is a distinctive 'fetal valproate' phenotype.",
"affiliations": "Kennedy Galton Centre for Clinical Genetics, Radlett, Hertfordshire.",
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"doi": "10.1136/jmg.24.11.692",
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"issue": "24(11)",
"journal": "Journal of medical genetics",
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"medline_ta": "J Med Genet",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000015:Abnormalities, Multiple; D004830:Epilepsy, Tonic-Clonic; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D011248:Pregnancy Complications; D014635:Valproic Acid",
"nlm_unique_id": "2985087R",
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"references": "6782218",
"title": "Fetal valproate syndrome: is there a recognisable phenotype?",
"title_normalized": "fetal valproate syndrome is there a recognisable phenotype"
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"abstract": "Gastrointestinal (GI) metastasis from primary lung cancer is a rare clinical finding. Lung cancer most often metastasizes to the brain, bone, liver, and adrenal glands; with gastrointestinal involvement being very rare. We report a case of a 39-year-old female with a diagnosis of poorly differentiated Squamous Cell Carcinoma (SCC) of the lung presenting with dizziness and melena. Esophagogastroduodenoscopy (EGD) showed a bleeding mass in the stomach. Final biopsy report and Immunohistochemistry (IHC) of the specimen were consistent with SCC lung metastasis. While it is imperative to have a high clinical suspicion for GI metastasis in patients with primary lung cancer presenting with GI symptoms, it may be challenging to establish diagnosis. Endoscopy along with pathology and immunohistochemistry play a crucial role in differentiating primary GI malignancies from metastasis.",
"affiliations": "Resident, Department of Internal Medicine, University of Connecticut, Farmington, Connecticut, USA.;Research Student, Department of Internal Medicine, University of Connecticut, Farmington, Connecticut, USA.;Resident, Department of Internal Medicine, University of Connecticut, Hartford, Connecticut, USA.;Attending Physician, Department of Gastroenterology and Hepatology, University of Connecticut, Farmington, Connecticut, USA.",
"authors": "Bhardwaj|Richa|R|;Bhardwaj|Gaurav|G|;Gautam|Arun|A|;Karagozian|Raffi|R|",
"chemical_list": null,
"country": "India",
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"doi": "10.7860/JCDR/2017/27040.10090",
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"issue": "11(6)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Gastrointestinal hemorrhage; Lung neoplasm; Metastasis; Non-small cell carcinoma lung",
"medline_ta": "J Clin Diagn Res",
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"nlm_unique_id": "101488993",
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"pages": "OD13-OD14",
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"pmid": "28764229",
"pubdate": "2017-06",
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"references": "25130083;21160891;25663792;8937139;15278035;17010474;17410025;23765532;10332019;23221041;25977750;6274500;26238344;3028602;10406253;22026313;27785223",
"title": "Upper Gastrointestinal Bleed as a Manifestation of Poorly Differentiated Metastatic Squamous Cell Carcinoma of the Lung.",
"title_normalized": "upper gastrointestinal bleed as a manifestation of poorly differentiated metastatic squamous cell carcinoma of the lung"
} | [
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"abstract": "Organ transplant recipients have a high incidence of cancer associated with persistent viral infections, such as human herpes virus 8. This virus is associated with Kaposi's sarcoma, and a change in the dose or type of immunosuppression regimen should be the first step in its treatment. A multidisciplinary approach with nephrologists, dermatologists and oncologists is necessary for the management of this disease. We report a clinical case with atypical presentation and discuss the treatment options.",
"affiliations": "Unidade de Investigação em Dermatologia, Clínica Universitária de Dermatologia de Lisboa, Faculdade de Medicina da Universidade de Lisboa, CHLN, IMM, Lisboa, Portugal Instituto de Higiene e Medicina Tropical, Lisboa, Portugal.;CHLN, Lisboa, Portugal.;Faculdade de Medicina da Universidade de Lisboa, CHLN, IMM, Unidade de Investigação em Dermatologia, Clínica Universitária de Dermatologia de Lisboa, Lisboa, Portugal.;Unidade de Transplante, CHLN, Lisboa, Portugal.",
"authors": "Borges-Costa|João|J|;Lopes|Leonor|L|;Soares-Almeida|Luís|L|;Guerra|José|J|",
"chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "England",
"delete": false,
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"journal": "BMJ case reports",
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"mesh_terms": "D005260:Female; D019288:Herpesvirus 8, Human; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008875:Middle Aged; D012514:Sarcoma, Kaposi; D016559:Tacrolimus",
"nlm_unique_id": "101526291",
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"pmid": "26759393",
"pubdate": "2016-01-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23278452;16780549;17874397;25420858;21377267;12711744;11750556;20709518;15800227;19775317;23382046;19009366",
"title": "Kaposi's sarcoma presenting as violaceous macules on the chest of a kidney transplanted patient.",
"title_normalized": "kaposi s sarcoma presenting as violaceous macules on the chest of a kidney transplanted patient"
} | [
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"companynumb": "PT-MYLANLABS-2020M1013482",
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"abstract": "Drug induced acute respiratory distress syndrome (ARDS) is a common clinical condition. Patients typically present with noncardiogenic pulmonary edema. Large number of ARDS cases reported induced by antineoplastic drugs and other drug intoxications. The pathophysiologic mechanisms of drug induced ARDS remains unknown. One of the postulated mechanisms of drug induced ARDS is anaphylaxis. We present a case of acute respiratory distress syndrome complicated by anaphylactic shock after use of two different nonsteroidal antiinflammatory drugs (NSAID). To the best of our knowledge, ARDS following normal doses of NSAID ingestion has not been reported previously. The case showed that ARDS may occur after ingestion of therapeutic doses of NSAID. NSAID ingestion should be considered in the differential diagnosis of patients with non-cardiogenic pulmonary edema.",
"affiliations": "Derince Training and Research Hospital, Department of Emergency Medicine, Kocaeli, Turkey. Electronic address: enes.ozbek@kocaeli.edu.tr.;Derince Training and Research Hospital, Department of Emergency Medicine, Kocaeli, Turkey.;Kocaeli University School of Medicine, Department of Emergency Medicine, Kocaeli, Turkey.;Derince Training and Research Hospital, Department of Emergency Medicine, Kocaeli, Turkey.;Derince Training and Research Hospital, Department of Emergency Medicine, Kocaeli, Turkey.",
"authors": "Özbek|Asım Enes|AE|;Divrikoğlu|Yavuz Selim|YS|;Yılmaz|Serkan|S|;Aytaş|Nurcihan Ülkü|NÜ|;Çelik|Emrah|E|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal",
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"issue": "36(10)",
"journal": "The American journal of emergency medicine",
"keywords": "Acute respiratory distress syndrome; Emergency medicine; NSAIDs",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000368:Aged; D000707:Anaphylaxis; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001416:Back Pain; D003422:Critical Care; D003937:Diagnosis, Differential; D004417:Dyspnea; D005260:Female; D006801:Humans; D012128:Respiratory Distress Syndrome; D016896:Treatment Outcome",
"nlm_unique_id": "8309942",
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"pages": "1929.e1-1929.e2",
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"pmid": "29983217",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nonsteroidal anti-inflammatory drug-induced acute respiratory distress syndrome.",
"title_normalized": "nonsteroidal anti inflammatory drug induced acute respiratory distress syndrome"
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"abstract": "Cancer patients presenting with altered mental status demand a broad differential with early recognition of the etiology. Failure to do so is associated with increased morbidity and mortality. Causes that must be considered include organ involvement of the cancer, electrolytes abnormalities, and even chemotherapeutic agents. A 32-year-old female patient had been recently started on FOLFOX for metastatic colon cancer. Her initial treatments were uneventful, but she later developed encephalopathy during day three of cycle five. During her evaluation, she was found to have hyperammonemia (84 mcmol/L), without hepatic failure, that resolved with stopping chemotherapy and supportive care. After a trial of home infusion fluorouracil, she developed hyperammonemic encephalopathy again. During both admissions, her symptoms resolved with IV hydration and cessation of chemotherapy. She was then successfully challenged with capecitabine (1000 mg/m2 daily), and additional hydration, and continued chemotherapy without recurrence of symptoms. Hyperammonemia is associated with fluorouracil though the mechanism is unclear. Suspected etiologies include either elevated levels of the drug due to slower metabolism or accumulation of certain metabolites. Additionally, risk factors such urease-producing bacterial infections, dehydration, and increased catabolism are thought to increase the risk for hyperammonemia. This case demonstrates the need for greater awareness of fluorouracil as a cause of hyperammonemic encephalopathy. Knowledge of this may allow for earlier recognition and reduced unnecessary testing.",
"affiliations": "University of Florida College of Medicine-Jacksonville, Department of Medicine, Division of Internal Medicine, USA.;University of Florida College of Medicine-Jacksonville, Department of Medicine, Division of Internal Medicine, USA.;University of Florida College of Medicine-Jacksonville, Department of Medicine, Division of Hematology and Oncology, USA.;University of Florida College of Medicine-Jacksonville, Department of Medicine, Division of Hematology and Oncology, USA.",
"authors": "Chahin|Michael|M|https://orcid.org/0000-0001-9371-0252;Krishnan|Nithya|N|https://orcid.org/0000-0002-2953-7288;Chhatrala|Hardik|H|;Shaikh|Marwan|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/4216752",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2020/4216752Case ReportA 5-Fluorouracil-Induced Hyperammonemic Encephalopathy Challenged with Capecitabine https://orcid.org/0000-0001-9371-0252Chahin Michael michael.chahin@jax.ufl.edu\n1\nhttps://orcid.org/0000-0002-2953-7288Krishnan Nithya \n1\nChhatrala Hardik \n2\nShaikh Marwan \n2\n\n1University of Florida College of Medicine–Jacksonville, Department of Medicine, Division of Internal Medicine, USA\n2University of Florida College of Medicine–Jacksonville, Department of Medicine, Division of Hematology and Oncology, USAAcademic Editor: Jose I. Mayordomo\n\n2020 31 1 2020 2020 421675223 11 2019 9 1 2020 Copyright © 2020 Michael Chahin 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.Cancer patients presenting with altered mental status demand a broad differential with early recognition of the etiology. Failure to do so is associated with increased morbidity and mortality. Causes that must be considered include organ involvement of the cancer, electrolytes abnormalities, and even chemotherapeutic agents. A 32-year-old female patient had been recently started on FOLFOX for metastatic colon cancer. Her initial treatments were uneventful, but she later developed encephalopathy during day three of cycle five. During her evaluation, she was found to have hyperammonemia (84 mcmol/L), without hepatic failure, that resolved with stopping chemotherapy and supportive care. After a trial of home infusion fluorouracil, she developed hyperammonemic encephalopathy again. During both admissions, her symptoms resolved with IV hydration and cessation of chemotherapy. She was then successfully challenged with capecitabine (1000 mg/m2 daily), and additional hydration, and continued chemotherapy without recurrence of symptoms. Hyperammonemia is associated with fluorouracil though the mechanism is unclear. Suspected etiologies include either elevated levels of the drug due to slower metabolism or accumulation of certain metabolites. Additionally, risk factors such urease-producing bacterial infections, dehydration, and increased catabolism are thought to increase the risk for hyperammonemia. This case demonstrates the need for greater awareness of fluorouracil as a cause of hyperammonemic encephalopathy. Knowledge of this may allow for earlier recognition and reduced unnecessary testing.\n==== Body\n1. Introduction\nConfusion in the cancer patient can present a diagnostic dilemma. It is often multifactorial, possibly due to the delirium from the malignancy itself, electrolyte abnormalities, organ involvement, and even the cancer treatment. Certain chemotherapy drugs, such as cytarabine and methotrexate, are associated with delirium. Early diagnosis is crucial as delirium in the cancer patient conveys increased morbidity and mortality [1]. Factors that increase the risk for the development of delirium include age > 70 years, cognitive impairment, and end-stage organ dysfunction [2]. One must keep in mind that these patients often develop hypoactive delirium, which could delay diagnosis if not recognized [1, 3]. We present a patient who developed hyperammonemic encephalopathy following treatment with 5-fluorouracil (5-FU) for metastatic colon cancer.\n\n2. Case Presentation\nA 32-year-old female with a history of iron deficiency anemia presented with bright red blood per rectum and worsening anemia that lead to the diagnosis of an invasive rectosigmoid colonic adenocarcinoma. The tumor was microsatellite stable, KRAs mutated, and BRAF wild type. A positron emission tomography scan revealed increased uptake in the rectosigmoid lesion, retroperitoneal lymph nodes, and numerous liver lesions. Brain magnetic resonance imaging did not show brain metastasis. Her Eastern Cooperative Oncology Group (ECOG) Performance Status was zero.\n\nShe was started on FOLFOX and bevacizumab chemotherapy. Her regimen was folinic acid 400 mg/m2 once on day one, 5-FU 400 mg/m2 bolus on day one followed by 2400 mg/m2 continuous infusion over 46 hours, oxaliplatin 85 mg/m2 once on day one, and bevacizumab 5 mg/kg once on day one. She tolerated cycles 1-4 with mild nausea and vomiting. During the third day of cycle five, she became acutely altered and developed nausea and vomiting beyond what she had with the initial two days of chemotherapy. The 46-hour infusion of 5-FU has been completed the night before, and she had presented to the infusion center that morning for pump removal. An emergency department evaluation was advised due marked lethargy. She was oriented to person and place but not to time or situation. Her gait was ataxic, she a mild tremor, and her speech was minimally comprehensible. Her Glasgow Coma Score (GCS) was 12. Her spouse endorsed that she felt weak and had some vomiting the night before. No recent constipation. CT head was unremarkable (Table 1).\n\nShe was given intravenous fluids, observed overnight, and discharged home after symptom resolution. Her lactic acidosis and acute kidney injury resolved. Empiric broad spectrum antibiotics had been given but were stopped due to negative infectious workup and rapid improvement with hydration. She received lactulose and her chemotherapy was held while inpatient. She did not recall much from her presentation.\n\nFor cycle six of chemotherapy she was started on 5-FU alone for a home infusion over 46 hours, folinic acid, and bevacizumab therapy. On day one of treatment, shortly after starting the 5-FU infusion, she again developed altered mental status. Her physical exam was significant for asterixis, nonverbal status, and not following commands. She was not ambulating. Her GCS was eight this time. She was treated with fluids until symptom resolution and was discharged. Lactulose had been resumed while inpatient, and she was to continue it at discharge (Table 2).\n\nHaving developed hyperammonemic encephalopathy in the previous two chemotherapy regimens, she was then switched to capecitabine 1000 mg/m2 and oxaliplatin (CAPEOX) and bevacizumab. Her weight had remained stable since starting chemotherapy, but she had appeared dehydrated during clinic visits. She was encouraged to take in more fluids and was given IV fluids during chemotherapy sessions. She was advised to cease using lactulose since there was no overt hepatic failure. She had no recurrence of hyperammonemia symptoms while on CAPEOX, for a total of eight cycles. A dihydropyrimidine dehydrogenase (DPD) level had been ordered during the previous admission and was normal. Based on these findings, her hyperammonemia was attributed to 5-FU.\n\n3. Discussion\nColon cancer is the third most common cause of cancer-related death in the United States [4]. The mainstays of chemotherapy are folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX), and folinic acid, 5-FU, and irinotecan (FOLFIRI) [5]. Capecitabine and oxaliplatin (CAPOX) can be used as an oral alternative to FOLFOX [5, 6]. This patient tolerated capecitabine, without recurrence of her hyperammonemia.\n\nThe mechanism of fluorouracil-induced hyperammonemic encephalopathy is unclear but likely multifactorial. Deficiency in DPD, the primary enzyme in the metabolism of 5-FU, may play a role though this patient's DPD activity was normal [7]. Another possible etiology is inhibition of the Krebs cycle by fluoroacetate or fluorocitrate, metabolites of 5-FU, leading to excess urea and the subsequent accumulation of ammonia [7, 8].\n\nIt has been proposed as well that 5-FU therapy alone does not generally induce hyperammonemia. Rather, weight loss, dehydration, constipation, bacterial infection, and renal impairment are predisposing factors. Chronic constipation leading to increased bacterial urease and amino acid oxidase activity and increased catabolism in chronically anorexic patients also contribute to a hyperammonemic state [9]. Urinary tract infection due to urease-producing bacteria is associated with hyperammonemia, independently of 5-FU [10]. Renal impairment is thought to increase levels of 5-FU and 5-fluoro-beta-alanine (FBAL), another metabolite of 5-FU [9, 11]. Direct neurotoxicity from these agents is possible based on a study conducted in cats that revealed, similar, neuropathologic changes in subjects with intraventricular administration of FBAL and 5-FU given orally [12].\n\nHyperammonemia, in general, is most commonly due to liver damage but there are many other causes that must be considered. Some causes, in addition to urinary tract infection, are due to urease-producing bacteria, excessive amino acid load from gastrointestinal hemorrhage, anticonvulsants, such as topiramate, and urea cycle defects [10]. Multiple chemotherapy agents, in addition to 5-FU, have been implicated in hyperammonemic encephalopathy [13]. Though these have not been specifically associated with fluorouracil-induced hyperammonemic encephalopathy, they likely predispose patients to developing it. A case series demonstrated hyperammonemic encephalopathy in 5-FU and oral fluoropyrimidine agents. Most of the patients had risk factors in common such as dehydration and sarcopenia [14].\n\nA rechallenge protocol has been suggested in the context of hyperammonemic encephalopathy after receiving 5-FU, oxaliplatin, irinocetan, and folinic acid (FOLFIRINOX) [15]. The management of the patient presented above was focused on mitigating her primary risk factor for hyperammonemia, which was dehydration. It is likely that the acute kidney injury in this patient was a result of dehydration but could still have been a risk factor for hyperammonemia.\n\n4. Conclusion\nGiven the prevalence of colon cancer, the primary care, hospitalist, and emergency physician should be wary of 5-FU causing hyperammonemia. This patient was treated with lactulose despite not having hepatic damage. Though one should have a broad differential, in a cancer patient, presenting with confusion recognition of this adverse effect of 5-FU may reduce unnecessary testing. Additionally, this case demonstrates that patients with 5-FU-induced hyperammonemic encephalopathy may be challenged with capecitabine though the risk of encephalopathy remains. Treatment should be focused on reducing risk factors for hyperammonemia.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nTable 1 \tReference range\tTwo days before admission\tDay of admission\t\nSodium\t135-145 mmol/L\t142\t144\t\nPotassium\t3.3-4.6 mmol/L\t4.0\t4.9\t\nChloride\t101-110 mmol/L\t106\t108\t\nCarbon dioxide\t21-29 mmol/L\t25\t13\t\nUrea nitrogen\t6-22 mg/dL\t9\t17\t\nCreatinine\t0.51-0.95 mg/dL\t0.65\t0.96\t\nGlucose\t71-99 mg/dL\t96\t73\t\nCalcium\t8.6-10.0 mg/dL\t9.4\t9.4\t\nAnion gap\t4-16 mmol/L\t11\t23\t\nTotal protein\t6.5-8.3 g/dL\t7.3\t7.7\t\nAlbumin\t3.8-4.9 g/dL\t4.3\t4.6\t\nAST\t14-33 IU/L\t17\t40\t\nALT\t10-42 IU/L\t14\t48\t\nDirect bilirubin\t0.0-0.2 mg/dL\t\t0.3\t\nIndirect bilirubin\t<0.8 mg/dL\t\t1.4\t\nTotal bilirubin\t0.2-1.0 mg/dL\t0.4\t1.7\t\nAlkaline phosphatase\t35-104 IU/L\t66\t82\t\nAmmonia\t11-35 mcmol/L\t\t84\t\nLactic acid\t0.7-2.7 mmol/L\t\t10.4\t\nTable 2 \tReference range\tDay of second admission\t\nSodium\t135-145 mmol/L\t139\t\nPotassium\t3.3-4.6 mmol/L\t4.5\t\nChloride\t101-110 mmol/L\t101\t\nCarbon dioxide\t21-29 mmol/L\t15\t\nUrea nitrogen\t6-22 mg/dL\t18\t\nCreatinine\t0.51-0.95 mg/dL\t1.13\t\nGlucose\t71-99 mg/dL\t94\t\nCalcium\t8.6-10.0 mg/dL\t10.6\t\nAnion gap\t4-16 mmol/L\t23\t\nTotal protein\t6.5-8.3 g/dL\t9.0\t\nAlbumin\t3.8-4.9 g/dL\t5.1\t\nAST\t14-33 IU/L\t24\t\nALT\t10-42 IU/L\t27\t\nDirect bilirubin\t0.0-0.2 mg/dL\t0.3\t\nIndirect bilirubin\t<0.8 mg/dL\t1.1\t\nTotal bilirubin\t0.2-1.0 mg/dL\t1.4\t\nAlkaline phosphatase\t35-104 IU/L\t89\t\nAmmonia\t11-35 mcmol/L\t290\t\nLactic acid\t0.7-2.7 mmol/L\t8.2\n==== Refs\n1 Nolan C. Deangelis L. M. The confused oncologic patient: a rational clinical approach Current Opinion in Neurology 2016 29 6 789 796 10.1097/wco.0000000000000392 2-s2.0-84988698721 27676278 \n2 Bush S. H. Lawlor P. G. Ryan K. Delirium in adult cancer patients: ESMO Clinical Practice Guidelines Annals of Oncology 2018 29 Supplement 4 iv143 iv165 10.1093/annonc/mdy147 2-s2.0-85054358343 29992308 \n3 De la Cruz M. Fan J. Yennu S. The frequency of missed delirium in patients referred to palliative care in a comprehensive cancer center Supportive Care in Cancer 2015 23 8 2427 2433 10.1007/s00520-015-2610-3 2-s2.0-84933181555 25617070 \n4 Marley A. R. Nan H. Epidemiology of colorectal cancer International Journal of Molecular Epidemiology and Genetics 2016 7 3 105 114 27766137 \n5 National Comprehensive Cancer Network Colon cancer (Version 2.2019) September 2019, https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf \n6 Aguado C. Garcia-Paredes B. Sotelo M. J. Sastre J. Diaz-Rubio E. Should capecitabine replace 5-fluorouracil in the first-line treatment of metastatic colorectal cancer? World Journal of Gastroenterology 2014 20 20 6092 6101 10.3748/wjg.v20.i20.6092 2-s2.0-84901487360 24876731 \n7 Kim Y. A. Chung H. C. Choi H. J. Rha S. Y. Seong J. S. Jeung H. C. Intermediate dose 5-fluorouracil-induced encephalopathy Japanese Journal of Clinical Oncology 2006 36 1 55 59 10.1093/jjco/hyi214 2-s2.0-32244443581 16436463 \n8 Thomas S. A. Tomeh N. Theard S. Fluorouracil-induced hyperammonemia in a patient with colorectal cancer Anticancer Research 2015 35 12 6761 6763 26637893 \n9 Kikuta S. Asakage T. Nakao K. Sugasawa M. Kubota A. The aggravating factors of hyperammonemia related to 5-fluorouracil infusion—a report of two cases Auris, Nasus, Larynx 2008 35 2 295 299 10.1016/j.anl.2007.04.012 2-s2.0-41549149037 17826933 \n10 Walker V. Severe hyperammonaemia in adults not explained by liver disease Annals of Clinical Biochemistry 2012 49 Part 3 214 228 10.1258/acb.2011.011206 2-s2.0-84861498443 22349554 \n11 Liaw C. C. Wang H. M. Wang C. H. Risk of transient hyperammonemic encephalopathy in cancer patients who received continuous infusion of 5-fluorouracil with the complication of dehydration and infection Anti-Cancer Drugs 1999 10 3 275 281 10.1097/00001813-199903000-00004 2-s2.0-0032796813 10327032 \n12 Okeda R. Shibutani M. Matsuo T. Kuroiwa T. Shimokawa R. Tajima T. Experimental neurotoxicity of 5-fluorouracil and its derivatives is due to poisoning by the monofluorinated organic metabolites, monofluoroacetic acid and alpha-fluoro-beta-alanine Acta Neuropathologica 1990 81 1 66 73 10.1007/bf00662639 2-s2.0-0025010640 2128162 \n13 Willson K. J. Nott L. M. Broadbridge V. T. Price T. Hepatic encephalopathy associated with cancer or anticancer therapy Gastrointestinal Cancer Research 2013 6 1 11 16 23505573 \n14 Mitani S. Kadowaki S. Komori A. Acute hyperammonemic encephalopathy after fluoropyrimidine-based chemotherapy Medicine 2017 96 22, article e6874 10.1097/MD.0000000000006874 2-s2.0-85020633483 28562536 \n15 Boilève A. Wicker C. Verrt B. 5-fluorouracil rechallenge after 5-fluorouracil-induced hyperammonemic encephalopathy Anti-Cancer Drugs 2019 30 3 313 317 10.1097/CAD.0000000000000730 2-s2.0-85061578389 30531368\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2020()",
"journal": "Case reports in oncological medicine",
"keywords": null,
"medline_ta": "Case Rep Oncol Med",
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"nlm_unique_id": "101581035",
"other_id": null,
"pages": "4216752",
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"pmid": "32082663",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "30531368;29992308;23505573;27766137;2128162;16436463;25617070;26637893;27676278;10327032;22349554;24876731;28562536;17826933",
"title": "A 5-Fluorouracil-Induced Hyperammonemic Encephalopathy Challenged with Capecitabine.",
"title_normalized": "a 5 fluorouracil induced hyperammonemic encephalopathy challenged with capecitabine"
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"occurcountry": "US",
"patient": {
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"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "Topical carbonic anhydrase inhibitors (CAI), used for treatment of glaucoma, are generally regarded as safe and unconnected with systemic side effects. We report an unusual case of fatigue, metabolic acidosis, and normocytic anaemia associated with ocular administration of the CAI, dorzolamide, in a patient with impaired renal function. In chronic kidney disease, where CAI elimination may be decreased, and patients prone to develop metabolic acidosis, systemic absorption of ocular administered CAI could lead to rare, but potentially serious adverse reaction, that are a consequence of inhibition of extraocular carbonic anhydrase isoenzymes.",
"affiliations": "Second Department of Internal Medicine, Third Faculty of Medicine, Charles University, Prague, Czech Republic.;Laboratory of Cellular and Molecular Immunology, Institute of Microbiology of the Czech Academy of Sciences, v.v.i., Prague, Czech Republic.",
"authors": "Hoffmanová|Iva|I|0000-0002-1546-6853;Sánchez|Daniel|D|",
"chemical_list": "D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; C062765:dorzolamide",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.13499",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "84(4)",
"journal": "British journal of clinical pharmacology",
"keywords": "carbonic anhydrase inhibitor; dorzolamide; drug-induced anaemia; drug-induced metabolic acidosis",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000138:Acidosis; D060433:Administration, Ophthalmic; D000740:Anemia; D002257:Carbonic Anhydrase Inhibitors; D005221:Fatigue; D005901:Glaucoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency; D013449:Sulfonamides; D013876:Thiophenes",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "796-799",
"pmc": null,
"pmid": "29333622",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports",
"references": "11929320;26878088;9143858;24611470;27453705;29055034;10448757;11316096;29055040;12881361;10665514;11004298;29149325;15477470;16424547;20931926;2280240;10682964;29333622;25370778;4014383;4964060;3211478;17170419",
"title": "Metabolic acidosis and anaemia associated with dorzolamide in a patient with impaired renal function.",
"title_normalized": "metabolic acidosis and anaemia associated with dorzolamide in a patient with impaired renal function"
} | [
{
"companynumb": "CZ-009507513-1804CZE008847",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
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"activesubstance": {
"activesubstancename": "INSULIN NOS"
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... |
{
"abstract": "Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (EBV-PTLD) is a complication of hematopoietic stem cell transplantation (HSCT). Standard initial treatment of patients with EBV-PTLD includes administration of rituximab or dose reduction of a calcineurin inhibitor. We report successful chemotherapeutic treatment of rituximab-resistant EBV-PTLD after HSCT in a patient with severe aplastic anemia (AA). A 38-year-old woman with antithymocyte globulin (ATG)-resistant severe AA received bone marrow transplantation from an unrelated donor (human leukocyte antigen-DR single-locus mismatch). The conditioning regimen included fludarabine, cyclophosphamide, ATG, and total body irradiation, and prophylaxis for graft-versus-host disease consisted of short methotrexate and tacrolimus. Neutrophil engraftment occurred on day 21. Left cervical lymph node swelling was observed after day 45, and analysis of a biopsy specimen revealed EBV-PTLD and a high blood EBV load (56,000 copies). The patient was treated with rituximab 4 times per week, but the lymphadenopathy continued and the blood EBV load increased to 96,000 copies. Half-dose treatment with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone (R-CHOP) was initiated on day 71. After 32 days of treatment with R-CHOP, the patient's neutrophil level was restored to > 0.5 × 10(9)/L and both the lymphadenopathy and the blood EBV load (< 100 copies) were rapidly reduced. Although chemotherapy is not preferred soon after HSCT, it may be an effective strategy for treating patients with rituximab-resistant EBV-PTLD.",
"affiliations": "Department of Internal Medicine, Miyazaki Prefectural Miyazaki Hospital.",
"authors": "Kuriyama|Takuro|T|;Kawano|Noriaki|N|;Yamashita|Kiyoshi|K|;Ueda|Akira|A|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Japan",
"delete": false,
"doi": "10.3960/jslrt.54.149",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1346-4280",
"issue": "54(2)",
"journal": "Journal of clinical and experimental hematopathology : JCEH",
"keywords": null,
"medline_ta": "J Clin Exp Hematop",
"mesh_terms": "D000328:Adult; D000741:Anemia, Aplastic; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D020031:Epstein-Barr Virus Infections; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D004854:Herpesvirus 4, Human; D006801:Humans; D008232:Lymphoproliferative Disorders; D011241:Prednisone; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "101141257",
"other_id": null,
"pages": "149-53",
"pmc": null,
"pmid": "25318948",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of Rituximab-resistant Epstein-Barr virus-associated post-transplant lymphoproliferative disorder using R-CHOP.",
"title_normalized": "successful treatment of rituximab resistant epstein barr virus associated post transplant lymphoproliferative disorder using r chop"
} | [
{
"companynumb": "JP-SA-2014SA159803",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Amiodarone is an antiarrhythmic agent that is used commonly in clinical practice. It is associated with many side effects, the most common being pulmonary manifestations. Interstitial pneumonitis is one of the most common complications, however rarely amiodarone can cause diffuse alveolar haemorrhage (DAH) too. We describe the case of a 73-year-old woman who presented with shortness of breath and haemoptysis 4 days after starting amiodarone. She was diagnosed with amiodarone-induced DAH based on imaging and bronchoalveolar lavage. She was treated with intravenous and then oral steroids, and amiodarone was discontinued. The patient made a significant clinical and radiological recovery. She was discharged 10 days after her presentation. This case highlights a rare but potentially life-threatening complication of a commonly used medication.",
"affiliations": "Internal Medicine, Khyber Medical College, Peshawar, Pakistan.;Internal Medicine, University of South Dakota Sanford, School of Medicine, Sioux Falls, South Dakota, USA.;Internal Medicine, Khyber Teaching Hospital, Peshawar, Pakistan.;Internal Medicine, University of South Dakota Sanford, School of Medicine, Sioux Falls, South Dakota, USA ammar.abdullah@usd.edu.",
"authors": "Saeed|Jamaluddin|J|;Waqas|Qazi Ahmed|QA|;Khan|Uzma Ikhtiar|UI|;Abdullah|Hafez Mohammad Ammar|HMA|http://orcid.org/0000-0002-8261-6997",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D013256:Steroids; D000638:Amiodarone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-232149",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(10)",
"journal": "BMJ case reports",
"keywords": "arrhythmias; respiratory medicine; unwanted effects/adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D003937:Diagnosis, Differential; D005260:Female; D006470:Hemorrhage; D006801:Humans; D017563:Lung Diseases, Interstitial; D011859:Radiography; D013256:Steroids",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31653638",
"pubdate": "2019-10-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10385163;8275760;11909587;9149610;22781588;15062598;15078784;9856693;18591791;3799544;6695354;16634249;20356785;22338993;2182274;18307045;7789497;7405817;3763811",
"title": "Amiodarone-induced diffuse alveolar haemorrhage: a rare but potentially life-threatening complication of a commonly prescribed medication.",
"title_normalized": "amiodarone induced diffuse alveolar haemorrhage a rare but potentially life threatening complication of a commonly prescribed medication"
} | [
{
"companynumb": "PK-PFIZER INC-2019485853",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMIODARONE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Vilazodone is an FDA approved medication used to treat major depressive disorder. The authors describe two cases of accidental vilazodone exposure in toddlers who presented with symptoms similar to amphetamine exposure and also with unexplained positive amphetamine urine immunoassay drug screens. Given a lack of published data on cross-reactivity of vilazodone and its metabolites with drug of abuse screening tests, the authors investigated drug of abuse immunoassay cross-reactivity of vilazodone and metabolites using computational and empirical approaches.\nTo ascertain the likelihood that vilazodone would cross-react with drug of abuse screening immunoassays, the authors assessed the two-dimensional (2D) similarity of the vilazodone parent molecule and known metabolites to an array of antigenic targets for urine immunoassay drug screens. To facilitate studies of the commercially unavailable M17 metabolite, it was prepared synthetically through a novel scheme. Urine and serum were spiked with vilazodone and M17 into urine (200-100,000 ng/mL) and serum (20-2000 ng/mL) samples and tested for cross-reactivity.\nComputational analysis using 2D similarity showed that vilazodone and metabolites have generally low similarity to antigenic targets of common drug of abuse screening immunoassays, predicting weak or no cross-reactivity. The M17 metabolite had 2D similarity to amphetamines and tricyclic antidepressants in a range similar to some other compounds exhibiting weak cross-reactivity on these immunoassays. Cross-reactivity testing was therefore performed on two different urine amphetamines immunoassays and a serum tricyclic antidepressant immunoassay. However, actual testing of cross reactivity for vilazodone and the M17 metabolite did not detect cross-reactivity for any urine amphetamines screen at concentrations up to 100,000 ng/mL and for a serum tricyclic antidepressants assays at concentrations up to 2000 ng/mL.\nWhile the vilazodone metabolite M17 has weak 2D structural similarity to amphetamines and tricyclic antidepressants, the current study did not demonstrate any experimental cross-reactivity with two different urine amphetamines immunoassays and a serum tricyclic antidepressant immunoassay. Vilazodone ingestions in young children present a diagnostic challenge in their similarity to amphetamine ingestions and the lack of routine laboratory tests for vilazodone. Further work is needed to understand the metabolic profile for vilazodone in children versus adults.",
"affiliations": "1Department of Chemistry, College of Sciences, NC State University, Raleigh, NC 27695 USA.;3Department of Emergency Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242 USA.;1Department of Chemistry, College of Sciences, NC State University, Raleigh, NC 27695 USA.;4Department of Pathology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242 USA.;5Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, NC 27606 USA.;6Stead Family Department of Pediatrics, University of Iowa Stead Family Children's Hospital, Iowa City, Iowa 52242 USA.;4Department of Pathology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242 USA.;7Clinical Laboratories, University of Pittsburgh Medical Center Presbyterian Hospital, Pittsburgh, PA USA.;7Clinical Laboratories, University of Pittsburgh Medical Center Presbyterian Hospital, Pittsburgh, PA USA.;4Department of Pathology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242 USA.",
"authors": "Martinez-Brokaw|Christina D|CD|;Radke|Joshua B|JB|;Pierce|Joshua G|JG|;Ehlers|Alexandra|A|;Ekins|Sean|S|;Wood|Kelly E|KE|;Maakestad|Jon|J|;Rymer|Jacqueline A|JA|;Tamama|Kenichi|K|;Krasowski|Matthew D|MD|0000-0003-0856-8402",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12907-019-0084-9",
"fulltext": "\n==== Front\nBMC Clin PatholBMC Clin PatholBMC Clinical Pathology1472-6890BioMed Central London 8410.1186/s12907-019-0084-9Research ArticleAccidental intoxications in toddlers: lack of cross-reactivity of vilazodone and its urinary metabolite M17 with drug of abuse screening immunoassays Martinez-Brokaw Christina D. cdmarti3@ncsu.edu 12Radke Joshua B. joshua-radke@uiowa.edu 3Pierce Joshua G. jgpierce@ncsu.edu 12Ehlers Alexandra alexandra-ehlers@uiowa.edu 4Ekins Sean collaborationspharma@gmail.com 5Wood Kelly E. kelly-wood@uiowa.edu 6Maakestad Jon jon-maakestad@uiowa.edu 4Rymer Jacqueline A. rymerja@upmc.edu 7Tamama Kenichi tamamakj@upmc.edu 78910http://orcid.org/0000-0003-0856-8402Krasowski Matthew D. 319-384-9380mkrasows@healthcare.uiowa.edu 41 0000 0001 2173 6074grid.40803.3fDepartment of Chemistry, College of Sciences, NC State University, Raleigh, NC 27695 USA 2 0000 0001 2173 6074grid.40803.3fComparative Medicine Institute, NC State University, Raleigh, NC 27695 USA 3 0000 0004 0434 9816grid.412584.eDepartment of Emergency Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242 USA 4 0000 0004 0434 9816grid.412584.eDepartment of Pathology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242 USA 5 grid.492575.8Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, NC 27606 USA 6 0000 0004 1936 8294grid.214572.7Stead Family Department of Pediatrics, University of Iowa Stead Family Children’s Hospital, Iowa City, Iowa 52242 USA 7 0000 0004 0462 9068grid.461860.dClinical Laboratories, University of Pittsburgh Medical Center Presbyterian Hospital, Pittsburgh, PA USA 8 0000 0004 1936 9000grid.21925.3dDepartment of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA 9 0000 0004 1936 9000grid.21925.3dMcGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA USA 10 0000 0000 9753 0008grid.239553.bClinical Laboratory, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA USA 18 2 2019 18 2 2019 2019 19 218 5 2018 7 2 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nVilazodone is an FDA approved medication used to treat major depressive disorder. The authors describe two cases of accidental vilazodone exposure in toddlers who presented with symptoms similar to amphetamine exposure and also with unexplained positive amphetamine urine immunoassay drug screens. Given a lack of published data on cross-reactivity of vilazodone and its metabolites with drug of abuse screening tests, the authors investigated drug of abuse immunoassay cross-reactivity of vilazodone and metabolites using computational and empirical approaches.\n\nMethods\nTo ascertain the likelihood that vilazodone would cross-react with drug of abuse screening immunoassays, the authors assessed the two-dimensional (2D) similarity of the vilazodone parent molecule and known metabolites to an array of antigenic targets for urine immunoassay drug screens. To facilitate studies of the commercially unavailable M17 metabolite, it was prepared synthetically through a novel scheme. Urine and serum were spiked with vilazodone and M17 into urine (200–100,000 ng/mL) and serum (20–2000 ng/mL) samples and tested for cross-reactivity.\n\nResults\nComputational analysis using 2D similarity showed that vilazodone and metabolites have generally low similarity to antigenic targets of common drug of abuse screening immunoassays, predicting weak or no cross-reactivity. The M17 metabolite had 2D similarity to amphetamines and tricyclic antidepressants in a range similar to some other compounds exhibiting weak cross-reactivity on these immunoassays. Cross-reactivity testing was therefore performed on two different urine amphetamines immunoassays and a serum tricyclic antidepressant immunoassay. However, actual testing of cross reactivity for vilazodone and the M17 metabolite did not detect cross-reactivity for any urine amphetamines screen at concentrations up to 100,000 ng/mL and for a serum tricyclic antidepressants assays at concentrations up to 2000 ng/mL.\n\nConclusion\nWhile the vilazodone metabolite M17 has weak 2D structural similarity to amphetamines and tricyclic antidepressants, the current study did not demonstrate any experimental cross-reactivity with two different urine amphetamines immunoassays and a serum tricyclic antidepressant immunoassay. Vilazodone ingestions in young children present a diagnostic challenge in their similarity to amphetamine ingestions and the lack of routine laboratory tests for vilazodone. Further work is needed to understand the metabolic profile for vilazodone in children versus adults.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12907-019-0084-9) contains supplementary material, which is available to authorized users.\n\nKeywords\nAmphetaminesFalse positive reactionsImmunoassaySimilarityToxicologyissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nVilazodone is a medication that is used to treat major depressive disorder [1, 2]. Vilazodone was approved by the United States Food and Drug Administration in 2011 and is a selective serotonin reuptake inhibitor (SSRI) that also has partial serotonin (5-hydroxytryptamine; 5-HT) agonist activity at the 5-HT1A receptor [3]. Efficacy and tolerability in adult patients appear to be similar to other SSRIs [2]. Vilazodone is marketed for adult patients, and there are no published studies of metabolism, pharmacokinetics or clinical efficacy of vilazodone in children.\n\nWhile overdose data for vilazodone is limited, toxic effects appear to be similar to effects seen with other SSRIs [2]. The medication reaches peak serum concentration 4 to 5 h after ingestion [4]. The most commonly reported effects in overdose are drowsiness, vomiting, tachycardia, and agitation [5–12]. Seizures and serotonin syndrome have been reported in accidental pediatric ingestions [5, 6, 9, 10]. The United States National Poison Data System contained 753 reports of vilazodone ingestions in children younger than 6 years of age from 2011 through 2016 [8]. Overall, tachycardia, agitation, tremor, and seizures (or seizure-like activity) appear to be more common with accidental vilazodone poisonings in young children as compared with similar ingestions of other SSRIs [8, 12].\n\nVilazodone has a complicated metabolic pathway in humans and other mammals [4, 13–15]. To date, vilazodone pharmacokinetic studies have only been done in adults. Two of the main metabolites in human urine have been designated M10 and M17 [14]. M10 is the carboxylic acid derivative of vilazodone, while M17 is the butyric acid of the indole fragment of the N-dealkylation product of vilazodone (Fig. 1). Additional metabolites include M13 (6-hydroxyvilazodone), the 5-cyano-6-hydroxy indole metabolite of vilazodone [14]. M13 is further modified by glucuronidation or sulfation of the 6-hydroxyurea moiety. While vilazodone and the M10 and M13 metabolites are identical in chemical structure except for one functional group, M17 is much more distinct, being a smaller fragment and modification of the vilazodone structure.Fig. 1 Metabolic Pathways of Vilazodone. Information compiled from multiple sources [4, 13–15]\n\n\n\nIn previous publications, we reported case series of accidental ingestions of amphetamine and other drugs associated with similar clinical signs and symptoms on overdose. This also included retrospective analysis of potential causes of amphetamine positive immunoassay screens [16, 17]. Vilazodone was identified as a drug associated with unexplained positive amphetamine urine immunoassay drug screens in 2 toddlers. We found no published data, either in journal articles or assay package inserts, on vilazodone or vilazodone metabolite cross-reactivity with drug of abuse immunoassay screening tests. In addition, we found no commercial sources for any of the recognized vilazodone metabolites.\n\nWe thus investigated whether vilazodone and metabolites were likely to produce cross-reactivity on drug of abuse immunoassay screens using two main approaches. First, we utilized computational two-dimensional (2D)-similarity methods to compare the structural similarity of vilazodone and its recognized metabolites to the antigenic targets of urine immunoassay screens including amphetamines. We have previously used this methodology for the prediction of cross-reactivity of compounds to drug of abuse screening and therapeutic drug monitoring assays [18–22]. In the present study, these methods identified the M17 metabolite as potentially weakly cross-reactive with amphetamines and tricyclic antidepressant (TCA) immunoassays, although with relatively low 2D similarity compared to known cross-reactive compounds for these assays. Because M17 was not commercially available, we developed a novel synthetic scheme for this compound and report the synthetic details in this report along with cross-reactivity testing. Second, we tested vilazodone and the M17 metabolite for cross-reactivity on two different urine amphetamines screens and also a serum TCA immunoassay.\n\nMethods\nInstitutional setting and electronic medical record review\nUniversity of Iowa Hospitals and Clinics (UIHC) is a 761 bed tertiary/quaternary care academic medical center located in Iowa City, Iowa. As described in our previous studies, Epic Reporting Workbench (RWB) search functions were used to identify patients from data in the electronic medical record (EMR) based on specific parameters [23]. RWB search queries identified patients who had urine amphetamine screening performed and who were known to be prescribed vilazodone. RWB queries also interrogated problem lists and diagnosis codes for drug overdoses to identify any additional vilazodone ingestions treated at UIHC.\n\n2D molecular similarity analysis\nComparison of similarity of test molecules to the target compounds of drug of abuse screening immunoassays used 2D similarity analysis, which determines the similarity between molecules independent of any in vitro data [24–26]. We have applied these methods in previous publications on cross-reactivity of drug of abuse screening and other immunoassays [18, 19, 21, 22, 27]. 2D similarity searching used the “find similar molecules by fingerprints” protocol in Discovery Studio version 3.5 (Biovia, San Diego, California, USA). MDL public keys (a specific 2D similarity algorithm) were used with an input query and with the Tanimoto similarity coefficient as the output (the coefficient ranges from 0 to 1, with 1 being maximally similar and 0 being maximally dissimilar; a comparison of a compound with itself or to a very closely related molecule can produce an output of 1). 2D similarity for each test compound was compared to the target molecule of the immunoassay. We compared the 2D similarities to our previous studies modelling immunoassay cross-reactivity [18, 19, 21, 22].\n\nChemical synthesis of Vilazodone metabolite M17\nThe synthesis scheme for the vilazodone metabolite M17 is summarized in Fig. 2, and the detailed procedures and characterization data can be found in Additional File 1.Fig. 2 Chemical Synthetic Scheme for the M17 Metabolite of Vilazodone\n\n\n\nCross-reactivity studies\nAs detailed in the Results section, 2D molecular similarity analysis revealed potential weak cross-reactivity of the vilazodone M17 metabolite with the targets of amphetamines and TCA immunoassays. We therefore tested the vilazodone parent drug (Sigma-Aldrich, St. Louis, MO) and M17 metabolite on two different urine amphetamines immunoassays – Roche Diagnostics (Indianapolis, IN) Amphetamines II Assay (version 9.0) run on cobas c502 analyzer and Siemens Syva Emit II plus Amphetamines Assay (version 2013–07) run on a Viva-E analyzer (Siemens Diagnostics, Tarrytown, NY). We also tested the compounds on the Roche Diagnostics Benzodiazepines Plus (version 10.0), Cocaine II (version 7.0), Opiates II (version 11.0), Oxycodone (version 7.0), and Cannabinoids II (version 9.0). Serum TCA screening was performed with the Syva Emit tox Serum Tricyclic Antidepressants Assay (version 2012–06) run on a Viva-E analyzer.\n\nCross-reactivity testing was performed as previously described [21] up to a concentration of 100,000 ng/mL spiked in drug-free urine (200 ng/mL, 2000 ng/mL, 10,000 ng/mL, and 100,000 ng/mL). We found no prior literature on urine vilazodone concentrations but, as described below, case #1 had a urine vilazodone concentration of 120 ng/mL. We tested up to 100,000 ng/mL for vilazodone and the metabolite M17 as this covers approximately three orders of magnitude beyond the 120 ng/mL and was the highest feasible concentration given limited availability of the custom-synthesized M17 compound.\n\nPublished pharmacokinetic studies of vilazodone in adults show maximum serum/plasma concentrations of approximately 150 ng/mL or below for vilazodone and M17 [4, 13]. A report of two children who experienced seizures following accidental vilazodone ingestion reported serum concentrations of vilazodone [7]. A 3 year old boy who ingested up to seven 40-mg tablets from a foil pack had serum vilazodone concentrations of 1600 ng/mL and 360 ng/mL, respectively, from samples drawn 4 and 27 h after ingestion. A 28 month old boy who ingested a single 40 mg tablet had a serum concentration of 370 ng/mL in a sample drawn 4 h after ingestion. For serum TCA testing, compounds were spiked into drug-free serum at concentrations up to 2000 ng/mL (20 ng/mL, 200 ng/mL, and 2000 ng/mL) to cover the range of serum concentrations observed in these studies.\n\nResults\nCase histories of toddlers with accidental vilazodone ingestions\nCase #1\nA previously healthy 2 year old boy was noted by his father at 2200 to have a “blank stare”, clenched teeth, and unresponsiveness to verbal, visual, or tactile stimuli. The patient had been normal at 1930 prior to bedtime. The patient was unable to walk and had “shaking” and restless movements of his extremities. He was taken to outside hospital (OSH) where examination showed heart rates in the 130–170 beats per minute (bpm) range, blood pressure (BP) of 110/72 mmHg, respiratory rate (RR) 30/min, body temperature 38.2 °C, and oxygen saturation of 95% on room air. On neurologic exam, he was moving all extremities but was not speaking or making eye contact.\n\nDiagnostic testing included a complete metabolic panel, a complete blood count, urinalysis, UDS, and non-contrast computed tomography (CT) of the head. All laboratory and radiology studies were within normal limits except a result of “presumptive positive” for amphetamines on urine drug screening (UDS), with the remainder of the UDS panel (barbiturates, benzodiazepines, cocaine metabolite, opiates, phencyclidine, and tetrahydrocannabinol) being negative (Roche Diagnostics cobas 6000 system). Confirmatory amphetamine testing was not pursued. The patient was given 0.25 mg (0.02 mg/kg based on patient weight of 12.4 kg) of lorazepam for continued seizure-like activity. The presumptive diagnosis upon transfer was amphetamines intoxication.\n\nThe patient was transferred to UIHC on day #2 at 0430. On neurologic examination, his mental status was appropriate, with markedly dilated pupils responsive to light. Similar to the OSH, UDS performed at UIHC revealed a presumptive positive amphetamines screen with remainder of UDS panel (benzodiazepines, cocaine metabolite, opiates, and oxycodone/oxymorphone) negative (Roche Diagnostics cobas 8000 system). He continued to have unsteady gait with tremoring of his legs when bearing weight which steadily improved. The patient was discharged home on day #3 at 1130 with normal vital signs and physical examination.\n\nMedications in the home included vilazodone (mother’s medication), doxylamine/vitamin B6, and multivitamins. Parents denied the presence of any amphetamine-containing medications in the house or other possible exposure to amphetamine or methamphetamine. Confirmatory urine amphetamines testing by liquid chromatography/tandem mass spectrometry (LC/MS/MS) was performed by reference laboratory (ARUP Laboratories, Salt Lake City, UT) and was negative for amphetamine, methamphetamine, methylenedioxyamphetamine (MDA), methylenedioxymethamphetamine (MDMA), and methylenedioxyethylamphetamine (MDEA) (lower limit of quantitation 200 ng/mL for all 5 analytes). Analysis of the urine specimen for vilazodone by LC/MS/MS (NMS Labs, Willow Grove, PA) was performed and returned a quantitative level of 130 ng/mL.\n\nCase #2\nA 2 year old girl was noted by family members to exhibit odd behavior starting at 1130 with restlessness, flailing limbs, and rolling around on the ground. This progressed to periods of unresponsiveness where she would stare blankly. The patient had been playing while the mother was in another room around 1000. The mother noticed that the patient had taken out a pen from her purse but did not immediately suspect that she may have gotten into medications in the purse.\n\nThe patient was taken to a local emergency department at an OSH. Physical examination showed heart rates in the 150–170 bpm range, blood pressure of 106/75 mmHg, respiratory rate 30/min, body temperature 38.5 °C, and oxygen saturation of 97–100% on room air. The patient was unresponsive to verbal commands and showed involuntary movements of all extremities. Pupils were bilaterally dilated and equally reactive to light. She was given 1 mg of lorazepam (0.07 mg/kg based on weight of 14.1 kg) for the presumed seizure-like movements and transferred to UIHC for further management.\n\nOn arrival at UIHC emergency department at 1510, she was more talkative but still not at baseline mental status per family. Physical examination showed heart rates in the 130–160 bpm range, BP of 110/68 mmHg, RR 26–30/min, body temperature 37.1 °C, and oxygen saturation of 98–100% on room air. UDS revealed a presumptive positive amphetamines screen with remainder of UDS panel (benzodiazepines, cocaine metabolite, opiates, and oxycodone/oxymorphone) negative. Confirmatory urine drug testing and urine vilazodone levels were not ordered by the clinical team. On neurologic examination, the patient was more talkative and showed disorganized persistent extremity movements. These were not thought to be seizures. After examination, the patient became tired and fell asleep shortly after arrival and was back to her baseline on waking. She was discharged home on morning of day #2 with normal vital signs and physical examination.\n\nQuestioning of the family for medications that might be accessible to the child revealed that the mother’s purse contained both a bottle and foil pack of vilazodone tablets. The foil packet was missing tablets, and the mother could not recall how many tablets were there before the patient played with the purse. Further investigation revealed no likely source of amphetamines.\n\nSearch for additional cases\nInterrogation of the EMR database at UIHC did not reveal any other vilazodone ingestions in children 8 years of age or younger during the retrospective period, including in 4407 negative amphetamine screens in patients in this age range. We also searched for overlap between patients known to be actively prescribed vilazodone and positive amphetamine screens. Of 1430 adult patients (18 year or older) and 20 pediatric patients (younger than 18 years old) prescribed vilazodone and who presented at our hospital for care, none had a positive amphetamines screen during the retrospective analysis period.\n\n2D similarity of vilazodone and metabolites to amphetamines\nGiven that only vilazodone reference standards are available commercially, studies of vilazodone metabolites for cross-reactivity require novel synthesis. To help prioritize which metabolites to pursue for novel synthesis and subsequent cross-reactivity testing, we performed computational 2D similarity analysis of vilazodone and its metabolites to the target compounds of amphetamines (Table 1). Vilazodone and the M10 and M13 metabolites each had 2D similarity to amphetamine and methamphetamine below any previously characterized compound that showed detectable cross-reactivity to amphetamines immunoassay screen (Table 1) [19, 21, 22], thus predicting low likelihood of cross-reactivity.Table 1 2D Similarity of Vilazodone and its Metabolites to Target Molecules of Drug of Abuse Immunoassays1\n\n\tVilazodone\tM10 metabolite\tM17 metabolite\tM13 (6-Hydroxyvilazodone)\tLowest 2D similarity of cross-reactive compound\n(previous studies)\t\n\nAmphetamines\n\t\n Amphetamine\t0.18\t0.17\t\n0.24\n\t0.16\tmCPP, TFMPP (0.23)2\t\n Methamphetamine\t0.16\t0.16\t\n0.23\n\t0.14\tmCPP, TFMPP (0.22) 2\t\n MDMA/ecstasy\t\n0.33\n\t\n0.38\n\t\n0.37\n\t\n0.35\n\tmCPP, TFMPP (0.25) 2\t\n\nBarbiturates\n\t\n Secobarbital\t0.39\t0.36\t0.28\t0.42\tp-Hydroxyphenobarbital (0.72)\t\n\nBenzodiazepines\n\t\n Nordiazepam\t0.44\t0.37\t0.33\t0.43\tα-Hydroxytriazolam (0.52)\t\n Oxazepam\t0.44\t0.41\t0.36\t0.46\tAlprazolam (0.47)\t\n\nCannabinoids\n\t\n Δ9-THC-COOH\t0.25\t0.29\t0.27\t0.30\tCannabinol (0.80)\t\n\nCocaine metabolites\n\nBenzoylecgonine\t0.41\t0.50\t0.34\t0.46\tCocaethylene (0.85)\t\n\nOpiates\n\t\n Morphine\t0.50\t0.57\t0.30\t0.57\tRifampin (0.59)\t\n Oxycodone\t0.51\t0.55\t0.34\t0.57\tNoroxycodone (0.79)\t\n Phencyclidine\t0.46\t0.46\t0.22\t0.41\tDextromethorphan (0.57)\t\n\nSynthetic opioids\n\t\n Buprenorphine\t0.50\t0.57\t0.33\t0.58\tBuprenorphine glucuronide (0.78)\t\n Methadone\t0.31\t0.31\t0.31\t0.28\tMethadol (0.86)\t\n\nTricyclic compounds\n\t\n Desipramine\t\n0.45\n\t\n0.45\n\t0.33\t\n0.42\n\tCarbamazepine epoxide (0.40)\t\n Imipramine\t\n0.43\n\t\n0.44\n\t0.27\t\n0.41\n\tCarbamazepine epoxide (0.38)\t\n1 Values in bold are cases where the 2D similarity is higher than a known cross-reactive compound reported in an assay package insert or published literature\n\n2 Abbreviations: mCPP, Meta-chlorophenylpiperazine; TFMPP, Trifluoromethylphenylpiperazine\n\n\n\nThe M17 metabolite had 2D similarity to amphetamine and methamphetamine of Tanimoto coefficients of 0.24 and 0.23, respectively (scale of 0–1, with 0 being maximally dissimilar and 1 being very similar). This is only slightly higher than the lowest 2D similarity of compounds observed to be cross-reactive with amphetamines immunoassays (meta-chlorophenylpiperazine, mCPP; trifluoromethylphenylpiperazine, TFMPP); note that many compounds with this low of a 2D similarity to amphetamine or methamphetamine show no cross-reactivity and only a small fraction demonstrate weak cross-reactivity in experimental testing [19, 21, 22]. Vilazodone, M10, M13, and M17 all had low 2D similarities to MDMA/ecstasy, predicting no cross-reactivity or only by challenge with very high concentrations of the compound [21, 22].\n\nWe also compared 2D similarity of vilazodone and its metabolites to common target compounds of other drug of abuse immunoassays (barbiturates, benzodiazepines, buprenorphine, cannabinoids, cocaine metabolite, methadone, opiates, phencyclidine, and TCAs). In general, this revealed that vilazodone and its metabolites had lower 2D similarity to the target compounds of these immunoassays than compounds recognized to be cross-reactive to these assays (Table 1) [19, 21, 22]. The only exception was for the TCA immunoassay targets (desipramine and imipramine), for which vilazodone, M10, and M13 had 2D similarity slightly above that of carbamazepine epoxide, a drug metabolite with weak cross-reactivity to some marketed TCA immunoassays [21].\n\nCross-reactivity testing\nWe therefore pursued novel chemical synthesis of M17, reasoning that it would be more likely distinct from vilazodone in immunoassay cross-reactivity testing based on the 2D similarity predictions. An overview of the chemical synthesis of M17 is provided in Fig. 2, with the detailed procedures and characterization data in Additional File 1. We tested vilazodone and its metabolite M17 for cross-reactivity to the Roche cobas 8000 urine drug immunoassays for amphetamines, benzodiazepines, cocaine metabolite, opiates, oxycodone/oxymorphone, and THC. However, we detected no cross-reactivity at concentrations up to 100,000 ng/mL for vilazodone and M17 (spiked into drug-free urine) for any of the immunoassays including amphetamines. We also did not detect any cross-reactivity for a serum TCA immunoassay at concentrations up to 2000 ng/mL.\n\nDiscussion\nThere have been case reports/series and analyses of poison center reports on the signs and symptoms of vilazodone overdose in young children [5–12]. Tachycardia, agitation, tremor, and seizures were more common in poison center data with pediatric vilazodone ingestions as compared to other SSRIs [8, 12]. Ingestions in young children generally show complete recovery of function following resolution of symptoms of intoxication.\n\nThe two cases of vilazodone intoxication described in the present study caused some diagnostic confusion due to presumptive positive drug screens for amphetamines at two different hospitals (albeit by same methodology) along with clinical signs and symptoms resembling amphetamines overdose [16, 17]. Case #1 had confirmatory testing negative for amphetamines by LC/MS/MS and specialty laboratory analysis (also by LC/MS/MS) that detected vilazodone in urine, although these results came back after the child was discharged from the hospital. Case #2 occurred prior to the availability of vilazodone testing at reference laboratories. The similarity of vilazodone overdoses to amphetamines toxicity demonstrate the importance of confirmatory analysis to rule out amphetamine and methamphetamine exposure. Consideration of vilazodone ingestion in both cases only came after more detailed household history could be elicited. Analysis of vilazodone in serum or urine is not routinely available at most clinical laboratories but is performed by some specialty reference laboratories.\n\nAccidental ingestion of amphetamines, including methamphetamine or prescription amphetamines, is common in young children, and the presenting signs and symptoms overlap to some degree with those potentially caused by vilazodone [16, 17, 28–30]. Symptoms of tremor/seizure-like movements, tachycardia, mydriasis, and agitation may also be seen with amphetamine toxicity. One clinical benefit of confirmatory testing is to help rule out child exposure to methamphetamine, which could be associated with additional risks such as living at a home illicitly manufacturing this drug.\n\nImmunoassays for amphetamines are generally intended to optimally detect amphetamine, methamphetamine, and sometimes related drugs such as MDMA/ecstasy, MDA, and MDEA [18, 19, 21, 22, 31]. The target hapten for these assays may be amphetamine, methamphetamine, and/or MDMA, contributing to observed differences in cross-reactivity for various marketed amphetamines immunoassays [18, 21, 22]. Amphetamines assays have highly variable cross-reactivity with other structurally related compounds such as ephedrine, pseudoephedrine, phenylpropanolamine, and various ‘designer amphetamines’ such as mephedrone and methcathinone [21, 22, 32]. Amphetamines immunoassays are also subject to false positives by less obviously structurally related compounds such as 1-methyl-3-phenylpiperazine (a metabolite of the antihypertensive medication labetalol) [33–35] and mCPP (metabolite of trazodone) [36–39]. There is significant variability in testing and reporting of cross-reactive compounds, especially drug metabolites, in package inserts of commercially marketed amphetamines screening assays [40].\n\nWe investigated whether vilazodone and its major metabolites were likely to cross-react with amphetamines immunoassays using computational prediction by 2D similarity analysis. We chose 2D analysis, because we have explored 3D methods with our previous studies with amphetamines and amphetamine-like drugs but found that these do not perform well for predictions except for very closely related compounds (e.g., amphetamine, methamphetamine, MDMA) [18, 21, 22]. Among many challenges, predicting the correct molecular conformation for 3D modeling is difficult.\n\nThe 2D computational studies showed vilazodone and two metabolites (M10 and M13) were unlikely to show cross-reactivity with commonly used drug of abuse immunoassays. On the other hand, the M17 metabolite (a cleavage product of vilazodone) had some 2D similarity with amphetamines in a range in which some compounds such as mCPP and 4-chlorophenypiperazine show weak cross-reactivity with some amphetamines immunoassays. However, multiple other compounds that show no cross-reactivity to amphetamines immunoassays, including methylphenidate and labetalol (parent drug), have a similar 2D similarity profile, illustrating the challenges in predicting compounds with weak cross-reactivity [18, 22].\n\nOur own empirical testing of the Roche Diagnostics Amphetamines II and Siemens Emit II plus Amphetamines immunoassays showed no cross-reactivity with either vilazodone or the M17 metabolite at concentrations up to 100,000 ng/mL. In addition, serum samples spiked with vilazodone or M17 up to 2000 ng/mL did not cross-react with a serum TCA immunoassay, another categories of compounds to which vilazodone has some 2D similarity. This lack of experimental cross-reactivity with urine amphetamines immunoassays suggest that the positive screens in the clinical cases are either coincidental (and caused by some other factor) or result from an additional metabolite of vilazodone not tested. We think it is unlikely that metabolites M10 or M13 cross-react with amphetamines immunoassays as these are very close in structure to vilazodone. However, it should be pointed out that the reported metabolic pathway for vilazodone has only been worked out in adults, with essentially no data on the metabolic pathway for vilazodone in young children [4, 13–15]. A number of drug-metabolizing enzymes show significant age-dependent differences in expression and functional activity [41]. There is precedence for uncharacterized metabolites in young children cross-reacting with immunoassays. Such a phenomenon has been proposed to explain positive THC immunoassay screens in newborns with known exposure to cannabis in utero, where the immunoassay screen is positive but with a mass spectrometry-based THC confirmatory assay negative for THC metabolites common in adults [42].\n\nConclusions\nIn summary, vilazodone and its M17 metabolite did not demonstrate cross-reactivity with amphetamines, tricyclic antidepressants, or other common drug of abuse screening immunoassays. Healthcare professionals and clinical laboratories should be aware of the similarities in the clinical presentations of vilazodone and amphetamine toxicity in children and utilize confirmatory testing when indicated. Future studies can also aim to elucidate the metabolism profile for vilazodone in children versus adults, including in overdose situations.\n\nAdditional file\n\nAdditional file 1: Chemical Synthesis and Characterization of Vilazodone Metabolite M17. (DOCX 27 kb)\n\n \n\n\nAbbreviations\n2DTwo-dimensional\n\n5-HTSerotonin or 5-hydroxytryptamine\n\nLC/MS/MSLiquid chromatography-tandem mass spectrometry\n\nmCPPMeta-chlorophenylpiperazine\n\nMDMA3,4-methylenedioxymethamphetamine (ecstasy)\n\nSSRISelective serotonin reuptake inhibitor\n\nTFMPPTrifluoromethylphenylpiperazine\n\nUDSUrine drug screening\n\nAcknowledgements\nSE kindly acknowledges Biovia for providing Discovery Studio.\n\nFunding\nCDM and JGP acknowledge NC State University for financial support. The authors are grateful for the Molecular Education, Technology and Research Innovation Center (METRIC) at NC State University for analytical support (1H and 13C NMR).\n\nAvailability of data and materials\nThe datasets and materials used and analysed during the current study are available from the corresponding author on request.\n\nAuthors’ contributions\nSE and MDK were involved in the study concept and design along with analysis and interpretation of the data. CDM and JGP prepared the novel synthesis of the M17 metabolite. AE, JM, JAS, and KT performed cross-reactivity testing. JBR and KEW were involved with description of the case studies and associated literature review on vilazodone and amphetamines toxicity. All authors participated in drafting and revisions of the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThis study had approval from the University of Iowa Institutional Review Board as a retrospective study (protocol #201705809).\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors all declare no conflicts of interest apart from SE who is the Chief Executive Officers of Collaborations Pharmaceuticals, Inc.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. 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"fulltext_license": "CC BY",
"issn_linking": "1472-6890",
"issue": "19()",
"journal": "BMC clinical pathology",
"keywords": "Amphetamines; False positive reactions; Immunoassay; Similarity; Toxicology",
"medline_ta": "BMC Clin Pathol",
"mesh_terms": null,
"nlm_unique_id": "101088665",
"other_id": null,
"pages": "2",
"pmc": null,
"pmid": "30820187",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "11407508;15534697;17549046;17555644;17696867;19333148;19342505;19400959;21073812;21252805;21699273;21740694;21775860;22829312;22939301;23178026;23193148;23387345;23578403;23757186;24851137;25071417;25236915;25474324;25646639;25832473;25945081;26099909;26203623;27277955;28271676;28350718;28421837;28590988;28594246;28705022;28875544;28922349;30480089;7769792",
"title": "Accidental intoxications in toddlers: lack of cross-reactivity of vilazodone and its urinary metabolite M17 with drug of abuse screening immunoassays.",
"title_normalized": "accidental intoxications in toddlers lack of cross reactivity of vilazodone and its urinary metabolite m17 with drug of abuse screening immunoassays"
} | [
{
"companynumb": "US-ALLERGAN-1908941US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VILAZODONE HYDROCHLORIDE"
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"drugadditional": "3... |
{
"abstract": "BACKGROUND\nPostoperative thrombotic thrombocytopenic purpura (pTTP) after cardiovascular operations has an alarmingly high mortality rate if untreated. Five patients after coronary artery bypass graft (CABG) procedure were diagnosed with pTTP when they were observed to have a persistent thrombocytopenia associated with symptoms of fever, renal insufficiency, thromboembolic events, or altered mental status in conjunction with a microangiopathic hemolytic anemia (MAHA). A guideline for early diagnosis, followed by timely treatment in these cases, is reviewed.\n\n\nMETHODS\nA retrospective record review of postoperative patients with thrombocytopenia identified 5 patients that met the criteria for pTTP from 2004 to 2008. We examined these 5 cardiovascular surgical patients in terms of clinical presentation, laboratory data, and outcomes.\n\n\nRESULTS\nAll patients had the combination of an unexplained thrombocytopenia (platelets < 50,000 mm(3)) in conjunction with a MAHA as determined by the presence of schistocytes. Symptoms of neurologic dysfunction and renal insufficiency developed in all patients. Thromboembolic events were noted in 1 patient. All patients underwent plasmapheresis. In 3 patients, response time to clinical recovery and normalization of hematologic laboratory values after plasmapheresis was 3, 4, and 8 days. Two patients did not recover and died. One patient had a clinical and laboratory recovery after 19 days of plasmapheresis; however, after 11 days, thrombocytopenia with MAHA developed and he died on day 53 from complications related to the operation.\n\n\nCONCLUSIONS\nPostoperative TTP should be recognized as a possible pathophysiologic mechanism for unexplained postoperative thrombocytopenia and treatment should be initiated once the diagnosis is established.",
"affiliations": "Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles 90095, USA. dsaltzman@mednet.ucla.edu",
"authors": "Saltzman|Darin J|DJ|;Chang|Jae C|JC|;Jimenez|Juan C|JC|;Carson|John G|JG|;Abolhoda|Amir|A|;Newman|Richard S|RS|;Milliken|Jeffrey C|JC|",
"chemical_list": "D014841:von Willebrand Factor",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.athoracsur.2009.09.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "89(1)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D000368:Aged; D006348:Cardiac Surgical Procedures; D003937:Diagnosis, Differential; D005260:Female; D005500:Follow-Up Studies; D006331:Heart Diseases; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010956:Plasmapheresis; D011379:Prognosis; D011697:Purpura, Thrombotic Thrombocytopenic; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed; D014841:von Willebrand Factor",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "119-23",
"pmc": null,
"pmid": "20103218",
"pubdate": "2010-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Postoperative thrombotic thrombocytopenic purpura after open heart operations.",
"title_normalized": "postoperative thrombotic thrombocytopenic purpura after open heart operations"
} | [
{
"companynumb": "US-PFIZER INC-PV202200002335",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nWe describe a case of pemetrexed toxicities related to reabsorption by an ileal neobladder, which caused prolonged hematotoxicity and nephrotoxicity.\n\n\nMETHODS\nA 59-year-old white man was diagnosed with metastatic wild-type adenocarcinoma of the upper lobe of his right lung. After a first cycle of cisplatin and pemetrexed, he had unusually prolonged aplasia and acute kidney injury. The prolonged aplasia was caused by pemetrexed reabsorption by the ileal mucosa of the neobladder as pemetrexed was eliminated renally in an active form and is partly lipophilic.\n\n\nCONCLUSIONS\nPemetrexed may be reabsorbed by the ileal mucosa of the neobladder because of its hydrophobic structure and renal excretion in its active form. Acute urinary retention may maintain this phenomenon. Published data excluded a potential role for cisplatin in this toxicity; furthermore, we could not assess pemetrexed concentrations in the blood or urine as these assay techniques are not validated. Thus, care is needed when giving chemotherapy to patients with a neobladder.",
"affiliations": "Institut de Cancérologie Daniel Hollard, Groupe Hospitalier Mutualiste, 124 rue d'Alembert, 38000, Grenoble, France. l.sakhri@ghm-grenoble.fr.;UM Oncologie Thoracique, Clinique de pneumologie, Pôle Thorax et vaisseaux, Centre Hospitalier Universitaire Michallon, BP217, 38043, Grenoble cedex 9, France.;UM Oncologie Thoracique, Clinique de pneumologie, Pôle Thorax et vaisseaux, Centre Hospitalier Universitaire Michallon, BP217, 38043, Grenoble cedex 9, France.;UM Pharmacie Clinique, Pôle Pharmacie, Centre Hospitalier Universitaire Michallon, BP217, 38043, Grenoble cedex 9, France.",
"authors": "Sakhri|Linda|L|;Pinsolle|Julian|J|;Moro-Sibilot|Denis|D|;Pluchart|Hélène|H|",
"chemical_list": "D000970:Antineoplastic Agents; D000068437:Pemetrexed; D003401:Creatine; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-017-1436-7",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 143610.1186/s13256-017-1436-7Case ReportUnusually prolonged pemetrexed cytotoxicity in a patient with a lung adenocarcinoma: a case report Sakhri Linda +33 (0) 4 76 28 52 32l.sakhri@ghm-grenoble.fr 1Pinsolle Julian jpinsolle@chu-grenoble.fr 2Moro-Sibilot Denis dmoro-sibilot@chu-grenoble.fr 2Pluchart Hélène hpluchart@chu-grenoble.fr 31 Institut de Cancérologie Daniel Hollard, Groupe Hospitalier Mutualiste, 124 rue d’Alembert, 38000 Grenoble, France 2 UM Oncologie Thoracique, Clinique de pneumologie, Pôle Thorax et vaisseaux, Centre Hospitalier Universitaire Michallon, BP217, 38043 Grenoble cedex 9, France 3 UM Pharmacie Clinique, Pôle Pharmacie, Centre Hospitalier Universitaire Michallon, BP217, 38043 Grenoble cedex 9, France 16 9 2017 16 9 2017 2017 11 26220 4 2017 27 8 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\nWe describe a case of pemetrexed toxicities related to reabsorption by an ileal neobladder, which caused prolonged hematotoxicity and nephrotoxicity.\n\nCase presentation\nA 59-year-old white man was diagnosed with metastatic wild-type adenocarcinoma of the upper lobe of his right lung. After a first cycle of cisplatin and pemetrexed, he had unusually prolonged aplasia and acute kidney injury.\n\nThe prolonged aplasia was caused by pemetrexed reabsorption by the ileal mucosa of the neobladder as pemetrexed was eliminated renally in an active form and is partly lipophilic.\n\nConclusions\nPemetrexed may be reabsorbed by the ileal mucosa of the neobladder because of its hydrophobic structure and renal excretion in its active form. Acute urinary retention may maintain this phenomenon. Published data excluded a potential role for cisplatin in this toxicity; furthermore, we could not assess pemetrexed concentrations in the blood or urine as these assay techniques are not validated. Thus, care is needed when giving chemotherapy to patients with a neobladder.\n\nKeywords\nLung cancerNeobladderPemetrexedToxicityNeutropeniaissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nWe present a case of pemetrexed toxicities due to reabsorption by an ileal neobladder that occurred in a 59-year-old white man with wild-type metastatic lung adenocarcinoma. He developed unusually extended aplasia and acute kidney injury after a cycle of cisplatin and pemetrexed. We considered that ileal reabsorption of pemetrexed by the neobladder was responsible for the prolonged hematotoxicity. In fact, ileal mucosa absorption is possible because pemetrexed is partly lipophilic and eliminated in an active form.\n\nCase presentation\nWe report a case of a 59-year-old white man with a metastatic adenocarcinoma of the lung diagnosed in April 2013. This tumor was EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), KRAS (V-Ki ras2 Kirsten rat sarcoma viral oncogene homolog), ERBB2 (erb-b2 receptor tyrosine kinase 2), and B-Raf (V-raf murine sarcoma viral oncogene homolog B1) wild-types. He had a previous history of radical cystectomy, prostatectomy, and vesiculectomy and received a Hautmann neobladder in 2001. The neobladder was constructed from ~ 70 cm of distal ileum, which was anastomosed to his ureters and urethra. He initiated cisplatin and pemetrexed chemotherapy, and a vitamin B12 and folic acid supplementation had been prescribed prior to the initiation of treatment.\n\nAfter 10 days of chemotherapy he was hospitalized because of fever above 39.9 °C. A blood sample showed neutropenia > 0.3 G/L and thrombocytopenia > 21 G/L. Thus, amoxicillin-clavulanate plus ciprofloxacin treatment was started.\n\nOn the 4th day after hospitalization he had acute renal failure, metabolic acidosis, hyponatremia, and hyperchloremia.\n\nAn abdominopelvic computed tomography (CT) scan showed major distension of the neobladder and bilateral pyelocaliceal dilatation. Urethral catheterization collected 2 L of a gelatinous liquid.\n\nThe electrolyte disorders were corrected by 23 days after hospitalization and his renal function was restored at 16 days of hospitalization (Fig. 1). His neutrophil levels became standardized by 22 days after hospitalization and platelets by 34 days after hospitalization. He received several transfusions with platelets (Figs. 2 and 3).Fig. 1 Evolution of plasma creatinine level during the hospitalization\n\n\nFig. 2 Evolution of neutrophil count during the hospitalization\n\n\nFig. 3 Evolution of platelet count during the hospitalization\n\n\n\n\nDiscussion\nOur patient presented unusual hematological adverse effects after a first cycle of chemotherapy. In patients with an advanced stage of non-small-cell lung cancer, pemetrexed is known to cause grade 3 and 4 neutropenia in 15% of cases, grade 3 and 4 thrombocytopenia in 4% of cases [1], and all grades of acute renal failure in 2.4% of cases [2]. In contrast, cisplatin can cause anemia [3], but medullary aplasia is rarely described after only cisplatin [4].\n\nIt is to be noted that in patients with locally advanced or metastatic bladder cancer treated with pemetrexed, the hematotoxicity rate is more significant so that cases of grade 3 to 4 neutropenia are up to 75% [5–10]. The hematotoxicity seems more important in patients who had cystectomy. Another study, testing intravesical injections of pemetrexed in pigs, highlighted no myelosuppression and no systemic absorption [11].\n\nBecause of the hydrophilicity and the low oral bioavailability of cisplatin, it can be assumed that cisplatin was not absorbed by the ileal mucosa. In a phase I study of pemetrexed, 78% of the administrated dose was found in its active form within the urine. Its plasma half-life is ~ 3.1 hours when renal function is normal [12].\n\nDuring our patient’s urine-retention episode, we supposed that pemetrexed was stored in an active form by the ileal neobladder due to its lipophilic nature, which maintains toxicities. Cisplatin could not have caused this prolonged toxicity because of its hydrophilicity and so could not be reabsorbed by the ileal mucosa.\n\nConclusions\nPemetrexed was the main cause of the adverse effects observed because of its absorption by the ileal neobladder, with this being exacerbated by our patient’s urinary retention.\n\nIt was not possible to determine the plasma and urine concentrations of pemetrexed as these techniques are not routinely validated.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNone.\n\nAvailability of data and materials\nAvailable.\n\nAuthors’ contributions\nLS, JP, and HP wrote the article; DMS helped with patient management and medical reasoning when writing the article. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Scagliotti GV Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer J Clin Oncol Off J Am Soc Clin Oncol 2008 26 3543 51 10.1200/JCO.2007.15.0375 \n2. Hazarika M White RM Johnson JR Pazdur R FDA drug approval summaries: pemetrexed (alimta) Oncologist 2004 9 482 8 10.1634/theoncologist.9-5-482 15477632 \n3. Kuzur ME Greco FA Cisplatin-induced anemia N Engl J Med 1980 303 110 1 7189822 \n4. Rabik CA Dolan ME Molecular mechanisms of resistance and toxicity associated with platinating agents Cancer Treat Rev 2007 33 9 23 10.1016/j.ctrv.2006.09.006 17084534 \n5. von der Maase H A phase II trial of pemetrexed plus gemcitabine in locally advanced and/or metastatic transitional cell carcinoma of the urothelium Ann Oncol 2006 17 1533 8 10.1093/annonc/mdl154 16873433 \n6. Dreicer R Phase 2 trial of pemetrexed disodium and gemcitabine in advanced urothelial cancer (E4802): a trial of the eastern cooperative oncology group Cancer 2008 112 2671 5 10.1002/cncr.23503 18459175 \n7. Sweeney CJ Phase II Study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium J Clin Oncol 2006 24 3451 7 10.1200/JCO.2005.03.6699 16849761 \n8. Choi YJ Phase II study of pemetrexed in combination with cisplatin in patients with advanced urothelial cancer: the PECULIAR study (KCSG 10–17) Br J Cancer 2015 112 260 5 10.1038/bjc.2014.591 25429526 \n9. Galsky MD Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma Invest New Drugs 2007 25 265 70 10.1007/s10637-006-9020-9 17146733 \n10. Hutson TE Phase I study of a 3-drug regimen of gemcitabine/cisplatin/pemetrexed in patients with metastatic transitional cell carcinoma of the urothelium Invest New Drugs 2008 26 151 8 10.1007/s10637-007-9111-2 18236006 \n11. Hendricksen K Potential and toxicity of intravesical pemetrexed: a preclinical study in pigs Clin Cancer Res 2006 12 2597 601 10.1158/1078-0432.CCR-05-2644 16638871 \n12. Rinaldi DA A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation Cancer Chemother Pharmacol 1999 44 372 80 10.1007/s002800050992 10501910\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "11(1)",
"journal": "Journal of medical case reports",
"keywords": "Lung cancer; Neobladder; Neutropenia; Pemetrexed; Toxicity",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D003401:Creatine; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed; D014057:Tomography, X-Ray Computed; D014547:Urinary Diversion; D016476:Urinary Reservoirs, Continent",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "262",
"pmc": null,
"pmid": "28915906",
"pubdate": "2017-09-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18506025;25429526;17084534;15477632;18236006;16873433;16849761;10501910;17146733;7189822;18459175;16638871",
"title": "Unusually prolonged pemetrexed cytotoxicity in a patient with a lung adenocarcinoma: a case report.",
"title_normalized": "unusually prolonged pemetrexed cytotoxicity in a patient with a lung adenocarcinoma a case report"
} | [
{
"companynumb": "FR-FRESENIUS KABI-FK201708527",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAntimicrobial-associated anaphylaxis occurs at different rates and can lead to worsening infection-related outcomes, we sought to describe the incidence and complications of such episodes at a tertiary care hospital.\n\n\nMETHODS\nA retrospective cohort study was conducted between January 2016 and December 2019. Cases of antimicrobial-associated anaphylaxis were identifiedusing the hospital's electronic healthcare records. Outcomes included: mortality related to anaphylaxis, infection-related mortality, hospitalization and impact on antimicrobial prescribing.\n\n\nRESULTS\nThe estimated rate of antimicrobial-associated anaphylaxis was 18.6 (95% CI: 11.8-29.5) cases per 100,000 exposures, which required hospitalization in 23.8% of the cases and ICU admission in 19% of the cases.\n\n\nCONCLUSIONS\nImplications from antimicrobial-associated anaphylaxis is beyond the episode itself, and can be associated with poor clinical outcomes such as infection-related mortality and hospitalization.",
"affiliations": "Pharmaceutical Care Services, King Abdulaziz Medical City - Ministry of National Guard, Health Affairs, Saudi Arabia; College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Saudi Arabia; King Abdullah International Medical Research Centre, Saudi Arabia. Electronic address: abuesbala@ngha.med.sa.;Pharmaceutical Care Services, King Abdulaziz Medical City - Ministry of National Guard, Health Affairs, Saudi Arabia; College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Saudi Arabia; King Abdullah International Medical Research Centre, Saudi Arabia. Electronic address: Sehlief@ngha.med.sa.",
"authors": "Abu Esba|Laila Carolina|LC|;Al Sehli|Faisal Aqeel|FA|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.intimp.2021.108228",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1567-5769",
"issue": "101(Pt B)",
"journal": "International immunopharmacology",
"keywords": "Allergy; Anaphylaxis; Antimicrobial; Antimicrobial stewardship",
"medline_ta": "Int Immunopharmacol",
"mesh_terms": null,
"nlm_unique_id": "100965259",
"other_id": null,
"pages": "108228",
"pmc": null,
"pmid": "34655848",
"pubdate": "2021-10-14",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Antimicrobial-associated anaphylaxis at a tertiary care medical city.",
"title_normalized": "antimicrobial associated anaphylaxis at a tertiary care medical city"
} | [
{
"companynumb": "SA-GILEAD-2022-0569416",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nDiabetes nephropathy is one of the most common causes of end-stage kidney disease (ESKD) worldwide. The data are clear that kidney transplantation is superior to remaining on dialysis for patients with diabetes. However, there have been no reports on ABO-incompatible kidney transplantation in patients with ESKD due to diabetes nephropathy.\n\n\nMETHODS\nWe conducted a retrospective, observational study to investigate the clinical outcomes of ABO-incompatible kidney transplantation for patients with pre-existing diabetes nephropathy at our institution from April 2011 to October 2017. A total of 14 recipients were enrolled in this study.\n\n\nRESULTS\nAll 14 patients underwent successful kidney transplantation. Both overall patient and graft survival rates were 100, 89.9, and 89.9% at 1, 3, and 5 years, respectively. One patient died 20 months after transplantation with a functioning graft due to pancreas cancer. Two of the 14 patients (14.3%) developed biopsy-proven acute cellular rejection during the follow-up period. The median observation period was 32.0 months (range 5-83 months).\n\n\nCONCLUSIONS\nABO-incompatible kidney transplantation may be an acceptable renal replacement therapy for ESKD patients with diabetes.",
"affiliations": "Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan, m9492120@msic.med.osaka-cu.ac.jp.;Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Nursing, Osaka City University Hospital, Osaka, Japan.;Department of Urology, Suita Municipal Hospital, Suita, Japan.;Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.",
"authors": "Uchida|Junji|J|;Kosoku|Akihiro|A|;Kabei|Kazuya|K|;Nishide|Shunji|S|;Shimada|Hisao|H|;Iwai|Tomoaki|T|;Kuwabara|Nobuyuki|N|;Naganuma|Toshihide|T|;Maeda|Keiko|K|;Kumada|Norihiko|N|;Takemoto|Yoshiaki|Y|;Nakatani|Tatsuya|T|",
"chemical_list": "D000017:ABO Blood-Group System; D007074:Immunoglobulin G; D007075:Immunoglobulin M",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000496029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0042-1138",
"issue": "102(3)",
"journal": "Urologia internationalis",
"keywords": "ABO-incompatible; Diabetes mellitus; Kidney transplantation",
"medline_ta": "Urol Int",
"mesh_terms": "D000017:ABO Blood-Group System; D000328:Adult; D000368:Aged; D001706:Biopsy; D001787:Blood Group Incompatibility; D003928:Diabetic Nephropathies; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007165:Immunosuppression Therapy; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0417373",
"other_id": null,
"pages": "341-347",
"pmc": null,
"pmid": "30630163",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "10580071;11844152;15196066;16801596;17333109;18294155;18322053;18790213;19535812;19604443;20925547;21168610;21358172;22310615;22828739;22872422;23927899;24694990;24932811;25050471;25817610;26324199;26555133;28010785;28510327;28740069;28823116;30300894",
"title": "Clinical Outcomes of ABO-Incompatible Kidney Transplantation in Patients with End-Stage Kidney Disease due to Diabetes Nephropathy.",
"title_normalized": "clinical outcomes of abo incompatible kidney transplantation in patients with end stage kidney disease due to diabetes nephropathy"
} | [
{
"companynumb": "JP-STRIDES ARCOLAB LIMITED-2019SP004998",
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RITUXIMAB"
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"drugadditional"... |
{
"abstract": "Scrambler therapy (ST) is a relatively new neuromodulation technique that is useful in treatment of medication-resistant pain syndromes, including chemotherapy-induced peripheral neuropathy and other chronic pain syndromes. Amyloidosis commonly leads to peripheral neuropathy, and although the mechanism is unclear, it is possibly related to amyloid deposits on the nerve. In this case presentation, we describe the novel use of ST for a patient with 13 years of neuropathic pain related to amyloidosis and worsened by chemotherapy. The patient reported bilateral hand pain with burning and aching and bilateral numbness on the soles of her feet. Her upper extremities were treated with 4 days of 40 minute ST treatment sessions providing reduction in her pain scores to zero. Current therapy for amyloid peripheral neuropathy aims at treating the underlying condition, and then medical management with gabapentinoids. This is first case presentation showing successful treatment with ST.",
"affiliations": "Pediatric Anesthesiology and Pediatric Pain Management, Division of Pediatric Anesthesiology, Department of Anesthesiology and CCM, Johns Hopkins Charlotte R. Bloomberg Children's Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Hospice and Palliative Medicine, Johns Hopkins Medical Institutions, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Section of Palliative Medicine, Division of General Internal Medicine, Johns Hopkins Medical Institutions, JHUSOM, Baltimore, Maryland, USA.",
"authors": "Hunsberger|Joann B|JB|;Rathee|Vaishali|V|;Smith|Thomas J|TJ|0000-0003-3040-6434",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/jpm.2020.0786",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1557-7740",
"issue": "24(10)",
"journal": "Journal of palliative medicine",
"keywords": "amyloidosis; neuromodulation; neuropathic pain; scrambler therapy",
"medline_ta": "J Palliat Med",
"mesh_terms": "D000686:Amyloidosis; D005260:Female; D005528:Foot; D006801:Humans; D009437:Neuralgia; D059408:Pain Management; D010147:Pain Measurement",
"nlm_unique_id": "9808462",
"other_id": null,
"pages": "1579-1581",
"pmc": null,
"pmid": "34314620",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "30714486;21763099;32394815;33099426;31209630;31639841;32967392;31014125;32269109;33249081;32709170;25572279",
"title": "Use of Scrambler Therapy in the Treatment of Amyloidosis Neuropathic Pain.",
"title_normalized": "use of scrambler therapy in the treatment of amyloidosis neuropathic pain"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2021-26528",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
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"abstract": "BACKGROUND\nHypertrophic cardiomyopathy (HCM) is a heterogeneous, usually familial disorder of heart muscle. The hypertrophic form of cardiomyopathy is frequently genetic, or as part of several neuromuscular disorders. In neonates, especially prematurity, HCM could also be secondary to corticosteroid treatment.\nWe reported here a 34 weeks gestational age preterm infant presented with profound cardiomegaly after multiple doses of hydrocortisone used to treat blood pressure instability associated with septic shock and persistent pulmonary hypertension (PPHN).\n\n\nMETHODS\nPatient presented auscultation of a grade III/IV harsh systolic ejection murmur from day 14, which was absent before. Profound cardiomegaly was indicated at chest film at day 30. Echocardiography showed severe thickening of the IVS (13.8 mm, z score = 8.29) and mild thickening of the posterior left ventricular wall (LVPW, 6 mm).\n\n\nMETHODS\nPropranolol and captopril were started along with supportive care. The patient was also admitted to NICU for further treatment with 24-hour Holter electrocardiographic monitoring.\n\n\nRESULTS\nA reversible course was observed without left ventricular outflow tract obstruction nor arrhythmias within 4 weeks.\n\n\nCONCLUSIONS\nThe risk/benefit ratio must be carefully considered when corticosteroids are used in prematurity. Monitors such as echocardiography and electrocardiograph should be conducted in order to guide cardiovascular management. Systematic surveys of the incidence of cardiac complications in a larger population of preterm infant treated with corticosteroid are needed in the future.",
"affiliations": "Department of Neonatology, Shenzhen Children's Hospital, Shenzhen.;Department of Neonatology, Guangdong Women and Children's Hospital, Guangzhou, China.;Department of Neonatology, Guangdong Women and Children's Hospital, Guangzhou, China.;Department of Neonatology, Guangdong Women and Children's Hospital, Guangzhou, China.",
"authors": "Jiang|Jingbo|J|;Zhang|Jiawen|J|;Kang|Mengmeng|M|;Yang|Jie|J|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31415406MD-D-19-0050610.1097/MD.0000000000016838168386200Research ArticleClinical Case ReportTransient hypertrophic cardiomyopathy and hypertension associated with hydrocortisone in preterm infant A case reportJiang Jingbo MD, PhDaZhang Jiawen MDbKang Mengmeng MD, PhDbYang Jie MD, PhDb∗NA. \na Department of Neonatology, Shenzhen Children's Hospital, Shenzhen\nb Department of Neonatology, Guangdong Women and Children's Hospital, Guangzhou, China.∗ Correspondence: Jie Yang, Guangdong Women and Children's Hospital, Guangzhou, China (e-mail: ball.1361@icloud.com).8 2019 16 8 2019 98 33 e1683823 1 2019 11 6 2019 23 7 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0\nAbstract\nRationale:\nHypertrophic cardiomyopathy (HCM) is a heterogeneous, usually familial disorder of heart muscle. The hypertrophic form of cardiomyopathy is frequently genetic, or as part of several neuromuscular disorders. In neonates, especially prematurity, HCM could also be secondary to corticosteroid treatment.\n\nPatient concerns:\nWe reported here a 34 weeks gestational age preterm infant presented with profound cardiomegaly after multiple doses of hydrocortisone used to treat blood pressure instability associated with septic shock and persistent pulmonary hypertension (PPHN).\n\nDiagnosis:\nPatient presented auscultation of a grade III/IV harsh systolic ejection murmur from day 14, which was absent before. Profound cardiomegaly was indicated at chest film at day 30. Echocardiography showed severe thickening of the IVS (13.8 mm, z score = 8.29) and mild thickening of the posterior left ventricular wall (LVPW, 6 mm).\n\nInterventions:\nPropranolol and captopril were started along with supportive care. The patient was also admitted to NICU for further treatment with 24-hour Holter electrocardiographic monitoring.\n\nOutcomes:\nA reversible course was observed without left ventricular outflow tract obstruction nor arrhythmias within 4 weeks.\n\nLessons:\nThe risk/benefit ratio must be carefully considered when corticosteroids are used in prematurity. Monitors such as echocardiography and electrocardiograph should be conducted in order to guide cardiovascular management. Systematic surveys of the incidence of cardiac complications in a larger population of preterm infant treated with corticosteroid are needed in the future.\n\nKeywords\nhydrocortisonehypertrophic cardiomyopathyneonatal intensive careseptic shockOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nHydrocortisone (HC) is widely used in infants with increased inotropic support in septic shock and severe pulmonary disease.[1] The most recent Surviving Sepsis Guidelines use the term “catecholamine resistant shock” and recommend consideration of corticosteroids at this point.[2] However, question still needs to be resolved regarding the appropriate target population. In certain subgroups, increased risks of mortality, suppression of adaptive immunity, and secondary infections from corticosteroid administration have been suggested in several retrospective controlled trials (RCTs) in pediatric critical care.[3,4] Herein, we present a preterm infant with transient myocardial hypertrophy after multiple dose of hydrocortisone used to treat septic shock.\n\n2 Case report\nA 2260-g male infant was born at 34 weeks of gestation via caesarean section due to central placenta previa with hemorrhage to a 36-year-old multipara whose pregnancy was complicated with hyperthyroidism. Full dose of dexamethasone was given to the mother prior to delivery. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. The patient was admitted to the neonatal intensive care unit and intubated because of respiratory distress within the first 30 minutes of life. Pulmonary hemorrhage presented shortly after high-frequency oscillatory ventilation (HFOV). Inhalational nitric oxide was applied because of PPHN from day 3 to day 7. He received 2 doses of surfactant, umbilical venous catheter (UVC), and umbilical artery catheter (UAC) were conducted thereafter to monitor central artery pressure.\n\nDuring the first 3 days, HC 2 mg/kg q8 h was given intravenously because of circulatory failure indicated by hypotension responsive to substantial fluid administration and intensive inotropic support. When the epinephrine and dopamine requirement were reduced, HC was weaned gradually over a period of 5 days. The mean arterial pressure (MAP) raised up to 92 mmHg from day 7 and remained at 85 ± 7.4 mmHg until discharge. The patient also accepted blood exchange and albumin (2 g as a total dose) because of hyperbilirubinemia (greatest indirect bilirubin 434 μmol/L).\n\nAcute hypokalemia arised on day 14, serum potassium decreased to as low as 2.1 mmol/L. Potassium replacement was given as 0.3 mmol/kg/h intravenously, as well as oral repletion 4 mmol/kg/d in divided doses. Serum potassium was between 2.8 and 3.3 mmol/L in the following 2 weeks and remain normal thereafter.\n\nFetal echocardiography had been performed at 24 weeks of gestation, which showed a structurally normal heart without ventricular hypertrophy. The first pediatric cardiology consultation was requested at day 1. Transthoracic echocardiogram (TTE) revealed 3 mm right-to-left shunting of blood across the foramen ovale and a large patent ductal arteriosus (PDA) with bidirectional shunting. The second TTE, performed at day 3, indicated mean pulmonary artery pressure (PAP) 35 mmHg, LVEF 67% and similar atrial left-right shunt and patent ductal shunt when PPHN was persistent. At day 11, PPHN was ameliorated clinically, and the mean PAP had decreased to 23 mmHg suggested by 3rd TTE. The thickness of the interventricular septum (IVS) was normal at all these abovementioned TTE.\n\nEchocardiography was repeated at day 30 because of profound cardiomegaly indicated at chest film and auscultation of a grade III/IV harsh systolic ejection murmur. This TTE showed severe thickening of the IVS (13.8 mm, z score = 8.29) and mild thickening of the posterior left ventricular wall (LVPW, 6 mm). Thicken of the ventricle affect the septum more than the ventricular free wall (IVS/LVPW 2.3, Fig. 1A and B). For children, IVS z-score of ≥2 related to body surface area is compatible with the diagnosis of hypertrophic cardiomyopathy. Outflow tract obstruction was not observed, with a peak velocity of 0.85 m per second. Aortic coarctation (COA) was ruled out. Prenatal history was negative for maternal risk factors as well as the familial history regarding genetic and metabolic diseases, sudden death, or syncope history. Maternal oral glucose tolerance test and glycated hemoglobin (HbA1c) were normal (Fig. 2).\n\nFigure 1 Cardiomyopathy and hypertension track against the steroid dose. Hydrocortisone (2 mg/kg) was administrated in the first 5 days, duration shown as blue shadow in the chart.\n\nFigure 2 Postnatal TTE at 30 days (A, B) and 60 days (C, D) of life. A, Parasternal long-axis view showing the severely narrowed left ventricular cavity as well as the hypertrophic interventricular septum. IVS/LVPW: 2.3; B, Parasternal 4 chamber view with color-flow Doppler showing no restriction of flow through the left ventricular outflow tract. EF 51%; C, Significant remission of left ventricular hypertrophy. D, Improvement of septal configuration. AO = aorta; IVS = interventricular septum; LA = left atrium; LVOT = left ventricular outflow tract; PW = posterior wall.\n\nPropranolol (0.2 mg q8 h) and captopril (0.02 mg q8 h) were administrated. 24-hour Holter electrocardiographic monitoring demonstrated no arrhythmia. Serial transesophageal echocardiograms were performed the next few weeks. Thickness of the IVS decreased to 3 mm progressively on day 60 (Fig. 1C and D). Except increased MAP, the baby remained completely asymptomatic. Supplemental oxygen was discontinued on the 30th day. Tandem mass spectroscopy analysis was normal. Exome sequencing targeting over 4000 genes was negative. The patient was discharged from hospital at 45th of life. At post-discharge follow-up, MAP was 65 mmHg 60th postnatal day, cardiologic evaluation was normal.\n\n3 Discussion\nThis report provides evidence that HC treatment is associated with hypertrophic cardiomyopathy (HCM) in prematurity. It is a well-established notion that HCM is the most common of the genetic cardiovascular diseases, caused by a multitude of mutations in gene encoding proteins of the cardiac sarcomere. Eleven mutated genes, most commonly encoding beta-myosin heavy chain, are presently associated with HCM, accounting for about 50% patients. Other causes may include non-sarcomeric protein mutations cause storage diseases that are phenocopies of sarcomeric HCM and require molecule diagnosis, namely, Fabry disease, Pompe disease, Friedreich ataxia, mitochondrial disorders, and medications such as tacrolimus. Several epidemiologic studies have reported a prevalence of the HCM phenotype as 2‰, however, it is notable that most affected individuals remain asymptomatic and unidentified. Notably this condition is No. 1 cause of sudden death in the young, including competitive athletes. On the other hand, myocardium of prematurity is susceptible. In this population, dietary deficiency, or enzymatic defects that affect energy utilization may impair myocardial function. Occasionally, low calcium or magnesium, hypophosphatemia, and severe hypoglycemia cause reversible cardiac dilation and heart failure. Infants of diabetic mother can also have hypertrophic hearts with or without obstruction that resemble HCM with asymmetric septal hypertrophy, notably, this prevalence is higher in prematurity.[5,6,7] In this case, the fetal echocardiography was normal, the patient did not have any clinical and laboratory evidence of genetic disorder nor persistent metabolic disturbance, which indicates prenatal and maternal causes could not be responsible for the myocardial hypertrophy after birth. Moreover, the spontaneous reversal nature makes familial and metabolic causes less likely.\n\nIn the immediate postnatal period, abnormal regulation of peripheral vascular resistance with or without myocardial dysfunction is a frequent cause of hypotension underlying shock, especially in preterm infants. Shock secondary to sepsis is also related with release of proinflammatory cascades that lead to vasodilation. HC infusion at stress dose (50 mg/m2/d) is powerful drug in extremely premature infants with hypotension refractory to volume expansion and vasopressors via a number of different mechanisms.[1,4] HC suppresses the inflammatory response, induces the expression of cardiovascular adrenergic receptors that are downregulated by prolonged use of sympathomimetic agents and also inhibits catecholamine metabolism. After HC administration, there is a rapid increase in intracellular calcium availability, resulting in enhanced response to adrenergic agents as evident as 2 hours. Short-term side effects of HC are hypertension, hyperglycemia, GI hemorrhage, and perforation, moreover, cerebral palsy is the most important long-term sequela.[8,9]\n\n\nThe mechanism of HC-related myocardial thickening is less clear. HC may act through insulin-like growth factor 1 (IGF1) or its receptors on cardiac myocytes to induce left ventricular hypertrophy, as a result, synthesis of various intracellular cardiac protein increased, contributing to hypertrophy of myocytes.[10,11] Although the ventricle size often remains normal, the thickening may block blood flow out of the ventricle, result in obstructive hypertrophic cardiomyopathy.\n\nEchocardiography is the primary tool for diagnosis of HCM. HCM can raise pressure in the ventricles and the blood vessels of the lungs. Changes also occur to the cells in the damaged heart muscle, which may disrupt the heart's electrical signals and lead to arrhythmias. Very vigorous physical activity which triggers arrhythmias may cause sudden cardiac arrest in some case with HCM. The goal of hypertrophic cardiomyopathy treatment is to relieve symptoms and prevent sudden cardiac death in people at high risk. Medications such as beta blockers and calcium channel blockers are used to reduce myocardia oxygen demand and to slow the heart rate, therefore improve the compliance. Other treatments include septal myectomy or ablation, and implantable cardioverter-defibrillator. HC-induced HCM is usually a benign condition and was resolved a few weeks after discontinuation, furthermore, none of case in the literature present hypertension related to HCM. The precise incidence is lacking, however, the frequency and severity of myocardial hypertrophy may increase with dose and duration of HC treatment, infants receiving insulin in addition to HC may present in greater level of hypertrophy.\n\nIn conclusion, we strongly recommend that the risk/benefit ratio must be carefully considered when corticosteroids are used in neonatal septic shock, especially in prematurity. Since HCM is associated with lethiferous arrythmias in some cases, adequate monitor such as echocardiography and electrocardiograph should be conducted in order to guide cardiovascular management. Novel therapeutic approaches to be applied in controlling its harmful consequences are suggested.\n\nAcknowledgments\nThe authors thank Xiaobi Liang for productive discussions and thoughtful suggestions.\n\nAuthor contributions\n\nData curation: Jiawen Zhang.\n\n\nInvestigation: Jingbo Jiang, Mengmeng Kang.\n\n\nMethodology: Jingbo Jiang.\n\n\nResources: Jingbo Jiang, Mengmeng Kang.\n\n\nSupervision: Jie Yang.\n\n\nWriting – original draft: Jingbo jiang.\n\n\nWriting – review & editing: Jingbo Jiang, Jiawen Zhang, Mengmeng Kang, Jie Yang.\n\nJingbo Jiang orcid: 0000-0001-7453-904X.\n\nAbbreviations: AO = aorta, COA = aortic coarctation, HbA1c = glycated hemoglobin, HCM = hypertrophic cardiomyopathy, HFOV = high-frequency oscillatory ventilation, HC = hydrocortisone, IVS = interventricular septum, LA = left atrium, LVOT = left ventricular outflow tract, LVPW = posterior left ventricular wall, MAP = mean arterial pressure, PAP = pulmonary artery pressure, PDA = patent ductal arteriosus, PPHN = persistent pulmonary hypertension, PW = posterior wall, TTE = transthoracic echocardiogram, UAC = umbilical artery catheter, UVC = umbilical venous catheter.\n\nThe written consent we obtained from study participants was approved by the ethics committee of Guangdong Women and Children's Hospital.\n\nWritten consent for publication of the patient's data was provided by his father.\n\nAll datasets are deposited in the patient's digital health care file. All datasets are also presented in machine readable format.\n\nNo funding was obtained for this study.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] \nMenon K Wong HR \nCorticosteroids in pediatric shock: a call to arms . Pediatr Crit Care Med \n2015 ;16 :e313 –7 .26226342 \n[2] \nDellinger RP Levy MM Rhodes A \nSurviving sepsis campaign guidelines Committee including the pediatric, surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012 . Intensive Care Med \n2013 ;39 :165 –228 .23361625 \n[3] \nWong HR Cvijanovich NZ Allen GL \nCorticosteroids are associated with repression of adaptive immunity gene programs in pediatric septic shock . Am J Respir Crit Care Med \n2014 ;189 :940 –6 .24650276 \n[4] \nDoyle LW Cheong JL Ehrenkranz RA \nEarly (< 8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants . Cochrane Database Syst Rev \n2017 ;10 :CD001146 .29063585 \n[5] \nPaech C Wolf N Thome UH \nHypertrophic intraventricular flow obstruction after very-low-dose dexamethasone (Minidex) in preterm infants: case presentation and review of the literature . J Perinatol \n2014 ;34 :244 –6 .24573211 \n[6] \nGoldberg JF Mery CM Griffiths PS \nExtracorporeal membrane oxygenation support in severe hypertrophic obstructive cardiomyopathy associated with persistent pulmonary hypertension in an infant of a diabetic mother . Circulation \n2014 ;130 :1923 –5 .25403599 \n[7] \nCloherty JP Eichenwald EC Stark AR \nManual of Neonatal Care . The Netherlands : Lippincott Williams & Wilkins ; 2008 .\n[8] \nDoyle LW Ehrenkranz RA Halliday HL \nDexamethasone treatment in the first week of life for preventing bronchopulmonary dysplasia in preterm infants: a systematic review . Neonatology \n2010 ;98 :217 –24 .20389126 \n[9] \nAltit G Vigny-Pau M Barrington K \nCorticosteroid therapy in neonatal septic shock-do we prevent death? \nAm J Perinatol \n2018 ;35 :146 –51 .28838003 \n[10] \nBassareo PP Abella R Fanos V \nBiomarkers of corticosteroid-induced hypertrophic cardiomyopathy in preterm babies . Front Biosci (Elite Ed) \n2010 ;2 :1460 –71 .20515817 \n[11] \nAoyama T Matsui T Novikov M \nSerum and glucocorticoid-responsive kinase-1 regulates cardiomyocyte survival and hypertrophic response . Circulation \n2005 ;111 :1652 –9 .15795328\n\n",
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"title": "Transient hypertrophic cardiomyopathy and hypertension associated with hydrocortisone in preterm infant: A case report.",
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"affiliations": "Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Japan.",
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"abstract": "Severe hypertension in infancy is a rare cause of failure to thrive. The successful surgical management of this disease in an infant having refractory renovascular hypertension and growth failure is reported.",
"affiliations": "Section of Vascular Surgery, University of Michigan Frankel Cardiovascular Center, Ann Arbor, MI.;Section of Vascular Surgery, University of Michigan Frankel Cardiovascular Center, Ann Arbor, MI.;Section of Vascular Surgery, University of Michigan Frankel Cardiovascular Center, Ann Arbor, MI.;Section of Vascular Surgery, University of Michigan Frankel Cardiovascular Center, Ann Arbor, MI. Electronic address: dawnbarn@umich.edu.",
"authors": "Phillips|Amanda R|AR|;Eliason|Jonathan L|JL|;Stanley|James C|JC|;Coleman|Dawn M|DM|",
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"abstract": "OBJECTIVE\nTo describe demographic, clinical and immunologic features of children with human immunodeficiency virus.\n\n\nMETHODS\nThis descriptive study was conducted at the Shifa International Hospital, Islamabad, Pakistan, from 2005 to 2011, and comprised children with human immunodeficiency virus and acquired immune deficiency syndrome. Patients with detailed physical examination and appropriate investigations and those eligible for therapy were included. SPSS 21 was used for data analysis.\n\n\nRESULTS\nOf the 43 patients, 27(62.8%) were boys and 16(37.2%) were girls. The overall median age was 5 years (interquartile range: 3-8.5 years). Moreover, 18(42%) children were aged equal to or below 5 years. Fathers of 5(12%) children and mothers of 6(14%) children had died. Siblings of 3(7%) patients, fathers of 20(47%) patients and mothers of 31(72%) patients had human immunodeficiency virus or acquired immune deficiency syndrome. The median duration of breastfeeding was 24 months (interquartile range: 15-24 months). Risk factors identified were foreign job by father in 12(28%) patients, birth by vaginal delivery in 20(47%), breastfeeding >6 months in 34(79%), fathers with human immunodeficiency virus or acquired immune deficiency syndrome in 20(47%), mothers with human immunodeficiency virus or acquired immune deficiency syndrome in 31(72%) and lack of maternal anti-retrovirals during pregnancy in all (100%). There were 27(63%) children being symptomatic and 29(67%) had advanced disease at diagnosis with World Health Organisation's classification stage 3 or 4. The pretreatment median CD4 count was 294.5 cells/mm3 (IQR, 208.5-808) and a follow-up CD4 of 757 cells/mm3 (IQR, 352-874) which was significant (p <0.005). The intial median HIV viral load was 83 RNA copiesx105/mm3 (IQR, 1.8-8.25). Anti-retroviral therapy (ARV) was initiated in 65% (28/43) with good compliance. The mean duration of follow-up was 12 months. There was clinical and immunologic improvement in 65% (18/28) in first 12 months. There were opportunistic infections in 20 children (46%), serious side effects in 5 (18%), progression of disease or poor response in 7 (16%) and discontinuation or switch of therapy in 2 (7%). Four children had suspected HIV drug resistance but confirmed in 2 (6.7%) requiring second-line therapy. Five children (12%) died, two within one week of diagnosis.\n\n\nCONCLUSIONS\nMost human immunodeficiency virus-infected children had risk factors, present with severe immune suppression and had improved CD-4 after anti-retroviral therapy.",
"affiliations": "Department of Pediatrics, Shifa International Hospital, Islamabad.",
"authors": "Khan|Ejaz Ahmed|EA|",
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"issue": "67(1)",
"journal": "JPMA. The Journal of the Pakistan Medical Association",
"keywords": "HIV, Paediatric AIDS, Antiretroviral therapy, Pakistan. ",
"medline_ta": "J Pak Med Assoc",
"mesh_terms": "D044966:Anti-Retroviral Agents; D001942:Breast Feeding; D002648:Child; D002675:Child, Preschool; D005260:Female; D015658:HIV Infections; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D010154:Pakistan; D010290:Parents; D012307:Risk Factors",
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"title": "Lessons from a seven-year experience of paediatric HIV in Pakistan: A single centre experience.",
"title_normalized": "lessons from a seven year experience of paediatric hiv in pakistan a single centre experience"
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"abstract": "Previous studies have shown that vinorelbine/capecitabine (NX) and docetaxel/capecitabine (TX) chemotherapy has a certain effect in advanced breast cancer. However, there are few clinical studies directly comparing TX and NX regimen chemotherapy, especially in patients with advanced breast cancer previously treated with anthracycline and taxane. The purpose of this Phase II study was to compare survival and side effects between patients with anthracycline- and taxane-resistant advanced breast cancer treated with NX and those treated with TX chemotherapy.\nFrom February 2012 to March 2014, a total number of 97 patients were randomly assigned to NX (n = 55) or TX (n = 42). Baseline characteristics were relatively well-balanced in the two treatment arms. The clinical trial registration number (clincaltrials.gov) is NCT01635465.\nAfter a median follow-up of 46.0 months, there was no significant difference between the NX and TX arms in objective response rate (17.9% vs. 21.1%; P = 0.686) and progression-free survival (6 months vs. 7 months; P = 0.560). The overall survival period of the TX arm was longer than that of the NX arm (32 months vs. 27 months) but without statistical significance. Both regimens were well-tolerated. The main toxicities were neutropenia, leukopenia, and anemia. In the TX arm, hand-foot syndrome occurred more frequently than in the NX arm (P < 0.01), but frequencies of other minor adverse effects were similar between the two arms.\nNX and TX regimens are both alternative treatments for patients with anthracycline- and taxane-resistant advanced breast cancer, but the safety profile was more favorable and manageable with the NX regimen.\nClinicalTrials.gov NCT01635465. Registered 09 July 2012.",
"affiliations": "Department of Breast Oncology, Cancer Hospital of Tianjin, Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.;Department of Breast Oncology, Cancer Hospital of Tianjin, Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.;Department of Oncology, Hebei Province Xingtai People's Hospital, Hebei Medical University Affiliated Hospital, Xingtai, China.;Department of Oncology, Xiamen No. 2 Hospital, Xiamen, China.;Department of Breast Oncology, Cancer Hospital of Tianjin, Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.;Department of Breast Oncology, Cancer Hospital of Tianjin, Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.;Department of Breast Oncology, Cancer Hospital of Tianjin, Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.",
"authors": "Li|Shufen|S|;Meng|Wenjing|W|;Zhang|Jibo|J|;Xie|Xiaojuan|X|;Hao|Chunfang|C|;Jia|Yongsheng|Y|;Tong|Zhongsheng|Z|",
"chemical_list": "D018943:Anthracyclines; D000077143:Docetaxel; D000069287:Capecitabine; D000077235:Vinorelbine",
"country": "India",
"delete": false,
"doi": "10.4103/jcrt.JCRT_792_19",
"fulltext": null,
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"issn_linking": "1998-4138",
"issue": "16(5)",
"journal": "Journal of cancer research and therapeutics",
"keywords": "Anthracycline-pretreated; capecitabine; docetaxel; metastatic breast cancer; vinorelbine",
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D018943:Anthracyclines; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000069287:Capecitabine; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D015996:Survival Rate; D016896:Treatment Outcome; D000077235:Vinorelbine",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "1069-1076",
"pmc": null,
"pmid": "33004749",
"pubdate": "2020-09",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "A randomized controlled Phase II trial of vinorelbine plus capecitabine versus docetaxel plus capecitabine in anthracycline-pretreated women with metastatic breast cancer.",
"title_normalized": "a randomized controlled phase ii trial of vinorelbine plus capecitabine versus docetaxel plus capecitabine in anthracycline pretreated women with metastatic breast cancer"
} | [
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"companynumb": "CN-ROCHE-2691206",
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"activesubstancename": "CAPECITABINE"
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{
"abstract": "BACKGROUND\nInvestigation of a possible effect of metformin on androgen levels in pregnant women with polycystic ovary syndrome (PCOS).\n\n\nMETHODS\nA prospective, randomized, double-blind, placebo-controlled pilot study was conducted. Forty pregnant women with PCOS received diet and lifestyle counselling and were randomized to either metformin 850 mg twice daily or placebo. Primary outcome measures were changes in serum levels of dehydroepiandrosterone sulphate, androstenedione, testosterone, sex hormone-binding globulin, and free testosterone index. Secondary outcome measures were pregnancy complications and outcome. Two-tailed t-tests and chi2-tests were used.\n\n\nRESULTS\nMaternal androgen levels were unaffected by metformin treatment in pregnant women with PCOS. While none of the 18 women in the metformin group experienced a severe pregnancy or post-partum complication, seven of the 22 (32%) women experienced severe complications in the placebo group (P = 0.01).\n\n\nCONCLUSIONS\nMetformin treatment did not reduce maternal androgen levels in pregnant women with PCOS. In the metformin-treated group we observed a reduction of severe, pregnancy and post-partum complications. Metformin treatment of pregnant PCOS women may reduce complications during pregnancy and in the post-partum period.",
"affiliations": "Department of Obstetrics and Gynaecology, St Olavs Hospital, University Hospital of Trondheim, Norway. eszter.vanky@medisin.ntnu.no",
"authors": "Vanky|E|E|;Salvesen|K A|KA|;Heimstad|R|R|;Fougner|K J|KJ|;Romundstad|P|P|;Carlsen|S M|SM|",
"chemical_list": "D000728:Androgens; D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "England",
"delete": false,
"doi": "10.1093/humrep/deh347",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-1161",
"issue": "19(8)",
"journal": "Human reproduction (Oxford, England)",
"keywords": null,
"medline_ta": "Hum Reprod",
"mesh_terms": "D000328:Adult; D000728:Androgens; D001724:Birth Weight; D016640:Diabetes, Gestational; D005260:Female; D005865:Gestational Age; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents; D007231:Infant, Newborn; D008687:Metformin; D010865:Pilot Projects; D011085:Polycystic Ovary Syndrome; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011446:Prospective Studies",
"nlm_unique_id": "8701199",
"other_id": null,
"pages": "1734-40",
"pmc": null,
"pmid": "15178665",
"pubdate": "2004-08",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study.",
"title_normalized": "metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women results of a randomized study"
} | [
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"companynumb": "NO-ALKEM LABORATORIES LIMITED-NO-ALKEM-2021-06376",
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"actiondrug": "6",
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"activesubstancename": "METFORMIN HYDROCHLORIDE"
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... |
{
"abstract": "OBJECTIVE\nA case showing sustained structural and functional responses 2 years after a single treatment with ILUVIEN (0.2 µg/day fluocinolone acetonide, FAc) despite suboptimal responses to ranibizumab.\n\n\nMETHODS\nA 68-year-old female patient with diabetic macular oedema (DME) from type 2 diabetes mellitus was first diagnosed in October 2010 and had a baseline visual acuity (VA) of 46 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in the left eye. Central foveal thickness (CFT) was 712 microns. The patient was treated with 11 intravitreal injections of ranibizumab (5 in combination with a small-interfering RNA agent), and by March 2014, VA and CFT were largely unchanged (55 ETDRS letters and 774 microns). The patient was treated with ILUVIEN as she had a pseudophakic lens and a clearly suboptimal response to the prior therapy with ranibizumab. An implant releasing FAc at a dosage of 0.2 µg/day was administered in March 2014, and the optical coherence tomography indicated that the macula was dry after 7 days (CFT was below 300 microns). This was sustained at 6, 12, and 24 months after the treatment. VA improved by 5 letters within 7 days and by 15 letters within 14 days, and this was maintained after 24 months. Throughout the duration of this study, the intraocular pressure was ≤22 mm Hg, and no glaucoma medication was administered.\n\n\nCONCLUSIONS\nIn real-life UK practice, this DME patient showed a suboptimal response to multiple intravitreal injections of ranibizumab. When subsequently treated with a single injection of ILUVIEN, there were large and rapid improvements in VA and CFT that were maintained for the following 2 years.",
"affiliations": "Royal Hallamshire Hospital, Sheffield, UK.;Royal Hallamshire Hospital, Sheffield, UK.",
"authors": "Quhill|Hibba|H|;Quhill|Fahd|F|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000452883",
"fulltext": "\n==== Front\nCase Rep OphthalmolCase Rep OphthalmolCOPCase Reports in Ophthalmology1663-2699S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000452883cop-0007-0301Case ReportReal-Life ILUVIEN (Fluocinolone Acetonide) Case Study: Rapid Drying of the Macula and Improved Vision within 2 Years after Therapy Initiation Quhill Hibba Quhill Fahd *Royal Hallamshire Hospital, Sheffield, UK*Fahd Quhill, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF (UK), E-Mail Fahd.Quhill@sth.nhs.ukSep-Dec 2016 28 12 2016 28 12 2016 7 3 301 307 15 9 2016 25 10 2016 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Importance\nA case showing sustained structural and functional responses 2 years after a single treatment with ILUVIEN (0.2 µg/day fluocinolone acetonide, FAc) despite suboptimal responses to ranibizumab.\n\nObservations\nA 68-year-old female patient with diabetic macular oedema (DME) from type 2 diabetes mellitus was first diagnosed in October 2010 and had a baseline visual acuity (VA) of 46 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in the left eye. Central foveal thickness (CFT) was 712 microns. The patient was treated with 11 intravitreal injections of ranibizumab (5 in combination with a small-interfering RNA agent), and by March 2014, VA and CFT were largely unchanged (55 ETDRS letters and 774 microns). The patient was treated with ILUVIEN as she had a pseudophakic lens and a clearly suboptimal response to the prior therapy with ranibizumab. An implant releasing FAc at a dosage of 0.2 µg/day was administered in March 2014, and the optical coherence tomography indicated that the macula was dry after 7 days (CFT was below 300 microns). This was sustained at 6, 12, and 24 months after the treatment. VA improved by 5 letters within 7 days and by 15 letters within 14 days, and this was maintained after 24 months. Throughout the duration of this study, the intraocular pressure was ≤22 mm Hg, and no glaucoma medication was administered.\n\nConclusions and Relevance\nIn real-life UK practice, this DME patient showed a suboptimal response to multiple intravitreal injections of ranibizumab. When subsequently treated with a single injection of ILUVIEN, there were large and rapid improvements in VA and CFT that were maintained for the following 2 years.\n\nKeywords\nILUVIENDiabetic macular oedemaVisual acuityCentral foveal thickness\n==== Body\nBackground\nWorldwide diabetic macular edema (DME) is reported to have a prevalence of 6.8% and results in vision loss [1]. DME management can be difficult, with only around 15% of the patients achieving significant vision recovery with laser, the current standard of care [2]. A number of pharmacotherapies are now licensed for the treatment of DME in Europe, including anti-vascular endothelial growth factor agents and corticosteroid therapies [3], which are used to target vascular endothelial growth pathways and inflammatory pathways, respectively.\n\nIn diabetes, there is increased expression of leukocyte adhesion molecules on the endothelial cell walls. Leukocytes release free radicals and enzymes that cause direct damage to endothelial cells, increasing blood retinal barrier leakage. They also release cytokines, including vascular endothelial growth factor, tumor necrosis factor-α, and interleukin-6, which act through various signaling pathways to increase vascular permeability [4].\n\nCorticosteroids are known anti-inflammatory and angiostatic agents. Inhibiting the release of cytokines with a corticosteroid – such as dexamethasone, triamcinolone or fluocinolone – has been shown to reduce DME and rehabilitate vision in several pivotal clinical studies [3]. ILUVIEN contains the corticosteroid fluocinolone acetonide (FAc) and uses microdosingTM technology to release FAc at a daily rate of 0.2 μg for up to 3 years [5]. This differs significantly from both the dexamethasone delivery system and that of triamcinolone, which are reported to have a duration of action of only up to 3 and 4 months, respectively [6]. The effectiveness of ILUVIEN was demonstrated in the FAME trials (NCT00344968) in which patients with DME who had previously shown an insufficient response to laser were treated with either a 0.2 μg/day (ILUVIEN) or 0.5 μg/day FAc implant and were compared against a sham-control treated population. Both FAME trials independently met their primary endpoint and showed that significantly more patients with chronic DME treated with the 0.2 μg/day FAc implant experienced a ≥15-letter improvement in visual acuity (VA) at month 24 than sham-control patients (pooled data; 34.4 vs. 13.4%; p < 0.001) and that this benefit was sustained to month 36. Functional improvements were accompanied by rapid and sustained improvements in central foveal thickness (CFT) [5].\n\nIn Europe, ILUVIEN was first licensed in 2012. ILUVIEN is indicated for the treatment of vision impairment associated with chronic diabetic macular oedema considered insufficiently responsive to available therapies. Since then, its usage in real-life clinical practice has steadily been increasing. Miss Clare Bailey presented the real world outcomes from a UK audit of patients treated with ILUVIEN at the annual meeting of the Royal College of Ophthalmologists in Birmingham, UK, between June 24 and 26, 2016. This unpublished interim analysis showed that the majority of treated eyes (≥69.4% of 290 eyes) maintained or improved VA. To date, however, relatively limited data with a longer-term follow-up of the functional and structural responses following treatment with ILUVIEN have been reported. The case described herein provides data for both VA and CFT over a 24-month follow-up period.\n\nCase Presentation\nA 68-year-old Caucasian female with type 2 diabetes mellitus had diffuse DME diagnosed in her left eye in October 2010. The treatment history is summarised in Table 1 and was previously reported when only 6 months of follow-up were available. At diagnosis, VA was 46 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, converted from Snellen VA using the equation 85 + 50 x log (Snellen fraction), CFT was 712 microns, and intraocular pressure (IOP) was ≤22 mm Hg.\n\nThe patient had phacoemulsification plus intraocular lens insertion in the left eye in February 2012. Intravitreal triamcinolone acetonide was also administered to treat the persistent DME postoperatively. At the first postoperative visit, VA was 70 ETDRS letters, CFT was 278 microns, and IOP was 20 mm Hg. Over the next 5 months, VA (50 ETDRS letters) and CFT (805 microns) progressively worsened, and the patient was admitted into the Matisse trial in September 2012 to test the effects of ranibizumab plus a small-interfering RNA agent.\n\nBetween October 2012 and March 2014, the patient received 5 injections of ranibizumab plus the small-interfering RNA agent and then subsequently listed for 2 further courses of 3 intravitreal injections of ranibizumab. By the end of this stage of treatment, by 1 month after the final injection of ranibizumab, the DME had recurred, VA was 55 ETDRS letters, CFT was 774 microns, and IOP was 17 mm Hg.\n\nThe patient's DME was now chronic (over 18 months of duration), relapsing, and her CRT had fluctuated wildly through the different treatment phases, which is believed to have a deleterious effect on the function of the retina and, more specifically, on the visual function due to the presence of submacular fluid [7]. It was at this stage that the patient was treated with ILUVIEN according to NICE TA301 (please see http://www.nice.org.uk/guidance/ta301/chapter/1-Guidance). Figure 1 shows the response of VA and CFT after a single ILUVIEN implant without any further treatment to this eye over the next 2 years. Within 7 days, VA had increased to 61 ETDRS letters and CFT had decreased to 267 microns. Within 2 weeks, VA had improved further to 70 ETDRS letters, which is the legal requirement to hold a driving license in the UK. These early improvements were then largely maintained throughout the next 24 months without further intervention, as shown in Figure 1. Figure 2 shows optical coherence tomography scans before and after ILUVIEN implantation, illustrating the structural improvement that occurred alongside the functional improvement in vision. Over the course of the 2-year period, IOP remained below 21 mm Hg, and no IOP-lowering medication was required.\n\nConclusion\nThis is the first case that the authors are aware of, which shows that a single injection of the 0.2 μg/day FAc implant leads to rapid improvements (within 7 days) in VA and CFT that are maintained over 2 years of follow-up. This was despite 11 previous injections of ranibizumab, which failed to control the DME prior to treatment with ILUVIEN. The functional and structural responses presented herein are consistent with those reported in the FAME trials, with rapid and marked responses observed early and being sustained in the long term. This patient will continue to be monitored to see if the responses reported in controlled clinical trials are replicated with a single injection in real-life UK practice over a 36-month period.\n\nStatement of Ethics\nThis article does not contain any new studies with human or animal subjects performed by any of the authors.\n\nDisclosure Statement\nDr. H. Quhill and Mr. F. Quhill have no conflicts of interest relating to this publication. Mr. F. Quhill has attended advisory boards and speaker engagements and has been remunerated for these by Alimera Sciences.\n\nAcknowledgements\nThe publication of this article was supported by Alimera Sciences Ltd. The authors would like to thank Mr. Acharya and Mr. Brand for their help with the management of the patient.\n\nFig. 1 The change in central foveal thickness (top panel) and visual acuity (bottom panel) following intravitreal injection of ILUVIEN.\n\nFig. 2 Optical coherence tomography scan showing the foveal thickness prior to (a; March 2011) and 2 years after intravitreal ILUVIEN (b; April 2016) in the left eye.\n\nTable 1 Treatment history of the left eye\n\nDate\tNumber of days between visits\tDescription\tVA\tETDRS letters\tCFT, microns\t\n13/07/2009\t224\tProliferative retinopathy diagnosed\tNN\tNN\tNN\t\n14/08/2009\t32\tPanretinal laser photocoagulation\t6/6\t85\tNN\t\n21/10/2009\t68\tQuiecscent laser-treated retinopathy\t6/6\t85\tNN\t\n20/10/2010\t364\tDiffuse DME diagnosed\t6/36\t46\t712\t\n19/11/2010\t30\tIVTA injection\tNN\tNN\tNN\t\n14/12/2010\t25\tUnderwent macular grid\t6/18\t61\t304\t\n25/01/2011\t42\tVisit\t6/18\t61\t283\t\n02/03/2011\t36\tVisit\t6/12\t70\t279\t\n18/01/2012\t322\tDense cataract\t6/36\t46\t612\t\n02/02/2012\t15\tPhacoemulsification; +IOL; IVTA to treat cataract and recurrent DME\tNN\tNN\tNN\t\n16/04/2012\t74\tVisit\t6/12\t70\t278\t\n31/08/2012\t137\tVisit\t6/36\t46\t769\t\n24/09/2012\t24\tVisit; admitted into the Matisse trial (ranibizumab + siRNA agent)\t6/30\t50\t805\t\n08/10/2012\t14\t1st study injection\tNN\tNN\tNN\t\n12/11/2012\t35\t2nd study injection\t6/15\t65\t352\t\n10/12/2012\t28\t3rd study injection\t6/12\t70\t279\t\n07/01/2013\t28\t4th study injection\t6/9\t76\t271\t\n04/02/2013\t28\t5th study injection\t6/9\t76\t304\t\n04/03/2013\t28\tVisit\t6/9\t76\t332\t\n08/04/2013\t35\tPatient exits study listed for ranibizumab injection due to residual and progressive DME\t6/12\t70\t577\t\n06/06/2013\t59\tRanibizumab injection\tNN\tNN\tNN\t\n09/07/2013\t33\tRanibizumab injection\tNN\tNN\tNN\t\n23/08/2013\t45\tRanibizumab injection\tNN\tNN\tNN\t\n07/09/2013\t15\tVisit\t6/36\t46\t451\t\n17/10/2013\t40\tRanibizumab injection\tNN\tNN\tNN\t\n21/11/2013\t35\tRanibizumab injection\tNN\tNN\tNN\t\n10/01/2014\t50\tRanibizumab injection\tNN\tNN\tNN\t\n03/03/2014\t52\tVisit\t6/24\t55\t774\t\n21/03/2014\t18\tILUVIEN injection\tNN\tNN\tNN\t\n28/03/2014\t7\tVisit\t6/18\t61\t267\t\n04/04/2014\t7\tVisit\t6/12\t70\t241\t\n06/06/2014\t63\tVisit\t6/12\t70\t234\t\n04/09/2014\t90\tVisit\t6/12\t70\t245\t\n30/09/2014\t26\tVisit\t6/18\t61\t245\t\n01/02/2015\t124\tVisit\t6/12\t70\t239\t\n28/03/2015\t55\tVisit\t6/18\t61\t240\t\n08/05/2015\t41\tVisit\t6/6\t85\t251\t\n25/09/2015\t140\tVisit\t6/9\t76\t252\t\n24/10/2015\t29\tVisit\t6/18\t61\tNN\t\n28/01/2016\t96\tVisit\t6/12\t70\t250\t\n02/03/2016\t34\tVisit\t6/12\t70\tNN\t\n06/04/2016\t94\tVisit\t6/12\t70\t250\t\nVA, visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; CFT, central foveal thickness; IVTA, intravitreal triamcinolone acetonide; NN, no numbers; IOL, intraocular lens; siRNA, small-interfering RNA; DME, diabetic macular oedema.\n==== Refs\nReferences\n1 Yau JW Rogers SL Kawasaki R Global prevalence and major risk factors of diabetic retinopathy Diabetes Care 2012 35 556 564 22301125 \n2 Boyer DS Hopkins JJ Sorof J Ehrlich JS Anti-vascular endothelial growth factor therapy for diabetic macular edema Ther Adv Endocrinol Metab 2013 4 151 169 24324855 \n3 Singer MA Kermany DS Waters J Jansen ME Tyler L Diabetic macular edema: it is more than just VEGF. F1000Res pii: F1000Faculty Rev-1019. \n4 Wenick A Bressler N Diabetic macular edema: current and emerging therapies Middle East Afr J Ophthalmol 2012 19 4 12 22346109 \n5 ILUVIEN Summary of Product Characteristics. https://www.medicines.org.uk/emc/medicine/27636 (accessed June 22, 2016).\n6 Stewart MW Flynn HW Jr Schwartz SG Scott IU Extended duration strategies for the pharmacologic treatment of diabetic retinopathy: current status and future prospects Expert Opin Drug Deliv 2016 Epub ahead of print \n7 Sophie R Lu N Campochiaro PA Predictors of functional and anatomic outcomes in patients with diabetic macular edema treated with ranibizumab Ophthalmology 2015 122 1395 1401 25870079\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1663-2699",
"issue": "7(3)",
"journal": "Case reports in ophthalmology",
"keywords": "Central foveal thickness; Diabetic macular oedema; ILUVIEN; Visual acuity",
"medline_ta": "Case Rep Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101532006",
"other_id": null,
"pages": "301-307",
"pmc": null,
"pmid": "28203186",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "25870079;22346109;27303642;24324855;27293138;22301125",
"title": "Real-Life ILUVIEN (Fluocinolone Acetonide) Case Study: Rapid Drying of the Macula and Improved Vision within 2 Years after Therapy Initiation.",
"title_normalized": "real life iluvien fluocinolone acetonide case study rapid drying of the macula and improved vision within 2 years after therapy initiation"
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"abstract": "Several cases of symptomatic hemicrania continua (HC) have been reported. A 66-year-old man, suffering from migraine without aura, presented with a four month history of a new headache fulfilling the ICHD 3beta clinical criteria for HC. HC onset was strictly related to the use of transdermal nitroglycerine patch (TNP). In agreement with the cardiologist, TNP was discontinued and the headache promptly disappeared; symptoms reappeared within 6-12 hours after nitroglycerine reintroduction. After permanent discontinuation of TNP, headache disappeared at one year follow-up. To the best of our knowledge, this is the first report of the occurrence of an HC-like headache related to TNP.",
"affiliations": "Headache Centre, Neurological Division, SS Giovanni e Paolo Hospital, Venice, Italy.;Headache Centre, Department of Neurosciences, Padua University, Padua, Italy.;Headache Centre, Department of Neurosciences, Padua University, Padua, Italy.",
"authors": "Mainardi|Federico|F|;Zanchin|Giorgio|G|;Maggioni|Ferdinando|F|",
"chemical_list": "D014665:Vasodilator Agents; D005996:Nitroglycerin",
"country": "United States",
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"issn_linking": "0017-8748",
"issue": "57(3)",
"journal": "Headache",
"keywords": "hemicrania continua; hemicrania continua-like headache; secondary headaches; symptomatic hemicrania continua; transdermal nitroglycerine",
"medline_ta": "Headache",
"mesh_terms": "D000279:Administration, Cutaneous; D000368:Aged; D006261:Headache; D006801:Humans; D008297:Male; D005996:Nitroglycerin; D051302:Paroxysmal Hemicrania; D014665:Vasodilator Agents",
"nlm_unique_id": "2985091R",
"other_id": null,
"pages": "494-496",
"pmc": null,
"pmid": "27933631",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hemicrania Continua-Like Headache Related to Transdermal Nitroglycerine Therapy.",
"title_normalized": "hemicrania continua like headache related to transdermal nitroglycerine therapy"
} | [
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"companynumb": "IT-BAUSCH-BL-2017-000653",
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"abstract": "Clinical efficacy of combination therapy using vasodilators for pulmonary arterial hypertension (PAH) is well established. However, information on its safety are limited. We experienced a case of primary Sjogren's syndrome associated with PAH where the patient developed pulmonary edema immediately after the introduction of upfront triple combination therapy. Although the combination therapy successfully stabilized her pre-shock state, multiple ground glass opacities (GGO) emerged. We aborted the dose escalation of epoprostenol and initiated continuous furosemide infusion and noninvasive positive pressure ventilation (NPPV), but this did not prevent an exacerbation of pulmonary edema. Chest computed tomography showing diffuse alveolar infiltrates without inter-lobular septal thickening suggests the pulmonary edema was unlikely due to cardiogenic pulmonary edema and pulmonary venous occlusive disease. Acute respiratory distress syndrome was also denied from no remarkable inflammatory sign and negative results of drug-induced lymphocyte stimulation tests (DLST). We diagnosed the etiological mechanism as pulmonary vasodilator-induced trans-capillary fluid leakage. Following steroid pulse therapy dramatically improved GGO. We realized that overmuch dose escalation of epoprostenol on the top of dual upfront combination poses the risk of pulmonary edema. Steroid pulse therapy might be effective in cases of vasodilator-induced pulmonary edema in Sjogren's syndrome associated with PAH.",
"affiliations": "Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.",
"authors": "Takeuchi|Kimikazu|K|;Nakayama|Kazuhiko|K|;Okano|Mitsumasa|M|;Tamada|Naoki|N|;Suehiro|Hideya|H|;Shinkura|Yuto|Y|;Yanaka|Kenichi|K|;Onishi|Hiroyuki|H|;Tanaka|Hidekazu|H|;Shinke|Toshiro|T|;Emoto|Noriaki|N|;Hirata|Ken-Ichi|KI|",
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"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(17)30289-710.1016/j.rmcr.2017.12.003Case ReportUpfront triple combination therapy-induced pulmonary edema in a case of pulmonary arterial hypertension associated with Sjogren's syndrome Takeuchi Kimikazu k.takeuchi.6008@gmail.comaNakayama Kazuhiko nakayama@med.kobe-u.ac.jpa∗Okano Mitsumasa m_okano_hiyokouser@yahoo.co.jpaTamada Naoki nk.tamada@gmail.comaSuehiro Hideya hidebonnation@yahoo.co.jpaShinkura Yuto tsumotsumo_ron@yahoo.co.jpaYanaka Kenichi yanadoushies@yahoo.co.jpaOnishi Hiroyuki oh010h@gmail.comaTanaka Hidekazu tanakah@med.kobe-u.ac.jpaShinke Toshiro shinke@med.kobe-u.ac.jpaEmoto Noriaki noriaki.emoto@mac.comabHirata Ken-ichi hiratak@med.kobe-u.ac.jpaa Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japanb Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, Japan∗ Corresponding author. Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki, Chuo, Kobe 650-0017, Japan. nakayama@med.kobe-u.ac.jp07 12 2017 2018 07 12 2017 23 55 59 6 9 2017 6 12 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Clinical efficacy of combination therapy using vasodilators for pulmonary arterial hypertension (PAH) is well established. However, information on its safety are limited. We experienced a case of primary Sjogren's syndrome associated with PAH where the patient developed pulmonary edema immediately after the introduction of upfront triple combination therapy. Although the combination therapy successfully stabilized her pre-shock state, multiple ground glass opacities (GGO) emerged. We aborted the dose escalation of epoprostenol and initiated continuous furosemide infusion and noninvasive positive pressure ventilation (NPPV), but this did not prevent an exacerbation of pulmonary edema. Chest computed tomography showing diffuse alveolar infiltrates without inter-lobular septal thickening suggests the pulmonary edema was unlikely due to cardiogenic pulmonary edema and pulmonary venous occlusive disease. Acute respiratory distress syndrome was also denied from no remarkable inflammatory sign and negative results of drug-induced lymphocyte stimulation tests (DLST). We diagnosed the etiological mechanism as pulmonary vasodilator-induced trans-capillary fluid leakage. Following steroid pulse therapy dramatically improved GGO. We realized that overmuch dose escalation of epoprostenol on the top of dual upfront combination poses the risk of pulmonary edema. Steroid pulse therapy might be effective in cases of vasodilator-induced pulmonary edema in Sjogren's syndrome associated with PAH.\n\nKeywords\nSteroid therapyGround glass opacityInter-lobular septal thickeningEpoprostenolAcute respiratory distress syndromeTrans-capillary fluid leakage\n==== Body\nAbbreviation\nPAHpulmonary arterial hypertension\n\nGGOground glass opacities\n\nDLSTdrug-induced lymphocyte stimulation tests\n\nPVODpulmonary veno-occlusive disease\n\n1 Introduction\nCombination therapy with pulmonary vasodilators for patients with pulmonary arterial hypertension (PAH) has been proven to be effective in improving the prognosis by recent clinical trials. Upfront dual combination is more effective than mono-therapy [1], [2]. Furthermore, sequential triple combination is superior to dual combination [3], which led to the new clinical trial on upfront triple combination (TRITON study: NCT02558231). However, the safety profile of upfront triple combination and the approach to possible complications remain unclear [4].\n\nHere we report a case of pulmonary edema emerging in the treatment of a connective tissue disease (CTD) associated with PAH with upfront triple combination therapy. Although we were unable to control the pulmonary edema by continuous intravenous diuretic infusion under noninvasive positive pressure ventilation (NPPV), steroid pulse therapy successfully ameliorated the pulmonary edema.\n\n2 Case description\nA 67-year-old woman complained of exertional dyspnea for four months and was admitted to our hospital with deteriorating resting dyspnea in recent weeks. She had no past history of previous respiratory or cardiac disease. Her blood pressure was 118/90 mmHg and heart rate was 120/minute. Clinical evaluation revealed mild jugular venous distention, bilateral leg edema, and a pan-systolic murmur at the 4th left sternal border. The plasma brain natriuretic peptide level was high (930 pg/mL). Electrocardiography revealed right axis deviation with SIQIIITIII (Fig. 1A). A chest X-ray showed cardiomegaly with a dilated right pulmonary artery (Fig. 1B). Echocardiography detected 56 mmHg of a tricuspid regurgitation pressure gradient, hypertrophy (RV free wall thickness: 7.3 mm) and low systolic function of right ventricle (TAPSE: 12 mm), and a compressed left ventricle forming a D-shape (Fig. 1C). Chest contrast-enhanced computed tomography (CT) revealed no lung diseases, pulmonary embolism, pleural effusion, or lymphadenopathy (Fig. 3B). Right heart catheterization (RHC) documented an increase in mean pulmonary arterial pressure (mPAP: 45 mmHg) with a normal pulmonary capillary wedge pressure (PCWP: 7 mmHg), and elevated pulmonary vascular resistance (PVR: 2156 dyne·sec/cm5), decreased cardiac index (CI: 0.85L/min/m2) as measured by Fick method. Antinuclear antibodies were positive at a titer of 1: 320 without positive findings of any specific antibodies including both Ro (SS-A) and La (SS-B) antibodies. On the basis of the complaint of a dry mouth, the patient underwent salivary gland scintigraphy showing reduced uptake in the left parotid gland (Fig. 1D). Shilmer's test and lip biopsy (Fig. 1E) were positive. Serum complement protein C3, C4, and total hemolytic complement (CH50) were within the normal range (103 mg/dl, 21.4 mg/dl, 48U/ml). Immunoglobulin G (IgG), A (IgA), and M (IgM) were also normal (930 mg/dl, 123 mg/dl, 85 mg/dl). Based on all the above findings, we diagnosed the patient with primary Sjogren's syndrome associated with pulmonary arterial hypertension.Fig. 1 A: Electrocardiography shows a normal sinus rhythm with right axis deviation and SIQIIITIII. B: A chest X-ray documents cardiac dilation and dilated right pulmonary artery. C: The echocardiographic findings reveal compression of the left ventricular. D: Reduced trace uptake in left parotid gland (⇨). E: Lymphocyte infiltration around acinus were detected in subcutaneous tissue of lip.\n\nFig. 1\n\nDue to the severity of the patient's hemodynamics and resting dyspnea with a WHO functional class IV, upfront combination therapy using intravenous epoprostenol, macitentan, (10 mg/day), and sildenafil (60 mg/day) was initiated from day 0 together with dobutamine (Fig. 2A). The epoprostenol was initiated at a dose of 1 μg/kg/min, and was increased by 1–2 μg/kg/min every day up to 7 μg/kg/min. Her cardiac index markedly improved from 0.85 to 2.8 L/min/m2 on day 4. However, multiple slight ground glass opacities (GGO) and bilateral pleural effusion (PE) emerged as well (Fig. 3B). To improve the congestion, we introduced continuous intravenous furosemide and a NPPV with 6 cmH2O positive end-expiratory pressure (PEEP) (Fig. 2B) and stopped the dose escalation of epoprostenol. Regardless, the patient experienced intensive dehydration (2.2–5.7 L of urine volume/day), weight loss (64–54 kg), and a reduced PE during days 5–10, and low oxygen saturation (SpO2 93%) (Fig. 2C) and GGO exacerbated (Fig. 3B) during days 10–14. We excluded left sided heart failure by a low PCWP (7 mmHg) and no feature of left ventricular diastolic dysfunction (E-Dct: 226msec from trans-mitral inflow, S/D 2.05 from pulmonary venous flow), infectious pneumonia by the negative sputum culture result, and interstitial pneumonitis by a normal level of KL-6 (231 U/ml). Drug-induced lymphocyte stimulation tests (DLST) for epoprostenol and the other medications used (heparin, atorvastatin, lansoprazole) were all negative.Fig. 2 A: Hemodynamic improvement after upfront combination therapy in the first 3 days. B: Fluid retention was also treated by diuretics from day 4–8. C: Low oxygen saturation sustained until day 14 under noninvasive positive pressure ventilation (NPPV: day 5-). Pulmonary edema was dramatically improved steroid pulse therapy (day 14–16). CI: Cardiac index, BW: Body weight, UV: Urine volume.\n\nFig. 2Fig. 3 A: In chest X-ray, pulmonary edema worsening from day 4 to day 14 in spite of reduced cardiomegaly, which improved by steroid at day 15. B: A chest CT-scan at day 0 is within normal limit. Multiple ground glass opacities (GGO) and pleural effusion (PE:▼) emerged from day 4. Regardless PE improvement, GGO without inter-lobular septal thickening became worse from day 10–14. Intravenous prednisolone pulse (1000 mg/day for 3 days) improved GGO at day 18 to normal limit (day 32).\n\nFig. 3\n\nWe doubted that the pathophysiology of the pulmonary edema was due to transcapillary fluid leakage promoted by upfront triple combination of pulmonary vasodilators. We then tried intravenous steroid pulse therapy (Methlprednisolone 1000 mg/day for 3 days) from day 14. After steroid administration, pulmonary edema dramatically improved (Fig. 2, Fig. 3B) and finally returned to baseline (Fig. 3B) on day 32. We continued the upfront combination therapy, terminated NPPV on day 24, and discontinued daytime-oxygen therapy on day 32. Follow-up RHC at day 31 showed a significant improvement of hemodynamics (mPAP: 20 mmHg, PCWP: 2 mmHg, PVR: 236 dyne·sec/cm5, CI: 3.94 L/min/m2). Upon notification of stable hemodynamics, we replaced intravenous epoprostenol with oral beraprost (360 μg/day) on days 33–43 without any deterioration of hemodynamics or symptoms (WHO functional class II). She was discharged on day 57 and was followed for over one year without any worsening of symptoms.\n\n3 Discussion\n3.1 Pulmonary edema induced by upfront combination therapy\nIn this case report, we described an instructive case that emphasized the complications of upfront triple combination therapy in treating PAH associated with Sjogren's syndrome. Although pulmonary edema as a side effect of oral combination therapy has not been reported in previous clinical trials [1], [2], [3], [4], similar findings have been reported in cases where epoprostenol infusion was used in idiopathic PAH [5], [6], [7], scleroderma [8], [9], [10], pulmonary capillary hemangiomatosis [11], and pulmonary veno-occlusive disease (PVOD) [12], [13]. Amelioration by steroid pulse therapy was also reported in some of those cases [6], [7]. But, the mechanism of drug-induced pulmonary edema was not well described. This case let highlights a rare complication of upfront combination with pulmonary vasodilators and the optimal management for it.\n\n3.2 Underlying pathophysiology of pulmonary vasodilator-induced pulmonary edema\nFor an accurate diagnosis of unexpected pulmonary edema, we excluded the possibility of interstitial and bacterial pneumonia. Cardiac pulmonary edema was also unlikely because of worsening chest CT findings after sufficient diuresis. No kerley B lines in chest X-ray (Fig. 3A) and reduced pleural effusion and cardiomegaly after diuretics and diffuse alveolar infiltration without inter-lobular septal thickening in chest CT (Fig. 3B), all these non-cardiogenic signs denied the possibility of increased capillary hydrostatic pressure from left heart failure [14]. Despite the availability of one case report with Sjogren's syndrome complicating PVOD [15], we also undoubted PVOD because chest CT at admission showed no GGO, thickened inter-lobular septal thickening, or lymphadenopathy. Ogawa et al. established a scoring system to predict PVOD when the score is over 4, sensitivity is 94% and specificity is 91% [16]. The score of our case is 3 (female:0, smoking history:0, ≧9% of oxygen desaturation during 6 minutes walking test:0, %DLco<34%:0, GGO:1, inter-lobular septal thickening:0, centrilobular nodules:0, upper lobe defects in lung perfusion scintigraphy:0, and pulmonary edema after vasodilator:2). Kudelko et al. suggested that the pathophysiology of epoprostenol-induced interstitial pneumonitis is that of hypersensitive inflammatory response to epoprostenol, which is confirmed by a positive T cell proliferation assay [7]. In this case, however, acute respiratory distress syndrome was also denied from no remarkable inflammatory sign and negative results of DLST for epoprostenol. We speculated that the pathophysiology of pulmonary edema in this case might be due to transcapillary fluid leakage elicited by upfront triple combination therapy. We realized that overmuch dose escalation of epoprostenol on the top of dual upfront combination poses the risk of pulmonary edema.\n\n3.3 Optimal management including steroid therapy\nPulmonary edema in previous reports occurred 15 minutes to 28 days after epoprostenol induction at a dose of 2–20 ng/kg/min. The dose escalation speed of epoprostenol was 1–2 ng/kg/min per day, similar to our protocol. Although the frequency of epoprostenol-induced pulmonary edema on the top of oral combination therapy is not known, we should be aware of the possibility of critical side effects so as to appropriately monitor the patient's condition. As we did not perform bronchoalveolar lavage or transbronchial lung biopsy, it was difficult to accurately determine the pathology. However, as seen from a dramatic amelioration by steroid therapy, the strategy to stabilize transcapillary fluid leakage by steroid pulse therapy [17] could be effective as a treatment option for similar cases.\n\n4 Conclusion\nWe highlighted the rare but critical complication occurring in a patient with PAH associated with connective tissue disease. Exacerbating pulmonary edema against sufficient diuresis emphasized the existence of non-cardiogenic pulmonary edema in this case. The strategy to stabilize trans-capillary fluid leakage by steroid pulse therapy could be effective and considered as a treatment option for similar cases.\n\nSources of funding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nConflicts of interest (COI)\nKazuhiko Nakayama have received research grants from Actelion Pharmaceuticals Japan Ltd., Bayer Holding Ltd., and GlaxoSmithKline plc. Ken-ichi Hirata received research grants from Actelion Pharmaceuticals Japan Ltd., and Bayer Holding Ltd. The other authors have no conflicts of interest to declare.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 Humbert M. Barst R.J. Robbins I.M. Channick R.N. Galiè N. Boonstra A. Rubin L.J. Horn E.M. Manes A. Simonneau G. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2 Eur. Respir. J. 24 2004 353 359 15358690 \n2 Galiè N. Barberà J.A. Frost A.E. Ghofrani H.-A. Hoeper M.M. McLaughlin V.V. Peacock A.J. Simonneau G. Vachiery J.-L. Grünig E. Oudiz R.J. Vonk-Noordegraaf A. White R.J. Blair C. Gillies H. Miller K.L. Harris J.H.N. Langley J. Rubin L.J. Initial use of Ambrisentan plus Tadalafil in pulmonary arterial hypertension N. Engl. J. Med. 373 2015 834 844 26308684 \n3 Sitbon O. Channick R. Chin K.M. Frey A. Gaine S. Galiè N. Ghofrani H.-A. Hoeper M.M. Lang I.M. Preiss R. Rubin L.J. Di Scala L. Tapson V. Adzerikho I. Liu J. Moiseeva O. Zeng X. Simonneau G. McLaughlin V.V. GRIPHON Investigators Selexipag for the treatment of pulmonary arterial hypertension N. Engl. J. Med. 373 2015 2522 2533 26699168 \n4 Sitbon O. Jaïs X. Savale L. Cottin V. Bergot E. Macari E.A. Bouvaist H. Dauphin C. Picard F. Bulifon S. Montani D. Humbert M. Simonneau G. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study Eur. Respir. J. 43 2014 1691 1697 24627535 \n5 Batra A.K. Segall P.H. Ahmed T. Pulmonary edema with nifedipine in primary pulmonary hypertension Respiration 47 1985 161 163 4001571 \n6 Morimatsu H. Goto K. Matsusaki T. Katayama H. Matsubara H. Ohe T. Morita K. Rapid development of severe interstitial pneumonia caused by epoprostenol in a patient with primary pulmonary hypertension Anesth. Analg. 99 2004 1205 1207 \\\\\\\\r99/4/1205 [pii] 15385376 \n7 Kudelko K.T. Nadeau K. Leung A.N. Liu J. Haddad F. Zamanian R.T. De Jesus Perez V. Epoprostenol-associated pneumonitis: diagnostic use of a T-cell proliferation assay J. Heart Lung Transplant. 29 2010 1071 1075 20627625 \n8 Farber H.W. Graven K.K. Kokolski G. Korn J.H. Pulmonary edema during acute infusion of epoprostenol in a patient with pulmonary hypertension and limited scleroderma J. Rheumatol. 26 1999 1195 1196 10332990 \n9 Gugnani M.K. Pierson C. Vanderheide R. Girgis R.E. Pulmonary edema complicating prostacyclin therapy in pulmonary hypertension associated with scleroderma: a case of pulmonary capillary hemangiomatosis Arthritis Rheum. 43 2000 699 703 10728766 \n10 Preston I.R. Klinger J.R. Houtchens J. Nelson D. Mehta S. Hill N.S. Pulmonary edema caused by inhaled nitric oxide therapy in two patients with pulmonary hypertension associated with the CREST syndrome Chest 121 2002 656 659 11834688 \n11 Humbert M. Maitre S. Capron F. Rain B. Musset D. Simonneau G. Pulmonary edema complicating continuous intravenous prostacyclin in pulmonary capillary hemangiomatosis Am. J. Respir. Crit. Care Med. 157 1998 1681 1685 9603154 \n12 Palmer S.M. Robinson L.J. Wang A. Gossage J.R. Bashore T. Tapson V.F. Massive pulmonary edema and death after prostacyclin infusion in a patient with pulmonary veno-occlusive disease Chest 113 1998 237 240 9440597 \n13 Creagh-Brown B. Nicholson A. Showkathali R. Gibbs J. Howard L. Pulmonary veno-occlusive disease presenting with recurrent pulmonary oedema and the use of nitric oxide to predict response to sildenafil Thorax 63 2008 933 934 18820120 \n14 Milne E.N.C. Pistolesi M. Miniati M. Giuntini C. The radiologic distinction of cardiogenic and noncardiogenic edema Am. J. Roentgenol. 144 1985 879 894 3872571 \n15 Naniwa T. Takeda Y. Long-term remission of pulmonary veno-occlusive disease associated with primary Sjogren's syndrome following immunosuppressive therapy Mod. Rheumatol. 21 2011 637 640 21394665 \n16 Ogawa A. Miyaji K. Matsubara H. Clinical prediction rule for identifying patients with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis Eur. Heart J. 34 Suppl. 1 2013 314 23284098 \n17 Salvador E. Shityakov S. Förster C. Glucocorticoids and endothelial cell barrier function Cell Tissue Res. 355 2014 597 605 24352805\n\n",
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"title": "Upfront triple combination therapy-induced pulmonary edema in a case of pulmonary arterial hypertension associated with Sjogren's syndrome.",
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"abstract": "Aciclovir is an anti-viral frequently used for herpes virus infections. Neurotoxicity and nephrotoxicity are uncommon but serious side effects of aciclovir treatment. This case illustrates how aciclovir induced neurotoxicity can present and how it can be diagnosed using quantitative assays of aciclovir and its metabolite in the CSF and serum.",
"affiliations": "Department of Infectious Diseases, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, United Kingdom(1). Electronic address: Louise.berry@nuh.nhs.uk.;Department of Infectious Diseases, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, United Kingdom(1).",
"authors": "Berry|L|L|;Venkatesan|P|P|",
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"mesh_terms": "D000212:Acyclovir; D000368:Aged; D000998:Antiviral Agents; D002555:Cerebrospinal Fluid; D005260:Female; D006147:Guanine; D006801:Humans; D020258:Neurotoxicity Syndromes; D044967:Serum",
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"title": "Aciclovir-induced neurotoxicity: Utility of CSF and serum CMMG levels in diagnosis.",
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"abstract": "BACKGROUND\nLoiasis is a vector-borne parasitic infection endemic across many areas of Central and West Africa. Its treatment is tricky due to the risk of serious neurologic adverse events occurring after the administration of microfilaricidal drugs, like diethylcarbamazine or ivermectin, in subjects with high pre-treatment microfilarial load. Albendazole is currently recommended to slowly reduce microfilaremia before curative regimen is prescribed.\n\n\nMETHODS\nWe report the case of a 25-year-old man from Guinea-Conakry who was incidentally diagnosed with highly microfilaremic Loa loa infection. A three weeks regimen of albendazole was prescribed. Minor neurologic side effects occurred after two weeks of administration, while serious encephalopathy developed one week later. Clinical and electroencephalographic features of the patient resembled those of an immune-mediated encephalitis. After exclusion of other causes of encephalopathy, treatment-related Loa loa encephalopathy induced by albendazole was suspected. Corticosteroid treatment was administered and the patient recovered.\n\n\nCONCLUSIONS\nOur case confirms that Loa loa treatment-related encephalopathy may occur even during albendazole treatment. The clinical and electroencephalographic similarities between Loa loa albendazole-related encephalopathy and immune-mediated encephalitis suggest the possibility of an underlying inflammation-based pathogenesis. Although corticosteroid administration is not recommended in Loa loa ivermectin-induced encephalopathy, in this case of Loa loa albendazole-induced encephalopathy it may have played a therapeutic role.",
"affiliations": "Hepatology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy. Electronic address: lorenzo.volpicelli@uniroma1.it.;Hepatology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy. Electronic address: mauriziodeangelis@yahoo.com.;Epilepsy Unit, Department of Human Neurosciences, Sapienza University, Rome, Italy. Electronic address: alessandra.morano@hotmail.it.;Hepatology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy. Electronic address: elisa.biliotti@uniroma1.it.;Hepatology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy. Electronic address: cristiana.franchi@gmail.com.;Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy. Electronic address: simona.gabrielli@uniroma1.it.;Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy. Electronic address: simonetta.mattiucci@uniroma1.it.;Epilepsy Unit, Department of Human Neurosciences, Sapienza University, Rome, Italy. Electronic address: c_dibonaventura@yahoo.it.;Hepatology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy. Electronic address: gloria.taliani@uniroma1.it.",
"authors": "Volpicelli|Lorenzo|L|;De Angelis|Maurizio|M|;Morano|Alessandra|A|;Biliotti|Elisa|E|;Franchi|Cristiana|C|;Gabrielli|Simona|S|;Mattiucci|Simonetta|S|;Di Bonaventura|Carlo|C|;Taliani|Gloria|G|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D005369:Filaricides; D015766:Albendazole",
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"keywords": "Albendazole; Autoimmune encephalitis; Corticosteroids; Encephalopathy; Loa loa; Neurological adverse events",
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"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D015766:Albendazole; D000818:Animals; D003937:Diagnosis, Differential; D005369:Filaricides; D016701:Guinea; D006801:Humans; D007558:Italy; D008117:Loa; D008118:Loiasis; D008297:Male; D008842:Microfilariae; D016896:Treatment Outcome",
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"title": "Encephalopathy in a patient with loiasis treated with albendazole: A case report.",
"title_normalized": "encephalopathy in a patient with loiasis treated with albendazole a case report"
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"companynumb": "IT-EDENBRIDGE PHARMACEUTICALS, LLC-IT-2019EDE000067",
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"abstract": "Late occurrence of antibody-mediated rejection (AMR), defined as occurring 6 months after transplantation, is associated with poor renal allograft survival, compared to early acute AMR and acute cellular rejection. The proteasome inhibitor bortezomib has multiple immunomodulatory effects on plasma cells, the source of donor-specific HLA antibodies which mediate AMR.\n\n\nMETHODS\nConsecutive patients who presented with biopsy-proven AMR and donor-specific anti-HLA antibodies (DSA) at a single institution between July 2011 and February 2015 were included. They received rituximab 375 mg/m<sup>2</sup> on day 1, bortezomib 1.3 mg/m<sup>2</sup> and methylprednisolone on days 1, 4, 8, 11, and plasmapheresis on days -1, 4, 8, 11, 14, 15, 17, with herpes zoster prophylaxis. The primary outcome was graft survival independent of dialysis. Patients were prospectively assessed with serial monitoring of renal function and proteinuria, and neuropathy symptoms. Toxicity determination was made by medical record review for hospitalizations within 3 months of therapy, or documentation of opportunistic infection.\n\n\nRESULTS\nEleven patients were treated for late AMR (diagnosed at a median of 38 months post renal transplant) with this bortezomib-based protocol; 2 patients underwent the regimen twice. Of the 11 patients, 9 have functioning allografts (82% graft survival) with a median creatinine of 2.1 mg/dL (range 1.1 - 3.4 mg/dL), at a median follow-up of 50 months after AMR therapy (range 24 - 63 months). One patient was re-transplanted at 4 years post AMR treatment with no AMR recurrence to date at 2-years' follow-up, and a second patient re-initiated dialysis at 2 years post AMR treatment. Patient survival is 91% (10/11): 1 patient relocated out of state and was reported to have died from complications of hypertensive encephalopathy. The majority of patients (7/11) had several class I and class II DSA specificities; of these, 4 patients had negative class I DSA but persistent class II DSAs at 2 - 3 months post therapy. Only 1 patient who was positive for class II DSAs alone (DR53 and DQ2) converted to negative DSA, although DSA testing was delayed to 2 years' follow-up. Two patients were hospitalized within 1 month of the protocol, 1 for ileus and 1 for urinary tract infection and ruptured ovarian cyst. One other patient had herpes zoster.\n\n\nCONCLUSIONS\nRenal allograft survival was 82% at 4 years after bortezomib-based therapy for late onset AMR; toxicity profile of this regimen was acceptable. Eradication of DSAs may not be necessary for meaningful and durable renal response.
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"authors": "Ding|Yanli|Y|;Francis|Jean|J|;Gautam|Amitabh|A|;Pelletier|Linda|L|;Sanchorawala|Vaishali|V|;Quillen|Karen|K|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007518:Isoantibodies; D000069283:Rituximab; D000069286:Bortezomib",
"country": "Germany",
"delete": false,
"doi": "10.5414/CN109278",
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"issue": "89(4)",
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"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D001706:Biopsy; D000069286:Bortezomib; D002908:Chronic Disease; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007518:Isoantibodies; D007668:Kidney; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010956:Plasmapheresis; D000069283:Rituximab; D014019:Tissue Donors; D014184:Transplantation, Homologous",
"nlm_unique_id": "0364441",
"other_id": null,
"pages": "252-259",
"pmc": null,
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"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
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"title": "Durable renal response after combination of bortezomib, corticosteroids, rituximab, and plasmapheresis for late antibody-mediated renal transplant rejection
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"title_normalized": "durable renal response after combination of bortezomib corticosteroids rituximab and plasmapheresis for late antibody mediated renal transplant rejection"
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"abstract": "The continuous delivery of a levodopa/carbidopa gel suspension (Duodopa®) into the small bowel through a jejunal tube inserted via percutaneous endoscopic gastrostomy represents a new treatment method in advanced Parkinson disease. Some severe device-related complications have been described in the last few years. Some of them are associated with phytobezoar formation at the pigtail of the catheter. We present the case of a Parkinson disease patient treated with the Duodopa infusion system complicated by jejunal tube fistulization into the colon. We suggest a possible treatment strategy for this complication, which has not been described in the literature to date.",
"affiliations": "Department of Gastroenterology, Hospital de Santo António dos Capuchos, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Department of Gastroenterology, Hospital de Santo António dos Capuchos, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Department of Gastroenterology, Hospital de Santo António dos Capuchos, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Department of Neurology, Hospital de Santo António dos Capuchos, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Department of Gastroenterology, Hospital de Santo António dos Capuchos, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Department of Gastroenterology, Hospital de Santo António dos Capuchos, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.;Department of Transplantation Unit, Hospital Curry Cabral, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.",
"authors": "Russo|Pedro|P|;Costa|Mariana|M|;Silva|Mário|M|;de Sousa|Ary|A|;Carvalho|Diana|D|;Saiote|Joana|J|;Mendes|Milena|M|",
"chemical_list": null,
"country": "Switzerland",
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"keywords": "Antiparkinson agents; Gastrointestinal endoscopy; Gastrostomy/adverse effects; Parkinson disease",
"medline_ta": "GE Port J Gastroenterol",
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"references": "16857573;23192929;21961105;12782919;20933456;22544946;15668416",
"title": "Fistulization of J-PEG Jejunal Tube into the Colon in a Patient Treated with Duodopa® Infusion: A Case Report.",
"title_normalized": "fistulization of j peg jejunal tube into the colon in a patient treated with duodopa infusion a case report"
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"abstract": "A woman who developed acute pancreatitis following ingestion of low dose codeine, with positive rechallenge, is described. As this is the first case report of pancreatitis being induced solely by codeine, this side effect must be rare in view of the widespread consumption of this drug.",
"affiliations": "Department of Hepatogastroenterology, Hôpital de l'Archet II, Nice, France.",
"authors": "Hastier|P|P|;Longo|F|F|;Buckley|M|M|;Chichmanian|R M|RM|;Delmont|J P|JP|",
"chemical_list": "D009294:Narcotics; D003061:Codeine",
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"mesh_terms": "D000208:Acute Disease; D000328:Adult; D003061:Codeine; D005260:Female; D006801:Humans; D009294:Narcotics; D009336:Necrosis; D010179:Pancreas; D010195:Pancreatitis; D014057:Tomography, X-Ray Computed",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pancreatitis induced by codeine: a case report with positive rechallenge.",
"title_normalized": "pancreatitis induced by codeine a case report with positive rechallenge"
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"abstract": "This article is co-authored by a parent of a 32-year-old male patient with Lennox-Gastaut syndrome (LGS) and his epileptologist. It discusses the parent's experience of having a child with LGS from diagnosis through living day-to-day with the disease and the physician's perspective when treating this devastating epilepsy syndrome. The patient's mother, who is his legal representative, provided written consent for publication of this article.",
"affiliations": "Department of Neurology, Epilepsy Division, University of Cincinnati Gardner Neuroscience Institute, Cincinnati, OH, USA. heather.mckee@uc.edu.;, Cincinnati, OH, USA.",
"authors": "McKee|Heather R|HR|;Glasgow|Barbara|B|",
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"doi": "10.1007/s40120-020-00222-3",
"fulltext": "\n==== Front\nNeurol Ther\nNeurol Ther\nNeurology and Therapy\n2193-8253\n2193-6536\nSpringer Healthcare Cheshire\n\n33113098\n222\n10.1007/s40120-020-00222-3\nCommentary\nLennox–Gastaut Syndrome: Perspective of a Parent and a Physician\nMcKee Heather R. heather.mckee@uc.edu\n\n1\nGlasgow Barbara 2\n1 grid.24827.3b 0000 0001 2179 9593 Department of Neurology, Epilepsy Division, University of Cincinnati Gardner Neuroscience Institute, Cincinnati, OH USA\n2 Cincinnati, OH USA\n28 10 2020\n28 10 2020\n6 2021\n10 1 15\n25 9 2020\n14 10 2020\n© The Author(s) 2020\nhttps://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial 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-nc/4.0/.\nThis article is co-authored by a parent of a 32-year-old male patient with Lennox–Gastaut syndrome (LGS) and his epileptologist. It discusses the parent’s experience of having a child with LGS from diagnosis through living day-to-day with the disease and the physician’s perspective when treating this devastating epilepsy syndrome. The patient’s mother, who is his legal representative, provided written consent for publication of this article.\n\nKeywords\n\nCannabidiol\nEpilepsy treatment\nLennox–Gastaut syndrome\nMedically refractory epilepsy\nPatient perspective\nissue-copyright-statement© The Author(s) 2021\n==== Body\nKey Summary Points\n\nLennox–Gastaut syndrome is a devastating epilepsy syndrome which is characteristically refractory to antiseizure medications.\t\nDespite drug resistance, antiseizure medications are the mainstay of treatment.\t\nThe study looks at the perspective of a parent and a physician regarding treatment of this syndrome.\t\nSuccess with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed.\t\n\nDigital Features\n\nThis article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13079411.\n\nPatient’s Story From His Mother’s Perspective\n\nI never thought I would feel relief when my son was given the diagnosis of Lennox–Gastaut syndrome. After many years of seizures, tests, medication trials and changes, and suggestions of very invasive surgeries, we finally received a definitive diagnosis that I could wrap my mind around. I knew what we were facing and we would handle it as we had handled the previous health issues my son had been dealing with since birth.\n\nInitially we had assumed that the seizures started due to brain damage from his preterm birth. My son was 19 months old when his seizures began, and it was not until he was 10 years old that we got the diagnosis that gave us a sense of direction. We knew that, by definition, his seizures would be forever changing and very hard to control; but it is easier when you know what you are facing. For years, we kept records of each seizure as well as how often they were, how long they lasted, and what precipitated them. We did not do that any longer. It sounds weird but we were able to relax for a minute.\n\nI never opted for surgical intervention as a form of seizure control. My son had and still has many other underlying serious medical conditions that took precedence over his seizures. Throughout his early years, he was off and on a ventilator for severe lung damage from birth. He was essentially fighting to breathe every day of his life and just to remain healthy. We did not enroll in any drug trials and, unfortunately, there were not a whole lot of new medications coming out for Lennox–Gastaut when he was young. He did receive some physical therapy for his delays over the years that would be interrupted from time to time by a seizure or an illness.\n\nOver the years, my son has been on almost every anti-epileptic medication on the market. Some of the older medications caused adverse side effects, such as extreme drowsiness, weight loss, and agitation. Each medication was increased every 3 to 6 months with no real positive effect on seizure control for a prolonged amount of time. They all required frequent blood work to monitor the drug levels versus the effectiveness and were eventually stopped as he was started on a new medication.\n\nAs he got older, some newer medications did help with different aspects. One made his personality come out more and made him more alert with less side effects. Another controlled a different type of seizure. Another was added to stop a movement disorder that he developed in addition to his seizures. However, none of them controlled his seizures completely; yet we did not let that stop our lives. We still played, we still attended family functions, we still attempted to participate in life as much as we could, and we still do.\n\nAfter 30 years of fighting this “syndrome”, this thing that we could not control or predict, we have come as close as we have ever been to stopping it. To not seeing it every day. To being able to focus solely on our daily life without any interruptions. To not have to worry that even in the middle of the night a horrible seizure can come out of the blue and disrupt a good night’s sleep. We have gone from almost one hundred seizures per day down to about two per month. I never thought that we would see this day. To say that two seizures per month was a good thing would have been unthinkable to us 30 years ago without the awareness brought to Lennox–Gastaut syndrome and the dedication of the researchers and neurologists from around the world. Moreover, for that… we are forever grateful.\n\nPhysician’s Perspective\n\nLennox–Gastaut syndrome (LGS) is a form of encephalopathic generalized epilepsy (EGE) and is a devastating epilepsy syndrome that typically begins within the second and sixth year of life. It is characteristically refractory to antiseizure drugs (ASDs). The diagnostic clinical triad of LGS is (1) multiple mixed seizure types, including tonic, atonic, and atypical absence with high seizure frequency, and often with status epilepticus, (2) impaired intellectual function or behavior disturbance, (3) abnormal EEG background with diffuse slow activity and characteristic epileptiform discharges described as slow spike-and-wave discharges while awake [1]. LGS accounts for approximately 1–4% of all childhood epilepsies [2, 3]. EGE represents approximately 11.6% of all childhood epilepsies [4].\n\nTreatment for LGS includes efforts to manage the underlying cause of their associated cognitive and behavioral dysfunction, attempting to control seizures, and providing support for the patient’s family or caretaker [1]. Despite characteristic drug resistance, ASD therapy is the primary treatment. It is a challenge to optimize seizure control and medication side effects, while maintaining a favorable quality of life. The multiple seizure types in LGS often require broad-spectrum ASDs and combination therapies. Certain medications have proven higher utility in LGS, including valproic acid, lamotrigine, and topiramate [5–7]. Felbamate is effective in seizure reduction and neurocognitive profile but is limited by serious side effects of hepatic failure and aplastic anemia [8]. Clobazam and rufinamide are also approved for LGS, and other ASDs have been reported to have possible benefit but without consistent efficacy, such as levetiracetam, zonisamide, and clonazepam [1, 9, 10]. Oral purified cannabidiol (Epidiolex), the natural cannabidiol from the marijuana plant, is an oral solution that was approved by the US Food and Drug Administration (FDA) for use in LGS in June 2018 and has shown significant effectiveness in clinical trials for refractory seizures [11–14] and for improvement in global functioning of these patients [15–18]. This was also the case for my patient.\n\nMy patient has static encephalopathy and spastic quadriplegia with diffuse cerebral volume loss. He was born by cesarean section at 28 weeks and was ventilator dependent. He has been severely delayed since birth, which worsened when his seizures started at 19 months old. His seizure history includes at least four seizure types: type 1, staring blankly then smiles and may drool; type 2, tonic; type 3, generalized tonic–clonic (GTC); type 4, atonic with fall. He had been on lamotrigine and levetiracetam for many years with effectiveness but continued to have daily to weekly seizures with frequent seizure clusters. His current doses are lamotrigine 150 mg three times daily and levetiracetam 1000 mg three times daily and he could not tolerate higher doses. Past medication included phenobarbital, valproic acid, phenytoin, carbamazepine, and topiramate, all of which did not produce significant seizure control or caused side effects.\n\nHis mother reports him having a decline in functioning at around 10 years of age. Prior to that he was pulling up and was taking a bottle himself, but after the decline he never walked or talked; a feeding tube was placed for nutritional supplementation and a tracheostomy was placed as a result of repeated aspiration. At that time, he was initiated on primidone for abnormal movements and had remained on a dose of 100 mg three times daily. It was reported that his seizure frequency on lamotrigine, levetiracetam, and primidone was daily of type 1 and weekly seizures of type 2, 3, and 4. He was initiated on rufinamide in the fall of 2010 and titrated according to response to 600 mg twice daily. As a result, his atonic seizures (type 4) resolved completely. Higher doses of rufinamide resulted in increased seizures. A vagus nerve stimulator was considered but felt to be too risky with his respiratory status. There was a lapse in care for several years and he returned to the epilepsy specialist clinic in 2018 following the approval of cannabidiol. At that point, he initially tried clobazam, but had sedation and no reduction in seizures. He was initiated on orally administered cannabidiol in January 2019. Within the first month of treatment on 2.5 mg/kg/dose twice daily his type 1 seizures had resolved, type 2 seizures were reported to be less severe and shorter in duration, and there were no type 3 seizures. His mother reported that he was more awake and alert and was doing more activity. She reported that he was “like he used to be”. He started sleeping through the night and holding himself up better. It also improved his bowel motility. Since that time, his response to titration of cannabidiol has continued to reduce his seizure frequency and improve his functioning. His primary seizure that has remained refractory is type 3, his GTC. His main precipitant is having a bowel movement and stress. These seizures continue to occur approximately two times per month and dosing titration has and will continue, to obtain maximal benefit.\n\nWhen deciding on medication therapy for this patient, several issues were considered. First and foremost, it is critical to understand and confirm the diagnosis. For this patient, it is unclear why the diagnosis was not confirmed until he was 10 years old, but it seems that this timeframe related to his significant functional decline. Secondly, patient characteristics must be considered to tailor a medication choice. Medications can carry risks to organ systems and to quality of life. For my patient, his mother reports that it took years to make a diagnosis of Lennox–Gastaut and, therefore, treatments tried prior to this had the risk of being suboptimal. Additionally, with LGS the treatment options available are generally ineffective and refractory. As his mother stated, he tried many antiseizure medications and yet remained with excessive seizures. Over the years, certain treatments were found that were both more effective and more tolerable for this patient. With the approval of orally administered cannabidiol, the patient has been able to add its unique mechanism of action to his medication regimen and his seizure frequency has reduced substantially, down to approximately two per month.\n\nTo get my patient to a seizure frequency where he is today has not been an easy feat. It often takes trial and error of medications and dosing to obtain success with medications and this is particularly true for devastating epilepsy syndromes. Effective communication with the patient’s response and the caretaker’s input is invaluable to obtain an optimal treatment regimen for a particular patient. I am thankful that my patient has achieved a significant reduction in seizures from baseline and that his care can focus on other aspects of his health. Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed. I look forward to the opportunity to see this progress unfold.\n\nAcknowledgements\n\nThank you to the participants of this study, both the patient and his mother.\n\nFunding\n\nNo funding or sponsorship was received for this study or publication of this article.\n\nAuthorship\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nDisclosures\n\nThe patient, his mother Barbara Glasgow, and Dr. Heather Ravvin McKee have nothing to disclose.\n\nCompliance with Ethics Guidelines\n\nThe patient’s mother, who is his legal representative, provided written consent for publication of this article. This article does not contain any new studies with human or animal subjects performed by any of the authors.\n==== Refs\nReferences\n\n1. Wyllie E Wyllie’s treatment of epilepsy principles and practice 2015 6 Philadelphia Wolters Kluwer 272 283\n2. Markand ON Lennox–Gastaut syndrome (childhood epileptic encephalopathy) J Clin Neurophsiol 2003 20 426 441 10.1097/00004691-200311000-00005\n3. Trevatham E Murphy CC Yeargin-Allsopp M Prevalence and descriptive epidemiology of Lennox–Gastaut syndrome among Atlanta children Epilepsia 1997 38 1283 1288 10.1111/j.1528-1157.1997.tb00065.x 9578523\n4. Camfield P Camfield C Long term prognosis for symptomatic (secondarily) generalized epilepsies: a population based study Epilepsia 2007 48 1128 1132 10.1111/j.1528-1167.2007.01072.x 17442010\n5. Arzimanoglou A Guerrini R Aicardi J Lennox–Gastaut syndrome in Aicardi’s epilepsy in children 2004 3 Philadelphia Lippincott Williams & Wilkins 38 50\n6. Motte J Trevathan E Arvidsson JFV The Lamictal Study Group Lamotrigine for generalized seizures associated with Lennox Gastaut syndrome N Engl J Med 1997 337 1807 1812 10.1056/NEJM199712183372504 9400037\n7. Sachedo RC Glauser TA Ritter F A double-blind, randomized trial of topiramate in Lennox–Gastaut syndrome Neurology 1999 52 1882 1887 10.1212/WNL.52.9.1882 10371538\n8. Pellock JM Fought E Leppik IE Felbamate: consensus of current clinical experience Epilepsy Res 2006 71 89 101 10.1016/j.eplepsyres.2006.06.020 16889941\n9. Ng YT Conry JA Drummond R Randomized phase III study results of clobazam in Lennox–Gastaut syndrome Neurology 2011 77 1473 1481 10.1212/WNL.0b013e318232de76 21956725\n10. Glauser T Kluger G Sachdeo R Rufinamide for generalized seizures with Lennox–Gastaut syndrome Neurology 2008 70 1950 1958 10.1212/01.wnl.0000303813.95800.0d 18401024\n11. Devinsky O Marsh E Friedman D Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial Lancet Neurol 2016 15 3 270 278 10.1016/S1474-4422(15)00379-8 26724101\n12. Devinsky O Cross JH Laux L Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome N Engl J Med 2017 376 2011 2020 10.1056/NEJMoa1611618 28538134\n13. Thiele E Marsh E French J Cannabidiol in patients with seizures associated with Lennox–Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial Lancet 2018 391 10125 1085 1096 10.1016/S0140-6736(18)30136-3 29395273\n14. Devinsky O Patel A Cross JH Effect of cannabidiol on drop seizures in the Lennox–Gastaut syndrome N Engl J Med 2018 378 1888 1897 10.1056/NEJMoa1714631 29768152\n15. Simona L Francesco B Eugen T Efficacy and safety of cannabidiol in epilepsy: a systematic review and meta-analysis Drugs 2018 78 1791 1804 10.1007/s40265-018-0992-5 30390221\n16. Szaflarski JP Benin EM Cutter G Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study Epilepsy Behav 2018 87 131 136 10.1016/j.yebeh.2018.07.020 30100226\n17. Rosenberg EC Louik J Conway E Devinsky O Friedman D Quality of life in childhood epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol Epilepsia 2017 58 8 e96 e100 10.1111/epi.13815 28617940\n18. Porter B Jacobson C Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy Epilepsy Behav 2013 29 3 574 577 10.1016/j.yebeh.2013.08.037 24237632\n\n",
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"title": "Lennox-Gastaut Syndrome: Perspective of a Parent and a Physician.",
"title_normalized": "lennox gastaut syndrome perspective of a parent and a physician"
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"abstract": "BACKGROUND\nControlled studies show high efficacy of budesonide in inducing short-term clinical remission in collagenous colitis (CC), but relapses are common after its withdrawal.\n\n\nOBJECTIVE\nTo evaluate the need for high-dose budesonide (≥6mg/d) to maintain clinical remission in CC.\n\n\nMETHODS\nAnalysis of a multicentre retrospective cohort of 75 patients with CC (62.3±1.5years; 85% women) treated with budesonide in a clinical practice setting between 2013 and 2015. Frequency of budesonide (9mg/d) refractoriness and safety, and the need for high-dose budesonide to maintain clinical remission, were evaluated. Drugs used as budesonide-sparing, including azathioprine and mercaptopurine, were recorded. Logistic regression analysis was performed to evaluate the risk factors associated with the need for high-dose budesonide (≥6mg/d) to maintain clinical remission.\n\n\nRESULTS\nBudesonide induced clinical remission in 92% of patients, with good tolerance. Fourteen of 68 patients (21%; 95% CI, 13-32%) needed high-dose budesonide to maintain remission. Only intake of NSAIDs at diagnosis (OR, 8.6; 95% CI, 1.6-44) was associated with the need for high-dose budesonide in the multivariate analysis.\n\n\nMETHODS\nwith thiopurines was effective in 5 out of 6 patients (83%; 95% CI, 44-97%), allowing for withdrawal from or a dose decrease of budesonide.\n\n\nCONCLUSIONS\nOne fifth of CC patients, especially those with NSAID intake at diagnosis, require high-dose budesonide (≥6mg/d) to maintain clinical remission. In this setting, thiopurines might be effective as budesonide-sparing drugs.",
"affiliations": "University Hospital Mutua Terrassa; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas. Electronic address: ffbanares@mutuaterrassa.es.;Consorci Sanitari Terrassa, Department of Gastroenterology, Terrassa, Spain.;Hospital Vall d'Hebron, Department of Gastroenterology, Barcelona, Spain.;Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; Hospital Vall d'Hebron, Department of Gastroenterology, Barcelona, Spain.;Hospital of Bellvitge.;Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; University Hospital La Princesa.;Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; University Hospital La Princesa.;University Hospital Dr Josep Trueta.;Hospital San Jorge, Department of Gastroenterology, Huesca, Spain.;Hospital Costa del Sol, Marbella, Spain.;University Hospital Clinico.;Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; Hospital General of Tomelloso.",
"authors": "Fernandez-Bañares|Fernando|F|;Piqueras|Marta|M|;Guagnozzi|Danila|D|;Robles|Virginia|V|;Ruiz-Cerulla|Alexandra|A|;Casanova|María José|MJ|;Gisbert|Javier P|JP|;Busquets|David|D|;Arguedas|Yolanda|Y|;Pérez-Aisa|Angeles|A|;Fernández-Salazar|Luis|L|;Lucendo|Alfredo J|AJ|;|||",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019819:Budesonide; D015122:Mercaptopurine; D001379:Azathioprine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.dld.2017.03.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-8658",
"issue": "49(9)",
"journal": "Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver",
"keywords": "Azathioprine; Budesonide; Collagenous colitis; Maintenance therapy",
"medline_ta": "Dig Liver Dis",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001379:Azathioprine; D019819:Budesonide; D046729:Colitis, Collagenous; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016015:Logistic Models; D060046:Maintenance Chemotherapy; D008297:Male; D015122:Mercaptopurine; D008875:Middle Aged; D015999:Multivariate Analysis; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D012307:Risk Factors; D013030:Spain",
"nlm_unique_id": "100958385",
"other_id": null,
"pages": "973-977",
"pmc": null,
"pmid": "28457904",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Collagenous colitis: Requirement for high-dose budesonide as maintenance treatment.",
"title_normalized": "collagenous colitis requirement for high dose budesonide as maintenance treatment"
} | [
{
"companynumb": "ES-TEVA-815818ROM",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BUDESONIDE"
},
"drugadditional": null,
"dru... |
{
"abstract": "Brain abscess remains a life-threatening condition. Here, we are reporting a case of brain abscess due to Bacteroides thetaiotaomicron in a previously known case of recurrent otitis media. A 15 years old boy with a history of recurrent otitis media presented with the complaints of right otalgia, headache and fever. Computed Tomography (CT) brain and neck revealed fluid filled right middle ear cavity with bony destruction along the inner cortex of right temporal bone. The abscess was drained and culture showed growth of Bacteroides thetaiotaomicron. This report illustrates the importance of MALDI-TOF MS in the species level identification of anaerobes thereby facilitating the selection of appropriate and prompt adjuvant antibiotic therapy. This timely identification thus led to a favourable outcome in an era of increasing antimicrobial resistance.",
"affiliations": "Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Electronic address: archanaangrup@yahoo.com.",
"authors": "Kanaujia|Rimjhim|R|;Gupta|Swati|S|;Singla|Navneet|N|;Jani|Parth|P|;Angrup|Archana|A|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.1016/j.anaerobe.2020.102203",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-9964",
"issue": "63()",
"journal": "Anaerobe",
"keywords": "Bacteroides thetaiotaomicron; Brain abscess; MALDI; Recurrent otitis media",
"medline_ta": "Anaerobe",
"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D001442:Bacteroides Infections; D000070077:Bacteroides thetaiotaomicron; D001922:Brain Abscess; D006801:Humans; D008297:Male; D010033:Otitis Media; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization",
"nlm_unique_id": "9505216",
"other_id": null,
"pages": "102203",
"pmc": null,
"pmid": "32344014",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A child with recurrent otitis media due to Bacteroides thetaiotaomicron.",
"title_normalized": "a child with recurrent otitis media due to bacteroides thetaiotaomicron"
} | [
{
"companynumb": "IN-PFIZER INC-2020211332",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": "1",
... |
{
"abstract": "Background: The prognosis of patients with advanced gastric cancer remains overall poor despite some recent innovations and the development of new therapeutic approaches. Current European guidelines do not recommend any specific treatment for patients with advanced gastric cancer refractory to two or more previous chemotherapy regimens, making this setting \"orphan.\" Immunotherapy is quickly evolving also for this malignancy even if with controversial results and the correct patient selection is still debated, especially for Western patients. The phase III ONO-4538-12 \"ATTRACTION-2\" represents the current landmark trial for the development of immunotherapy for pretreated Asian patients and led to the approval of Nivolumab in some Asian countries, while only previous phase trials are available for Caucasians. Complete radiological response is anecdotic and has never been described both in the pivotal trial both in the others with Western patients enrolled. Case presentation: We report two cases of heavily pretreated Western elderly patients with metastatic gastric cancer who experienced durable complete radiological response to Nivolumab \"off label\" (more than 20 months to date) in a clinical practice context. Molecular analysis of potential predictive factors has been performed (PD-L1, EBV, MSI, and TMB) on primary tumor sample. Conclusions: Despite the lack of evidence for Western patients and the controversial outcome with the use of checkpoint inhibitors in previous settings, immunotherapy may dramatically change the prognosis and the natural history of pretreated Western metastatic gastric cancer, in a correctly selected population. Microsatellite instability and tumor mutational burden may be reliable predictive factors also for Caucasians. There is an urgent need for a change in clinical practice also for this \"orphan\" patients and more efforts are needed in order to clarify the role of predictive factors for a correct patient selection and better chances of survival for this awful malignancy.",
"affiliations": "Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.;Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.;Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.;Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.;Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.;Dipartimento di Salute Mentale e Fisica e Medicina Preventiva, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy.;Dipartimento di Salute Mentale e Fisica e Medicina Preventiva, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy.;Dipartimento di Salute Mentale e Fisica e Medicina Preventiva, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy.;Department of Translational Medical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy.;Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.;Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.",
"authors": "Tirino|Giuseppe|G|;Petrillo|Angelica|A|;Pompella|Luca|L|;Pappalardo|Annalisa|A|;Laterza|Maria Maddalena|MM|;Panarese|Iacopo|I|;Sabetta|Rosalaura|R|;Franco|Renato|R|;Galizia|Gennaro|G|;Ciardiello|Fortunato|F|;De Vita|Ferdinando|F|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2020.00130",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.00130\nOncology\nCase Report\nDurable Complete Radiological Response to Nivolumab in Two Heavily Pretreated Western Elderly Patients With Metastatic Gastric Cancer: A Case Report\nTirino Giuseppe 1* Petrillo Angelica 1 Pompella Luca 1 Pappalardo Annalisa 1 Laterza Maria Maddalena 1 Panarese Iacopo 2 Sabetta Rosalaura 2 Franco Renato 2 Galizia Gennaro 3 Ciardiello Fortunato 1 De Vita Ferdinando 1 1Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy\n2Dipartimento di Salute Mentale e Fisica e Medicina Preventiva, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy\n3Department of Translational Medical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy\nEdited by: Ignacio Melero, University of Navarra, Spain\n\nReviewed by: Romain Boidot, Centre Georges François Leclerc, France; Pierpaolo Correale, Azienda Ospedaliera ‘Bianchi-Melacrino-Morelli’, Italy\n\n*Correspondence: Giuseppe Tirino giuseppett@icloud.comThis article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology\n\n\n17 2 2020 \n2020 \n10 13016 7 2019 24 1 2020 Copyright © 2020 Tirino, Petrillo, Pompella, Pappalardo, Laterza, Panarese, Sabetta, Franco, Galizia, Ciardiello and De Vita.2020Tirino, Petrillo, Pompella, Pappalardo, Laterza, Panarese, Sabetta, Franco, Galizia, Ciardiello and De VitaThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background: The prognosis of patients with advanced gastric cancer remains overall poor despite some recent innovations and the development of new therapeutic approaches. Current European guidelines do not recommend any specific treatment for patients with advanced gastric cancer refractory to two or more previous chemotherapy regimens, making this setting “orphan.” Immunotherapy is quickly evolving also for this malignancy even if with controversial results and the correct patient selection is still debated, especially for Western patients. The phase III ONO-4538-12 “ATTRACTION-2” represents the current landmark trial for the development of immunotherapy for pretreated Asian patients and led to the approval of Nivolumab in some Asian countries, while only previous phase trials are available for Caucasians. Complete radiological response is anecdotic and has never been described both in the pivotal trial both in the others with Western patients enrolled.\n\nCase presentation: We report two cases of heavily pretreated Western elderly patients with metastatic gastric cancer who experienced durable complete radiological response to Nivolumab “off label” (more than 20 months to date) in a clinical practice context. Molecular analysis of potential predictive factors has been performed (PD-L1, EBV, MSI, and TMB) on primary tumor sample.\n\nConclusions: Despite the lack of evidence for Western patients and the controversial outcome with the use of checkpoint inhibitors in previous settings, immunotherapy may dramatically change the prognosis and the natural history of pretreated Western metastatic gastric cancer, in a correctly selected population. Microsatellite instability and tumor mutational burden may be reliable predictive factors also for Caucasians. There is an urgent need for a change in clinical practice also for this “orphan” patients and more efforts are needed in order to clarify the role of predictive factors for a correct patient selection and better chances of survival for this awful malignancy.\n\ngastric/GEJ adenocarcinomaimmunotherapynivolumabcheckpoint inhibitiongastrointestinal cancer\n==== Body\nBackground\nThe prognosis of patients with advanced gastric cancer (GC) remains poor and the median overall survival is still around 1 year despite some recent innovations and the development of new therapeutic approaches (1, 2).\n\nCurrent European guidelines do not recommend any specific treatment for patients with disease refractory to two or more previous regimens. Anyway, the amount of patients who reach this setting is increasing and nowadays only some Asian countries and the US registered immunotherapy for advanced GC in this specific population (3–5).\n\nImmunotherapy is quickly evolving also for GC even if it is not yet a standard of care worldwide and the results are controversial. Furthermore, the correct patient selection remains a target not fully achieved, especially for Western patients.\n\nFor Asian patients the phase III trial ONO-4538-12 “ATTRACTION-2” (6) represents the current milestone for the development of immunotherapy with Nivolumab (anti-PD-1 antibody) in the chemotherapy-refractory molecularly unselected population, while evidence for Western population is limited to early phase trials (7, 8). In this Asian trial surprising survival rates of 27.3 and 10.6% at 1- and 2 year, respectively, have been achieved in the Nivolumab arm (with a 86.7% 12 months survival rate in responders), suggesting the efficacy of immunotherapy and the presence of a subset of patients who greatly benefit from it even if molecular features of responders are still not well-understood.\n\nMoreover, in first and second line setting immunotherapy did not significantly improve survival compared to chemotherapy both in Asian and Western patients in recent phase III randomized trials KEYNOTE-062 (9) and KEYNOTE-061 (10).\n\nWith regards to biomarkers selection, a recent prospective phase II trial with Pembrolizumab (anti-PD-1 antibody) (11) clarified the positive predictive role of the Epstein-Barr Virus (EBV) and microsatellite instability status (MSI), but, once again, the population was entirely from Asia.\n\nThe same molecular features (Mismatch repair and EBV status), also with PD-L1 expression and tumor mutational burden (TMB), have been recently analyzed in a single institution Japanese study with 80 patients treated with Nivolumab after two or more chemotherapy regimens (12). These markers were strongly associated with favorable response to treatment and might represent useful selective and predictive factors.\n\nHowever, there are no results regarding the subgroup analysis according to MSI and programmed death-ligand 1 (PD-L1) status in the ATTRACTION-2 population.\n\nGenetic, epidemiologic, and molecular differences between Asian and western patients are well-known. Even if data from clinical trials are lacking for non-Asians, we should consider that there is some evidence that Western patients seem to have a more favorable “immune-environment” and a stronger immune-signature. In fact, a large global retrospective study with 1,600 GC samples from both Asian and non-Asian cohorts showed different tumor immune-signatures between Asian and non-Asian patients, particularly with infiltrating T-cells and T-cell gene expression patterns in Caucasians that might condition a possible more frequent and better response to immunotherapy (13, 14).\n\nHere we report two cases of elderly pretreated Western patients with metastatic GC who have experienced extraordinary and dramatic durable response with “off label” Nivolumab in a clinical practice context.\n\nIn particular, we report the first radiologic complete responses to Nivolumab in Western patients with advanced pretreated GC at our knowledge, highlighting that immunotherapy is not a standard of care for GC and complete responses are anecdotal at current time and still not described even in the landmark phase III trial such as in the other mentioned studies with Western patients enrolled (with the exception of a single possible complete response registered in the monotherapy arm of the phase II Checkmate-032, not confirmed by the independent central review).\n\nMaterials and Methods\nRadiological evaluation for advanced disease has been performed every 3 or 4 months approximately using total body computed tomography (CT) with contrast with consecutive comparisons and response assessment performed according to response evaluation criteria in solid tumors (RECIST) v1.1 (15). A 18- fluorodeoxyglucose positron emission tomography (18F-FDG PET) and magnetic resonance imaging (MRI) with contrast have been used as second level imaging in order to deepen radiological findings when clinically indicated.\n\nTreatment toxicity has been evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (16).\n\nHistological and molecular analysis have been performed on the surgical sample of primary tumor in local laboratory according to current guidelines, with the exception of “FoundationOne CDx” test (a next generation sequencing based comprehensive genomic profiling offered to patients free of charge at our institution as companion diagnostic) (17).\n\nImmunohistochemical evaluation of mismatch repair (MMR) proteins status (MLH1, MSH2, PMS2, and MSH6) and PD-L1 expression (tumor proportion score), Epstein-Barr early RNA (EBER) in situ hybridization for EBV, in addition to human epidermal growth factor receptor 2 (HER2) status evaluation, were performed in local laboratory according to the European Society of Medical Oncology recommendations (Table S1).\n\nTumors lacking either MLH1, MSH2, PMS2, or MSH6 expression were considered “MMR-deficient,” while MSI and TMB have been assessed only by FoundationOne CDx.\n\nAt the moment of disease progression after the second or third line of treatment, patients signed the informed consent and an off label use request for Nivolumab was submitted for each patient in light of the results of phase III Asian trial “ATTRACTION-2” presented at ASCO GI 2017 and ESMO congress 2017. It is noteworthy that current guidelines did not recommend any specific treatment for this specific setting. Nivolumab has been administered 3 mg/Kg iv in a 14 days cycle until progression of disease or unacceptable toxicity. Every biweekly administration has been considered a cycle of treatment.\n\nLocal ethical committee has been regularly updated about this off label program and a specific informed consent was obtained from both patients for the publication of this report.\n\nThe survival and safety follow up cut-off date for this report was June 2019, 20th.\n\nCase Presentation\nPatient 1\nPatient 1, a Caucasian 78 year-old female, has been diagnosed on February 2015 with a well-differentiated adenocarcinoma of the body of the stomach, intestinal type according to Lauren classification, with staging CT scan evidence of liver metastasis (28 mm at IV segment) (Figure 1). She was in good clinical condition (ECOG performance status 1); blood hypertension, hypothyroidism, arthrosis, and stage 1 chronic kidney disease with “contracted kidney” co-occurred at the moment of diagnosis. She was complaining of dyspepsia and slight unintentional weight loss since few weeks.\n\nFigure 1 Basal 28 mm liver metastasis at IV segment in 2015/2016 (patient 1).\n\nIn March 2015, she underwent a palliative total gastrectomy with roux-en-y esophagojejunostomy and D2 lymphadenectomy due to symptomatic luminal obstruction. The stage according to TNM was pT4 G1 pN0 (0/26) cM1 HER2 negative.\n\nFrom April 2015 to September 2015 she received 8 cycles of mFOLFOX-6 as first line chemotherapy, achieving a stable disease as best objective response, and subsequently continued maintenance treatment with capecitabine single agent in light of the side effects and the age until December 2015, when she was referred for follow-up due to worsening skin and GI toxicity.\n\nOn September 2016 (PFS = 16 months), a liver progression occurred (same known lesion of 47 mm, ECOG performance status 1 confirmed) and patient started the second line treatment with Ramucirumab 8 mg/kg (d1,15) plus Paclitaxel 80 mg/mq (d1,8,15) administered in a 28 days cycle (18).\n\nAfter 6 cycles, she obtained a partial response and continued Ramucirumab monotherapy until May 2017 due to grade 3 neurotoxicity.\n\nIn May 2017, patient underwent a hip bone and femurs MRI with contrast in order to evaluate a new onset skeletal pain. MRI showed a secondary osteolytic lesion at right femur (Figure S1) and the CT scan showed a slight progression of the known liver lesion in absence of new ones.\n\nTherefore, in June 2017 patient was referred for antalgic radiotherapy (8 Gray single fraction) and antiresorptive therapy with zoledronic acid iv. Moreover, she refused radiation therapy for liver lesion and further chemotherapy also considering age and the toxicity of previous chemotherapy regimens.\n\nAfter 3 months of follow up, the off label immunotherapy with Nivolumab was available and patient started treatment on 25 September 2017.\n\nIn January 2018, the first CT and PET evaluation demonstrated a stable disease according to RECIST criteria. No weight loss, skeletal pain, or other symptoms occurred. Meanwhile, patient experienced a global clinical condition improvement and a significant recovery from previous chemotherapy toxicity. No immune-related adverse events were recorded.\n\nIn June 2018, she experienced a slight deterioration of renal function (likely related to zoledronic acid use) with a serum creatinine of 2 mg/dl and ultrasound evidence of monolateral grade 1 hydroureteronephrosis and concurrent lithiasis. A CT scan without contrast confirmed the nephrological findings and no more evidence of liver disease (as already shown at abdominal ultrasound) as well as no potential signs or peritoneal involvement.\n\nZoledronic acid was discontinued and immunotherapy temporarily interrupted due to the persistence of creatinine increase. In July 2018, patient underwent ureteral stent placement (subsequently removed in October 2018 due to recurrent urinary tract infections) and creatinine returned to baseline levels during the next weeks.\n\nAfter about 2 months of interruption, patient resumed Nivolumab in August 2018 and performed subsequently a new PET and CT scan (with contrast) in October 2018, which confirmed the complete radiological response (Figure 2, Figure S3). Meanwhile a thyroid function deterioration occurred and was corrected with the increase of hormone replacement therapy. Patient still maintained good clinical conditions and was asymptomatic. An abdominal MRI with contrast was performed in December 2018 in order to confirm the complete response (showing a millimetric possible necrotic residue). At the same time a primary tumor sample was submitted for FoundationOne CDx, which revealed high microsatellite instability (MSI-H), a high TMB of 58 mutations per DNA mega base, and several additional genomic alterations (Table S2). Furthermore, PD-L1 expression was 10% (tumor proportion score) and immunohistochemical mismatch repair testing showed loss of MLH1 and PMS2 heterodimer (Figure 3).\n\nFigure 2 2017 pre-treatment (A = patient 1; C = patient 2) and 2019 complete response CT scans (B = patient 1; D = patient 2). Liver metastases at IV (A) and VIII (C) segment.\n\nFigure 3 (A,B) Loss of nuclear staining of MLH1/PMS2 heterodimer in neoplastic cells with nuclear positivity in the Tumor-Infiltrating Lymphocytes (Tils); (C,D) preserved nuclear staining of MSH2/MSH6 heterodimer in neoplastic cells; (E) expression of PD-Ll in the neoplastic cells with Moderate to Intense circumferential membrane staining (10%).\n\nIt is noteworthy that MLH1 promoter methylation analysis could be performed in order to explain the not mutation-caused changes in the protein functions (19).\n\nPatient continued treatment and a further PET and CT evaluation confirmed no evidence of disease in April 2019 with no new onset relevant symptoms or toxicity after more than a total of 25 cycles of immunotherapy.\n\nPatient 2\nAn 82 year-old Caucasian male presented with dyspepsia and was found to have a poorly differentiated adenocarcinoma of the gastroesophageal junction (GEJ) (Lauren type unknown) causing 70% luminal obstruction. He was in good clinical condition (ECOG performance status 0); relevant comorbidities were blood hypertension, allergic rhinitis and cataract.\n\nStaging CT scan confirmed a large mass of the GEJ with no evidence of distant disease (clinical stage III).\n\nHe subsequently underwent total gastrectomy with roux-en-y esophagojejunostomy and D2 lymphadenectomy in October 2015. The stage according to TNM was pT4a G3 pN3a (9+/16) cM0 HER2 negative (0 IHC score).\n\nFrom December 2015 to May 2016, he received adjuvant chemotherapy with mFOLFOX-6 with modified dose due age and passed to De Gramont regimen at seventh cycle because of hematological toxicity.\n\nIn July 2016, PET and CT scan demonstrated a liver (single 37 mm lesion at VIII segment) and abdominal nodes recurrence for which patient started the second line treatment with paclitaxel 80 mg/mq (d1,8,5) plus ramucirumab 8 mg/kg (d1,15) administered in a 28 days cycle.\n\nHe was still in good clinical condition (ECOG performance status 0) with the exception of a slight weight loss and sporadic episodes of abdominal pain. He received 6 cycles with no grade 3–4 toxicity and achieved after the third cycle a partial response.\n\nIn March 2017 (PFS = 7 months), treatment was interrupted due to further liver disease progression with volumetric increase (35 × 32 mm) of the known lesion as confirmed by abdominal MRI with contrast (with no evidence of new lesions).\n\nBecause of the age and the unavailability of standard additional therapeutic options, patient was referred for stereotactic radiotherapy (30 Gy on liver and 30 Gy on abdominal nodes, respectively, in April and May 2017) and subsequently continued with radiological and clinical follow up until further liver (same VIII segment lesion) and nodal progression diagnosed at the CT scan performed 4 months later in September 2017 (with concomitant high blood levels of carcinoembryonic antigen CEA: 230 ng/mL).\n\nOn October 2017, 16th, patient started treatment with Nivolumab off label. At baseline the CT scan demonstrated a 39 mm liver lesion and several abdominal lymph nodes.\n\nIn December 2017, he performed, due to abdominal pain, a first CT scan evaluation, which showed stable disease according to RECIST criteria; he was still in good clinical condition with no immune-related toxicities.\n\nAfter 4 months of treatment, he experienced episodes of pruritus without skin rash treated with oral cetirizine.\n\nIn April 2018, CT scan revealed a minor response both on liver and lymph nodes (with a normalization of blood levels of CEA: 3.5 ng/mL), while subsequently in September 2018 no evidence of disease was demonstrated with a completely negative evaluation (Figure 2, Figure S2).\n\nPatient refused to undergo Foundation One CDx test, but local laboratory analysis on primary tumor sample revealed a so-called “patchy” expression pattern of MLH1 and PMS2 (interpretable as a plausible MMR deficiency although not a full loss of expression) and PD-L1 negative status (Figure 4). Moreover, EBER ISH for EBV status assessment has been performed with negative finding.\n\nFigure 4 (A,B) “Patchy” nuclear staining of MLH1/PMS2 heterodimer in large neoplastic cells with scattering nuclear positivity of Tumor-Infiltrating Lymphocytes (TILs); (C,D) preserved nuclear staining of MSH2/MSH6 heterodimer in neoplastic cells; (E) lack of membranous staining of PD-Ll in large neoplastic cells with scattering positivity of Tumor-Infiltrating Lymphocytes (TILs); (F) lack of nuclear staining of Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) (Patient 2).\n\nIn January 2019 and May 2019, further CT scans confirmed complete radiological response and patient has been continuing immunotherapy with no new immune-related adverse events and good clinical condition after more than 30 cycles.\n\nDiscussion\nPrecision medicine has largely remained elusive in GC to date. Immunotherapy represents a promising weapon although it is not yet a standard of care and the majority of evidence is limited to Asian population. The effectiveness of checkpoint inhibitors remains controversial in different settings of treatment.\n\nFurthermore, the correct molecular patient selection is still debated and few data are available for Western patients although Pembrolizumab received US Food and Drug Administration approval across gastric tumors with PD-L1 positivity [as well as for MSI-H solid tumors in 2017 (20)]. The phase III trials available do not focus on the role of MSI and TMB as positive predictive factors.\n\nMolecular and genomic differences between Asian and non-Asian GC, and particularly ethnicity-related differences in tumor immunity, have been already demonstrated and it is noteworthy that the only positive phase III trial with immunotherapy for GC is fully Asian to date (ATTRACTION-02).\n\nNevertheless, our report presents one of the first complete radiological responses to immunotherapy ever described to our knowledge in Western GC patients and the first ever to Nivolumab, considering the results of trials available to date.\n\nAlthough only two cases are reported (with indolent course and low disease burden), we suggest that immunotherapy is promising also for non-Asian patients, and MSI testing and TMB are reliable and important also in this population despite the lack of evidence at current time.\n\nImmunotherapy led to a real “disruption” of the prognosis and the natural history of these patients.\n\nMore data are expected for this “orphan” population and dedicated phase III trials, with a correct molecular patient selection, are urgently needed for this specific setting also in Western patients, despite the failure of previous line immunotherapy studies.\n\nA further reflection regards the great benefit and good tolerability that also elderly patient (over 75 years old) can experience with immunotherapy and the results achievable thanks to a correct continuum of care strategy.\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by Comitato Etico AOU Università degli Studi della Campania Luigi Vanvitelli—AORN Ospedali dei Colli, Via Santa Maria di Costantinopoli no 104, 80138 Naples. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\nFD and GT designed the general outline of the paper supervising the writing of the paper. GT and APe wrote the main part and contributed to the clinical documentation collection and Supplementary Material selection. LP contributed to the clinical documentation collection and the literature review. APa and ML did the literature review and contributed to the English revision. IP, RS, and RF performed the molecular and histological analysis and created the corresponding images and figures. GG and FC critically contributed to the final review and the supervision giving the expert opinion. GT, APa, and LP also clinically followed during the years the patients treatments.\n\nConflict of Interest\nFC declares the following interests: Advisory Boards (Roche, Amgen, Merck, Pfizer, Sanofi, Bayer, Servier, BMS, Celgene, Lilly) and Institutional research grants (Bayer, Roche, Merck, Amgen, AstraZeneca, Takeda). FD declares the following interests: Advisory Boards (Roche, Amgen, Cellgene, Lilly). GT declares the following interests: Travel grant (Servier, Italfarmaco), Advisory (Lilly). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2020.00130/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n1. Tirino G Pompella L Petrillo A Laterza MM Pappalardo A Caterino M . What's new in gastric cancer: the therapeutic implications of molecular classifications and future perspectives\n. Int J Mol Sci. (2018 ) 19 :E2659 . 10.3390/ijms19092659 30205505 \n2. Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M . Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012\n. Int J Cancer. (2015 ) 136 :E359 –86\n. 10.1002/ijc.29210 25220842 \n3. Smyth EC Verheij M Allum W Cunningham D Cervantes A Arnold D . Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up\n. Ann Oncol. (2016 ) 27 (Suppl. 5 ):v38 –49\n. 10.1093/annonc/mdw350 27664260 \n4. FDA grants accelerated approval to pembrolizumab for advanced gastric cancer \nFDA. (2019 ). Available online at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-advanced-gastric-cancer (accessed May 15, 2019).\n5. The ASCO Post \nNivolumab Approved in Japan for Unresectable Advanced or Recurrent Gastric Cancer That Has Progressed After Chemotherapy. (2019 ). Available online at: https://www.ascopost.com/News/58104 (accessed May 15, 2019).\n6. Kang YK Boku N Satoh T Ryu MH Chao Y Kato K . Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial\n. Lancet. (2017 ) 390 :2461 –71\n. 10.1016/S0140-6736(17)31827-5 28993052 \n7. Janjigian YY Bendell J Calvo E Kim JW Ascierto PA Sharma P . CheckMate-032 study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer\n. J Clin Oncol. (2018 ) 36 :2836 –44\n. 10.1200/JCO.2017.76.6212 30110194 \n8. Bang YJ Kang YK Catenacci DV Muro K Fuchs CS Geva R . Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study\n. Gastric Cancer. (2019 ) 22 :828 –37\n. 10.1007/s10120-018-00909-5 30911859 \n9. Merck Newsroom Home \nMerck Provides Update on Phase 3 KEYNOTE-062 Trial Evaluating KEYTRUDA® (pembrolizumab) as Monotherapy and in Combination with Chemotherapy for First-Line Treatment of Patients with Advanced Gastric or Gastroesophageal Junction Adenocarcinoma. (2019 ). Available online at: https://investors.merck.com/news/press-release-details/2019/Merck-Provides-Update-on-Phase-3-KEYNOTE-062-Trial-Evaluating-KEYTRUDA-pembrolizumab-as-Monotherapy-and-in-Combination-with-Chemotherapy-for-First-Line-Treatment-of-Patients-with-Advanced-Gastric-or-Gastroesophageal-Junction-Adenocarcinoma/default.aspx (accessed May 15, 2019).\n10. Shitara K Özgüroglu M Bang YJ Di Bartolomeo M Mandalà M Ryu MH . Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial\n. Lancet. (2018 ) 392 :123 –33\n. 10.1016/S0140-6736(18)31257-1 29880231 \n11. Kim ST Cristescu R Bass AJ Kim KM Odegaard JI Kim K . Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer\n. Nat Med. (2018 ) 24 :1449 –58\n. 10.1038/s41591-018-0101-z 30013197 \n12. Mishima S Kawazoe A Nakamura Y Sasaki A Kotani D Kuboki Y . Clinicopathological and molecular features of responders to nivolumab for patients with advanced gastric cancer\n. J Immunother Cancer. (2019 ) 7 :24 . 10.1186/s40425-019-0514-3 30704511 \n13. Marrelli D Polom K Roviello F . Ethnicity-related differences in tumor immunity: a new possible explanation for gastric cancer prognostic variability?\n\nTransl Gastroenterol Hepatol. (2016 ) 1 :11 . 10.21037/tgh.2016.03.03 28138578 \n14. Lin SJ Gagnon-Bartsch JA Tan IB Earle S Ruff L Pettinger K . Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas\n. Gut. (2015 ) 64 :1721 –31\n. 10.1136/gutjnl-2014-308252 25385008 \n15. Schwartz LH Litière S de Vries E Ford R Gwyther S Mandrekar S . RECIST 1.1 – update and clarification: from the RECIST committee\n. Eur J Cancer. (2016 ) 62 :132 –7\n. 10.1016/j.ejca.2016.03.081 27189322 \n16. Common Terminology Criteria for Adverse Events (CTCAE) v5,.0. (2017 ). U.S. Department of Health and Human Services, NIH . Available online at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf (accessed January 3, 2018).\n17. Foundation Medicine \nA World-Leading Molecular Insights Company. (2019 ). Available online at: https://www.foundationmedicine.com/genomic-testing/foundation-one-cdx (accessed May 15, 2019).\n18. Wilke H Muro K Van Cutsem E Oh SC Bodoky G Shimada Y . Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial\n. Lancet Oncol. (2014 ) 15 :1224 –35\n. 10.1016/S1470-2045(14)70420-6 25240821 \n19. Hu G Qin L Zhang X Ye G Huang T . Epigenetic silencing of the MLH1 promoter in relation to the development of gastric cancer and its use as a biomarker for patients with microsatellite instability: a systematic analysis\n. Cell Physiol Biochem. (2018 ) 45 :148 –62\n. 10.1159/000486354 29334683 \n20. Marcus L Lemery SJ Keegan P Pazdur R . FDA Approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors\n. Clin Cancer Res. (2019 ) 25 :3753 –8\n. 10.1158/1078-0432.CCR-18-4070 30787022\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "checkpoint inhibition; gastric/GEJ adenocarcinoma; gastrointestinal cancer; immunotherapy; nivolumab",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "130",
"pmc": null,
"pmid": "32128313",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "27664260;25220842;28138578;30110194;30911859;30013197;27189322;25385008;29334683;30205505;30704511;29880231;28993052;25240821;30787022",
"title": "Durable Complete Radiological Response to Nivolumab in Two Heavily Pretreated Western Elderly Patients With Metastatic Gastric Cancer: A Case Report.",
"title_normalized": "durable complete radiological response to nivolumab in two heavily pretreated western elderly patients with metastatic gastric cancer a case report"
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"abstract": "Therapeutic hypothermia is often used for traumatic brain injury because of its neuroprotective effect and decreased secondary brain injury. However, this procedure lacks clinical evidence supporting its efficacy, and adverse outcomes have been reported during general anesthesia. A 61-year-old man with a history of percutaneous coronary intervention (PCI) was admitted with traumatic brain injury. Immediately after admission, he underwent mild therapeutic hypothermia with a target temperature of 33.0°C for neuroprotection. During general anesthesia for emergency surgery because he developed a mass effect, hypothermic cardiac arrest occurred following an additional decrease in the core body temperature. Moreover, myocardial infarction caused by restenosis of the previous PCI lesion also contributed to the cardiac arrest. Although the patient recovered spontaneous circulation after an hour-long cardiopulmonary resuscitation with rewarming, he eventually died of subsequent repetitive cardiac arrests. When anesthetizing patients undergoing therapeutic hypothermia, caution is required to prevent adverse outcomes that can be caused by unintentional severe hypothermia and exacerbation of underlying heart disease.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Eulji University Medical Center, Daejeon, Korea.;Department of Anesthesiology and Pain Medicine, Eulji University Medical Center, Daejeon, Korea.;Department of Anesthesiology and Pain Medicine, Eulji University Medical Center, Daejeon, Korea.;Department of Anesthesiology and Pain Medicine, Eulji University Medical Center, Daejeon, Korea.;Department of Anesthesiology and Pain Medicine, Eulji University Medical Center, Daejeon, Korea.;Department of Anesthesiology and Pain Medicine, Eulji University Medical Center, Daejeon, Korea.;Department of Anesthesiology and Pain Medicine, Eulji University Medical Center, Daejeon, Korea.",
"authors": "Park|Dong Ho|DH|https://orcid.org/0000-0002-6587-3756;Kim|Tae Woo|TW|https://orcid.org/0000-0002-2115-6448;Kim|Mo Se|MS|https://orcid.org/0000-0001-7362-0030;Han|Woong|W|;Lee|Da Eun|DE|;Kim|Gyu Seong|GS|;Jeong|Chang Young|CY|",
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"fulltext": "\n==== Front\nJ Int Med Res\nJ Int Med Res\nIMR\nspimr\nThe Journal of International Medical Research\n0300-0605 1473-2300 SAGE Publications Sage UK: London, England \n\n33499678\n10.1177/0300060520987945\n10.1177_0300060520987945\nCase Report\nCardiac arrest caused by accidental severe hypothermia and myocardial infarction during general anesthesia\nhttps://orcid.org/0000-0002-6587-3756Park Dong Ho https://orcid.org/0000-0002-2115-6448Kim Tae Woo https://orcid.org/0000-0001-7362-0030Kim Mo Se Han Woong Lee Da Eun Kim Gyu Seong Jeong Chang Young Department of Anesthesiology and Pain Medicine, Eulji University Medical Center, Daejeon, Korea\nDong Ho Park, Department of Anesthesiology and Pain Medicine, Eulji University Medical Center, 95, Dunsanseo-ro, Seo-gu, Daejeon 35233, Korea. Email: donghop6212@naver.com\n26 1 2021 \n1 2021 \n49 1 030006052098794526 9 2020 17 12 2020 © The Author(s) 20212021SAGE PublicationsCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Therapeutic hypothermia is often used for traumatic brain injury because of its neuroprotective effect and decreased secondary brain injury. However, this procedure lacks clinical evidence supporting its efficacy, and adverse outcomes have been reported during general anesthesia. A 61-year-old man with a history of percutaneous coronary intervention (PCI) was admitted with traumatic brain injury. Immediately after admission, he underwent mild therapeutic hypothermia with a target temperature of 33.0°C for neuroprotection. During general anesthesia for emergency surgery because he developed a mass effect, hypothermic cardiac arrest occurred following an additional decrease in the core body temperature. Moreover, myocardial infarction caused by restenosis of the previous PCI lesion also contributed to the cardiac arrest. Although the patient recovered spontaneous circulation after an hour-long cardiopulmonary resuscitation with rewarming, he eventually died of subsequent repetitive cardiac arrests. When anesthetizing patients undergoing therapeutic hypothermia, caution is required to prevent adverse outcomes that can be caused by unintentional severe hypothermia and exacerbation of underlying heart disease.\n\nTherapeutic hypothermiaaccidental hypothermiageneral anesthesiatraumatic brain injurypercutaneous coronary interventioncoronary restenosismyocardial infarctiontypesetterts2\n==== Body\nIntroduction\nTherapeutic hypothermia is an attractive strategy for traumatic brain injury (TBI), which demonstrates neuroprotective effects and decreases secondary brain injury.1 Despite the lack of clinical evidence regarding efficacy, therapeutic hypothermia after TBI has been used for at least half a century because of its potential benefits, which are supported by numerous preclinical studies.2,3 However, there have been no reports on the danger of unintentional severe hypothermia during general anesthesia caused by the additional drop in temperature of patients undergoing therapeutic hypothermia. When anesthetizing patients with comorbidities, such as ischemic heart disease, caution is required to prevent adverse outcomes that can be caused by unintentional severe hypothermia and exacerbation of underlying heart disease.4,5\n\nCase report\nA 61-year-old man (height, 168 cm; weight, 70 kg) presented to our emergency room (ER) with head trauma after falling on a cement floor from a 5-meter-tall construction site. Upon arrival at the ER, the patient had a Glasgow coma scale score of 11 and the following vital signs: blood pressure (BP), 147/83 mmHg; heart rate (HR), 86 beats per minute (bpm); respiratory rate, 24 breaths per minute; body temperature from the auditory canal, 36.8°C; and percutaneous oxygen saturation (SpO2), 97%. Upon discovering signs of acute subdural hemorrhage, subarachnoid hemorrhage, and intraventricular hemorrhage from a brain computed tomography (CT) scan performed in the ER, we admitted the patient to the intensive care unit (ICU) for close monitoring. After approximately 6 hours, we performed follow-up brain CT because the patient’s mental status had deteriorated from drowsy to stupor. Upon observing a mass effect characterized by an increase in the hemorrhage volume and a left midline shift on the CT images, the patient was scheduled for immediate intubation and emergency decompressive craniectomy (Figure 1).\n\nFigure 1. Brain computed tomography (CT) images taken 6 hours after intensive care unit admission. (a) Axial view showing acute subarachnoid hemorrhage in the peri-mesencephalic cistern (arrow A) and subdural hemorrhage in the right inferior temporal (arrow B) and right parietal (arrow C) regions. (b) Axial view showing acute subdural hemorrhage in the right temporal region (black arrow) and left midline shift.\n\nAlthough the patient had a history of ischemic heart disease with percutaneous coronary intervention (PCI), it was difficult to obtain accurate information because there was no relevant data in the patient’s medical records from the authors’ hospital, and his drowsy state interfered with detailed interviews. According to the chest CT scan performed immediately after admission, coronary stents had been inserted at the bifurcation site of the left main coronary artery (Figure 2). It also appeared that the inserted stents were drug-eluting stents (DES) considering that he had received dual antiplatelet therapy (DAPT) with aspirin and clopidogrel (Plavix®; Sanofi, Bridgewater, NJ, USA) a switching platelet P2Y12 inhibitor, for approximately 4 months. However, DAPT was discontinued owing to the worsening cerebral hemorrhage after hospitalization; bridging antiplatelet therapy was also not performed. Before the surgery, the patient showed a normal electrocardiogram (ECG), and cardiac biomarker testing revealed a troponin-T concentration of 0.006 µg/L, which was within normal limits (Figure 3). The patient demonstrated satisfactory functional capacity to be able to work at a construction site just before the trauma. Therefore, an additional preoperative cardiac evaluation was not considered necessary.\n\nFigure 2. Chest computed tomography (CT) images showing coronary stents in the main bifurcation of the left coronary arteries (white arrow in (a) and (b)).\n\nFigure 3. Preoperative electrocardiogram of the patient showing normal sinus rhythm with a heart rate of 95 bpm.\n\nbpm, beats per minute.\n\nImmediately after admission to the ICU, the patient’s bladder temperature was 38.0°C. Using a hydrogel-coated water-circulating pad (Arctic Sun®; Medivance Inc., Louisville, CO, USA), which is a surface cooling device, the patient underwent mild therapeutic hypothermia with a target temperature of 33.0°C. During therapeutic hypothermia, sedation and shivering control were performed using continuous rate infusions of midazolam at 5 mg/hour and remifentanil at 0.2 µg/kg/minute. The patient’s bladder temperature was 33.4°C just before he was transferred to the operating room. Preoperative laboratory tests showed no unusual findings except for mildly elevated aspartate aminotransferase (73 U/L) and alanine aminotransferase (51 U/L) concentrations.\n\nThe patient’s vital signs upon arrival at the operating room were a BP of 130/70 mmHg and SpO2 of 100%. Lead II of the ECG was monitored, and there were no unusual findings except sinus tachycardia with an HR of 100 bpm on the initial ECG. Arterial BP (ABP), central venous pressure (CVP), and esophageal temperature were monitored from the right radial artery, right subclavian vein, and lower third of the esophagus using a temperature sensor attached to the esophageal stethoscope, respectively. The initial ABP, CVP, and esophageal temperature were 140/85 mmHg, 6 mmHg, and 33.0°C, respectively. Arterial blood gas analysis was performed in the arterial line, with values calculated as for a body temperature of 37°C, which revealed the following: pH, 7.400; partial pressure of carbon dioxide (PCO2), 40 mmHg; partial pressure of oxygen (PO2), 174 mmHg; bicarbonate (HCO3), 24.8 mmol/L; base excess, 0.0; lactate, 0.17 mmol/L; ionized calcium, 1.04 mmol/L; and potassium, 3.3 mmol/L. Total intravenous (IV) anesthesia was performed using a target-controlled infusion of propofol and remifentanil in accordance with the Schnider6 and Minto7 models, respectively. Propofol and remifentanil were infused continuously with effect-site concentrations (Ce) of 1.5 µg/mL and 1.5 ng/mL, respectively. Concurrently, 50 mg of rocuronium was administered by IV bolus injection for neuromuscular blockade. Mechanical ventilation was adjusted to maintain the end-tidal carbon dioxide value at 30 to 33 mmHg.\n\nAs ABP decreased to 78/42 mmHg and CVP decreased to 4 mmHg within 10 minutes after anesthesia, the Ce of propofol and remifentanil were lowered to 0.8 µg/mL and 1.0 ng/mL, respectively, and approximately 1 L of balanced crystalloid fluid loading was performed. However, the patient’s BP did not recover, and a dopamine continuous infusion (5 µg/kg/minute) was initiated. When a surgical incision was made 10 minutes after beginning the dopamine infusion, the patient’s ABP and HR increased to 115/70 mmHg and 120 bpm, respectively, and marked ST-segment depression (−2.4 mm) was found, which was not observed on the preoperative or initial ECGs (Figure 4). Subsequently, the depth of anesthesia was increased by increasing the Ce of propofol to 1.0 to 1.2 µg/mL, followed by a continuous infusion of isosorbide dinitrate (1 µg/kg/minute). While HR was maintained at 110 to 120 bpm, ABP gradually decreased to 70/40 mmHg after approximately 5 minutes. To treat the hypotension, isosorbide dinitrate was discontinued, and a bolus injection of 100 µg phenylephrine was administered, after which, ABP increased temporarily to 95/60 mmHg. Subsequently, HR decreased suddenly and rapidly, and ventricular fibrillation occurred. The anesthesiologists immediately discontinued the surgery and performed cardiopulmonary resuscitation (CPR). The patient’s esophageal temperature at the time was 32.0°C.\n\nFigure 4. Intraoperative electrocardiogram of the patient showing sinus tachycardia with significant ST depression. The ST depression on the monitor represented approximately −2.4 at the time.\n\nChest compressions were performed with periodic defibrillation with 200 J, and epinephrine injections were administered every 3 minutes; these measures elicited no response. During CPR, ECG monitoring showed temporary severe bradycardia (HR, 10–30 bpm). However, this was considered pulseless electrical activity because no pulse was detected in the patient’s femoral artery. Soon afterward, there was a rapid transition to ventricular fibrillation, and CPR was repeated. At the time, the patient’s esophageal temperature dropped to 30.0°C. According to the refractory state after the defibrillation and drug injections, we considered that the cardiac arrest was caused by hypothermia. To reverse the cause, a forced-air warming device and a warming blanket (Bair Hugger®; Arizant Healthcare Inc., Eden Prairie, MN, USA) were used for surface warming, the IV fluids were warmed, and surgical wound closure and dressing were performed rapidly to prevent surface heat loss. The first arterial blood gas analysis after ventricular fibrillation, calculated as for a body temperature of 37°C, showed the following: pH, 7.690; PCO2, 15 mmHg; PO2, 260 mmHg; HCO3, 18.1 mmol/L; base excess, −1.2; lactate, 0.33 mmol/L; ionized calcium, 0.88 mmol/L; and potassium, 5.0 mmol/L. Follow-up arterial blood gas analyses were repeated periodically. As we continued to perform CPR, the patient developed severe metabolic acidosis and hypocalcemia characterized by a pH of 6.840, HCO3 of 15.4 mmol/L, and ionized calcium of 0.66 mmol/L. To correct the abnormal findings, we administered appropriate amounts of sodium bicarbonate and calcium chloride. After an hour-long CPR and rewarming, the patient’s esophageal temperature recovered to 33.0°C, which was followed by observing sinus rhythm characterized by an HR of 75 bpm on an ECG monitor and detecting a pulse in the femoral artery with a characteristic ABP waveform that eventually led to the recovery of BP to 130/55 mmHg. Upon confirming recovery of spontaneous circulation (ROSC), the patient was transported to the ICU while we administered dopamine (10 µg/kg/minute), norepinephrine (0.1 µg/kg/minute), and vasopressin (2 U/hour). ABP, HR, and esophageal temperature during anesthesia are shown in Figure 5.\n\nFigure 5. Changes in vital signs (blood pressure (BP), heart rate (HR), and esophageal temperature) over time (5-minute intervals).\n\nbpm, beats per minute.\n\nCardiac biomarker testing performed after the patient’s transfer to the ICU showed an increased troponin-T level of 1.432 µg/L. Portable Doppler transthoracic echocardiography (TTE) revealed total occlusion of the left main coronary artery, which had undergone PCI previously. Because emergency coronary artery bypass grafting (CABG) was impossible at the time, repeated PCI was considered an alternative treatment option. However, even after his transfer to the ICU, the patient experienced repetitive ventricular fibrillation. Four hours after the patient’s transfer to the ICU, the patient’s guardian requested that CPR should be stopped. Without resuscitation, the patient died.\n\nDiscussion\nIn this case, the patient, who was receiving therapeutic hypothermia, underwent emergency craniectomy owing to worsening brain hemorrhage, and cardiac arrest occurred during general anesthesia. We deduced that the cardiac arrest was owing to the additional decrease in the patient’s core body temperature and myocardial infarction caused by restenosis of the previous PCI-treated lesion.\n\nTherapeutic hypothermia is used to improve neurological outcomes in cardiac arrest, TBI, stroke, and hypoxic–ischemic encephalopathy.1,4 Studies on the efficacy of therapeutic hypothermia for TBI have been less convincing, and they show conflicting results. However, hypothermia is consistently used as an option for TBI because it reduces intracranial pressure and the cerebral metabolic rate, thereby protecting neuronal function in the brain and decreasing the wide range of injuries or reparative processes by attenuating temperature-sensitive mechanisms, such as excitotoxicity, free radical generation, apoptosis, and inflammation.1,2\n\nThe cardiovascular effects associated with hypothermia are complex. Hypothermia affects the electrical conduction of myocardial cells, which can induce hypotension or bradycardia and even increase the risk of ventricular fibrillation by prolonging repolarization.4,8 However, mild hypothermia of 32.0°C to 35.0°C demonstrates cardioprotective effects by decreasing myocardial oxygen demand and increasing myocardial perfusion through vasodilation of coronary vessels.9 Therefore, there has been a growing interest in the clinical use of mild therapeutic hypothermia as an adjunctive therapy during ischemic heart disease.10 Our patient received mild therapeutic hypothermia with a target core temperature of 33.0°C, which may have yielded cardioprotective as well as neuroprotective benefits.11\n\nDuring general anesthesia, hypothermia is induced following an increase in heat loss caused by peripheral vasodilation after the injection of anesthetic drugs, heat redistribution from the core to the periphery, and impaired normal thermoregulatory responses, such as vasoconstriction or shivering.5 In our patient, the cold operating room temperature and irrigating an uncovered surgical area in the brain with cold saline also may have contributed to the additional core body temperature drop in addition to the effects of general anesthesia.12 However, in our case, neurosurgeons requested that anesthesiologists not perform warming during anesthesia. Instead, esophageal temperature and signs that could result from hypothermia, such as ECG changes, were carefully monitored. The esophageal temperature decreased from 33.0°C, which was measured immediately after entering the operation room, to 32.0°C at the time of cardiac arrest. The esophageal temperature further decreased to a minimum of 30.0°C during CPR. With rewarming, the temperature recovered to 33.0°C and finally, ROSC was achieved. Considering that chest compressions, drugs, and defibrillation did not induce ROSC, which was achieved with the recovery of an esophageal temperature of 33.0°C, the additional rapid fall in the patient’s core body temperature during anesthesia may have caused the cardiac arrest.\n\nIn this case study, we suspected that restenosis at the site of the previous stent insertion contributed to the cardiac arrest, given the following three findings: First, the patient had a normal preoperative ECG with no signs of ischemia but developed ST-segment depression during anesthesia. Second, repetitive cardiac arrests occurred even after achieving ROSC with rewarming. Third, an increased troponin-T concentration was observed, and suspected re-stenotic occlusion of the left main coronary artery was confirmed by Doppler TTE after the patient’s transfer to the ICU. Accordingly, myocardial infarction was considered the main cause of death.\n\nThe mechanisms of myocardial infarction owing to stent restenosis after DES insertion are rapid stent thrombosis or profuse in-stent restenosis (ISR).13 We assume that the lesion characteristics in the left main bifurcation of the coronary artery and DAPT interruption owing to the increasing amount of cerebral hemorrhage contributed to the stent restenosis in this patient. As evidence in support of this assumption, previous studies have shown that stenting at the left main bifurcation and DAPT interruption are strong risk factors for stent thrombosis or ISR.14,15 While controversial, not interrupting aspirin perioperatively could have avoided poor outcomes.16 However, there were no clinical signs related to expected ongoing restenosis of the coronary artery or myocardial ischemia preoperatively in our patient. We suspect that the possible ischemic signs may have been masked by the aforementioned cardioprotective benefits of therapeutic hypothermia. We also believe that the following three conditions contributed to the intraoperative myocardial ischemia and infarction caused by acute restenosis of the coronary stent: First, intraoperative hypotension may have contributed to myocardial injury. The IV anesthetics used during anesthesia, propofol and remifentanil, induced redistribution of blood volume by peripheral vasodilation, resulting in profound hypotension.4 Profound hypotension was strongly associated with myocardial injury and especially harmful for this patient, who had preexisting ischemic heart disease.17 Second, tachycardia, which may have been caused by the inotrope dopamine, used to compensate for the low BP or the stress response to surgical stimulation from shallow anesthetic depth, may have triggered myocardial ischemia by decreasing oxygen delivery and increasing oxygen consumption.17,18 If cardiogenic shock is suspected, as in our case, norepinephrine could be a better option than dopamine.19 Third, the bolus injection of phenylephrine, a selective α1-adrenergic agonist, just before cardiac arrest may have temporarily and abruptly increased cardiac afterload and impaired myocardial perfusion.20\n\nHad we known that coronary artery occlusion would result from hypothermia-induced cardiac arrest and coronary stent restenosis, the treatment of choice would have been CABG surgery while maintaining circulation with emergency cardiopulmonary bypass (CPB) or extracorporeal membrane oxygenation (ECMO) via the femoral artery and vein.11 However, it was difficult to determine the etiology of the cardiac arrest at the time. Even if we had known the cause, ideal treatment would have been impossible, given circumstances beyond our control; all thoracic surgeons were busy operating, and emergency CPB and ECMO were not available. As an alternative, repeat PCI after the patient achieved ROSC could have been performed. However, the patient had a prolonged CPR duration, and he did not maintain the ROSC state for a period sufficient for intervention, which led to a poor outcome.\n\nIn this case, it was not possible to accurately determine the reason for the cardiac arrest and for not achieving consistent ROSC. Instead, we conclude that cardiac arrest developed and persisted as a result of the unintentional severe hypothermia that occurred during general anesthesia and/or coronary artery restenosis at the site of the previous PCI. A thorough evaluation of heart-related history is required for TBI patients who have a history of ischemic heart diseases and who undergo therapeutic hypothermia because there may be undiscovered coronary insufficiency owing to the cardioprotective effects of therapeutic hypothermia. In addition, careful monitoring of the patient’s core body temperature, and preventive and countermeasures should be fully prepared and taken against adverse hemodynamic effects, even cardiac arrest, which can occur because of additive hypothermic responses during anesthesia.\n\nEthics statement: This case report was approved by our Institutional Review Board (EMC 2020-05-005-001), and the case report was performed in compliance with the EQUATOR Network guidelines (the CARE guidelines). All patient details were de-identified, and written consent was obtained from the patient’s guardian for treatment and publication of this report.\n\nDeclaration of conflicting interest: The authors declare that there is no conflict of interest.\n\nFunding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nORCID iDs: Dong Ho Park https://orcid.org/0000-0002-6587-3756\n\nTae Woo Kim https://orcid.org/0000-0002-2115-6448\n\nMo Se Kim https://orcid.org/0000-0001-7362-0030\n==== Refs\nReferences\n1 Dietrich WD Bramlett HM. \nTherapeutic hypothermia and targeted temperature management in traumatic brain injury: clinical challenges for successful translation.\n\nBrain Res \n2016 ; \n1640 : 94 –103\n.26746342 \n2 Chen H Wu F Yang P , et al\nA meta-analysis of the effects of therapeutic hypothermia in adult patients with traumatic brain injury.\n\nCrit Care \n2019 ; \n23 : 396 .31806001 \n3 Hirst TC Klasen MG Rhodes JK , et al\nA systematic review and meta-analysis of hypothermia in experimental traumatic brain injury: why have promising animal studies not been replicated in pragmatic clinical trials?\n\nJ Neurotrauma \n2020 ; \n37 : 2057 –2068\n.32394804 \n4 Urits I Jones MR Orhurhu V , et al\nA comprehensive update of current anesthesia perspectives on therapeutic hypothermia.\n\nAdv Ther \n2019 ; \n36 : 2223 –2232\n.31301055 \n5 Sessler DI. \nTemperature monitoring and perioperative thermoregulation.\n\nAnesthesiology \n2008 ; \n109 : 318 –338\n.18648241 \n6 Schnider TW Minto CF Gambus PL , et al\nThe influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers\n. Anesthesiology \n1998 ; \n88 : 1170 –1182\n9605675 \n7 Minto CF Schnider TW Egan TD , et al\nInfluence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development\n. Anesthesiology \n1997 ; \n86 : 10 –23\n.9009935 \n8 Dietrichs ES Tveita T Smith G. \nHypothermia and cardiac electrophysiology: a systematic review of clinical and experimental data.\n\nCardiovasc Res \n2019 ; \n115 : 501 –509\n.30544147 \n9 Chaves LO Leon M Einav S , et al\nEditor’s choice-inside the cold heart: a review of therapeutic hypothermia cardioprotection\n. Eur Heart J Acute Cardiovasc Care \n2017 ; \n6 : 130 –141\n.26714973 \n10 Villablanca PA Rao G Briceno DF , et al\nTherapeutic hypothermia in ST elevation myocardial infarction: a systematic review and meta-analysis of randomised control trials.\n\nHeart \n2016 ; \n102 : 712 –719\n.26864673 \n11 Truhlář A Deakin CD Soar J , et al\nEuropean resuscitation council guidelines for resuscitation 2015: Section 4. Cardiac arrest in special circumstances.\n\nResuscitation \n2015 ; \n95 : 148 –201\n.26477412 \n12 Faulds M Meekings T. \nTemperature management in critically ill patients\n. Contin Educ Anaesth Crit Care Pain \n2013 ; \n13 : 75 –79\n.\n13 Nayak AK Kawamura A Nesto RW , et al\nMyocardial infarction as a presentation of clinical in-stent restenosis\n. Circ J \n2006 ; \n70 : 1026 –1029\n.16864936 \n14 Gori T Polimeni A Indolfi C , et al\nPredictors of stent thrombosis and their implications for clinical practice.\n\nNat Rev Cardiol \n2019 ; \n16 : 243 –256\n.30518952 \n15 Cassese S Byrne RA Tada T , et al\nIncidence and predictors of restenosis after coronary stenting in 10 004 patients with surveillance angiography.\n\nHeart \n2014 ; \n100 : 153 –159\n.24270744 \n16 Karkouti K Wijeysundera DN. \nThe clinical dilemma of managing patients who are on dual antiplatelet therapy and require major non-cardiac surgery.\n\nBr J Anaesth \n2019 ; \n122 : 162 –164\n.30686300 \n17 Sessler DI Khanna AK. \nPerioperative myocardial injury and the contribution of hypotension.\n\nIntensive Care Med \n2018 ; \n44 : 811 –822\n.29868971 \n18 Abbott TEF Pearse RM Archbold RA , et al\nA prospective international multicentre cohort study of intraoperative heart rate and systolic blood pressure and myocardial injury after noncardiac surgery: results of the VISION study\n. Anesth Analg \n2018 ; \n126 : 1936 –1945\n.29077608 \n19 Antonopoulos A Nikolopoulos D Georgiou EK , et al\nBlood pressure elevation after phenylephrine infusion may adversely affect myocardial perfusion in patients with coronary artery disease\n. Int J Cardiol \n2002 ; \n84 : 201 –209\n.12127373 \n20 De Backer D Biston P Devriendt J , et al\nComparison of dopamine and norepinephrine in the treatment of shock\n. N Eng J Med \n2010 ; \n362 : 779 –789\n.\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "49(1)",
"journal": "The Journal of international medical research",
"keywords": "Therapeutic hypothermia; accidental hypothermia; coronary restenosis; general anesthesia; myocardial infarction; percutaneous coronary intervention; traumatic brain injury",
"medline_ta": "J Int Med Res",
"mesh_terms": "D000768:Anesthesia, General; D016887:Cardiopulmonary Resuscitation; D006323:Heart Arrest; D006801:Humans; D007035:Hypothermia; D007036:Hypothermia, Induced; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D062645:Percutaneous Coronary Intervention",
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"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Cardiac arrest caused by accidental severe hypothermia and myocardial infarction during general anesthesia.",
"title_normalized": "cardiac arrest caused by accidental severe hypothermia and myocardial infarction during general anesthesia"
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"abstract": "BACKGROUND\nAcute compartment syndrome is a limb-threatening and occasionally life-threatening emergency that is rarely reported as a complication following childbirth. Prompt diagnosis is crucial to avoid permanent functional restriction or even the loss of the affected limb. Clinical signs and symptoms might be nonspecific, especially in the early stages; therefore, knowledge of predisposing risk factors and signs and symptoms of acute compartment syndrome is necessary to prevent long-term complications and amputation.\n\n\nMETHODS\nThis paper presents a case of a 26-year-old primiparous Sri Lankan woman who developed acute compartment syndrome of the lower right limb following childbirth by cesarean section.\n\n\nCONCLUSIONS\nAcute compartment syndrome is an important differential diagnosis in the setting of sudden onset of lower limb pain following childbirth. Predisposing factors for its manifestation within an obstetric environment are augmented labor, the lithotomy position, postpartum hemorrhage, hypotension following epidural analgesia, and the use of vasoconstrictive agents. If left undiagnosed and untreated, acute compartment syndrome may cause permanent neurovascular deficit, leading to a poor functional result, tissue ischemia, limb amputation, and rhabdomyolysis. If severe, and in large compartments, it can lead to renal failure and death. Alertness and a high index of clinical suspicion for the possibility of acute compartment syndrome are required to avoid a delay in diagnosis, and intracompartmental pressure measurement can be used to confirm the diagnosis.",
"affiliations": "School of Nursing and Midwifery, Western Sydney University, Sydney, Australia. 18848074@student.westernsydney.edu.au.;Hornsby Ku-Ring-Gai Hospital, Hornsby, NSW, 2077, Australia.;Hornsby Ku-Ring-Gai Hospital, Hornsby, NSW, 2077, Australia.;Hornsby Ku-Ring-Gai Hospital, Hornsby, NSW, 2077, Australia.;Obstetrics and Gynaecology, Hornsby Ku-Ring-Gai Hospital, Hornsby, NSW, 2077, Australia.",
"authors": "Coulton|Sharon|S|;Bourne|Sally|S|;Catliffe|Simon|S|;Brooks|Roderick|R|;Jollow|David|D|",
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"doi": "10.1186/s13256-020-02459-w",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947 BioMed Central London \n\n32883339\n2459\n10.1186/s13256-020-02459-w\nCase Report\nAcute compartment syndrome of the lower limb following childbirth: a case report\nCoulton Sharon 18848074@student.westernsydney.edu.au 1 Bourne Sally sallybourne6@gmail.com 2 Catliffe Simon simon_catliffe@hotmail.com 2 Brooks Roderick drrodbrooks@gmail.com 2 Jollow David dmjollow@bigpond.com 3 1 grid.1029.a0000 0000 9939 5719School of Nursing and Midwifery, Western Sydney University, Sydney, Australia \n2 grid.460725.2Hornsby Ku-Ring-Gai Hospital, Hornsby, NSW 2077 Australia \n3 grid.460725.2Obstetrics and Gynaecology, Hornsby Ku-Ring-Gai Hospital, Hornsby, NSW 2077 Australia \n4 9 2020 \n4 9 2020 \n2020 \n14 14023 5 2019 23 7 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\nAcute compartment syndrome is a limb-threatening and occasionally life-threatening emergency that is rarely reported as a complication following childbirth. Prompt diagnosis is crucial to avoid permanent functional restriction or even the loss of the affected limb. Clinical signs and symptoms might be nonspecific, especially in the early stages; therefore, knowledge of predisposing risk factors and signs and symptoms of acute compartment syndrome is necessary to prevent long-term complications and amputation.\n\nCase presentation\nThis paper presents a case of a 26-year-old primiparous Sri Lankan woman who developed acute compartment syndrome of the lower right limb following childbirth by cesarean section.\n\nConclusion\nAcute compartment syndrome is an important differential diagnosis in the setting of sudden onset of lower limb pain following childbirth. Predisposing factors for its manifestation within an obstetric environment are augmented labor, the lithotomy position, postpartum hemorrhage, hypotension following epidural analgesia, and the use of vasoconstrictive agents. If left undiagnosed and untreated, acute compartment syndrome may cause permanent neurovascular deficit, leading to a poor functional result, tissue ischemia, limb amputation, and rhabdomyolysis. If severe, and in large compartments, it can lead to renal failure and death. Alertness and a high index of clinical suspicion for the possibility of acute compartment syndrome are required to avoid a delay in diagnosis, and intracompartmental pressure measurement can be used to confirm the diagnosis.\n\nKeywords\nCase reportAcute compartment syndromeChildbirthCesareanObstetricsPostpartum painissue-copyright-statement© The Author(s) 2020\n==== Body\nStatement of significance\nProblem\nAcute compartment syndrome (ACS) is not currently recognized by midwives and obstetricians as a potential complication that may occur following childbirth. The published literature estimates a prevalence of 2 in 10,000 births [1]; however, its true incidence is unknown.\n\nWhat is already known\nAlertness and a high index of clinical suspicion are required to avoid delayed diagnosis and permanent neurovascular deficit.\n\nWhat this report adds\nThis case report highlights the need for midwives and obstetricians to have an understanding of the signs and symptoms of ACS to prevent delayed diagnosis and its consequences for the postpartum woman.\n\nBackground\nACS of the limb is a limb-threatening and occasionally life-threatening emergency. It is caused by an increased intracompartmental pressure (ICP) that causes a decrease in perfusion pressure, leading to hypoxemia of the tissues [2]. A decrease in tissue perfusion can lead to irreversible necrosis, which may result in functional impairment, loss of limb, and, in rare cases, death [2]. ACS most frequently occurs after a traumatic event; however, up to 30% of cases develop without evidence of fracture [2]. Other factors that have been associated with ACS include ischemia-reperfusion injury; hemorrhage; phlegmasia cerulea dolens; vascular puncture in patients with bleeding disorders; intravenous/arterial drug injection; and soft tissue injury resulting from prolonged limb compression due to lithotomy positioning during surgery, constricting casts or wraps, crush injury, or burns [2, 3]. ACS has also been associated with nephrotic syndrome, rhabdomyolysis, bleeding disorders, iatrogenic factors, and infections such as Streptococcus spp. [2].\n\nThe symptoms of ACS include swelling, pain on passive stretch, pain out of proportion to the injury, paresthesia, and paresis or paralysis [4]; however, it is important to note that not all characteristic of ACS may be present [5]. Clinical signs such as pallor, reduced capillary return, and absent peripheral pulses are late signs of ACS, and therefore the presence of distal pulses should not be relied on to exclude a diagnosis of ACS [4]. Significantly increased creatine kinase (CK) levels in the blood are also not a good indicator for early diagnosis of ACS, because they may indicate severe muscle damage or ischemia [2–4, 6, 7].\n\nBecause ACS is rarely reported as a complication in the obstetric literature, it is not currently recognized by midwives and obstetricians as a potential complication that may occur following childbirth. Available case reports indicate that it may occur at any stage during labor, birth, or the immediate postpartum period. The published literature estimates a prevalence of 2 in 10,000 births [1]; however, its true incidence is unknown. It has been reported in the settings of both vaginal [8–12] and cesarean births [13–19] and has been diagnosed on the basis of clinical evaluation and occasionally ICP measurement.\n\nPossible risk factors for ACS of the limb in an obstetric context has been associated with, but is not limited to, postpartum hemorrhage (PPH) [13, 16, 18, 19], epidural analgesia [16, 17], hypotension [9, 12, 17], vasoconstrictive agents [8, 13, 16–18], the lithotomy position [8], postpartum eclampsia [11, 16], and a combination of these factors [8, 9, 13, 16, 17].\n\nAugmentation and induction of labor with oxytocics, PPH, use of vasoconstrictive agents, lithotomy position, and epidural analgesia and related hypotension occur regularly in an obstetric environment, and a combination of these factors may predispose a woman to develop postpartum ACS of the limb. Because the functional outcome after ACS is directly related to urgent surgical intervention, it is essential for midwives and obstetricians to be aware of the potential for an ACS to develop and to consider it as a differential diagnosis when symptoms are present.\n\nThis report presents a case study of delayed diagnosis of ACS of the right lower leg following childbirth by cesarean section. The purpose of this report is to prevent further cases of delayed diagnosis by raising awareness of the need to have a high index of suspicion when signs and symptoms of ACS are present. Reporting of all cases of ACS following childbirth, regardless of the outcome, is strongly encouraged so that knowledge and awareness of the possibility of this complication are increased among midwives and obstetricians who provide care for women during labor, birth, and the immediate postpartum period. To prevent cases of delayed diagnosis, it is necessary for ACS to be recognized as a differential diagnosis and a potential complication in obstetrics when possible risk factors are present.\n\nCase presentation\nA 26-year-old Sri Lankan woman in early labor presented to the birthing unit at 40 weeks and 6 days of gestation with spontaneous onset of labor and rupture of membranes. She had experienced threatened premature labor at 22 weeks and 6 days of gestation, but the pregnancy was otherwise uncomplicated.\n\nThe woman progressed well into established labor; however, labor slowed following administration of morphine. Augmentation of labor was commenced with 10 IU of oxytocin (Syntocinon; Mylan Health Pty Ltd, Millers Point, Australia) in 1 L of Hartmann’s solution, after which labor progressed well. Seventeen hours following admission to the hospital, the laboring woman had not progressed beyond 7cm dilation. Epidural analgesia was commenced, but due to “failure to progress” in the first stage of labor and a nonreassuring fetal heart rate, the woman gave birth by cesarean section. A healthy male infant was born following 16 hours and 51 minutes of established labor, and an estimated blood loss of 450 ml was recorded.\n\nTwelve hours following the cesarean section, the woman started to experience pain in her lower right leg, and by 28 hours, she had developed clinical symptoms of an ACS. She was treated with antibiotics for possible cellulitis. Her symptoms did not improve, and a Doppler ultrasound examination was performed to exclude deep venous thrombosis (DVT) but showed no remarkable findings. ACS was definitively diagnosed on postpartum day 10 and confirmed by magnetic resonance imaging. The ACS was managed nonsurgically, and the woman remained in the hospital with her baby for 15 days following the birth. A detailed timeline of events and clinical management following the cesarean section is provided in Table 1.\nTable 1 Timeline of events following birth\n\nTime\tClinical details\t\n1.5 hours\tReturned to the postnatal ward following an emergency cesarean section; full sensation and movement were noted in both legs.\t\n12 hours\tOnset of pain and swelling in right lower leg.\t\n14 hours\tThe postpartum woman complained of pain in her right shin. An obstetrics and gynecology assessment revealed extreme pain on mobilization and weight bearing in the lower right leg, with worsening pain upon movement over the tibialis anterior with plantar flexion. A physical examination revealed a decreased range of motion in the right foot and decreased extension of the right great toe. Minimal pitting edema was noted on the right foot, and capillary refill was normal in both feet. A small and very painful soft lump was palpable over the anterior midshin area of the right leg. Range of motion in both knees and ankles was normal, as were the lower limb reflexes and pedal pulses. No calf tenderness or skin changes were noted, and skin temperature was normal. Sensation was normal, and the postpartum woman was afebrile. The impression at the time was deemed to be muscle-related pain, and therefore she was commenced on analgesia and encouraged to mobilize and to elevate the leg on a pillow. A deep venous thrombosis was not considered at this stage, because there was no calf tenderness. A heat pack was applied to the lower right leg and antiembolism stockings were applied to both legs.\t\n23 hours\tSwelling in the right leg and foot had worsened, and the postpartum woman experienced a burning sensation along the muscle. By this stage, she was no longer able to bear weight.\t\n28 hours\tThe antiembolism stockings were removed due to increased pain, and this resulted in sudden and extreme pain and further swelling in the right lower leg and foot. Assessment revealed that the right leg and foot were very swollen and the foot was curving inward and was painful to touch. The postpartum woman was unable to move her toes or lift her foot due to pain, and a review was conducted by the obstetrics and gynecology registrar.\n\nBy this stage, the woman was in extreme pain and reported constant throbbing in the leg. Examination revealed a decreased range of motion in the right foot; the right foot was markedly more swollen than the left; and the anterior right leg and anterior foot were very tender to touch. Pedal pulses were palpable, and perfusion to the toes was noted. The nodule over the anterior midshin remained palpable, and the skin now appeared red. There was no reported calf pain, and she remained afebrile. Cellulitis was diagnosed, and a blood sample collected at this time revealed deranged liver function test results. The woman was then commenced on intravenous antibiotics and enoxaparin sodium (Clexane; Sanofi-Aventis, Macquarie Park, Australia), an anticoagulant, prophylactically because she was now immobile. Subcutaneous morphine was administered with no effect, and the antiembolism stocking was unable to be reapplied to the right leg due to extreme pain. Six hours following this acute stage, the postpartum woman reported feeling more comfortable, and her right leg was less swollen and less tender; however, the limb remained red. An anesthetic review at this time excluded an epidural-related cause for the ongoing right great toe weakness.\n\n\t\nDay 2\tThere was still visible swelling and worsening of pain after mobilizing; therefore, the patient remained on bedrest. Clexane was changed to a therapeutic dose, and analgesia was continued (Endone [oxycodone hydrochloride], Alphapharm Pty Ltd, Millers Park, Australia; Panadol [acetaminophen], GlaxoSmithKline Australia, Ermington, Australia; and Voltaren [diclofenac], GlaxoSmithKline Australia). Venous Doppler ultrasound was performed to exclude deep venous thrombosis, and the findings were unremarkable. The leg was more inflamed and reddened following the Doppler ultrasound, and the postpartum woman was now completely unable to bear weight on the right leg.\t\nDay 3\tSome improvement in pain and redness was noted, but weakness of the right great toe remained. The postpartum woman was still unable to hyperflex the right great toe, and the results of her liver function tests were more deranged. Clexane was reverted to a prophylactic dose, and antibiotics were changed again; the woman remained afebrile. A second anesthetic examination confirmed ongoing weakness of the great toe, and sensation was intact. The differential diagnosis at this stage included possible neurological problems, cellulitis, or gout.\t\nDay 4\tSkin redness had started to improve, but mobility was limited due to pain. Neurological symptoms remained unchanged, and some reduction in plantar adduction was noted. Upon examination by a neurologist, the leg was tender and swollen below the knee. There was severe pain upon examination, and the neurologist was unable to check right inversion due to the pain. Sensation was found to be decreased to the peroneal region. The differential diagnoses queried by the neurologist included right peroneal nerve palsy, pressure effect, compartment syndrome, and cellulitis. The postpartum woman was referred to the infectious diseases team for management of cellulitis and for a vascular opinion regarding possible compartment syndrome. Antibiotics were changed again, and a surgical review deemed that symptoms were not diagnostic of compartment syndrome.\t\nDay 4 (95 hours)\tBy this stage, the postpartum woman reported numbness between the right great toe and the second toe, a new symptom.\t\nDay 5\tAn examination revealed increased redness and loss of sensation over the first web space of the right foot. The postpartum woman continued to complain of increased pain. The diagnosis at the time was worsening cellulitis and worsening of neurological symptoms secondary to the worsening cellulitis. Antibiotics were changed again, and the woman was continued on Clexane.\t\nDay 7\tSymptoms of cellulitis remained unchanged. Antibiotics were changed again in consultation with the infectious diseases team.\t\nDay 8\tNeurological symptoms remained unresolved, so a neurologist was consulted again.\t\nDay 10\tMagnetic resonance imaging was performed, and the findings were consistent with acute compartment syndrome.\t\nDay 11\tOrthopedic consultation was obtained. There were clinical features of a compartment syndrome affecting the anterior compartment of the right lower leg. An examination showed foot drop and paresthesia along the deep and superficial peroneal nerves. Pain had moderated by that time, but there was still evident swelling of the anterior compartment with associated tenderness and some dusky erythema. There was no active contraction of the great toe extensor, and there was reduced extensor function of the lesser toes and the tibialis anterior. The anterior compartment pressure was measured as 19 mmHg, and pressure in the peroneal compartment was 23 mmHg. Following consultation with other orthopedic and vascular surgeons at a tertiary referral hospital, the compartment syndrome was managed nonsurgically, given that 11 days had elapsed since the onset of symptoms and a fasciotomy at this stage would not prevent any further damage.\t\nDays 11–15\tThe woman was commenced on physiotherapy and fitted with a foot drop splint and a rollator frame to assist with mobilization. Intravenous antibiotics were continued until discharge from the postnatal ward.\t\nDay 15\tThe woman was discharged to home on a course of oral antibiotics.\t\n\n\nOrthopedic report\nOver the following months, the patient experienced improvement in tibialis anterior function. The main residual deficit was contracture of the extensor hallucis longus and the extensor digitorum longus to the lateral two toes. The patient had altered sensation over the dorsum of the first web space. Nerve conduction studies were conducted six weeks following the ACS and indicated a lesion of the superficial and deep branches of the right peroneal nerve, more markedly affecting the deep branch.\n\nFifteen months following the original diagnosis, the woman underwent tendon surgery. Percutaneous tenotomies were performed of the extensor tendons to the fourth and fifth toes, and a Z-lengthening of the extensor hallucis longus tendon was performed to correct the dorsiflexion contracture that had developed following the ACS. The woman recovered well from this procedure.\n\nAt long-term follow-up (5 years), the woman walks normally. She has no active dorsiflexion of the great toe. She can walk in bare feet but must be careful not to trip over the hallux, so she prefers closed-in footwear. Pain in the affected leg has diminished but not completely resolved. Dorsiflexion of the ankle is slightly reduced in power and in range, and there is slight persistent anterolateral wasting of the leg. There is slight weakness of extension of the lesser toes, and a contracture is evident when the ankle is plantarflexed.\n\nPhysiotherapy report\nFive years following a delayed diagnosis of ACS, there are some ongoing deficits in the right leg secondary to the ACS, including reduced ankle dorsiflexion power and a complete loss of function of the extensor hallucis longus following from release of the distal tendon due to contracture development. These ongoing deficits, along with compensatory movement patterns, have contributed to the development of further issues higher up in the kinetic chain. Findings of an assessment at this stage included reduced lumbar spine active range of motion (especially extension and left lateral flexion) with sharp right-sided lumbopelvic pain. There are signs of left sacral torsion and reduced right lower limb proprioception and lumbopelvic stability (poor single-leg balance and ability to perform single-leg bridge). Ongoing physiotherapy treatment now focuses on addressing these issues in the pelvis and spine.\n\nDiscussion\nACS of the limb is a relatively rare complication in obstetrics and has an estimated prevalence of 2 in 10,000 births [1]. Several predisposing risk factors have been described in the published case reports, such as PPH [13, 16, 18, 19], epidural analgesia [16, 17], hypotension [9, 12, 17], vasoconstrictive agents [8, 13, 16–18], lithotomy position [8], and postpartum eclampsia [11, 15]; however, a combination of factors may also be responsible [8, 9, 13, 16, 17].\n\nPPH has been identified as a contributing factor for the development of ACS of the limb in four obstetric case reports [13, 16, 18, 19] and was also described in a further three case reports [9, 10, 12]; however, PPH did not occur in one case [17]. In our patient’s case, the estimated blood loss was recorded as 450 ml. Although this does not meet the criteria for PPH (500 ml), it is important to note that our patient’s hemoglobin levels decreased from 128 g/L at the time of augmentation of labor to 88 g/L on day one following the birth. The woman in this case study was of small stature, and it is possible that her estimated blood loss was sufficient to cause hemodynamic compromise [20], although it is also possible that her estimated blood loss at the time of the cesarean section may have been underestimated [17].\n\nAdministration of vasoactive drugs is a known predisposing factor for ACS and has been reported in most of the published obstetric cases [8, 9, 11, 13, 16–18]. In addition to venous stasis of lower extremities, a physiologic event in all pregnancies, vasoactive agents may contribute to the deterioration of circulation [8]. In the present case study, Syntocinon, a uterotonic, was used for augmentation of labor and also immediately after birth to prevent PPH.\n\nLong-lasting hypotension and intraoperative hypotension induced by anesthetic agents have been reported as factors contributing to ACS in an obstetric context [8, 9]. Hypotension is described in three of the reported cases [9, 12, 18], and another author has suggested the possibility of an unnoticed hypotensive episode during a cesarean delivery [17]. The woman in the present case report was continuously monitored and developed intraoperative hypotension shortly following epidural insertion, and metaraminol, which also causes vasoconstriction, was administered in the operating theater.\n\nThe lithotomy position is well established in the literature as a predisposing factor for ACS of the limb [21–24]. This position increases the ICP and elevation above heart level, in addition to the head-down tilt, reduces limb perfusion, leading to ischemia [9]. Compartment syndrome usually develops from the reperfusion injury that occurs after the lithotomy position has been ceased [8, 9, 13]. Nonobstetric literature suggests that the incidence of ACS may be as high as 1 in 3500 surgical patients who are placed in the lithotomy position [25]. Obstetric cases that describe the use of lithotomy position are rarely reported in the literature, however, and only two of the reported cases identified the use of the lithotomy position [8, 9]. It is important to note that the woman in the present case study was not placed in the lithotomy position at any time during labor, supporting the possibility that a combination of factors in an obstetric context, rather than individual factors alone, may have contributed to the development of postpartum ACS of the limb.\n\nThe use of pneumatic calf compressors has been implicated in the development of ACS in the gynecologic and urologic literature [21, 26]; however, only one obstetric case identifies its use [13]. In the present case study, pneumatic calf compressors, as well as antiembolism stockings, were used for DVT prophylaxis following the cesarean section. Ill-fitting antiembolism stockings have been identified in the literature as a cause of lateral leg compartment syndrome [27], but this has yet to be described in other obstetric case reports.\n\nAnticoagulation treatment following surgery, such as for DVT prophylaxis, may also contribute to the development of ACS [6, 23]. The use of enoxaparin sodium (Clexane; Sanofi-Aventis, Macquarie Park, Australia) has been described in the nonobstetric literature to spontaneously cause serious bleeding associated with ACS [28]. Only one other obstetric case report described the use of heparin [10]. The woman in the present case report was commenced on Clexane after the onset of acute pain, and it is possible that this may have exacerbated the already-developing ACS.\n\nAlthough not previously identified as a predisposing factor for ACS in obstetrics, it is possible that the application of heat to a limb may contribute to or exacerbate a developing ACS [8]. In the present case study, a heat pack was applied to the right leg after the initial examination when muscle-related pain was considered. Authors of the only other obstetric case report describing the use of a heat pack suggested that the superficially applied heat may have changed the circulation of the extremity, further diminishing intracompartmental perfusion [8].\n\nRhabdomyolysis, a serious condition caused by muscle injury, may occur if the diagnosis of ACS is not made in time for urgent fasciotomy. The presence of high CK levels in the blood may indicate severe muscle damage or ischemia and may cause acute renal failure [3, 5, 9]. In the absence of clinical signs, raised CK levels could indicate an unsuspected ACS [6]; however, because rhabdomyolysis can lead to acute renal failure, and can be life-threatening [9], elevated CK levels should not be relied on for an early diagnosis of ACS [2–4, 6, 7], and creatinine clearance and plasma creatinine are late-stage markers of kidney damage that has already occurred [29]. In the present case study, the CK level on postpartum day 10 was 1150 U/L (normal range 30–190 U/L). CK readings commenced on day 10 only, and therefore it is impossible to determine the peak levels.\n\nConclusion\nIn an obstetric setting, the following clinical features should give rise to suspicion of the diagnosis of ACS: severe pain in the affected compartment; persistent sensory loss in the foot after the epidural has worn off; persistent weakness of the foot or ankle, such as foot drop or toe drop; and swelling, tenderness, or erythema of the affected leg compartment. Should ACS be suspected, orthopedic or surgical consultation should be requested urgently. Compartment pressures can be measured if the clinical diagnosis is in doubt, and an early fasciotomy can prevent permanent nerve and muscle damage. This case highlights the need for maternity care providers to be aware of acute compartment syndrome as a potential obstetric complication following childbirth. Midwives and obstetricians should have knowledge of the predisposing factors for ACS, and its signs and symptoms, so that a delayed diagnosis and its subsequent consequences can be prevented.\n\nAbbreviations\nACSAcute compartment syndrome\n\nCKCreatine kinase\n\nDVTDeep venous thrombosis\n\nICPIntracompartmental pressure\n\nPPHPostpartum hemorrhage\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthors’ contributions\nSCo planned and prepared the manuscript. SB reviewed and edited the manuscript. SCa prepared the clinical physiotherapy details for the manuscript. RB prepared the clinical orthopedic case details for the manuscript. DJ reviewed the manuscript to ensure clinical accuracy of the reported events in the Case presentation and Discussion sections. All authors read and approved the final manuscript.\n\nFunding\nNo funding was received by the authors.\n\nEthics approval and consent to participate\nEthics approval was not required for this case report.\n\nConsent for publication\n Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Bhardwaj A Nagandla K Musculoskeletal symptoms and orthopaedic complications in pregnancy: pathophysiology, diagnostic approaches and modern management Postgrad Med J 2014 90 1066 450 45l 10.1136/postgradmedj-2013-132377 24904047 \n2. Von Keudell AG Diagnosis and treatment of acute extremity compartment syndrome Lancet 2015 386 10000 1299 1310 10.1016/S0140-6736(15)00277-9 26460664 \n3. Ali P Santy-Tomlinson J Watson R Assessment and diagnosis of acute limb compartment syndrome: a literature review Int J Orthop Trauma Nurs 2014 18 4 180 190 10.1016/j.ijotn.2014.01.002 \n4. Duckworth AD McQueen MM The diagnosis of acute compartment syndrome: a critical analysis review JBJS Rev. 2017 5 12 e1 10.2106/JBJS.RVW.17.00016 \n5. Pechar J Lyons MM Acute compartment syndrome of the lower leg: a review J Nurse Pract 2016 12 4 265 270 10.1016/j.nurpra.2015.10.013 27499719 \n6. Gourgiotis S Acute limb compartment syndrome: a review J Surg Educ 2007 64 3 178 186 10.1016/j.jsurg.2007.03.006 17574182 \n7. Schmidt AH Acute compartment syndrome Orthop Clin North Am 2016 47 3 517 525 10.1016/j.ocl.2016.02.001 27241376 \n8. Bayar A Lower limb compartment syndrome after an uncomplicated labor Orthopedics 2007 30 11 972 973 10.3928/01477447-20071101-12 18019995 \n9. Jyothi NK Cox C Compartment syndrome following postpartum haemorrhage BJOG 2000 107 3 430 432 10.1111/j.1471-0528.2000.tb13243.x 10740344 \n10. Maassen M Complications and failure of uterine artery embolisation for intractable postpartum haemorrhage BJOG 2009 116 1 55 61 10.1111/j.1471-0528.2008.01939.x 19016685 \n11. Manson IW Post-partum eclampsia complicated by the anterior tibial syndrome Br Med J 1964 2 5417 1117 1118 10.1136/bmj.2.5417.1117 14198730 \n12. Maor P Iatrogenic Volkmann’s ischemia—a result of pressure-transfusion Int Surg 1972 57 5 415 416 5028634 \n13. Byers BD Silva PH Kost ER Delivery complicated by postpartum hemorrhage and lower extremity compartment syndrome Obstet Gynecol 2007 109 2 Pt 2 507 509 10.1097/01.AOG.0000222360.81498.67 17267875 \n14. Findlay S Liu D Rijhsinghani A Acute compartment syndrome: clinical course and laboratory findings in pregnant patients with McArdle’s disease Pain Med 2014 15 3 481 482 10.1111/pme.12279 24224978 \n15. Laska L Emergency surgery leads to compartment syndrome OBG Manag 2003 15 1 67 71 \n16. Lecky B Acute bilateral anterior tibial compartment syndrome after Caesarian section in a diabetic J Neurol Neurosurg Psychiatry 1980 43 1 88 90 10.1136/jnnp.43.1.88 7354364 \n17. Radosa J Radosa M Sütterlin M Acute lower limb compartment syndrome after Cesarean section: a case report J Med Case Rep 2011 5 161 10.1186/1752-1947-5-161 21513525 \n18. Rice T Bowser C Extrauterine abdominal pregnancy: report of a case CRNA 1999 10 4 181 183 10723297 \n19. Smyth S Compartment syndrome – an unusual complication of massive obstetric haemorrhage [abstract] BJOG 2013 120 Suppl 1 136 137 \n20. New South Wales Health Maternity – prevention, early recognition & management of postpartum haemorrhage (PPH) policy directive 2010 Sydney New South Wales Health \n21. Boesgaard-Kjer DH Boesgaard-Kjer D Kjer JJ Well-leg compartment syndrome after gynecological laparoscopic surgery Acta Obstet Gynecol Scand 2013 92 5 598 600 10.1111/aogs.12102 23488737 \n22. Frink M Compartment syndrome of the lower leg and foot Clin Orthop Relat Res 2010 468 4 940 950 10.1007/s11999-009-0891-x 19472025 \n23. Stracciolini A Hammerberg EM Moreira M Bachur R Acute compartment syndrome of the extremities UpToDate 2016 \n24. Tzioupis C Cox G Giannoudis PV Acute compartment syndrome of the lower extremity: an update Orthop Trauma 2009 23 6 433 440 10.1016/j.mporth.2009.09.003 \n25. Heppenstall B Tan V Well-leg compartment syndrome Lancet 1999 354 9183 970 10.1016/S0140-6736(98)00409-7 10501356 \n26. Raza A Byrne D Townell N Lower limb (well leg) compartment syndrome after urological pelvic surgery J Urol 2004 171 1 5 11 10.1097/01.ju.0000098654.13746.c4 14665832 \n27. Hinderland MD Lateral leg compartment syndrome caused by ill-fitting compression stocking placed for deep vein thrombosis prophylaxis during surgery: a case report J Foot Ankle Surg 2011 50 5 616 619 10.1053/j.jfas.2011.04.025 21616687 \n28. Limberg RM Dougherty C Mallon WK Enoxaparin-induced bleeding resulting in compartment syndrome of the thigh: a case report J Emerg Med 2011 41 1 e1 e4 10.1016/j.jemermed.2008.04.016 18993022 \n29. Lankadeva YR Intrarenal and urinary oxygenation during norepinephrine resuscitation in ovine septic acute kidney injury Kidney Int 2016 90 1 100 108 10.1016/j.kint.2016.02.017 27165831\n\n",
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"keywords": "Acute compartment syndrome; Case report; Cesarean; Childbirth; Obstetrics; Postpartum pain",
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"mesh_terms": "D000328:Adult; D000671:Amputation; D002585:Cesarean Section; D003161:Compartment Syndromes; D005260:Female; D006801:Humans; D007866:Leg; D011247:Pregnancy; D012206:Rhabdomyolysis",
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"title": "Acute compartment syndrome of the lower limb following childbirth: a case report.",
"title_normalized": "acute compartment syndrome of the lower limb following childbirth a case report"
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"abstract": "The symptoms and complications of intestinal parasitosis can occur with long-term corticosteroid therapy. We highlight the case of a young man who developed chronic gastrointestinal (GI) symptoms of diarrhea, crampy abdominal pain, and vomiting while on treatment for multisystemic sarcoidosis with corticosteroids. His symptoms were initially thought to be related to the gastrointestinal manifestations of sarcoidosis, but further evaluation revealed a combined case of intestinal strongyloidiasis and giardiasis as well as previously undiagnosed human T-cell lymphotropic virus (HTLV -1) infection. This distinctive case of dual intestinal parasitosis highlights the need for clinicians to maintain a high level of awareness to screen for intestinal parasites, particularly Strongyloides when prescribing corticosteroids in the long term given the potential risk of hyperinfection in the setting of immunosuppression..",
"affiliations": "Respiratory Department, Sandwell and West Birmingham Hospitals, NHS Trust, Birmingham, United Kingdom.;Respiratory Department, Sandwell and West Birmingham Hospitals, NHS Trust, Birmingham, United Kingdom.;Respiratory Department, Sandwell and West Birmingham Hospitals, NHS Trust, Birmingham, United Kingdom.;Gastroenterology Department, Sandwell and West Birmingham Hospitals, NHS Trust, Birmingham, United Kingdom.;Respiratory Department, Sandwell and West Birmingham Hospitals, NHS Trust, Birmingham, United Kingdom.",
"authors": "Ojuawo|Olutobi|O|;Htwe|Thidar|T|;Farah|Sakaria|S|;King|Dominic|D|;Ahmed|Imtiaz|I|",
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"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00290-0\n10.1016/j.idcr.2021.e01334\ne01334\nCase Report\nDual intestinal parasitosis unmasked by treatment for gastrointestinal sarcoidosis\nOjuawo Olutobi o.ojuawo@nhs.net\na⁎\nHtwe Thidar a\nFarah Sakaria a\nKing Dominic b\nAhmed Imtiaz a\na Respiratory Department, Sandwell and West Birmingham Hospitals, NHS Trust, Birmingham, United Kingdom\nb Gastroenterology Department, Sandwell and West Birmingham Hospitals, NHS Trust, Birmingham, United Kingdom\n⁎ Corresponding author. o.ojuawo@nhs.net\n08 11 2021\n2021\n08 11 2021\n26 e013341 11 2021\n6 11 2021\n7 11 2021\n© 2021 The Authors. Published by Elsevier Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nHighlights\n\n• Intestinal parasitosis can complicate treatment for gastrointestinal sarcoidosis.\n\n• Strongyloidiasis should be considered in cases of diarrhea and eosinophilia.\n\n• Multiple stool samples are required to improve detection of intestinal parasites.\n\n• HTLV- 1 co-infection should be considered in difficult to treat strongyloidiasis.\n\nThe symptoms and complications of intestinal parasitosis can occur with long-term corticosteroid therapy. We highlight the case of a young man who developed chronic gastrointestinal (GI) symptoms of diarrhea, crampy abdominal pain, and vomiting while on treatment for multisystemic sarcoidosis with corticosteroids. His symptoms were initially thought to be related to the gastrointestinal manifestations of sarcoidosis, but further evaluation revealed a combined case of intestinal strongyloidiasis and giardiasis as well as previously undiagnosed human T-cell lymphotropic virus (HTLV −1) infection. This distinctive case of dual intestinal parasitosis highlights the need for clinicians to maintain a high level of awareness to screen for intestinal parasites, particularly Strongyloides when prescribing corticosteroids in the long term given the potential risk of hyperinfection in the setting of immunosuppression..\n\nKeywords\n\nSarcoidosis\nGiardiasis\nStrongyloidiasis\nCorticosteroid therapy\n==== Body\npmcIntroduction\n\nSarcoidosis is a multisystemic granulomatous disease of unknown etiology, characterized by the presence of giant-cell non-necrotizing granulomas [1]. The involvement of the GI tract is uncommon, occurring in only 0.1 – 1.6% of cases [2]. The putative mechanisms of GI tract damage include mucosal infiltration, endoluminal lesions, dysfunction of the myenteric plexus, and extrinsic compression of structures [2]. This culminates in the clinical manifestations of abdominal pain, diarrhea, vomiting, and weight loss [2].\n\nSymptomatic sarcoidosis is treated with glucocorticoids, cytotoxic medications, or biologic agents; all of which carry a risk of systemic infections including parasitic GI tract infections [3]. There have been a few case reports of intestinal parasitosis in the context of corticosteroid therapy for sarcoidosis [4], [5], [6], however, our finding of dual parasitosis is unique particularly given the concomitant finding of asymptomatic human T- cell lymphotropic virus 1 (HTLV–1) co-infection.\n\nCase presentation\n\nA 32 year old Afro-Caribbean man with no prior medical condition presented with progressive exercise intolerance and worsening painful skin nodules in both legs for four weeks. He had no cough, chest pain, wheeze, or fever. He had resided in the United Kingdom for about 20 years without travel to his country of birth. He was a current smoker with a twenty pack-year history.\n\nClinical examination revealed tender nodules on the shins consistent with erythema nodosum and unremarkable systemic examinations. Blood investigations showed a normal complete blood count, erythrocyte sedimentation rate of 118 mm/h; C-reactive protein of 44 mg/L, with normal renal and liver function tests. Human immunodeficiency virus (HIV) screen was negative. High-resolution CT scan of the thorax revealed bilateral lung infiltrates and hilar adenopathy (Fig. 1). Serum adjusted calcium level was normal but angiotensin converting enzyme levels were raised at 154 U/L (12–82 U/L). Lung function tests revealed a restrictive pattern with reduced diffusion capacity: FEV1/FVC – 92% (111% predicted); FVC 3.49 L (73% predicted); FEV1 3.21 L (82% predicted); TLC 5.5 L (72% predicted); TLCO 6.62 L (56% predicted). He was treated for pulmonary sarcoidosis with oral prednisolone 30 mg daily for 4 weeks followed by a gradually tapering dose whilst monitoring his exercise tolerance and lung function parameters.Fig. 1 High resolution CT scan of the thorax showing lung infiltrates and hilar lymphadenopathy. Left – lung window; Right – mediastinal window.\n\nFig. 1\n\nFour months later, he presented in the emergency department with profuse foul-smelling non- bloody, non-mucoid diarrhea associated with crampy lower abdominal pain and nausea. Stool and blood cultures did not yield any pathogen. He was managed in the high dependency unit where he had inotropic support due to persistent hypotension and treatment for prerenal acute kidney injury.\n\nHe presented again two weeks after discharge with similar abdominal symptoms. Blood investigations were significant for eosinophilia (1280 cells/uL; 13.2% of total white blood cell count) and hypokalemia of 3.3 mmol/L. Stool analysis did not isolate any pathogen, and fecal elastase was normal. However, fecal calprotectin was mildly elevated at 159 ug/mL (<60). CT scan of the abdomen and pelvis showed mild distension of the small and large bowels. Upper and lower GI tract endoscopies were performed due to a clinical suspicion of GI sarcoidosis and were macroscopically normal. However, histologic assessment of gastric and duodenal biopsies revealed non-necrotizing epithelioid granulomas confirming a diagnosis of GI sarcoidosis. His corticosteroid dose was subsequently increased to 40 mg daily.\n\nA repeat stool sample was sent for microbiological analysis due to persistent symptoms. Giardia lamblia (GL) was detected by polymerase chain reaction (PCR) although cysts remained absent on microscopy. Also, rhabditiform larvae and an adult female form of Strongyloides stercoralis (SS) were identified. Stool PCR for Clostridium difficile, Salmonella and Shigella species were negative. Enzyme linked immunosorbent assay was strongly positive for Strongyloides at an optical density of 0.977 (cut-off: 0.702).\n\nFollowing consultations with the regional tropical disease departments, he was given intravenous metronidazole for symptomatic giardiasis at 500 mg three times a day for 5 days and oral ivermectin for strongyloidiasis at 200 ug/kg for 2 days. He had improvement in abdominal pain and the frequency of diarrhea episodes within 48 h of commencement; however, his loose stools persisted. Further stool examinations revealed clearance of GL; with persistent presence of rhabditiform larvae of SS. This prompted an extended course of ivermectin for a further 14 days with daily assessment of stool samples given the likelihood of a SS hyperinfection syndrome. Considering his persistent strongyloidiasis, a blood sample was also sent for HTLV-1 serology which returned positive.\n\nHis symptoms resolved afterwards with consistent evidence of negative stool examinations. He remains clinically stable on outpatient clinic visits on a stable prednisolone dose of 5 mg daily whilst being monitored for asymptomatic HTLV-1 infection.\n\nDiscussion\n\nOur case report is unique in highlighting dual intestinal parasitosis (giardiasis and strongyloidiasis) in an individual on corticosteroid treatment for sarcoidosis and previously unidentified HTLV-1 infection. Immunosuppressed patients are thought to be at a higher risk of symptomatic parasitic infections and although the exact mechanism for this susceptibility is not entirely clear, diminished adaptive and innate immune responses in GL impair the host’s ability to control infection [7]. Furthermore, the dysregulated immune response with sarcoidosis itself could potentially increase the risk of opportunistic parasitic infections as the inhibition of IL-2 production reduce the myeloid cell’s ability to stimulate T-cells which are fundamental for defense against the parasite [8].\n\nGL is a flagellated microscopic protozoon that is ubiquitous in many regions of the world especially in developing countries [9]. The transmission mode is through consumption of contaminated water and food with an incubation period of 5–25 days [9]. Symptomatic patients with GL commonly have abdominal cramps, bloating, and explosive non-bloody diarrhea [10]. In our subject’s case, GL was detected by PCR with negative stool microscopy. This is likely due to microscopy having about 60% sensitivity for detecting oocyte and trophozoites in stool samples [11]. Concomitant PCR testing is beneficial as it improves detection rates in patients who have low parasitic cyst count [11] which may have been the case in our patient. Once giardiasis is suspected, it is advocated that a minimum of six stool samples be sent for microbiological analysis to objectively exclude GL, with the first three samples taken two to three days apart [10]. If results are negative, a further three samples are taken weekly to account for the varying shedding rates of the parasite [10].\n\nThe other intestinal parasite detected was Strongyloides stercoralis which is a soil-transmitted helminth that commonly enters the human host transcutaneously [12]. In our subject, the potential for autoinfection was increased as the rhabditiform larvae can transform into invasive filariform larvae [12]. This process can culminate in chronic infection with SS which manifests with diarrhea, abdominal cramps and itching [12]. Unchecked autoinfection in the context of altered immune status can lead to hyper-infection due to accelerated larval migration or disseminated infection which is mostly associated with co-infection with HTLV-1, or immunosuppression secondary to corticosteroid use or HIV, [12], the former two of which were present in our subject.\n\nAnother interesting observation from our report is the presence of HTLV-1 infection in our subject who had been residing in a non-endemic area (United Kingdom) for two decades. It is important to note that HLTV-1 infection is increasing in non-endemic areas due to population movement and hence co-infections with helminths such as SS are also being observed [13].\n\nThe patient’s background of sarcoidosis, concurrent use of corticosteroid as well as the HLTV-1 co-infection increased the risk of hyper-infection in our patient. HLTV-1 infection and prolonged corticosteroid use interrupt granulocyte function which can promote severe strongyloidiasis [14]. HTLV-1 infection can also lead to reduced serum IL-4, IL-5, IgE levels, causing hampered immune response to SS [14].\n\nConclusion\n\nIntestinal parasitosis like strongyloidiasis should always be considered in cases of subacute to chronic diarrhea and eosinophilia. In addition, HTLV- 1 co-infection should be investigated in patients with difficult to treat or disseminated strongyloidiasis infection.\n\nClinicians need to maintain a high level of awareness for intestinal parasites when prescribing long-term corticosteroid therapy; particularly for strongyloidiasis which can become fatal in the setting of hyper infection due to immunosuppression and HTLV-1 co-infection.\n\nFunding source\n\nThere was no funding received from any individual or organization.\n\nCRediT authorship contribution statement\n\nOO: Conceptualization, Writing - original draft, reviewing and editing; TH: Conceptualization, Writing - original draft, reviewing and editing; SF: Writing original draft, reviewing, and editing; DK: Writing - reviewing and editing, consent from patient; IA: Writing – reviewing and editing, supervision.\n\nEthical approval\n\nWritten informed consent was obtained from the patient for publication of this case report as well as the accompanying images.\n\nConsent\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nConflict of interest\n\nThe authors do not have any conflict of interests.\n==== Refs\nReferences\n\n1 Valeyre D. Prasse A. Nunes H. Uzunhan Y. Brillet P.Y. Müller-Quernheim J. Sarcoidosis Lancet 383 9923 2014 1155 1167 10.1016/S0140-6736(13)60680-7 24090799\n2 Brito-Zerón P. Bari K. Baughman R.P. Ramos-Casals M. Sarcoidosis involving the gastrointestinal tract: Diagnostic and therapeutic management Am J Gastroenterol 114 8 2019 1238 1247 10.14309/ajg.0000000000000171 30865014\n3 Duréault A. Chapelon C. Biard L. Domont F. Savey L. Bodaghi B. Severe infections in sarcoidosis: incidence, predictors, and long-term outcome in a cohort of 585 patients Medicine 96 49 2017 e8846 10.1097/MD.0000000000008846\n4 Almasidou D. Maniatis M. Vassiou K. Damani E. Vakalis N. Fesoulidis I. Strongyloides hyperinfection in a patient with sarcoidosis Respirology 8 1 2003 105 106 10.1046/j.1440-1843.2003.00429.x 12856751\n5 Gao X, Joshi V, Thomas S, Grabscheid E. Strongyloidiasis with coexisting sarcoidosis: Steroids can be tricky. Abstract published at Hospital Medicine March 6–9, 2016, San Diego, California. Abstract 511. J Hosp Med 2016; 11: Suppl 1.\n6 Kumar A. Paulose R. Sadasivan S. Bajad C. Ramachandran A. Nair P. Sarcoidosis, steroids and strongyloides - what’s the catch? Clin Microbiol Infect 17 2020 708 709 10.1016/j.cmi.2020.09.012 S1198-743X (20)30561-9\n7 Espelage W. der Heiden M. Stark K. Alpers K. Characteristics, and risk factors for symptomatic Giardia lamblia infections in Germany BMC Public Health 28 2010 41 10.1186/1471-2458-10-41 10:41\n8 Lee N.S. Barber L. Kanchwala A. Childs C.J. Kataria Y.P. Judson M.A. Low levels of NF-κB/p65 mark anergic CD4+ T cells and correlate with disease severity in sarcoidosis Clin Vaccin Immunol 18 2 2011 223 234 10.1128/CVI.00469-10\n9 Horton B. Bridle H. Alexander C.L. Katzer F. Giardia duodenalis in the UK: current knowledge of risk factors and public health implications Parasitology 146 4 2019 413 424 10.1017/S0031182018001683 30318029\n10 Minetti C. Chalmers R.M. Beeching N.J. Probert C. Lamden K. Giardiasis Br Med J 27 355 2016 i5369 10.1136/bmj.i5369\n11 Sari Y. Suryawati B. Yudhani R.D. Artama W.T. Comparison of microscopic and PCR for detection of Giardia spp. in the human faecal sample at Bedog Watershed, Sleman, DIY Kne Life Sci 4 2019 103 10.18502/kls.v4i12.4162 (Accessed 19/10/2021)\n12 Nutman T.B. Human infection with Strongyloides stercoralis and other related Strongyloides species Parasitology 144 3 2017 263 273 10.1017/S0031182016000834 27181117\n13 Dykie A. Wijesinghe T. Rabson A.B. Madugula K. Farinas C. Wilson S. Human T-cell Leukemia virus type 1 and Strongyloides stercoralis: partners in pathogenesis Pathogens 9 11 2020 904 10.3390/pathogens9110904 29\n14 Montes M. Sawhney C. Barros N. Strongyloides stercoralis: there but not seen Curr Opin Infect Dis 23 5 2010 500 504 10.1097/QCO.0b013e32833df718 20733481\n\n",
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"title": "Dual intestinal parasitosis unmasked by treatment for gastrointestinal sarcoidosis.",
"title_normalized": "dual intestinal parasitosis unmasked by treatment for gastrointestinal sarcoidosis"
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"abstract": "Idiopathic intracranial hypertension (IIH) is a syndrome characterized by increased intracranial pressure (ICP), the absence of structural lesions on neuroimaging, and normal cerebrospinal fluid composition. Cerebral venous sinus thrombosis (CVST) is a common cause of increased ICP and can be differentiated from IIH with magnetic resonance venography. We describe a young woman with typical IIH who underwent lumbar puncture and was treated with a short course of high-dose corticosteroids followed by acetazolamide. She subsequently developed CVST, subarachnoid hemorrhage, and stroke. Risk factors that may have resulted in CVST are discussed.",
"affiliations": "Jones Eye Institute (JSH, JDP, PHP, JGC), University of Arkansas for Medical Sciences (UAMS), Little Rock, Arkansas Departments of Ophthalmology (PHP) and Radiology (RHR), Arkansas Children's Hospital, Little Rock, Arkansas.",
"authors": "Hardin|Joshua S|JS|;Ramakrishnaiah|Raghu H|RH|;Pemberton|John D|JD|;Phillips|Paul H|PH|;Chacko|Joseph G|JG|",
"chemical_list": "D005938:Glucocorticoids; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1097/WNO.0000000000000540",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1070-8022",
"issue": "38(1)",
"journal": "Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society",
"keywords": null,
"medline_ta": "J Neuroophthalmol",
"mesh_terms": "D000328:Adult; D003937:Diagnosis, Differential; D018450:Disease Progression; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008279:Magnetic Resonance Imaging; D008775:Methylprednisolone; D010690:Phlebography; D011559:Pseudotumor Cerebri; D012851:Sinus Thrombosis, Intracranial; D013129:Spinal Puncture; D020521:Stroke; D013345:Subarachnoid Hemorrhage; D014792:Visual Acuity",
"nlm_unique_id": "9431308",
"other_id": null,
"pages": "60-64",
"pmc": null,
"pmid": "28742639",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Idiopathic Intracranial Hypertension Progressing to Venous Sinus Thrombosis, Subarachnoid Hemorrhage, and Stroke.",
"title_normalized": "idiopathic intracranial hypertension progressing to venous sinus thrombosis subarachnoid hemorrhage and stroke"
} | [
{
"companynumb": "US-AVION PHARMACEUTICALS, LLC-2076138",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETHINYL ESTRADIOL\\LEVONORGESTREL"
},
... |
{
"abstract": "Anabolic-androgenic steroids (AASs) are frequently misused. To determine causes of death, characteristics, toxicology, and pathology of AAS positive cases, all cases (n = 24) presenting to the New South Wales Department of Forensic Medicine (1995-2012) were retrieved. All were male, and the mean age was 31.7 years. Deaths were mainly due to accidental drug toxicity (62.5%), then suicide (16.7%) and homicide (12.5%). Abnormal testosterone/epitestosterone ratios were reported in 62.5%, followed by metabolites of nandrolone (58.3%), stanozolol (33.3%), and methandienone (20.8%). In 23 of 24 cases, substances other than steroids were detected, most commonly psychostimulants (66.7%). In nearly half, testicular atrophy was noted, as was testicular fibrosis and arrested spermatogenesis. Left ventricular hypertrophy was noted in 30.4%, and moderate to severe narrowing of the coronary arteries in 26.1%. To summarize, the typical case was a male polydrug user aged in their thirties, with death due to drug toxicity. Extensive cardiovascular disease was particularly notable.",
"affiliations": "National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, 2052, Australia.",
"authors": "Darke|Shane|S|;Torok|Michelle|M|;Duflou|Johan|J|",
"chemical_list": "D045930:Anabolic Agents; D000728:Androgens; D013739:Testosterone; D004845:Epitestosterone; D013197:Stanozolol; D009277:Nandrolone; D008696:Methandrostenolone",
"country": "United States",
"delete": false,
"doi": "10.1111/1556-4029.12424",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1198",
"issue": "59(4)",
"journal": "Journal of forensic sciences",
"keywords": "cardiovascular disease; demographics; forensic science; psychostimulants; steroids; toxicology",
"medline_ta": "J Forensic Sci",
"mesh_terms": "D000328:Adult; D045930:Anabolic Agents; D000728:Androgens; D001284:Atrophy; D023921:Coronary Stenosis; D004845:Epitestosterone; D006708:Homicide; D006801:Humans; D017379:Hypertrophy, Left Ventricular; D008297:Male; D008696:Methandrostenolone; D008875:Middle Aged; D009277:Nandrolone; D009517:New South Wales; D013197:Stanozolol; D019966:Substance-Related Disorders; D013405:Suicide; D013737:Testis; D013739:Testosterone; D055815:Young Adult",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "1025-8",
"pmc": null,
"pmid": "24611438",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Sudden or unnatural deaths involving anabolic-androgenic steroids.",
"title_normalized": "sudden or unnatural deaths involving anabolic androgenic steroids"
} | [
{
"companynumb": "AU-PFIZER INC-2018359152",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "We report 5 cases of acute liver failure related to herpes simplex (HSV) infection in 1 immunocompetent and 4 immunosuppressed patients. One patient was too ill for liver transplantation indication. Three patients, among the 4 listed, underwent liver transplantation. Three patients died 11 days to 1 year after transplantation and 2 patients died 2 to 3 days after admission. All presented with fever and none with skin lesions. The diagnosis of HSV-related hepatitis was made antemortem in only 2 patients on the basis of positive blood cultures and/or immunohistochemic findings. In the remaining patients, HSV diagnosis was made retrospectively on further histologic and virologic investigations. Primary HSV infection was certain or likely in all cases, including an HSV2 superinfection of an anti-HSV1-positive patient and two HSV superinfections of hepatitis B virus (HBV)-related chronic liver disease. In these latter patients, HSV diagnosis was totally unsuspected, despite fever. HSV superinfection has significantly contributed to liver dysfunction aggravation and death. In conclusion, the diagnosis of HSV hepatitis is difficult to establish in the absence of specific clinical signs. This may suggest the need for early administration of acyclovir in patients with suspected HSV hepatitis, without waiting for virologic confirmation. Diagnosis methods providing fast results (real-time polymerase chain reaction [PCR]) should be implemented.",
"affiliations": "Centre Hépatobiliaire, Assistance Publique-Hôpitaux de Paris, Université Paris Sud, Hôpital Paul Brousse, 12 Avenue Paul Vaillant Couturier, 94800 Villejuif Cedex, France. philippe.ichai@pbr.ap-hop-paris.fr",
"authors": "Ichai|Philippe|P|;Roque Afonso|Anne Marie|AM|;Sebagh|Mylène|M|;Gonzalez|Maria Eugenia|ME|;Codés|Liana|L|;Azoulay|Daniel|D|;Saliba|Faouzi|F|;Karam|Vincent|V|;Dussaix|Elisabeth|E|;Guettier|Catherine|C|;Castaing|Denis|D|;Samuel|Didier|D|",
"chemical_list": "D000914:Antibodies, Viral; D000212:Acyclovir",
"country": "United States",
"delete": false,
"doi": "10.1002/lt.20545",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-6465",
"issue": "11(12)",
"journal": "Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society",
"keywords": null,
"medline_ta": "Liver Transpl",
"mesh_terms": "D000212:Acyclovir; D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral; D001706:Biopsy; D003937:Diagnosis, Differential; D005260:Female; D005500:Follow-Up Studies; D006561:Herpes Simplex; D006801:Humans; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D018139:Simplexvirus; D016896:Treatment Outcome",
"nlm_unique_id": "100909185",
"other_id": null,
"pages": "1550-5",
"pmc": null,
"pmid": "16315311",
"pubdate": "2005-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Herpes simplex virus-associated acute liver failure: a difficult diagnosis with a poor prognosis.",
"title_normalized": "herpes simplex virus associated acute liver failure a difficult diagnosis with a poor prognosis"
} | [
{
"companynumb": "FR-ALKEM LABORATORIES LIMITED-FR-ALKEM-2017-01000",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"dru... |
{
"abstract": "OBJECTIVE\nTo determine the frequency of anaphylaxis in an allergy outpatient department, allowing a better understanding regarding aetiology, clinical manifestations and management, in children and adolescents.\n\n\nMETHODS\nFrom among 3646 patients up to 18 years old observed during one-year period, we included those with history of anaphylaxis reported by allergists.\n\n\nRESULTS\nSixty-four children had history of anaphylaxis (prevalence of 1.8%), with mean age 8.1±5.5 years, 61% being male. Median age of the first anaphylactic episode was 3 years (1 month-17 years). The majority of patients had food-induced anaphylaxis (84%): milk 22, egg 7, peanut 6, tree nuts 6, fresh fruits 6, crustaceans 4, fish 4 and wheat 2. Food-associated exercise-induced anaphylaxis was reported in 2 adolescents. Drug-induced anaphylaxis occurred in 8%: 4 non-steroidal anti-inflammatory drugs and 1 amoxicillin. Three children had cold-induced anaphylaxis, one adolescent had anaphylaxis to latex and one child had anaphylaxis to insect sting. The majority (73%) had no previous diagnosis of the etiologic factor. Symptoms reported were mainly mucocutaneous (94%) and respiratory (84%), followed by gastrointestinal (42%) and cardiovascular (25%). Fifty-one patients were admitted to the emergency department, although only 33% were treated with epinephrine. Recurrence of anaphylaxis occurred in 26 patients (3 or more episodes in 14).\n\n\nCONCLUSIONS\nIn our paediatric population, the main triggering agent of anaphylaxis was IgE-mediated food allergy. Epinephrine is underused, as reported by others. Often, children have several episodes before being assessed by an allergist. We stress the importance of systematic notification and improvement of educational programmes in order to achieve a better preventive and therapeutic management of this life-threatening entity.",
"affiliations": "Immunoallergy Department CUF Descobertas Hospital 1998-018 Lisbon, Portugal. E-mail: angela.gaspar@sapo.pt.;Immunoallergy Department, Centro Hospitalar de São João, Porto, Portugal.;Immunoallergy Department, CUF Descobertas Hospital, Lisbon, Portugal.;Immunoallergy Department, CUF Descobertas Hospital, Lisbon, Portugal.;Immunoallergy Department, CUF Descobertas Hospital, Lisbon, Portugal.;Immunoallergy Department, CUF Descobertas Hospital, Lisbon, Portugal.;Immunoallergy Department, CUF Descobertas Hospital, Lisbon, Portugal.;Immunoallergy Department, CUF Descobertas Hospital, Lisbon, Portugal. CEDOC, NOVA Medical School, Lisbon, Portugal.;Immunoallergy Department, CUF Descobertas Hospital, Lisbon, Portugal. CINTESIS, Center for Research in Health Technologies and Information Systems, Porto, Portugal.",
"authors": "Gaspar|Â|Â|;Santos|N|N|;Piedade|S|S|;Santa-Marta|C|C|;Pires|G|G|;Sampaio|G|G|;Arêde|C|C|;Borrego|L M|LM|;Morais-Almeida|M|M|",
"chemical_list": "D018926:Anti-Allergic Agents; D004837:Epinephrine",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1764-1489",
"issue": "47(6)",
"journal": "European annals of allergy and clinical immunology",
"keywords": "Anaphylaxis; children; epidemiology; epinephrine; management; notification",
"medline_ta": "Eur Ann Allergy Clin Immunol",
"mesh_terms": "D000293:Adolescent; D000486:Allergy and Immunology; D000707:Anaphylaxis; D018926:Anti-Allergic Agents; D002648:Child; D002675:Child, Preschool; D004342:Drug Hypersensitivity; D004837:Epinephrine; D005260:Female; D005512:Food Hypersensitivity; D019538:Health Care Surveys; D006748:Hospital Departments; D006801:Humans; D008297:Male; D010372:Pediatrics; D011174:Portugal; D010818:Practice Patterns, Physicians'; D011237:Predictive Value of Tests; D015995:Prevalence; D012008:Recurrence; D012017:Referral and Consultation; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101466614",
"other_id": null,
"pages": "197-205",
"pmc": null,
"pmid": "26549337",
"pubdate": "2015-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "One-year survey of paediatric anaphylaxis in an allergy department.",
"title_normalized": "one year survey of paediatric anaphylaxis in an allergy department"
} | [
{
"companynumb": "PHHY2015PT160554",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
"d... |
{
"abstract": "Neurological melioidosis, an extremely rare condition, is caused by the gram-negative bacterium Burkholderia pseudomallei. If treatment is suboptimal or delayed, this infection can produce diverse clinical symptoms and result in death.\n\n\n\nA healthy 65-year-old female who had been treated with antipsychotic medication for neurotic depression for over 2 years presented with acute-onset fever, headache, lead-pipe rigidity of all limbs, and delirium.\n\n\n\nMelioidosis meningitis was diagnosed by performing blood examinations and cerebrospinal fluid analysis and cultures.\n\n\n\nIntravenous ceftazidime (2 g/8 h for 3 weeks) was administered in-hospital and 240 mg trimethoprim/1200 mg sulfamethoxazole and 100 mg minocycline twice daily administered out-hospital.\n\n\n\nThe patient fully recovered after antibiotic therapy without cognitive deficits and associated neurological complications.\n\n\n\nBecause melioidosis is endemic in Southern Taiwan and the use of antipsychotics might mask the symptoms, physicians dealing with patients from endemic areas with a medical history of antipsychotics should always consider the possibility of neurological melioidosis and provide prompt empirical management to suspicious cases.",
"affiliations": "Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, National Defense Medical Center, Taipei, Taiwan (R.O.C.). Department of Neurology, Kaohsiung Armed Forces General Hospital, National Defense Medical Center, Taipei, Taiwan (R.O.C.). Department of Rehabilitation Medicine, Cishan Hospital, Ministry of Health and Welfare, Kaohsiung, Taiwan (R.O.C.).",
"authors": "Chen|Guan-Bo|GB|;Tuan|Sheng-Hui|SH|;Chen|Li-Hsiang|LH|;Lin|Wen-Sou|WS|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014150:Antipsychotic Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D002442:Ceftazidime; D008911:Minocycline",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000011110",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29901631MD-D-18-0136210.1097/MD.0000000000011110111104900Research ArticleClinical Case ReportNeurological melioidosis (Burkholderia pseudomallei) in a chronic psychotic patient treated with antipsychotics A case reportChen Guan-Bo MDaTuan Sheng-Hui MDcChen Li-Hsiang MDaLin Wen-Sou MDb∗NA. a Department of Internal Medicineb Department of Neurology, Kaohsiung Armed Forces General Hospital, National Defense Medical Center, Taipeic Department of Rehabilitation Medicine, Cishan Hospital, Ministry of Health and Welfare, Kaohsiung, Taiwan (R.O.C.).∗ Correspondence: Wen-Sou Lin, No. 2, Zhongzheng 1st Rd., Lingya Dist., Kaohsiung City 802, Taiwan (R.O.C.) (e-mail: paper10674@gmail.com).6 2018 15 6 2018 97 24 e111102 3 2018 23 5 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nNeurological melioidosis, an extremely rare condition, is caused by the gram-negative bacterium Burkholderia pseudomallei. If treatment is suboptimal or delayed, this infection can produce diverse clinical symptoms and result in death.\n\nPatient concerns:\nA healthy 65-year-old female who had been treated with antipsychotic medication for neurotic depression for over 2 years presented with acute-onset fever, headache, lead-pipe rigidity of all limbs, and delirium.\n\nDiagnoses:\nMelioidosis meningitis was diagnosed by performing blood examinations and cerebrospinal fluid analysis and cultures.\n\nInterventions:\nIntravenous ceftazidime (2 g/8 h for 3 weeks) was administered in-hospital and 240 mg trimethoprim/1200 mg sulfamethoxazole and 100 mg minocycline twice daily administered out-hospital.\n\nOutcomes:\nThe patient fully recovered after antibiotic therapy without cognitive deficits and associated neurological complications.\n\nLessons:\nBecause melioidosis is endemic in Southern Taiwan and the use of antipsychotics might mask the symptoms, physicians dealing with patients from endemic areas with a medical history of antipsychotics should always consider the possibility of neurological melioidosis and provide prompt empirical management to suspicious cases.\n\nKeywords\nBurkholderia pseudomalleineuroleptic malignant syndromeneurological melioidosisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nMelioidosis, a clinically infectious disease caused by the gram-negative bacterium Burkholderia pseudomallei, is endemic in Southeast Asia and Northern Australia.[1] Because of the early onset of fulminant sepsis, it is associated with a high mortality rate (20–43%),[1,2] suggesting the crucial need for early diagnosis with appropriate antibiotic therapy. Although commonly presenting as a lung infection or multiple abscesses in internal organs, melioidosis is considered a great mimicker owing to its ability to affect any organ in the body.[3] Herein, we report the case of a 65-year-old homemaker receiving neuroleptic medication whose symptoms resembled those of neuroleptic malignant syndrome (NMS), another life-threatening disease that is characterized by an altered state of consciousness, high fever, generalized rigidity, and dysautonomia following the use of neuroleptics. In addition, we highlight the diagnostic challenge posed by neurological melioidosis in psychotic patients.\n\n2 Case report\nA 65-year-old homemaker from Fengshan, Kaohsiung, Southern Taiwan, had been treated for over 2 years with 50 mg sulpiride and 0.5 mg alprazolam twice daily and 150 mg trazodone nightly for anorexia and depressive disorder. She had never traveled abroad and had no contact with contaminated water or soil in the 3 months before admission. Five days before admission, she developed a poor appetite, general weakness, and confusion. During evaluation in the emergency department, she reported acute-onset fever, headache, delirium, and lead-pipe rigidity of all limbs. Notably, no recent trauma, neck stiffness, diaphoresis, cough or shortness of breath, hearing loss, blurred vision, or fresh rashes were observed.\n\nOn examination, the following results were noted: body temperature, 40.5°C; blood pressure, 138/88 mm Hg; pulse, 143 beats/min; respiratory rate, 20 breaths/min; and blood oxygen saturation, 100% with the patient breathing ambient air. She was confused and disoriented, scored E3V4M5 on the Glasgow Coma Scale, and neither Kernig nor Brudzinski signs were present. Her complete blood count showed leukocytosis, and increased levels of C-reactive protein, serum aspartate transaminase, alanine transaminase, and creatine phosphokinase were noted. The complete blood, serum, and cerebrospinal fluid (CSF) laboratory results are presented in Tables 1 and 2.\n\nTable 1 General laboratory investigations performed on the patient.\n\nTable 2 Serum and cerebrospinal fluid analysis performed on the patient.\n\nBecause the laboratory results raised concerns of NMS or a central nervous system (CNS) infection, sulpiride, alprazolam, and trazodone were discontinued due to clinically suspicious NMS. Contrast magnetic resonance imaging of the brain revealed abnormalities consistent with those of diffuse meningitis. A CSF sample demonstrated pleocytosis with neutrophil predominance, a high protein level, and a low glucose level (Table 2). The CSF culture yielded B pseudomallei. Accordingly, intravenous ceftazidime (2 g/8 h for 3 weeks) was administered, which resolved the symptoms. In-hospital treatment was followed by co-trimoxazole and minocycline outpatient treatment.\n\n3 Discussion\nSeveral risk factors have been established as associated with melioidosis, including diabetes, chronic kidney disease, malignancy, and alcohol consumption.[4] Occasionally, as in our patient who denied any prior systemic diseases, the risk factors may be absent.[3] Although melioidosis can affect any organ in the body, the 2 most common clinical manifestations are pneumonia and bacteremia.[5] Here, we reported the case of a patient with neurological melioidosis, which is relatively rare in the literature. According to the Darwin study, the incidence of CNS involvement in melioidosis is 3%.[3] Previous studies have reported that approximately 1.5% to 2% of the patients with melioidosis in Southeast Asia exhibit neurological involvement.[6,7] In another study in Taiwan, male predominance was noted (male:female = 4:1), and CNS involvement was identified in 1.7% of melioidosis cases.[1]\n\nOur patient presented with the symptoms of an altered level of consciousness, high fever, muscle rigidity, and dysautonomia, which mimicked the features of NMS. However, these conditions could also present in many other clinical situations, including thyrotoxicosis or CNS infection. Although NMS is most often associated with first-generation antipsychotics such as haloperidol or fluphenazine, cases involving low-potency and second-generation antipsychotic drugs have also been reported.[8,9] Of note, age and sex are not risk factors of NMS. While NMS is mostly diagnosed in young adult males in the majority of studies, it is related to the population distribution of the exposure to neuroleptic agents.[10] Although the possibility of developing NMS 30 days after the initiation of neuroleptic medication is less likely, it was observed in 4% cases by Caroff and Mann.[11] Our patient was medicated with sulpiride, a low-potency antipsychotic drug, for over 2 years. She had not previously presented with any NMS symptoms, and NMS was unlikely based on the time course of her medical history. Moreover, a series of examinations resulted in the diagnosis of acute bacterial meningitis upon the positive culture of B pseudomallei from CSF.\n\nOn the basis of a Dutch study, 95% of patients with meningitis displayed at least 2 of the following 4 symptoms: fever, headache, neck stiffness, and altered mental status.[12] In the Darwin Prospective Melioidosis Study, headache was prominent on admission in the majority of cases. Furthermore, of the patients who developed neurological complications, approximately 50% demonstrated some evidence of neck stiffness.[13] Our patient presented with an altered level of consciousness, high fever, and headache, which are 3 of the 4 characteristic symptoms of bacterial meningitis. However, she also presented with generalized muscle rigidity, a rarity in neurological melioidosis. Muscle rigidity is a characteristic sign of extrapyramidal symptoms (EPS), which are drug-induced disorders caused by a dopamine blockade or depletion in the basal ganglia, frequently resulting from antipsychotic usage.[14] In patients with long-term antipsychotic treatment, EPS might mislead or affect the physicians’ clinical ability to identify neck rigidity as a potential harbinger of meningitis.[15] In addition, to the best of our knowledge, to date, there has only been 1 reported case of EPS following melioidosis in a patient who was not using antipsychotics, with the conclusion that the pathophysiological mechanism appeared to be secondary to the immunological response rather than as the result of direct CNS infiltration.[16] Therefore, meningitis should not be dismissed in patients with fever of an unknown origin and undergoing long-term antipsychotic treatment because they may not present with the cardinal features of bacterial meningitis.\n\nThis case highlights the diagnostic challenge posed by melioidosis in patients treated with antipsychotics because it is a great mimicker of other diseases, manifesting as miscellaneous clinical symptoms and causing a potentially fatal outcome. From 2000 to 2005, the mortality rates regionally varied, with 22%, 33% to 65%, 9.5%, and 14% in Southern Taiwan, the Southeast Asia region, India, and Northern Australia, respectively. Furthermore, 16% to 19% of patients with inappropriate empirical therapy died before the confirmatory diagnosis of melioidosis.[1,2] Melioidosis is endemic to Southern Taiwan, and antipsychotic use might mask its symptoms. Therefore, physicians dealing with patients from an endemic area with a medical history of antipsychotics should always consider the possibility of neurological melioidosis and provide suspicious cases with prompt empirical management.\n\nAcknowledgments\nWe acknowledge the support and help of all medical, nursing, and health worker colleagues who were involved in patient care and follow-up. We also acknowledge the expertise of the microbiology laboratory staff in Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan, in identifying B pseudomallei.\n\nAuthor contributions\nConceptualization: Guan-Bo Chen, Wen-Sou Lin.\n\nSupervision: Li-Hsiang Chen, Wen-Sou Lin.\n\nWriting – original draft: Guan-Bo Chen.\n\nWriting – review & editing: Guan-Bo Chen, Sheng-Hui Tuan, Li-Hsiang Chen, Wen-Sou Lin.\n\nAbbreviations: CNS = central nervous system, CSF = cerebrospinal fluid, EPS = extrapyramidal symptoms, GCS = Glasgow Coma Scale, NMS = neuroleptic malignant syndrome.\n\nFunding/support: This case report did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nA signed patient consent form was received before article submission.\n\nNo conflict of interest exists in the submission of this manuscript. All authors have approved the manuscript for publication.\n==== Refs\nReferences\n[1] Shih HI Chuang YC Cheung BM \nSporadic and outbreak cases of melioidosis in southern Taiwan: clinical features and antimicrobial susceptibility . Infection \n2009 ;37 :9 –15 .18854938 \n[2] Kingsley PV Leader M Nagodawithana NS \nMelioidosis in Malaysia: a review of case reports . PLoS Neglect Trop Dis \n2016 ;10 :e0005182 .\n[3] Currie BJ Ward L Cheng AC \nThe epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study . PLoS Neglect Trop Dis \n2010 ;4 :e900 .\n[4] Vidyalakshmi K Lipika S Vishal S \nEmerging clinico-epidemiological trends in melioidosis: analysis of 95 cases from western coastal India . Int J Infect Dis \n2012 ;16 :e491 –7 .22512851 \n[5] White NJ \nMelioidosis . Lancet (London, England) \n2003 ;361 :1715 –22 .\n[6] Limmathurotsakul D Chaowagul W Wongsrikaew P \nVariable presentation of neurological melioidosis in Northeast Thailand . Am J Trop Med Hygiene \n2007 ;77 :118 –20 .\n[7] Hassan MR Pani SP Peng NP \nIncidence, risk factors and clinical epidemiology of melioidosis: a complex socio-ecological emerging infectious disease in the Alor Setar region of Kedah, Malaysia . BMC Infect Dis \n2010 ;10 :302 .20964837 \n[8] Strawn JR Keck PE JrCaroff SN \nNeuroleptic malignant syndrome . Am J Psychiatry \n2007 ;164 :870 –6 .17541044 \n[9] Seitz DP Gill SS \nNeuroleptic malignant syndrome complicating antipsychotic treatment of delirium or agitation in medical and surgical patients: case reports and a review of the literature . Psychosomatics \n2009 ;50 :8 –15 .19213967 \n[10] Keck PE JrPope HG JrCohen BM \nRisk factors for neuroleptic malignant syndrome. A case-control study . Arch Gen Psychiatry \n1989 ;46 :914 –8 .2572206 \n[11] Caroff SN Mann SC \nNeuroleptic malignant syndrome . Psychopharmacol Bull \n1988 ;24 :25 –9 .3290944 \n[12] van de Beek D de Gans J Spanjaard L \nClinical features and prognostic factors in adults with bacterial meningitis . N Engl J Med \n2004 ;351 :1849 –59 .15509818 \n[13] Currie BJ Fisher DA Howard DM Burrow JN \nNeurological melioidosis . Acta Trop \n2000 ;74 :145 –51 .10674643 \n[14] Blair DT Dauner A \nExtrapyramidal symptoms are serious side-effects of antipsychotic and other drugs . Nurse Pract \n1992 ;17 :56, 62--64, 67 .\n[15] So R Hirota T Yamamoto Y \nLack of cardinal symptoms of meningitis in a hospitalized patient with chronic schizophrenia: lessons to be learned . Gen Hosp Psychiatry \n2015 ;37 :621.e623 –4 .\n[16] Ng CS Azmin S Law ZK \nAn unusual neurological complication from a garden-variety organism: post-melioidosis parkinsonism . Med J Aust \n2015 ;202 :333 –4 .25832163\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "97(24)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D014150:Antipsychotic Agents; D016957:Burkholderia pseudomallei; D002442:Ceftazidime; D002555:Cerebrospinal Fluid; D003866:Depressive Disorder; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008554:Melioidosis; D016920:Meningitis, Bacterial; D008911:Minocycline; D009459:Neuroleptic Malignant Syndrome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e11110",
"pmc": null,
"pmid": "29901631",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21152057;20964837;1359485;26324862;2572206;15509818;10674643;19213967;22512851;12767750;17541044;28005910;3290944;18854938;17620641;25832163",
"title": "Neurological melioidosis (Burkholderia pseudomallei) in a chronic psychotic patient treated with antipsychotics: A case report.",
"title_normalized": "neurological melioidosis burkholderia pseudomallei in a chronic psychotic patient treated with antipsychotics a case report"
} | [
{
"companynumb": "TW-ALVOGEN-2018-ALVOGEN-096560",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRAZODONE HYDROCHLORIDE"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nAngiotensin II receptor blockers (ARBs) are widely used to treat hypertension and heart failure. Photosensitivity reactions are cutaneous adverse events due to exposure to a drug and either ultraviolet or visible radiation. Among the ARB class, this type of adverse drug reaction is labeled only for losartan.\n\n\nOBJECTIVE\nThe aim of this study was to provide a descriptive evaluation of photosensitivity reports with ARBs in the World Health Organization Global Individual Case Safety Report database, VigiBase(®).\n\n\nMETHODS\nAll reports of photosensitivity reported with ARBs were identified from VigiBase(®). All variables contained in the reports were analyzed. Information component (IC) and its lower limit of a 95% credibility interval (IC025) values were considered as measures of disproportionality for the assessment of photosensitivity cases reported with ARBs. VigiGrade completeness score (C) was used as a measure of quality of each report. Well-documented reports (C > 0.8) were fully described and analyzed.\n\n\nRESULTS\nUp to December 2014, a total of 203 reports on photosensitivity reported with ARBs and submitted by 25 different countries had been recorded in VigiBase(®). Among them, 25.1% involved losartan, 23.1% involved irbesartan, and 21.7% involved valsartan. In 126 cases, the ARB was the only suspected drug and in 10% of them the reaction was serious. IC and IC025 values indicated a possible positive correlation between photosensitivity and both irbersartan and losartan. A focus on well-documented reports, after excluding those with a co-prescription of other drugs known to cause photosensitivity, showed that out of 18 cases, six were related to losartan, four to olmesartan, three to irbesartan, two to valsartan and to candesartan, and one to telmisartan. Causality assessment was 'probable' in ten cases and 'possible' in eight cases. Moreover, positive dechallenge was reported in ten cases and positive rechallenge in one case.\n\n\nCONCLUSIONS\nPhotosensitivity reactions have been reported with almost all ARBs in VigiBase(®) with a positive disproportionality for irbesartan and losartan. Considering that ARBs share the same chemical structure, which may have the same response to sunlight, it is plausible to consider photosensitivity as a possible class effect. Physicians and patients should be aware of potentially serious photosensitivity reactions related to treatment with ARBs.",
"affiliations": "Pharmacology Unit, Department of Public Health and Community Medicine, University of Verona, P.le L.A. Scuro, 10, 37134, Verona, Italy. ermelinda.viola@univr.it.;Pharmacology Unit, Department of Public Health and Community Medicine, University of Verona, P.le L.A. Scuro, 10, 37134, Verona, Italy.;Egis Pharmaceuticals PLC, Budapest, Hungary.;Pharmacology Unit, Department of Public Health and Community Medicine, University of Verona, P.le L.A. Scuro, 10, 37134, Verona, Italy.;Pharmacology Unit, Department of Public Health and Community Medicine, University of Verona, P.le L.A. Scuro, 10, 37134, Verona, Italy.",
"authors": "Viola|Ermelinda|E|;Coggiola Pittoni|Anna|A|;Drahos|Agnes|A|;Moretti|Ugo|U|;Conforti|Anita|A|",
"chemical_list": "D057911:Angiotensin Receptor Antagonists; D017319:Photosensitizing Agents",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40264-015-0323-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0114-5916",
"issue": "38(10)",
"journal": "Drug safety",
"keywords": null,
"medline_ta": "Drug Saf",
"mesh_terms": "D057911:Angiotensin Receptor Antagonists; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017319:Photosensitizing Agents; D012189:Retrospective Studies",
"nlm_unique_id": "9002928",
"other_id": null,
"pages": "889-94",
"pmc": null,
"pmid": "26187686",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article",
"references": "9696956;21879777;19415768;19132802;16689555;24891058;7249508;24343765;16004927;9692664;23464719;11072960;12020173",
"title": "Photosensitivity with Angiotensin II Receptor Blockers: A Retrospective Study Using Data from VigiBase(®).",
"title_normalized": "photosensitivity with angiotensin ii receptor blockers a retrospective study using data from vigibase"
} | [
{
"companynumb": "PHHY2015IT138014",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IRBESARTAN"
},
"drugadditional": null,
"drug... |
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