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"abstract": "Sarcoid Associated Pulmonary Hypertension (SAPH) is a common complication of sarcoidosis and is associated with poor prognosis. SAPH can be due to multiple synergistic mechanisms and current therapeutic strategies treat systemic sarcoidosis and pulmonary hypertension separately. Several studies have been performed to develop an effective therapy for SAPH but have been met with mixed results. The AMBITION trial successfully treated incident patients with pulmonary arterial hypertension (PAH) with the upfront combination of ambrisentan and tadalafil; however combination therapy has not yet been studied in patients with SAPH. Here we report a cohort of patients with newly diagnosed SAPH who were treated with upfront combination therapy per the AMBITION study protocol. We report three subjects with newly diagnosed SAPH who were treated with combination ambrisentan and tadalafil. Baseline hemodynamics were compared with those from surveillance right heart catheterization while on therapy. Mean follow up period was 17 months. Each subject demonstrated clinical and hemodynamic improvement with combination therapy. This series is the first to evaluate upfront combination ambrisentan and tadalafil therapy for treatment of newly diagnosed SAPH. Despite the impressive clinical and hemodynamic improvement, the study is limited by its small size and retrospective nature. While these initial results are promising, further work is needed to fully evaluate this regimen for treatment of SAPH. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 234-238).",
"affiliations": "Boston University Medical Center.;Boston University Medical Center.;Brigham and Womens Hospital.;Boston University Medical Center.;Boston University Medical Center.;Tufts Medical Center.",
"authors": "Abston|Eric|E|;Hon|Stephanie|S|;Lawrence|Romy|R|;Berman|Jeffrey|J|;Govender|Praveen|P|;Farber|Harrison W|HW|",
"chemical_list": "D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D010666:Phenylpropionates; D058986:Phosphodiesterase 5 Inhibitors; D011724:Pyridazines; D000068581:Tadalafil; C467894:ambrisentan",
"country": "Italy",
"delete": false,
"doi": "10.36141/svdld.v37i2.9343",
"fulltext": "\n==== Front\nSarcoidosis Vasc Diffuse Lung Dis\nSarcoidosis Vasc Diffuse Lung Dis\nSarcoidosis, Vasculitis, and Diffuse Lung Diseases\n1124-0490 2532-179X Mattioli 1885 Italy \n\nSVDLD-37-234\n10.36141/svdld.v37i2.9343\nCase Series\nTreatment of newly diagnosed sarcoid-associated pulmonary hypertension with ambrisentan and tadalafil combination therapy\nAbston Eric 1 Hon Stephanie 1 Lawrence Romy 2 Berman Jeffrey 3 Govender Praveen 1 Farber Harrison W. 4 1 Boston University Medical Center\n2 Brigham and Womens Hospital\n3 Boston University Medical Center\n4 Tufts Medical Center\nCorrespondence: Eric Abston Pulmonary Center 715 Albany St Boston, MA 02118\n2020 \n30 6 2020 \n37 2 234 238\n07 3 2020 20 5 2020 Copyright: © 2020 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES2020This work is licensed under a Creative Commons Attribution 4.0 International LicenseSarcoid Associated Pulmonary Hypertension (SAPH) is a common complication of sarcoidosis and is associated with poor prognosis. SAPH can be due to multiple synergistic mechanisms and current therapeutic strategies treat systemic sarcoidosis and pulmonary hypertension separately. Several studies have been performed to develop an effective therapy for SAPH but have been met with mixed results. The AMBITION trial successfully treated incident patients with pulmonary arterial hypertension (PAH) with the upfront combination of ambrisentan and tadalafil; however combination therapy has not yet been studied in patients with SAPH. Here we report a cohort of patients with newly diagnosed SAPH who were treated with upfront combination therapy per the AMBITION study protocol. We report three subjects with newly diagnosed SAPH who were treated with combination ambrisentan and tadalafil. Baseline hemodynamics were compared with those from surveillance right heart catheterization while on therapy. Mean follow up period was 17 months. Each subject demonstrated clinical and hemodynamic improvement with combination therapy. This series is the first to evaluate upfront combination ambrisentan and tadalafil therapy for treatment of newly diagnosed SAPH. Despite the impressive clinical and hemodynamic improvement, the study is limited by its small size and retrospective nature. While these initial results are promising, further work is needed to fully evaluate this regimen for treatment of SAPH. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 234-238)\n\nSarcoid associated pulmonary hypertensionsarcoidosispulmonary hypertensionAmbition Protocoltadalafilambrisentan\n==== Body\nIntroduction\nSarcoid Associated Pulmonary Hypertension (SAPH) is a well-known complication of sarcoidosis. SAPH is thought to develop as a result of complex interactions between sarcoid-associated inflammatory processes in both the lung parenchyma and the pulmonary vasculature. Mechanisms by which sarcoid disease can induce pulmonary hypertension include: hypoxia, pulmonary artery vasculitis, sarcoid associated heart failure, fibrotic destruction of pulmonary vasculature, occlusion of pulmonary vasculature by granulomatous tissue, and sarcoid-induced hepatic disease and subsequent portopulmonary hypertension1. Historically, SAPH has been difficult to study because any of these mechanisms can contribute to the development of SAPH2. While the epidemiology of SAPH has been the subject of several recent studies, its exact incidence remains unknown. In the largest cohorts of patients with known sarcoidosis who were screened for Pulmonary Hypertension (PH) by echocardiography SAPH was observed in 3-50%3,\n4,\n5,\n6. In studies using right heart catheterization, 49-73% of patients with known sarcoidosis were diagnosed with SAPH7,\n8. This broad range is likely due, in part to the heterogeneity of the sarcoid population and the varying severity of the underlying sarcoidosis. Yet, the presence of SAPH confers a poorer prognosis compared to sarcoidosis alone3,\n9,\n10,\n11.\n\nTreatment of SAPH has focused on optimizing treatment of the underlying sarcoidosis and management of the PH as distinct issues. Studies specifically evaluating the effect of treating the sarcoidosis with immunomodulatory therapy have demonstrated mixed results on pulmonary hemodynamics10,\n12,\n13,\n14. Use of pulmonary vasodilators approved for treatment of Pulmonary Arterial Hypertension (PAH) in patients with SAPH has been hampered by a lack of robust studies evaluating such treatment in this population. What is known is based on small studies15. For example, prostanoids have been effective vasodilators in SAPH16,\n17 whether administered by the inhaled or intravenous route18,\n19,\n20. In addition, endothelin receptor antagonists (bosentan) and phosphodiesterase-5 inhibitors (sildenafil) have improved SAPH in some patients21,\n22,\n23\n\nThe benefits of upfront combination therapy have recently been established in patients with newly diagnosed group 1 PH (PAH); AMBITION was the first randomized controlled trial to demonstrate improvement in outcomes with the upfront combination of ambrisentan and tadalafil in the treatment of newly diagnosed PAH24. Previously, ambrisentan mono-therapy had demonstrated improvement in exercise capacity and hemodynamics in patients with PAH. Likewise, tadalafil, as either monotherapy or add on therapy, also improved hemodynamics, six minute walk test, and time to clinical worsening25,\n26. In patients with SAPH treatment with either of these agents as monotherapy has led to variable results. Ambrisentan monotherapy did demonstrate improvement in functional class in one study27. Likewise, tadalafil monotherapy has demonstrated equivocal results in this patients population28. However, there are no studies that have evaluated combination therapy in patients with newly diagnosed SAPH.\n\nIn the current report, we describe a series of newly diagnosed SAPH patients treated with the upfront combination of ambrisentan and tadalafil (AMBITION protocol)24.\n\nDesign and Data Collection\nWe conducted a retrospective review of all patients with SAPH and identified those treated with the combination of ambrisentan and tadalafil (AMBITION protocol) in accordance with a protocol approved by the Boston University Institutional Review Board. For each case, we collected patient demographics, stage of sarcoidosis, treatment for sarcoidosis, pulmonary function testing, echocardiography, baseline and post-treatment hemodynamics, complications of therapy, and clinical outcome.\n\nThe diagnosis of sarcoidosis was confirmed by review of the medical record, including compatible historical information and/or pathology findings. Patients were classified as having SAPH if they had a mean pulmonary arterial pressure (mPAP) > 25 mm Hg (Patients were diagnosed and treated under the previous PH guidelines and not under the currently proposed definition24,\n29) by right heart catheterization (RHC) with PAOP < 15 mmHg and PVR > 3 WU. None of the patients included in this report, had evidence of any of the following: connective tissue disease, portal hypertension, congenital or valvular heart disease, HIV infection, history of anorexigen or methamphetamine use, or thromboembolic disease.\n\nTreatment Protocol\nPatients were treated in accordance with the AMBITION trial protocol. Daily ambrisentan and tadalafil were initiated following diagnostic RHC with goal of 10 mg and 40 mg daily, respectively. Dose adjustments were made as dictated by patient symptoms and clinical status. Patients were treated with supplemental oxygen as required to maintain oxygen saturation ≥90%. Patients underwent surveillance RHC to assess response to treatment as clinically indicated.\n\nBecause of its small size, this series was not powered for statistical analysis.\n\nResults\nThis case series contains 3 subjects with newly diagnosed SAPH who were treated with the AMBITION protocol, with a mean follow-up of 17 months. All subjects tolerated full dose ambrisentan and tadalafil with no significant side effects. Surveillance right heart catheterization (mean interval 12 months) demonstrated improvement in hemodynamics in each patient: mPAP 40 ± 10 baseline vs 24 ± 5 mmHg post treatment, CO 3.8 ± 1.9 baseline vs 7 ± 2 L/min post treatment, PVR 12.6 ± 12.4 baseline vs 2.4 ± 0.8 WU post treatment. In addition to hemodynamic improvement, there was also improvement in NYHA functional class from FC III at baseline to FC II post treatment and 6 minute walk distance from 305 ± 58m baseline to 427 ± 86m post treatment.\n\nCase Descriptions:\nPatient 1 is a Caucasian male with history of hypertension and distant smoking history. He was diagnosed with lung biopsy proven Scadding stage 4 sarcoidosis at age 44. He was initially managed with steroids, but two years later transitioned to hydroxychloroquine and minocycline because of disease progression. Seven years later, because of further progression, minocycline was stopped and methotrexate started with improvement in symptoms. He later developed a spontaneous pneumothorax with persistent air leak, ultimately treated by lobectomy.\n\nAt age 56, because of progressive DOE, hypoxia, and decline in lung function, he was evaluated for pulmonary hypertension; right heart catheterization demonstrated SAPH. Tadalafil and ambrisentan were started per AMBITION protocol. There were no side effects with tadalafil, but ambrisentan caused fluid retention that responded to diuretics. This treatment resulted in improved symptoms, exercise tolerance and hemodynamics. Eighteen months later he again noted progressive DOE, worsening hypoxia, and diminished exercise tolerance. Imaging demonstrated progressive fibrotic lung disease and surveillance right heart catheterization demonstrated worsening hemodynamics. Because of these findings, he eventually underwent bilateral lung transplant and is currently alive and well.\n\nPatient 2 is a 74 year old female with history of spinal stenosis, hypothyroidism, and Scadding stage 4 sarcoidosis. Initially diagnosed at age 63 because of uveitis and arthralgia, she later developed hypercalcemia, chronic lymphopenia, and palpitations associated with recurrent supraventricular tachycardia. Sarcoidosis was diagnosed by mediastinal biopsy. She was initially treated with prednisone for two years prior to initiation of methotrexate as a steroid sparing agent. She was stable on this regimen for ~8 years; then developed worsening pulmonary disease and was transitioned to infliximab.\n\nBecause of progressive dyspnea, limiting activities of daily living, and worsening hypoxia, despite stable lung disease, she underwent right heart catheterization that demonstrated severe SAPH. She was treated with tadalafil and ambrisentan per the AMBITION protocol without side effects. With this regimen, she had dramatic improvement in symptoms, clinical status and hemodynamics. Unfortunately, twelve months later, she died from urosepsis.\n\nPatient 3 is a 56 year old male, with history of hypertension, severe obstructive sleep apnea treated with BiPAP, type 2 diabetes, distant 33 pack/year smoking history, and Scadding stage 4 sarcoidosis. He was diagnosed with sarcoidosis in 2004 by transbronchial biopsy and treated with prednisone for several years. The sarcoidosis was difficult to control despite multiple regimens, including methotrexate, azathioprine, and infliximab; it was eventually controlled with a combination of methotrexate, adalimumab, and doxycycline.\n\nBecause of progressive dyspnea and stable lung disease, he underwent right heart catheterization that demonstrated SAPH. He was treated with tadalafil and ambrisentan per AMBITION protocol without side effects and with improvement in symptoms, clinical status, and hemodynamics. With advancing fibrotic lung disease his symptoms have again progressed and he is awaiting lung transplantation.\n\nDiscussion\nIn the current series of patients with biopsy proven sarcoidosis subsequently diagnosed with SAPH by right heart catheterization, we report the initial experience with upfront treatment with ambrisentan and tadalafil per the AMBITION protocol. Despite previous studies showing equivocal response to ambrisentan and tadalafil as monotherapy in patients with SAPH, these three patients responded to combination therapy with improvement in clinical status, functional class and hemodynamics. Moreover, this regimen was well-tolerated with minimal side effects.\n\nThe prospect that patients with newly diagnosed SAPH might receive significant benefit from upfront combination therapy is potentially important. The initial response to therapy seen in this small series is highly encouraging, especially since patients with a significant burden of fibrotic disease (Scadding stage 4) tend to respond poorly to vasodilator therapy. Clearly, additional studies are warranted to investigate the effects of combination therapy in a larger cohort of patients with SAPH.\n\nWhile it is difficult to generalize the results from three patients, two (patients 1 and 3) had a significant response to therapy initially, but later had progression of symptoms which was attributed to worsening fibrotic lung disease. This does suggest that combination therapy might not have long-term durability in patients suffering from progressive fibrotic disease and that these patients should be closely monitored for clinical worsening. However, the initial and extended improvement suggests that combination therapy might: 1) provide symptomatic relief and/or improvement in these patients; 2) allow time for more aggressive treatment of the advancing fibrosis; and/or 3) allow more time to evaluate the patient for lung transplantation and/or possibly delay the need for it.\n\nThe current study is limited by its small size, retrospective nature, and lack of randomization. Moreover, it was not adequately powered to detect statistically significant treatment effect changes. Conclusions: We report a cohort of three patients with biopsy proven sarcoidosis subsequently diagnosed with SAPH by right heart catheterization. Each patient was treated with an upfront combination of tadalafil and ambrisentan in accordance with the AMBITION protocol. All patients demonstrated marked improvement in hemodynamics, symptoms, and 6-minute walk distance. Although these initial results are encouraging, especially since all patients had Scadding stage 4 disease, additional studies are needed to evaluate the effect of combination therapy in patients with SAPH.\n\nTable 2: Hemodynamics at initial diagnosis (Baseline) and after treatment (mean followup catheterization 12 months). Hemodynamic measurements were obtained by right heart catheterization at baseline (diagnosis of SAPH) and during treatment with tadalafil and ambrisentan (Treatment). RV (right ventricle), PAP (pulmonary artery pressure), mPAP (mean PAP), PCWP (pulmonary capillary wedge pressure), CO Fick (cardiac output via Fick’s principle, CI cardiac index), PVR (pulmonary vascular resistance), NHYA FC (New York Heart Association Functional Class). mPAP improved from 40 ± 10 mmHg to 24 ± 5 mmHg, CI improved from 2.2 ± 0.3 to 4.0 ± 1.0 L/min/m2. The study was not powered for statistical analysis.\n\nTable 1. Patient Characteristics\n\n\tPatient 1\tPatient 2\tPatient 3\t\nAge\t57\t73\t57\t\nSex\tMale\tFemale\tMale\t\nRace\tCaucasian\tCaucasian\tCaucasian\t\nBMI\t23.4\t21.8\t30.1\t\nScadding Stage\t4\t4\t4\t\nSarcoid Treatment\tMethotrexate\tInfliximab\tCombination\t\nPulmonary Function Tests\t\nFVC L (% Pred)\t2.7 (59)\t1.52 (49)\t2.63 (57)\t\nFEV1 L (%Pred)\t1.49 (43)\t0.61 (26)\t1.58 (45)\t\nFEV1/FVC\t55\t40\t60\t\nDLCO mL/mmHg/min (% Pred)\t10.5 (44)\t4.85 (23)\t11.4 (44)\t\nEchocardiogram\t\t\t\t\nEF (%)\t60\t73\t58\t\nPASP (mmHg)\t47\t72\tNA\t\nRight Ventricle Size\tNormal\tNormal\tNormal\t\nRight Ventricle Hypertrophy\tNo\tYes\tYes\t\nTable 2. Patient Hemodynamics and Functional Capacity\n\n\tBaseline\tTreatment\t\n\tPatient 1\tPatient 2\tPatient 3\tAvg\tPatient 1\tPatient 2\tPatient 3\tAvg\t\nRV sys (mmHg)\t49\t58\t41\t49 ± 9\t36\t38\t38\t37 ± 1\t\nRA dia (mmHg)\t1\t5\t3\t3 ± 2\t0\t0\t0\t0 ± 0\t\nPAP sys (mmHg)\t54\t62\t40\t52 ± 11\t40\t40\t39\t40 ± 1\t\nPAP dia (mmHg)\t31\t31\t23\t28 ± 5\t23\t13\t6\t14 ± 9\t\nmPAP (mmHg)\t40\t50\t31\t40 ± 10\t29\t23\t20\t24 ± 5\t\nPCWP (mmHg)\t4\t7\t13\t8 ± 5\t11\t5\t6\t7 ± 3\t\nCO Fick (L/min)\t4.84\t1.61\t4.86\t3.8 ± 1.9\t5.53\t8.23\t8.5\t7 ± 2\t\nCI Fick (L/min/m2)\t2.48\t1.96\t2.29\t2.2 ± 0.3\t2.97\t4.9\t4.04\t4 ± 1\t\nPVR Fick (WU)\t7.4\t26.7\t3.7\t12.6 ± 12.4\t3.2\t2.3\t1.7\t2.4 ± 0.8\t\nNYHA FC\t2\t2\t2\t2\t3\t3\t3\t3\t\n6 Min walk (M)\t365\t250\t300\t305 ± 58\t450\t500\t332\t427 ± 86\n==== Refs\nReferences\n1 Shlobin OA Baughman RP Sarcoidosis-Associated Pulmonary Hypertension Semin Respir Crit Care Med 2017 38 450 462 28750460 \n2 Galie N Humbert M Vachiery JL Gibbs S Lang I Torbicki A Simonneau G Peacock A Vonk Noordegraaf A Beghetti M Ghofrani A Gomez Sanchez MA Hansmann G Klepetko W Lancellotti P Matucci M McDonagh T Pierard LA Trindade PT Zompatori M Hoeper M Group ESCSD 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT) Eur Heart J 2016 37 67 119 26320113 \n3 Alhamad EH Idrees MM Alanezi MO Alboukai AA Shaik SA Sarcoidosis-associated pulmonary hypertension: Clinical features and outcomes in Arab patients Ann Thorac Med 2010 5 86 91 20582173 \n4 Handa T Nagai S Miki S Fushimi Y Ohta K Mishima M Izumi T Incidence of pulmonary hypertension and its clinical relevance in patients with sarcoidosis Chest 2006 129 1246 52 16685015 \n5 Sulica R Teirstein AS Kakarla S Nemani N Behnegar A Padilla ML Distinctive clinical, radiographic, and functional characteristics of patients with sarcoidosis-related pulmonary hypertension Chest 2005 128 1483 9 16162747 \n6 Huitema MP Bakker ALM Mager JJ Rensing B Smits F Snijder RJ Grutters JC Post MC Prevalence of pulmonary hypertension in pulmonary sarcoidosis: the first large European prospective study Eur Respir J 2019 54 \n7 Baughman RP Engel PJ Meyer CA Barrett AB Lower EE Pulmonary hypertension in sarcoidosis Sarcoidosis Vasc Diffuse Lung Dis 2006 23 108 16 17937106 \n8 Shorr AF Helman DL Davies DB Nathan SD Pulmonary hypertension in advanced sarcoidosis: epidemiology and clinical characteristics Eur Respir J 2005 25 783 8 15863633 \n9 Baughman RP Engel PJ Taylor L Lower EE Survival in sarcoidosis-associated pulmonary hypertension: the importance of hemodynamic evaluation Chest 2010 138 1078 85 20348196 \n10 Nunes H Humbert M Capron F Brauner M Sitbon O Battesti JP Simonneau G Valeyre D Pulmonary hypertension associated with sarcoidosis: mechanisms, haemodynamics and prognosis Thorax 2006 61 68 74 16227329 \n11 Tiosano S Versini M Dar Antaki L Spitzer L Yavne Y Watad A Gendelman O Comaneshter D Cohen AD Amital H The long-term prognostic significance of sarcoidosis-associated pulmonary hypertension - A cohort study Clin Immunol 2019 199 57 61 30543925 \n12 Boucly A Cottin V Nunes H Jais X Tazi A Prevot G Reynaud-Gaubert M Dromer C Viacroze C Horeau-Langlard D Pison C Bergot E Traclet J Weatherald J Simonneau G Valeyre D Montani D Humbert M Sitbon O Savale L Management and long-term outcomes of sarcoidosis-associated pulmonary hypertension Eur Respir J 2017 50 \n13 Gluskowski J Hawrylkiewicz I Zych D Zielinski J Effects of corticosteroid treatment on pulmonary haemodynamics in patients with sarcoidosis Eur Respir J 1990 3 403 7 2365034 \n14 Parikh KS Dahhan T Nicholl L Ruopp N Pomann GM Fortin T Tapson VF Rajagopal S Clinical Features and Outcomes of Patients with Sarcoidosis-associated Pulmonary Hypertension Sci Rep 2019 9 4061 30858405 \n15 daSilva-deAbreu A Mandras SA Sarcoidosis-Associated Pulmonary Hypertension: An Updated Review and Discussion of the Clinical Conundrum Curr Probl Cardiol 2019 100506 31889552 \n16 Barst RJ Ratner SJ Sarcoidosis and reactive pulmonary hypertension Arch Intern Med 1985 145 2112 4 4062465 \n17 Preston IR Klinger JR Landzberg MJ Houtchens J Nelson D Hill NS Vasoresponsiveness of sarcoidosis-associated pulmonary hypertension Chest 2001 120 866 72 11555522 \n18 Baughman RP Judson MA Lower EE Highland K Kwon S Craft N Engel PJ Inhaled iloprost for sarcoidosis associated pulmonary hypertension Sarcoidosis Vasc Diffuse Lung Dis 2009 26 110 20 20560291 \n19 Bonham CA Oldham JM Gomberg-Maitland M Vij R Prostacyclin and oral vasodilator therapy in sarcoidosis-associated pulmonary hypertension: a retrospective case series Chest 2015 148 1055 1062 26437815 \n20 Fisher KA Serlin DM Wilson KC Walter RE Berman JS Farber HW Sarcoidosis-associated pulmonary hypertension: outcome with long-term epoprostenol treatment Chest 2006 130 1481 8 17099027 \n21 Barnett CF Bonura EJ Nathan SD Ahmad S Shlobin OA Osei K Zaiman AL Hassoun PM Moller DR Barnett SD Girgis RE Treatment of sarcoidosis-associated pulmonary hypertension. A two-center experience Chest 2009 135 1455 1461 19118270 \n22 Baughman RP Culver DA Cordova FC Padilla M Gibson KF Lower EE Engel PJ Bosentan for sarcoidosis-associated pulmonary hypertension: a double-blind placebo controlled randomized trial Chest 2014 145 810 817 24177203 \n23 Milman N Burton CM Iversen M Videbaek R Jensen CV Carlsen J Pulmonary hypertension in end-stage pulmonary sarcoidosis: therapeutic effect of sildenafil? J Heart Lung Transplant 2008 27 329 34 18342757 \n24 Galie N Barbera JA Frost AE Ghofrani HA Hoeper MM McLaughlin VV Peacock AJ Simonneau G Vachiery JL Grunig E Oudiz RJ Vonk-Noordegraaf A White RJ Blair C Gillies H Miller KL Harris JH Langley J Rubin LJ Investigators A Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension N Engl J Med 2015 373 834 44 26308684 \n25 Galie N Brundage BH Ghofrani HA Oudiz RJ Simonneau G Safdar Z Shapiro S White RJ Chan M Beardsworth A Frumkin L Barst RJ Pulmonary Arterial H Response to Tadalafil Study G Tadalafil therapy for pulmonary arterial hypertension Circulation 2009 119 2894 903 19470885 \n26 Galie N Olschewski H Oudiz RJ Torres F Frost A Ghofrani HA Badesch DB McGoon MD McLaughlin VV Roecker EB Gerber MJ Dufton C Wiens BL Rubin LJ Ambrisentan in Pulmonary Arterial Hypertension RD-BP-CMESG Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2 Circulation 2008 117 3010 9 18506008 \n27 Judson MA Highland KB Kwon S Donohue JF Aris R Craft N Burt S Ford HJ Ambrisentan for sarcoidosis associated pulmonary hypertension Sarcoidosis Vasc Diffuse Lung Dis 2011 28 139 45 22117505 \n28 Ford HJ Baughman RP Aris R Engel P Donohue JF Tadalafil therapy for sarcoidosis-associated pulmonary hypertension Pulm Circ 2016 6 557 562 28090299 \n29 Simonneau G Hoeper MM The revised definition of pulmonary hypertension: exploring the impact on patient management Eur Heart J 2019 Suppl 21 K4 K8\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1124-0490",
"issue": "37(2)",
"journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG",
"keywords": "Ambition Protocol; Sarcoid associated pulmonary hypertension; ambrisentan; pulmonary hypertension; sarcoidosis; tadalafil",
"medline_ta": "Sarcoidosis Vasc Diffuse Lung Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents; D062186:Arterial Pressure; D004359:Drug Therapy, Combination; D065130:Endothelin A Receptor Antagonists; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D010666:Phenylpropionates; D058986:Phosphodiesterase 5 Inhibitors; D011651:Pulmonary Artery; D011724:Pyridazines; D012189:Retrospective Studies; D017565:Sarcoidosis, Pulmonary; D000068581:Tadalafil; D016896:Treatment Outcome",
"nlm_unique_id": "9610928",
"other_id": null,
"pages": "234-238",
"pmc": null,
"pmid": "33093789",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17099027;29051269;26320113;4062465;22117505;18342757;20348196;30543925;15863633;31857795;20582173;31320453;26308684;28090299;16685015;19118270;30858405;20560291;18506008;24177203;26437815;2365034;16162747;17937106;16227329;19470885;11555522;31889552;28750460",
"title": "Treatment of newly diagnosed sarcoid-associated pulmonary hypertension with ambrisentan and tadalafil combination therapy.",
"title_normalized": "treatment of newly diagnosed sarcoid associated pulmonary hypertension with ambrisentan and tadalafil combination therapy"
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"abstract": "BACKGROUND\nAnaplastic thyroid carcinoma has an extremely poor prognosis, and no known drugs have exhibited acceptable efficacy. In recent years, novel anticancer tyrosine kinase inhibitors have been developed. We encountered a case of tracheal stenosis due to mediastinal and tracheal infiltration of anaplastic carcinoma for which lenvatinib exhibited remarkable effects; owing to this, airway management could be performed, even though the patient's condition was considered critical.\n\n\nMETHODS\nA 55-year-old man presented with locally advanced anaplastic thyroid carcinoma that was observed to have mediastinal infiltration. Tracheal stenosis due to infiltration of the trachea occurred, and the condition of the patient rapidly deteriorated. Radiation and chemotherapy consisting of cetuximab, cisplatin, and fluorouracil were ineffective, but his tracheal stenosis was relieved 2 weeks after initiation of lenvatinib, after which the patient could be discharged. However, the lenvatinib was ineffective for his liver, bone, and brain metastatic lesions, and the patient remained in a critical condition.\n\n\nCONCLUSIONS\nWe encountered a case in which lenvatinib was effective for locally advanced anaplastic thyroid carcinoma, leading to an improvement in quality of life and a prolonged life. The drug was effective for the primary lesion, but mixed efficacy was noted for distant metastatic lesions.",
"affiliations": "Department of Otolaryngology-Head and Neck Surgery, Tottori University Faculty of Medicine, Yonago, Japan.;Department of Otolaryngology-Head and Neck Surgery, Tottori University Faculty of Medicine, Yonago, Japan.;Department of Otolaryngology-Head and Neck Surgery, Tottori University Faculty of Medicine, Yonago, Japan.;Department of Otolaryngology-Head and Neck Surgery, Tottori University Faculty of Medicine, Yonago, Japan.;Department of Otolaryngology-Head and Neck Surgery, Tottori University Faculty of Medicine, Yonago, Japan.;Department of Otolaryngology-Head and Neck Surgery, Tottori University Faculty of Medicine, Yonago, Japan.;Department of Otolaryngology-Head and Neck Surgery, Tottori University Faculty of Medicine, Yonago, Japan.;Department of Otolaryngology-Head and Neck Surgery, Tottori University Faculty of Medicine, Yonago, Japan.",
"authors": "Fukuhara|Takahiro|T|;Donishi|Ryohei|R|;Koyama|Satoshi|S|;Miyake|Naritomo|N|;Matsuda|Eriko|E|;Fujiwara|Kazunori|K|;Kitano|Hiroya|H|;Takeuchi|Hiromi|H|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000457831",
"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 10.1159/000457831cro-0010-0175Case ReportSignificant Amelioration of Tracheal Stenosis following Lenvatinib in a Patient Who Has Anaplastic Thyroid Carcinoma with Bronchomediastinal Infiltration: A Case Report Fukuhara Takahiro *Donishi Ryohei Koyama Satoshi Miyake Naritomo Matsuda Eriko Fujiwara Kazunori Kitano Hiroya Takeuchi Hiromi Department of Otolaryngology-Head and Neck Surgery, Tottori University Faculty of Medicine, Yonago, Japan*Takahiro Fukuhara, MD, PhD Department of Otolaryngology-Head and Neck Surgery Tottori University Faculty of Medicine 36-1 Nishicho, Yonago 683-8504 (Japan) E-Mail tfukuhara3387@med.tottori-u.ac.jpJan-Apr 2017 15 2 2017 15 2 2017 10 1 175 181 23 1 2017 23 1 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.Background\nAnaplastic thyroid carcinoma has an extremely poor prognosis, and no known drugs have exhibited acceptable efficacy. In recent years, novel anticancer tyrosine kinase inhibitors have been developed. We encountered a case of tracheal stenosis due to mediastinal and tracheal infiltration of anaplastic carcinoma for which lenvatinib exhibited remarkable effects; owing to this, airway management could be performed, even though the patient's condition was considered critical.\n\nCase Report\nA 55-year-old man presented with locally advanced anaplastic thyroid carcinoma that was observed to have mediastinal infiltration. Tracheal stenosis due to infiltration of the trachea occurred, and the condition of the patient rapidly deteriorated. Radiation and chemotherapy consisting of cetuximab, cisplatin, and fluorouracil were ineffective, but his tracheal stenosis was relieved 2 weeks after initiation of lenvatinib, after which the patient could be discharged. However, the lenvatinib was ineffective for his liver, bone, and brain metastatic lesions, and the patient remained in a critical condition.\n\nConclusion\nWe encountered a case in which lenvatinib was effective for locally advanced anaplastic thyroid carcinoma, leading to an improvement in quality of life and a prolonged life. The drug was effective for the primary lesion, but mixed efficacy was noted for distant metastatic lesions.\n\nKeywords\nAnaplastic thyroid cancerLenvatinibTyrosine kinase inhibitorAdvanced thyroid cancerTracheal infiltration\n==== Body\nIntroduction\nAnaplastic thyroid carcinoma is one of the carcinomas with the poorest prognosis. The frequency of its occurrence is low but it is highly malignant, and local expansion and distant metastasis progress rapidly; to date, no effective treatment has been established [1, 2]. Multimodal therapy has been performed, but there are no known effective anticancer drugs [3, 4, 5, 6, 7, 8].\n\nIn recent years, many molecular targeted therapies have been developed, and therapies targeting the thyroid are no exception [9, 10]. In Japan, the tyrosine kinase inhibitor lenvatinib was approved in March 2015 for the treatment of all types of thyroid cancer, including anaplastic carcinoma. Because there is little clinical experience in using lenvatinib for anaplastic carcinoma, its efficacy is unknown.\n\nWe administered lenvatinib to a patient who rapidly developed tracheal stenosis due to tracheal infiltration of advanced anaplastic thyroid carcinoma, and remarkable efficacy was observed. Here, we report the clinical course of a patient in whom tracheal stenosis was relieved and who could be discharged following lenvatinib administration.\n\nCase Report\nA 55-year-old man presented with the chief complaint of dysphagia. A suspected right level IV lymph node metastasis and a neoplastic lesion located in the inferior pole of the thyroid to the mediastinum were observed. Because the boundary between the inferior pole of the thyroid gland and the tumor was unclear, and a calcified lesion was observed in the tumor, thyroid cancer was suspected.\n\nWe performed fine needle biopsy on the caudal thyroid tumor and right level IV lymph node, created cell blocks at the time of cytodiagnosis, and performed thyroglobulin, thyroid transcription factor-1 (TTF-1) and Hecter Battifora mesothelial epitope-1 (HBME-1) immunostaining. However, the results of immunostaining were negative, and based on the results of the cytodiagnosis, poorly differentiated squamous cell carcinoma was suspected. A generalized examination consisting of contrast-enhanced computed tomography (CT), FDG-positron emission tomography (PET), and endoscopy did not reveal a clear primary site in the head and neck region, and in addition to the mediastinal tumor, a right level IV cervical lymph node metastasis, pulmonary metastases, and bone metastases were observed (Fig. 1a).\n\nThe results of the biopsy performed on the level IV lymph node metastasis to determine the tissue type revealed a metastasis of a squamous cell carcinoma. Based on this, we diagnosed occult primary squamous cell carcinoma and initiated treatment. Chemotherapy consisting of cetuximab, cisplatin, and fluorouracil was initiated 1 month following the initial presentation. The result was stable disease. We administered an additional course of chemotherapy consisting of cetuximab, cisplatin, and fluorouracil, but the result was progressive disease, and edema of his cervical and facial regions and tracheal stenosis worsened.\n\nEndotracheal fiber examination showed tracheal invasion of the tumor, and CT revealed mediastinal tumor infiltration of the large vessels of the chest (left common carotid artery, brachiocephalic artery, and brachiocephalic vein) and thrombosis of the bilateral internal jugular veins (Fig. 1b).\n\nBecause the airway was becoming blocked, we performed a tracheotomy and placed a long intubation tube just above the tracheal bifurcation. A mediastinal tumor biopsy was also simultaneously performed. After performing airway management, we administered palliative irradiation (16 Gy/2 Fr) but no efficacy was noted. Biopsy results revealed papillary thyroid carcinoma and partially anaplastic transformation (Fig. 1c).\n\nThe anaplastic thyroid carcinoma was stage IVC, and the tracheal stenosis progressed to the region just above the bifurcation of the trachea because of the infiltrated tumor. Therefore, we thought that suffocation would be unavoidable in the near future (Fig. 2).\n\nBecause there are no conventional treatments that are believed to be effective for anaplastic carcinoma, we initiated the administration of lenvatinib (full dose, 24 mg) after having obtained consent from the patient and his family members and having performed a heart evaluation and screening for brain metastases.\n\nEffects of Lenvatinib\nOn the fourth day after lenvatinib administration, his facial edema began to be ameliorated, followed by amelioration of the edema of his upper limbs. The tumor that had infiltrated the trachea shrank starting on day 10 of administration, and a space between the intubation tube and tracheal wall was observed. On day 14 of administration, the tumor in the trachea disappeared, and because there was no need to maintain a cavity with the intubation tube, the tube was changed to a common short cannula.\n\nCT showed a rapid prominent reduction of the mediastinal tumor, reduction of the pulmonary lesion, and a decrease in pleural effusion. Necrosis of the mediastinal tumor developed, and a necrotic cavity formed without development of granulomas or scarring; as a result, a dead space developed in the anterior region of the trachea (Fig. 3a). In contrast, an increase in the size and number of bone and liver metastases was noted (Fig. 3b).\n\nComplications of Lenvatinib\nThe patient's blood pressure increased to 168/96 mm Hg 3 days after initiation of lenvatinib, but it improved after he had been receiving nifedipine for several days. Five days after initiating lenvatinib, his thyroid function began to decrease, and the decrease in function reached the lowest point 2 weeks after initiation. For this reason, we finally decided to administer levothyroxine (100 μg). No other side effects were noted. On day 19, the patient began to make utterances using a speech valve, and he was discharged 4 weeks following the initiation of lenvatinib.\n\nPrognosis\nThe tracheal stenosis was relieved, and the patient's life was temporarily prolonged, but the drug was completely ineffective for his liver and bone metastatic lesions, which increased in size and number. Because the tumor necrosis and dead space following necrosis of the tumor surrounding the trachea were not filled after discharge, the dose of the drug was decreased to 14 mg at 6 weeks after initiation.\n\nBecause the effects of anticancer drugs greatly differ between mediastinal primary site and liver field foci, we performed tissue biopsy of the suspected liver metastasis to rule out metastases from another site or primary liver cancer. However, histological findings similar to those of the primary focus were noted.\n\nA large dead space remained in the mediastinum, and because mediastinitis due to the influx of saliva from the trachea hole was also a concern, and further brain metastases were revealed, administration of lenvatinib was discontinued 7 weeks and 3 days after initiation. The brain and liver metastases advanced, and the patient died 3 months after initiation of lenvatinib.\n\nDiscussion\nLenvatinib is a tyrosine kinase inhibitor-type anticancer drug with a novel mechanism that is not seen in conventional anticancer drugs. It exhibits selective inhibitory activity for receptor tyrosine kinases (RTK) that contribute to tumor angiogenesis or tumor malignancy such as vascular endothelial growth factor receptors (VEGFR) VEGFR1, VEGFR2, VEGFR3; fibroblast growth factors (FGFR) FGFR1, FGFR2, FGFR3, FGFR4; and platelet-derived growth factors (PDGFR) PDGFRα, KIT, and RET [11, 12, 13]. Currently, the drug has been approved for the treatment of differentiated thyroid cancer in Western countries, but the indication for anaplastic cancer was approved in March 2015 in Japan ahead of other countries. Because not much time has passed since the drug was approved in Japan, there are almost no reports concerning the use of lenvatinib for anaplastic cancer.\n\nWe encountered a patient in whom tracheal stenosis developed due to infiltration of locally advanced anaplastic thyroid carcinoma, making airway management difficult. Because a reduction was observed and tracheal stenosis was relieved 2 weeks after lenvatinib administration, the patient could be discharged. In this case, lenvatinib exhibited remarkable effects on the locally advanced anaplastic cancer, and the avoidance of tracheal occlusion contributed to the dramatic improvement of the patient's quality of life and prolonged his life. The patient could return home, and he and his family had time to accept the situation.\n\nHowever, multiple distant metastases were noted, and the lenvatinib was not found to be effective for the patient's distant metastases except for those in the lungs. A histopathological comparison of the primary tumor site for which efficacy was noted and the liver metastatic lesion for which no efficacy was noted revealed no differences. Because in cases of lung lesions, there are lesions for which efficacy is noted and lesions for which efficacy is not observed, it is still unclear whether the difference of the efficacy for the lesions was due to differences in drug concentration or to differences in tissue type and hemodynamics, but the possibility of mutations affecting the metastasis sites was also considered.\n\nIn this patient, lenvatinib exhibited a rapid shrinking effect on the tumors without forming scar tissue or granulation tissue in the tumor necrosis site, creating a large dead space. The tyrosine kinase inhibitor lenvatinib does not appear to cause the scarring and granulation generally seen following tumor necrosis when other anticancer drugs are used. Based on these findings, when using lenvatinib, it is necessary to be aware from the start that tissue defects and dead space formation may occur after tumor necrosis in addition to the possibility of fistula formation of the trachea and esophagus and rupture-induced hemorrhage of large blood vessels. In fact, the rupture of a major artery has been previously reported in Japan [14].\n\nTo date, no efficacy of anticancer drugs for anaplastic thyroid carcinoma has been reported. However, the present case shows the possibility that lenvatinib can be a first-line anticancer drug for the treatment of anaplastic cancer.\n\nConclusion\nWe treated a case in which lenvatinib was effective for locally advanced anaplastic thyroid carcinoma, leading to improved quality of life and a prolonged life span. A remarkable effect on the primary lesion was noted, but the efficacy for distant metastatic lesions was mixed. In the site in which the tumor rapidly shrank, a delay in granuloma formation was observed only in the tumor necrotic tissue.\n\nStatement of Ethics\nThe authors declare that the subject has given informed consent and that the study was performed in accordance with the ethical guidelines of the Helsinki Declaration.\n\nDisclosure Statement\nThe authors declare that there is no conflict of interest regarding the publication of this paper.\n\nFig. 1. a The PET/CT image shows an increase in FDG uptake in the mediastinum (black arrow) and the cervical metastatic lymph node (white arrow). b The chest CT shows the mediastinal tumor infiltration of the large vessels and the trachea. c The histopathological finding shows anaplastic carcinoma. Hematoxylin and eosin staining. ×60.\n\nFig. 2. CT shows severe tracheal stenosis as a result of tumor invasion.\n\nFig. 3. a A rapid, prominent reduction of the mediastinal tumor led to the dead space in the mediastinum. The air within the mediastinal tumor represents the dead space caused by tumor necrosis after lenvatinib administration (arrow). b Abdominal CT shows progression of the liver metastases.\n==== Refs\nReferences\n1 Sugitani I Miyauchi A Sugino K Okamoto T Yoshida A Suzuki S Prognostic factors and treatment outcomes for anaplastic thyroid carcinoma: ATC Research Consortium of Japan cohort study of 677 patients. World J Surg 2015 36 1247 1254 \n2 Smallridge RC Ain KB Asa SL Bible KC Brierley JD Burman KD Kebebew E Lee NY Nikiforov YE Rosenthal MS Shaha AR Tuttle RM American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 2012 22 1104 1139 23130564 \n3 Gottlieb JA Hill CS Jr Chemotherapy of thyroid cancer with adriamycin. Experience with 30 patients. N Engl J Med 1974 290 193 197 4808917 \n4 Shimaoka K Schoenfeld DA DeWys WD Creech RH DeConti R A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 1985 56 2155 2160 3902203 \n5 Biganzoli L Gebbia V Maiorino L Caraci P Iirillo A Thyroid cancer: different outcomes to chemotherapy according to tumour histology. Eur J Cancer 1995 31 2423 2424 \n6 Santini F Bottici V Elisei R Montanelli L Mazzeo S Basolo F Pinchera A Pacini F Cytotoxic effects of carboplatinum and epirubicin in the setting of an elevated serum tyrotropin for advanced poorly differentiated thyroid cancer. J Clin Endocrinol Metab 2002 87 4160 4165 12213865 \n7 Matuszczyk A Petersenn S Voigt W Kegel T Dralle H Schmoll HJ Bockisch A Mann K Chemotherapy with paclitaxel and gemcitabine in progressive medullary and thyroid carcinoma of the follicular epithelium. Horm Metab Res 2010 42 61 64 19735058 \n8 Ain KB Lee C Williams KD Phase 2 trial of thalidomide for therapy of radioiodine-unresponsive and rapidly progressive thyroid carcinomas. Thyroid 2007 17 663 670 17696837 \n9 Schlumberger M Tahara M Wirth LJ Robinson B Brose MS Elisei R Habra MA Newbold K Shah MH Hoff AO Gianoukakis AG Kiyota N Kim SB Krzyzanowska MK Dutcus CE de las Heras B Zhu J Sherman SI Lenvatinib versus placebo in radioiodine-refactory thyroid cancer. N Engl J Med 2015 372 621 630 25671254 \n10 Brose MS Nutting CM Jarzab B Elisei R Siena S Bastholt L de la Fouchardiere C Pacini F Paschke R Shong YK Sherman SI Smit JW Chung J Kappeler C Pena C Molnar I Schlumberger MJ Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomized, double-blind, phase 3 trial. Lancet 2014 384 319 328 24768112 \n11 Matsui J Yamamoto Y Funahashi Y Tsuruoka A Watanabe T Wakabayashi T Uenaka T Asada M E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer 2008 122 664 671 17943726 \n12 Matsui J Funahashi Y Uenaka T Watanabe T Tsuruoka A Asada M Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res 2008 14 5459 5465 18765537 \n13 Okamoto K Ikemori-Kawada M Jestel A von Konig K Funahashi Y Matsushima T Tsuruoka A Inoue A Matsui J Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization. ACS Med Chem Lett 2014 6 89 94 25589937 \n14 Onoda N Tokumoto M Noda S A case of recurrent anaplastic thyroid cancer treated by lenbatinib after successful long-term multimodal therapy (in Japanese). J Japan Surg Assoc 2016 77 291 295\n\n",
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"keywords": "Advanced thyroid cancer; Anaplastic thyroid cancer; Lenvatinib; Tracheal infiltration; Tyrosine kinase inhibitor",
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"title": "Significant Amelioration of Tracheal Stenosis following Lenvatinib in a Patient Who Has Anaplastic Thyroid Carcinoma with Bronchomediastinal Infiltration: A Case Report.",
"title_normalized": "significant amelioration of tracheal stenosis following lenvatinib in a patient who has anaplastic thyroid carcinoma with bronchomediastinal infiltration a case report"
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"abstract": "In current practice, gadolinium-based contrast agents have been considered safe when used at clinically recommended doses in patients without severe renal insufficiency. The causal relationship between gadolinium-based contrast agents and nephrogenic systemic fibrosis in patients with renal insufficiency resulted in new policies regarding the administration of these agents. After an effective screening of patients with renal disease by performing either unenhanced or reduced-dose-enhanced studies in these patients and by using the most stable contrast agents, nephrogenic systemic fibrosis has been largely eliminated since 2009. Evidence of in vivo gadolinium deposition in bone tissue in patients with normal renal function is well-established, but recent literature showing that gadolinium might also deposit in the brain in patients with intact blood-brain barriers caught many individuals in the imaging community by surprise. The purpose of this review was to summarize the literature on gadolinium-based contrast agents, tying together information on agent stability and animal and human studies, and to emphasize that low-stability agents are the ones most often associated with brain deposition.",
"affiliations": "From the Departments of Neuroradiology (J.R., R.H.N., M.C.) Centro Hospitalar de Lisboa Central (J.R.), Lisbon, Portugal Joana-Ramalho@netcabo.pt.;Radiology (R.C.S., M.R., R.H.N., M.A.), University of North Carolina Hospital, Chapel Hill, North Carolina.;Radiology (R.C.S., M.R., R.H.N., M.A.), University of North Carolina Hospital, Chapel Hill, North Carolina Hospital Garcia de Orta (M.R.), Almada, Portugal.;From the Departments of Neuroradiology (J.R., R.H.N., M.C.) Radiology (R.C.S., M.R., R.H.N., M.A.), University of North Carolina Hospital, Chapel Hill, North Carolina Santa Casa de Misericórdia de São Paulo (R.H.N.), São Paulo, Brazil.;Radiology (R.C.S., M.R., R.H.N., M.A.), University of North Carolina Hospital, Chapel Hill, North Carolina King Faisal Specialist Hospital and Research Center (M.A.), Riyadh, Saudi Arabia.;From the Departments of Neuroradiology (J.R., R.H.N., M.C.).",
"authors": "Ramalho|J|J|0000-0003-4067-0589;Semelka|R C|RC|0000-0001-5773-8071;Ramalho|M|M|0000-0003-2522-1670;Nunes|R H|RH|0000-0002-2483-964X;AlObaidy|M|M|0000-0002-9081-0087;Castillo|M|M|0000-0003-2960-1064",
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"title": "Gadolinium-Based Contrast Agent Accumulation and Toxicity: An Update.",
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"abstract": "Recurrent thrombotic events still occur despite dual antiplatelet therapy in patient's post percutaneous coronary intervention (PCI) could be attributed to high on-treatment platelet reactivity.\n\n\n\nA 44-year-old male, who had staged PCI to left anterior descending (LAD) 2 weeks after an anterior MI, with a drug-coated stent was readmitted with new anterior STEMI 35 days later. Coronary angiogram revealed mid-stent thrombus in situ. He had further uncomplicated PCI. Platelet function testing and genotyping showed clopidogrel high on-treatment platelet reactivity and CYP2C19*3/*17 genotype. Ticagrelor was commenced.\n\n\n\nThis case study is the first reported in Malaysia to document a patient with a CYP2C19*3/*17 genotype presenting with a stent thrombosis after an uncomplicated index PCI procedure.",
"affiliations": "Clinical Research Center, Sarawak General Hospital, Sarawak, Malaysia.;Department of Cardiology, Sarawak Heart Center, Sarawak, Malaysia.;Clinical Research Center, Sarawak General Hospital, Sarawak, Malaysia.;Department of Cardiology, Sarawak Heart Center, Sarawak, Malaysia.;Clinical Research Center, Sarawak General Hospital, Sarawak, Malaysia.",
"authors": "Tan|Shirley Siang Ning|SSN|;Koh|Keng Tat|KT|;Tiong|Lee Len|LL|;Ong|Tiong Kiam|TK|;Fong|Alan Yean Yip|AYY|",
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"title": "Late stent thrombosis in a patient with CYP2C19*3/*17 genotype and clopidogrel high on-treatment platelet reactivity.",
"title_normalized": "late stent thrombosis in a patient with cyp2c19 3 17 genotype and clopidogrel high on treatment platelet reactivity"
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"abstract": "BACKGROUND\nWe report a case of unilateral leukemic infiltration of the optic nerve caused by acute lymphoblastic leukemia.\n\n\nMETHODS\nA 30-year-old woman with acute lymphoblastic leukemia beginning 3 months before was referred for left visual loss. The left fundus showed optic disc engorgement by infiltrating tumor, with numerous hemorrhages and exudates caused by optic nerve leukemic infiltration.\n\n\nCONCLUSIONS\nOptic nerve leukemic infiltration is considered as central nervous system damage with severe prognosis. Treatment is based upon systemic and intrathecal chemotherapy and central nervous system radiation.",
"affiliations": "Service d'Ophtalmologie, CHU de Fort de France, Hôpital Pierre Zobda-Quitman, BP 632, 97261 Fort de France Cedex. harold.merle@chu-fortdefrance.fr",
"authors": "Merle|H|H|;Richer|R|R|;Donnio|A|A|;Jean-Charles|A|A|",
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"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D017254:Leukemic Infiltration; D009900:Optic Nerve; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
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"title": "Leukemic infiltration of the optic nerve.",
"title_normalized": "leukemic infiltration of the optic nerve"
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"abstract": "Attempted and completed self-enucleation, or removal of one's own eyes, is a rare but devastating form of self-mutilation behavior. It is often associated with psychiatric disorders, particularly schizophrenia, substance induced psychosis, and bipolar disorder. We report a case of a patient with a history of bipolar disorder who gouged his eyes bilaterally as an attempt to self-enucleate himself. On presentation, the patient was manic with both psychotic features of hyperreligous delusions and command auditory hallucinations of God telling him to take his eyes out. On presentation, the patient had no light perception vision in both eyes and his exam displayed severe proptosis, extensive conjunctival lacerations, and visibly avulsed extraocular muscles on the right side. An emergency computed tomography scan of the orbits revealed small and irregular globes, air within the orbits, and intraocular hemorrhage. He was taken to the operating room for surgical repair of his injuries. Attempted and completed self-enucleation is most commonly associated with schizophrenia and substance induced psychosis, but can also present in patients with bipolar disorder. Other less commonly associated disorders include obsessive-compulsive disorder, depression, mental retardation, neurosyphilis, Lesch-Nyhan syndrome, and structural brain lesions.",
"affiliations": "School of Medicine, University of California, Irvine, CA.;Department of Psychiatry, University of California, Irvine, CA.;Department of Psychiatry, University of California, Irvine, CA.;Department of Ophthalmology, Gavin Herbert Eye Institute, CA, USA.;Department of Ophthalmology, Gavin Herbert Eye Institute, CA, USA.",
"authors": "Castro|Hannah Muniz|HM|;Alvarez|John|J|;Bota|Robert G|RG|;Yonkers|Marc|M|;Tao|Jeremiah|J|",
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"country": "England",
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"fulltext": "\n==== Front\nMent IllnMent IllnMIMental Illness2036-74572036-7465PAGEPress Publications, Pavia, Italy 10.4081/mi.2017.7141Case ReportA Case of Attempted Bilateral Self-Enucleation in a Patient with Bipolar Disorder Castro Hannah Muniz 1Alvarez John 2Bota Robert G. 2Yonkers Marc 3Tao Jeremiah 31 School of Medicine, University of California, Irvine, CA2 Department of Psychiatry, University of California, Irvine, CA3 Department of Ophthalmology, Gavin Herbert Eye Institute, CA, USAUniversity of California, Irvine School of Medicine, 1001 Health Sciences Rd, Irvine, CA 92617, USA. hmunizca@uci.eduContributions: the authors contributed equally.\n\n26 6 2017 22 3 2017 9 1 714122 3 2017 22 3 2017 ©Copyright H. Muniz Castro et al. 20172017Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Attempted and completed self-enucleation, or removal of one’s own eyes, is a rare but devastating form of self-mutilation behavior. It is often associated with psychiatric disorders, particularly schizophrenia, substance induced psychosis, and bipolar disorder. We report a case of a patient with a history of bipolar disorder who gouged his eyes bilaterally as an attempt to self-enucleate himself. On presentation, the patient was manic with both psychotic features of hyperreligous delusions and command auditory hallucinations of God telling him to take his eyes out. On presentation, the patient had no light perception vision in both eyes and his exam displayed severe proptosis, extensive conjunctival lacerations, and visibly avulsed extraocular muscles on the right side. An emergency computed tomography scan of the orbits revealed small and irregular globes, air within the orbits, and intraocular hemorrhage. He was taken to the operating room for surgical repair of his injuries. Attempted and completed self-enucleation is most commonly associated with schizophrenia and substance induced psychosis, but can also present in patients with bipolar disorder. Other less commonly associated disorders include obsessive-compulsive disorder, depression, mental retardation, neurosyphilis, Lesch-Nyhan syndrome, and structural brain lesions.\n\nKey words\nself-enucleationbipolar disorderhyperreligiosity\n==== Body\nCompeting interest statement\nConflict of interest: the authors declare no potential conflict of interest.\n\nIntroduction\nSelf-enucleation, autoenucleation, or oedipism, is one of the major forms of self-mutilation. While it was previously thought to occur equally in men and women, a recent review revealed that the incidence may be higher in males than females.1 Prevalence is reported between 2.8-4.2 in 100,000 and incidence of 1 in 30 million people.2 A review of 56 cases found that one third of the cases are bilateral.3 The most common underlying motivations for self-enucleation are biblical interpretation, hypersexual or hyperreligious delusions, and paranoia regarding the eye.\n\nThe term oedipism was coined after Oedipus Rex, the mythological protagonist in Sophocles’ tragedy Oedipus the King, who blinded himself after unknowingly killing his father and marrying his mother.4 A commonly cited biblical reference from the New Testament in the Book of Matthew 5:29 is often cited by patients after self inflicting injuries to the eye: If thy right eye causeth thee to stumble, pluck it out, and cast it from thee.5 Hyperreligiosity tends to be more common among patients who attempt or complete self-enucleation, as in the patient we report. Approximately half of all cases of self-inflicted eye injuries are associated with religious delusions.6\n\nIn a recent review of 60 cases of complete and 9 cases of attempted self-enucleation, 43% of the cases were associated with schizophrenia, 25% were drug induced, and only 4% were associated with bipolar disorder.1 It is therefore imperative for physicians to be aware of the self-destructive behavior of patients, especially those with underlying mental disorders or drug abuse.\n\nCase Report\nA 52-year-old Caucasian male with history of bipolar disorder was brought in by his son to the emergency room (ER) following severe bilateral injuries to his eyes as an attempt to self-enucleate. The patient called his son to his bedroom after attempting to manually pull his eyes out with his fingers because he was instructed to do so by God and felt the need to cleanse myself from sin. The patient was transferred to the ER by ambulance and appeared calm. The son reports that the patient had been acting strange and displayed decreased appetite and increased wakefulness. He was noted to draw complex numerical pyramid schematics in a notebook, and endorsed that God was speaking to him more over the past week. He was diagnosed with bipolar disorder 18 years ago with most recent manic episode occurring 16 years ago, resulting in a failed suicide attempt by hanging and subsequent hospitalization. Since then, the patient followed up with an outpatient psychiatrist on Risperdal 1 mg every night (QHS) and lithium 900 mg QHS and was otherwise noted to be highly functional and performed well at a high functioning professional. The patient had no other history of self-harming behavior.\n\nOn mental status exam he appeared well groomed with good hygiene and was dressed appropriately for the weather. Speech was within normal limits for rate, rhythm, and volume. He exhibited normal psychomotor behavior; mood was good, and affect was inappropriately flat given the severity of his injuries. He related to his examiners in a nonchalant demeanor. His thought process was linear and goal-directed as evidenced by his stating I do not feel any pain or remorse, I feel I have done the right thing. What I was supposed to do and I am cleansed now. He endorsed auditory hallucinations of God’s voice, and denied visual hallucinations, paranoid ideation, and suicidal or homicidal ideations. He had no overt impairment of impulse control and was able to answer questions appropriately. His insight and judgment were impaired.\n\nOn ophthalmology exam the patient’s visual acuity (VA) was no light perception (NLP) for both eyes (OU). The patient’s eyes were found to have severe proptosis, extensive conjunctival lacerations and hemorrhage, and visibly avulsed extraocular muscles (Figure 1). A CT scan of the orbits demonstrated small and irregular globes, air within the orbits, and intraocular hemorrhage (Figure 2). Multiple foci of air and soft tissue stranding is also seen (Figure 3). The optic nerves were on stretch with posterior tenting of the globe suggesting severe optic nerve injury. Due to the optic nerve injury, the patient was started on intravenous (IV) methylprednisolone to reduce orbital edema and optic nerve inflammation and placed on IV and topical antibiotics. He was taken to the operating room by ophthalmology to repair the conjunctival lacerations, reattach the extraocular muscles and to limit the exposure of his eyes by detaching his lateral canthal tendons and suturing his eyelids closed with tarsorraphies (Figure 4).\n\nPostoperatively, the patient was admitted inpatient for medical and psychiatric stabilization. The psychiatry team evaluated the patient and gave the diagnosis of bipolar mania with psychotic features, with the most recent episode constituted by hyperreligious delusions and command auditory hallucinations. When he arrived on the inpatient psychiatric unit he was disorganized, responded to internal stimuli, and expressed thoughts of self-harm such as cutting off his arm to further cleanse himself. As his lithium level was therapeutic on admission (1.22), his mood stabilizer was switched to Depakote 1500 mg QHS and Risperdal was increased to 1 mg twice a day (BID). An ophthalmic examination one week after surgery demonstrated NLP vision OU with nonreactive pupils OU and complete ophthalmoplegia. Over the course of 3 weeks he slowly gained insight to the extent of the damage he caused and expressed some regret. He was discharged in stable psychiatric condition with close outpatient psychiatric follow-up.\n\nDiscussion and Conclusions\nAttempted self-enucleation is important to diagnose and manage as it can have both devastating ophthalmologic consequences. One of the most dreaded complications is complete visual loss, such as in this patient we report. Management requires assessment for visual potential, closure of wounds, and limitation of ophthalmic exposure in cases of severe proptosis. Orbital inflammation and edema can be controlled with intravenous corticosteroids if there is no concomitant head injury, as blunt head injuries were shown to have a higher mortality rate in patients receiving high dose steroids.7 Torn muscles should be reattached to circumvent permanent ophthalmoplegia. The retina should be evaluated for any tears or detachment. In cases of unilateral involvement, visual field testing should be performed as attempted self-enucleation may cause damage to the optic chiasm and affect the uninvolved eye.8 If the involved eye is damaged beyond repair, surgical enucleation may be necessary to reduce the risk of sympathetic ophthalmia,6 a rare condition of autoimmune damage against the uninvolved eye.\n\nThe medical and psychiatric literature suggest that patients who engage in attempts of self-enucleation are at risk for further self-mutilating behaviors. Dilly et al. presented a case in which a man engaged in self-enucleation of an eye which had already been enucleated via a previous attempt.9 This demonstrated that vison is not required for a psychotic patient to self-enucleate an eye. Witherspoon et al.10 demonstrated that patients who have engaged in unilateral self-enucleation are at increased risk of completing bilateral enucleation in the future. This supports the notion that recidivism is a strong component of self-enucleation behaviors even in the setting of grave consequences experienced due to a prior episode. Lack of pain and remorse have been common features of self-enucleation during psychosis and is consistent with our patient’s presentation.\n\nCases of attempted and completed self-enucleation are rare, but require comprehensive care and interdisciplinary management between teams in emergency medicine, internal medicine, psychiatry, and ophthalmology. Our case contributes to the literature by reporting a more uncommon situation of self-enucleation attempted by a previously high-functioning patient who developed an episode of bipolar mania and acute psychosis. Furthermore, our patient became psychotic even in the setting of supratherapeutic lithium dose on admission, therefore requiring the selection of alternative mood stabilizer and increase in antipsychotic dosage. Future studies of the most effective antipsychotic and mood stabilizers and doses would greatly benefit the psychiatric literature in management of this severe self-mutilation behavior.\n\nFigure 1. Appearance on presentation after attempted bilateral self-enucleation. The globes have been pulled anteriorly and display significant conjunctival lacerations and hemorrhage. Due to the anterior displacement there is severe exposure keratopathy with poor eyelid coverage of the corneas bilaterally. The superior rectus muscle is exposed and dehisced from its attachment in the right eye.\n\nFigure 2. Axial computed tomography scan of the orbits without contrast showring small, irregular globes anteriorly displaced. There is bilateral intraocular hemorrhage and disorganization of the intraocular contents.\n\nFigure 3. Coronal computed tomography scan of the orbits without contrast showing multiple foci of air and trace fat stranding within the extraconal and intraconal orbits bilaterally.\n\nFigure 4. Appearance during intraoperative wound exploration and repair. There is severe bilateral proptosis and conjunctival lacerations. The right eye shows a dehisced superior rectus muscle from the injury.\n==== Refs\nReferences\n1. Zhang M Tanaka S Mercier M \nGender and racial disparities in cases of auto enucleation . Semin Ophthalmol \n2016 ;31 :415 -25 .27142085 \n2. Fan AH \nAutoenucleation: a case report and literature review . Psychiatry (Edgmont) \n2007 ;4 :60 -2 .\n3. Gauger EH Sobel RK Allen RC \nComplications and outcomes after autoenucleation . Curr Opin Ophthalmol \n2015 ;26 :429 -38 .26163777 \n4. Sophocles GD \nOedipus the King . Chicago : University of Chicago Press ; 2010 .\n5. Holy Bible . American Standard Version . Camden : Thomas Nelson & Sons ; 2010 .\n6. Patton N \nSelf-inflicted eye injuries: a review . Eye (Lond) \n2004 ;18 :867 -72 .15002007 \n7. Edwards P Arango M Balica L \nFinal results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months . Lancet \n2005 ;365 :1957 -9 .15936423 \n8. Wolff RS Wright MM Walsh AW \nAttempted autoenucleation . Am J Ophthalmol \n1996 ;121 :726 -8 .8644825 \n9. Dilly JS Imes RK \nAutoenucleation of a blind eye . J Neuroophthalmol \n2001 ; 21 :30 -1 .11315978 \n10. Witherspoon D Feist FW Morris RE Feist RM \nOcular self-mutilation . Ann Ophthalmol \n1989 ; 21 :255 -9 .2774433\n\n",
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"abstract": "Metastatic squamous cell carcinoma anal cancer (SCCA) is rare. Prospective data recommends front-line platinum doublet combinations and second-line anti-programmed death-1 therapy. Standard therapy beyond these treatments are currently unknown. We evaluated anti-EGFR monoclonal antibody (mAb) outcomes in metastatic SCCA.\n\n\n\nMetastatic SCCA patients given anti-EGFR mAb from Oct 2011-May 2018 were included. Primary endpoints included best response, progression-free survival, and overall survival.\n\n\n\n56 patients were evaluated with a median of one prior therapy. Most patients (~90%) received anti-EGFR mAbs with chemotherapy. Response rate (any response) was 41%. Median PFS was 4.3 months with a median OS of 16 M. Seven patients with disease control proceeded onto maintenance therapy (anti-EGFR mAb ± a fluoropyrimidine) with a median PFS of 13.8 M. Next generation sequencing of 16 pts (28%) showed 4 pts had a PIK3CA mutation with 3 of these 4 patients demonstrating progression on initial restaging.\n\n\n\nOur analysis suggests anti-EGFR mAb therapy with chemotherapy provides clinical benefit in previously treated metastatic SCCA. Our maintenance therapy and the role of PIK3CA MT outcomes were thought-provoking.\n\n\n\nMetastatic SCCA patients have limited options; therefore, anti-EGFR mAbs may provide benefit in the treatment armamentarium and should be further explored.",
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"authors": "Rogers|Jane E|JE|;Jácome|Alexandre A A|AAA|0000-0001-9070-4383;Ohinata|Aki|A|;Wolff|Robert|R|;Morris|Van K|VK|;Johnson|Benny|B|;Mehdizadeh|Amir|A|;Rothschild|Nicole D|ND|;Ahmed|Shahab U|SU|;Guerra|Jennifer L|JL|;Eng|Cathy|C|",
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"abstract": "Primary autoimmune neutropenia (P-AIN) is an extremely rare disease. The most effective treatment for primary P-AIN is a granulocyte colony-stimulating factor; however, no curative treatment has been reported. We herein report a case of an adult P-AIN patient with a relatively mild medical history (irrespective of the severe neutropenia) who showed a sustained hematological response over seventeen months after the initiation of treatment with subcutaneous Alemtuzumab.",
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"abstract": "Sunitinib is an oral tyrosine kinase inhibitor (TKI) commonly used in the treatment of renal cell carcinoma (RCC). Among a broad range of toxicities, anemia and macrocytosis are common in patients treated with sunitinib. Correlation between sunitinib-associated macrocytosis and cobalamin deficiency has been reported in small case series and retrospective analyses, although others have not found an association. Here, we present a case of transfusion-dependent macrocytic anemia with cobalamin and folate deficiency in a patient with RCC treated with sunitinib.",
"affiliations": "Oncology, Olive View - University of California Los Angeles Medical Center, Sylmar, USA.;Internal Medicine, Olive View - University of California Los Angeles Medical Center, Sylmar, USA.;Oncology, Olive View - University of California Los Angeles Medical Center, Sylmar, USA.",
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"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.4310UrologyOncologyOtherA Case of Cobalamin Deficiency and Macrocytic Anemia Secondary to Sunitinib Muacevic Alexander Adler John R Reed Jarred P 1Chung Joan 2Banerjee Natasha 1\n1 \nOncology, Olive View - University of California Los Angeles Medical Center, Sylmar, USA \n2 \nInternal Medicine, Olive View - University of California Los Angeles Medical Center, Sylmar, USA \nJarred P. Reed jreed2@dhs.lacounty.gov25 3 2019 3 2019 11 3 e431015 3 2019 25 3 2019 Copyright © 2019, Reed et al.2019Reed 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/18669-a-case-of-cobalamin-deficiency-and-macrocytic-anemia-secondary-to-sunitinibSunitinib is an oral tyrosine kinase inhibitor (TKI) commonly used in the treatment of renal cell carcinoma (RCC). Among a broad range of toxicities, anemia and macrocytosis are common in patients treated with sunitinib. Correlation between sunitinib-associated macrocytosis and cobalamin deficiency has been reported in small case series and retrospective analyses, although others have not found an association. Here, we present a case of transfusion-dependent macrocytic anemia with cobalamin and folate deficiency in a patient with RCC treated with sunitinib.\n\nsunitinibmacrocytic anemiacobalaminfolatetoxicityrenal cell carcinomatyrosine kinase inhibitorThe 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\nSunitinib is an oral inhibitor of tyrosine kinases including vascular endothelial growth factor receptor (VEGFR), and has classically been used as a first-line treatment in advanced RCC. Due to off-target effects, the VEGFR-targeted TKIs have a number of class-specific side effects including hematologic toxicity. In a pivotal phase III trial, anemia (71%), neutropenia (72%), and thrombocytopenia (65%) were frequent events in patients treated with sunitinib for metastatic RCC [1]. Elevations in mean corpuscular volume (MCV) are also common, and in previous reports have been shown to occur in at least of patients on sunitinib after a median of 3 cycles of treatment [2]. Associations between sunitinib and deficiencies of folate and cobalamin (or vitamin B12) are less well-described but have been shown in small case series [3-5]. The case below involves a patient who developed macrocytic anemia with deficiencies of cobalamin and folate and bolsters evidence that megaloblastic anemia can occur in a subset of patients treated with sunitinib.\n\nCase presentation\nA 71-year-old male presented with metastatic clear-cell RCC. In November 2016, he was incidentally found on imaging to have a left renal mass but declined further workup and was lost to follow-up. The patient was subsequently noted on routine laboratories in September 2017 to have creatinine elevation to 1.45 mg/dL from an unknown baseline. Renal ultrasound revealed a solid left kidney mass measuring up to 10 cm. Systemic imaging with computed tomography of the chest, abdomen, and pelvis showed a 13.5 x 7.6 cm enhancing, exophytic mass of the left kidney and innumerable bilateral pulmonary nodules concerning for metastatic malignancy. Cytoreductive nephrectomy was performed in November 2017 and pathology showed clear-cell RCC with sarcomatoid features. Approximately five weeks later, he was initiated on systemic treatment with sunitinib 50 mg daily, six-week cycles with a two-weeks on, one-week off schedule.\n\nLaboratories at baseline showed hemoglobin 9.1 g/dL and MCV 88.1 fL. Imaging with computed tomography after three cycles of sunitinib showed a partial response; however, serial laboratories showed the development of worsening macrocytic anemia with hemoglobin 6.6 g/dL and MCV 106.9 fL. Further laboratory workup showed total bilirubin 2.6 mg/dL, direct bilirubin 0.2 m/dL, lactate dehydrogenase 210 U/L, and haptoglobin 27 mg/dL. Direct antiglobulin testing was negative and iron studies, thyroid function tests, and liver tests were normal. Notably, the patient was found to have significant deficiencies in cobalamin (<146 pg/dL; normal, 213-816) and folate (5.9 ng/dL; normal, > 7) and peripheral smear showed numerous hypersegmented neutrophils. Testing for antibodies against parietal cells and the intrinsic factor was negative. There were no prior values of cobalamin or folate for comparison. On review of history, the patient endorsed a balanced diet with adequate intake of sources of folate and cobalamin, had no history of gastrointestinal surgeries, and denied significant alcohol use. Treatment of nutritional deficiencies was initiated with folic acid one milligram by mouth daily and cobalamin intramuscular 1000 mcg for one dose followed by cobalamin one gram by mouth daily. The patient was transfused with two units of packed red blood cells. Although there was some concern that these findings represented toxicity from sunitinib, given evidence of clinical benefit the decision was made to continue treatment with close monitoring of hematologic parameters.\n\nRepeat laboratories during cycle four of sunitinib showed stable blood counts and normalization of cobalamin (813 pg/dL) and folate (>20 ng/mL) levels, however during cycle five the patient complained of worsening fatigue and exertional dyspnea, and laboratories showed worsening macrocytic anemia with hemoglobin 7.1 g/dL and MCV 108.0 fL. Cobalamin and folate levels remained normal. The patient was transfused with two units packed red blood cells and sunitinib was held.\n\nAfter four weeks of sunitinib, laboratories showed hemoglobin 9.2 g/dL and MCV 100.5 fL, and the patient reported a marked improvement in energy. Sunitinib was restarted at a reduced dose of 37.5 mg daily on two weeks on and one week off schedule. The patient was also started on a regimen of parenteral cobalamin (1000 mcg subcutaneous daily for seven days, then weekly for four weeks, then monthly) and continued on oral folate. Following one cycle, hemoglobin was relatively stable at 8.6 g/dL and MCV had improved to 93.9 fL. Labs for several cycles thereafter showed stable levels of hemoglobin, folate, and cobalamin. Current treatment plans are to continue sunitinib with close hematological monitoring and ongoing supplementation with oral folate and parenteral cobalamin.\n\nDiscussion\nMacrocytosis is a well-documented side effect of sunitinib. Retrospective analyses have shown that macrocytosis develops in a large proportion of patients after approximately three months of treatment, worsens with continued treatment, and resolves with discontinuation of sunitinib [1]. In the largest study, Rini et al. showed that in a cohort of patients treated with sunitinib for at least three months, 41 out of 61 patients (67%) had macrocytosis at some point during their course, with a median increase in MCV of 5.1 fL (p < 0.001) at three months. Additionally, among 10 patients in the analysis who had laboratories 2-3 months after discontinuation of sunitinib, MCV decreased by a median of 9.7 pL (p = 0.002) [2]. Notably, some studies suggest macrocytosis secondary to treatment with sunitinib could be a marker of progression-free survival in RCC, as has been found with other TKI-associated toxicities such as hypertension and abnormal thyroid function [3,6]. \n\nSunitinib-associated macrocytosis has been hypothesized to occur via off-target inhibition of the stem cell growth factor c-Kit, leading to impaired erythrocyte maturation [2]. This conjecture is bolstered by the observation that macrocytosis is seen in 42% of patients treated with imatinib, a potent inhibitor of c-Kit, but is not seen with the VEGFR-targeted TKI sorafenib, which has only weak activity against c-Kit [2-3].\n\nAlthough sunitinib-associated macrocytosis and anemia may occur secondary to the inhibition of erythrocyte maturation, there have also been, to our knowledge, at least three reports of an association with cobalamin deficiency. In 2007, two small case series were published successively in The New England Journal of Medicine. Gilleson et al. reported on six patients who developed macrocytosis after treatment with sunitinib. All patients had deficiencies in cobalamin and five had reduced levels of holotranscobalamin. Folate was normal in all patients and none developed worsening anemia or symptoms of cobalamin deficiency [5]. Shortly thereafter, Billemont et al. showed that in a cohort of 10 patients receiving sunitinib who developed marked macrocytosis (MCV > 105 fL), mean levels of cobalamin (112 pmol/L; normal level, >133) and folate (4.03 nmol/L; normal level, >6.8) were decreased, and five of 10 patients had anemia (mean hemoglobin 8.84 g/dL) [4]. In a later retrospective study of 27 patients treated with sunitinib, eight patients who developed macrocytosis had levels of cobalamin and folate examined. Four patients were found to have cobalamin deficiency, while none had evidence of folate deficiency. Patients with cobalamin deficiency had a non-significant trend toward higher MCV compared to those with normal levels (104.9 + 4.9 vs 100 + 0.6 fL after three cycles; p = 0.2) [3].\n\nOther reports have contradicted these findings. In a retrospective analysis of 21 patients with sunitinib-related macrocytosis, Price et al found cobalamin deficiency in only two of seven patients for whom data were available, a smaller proportion than other studies. Folate deficiency was not found in eight patients [7]. Additionally, the previously mentioned retrospective analysis by Rini et al did not find abnormal levels of cobalamin (n = 12; median, 422 pg/mL; normal, 221-700) or folate (n = 10; median, 15.4 ng/mL; normal, 2.8-18) [2].\n\nA theoretical mechanism for sunitinib-associated cobalamin deficiency has not been clearly elucidated. In general, cobalamin deficiency can occur via reduced absorption, reduced release from stores, or increased cellular consumption [8]. Gilleson hypothesized that given that there is no known association between TKIs and cobalamin metabolism, impairment of gastrointestinal absorption may be the most likely mechanism. Patients in their series were treated with parenteral cobalamin, and none developed worsening anemia [5]. Our patient had evidence of megaloblastic anemia that persisted despite oral cobalamin replacement and improved with parenteral replacement. Although his cobalamin level did improve with oral therapy, laboratory testing of cobalamin comes with caveats: various conditions including malignancy can lead to inaccurate measurement and tissue stores of cobalamin are only moderately correlated with serum levels [8]. On the other hand, it is known that cobalamin stores in healthy adults are usually large and cobalamin deficiency typically takes years to develop. Given deficiency developed over only a few months in these series, this argues against impaired gut absorption as the sole cause of sunitinib-associated deficiency and we hypothesize that the mechanism may be multifactorial. Further studies to clarify the frequency of sunitinib-associated cobalamin deficiency and determination of its cause would be useful.\n\nConclusions\nMacrocytosis and anemia are common effects in patients treated with sunitinib and likely occur via inhibition of c-Kit. Data from several small studies suggest that a subset of patients can also develop megaloblastic anemia secondary to cobalamin deficiency. The mechanism for this effect is not clear. Patients with more severe macrocytosis may be more likely to have evidence of cobalamin deficiency. In a small case series, parenteral cobalamin replacement therapy appeared to mitigate these effects. Our patient had evidence of severe, transfusion-dependent megaloblastic anemia which persisted despite oral cobalamin replacement but has improved over a short interval of parenteral replacement. While our patient also had decreased levels of folate, evidence for an association with folate deficiency is less convincing and has been seen in only one small case series. Given good evidence for cobalamin deficiency as a rare side effect of sunitinib, this should be added to materials describing the possible toxicities associated with sunitinib in order to promote physician awareness. Further studies would be useful, and clinicians should consider monitoring cobalamin levels in patients who develop macrocytosis while on treatment with sunitinib.\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 Sunitinib versus interferon alfa in metastatic renal-cell carcinoma N Engl J Med Motzer RJ Hutson TE Tomczak P 115 124 356 \n2 Sunitinib-induced macrocytosis in patients with metastatic renal cell carcinoma Cancer Rini BI Choueiri TK Elson P 1309 1314 113 2008 18618496 \n3 Macrocytosis during sunitinib treatment predicts progression-free survival in patient with metastatic renal cell carcinoma Med Oncol Kucharz J Giza A Dumnicka P 109 33 2016 27573381 \n4 Macrocytosis due to treatment with sunitinib N Engl J Med Billemont B Izzedine H Rixe O 1351 1352 357 2007 17898111 \n5 Macrocytosis and cobalamin deficiency in patients treated with sunitinib N Engl J Med Gillessen S Graf L Korte W Cerny T 2330 2331 356 2007 17538098 \n6 Macrocytosis as a potential parameter associated with survival after tyrosine kinase inhibitor treatment Eur J Cancer Kloth JSL Hamberg P Mendelaar PAJ 101 106 56 2016 26841094 \n7 Sunitinib causes macrocytosis in patients with advanced renal cell carcinoma Curr Oncol Price J Shaarbaf R Wood L 30 33 17 2010 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854633/ 20404975 \n8 Laboratory testing for cobalamin deficiency in megaloblastic anemia Am J Hematol Oberley MJ Yang DT 6 88 2013\n\n",
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"issue": "11(3)",
"journal": "Cureus",
"keywords": "cobalamin; folate; macrocytic anemia; renal cell carcinoma; sunitinib; toxicity; tyrosine kinase inhibitor",
"medline_ta": "Cureus",
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"pubdate": "2019-03-25",
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"title": "A Case of Cobalamin Deficiency and Macrocytic Anemia Secondary to Sunitinib.",
"title_normalized": "a case of cobalamin deficiency and macrocytic anemia secondary to sunitinib"
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"abstract": "OBJECTIVE\nTo determine the incidence of skeletal-related events among multiple myeloma patients who received chemotherapy without a bone-modifying agent (zoledronic acid and denosumab) versus those who received chemotherapy with a bone-modifying agent. The secondary objective was to determine the incidence of skeletal-related events in patients without any prior history of skeletal-related events and who were treated with zoledronic acid every four weeks versus those who received zoledronic acid at an extended interval of every twelve weeks. Additional secondary objectives included the incidence of nephrotoxicity, hypocalcemia and osteonecrosis of the jaw in all patients.\n\n\nMETHODS\nThis institutional review board-approved, retrospective cohort study included patients 18 to 89 years old with a diagnosis of multiple myeloma, who were being treated with chemotherapy between July 1, 2016 and October 31, 2019. Safety and efficacy were assessed through analysis of pertinent data collected: patient demographics, baseline skeletal-related events, development of new skeletal-related events, number and type of bone-modifying agent doses administered, and drug-related toxicities such as nephrotoxicity, hypocalcemia, and osteonecrosis of the jaw.\n\n\nRESULTS\nA total of 73 patients were included. New skeletal-related events occurred in 12 patients (27%) in the chemotherapy without a bone-modifying agent group and in 5 patients (17%) in the chemotherapy with a bone-modifying agent group (OR = 0.56, 95% CI [0.172-1.8]; P = 0.32). The incidence of skeletal-related events was similar among patients receiving zoledronic acid every four weeks versus every twelve weeks in patients without a prior skeletal-related event (N = 0 vs. N = 2 respectively; P = 0.47). There were no statistically significant differences observed in each of the three secondary safety endpoints: incidence of hypocalcemia, nephrotoxicity and osteonecrosis of the jaw.\n\n\nCONCLUSIONS\nMultiple myeloma patients receiving chemotherapy without a bone-modifying agent had higher rates of skeletal-related events compared to those being treated with chemotherapy and a bonemodifying agent. Our results highlight the benefit of utilizing bonemodifying agents for the prevention of skeletal-related events in all multiple myeloma patients being treated with chemotherapy.",
"affiliations": "Allegheny Health Network, Pittsburgh, PA, USA.;Allegheny Health Network, Pittsburgh, PA, USA.;Allegheny Health Network, Pittsburgh, PA, USA.;Highmark Inc., Pittsburgh, PA, USA.",
"authors": "Billias|Christina|C|;Langer|Megan|M|https://orcid.org/0000-0002-0383-3564;Ursu|Sorana|S|https://orcid.org/0000-0002-0496-5788;Schorr|Rebecca|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1078155221996039",
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"issn_linking": "1078-1552",
"issue": null,
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Zoledronic acid; bone-modifying agents; denosumab; multiple myeloma; skeletal related events",
"medline_ta": "J Oncol Pharm Pract",
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"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1078155221996039",
"pmc": null,
"pmid": "33593137",
"pubdate": "2021-02-16",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety and efficacy of bone-modifying agents among multiple myeloma patients: A retrospective cohort study.",
"title_normalized": "safety and efficacy of bone modifying agents among multiple myeloma patients a retrospective cohort study"
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{
"abstract": "Oral lichen planus is a chronic inflammatory mucocutaneous disease. Topical use of steroids and other immuno-modulating therapies have been tried for this intractable condition. Nowadays, tacrolimus ointment is used more commonly as a choice for treatment. However, a number of discussions have taken place after tacrolimus was reported to be carcinogenic. This report describes a patient who applied tacrolimus ointment to the lower lip after being diagnosed with oral lichen planus in 2008, and whose lesion developed squamous cell carcinoma in 2010. Since the relationship between tacrolimus and cancer development has been reported in only a few cases, including this case report, the clinician must be careful selecting tacrolimus as a second-line treatment for oral lichen planus.",
"affiliations": "Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.;Oral and Maxillofacial Surgery, Nippon Dental University Hospital, Tokyo, Japan.;Oral and Maxillofacial Surgery, Nippon Dental University Hospital, Tokyo, Japan.;Division of Oral Diagnosis, Dental and Maxillofacial Radiology and Oral Pathology Diagnostic Services, Nippon Dental University Hospital, Tokyo, Japan.;Samoncho Dermatological Clinic, Tokyo, Japan.;Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. kawana@z6.keio.jp.",
"authors": "Morita|Mayu|M|;Asoda|Seiji|S|;Tsunoda|Kazuyuki|K|;Soma|Tomoya|T|;Nakagawa|Taneaki|T|;Shirakawa|Masayori|M|;Shoji|Hirofumi|H|;Yagishita|Hisao|H|;Nishikawa|Takeji|T|;Kawana|Hiromasa|H|",
"chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10266-016-0255-4",
"fulltext": "\n==== Front\nOdontologyOdontologyOdontology1618-12471618-1255Springer Japan Tokyo 25510.1007/s10266-016-0255-4Case ReportThe onset risk of carcinoma in patients continuing tacrolimus topical treatment for oral lichen planus: a case report Morita Mayu 12Asoda Seiji 1Tsunoda Kazuyuki 1Soma Tomoya 1Nakagawa Taneaki 1Shirakawa Masayori 3Shoji Hirofumi 3Yagishita Hisao 4Nishikawa Takeji 5Kawana Hiromasa (81 3) 3353 1211kawana@z6.keio.jp 11 0000 0004 1936 9959grid.26091.3cDivision of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582 Japan 2 0000 0004 1772 3416grid.415801.9Department of Oral Surgery, Shizuoka City Shimizu Hospital, Shizuoka, Japan 3 0000 0004 1762 168Xgrid.470109.bOral and Maxillofacial Surgery, Nippon Dental University Hospital, Tokyo, Japan 4 0000 0004 1762 168Xgrid.470109.bDivision of Oral Diagnosis, Dental and Maxillofacial Radiology and Oral Pathology Diagnostic Services, Nippon Dental University Hospital, Tokyo, Japan 5 Samoncho Dermatological Clinic, Tokyo, Japan 1 7 2016 1 7 2016 2017 105 2 262 266 14 12 2015 30 4 2016 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Oral lichen planus is a chronic inflammatory mucocutaneous disease. Topical use of steroids and other immuno-modulating therapies have been tried for this intractable condition. Nowadays, tacrolimus ointment is used more commonly as a choice for treatment. However, a number of discussions have taken place after tacrolimus was reported to be carcinogenic. This report describes a patient who applied tacrolimus ointment to the lower lip after being diagnosed with oral lichen planus in 2008, and whose lesion developed squamous cell carcinoma in 2010. Since the relationship between tacrolimus and cancer development has been reported in only a few cases, including this case report, the clinician must be careful selecting tacrolimus as a second-line treatment for oral lichen planus.\n\nKeywords\nOral lichen planusSquamous cell carcinomaTacrolimusLipissue-copyright-statement© The Society of The Nippon Dental University 2017\n==== Body\nIntroduction\nOral lichen planus (OLP) is a chronic mucocutaneous disease, and the etiology of OLP has been reported that stress, systemic medications, dental materials, chronic liver disease, hepatitis C virus and graft-versus-host disease have been put forward to explain the pathogenesis [1]. It has been reported that this intractable disease has a 0.1–4 % risk of malignant transformation [2]. Up until now, the topical use of steroids and other immuno-modulating therapies have been the standard treatment for OLP.\n\nSince 1999, when Vente et al. [3] reported the validity of tacrolimus ointment for OLP, a number of pilot studies have been performed [4–6]. Tacrolimus, also called FK506, is a macrolide immunosuppressant produced by Streptomyces tsukubaensis and has similar effects as cyclosporin A. It acts by inhibiting calcineurin, a ubiquitous calcium-dependent protein phosphatase that is responsible for immune response [7]. However, in recent years there have been a number of discussions held after reports regarding its carcinogenicity appeared.\n\nWe hereby report a case of a patient with OLP who, after using tacrolimus ointment for 14 months, developed squamous carcinoma of the lower lip.\n\nCase report\nIn October 2003, a 63-year-old male patient was referred to the Department of Oral and Maxillofacial Surgery at a regional hospital (Fig. 1a, Hospital A) for evaluation of a white slightly eroded lesion with white streaks on the lower lip (Fig. 1b). The patient had a history of hypertension and an adrenal gland tumor and was an occasional social drinker, but had no history of smoking and reported no allergies. The first biopsy was taken in October 2003, and the histopathological diagnosis was “oral lichen planus” (Fig. 1f). The patient had dental silver fillings in molar teeth, but did not have any intraoral lesions consistent with OLP except on the lower lip. Topical steroids were first used to treat OLP at the first hospital (Fig. 1a, Hospital A). Because the clinical appearance of the lesion continued to change among visits (Fig. 1c–e), biopsies were taken 4 times from March 2004 to March 2007 at Hospital A. The histopathological diagnosis was either “oral lichen planus” or “hyperkeratosis without dysplasia,” but the clinical appearance of the lesion became gradually worse. The reason why we diagnosed it as OLP in histological section is: (1) the typical band-like lymphocytic infiltrates were seen in the whole section (Fig. 1g). (2) Epithelial surface hyperkeratosis or hyperparakeratosis was seen. (3) Civatte bodies were seen in the bottom of epithelial or lamina propria (Fig. 1h). (4) The histological patterns in B cell and T cell. B cells and plasma cells are infrequent in OLP, and in this case, we could not observe B cells, because plasma cells were not observed in HE staining (Fig. 1h). Immunostaining was performed, and the results showed most lymphocytes were positive to CD3; however, only few CD20 positive cells were observed (Fig. 1i, j). The patient used topical steroids at Hospital A (Fig. 1a) when the lesion got worse. We did not diagnose as oral lichenoid lesions (OLL), because B cell follicles, also known as lymphoid follicles, were not observed in histological section.Fig. 1 \na Summarized schema of the course. Clinical appearances of the lesion from 2003 to 2007. b Photograph taken in October 2003. White lesions seen on both sides of the lower lip. c Photograph taken in August 2004. The surface appearance of the lower lip returned to normal. d Photograph taken in March 2007. The white spot of the lesion appeared again on the left\nside of the lower lip. e Photograph taken in June 2007. Biopsy was performed in 2007 from left\nside of lower lip (indicated by an arrow). f A biopsy in 2003 from the lower lip suggests “oral lichen planus with mild dysplasia from reactive” biopsy specimen showing band-like infiltration of lymphocytes at the dermo-epidermal interface (HE stain, original magnification ×100). A biopsy in 2007 from the lower lip suggests “oral lichen planus.” g Loupe imaging stained with HE. Enhancement of partial cornified layer of the mucosal epithelial layer and typical band-like lymphocytic infiltrate were seen in this section. h High magnification of g (HE stain, high magnification ×20). Infiltration of lymphocytes in the epithelial layer, and mild liquefactive degeneration were seen in this section. i Immunostaining using anti-CD3 antibody. j Immunostaining using anti-CD20 antibody\n\n\n\n\nIn August 2008, the patient was referred to another hospital (Fig. 1a, Hospital B), Department of Dentistry, School of Medicine in Tokyo, since the clinical appearance was clearly becoming worse. The clinical diagnosis made there was again OLP, and the patient was given tacrolimus 0.1 % ointment for topical application. The patient used the topical ointment intermittently based on the condition of his lesion for 14 months. Tacrolimus was not used per the recommendations that are shown in Table 1, because the patient tried 3 times a day to speed up the cure. The surface appearance of the lower lip returned to normal when he used tacrolimus, but the stinging sensation remained. Again the symptoms got worse when the patient stopped using the ointment, so the patient had to continue using it for 14 months. A biopsy was taken from the lower lip when the lesion got worse again when the tacrolimus treatment was terminated in 2009, and the histopathological report was not diagnostic and described as “inflammation, and no malignancy is seen.”Table 1 Information for healthcare professionals: tacrolimus ointment (FDA) [13]\n\nApply a thin layer of tacrolimus ointment twice daily to the areas of skin affected by eczema\t\nAvoid getting tacrolimus ointment in the eyes or mouth. Do not swallow tacrolimus ointment\t\nDo not use ultraviolet light therapy, sun lamps, or tanning beds during treatment with tacrolimus ointment\t\nUse tacrolimus ointment only as a second-line agent for short-term and intermittent treatment of atopic dermatitis, a form of eczema, in patients unresponsive to, or intolerant of other treatments\t\nUse tacrolimus ointment only for short periods of time, not continuously. The long-term safety of tacrolimus ointment is unknown\t\nUse the minimum amount of tacrolimus ointment needed to control the patient’s symptoms. In animals, increasing the dose resulted in higher rates of cancer\t\n\n\n\nIn September 2009, the patient visited a dermatology specialist at Samoncho Dermatological Clinic, Tokyo, because the lesion did not improve, even though the tacrolimus ointment had been applied to the lower lip. The stinging sensation was still present. When the patient visited to Samoncho Dermatological Clinic for the first time, the tacrolimus treatment was terminated. Wet scrapings from the lower lip mounted in 15 % potassium hydroxide (KOH preparation) revealed pseudomycelia and blastospores, suggesting oral candidiasis. The patient was given 1 % lanoconazole ointment for 4 weeks, which healed the lesion on the lower lip. Then, 3 small infiltrated lesions with rough surfaces appeared on the lower lip, where 0.1 % triamcinolone acetonide patches were applied for 2 months. At the following visit in January 2010, the left lower lip had worsened to grow into an ulcerated papillomatous nodule on its left side. Because of these changes in the lesion, the patient was finally referred to the Department of Oral and Maxillofacial Surgery, Keio University School of Medicine, in January 2010. The ulcerated lesion was 22 × 18 × 8 mm with indurated borders, and white spots were found around the periphery (Fig. 2a). Computed tomography and magnetic resonance imaging were performed, but it only showed exophytic lesions on the lower lip. A biopsy was taken from the exophytic lesion, and the histopathological diagnosis was “well-differentiated squamous cell carcinoma” (Fig. 2b). Positron emission tomography–computed tomography was then performed, and the tumor was classified as T2N0M0. The patient was given the choice of radiation therapy or surgery, and the patient chose to undergo surgery. The extent of resection of the lesion from the tumor was about 10 mm, and a white lesion around 5 mm was removed. Both flaps were designed as V-Yflap, and red lips used a pedicle flap of buccal mucosa on both sides. Five years have passed since the operation, and there has been no recurrence. The patient is satisfied and has no complaints regarding the aesthetics and the functional capabilities of the lower lip.Fig. 2 \na Photograph taken in January 2010. The ulcerated lesion of the lower lip (22 × 18 × 8 mm) with indurated borders. b A biopsy from the lower lip suggests “well-differentiated squamous cell carcinoma.” A horn pearl is prominent in the right\npart of the image (HE stain, original magnification a ×40; b ×100)\n\n\n\n\nDiscussion\nOLP is a chronic inflammatory mucocutaneous disease, and topical use of steroids and other immuno-modulating therapies have been used for this intractable condition. Nowadays, tacrolimus ointment is used more commonly and seems effective as a second choice to treat it [8]. The question in this case lies in whether OLP was diagnosed properly in the early stages. As Jing-Ling Xue et al. reported, most patients had multiple oral sites of involvement; the disease was confined to the lower lips in only 60 patients out of 674 patients with OLP [9]. In the case of this patient, the lesion on the lower lip could not be firmly diagnosed as OLP in clinical appearance, which was the reason why a biopsy was performed several times.\n\nCurrently, OLL is considered by some to put the lesion at risk of malignant transformation [10]. In a recent study, it was shown that all cases of malignant transformation showed cases of OLL but not OLP; however, both lesions are likely to have a risk of malignant transformation. Very recently, Fitzpatrick et al. reported about oral lichenoid mucositis and cancer development and discussed the difficulties in evaluating lichenoid responses in oral lesions with or without dysplasia [11]. The potential for malignant transformation is still controversial. We also think that while OLP, which was the diagnosis from 2003 to 2007, did not become malignant directly in this case, OLL may follow after the use of tacrolimus ointment.\n\nTacrolimus ointment is known to cause both skin cancers and lymphoma in humans by suppressing the body’s normal immune defenses against cancer. In animals, increasing the dose resulted in higher rates of cancer. Tacrolimus ointment is sometimes absorbed through the skin, although usually at very low amounts. In case of OLP, the blood concentration absorbed from the oral mucosa is reported between lower than 1.3–9.6 ng/ml [12]. This number is lower than 20 ng/ml, the safe blood concentration for the body using tacrolimus after a kidney transplantation [13]. A pharmaceutical company producing tacrolimus in Japan has received 21 post-marketing reports linking tacrolimus ointment with cancer-related adverse effects, including 16 lymphomas, 3 cutaneous tumors, and 2 other tumor types. On the other hand, it is reported that the risk of cancer while using tacrolimus is lower than the risk of cancer naturally developing (i.e., not using immunosuppressants) [14].\n\nThe Food and Drug Administration (FDA) issued a public health advisory in June 2006. The advice to physicians is shown in Table 1. The British Society of Oral Medicine issued guidelines for the management of OLP in 2010 [15].\n\nIn this case as in others, OLP might have transformed to SCC naturally, as already reported [10]. However, the tumor developed from the lower lip where the patient applied the tacrolimus ointment, and as such we could not rule out the relationship between the long-term use of tacrolimus and cancer development. In addition, until distinct clinical and histological criteria have been developed on how to differentiate OLP from OLL, both lesions have to be considered as at risk of malignant transformation.\n\nCompliance with ethical standards\nConflict of interest\nThe authors declare that they have no conflict of interest.\n==== Refs\nReferences\n1. Jayasri Krupaa R Leena Sankari S Masthan KMK Rajesh E Oral lichen planus: an overview J Pharm Bioallied Sci 2015 7 S158 S161 26015696 \n2. Silverman S Jr Bahl S Oral lichen planus update Am J Dent 1997 10 259 263 9590911 \n3. Vente C Reich K Rupprect R Neumann C Erosive mucosal lichen planus: response to topical treatment with tacrolimus Br J Dermatol 1999 140 338 342 10.1046/j.1365-2133.1999.02672.x 10233234 \n4. Kaliakatsou F Hodgson TA Lewsey JD Hegarty AM Murphy AG Porter SR Management of recalcitrant ulcerative oral lichen planus with topical tacrolimus J Am Acad Dermatol 2002 46 35 41 10.1067/mjd.2002.120535 11756943 \n5. Rozycki TW Rogers RS 3rd Pittelkow McEvoy MT el-Azhary RA Bruce AJ Topical tacrolimus in the treatment of symptomatic oral lichen planus: a series of 13 patients J Am Acad Dermatol 2002 46 27 34 10.1067/mjd.2002.119648 11756942 \n6. Mattsson U Magnusson B Jontell M Squamous cell carcinoma in a patient with oral lichen planus treated with topical application of tacrolimus Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010 110 19 25 10.1016/j.tripleo.2010.02.030 \n7. Greaf IA Mermelstein PG Stankunas K Neilsonb JR Deisseroth K Tsien RW L-Type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons Nature 1994 401 703 708 10.1038/44378 \n8. Shichiohe R Shibaki A Nishie W Tateishi Y Shimizu H Successful treatment of severe recalcitrant erosive oral lichen planus with topical tacrolimus J Eur Acad Dermatol Venereol 2006 20 66 68 10.1111/j.1468-3083.2005.01338.x 16405611 \n9. Xue Jing-Ling Fan Ming-Wen Wang Shuo-Zhi Chen Xin-Ming Li Yuan Wang Li A clinical study of 674 patients with oral lichen planus in China J Oral Pathol Med 2005 34 467 472 10.1111/j.1600-0714.2005.00341.x 16091113 \n10. van der Meij EH Mast H van der Waal I The possible premalignant character of oral lichen planus and oral lichenoid lesions: a prospective 5-year follow-up study of 192 patients Oral Oncol 2007 43 742 748 10.1016/j.oraloncology.2006.09.006 17112770 \n11. Fitzpatrick SG Honda KS Sattar A Hirsch SA Histologic lichenoid features in oral dysplasia and squamous cell carcinoma Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2014 117 511 520 10.1016/j.oooo.2013.12.413 \n12. Morrison L Kratochvil FJ 3rd Gorman A An open trial of topical tacrolimus for erosive oral lichen planus J Am Acad Dermatol 2002 47 617 620 10.1067/mjd.2002.126275 12271312 \n13. Kershner RP Fitzsimmons WE Relationship of FK506 whole blood concentrations and efficacy and toxicity after liver and kidney transplantation Transplanation 1996 62 920 926 10.1097/00007890-199610150-00009 \n14. Fonacier L Spergel J Charlesworth EN Weldon D Beltrani V Bernhisel-Broadbent J Report of the topical calcineurin inhibitor task force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology J Allergy Immunol 2005 115 6 10.1016/j.jaci.2005.04.006 \n15. Neill SM Lewis FM Tatnall FM Cox NH British Association of Dermatologists’ guidelines for the management of lichen sclerosus 2010 Br J Dermatol 2010 163 672 682 10.1111/j.1365-2133.2010.09997.x 20854400\n\n",
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"issn_linking": "1618-1247",
"issue": "105(2)",
"journal": "Odontology",
"keywords": "Lip; Oral lichen planus; Squamous cell carcinoma; Tacrolimus",
"medline_ta": "Odontology",
"mesh_terms": "D000287:Administration, Topical; D001706:Biopsy; D002180:Candidiasis, Oral; D002294:Carcinoma, Squamous Cell; D003937:Diagnosis, Differential; D003951:Diagnostic Errors; D006801:Humans; D007166:Immunosuppressive Agents; D017676:Lichen Planus, Oral; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms; D013524:Surgical Flaps; D016559:Tacrolimus",
"nlm_unique_id": "101134822",
"other_id": null,
"pages": "262-266",
"pmc": null,
"pmid": "27368962",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8878385;16405611;9590911;12271312;11756943;16091113;20610291;20854400;15940142;24560560;26015696;11756942;10233234;17112770;10537109",
"title": "The onset risk of carcinoma in patients continuing tacrolimus topical treatment for oral lichen planus: a case report.",
"title_normalized": "the onset risk of carcinoma in patients continuing tacrolimus topical treatment for oral lichen planus a case report"
} | [
{
"companynumb": "JP-LEO PHARMA-287324",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CANDESARTAN CILEXETIL"
},
"drugadditional": null,
... |
{
"abstract": "HIV-infected patients have a higher risk of developing cutaneous reactions to drugs than the general population. Severe cutaneous adverse reactions (SCARs) are not uncommon in patients taking antiretroviral therapy (HAART]. To evaluate HLA class I and II allele frequencies in HIV patients on HAART who develop SCARs due to nevirapine (NVP] or efavirenz (EFZ] containing regime and compare this genotype composition with HAART tolerant patients and healthy organ donors. A case-control study for 4 years was conducted with four subsets of patients hailing from north-east India:Cohort 1- HIV seropositive patients who developed SCARs due to EFZ (n = 8];Cohort 2 - HIV seropositive patients who developed SCARs due to NVP (n = 15]; Cohort 3 -HIV seropositive NVP/EFZ-tolerant patients (n = 18]; Cohort 4 - Healthy HIV seronegative organ donors (n = 169].Cohort 3 & 4 acted as control-group. These patients were genotyped for the HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 by a sequence-based HLA typing method. HLA-DRB1*03:01 allele revealed a significant association with EFZ regimen-induced SCARs in 62.5% patients compared with only 5.56% observed in HAART-tolerant patients and 4.14% in healthy organ. HLA-B*3505was found to be significantly associated with NVP induced SCARs. We found significant novel association of HLA-DRB1*03:01 with EFZ induced SCARs in North-East Indian HIV patients. Thus, HLA-DRB*03:01 may be useful as a genetic marker to avoid EFZ induced serious cutaneous rashes. The molecular HLA characterization of these alleles may provide a novel insight into the immunological basis of the antiretroviral drug reactions.",
"affiliations": "Department of Dermatology, LN Medical college and JK hospital, Bhopal, India.;Department of Dermatology, Varun Arjun Medical College, Shahajahanpur, U.P., India.;Department of Dermatology, R. D. Gardi Medical College, Ujjain, India.;Department of General Medicine, LN Medical College and JK hospital, Bhopal, India.;Department of Dermatology, Gauhati Medical College and Hospital, Guwahati, India.",
"authors": "Singh|Mehak|M|0000-0001-9180-7931;Pawar|Manoj|M|0000-0001-6076-4908;Bhargava|Shashank|S|0000-0003-4141-5520;Gupta|Prakhar|P|0000-0001-9337-4244;Adhicari|Pankaj|P|",
"chemical_list": "D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D059811:HLA-DRB1 Chains; C098320:efavirenz",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.14760",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "34(2)",
"journal": "Dermatologic therapy",
"keywords": "AGEP; AIDS; Efavirenz; HIV; SJS; TEN; drug rash; nevirapine",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000480:Alkynes; D048588:Benzoxazines; D016022:Case-Control Studies; D003521:Cyclopropanes; D005787:Gene Frequency; D015658:HIV Infections; D059811:HLA-DRB1 Chains; D006801:Humans; D007194:India",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e14760",
"pmc": null,
"pmid": "33421254",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A novel association of efavirenz induced severe cutaneous adverse reactions with HLA- DRB1*03:01: A case-control study from North-East India.",
"title_normalized": "a novel association of efavirenz induced severe cutaneous adverse reactions with hla drb1 03 01 a case control study from north east india"
} | [
{
"companynumb": "IN-MICRO LABS LIMITED-ML2021-01762",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
"drugadditional": "3"... |
{
"abstract": "The case of a 29 year-old man who suffered a cardiac arrest due to a massive pulmonary embolism while he was undergoing surgical repair of a complex tibial plateau fracture is presented. After 70 min of unsuccessful cardiopulmonary resuscitation a bolus of 20 mg tenecteplase was given, with a return of spontaneous circulation 2 min after administration of the drug. Pulmonary embolism was subsequently demonstrated on a pulmonary angiogram. To our knowledge this is the first report to show that the use of a low dose of tenecteplase might be useful to achieve the return of spontaneous circulation in the resuscitation of patients with cardiac arrest secondary to massive pulmonary embolism. Previously reported cases are reviewed.",
"affiliations": "Cardiovascular Research Center, University of Vermont, College of Medicine, Burlington, Vermont, USA. dhefer@uvm.edu",
"authors": "Hefer|David Václav Fred|DV|;Munir|Aman|A|;Khouli|Hassan|H|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator; D000077785:Tenecteplase",
"country": "England",
"delete": false,
"doi": "10.1097/MBC.0b013e3282a167a7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0957-5235",
"issue": "18(7)",
"journal": "Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis",
"keywords": null,
"medline_ta": "Blood Coagul Fibrinolysis",
"mesh_terms": "D000328:Adult; D001775:Blood Circulation; D016887:Cardiopulmonary Resuscitation; D017809:Fatal Outcome; D005343:Fibrinolytic Agents; D006323:Heart Arrest; D006801:Humans; D007431:Intraoperative Complications; D008297:Male; D011655:Pulmonary Embolism; D012131:Respiratory Insufficiency; D000077785:Tenecteplase; D013978:Tibial Fractures; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "9102551",
"other_id": null,
"pages": "691-4",
"pmc": null,
"pmid": "17890959",
"pubdate": "2007-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Low-dose tenecteplase during cardiopulmonary resuscitation due to massive pulmonary embolism: a case report and review of previously reported cases.",
"title_normalized": "low dose tenecteplase during cardiopulmonary resuscitation due to massive pulmonary embolism a case report and review of previously reported cases"
} | [
{
"companynumb": "US-ROCHE-GNE259834",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TENECTEPLASE"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nDrug-induced liver injury (DILI) is the leading cause of acute liver failure in the United States. DILI is mainly caused by painkillers and fever reducers, and it is often characterized by the type of hepatic injury (hepatocellular or cholestatic). This report presents a case of fenofibrate-induced severe jaundice in a 65-year-old Korean male with no prior history of liver disease. We offer a strategy for patients who present signs of severe liver injury with jaundice and high elevations in serum transaminases.\n\n\nMETHODS\nA 65-year-old male visited the gastroenterology outpatient clinic of a tertiary hospital due to increased levels of liver enzyme and total bilirubin which were incidentally detected through a preoperative screening test. Abdominal ultrasound and computed tomography showed no biliary obstruction or non-specific findings in the liver. Liver biopsy was performed and the patient was finally diagnosed with acute cholestatic hepatitis. Following the biopsy, steroid therapy was initiated and after 3 wk of treatment, the total bilirubin level was reduced to 7.22 mg/dL.\n\n\nCONCLUSIONS\nIn patients with hyperlipidemia, treatment including fenofibric acid induces rare complications such as severe jaundice and acute cholestatic hepatitis, warranting clinical attention.",
"affiliations": "Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, South Korea.;Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, South Korea.;Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, South Korea. puby17@naver.com.;Department of Pathology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon 14584, South Korea.;Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, South Korea.;Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, South Korea.",
"authors": "Lee|Hye Young|HY|;Lee|Ae-Ra|AR|;Yoo|Jeong-Ju|JJ|;Chin|Susie|S|;Kim|Sang Gyune|SG|;Kim|Young Seok|YS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v9.i30.9295",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960\nBaishideng Publishing Group Inc\n\njWJCC.v9.i30.pg9295\n10.12998/wjcc.v9.i30.9295\nCase Report\nBiopsy-confirmed fenofibrate-induced severe jaundice: A case report\nLee H.Y et al. Fenofibrate-induced severe jaundice\nLee Hye Young Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, South Korea\n\nLee Ae-Ra Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, South Korea\n\nYoo Jeong-Ju Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, South Korea. puby17@naver.com\n\nChin Susie Department of Pathology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon 14584, South Korea\n\nKim Sang Gyune Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, South Korea\n\nKim Young Seok Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, South Korea\n\nAuthor contributions: Lee HY and Lee AR contributed equally to this manuscript; Lee HY and Lee AR draft the original manuscript and managed the data; Yoo JJ contributed to the conceptualization, investigation, project administration and reviewed and edited the manuscript; Lee HY contributed to the formal analysis, visualization and provided the resources; Kim SG contributed to the methodology and supervision; all authors approval of final manuscript.\n\nSupported by Soonchunhyang University Research Fund, No. 20200037 .\n\nCorresponding author: Jeong-Ju Yoo, MD, Professor, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Jomaruro, Bucheon 14584, South Korea. puby17@naver.com\n\n26 10 2021\n26 10 2021\n9 30 92959301\n6 6 2021\n5 7 2021\n27 8 2021\n©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.\nBACKGROUND\n\nDrug-induced liver injury (DILI) is the leading cause of acute liver failure in the United States. DILI is mainly caused by painkillers and fever reducers, and it is often characterized by the type of hepatic injury (hepatocellular or cholestatic). This report presents a case of fenofibrate-induced severe jaundice in a 65-year-old Korean male with no prior history of liver disease. We offer a strategy for patients who present signs of severe liver injury with jaundice and high elevations in serum transaminases.\n\nCASE SUMMARY\n\nA 65-year-old male visited the gastroenterology outpatient clinic of a tertiary hospital due to increased levels of liver enzyme and total bilirubin which were incidentally detected through a preoperative screening test. Abdominal ultrasound and computed tomography showed no biliary obstruction or non-specific findings in the liver. Liver biopsy was performed and the patient was finally diagnosed with acute cholestatic hepatitis. Following the biopsy, steroid therapy was initiated and after 3 wk of treatment, the total bilirubin level was reduced to 7.22 mg/dL.\n\nCONCLUSION\n\nIn patients with hyperlipidemia, treatment including fenofibric acid induces rare complications such as severe jaundice and acute cholestatic hepatitis, warranting clinical attention.\n\nDrug-induced liver injury\nToxic hepatitis\nFenofibrate\nFenofibric acid\nJaundice\nHepatotoxicity\nHyperlipidemia\nCase report\n==== Body\npmc Core Tip: In patients with hyperlipidemia, treatment including fenofibric acid causes rare complications such as severe jaundice and acute cholestatic hepatitis, which requires clinical attention.\n\nINTRODUCTION\n\nDrug-induced liver injury (DILI) accounts for approximately 10% of all cases of acute hepatitis, and it is the most common cause of acute liver failure in the United States[1]. DILI is usually caused by medications, herbal medications, ethanol and dietary supplements. In particular, painkillers and fever reducers taken in doses more than recommended are the main causes of DILI[2]. DILI is often characterized by the type of hepatic injury, which is divided into hepatocellular or cholestatic injury[3]. Hepatocellular injury leads to increased serum aminotransferases in comparison to alkaline phosphatase. Cholestatic liver injury causes elevated alkaline phosphatase (ALP) levels compared to serum aminotransferases. DILI cholestasis is defined as an increase in ALP > 2 × upper limit of normal (ULN) and an alanine aminotransferase (ALT)-to-ALP ratio less than 2[4].\n\nThis report presents a case of fenofibrate-induced severe jaundice in a 65-year-old Korean male patient with no prior history of liver disease. We discuss our investigative and management approach, and present a review of prior cases. A strategy for patients with signs of severe liver injury accompanied by jaundice and elevation in serum transaminases is also suggested.\n\nCASE PRESENTATION\n\nChief complaints\n\nA 65-year-old male with severe jaundice visited the outpatient referral university hospital.\n\nHistory of present illness\n\nA 65-year-old male was referred to a gastroenterology outpatient clinic of a tertiary hospital due to jaundice and increased levels of liver enzyme which were incidentally detected during a preoperative screening at a local clinic.\n\nIn early February 2021, the patient was treated with 135 mg of fenofibric acid due to hyperlipidemia. In mid-February 2021, he was incidentally diagnosed with a ureteric stone and was recommended to undergo surgery at a local hospital. In Korea, routine blood tests are performed prior to surgery in clinical practice that requires general anesthesia. The patient’s jaundice was discovered incidentally through a preoperative blood test. Prior to visiting the outpatient clinic, the patient experienced symptoms of mild itching and jaundice for 2 wk. Thus, we can assume that the patient developed jaundice during the first week of March, four weeks after the initiation of the drug.\n\nLaboratory tests showed increased ALT (172 U/L), aspartate aminotransferase (AST) (133 U/L), ALP (1182 U/L), and total bilirubin (15.99 mg/dL) (Figure 1). Abdominal ultrasound and computed tomography (Figure 2) showed non-specific findings in the liver and no evidence of biliary obstruction.\n\nFigure 1 Clinical course of the patient. AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.\n\nFigure 2 Computed tomography of the patient. Contrast-enhanced abdominal computed tomography revealed no bile duct obstruction. A: Transverse plane; B: Coronal view.\n\nHistory of past illness\n\nThe patient was a non-drinker and former smoker who quit smoking 10 years ago. He was diagnosed with hypertension 5 years ago and was administered with a daily dosage of amlodipine 5 mg and valsartan 160 mg.\n\nPersonal and family history\n\nThere is no personal and family history.\n\nPhysical examination\n\nAt the time of admission, his height was 165.9 cm, weight 66.3kg, and BMI 24 kg/m2. His blood pressure was normal with a systolic blood pressure of 125 mmHg and a diastolic blood pressure of 80 mmHg. He had a normal body temperature (36.5°C) and normal heart rate (100 bpm). He also showed a normal breathing rate at 18 breaths per minute. He had a soft abdomen. He had a slight itching sensation and jaundice.\n\nLaboratory examinations\n\nBefore visiting our hospital, the patient underwent blood tests at a local hospital. His AST, ALT, and ALP counts were 133 U/L, 172 U/L, and 1182 U/L, respectively. Initial PT and aPTT values were 12.4 s and 34.2 s, respectively. The total bilirubin level was 15.99 mg/dL. However, after admission, the AST, ALT and ALP counts were reduced to 120 U/L, 144 U/L, and 366 U/L, respectively. Over the course of several days after admission, the patient’s serum bilirubin level rose up to a maximum of 22.13 mg/dL (Figure 1). His prothrombin time international normalized ratio (PT INR) was 0.92. All viral hepatitis markers (hepatitis B virus surface antigen, immunoglobulin M antibody to hepatitis A, hepatitis C antibody, immunoglobulin M antibody to hepatitis E virus) were negative. Serum ferritin and ceruloplasmin were in the normal range at 128 ng/mL and 36.9 mg/dL, respectively. All of the following autoantibody tests showed negative results: anti-nuclear antibody, anti-mitochondrial antibody, anti-smooth muscle antibody, anti-liver/kidney microsomal antibodies type 1. Factor V levels were not determined.\n\nImaging examinations\n\nContrast-enhanced abdominal computed tomography revealed a few small cysts in both liver lobes. The patient’s gall bladder was not well expanded and the wall showed diffuse thickening, without bile duct obstruction (Figure 2).\n\nFINAL DIAGNOSIS\n\nA liver biopsy to establish the cause of jaundice was performed. Liver biopsy showed acute cholestatic hepatitis consistent with toxic hepatitis (Figure 3). The Roussel Uclaf Causality Assessment Method score was 6 (time to onset from the beginning of the drug/herb: 2 points; course of ALP after cessation of the drug/herb: 2 points; risk factors such as age: 1 point; search for alternative causes: 1 point) which indicates that fenofibrate is the probable cause of DILI. Thus, we diagnosed the patient with severe DILI due to fenofibrate.\n\nFigure 3 Results of liver biopsy. Magnification: 400 ×; scale bar: 25 μm. A: The overall findings of sinusoidal inflammation in the portal tract increased. Hepatocytes are pinkish and ballooned. Portal vein fibrosis and increased nodular activity are found. Bile pigment is deposited in cytoplasm, resulting in a yellow tinge; B: Central vein is visible and cholestasis necrosis is concentrated around it. The lobule is concentrated in zone 3 with typical findings of acute cholestatic hepatitis.\n\nTREATMENT\n\nAfter the biopsy, the patient was treated empirically for DILI with prednisolone 40 mg daily for one week. The dose of prednisolone was subsequently rapidly reduced.\n\nOUTCOME AND FOLLOW-UP\n\nSteroid therapy was initiated the day after liver biopsy. At the time of discharge, the AST and ALT levels of the patient were reduced to 53 U/L and 27 U/L, respectively. The total bilirubin level decreased to 10.03 mg/dL. The patient was discharged after 3 wk of inpatient treatment. After discontinuation of fibrate treatment, jaundice improved rapidly and the patient is currently being observed in the outpatient clinic (Figure 1).\n\nDISCUSSION\n\nFenofibrate is a fibric acid derivative commonly used to reduce cholesterol and triglycerides[5,6]. The most common adverse effects of fibrates include gastrointestinal upset, nausea, headache and muscle cramps and rash, which are mostly mild and generally transient symptoms[5,7-9]. Despite its widespread use, fenofibrate rarely causes clinically significant hepatotoxicity[5,10-12]. Mild and transient elevations in serum aminotransferase develop in 5%-10% of patients[6]. DILI associated with fenofibrate occurs very rarely, in only 0.6% of patients[6]. Although most fenofibrate-induced liver injuries are self-limited, serious DILIs associated with fenofibrate can occur, if discontinuation of drug is delayed.\n\nCharacteristics of fibrateinduced liver injury\n\nThe characteristics of fibrate-induced hepatitis are not well known due to its rare occurrence. Demographic and clinical characteristics of the 11 cases are presented in Table 1. Fenofibrate-induced liver injury appears to afflict older men. Seven of the 11 patients were male (63.6%) and the median age was 54 years, with an age range of 37-74 years[6,7,13,14]. BMI was reported in 7 patients. All patients reported BMI values which were either overweight [body mass index (BMI) 25–30 kg/m2] or obese (BMI > 30 kg/m2)[6]. Four out of the 11 total patients had diabetes mellitus. The onset of injury was variable. Latency was short (2 d to 8 wk) in 7 patients [7,8,13], and prolonged up to 2 years (18 wk-2 years) in the other 4 patients[6,14].\n\nTable 1 Characteristics of fenofibrate-induced liver injury based on prior case reports\n\nRef.\tDemographic and clinical characteristics\tCourse of illness\t\tInitial values\t\nLocation\tSex\tAge, yr\tDaily dose (mg)\tSymptoms\tLatency\tOutcome\tALT(U/L)\tALP(U/L)\tTotal Bilirubin (mg/dL)\tINR\t\nPresent case\tSouth Korea\tM\t65\t135 mg\tJaundice, pruritis\t6 wk\tRecovery, 3 wk\t172\t1182\t15.99\t0.92\t\nMa et al[13], 2019\tChina\tM\t65\t200 mg\tEpigastric discomfort, nausea,fatigue\t2 d\tRecovery, 2 wk\t1136.7\t279.7\t1.91\tNA\t\nDohmen et al[7], 2005\tJapan\tF\t66\t150 mg\tFever, anorexia, hypochondrial discomfort\t11 d\tRecovery, 2 wk\t216\t537\t1.8\tNA\t\nRigal et al[14], 1989\tFrance\tF\t74\t200 mg\tJaundice\t2 yr\tRecovery, 2 mo\t1430\t315\t4.6\tNA\t\nHo et al[8], 2004\tTaiwan\tM\t61\t300 mg\tJaundice, dark urine, fatigue\t2 wk\tRecovery, 2 mo\t249\t259\t9.3\tNA\t\nCase 1 (Ahmad et al[6], 2017)\tCaucasian\tM\t43\t145 mg\tJaundice, dark urine, pale stool, pruritis\t6 wk\tRecovery\t533\t440\t20.6\t1.04\t\nCase 2 (poor prognosis) (Ahmad et al[6], 2017)\tCaucasian\tM\t61\t48 mg\tJaundice, rash, pruritis\t8 wk\tDeath (renal failure) at 26 mo\t83\t518\t4.7\t1.40\t\nCase 3 (Ahmad et al[6], 2017)\tHispanic\tF\t37\t160 mg\tJaundice, nausea, fatigue, myalgia, abdo pain\t5 wk\tRecovery\t332\t344\t8.4\t0.80\t\nCase 4 (Ahmad et al[6], 2017)\tCaucasian\tM\t43\t145 mg\tJaundice, nausea, fatigue, dark urine, pale stool, fever, pruritis\t7 wk\tUnknown\t100\t218\t5.9\t1.00\t\nCase 5 (poor prognosis) (Ahmad et al[6], 2017) Jaward et al. 2017[6]\tCaucasian\tM\t41\t160 mg\tJaundice, abdominal pain, nausea\t40 wk\tLiver Transplant, at 8 mo\t78\t195\t8.0\t4.3\t\nCase 6 (Ahmad et al[6], 2017)\tHispanic\tM\t54\t134 mg\tFatigue\t56 wk\tRecovery\t584\t106\t0.5\tNA\t\nCase 7 (Ahmad et al[6], 2017)\tCaucasian\tF\t44\t48 mg\tJaundice, dark urine, fatigue\t18 wk\tRecovery\t1197\t79\t5.1\t1.00\t\nM: Male; F: Female; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; INR: International normalized ratio; NA: Not available.\n\nBiochemical and histopathological findings\n\nBiochemically, the initial pattern of liver injury (based on the R ratio) was variable but patients who manifested initial cholestatic patterns of liver injury showed severe clinical outcomes. In particular, the clinical prognosis was poor when the initial prolongation of PT INR was high. Both patients with severe injury and PT prolongation were characterized by delayed drug discontinuation. In the case of death, PT INR was 1.4 and in the case of liver transplantation 4.3. Data from published cases reflect an average elevation of ALT of 13 × ULN (539.88), ALP 3 × ULN (373), and total bilirubin of 6 × ULN (7.23).\n\nPatients with high levels of serum total bilirubin at the time of admission were hospitalized longer and showed delayed recovery. Of the 4 cases with prolonged hospital stay or slow recovery, one recovered in a relatively short time, and all of them showed acute hepatitis on biopsy. In this case, the total bilirubin level rose to 22.13 mg/dL, but recovered within 3 wk, and histological findings showed acute hepatitis.\n\nThe common pathological findings of toxic hepatitis include necrosis and cholestasis, although these are not specific to toxic hepatitis. Five of the 11 cases reviewed underwent liver biopsy. Liver biopsy showed diverse patterns of injury, based on published literature, with most of the cases showing cholestasis. The clinical prognosis was worse in the case of chronic cholestasis in the liver biopsy than in the case of acute cholestasis. Chronic cholestasis was associated with duct injury that was characterized by reactive epithelial changes rather than direct inflammation[6].\n\nOutcomes of fibrate-induced liver injury\n\nWhile the majority of DILIs resolve with prompt discontinuation of the offending drug, DILIs can worsen and progress to liver failures that require transplantation or result in death, particularly if drug withdrawal is delayed. Nine of the 11 cases with acute hepatotoxicity fully recovered and 2 developed a severe clinical course. One underwent liver transplantation at 8 mo and the other eventually died of renal failure at 26 mo. Both severe cases had delayed cessation of fenofibrate therapy, which resulted in chronic progressive cholestatic liver injury[6]. Reported cases of fenofibrate-induced hepatitis appear to be idiosyncratic. The mechanism of idiosyncratic DILI remains unresolved. However, sufficient evidence exists that most idiosyncratic cases are mediated by adaptive immune systems which depend on stimulation of the innate immune system, although the triggering factors are unknown. One of the patients receiving the minimal recommended dose (48 mg) died.\n\nPossible risk factors for fibrate-induced liver injury\n\nPossible risk factors for severe hepatic injury may include older age, prolonged PT, cholestatic pattern of initial liver injury, multiple gallstones and history of cholecystectomy. In patients with these risk factors, delayed drug discontinuation can lead to poor outcomes. However, well-controlled studies are needed to corroborate these findings.\n\nHigh BMI is frequently reported in patients with fibrate-induced liver injury. Hyperlipidemia is one of the metabolic syndrome items, and such patients are often accompanied by obesity. In fact, in most of the previous case reports of fibrate-induced jaundice, the majority of patients were obese with a BMI of 25 mg/m2 or higher. However, it is not yet known whether high BMI is a simple bias or a real risk factor. Further research is needed to determine whether the two factors have a simple association or a temporal causal relationship. In our case as well, the patient's BMI was 24, demonstrating that fibrate-induced jaundice can sufficiently occur even in patients with low BMI.\n\nCONCLUSION\n\nFenofibrate is widely prescribed for patients with hypertriglycemia to decrease the risk of cardiovascular diseases. Fenofibrate-induced hepatitis is a rare type of DILI. However, fenofibrate–induced DILI can be severe and prolonged with the potential for chronicity due to delayed discontinuation. Older males with high BMI, prolonged PT, cholestatic pattern of liver injury, and history of cholestatic hepatobiliary disease are more likely to develop severe liver injury associated with jaundice and high elevations in serum transaminases.\n\nRoutine liver biochemistry monitoring is recommended at least 2 wk after initial fenofibrate ingestion followed by regular monitoring every 3 mo within the first 1 to 2 years of therapy. Discontinuation is recommended if liver enzymes persist at levels above 3 times the ULN or if jaundice is detected. Clinicians need to discontinue treatment in patients with jaundice and highly elevated liver enzymes during fenofibrate therapy.\n\nInformed consent statement: Informed consent statement was waived due to the retrospective nature of this case report.\n\nConflict-of-interest statement: The authors declare that they have no conflict of interest.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016). The manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: June 6, 2021\n\nFirst decision: June 25, 2021\n\nArticle in press: August 27, 2021\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry/Territory of origin: South Korea\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Malnick SDH S-Editor: Wu YXJ L-Editor: A P-Editor: Zhang YL\n==== Refs\n1 Ghabril M Chalasani N Björnsson E Drug-induced liver injury: a clinical update Curr Opin Gastroenterol 2010 26 222 226 20186054\n2 Kumar N Surani S Udeani G Mathew S John S Sajan S Mishra J Drug-induced liver injury and prospect of cytokine based therapy; A focus on IL-2 based therapies Life Sci 2021 278 119544 33945827\n3 Yu YC Mao YM Chen CW Chen JJ Chen J Cong WM Ding Y Duan ZP Fu QC Guo XY Hu P Hu XQ Jia JD Lai RT Li DL Liu YX Lu LG Ma SW Ma X Nan YM Ren H Shen T Wang H Wang JY Wang TL Wang XJ Wei L Xie Q Xie W Yang CQ Yang DL Yu YY Zeng MD Zhang L Zhao XY Zhuang H Drug-induced Liver Injury (DILI) Study Group Chinese Society of Hepatology (CSH) Chinese Medical Association (CMA) CSH guidelines for the diagnosis and treatment of drug-induced liver injury Hepatol Int 2017 11 221 241 28405790\n4 Katarey D Verma S Drug-induced liver injury Clin Med (Lond) 2016 16 s104 s109 27956449\n5 Bhardwaj SS Chalasani N Lipid-lowering agents that cause drug-induced hepatotoxicity Clin Liver Dis 2007 11 597 613, vii 17723922\n6 Ahmad J Odin JA Hayashi PH Chalasani N Fontana RJ Barnhart H Cirulli ET Kleiner DE Hoofnagle JH Identification and Characterization of Fenofibrate-Induced Liver Injury Dig Dis Sci 2017 62 3596 3604 29119413\n7 Dohmen K Wen CY Nagaoka S Yano K Abiru S Ueki T Komori A Daikoku M Yatsuhashi H Ishibashi H Fenofibrate-induced liver injury World J Gastroenterol 2005 11 7702 7703 16437706\n8 Ho CY Kuo TH Chen TS Tsay SH Chang FY Lee SD Fenofibrate-induced acute cholestatic hepatitis J Chin Med Assoc 2004 67 245 247 15357112\n9 Kiskac M Zorlu M Cakirca M Karatoprak C Peru C Erkoc R Yavuz E A case of rhabdomyolysis complicated with acute renal failure after resumption of fenofibrate therapy: a first report Indian J Pharmacol 2013 45 305 306 23833382\n10 Parra JL Reddy KR Hepatotoxicity of hypolipidemic drugs Clin Liver Dis 2003 7 415 433 12879992\n11 Chitturi S George J Hepatotoxicity of commonly used drugs: nonsteroidal anti-inflammatory drugs, antihypertensives, antidiabetic agents, anticonvulsants, lipid-lowering agents, psychotropic drugs Semin Liver Dis 2002 22 169 183 12016548\n12 Keech A Simes RJ Barter P Best J Scott R Taskinen MR Forder P Pillai A Davis T Glasziou P Drury P Kesäniemi YA Sullivan D Hunt D Colman P d'Emden M Whiting M Ehnholm C Laakso M FIELD study investigators Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial Lancet 2005 366 1849 1861 16310551\n13 Ma S Liu S Wang Q Chen L Yang P Sun H Fenofibrate-induced hepatotoxicity: A case with a special feature that is different from those in the LiverTox database J Clin Pharm Ther 2020 45 204 207 31518450\n14 Rigal J Furet Y Autret E Breteau M [Severe mixed hepatitis caused by fenofibrate? Rev Med Interne 1989 10 65 67 2655052\n\n",
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"journal": "World journal of clinical cases",
"keywords": "Case report; Drug-induced liver injury; Fenofibrate; Fenofibric acid; Hepatotoxicity; Hyperlipidemia; Jaundice; Toxic hepatitis",
"medline_ta": "World J Clin Cases",
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"nlm_unique_id": "101618806",
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"pubdate": "2021-10-26",
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"title": "Biopsy-confirmed fenofibrate-induced severe jaundice: A case report.",
"title_normalized": "biopsy confirmed fenofibrate induced severe jaundice a case report"
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"abstract": "The current pandemic of novel coronavirus disease 2019 (COVID-19) has posed a great threat to people's health worldwide, with specific implications on patients with underlying heart diseases. During this challenging period, nearly all major societies have recommended for conservative approach, even for patients with relatively stable acute cardiovascular diseases. Selection of specific antiplatelet therapy in an uncomplicated post percutaneous coronary intervention (PCI) patient can, at times, be crucial issue in such strained circumstances. We report a case of 64-year-old male, who was taken for urgent coronary angiogram (CAG) in view of non ST elevation acute coronary syndrome. Successful PCI with implantation of drug eluting stent was done for right coronary artery (RCA) and left anterior descending (LAD) artery lesions. On day 5th post-PCI, he developed acute inferior wall STEMI due to subacute stent thrombosis (ST), and despite all efforts, patient could not be saved as he didn't receive timely intervention. Increased travel time to emergency department due to lockdown because of COVID-19 and along with extra time required for donning of personal protection equipment (PPE) and other COVID-19 related safety measures prolonged the ischemic time. Potent P2Y12 inhibitor based dual antiplatelet therapy might have prevented this subacute ST, and thus mortality, as the patient was discharged on clopidogrel after PCI. While selecting specific P2Y12 inhibitor in a post PCI patient, apart from clinical condition of patient and complexity of procedure, we should also consider current COVID-19 pandemic. Current circumstances may favour ticagrelor over other P2Y12 inhibitors in view of its potent, rapid, and reversible antiplatelet action along with its optimistic effect in pneumonia.",
"affiliations": "All India Institute of Medical Sciences, Jodhpur, India.;All India Institute of Medical Sciences, Jodhpur, India.;All India Institute of Medical Sciences, Jodhpur, India.",
"authors": "Choudhary|Rahul|R|;Kaushik|Atul|A|;Sharma|Jai Bharat|JB|",
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"issue": "10(4)",
"journal": "Cardiovascular diagnosis and therapy",
"keywords": "COVID-19; P2Y12 inhibitor; Stent thrombosis (ST); acute coronary syndrome; case report",
"medline_ta": "Cardiovasc Diagn Ther",
"mesh_terms": null,
"nlm_unique_id": "101601613",
"other_id": null,
"pages": "898-901",
"pmc": null,
"pmid": "32968646",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports",
"references": "17296821;19717846;25443607;17982182;32199938;24127651;32182131;27436867;30175268",
"title": "COVID-19 pandemic and stent thrombosis in a post percutaneous coronary intervention patient-a case report highlighting the selection of P2Y12 inhibitor.",
"title_normalized": "covid 19 pandemic and stent thrombosis in a post percutaneous coronary intervention patient a case report highlighting the selection of p2y12 inhibitor"
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"abstract": "OBJECTIVE\nInterferon alfa-based regimens used to treat recurrent hepatitis C virus (HCV) infection after liver transplantation are poorly tolerated, associated with generally modest efficacy, and can interact with immunosuppressive agents. We evaluated the efficacy and safety of an interferon-free regimen of the nucleotide polymerase inhibitor sofosbuvir combined with ribavirin for 24 weeks in treating post-transplantation HCV infection.\n\n\nMETHODS\nIn a prospective, multicenter, open-label pilot study, we enrolled patients with compensated recurrent HCV infection of any genotype after a primary or secondary liver transplantation. All patients received 24 weeks of sofosbuvir 400 mg daily and ribavirin starting at 400 mg daily, which was adjusted according to creatinine clearance and hemoglobin values. The primary end point was sustained virologic response 12 weeks after treatment.\n\n\nRESULTS\nOf the 40 patients enrolled and treated, 78% were male, 85% were white, 83% had HCV genotype 1, 40% had cirrhosis (based on biopsy), and 88% had been previously treated with interferon. Sustained virologic response 12 weeks after treatment was achieved by 28 of 40 patients (70%; 90% confidence interval: 56%-82%). Relapse accounted for all cases of virologic failure. No patients had detectable viral resistance during or after treatment. The most common adverse events were fatigue (30%), diarrhea (28%), and headache (25%). In addition, 20% of the subjects experienced anemia. Two patients discontinued study treatment because of adverse events, which were considered unrelated to study treatment. No deaths, graft losses, or episodes of rejection occurred. No interactions with any concomitant immunosuppressive agents were reported.\n\n\nCONCLUSIONS\nSofosbuvir and ribavirin combination therapy for 24 weeks is an effective and well-tolerated interferon-free treatment for post-transplantation HCV infection. EudraCT, Number: 2012-002417-19; ClinicalTrials.gov, Number: NCT01687270.",
"affiliations": "Mayo Clinic, Rochester, Minnesota. Electronic address: michael.charlton@imail.org.;Auckland City Hospital, Auckland, New Zealand.;Hannover Medical School, Hannover, Germany.;Columbia University, New York, New York.;Beth Israel Deaconess Medical Center, Boston, Massachusetts.;Indiana School of Medicine, Indianapolis, Indiana.;University of Michigan, Ann Arbor, Michigan.;Kansas University Medical Center, Kansas City, Kansas.;NYU Medical Center, New York, New York.;Duke University Medical Center, Durham, North Carolina.;Gilead Sciences, Foster City, California.;Gilead Sciences, Foster City, California.;Gilead Sciences, Foster City, California.;Gilead Sciences, Foster City, California.;Gilead Sciences, Foster City, California.;Gilead Sciences, Foster City, California.;Gilead Sciences, Foster City, California.;AP-HP Hôpital Paul Brousse, Centre Hépatobiliaire, and Université Paris Sud, Villejuif, France.;Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain.;University of California at San Francisco, San Francisco, California.",
"authors": "Charlton|Michael|M|;Gane|Edward|E|;Manns|Michael P|MP|;Brown|Robert S|RS|;Curry|Michael P|MP|;Kwo|Paul Y|PY|;Fontana|Robert J|RJ|;Gilroy|Richard|R|;Teperman|Lewis|L|;Muir|Andrew J|AJ|;McHutchison|John G|JG|;Symonds|William T|WT|;Brainard|Diana|D|;Kirby|Brian|B|;Dvory-Sobol|Hadas|H|;Denning|Jill|J|;Arterburn|Sarah|S|;Samuel|Didier|D|;Forns|Xavier|X|;Terrault|Norah A|NA|",
"chemical_list": "D000998:Antiviral Agents; D015415:Biomarkers; D012367:RNA, Viral; D012254:Ribavirin; D014542:Uridine Monophosphate; D000069474:Sofosbuvir",
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"issue": "148(1)",
"journal": "Gastroenterology",
"keywords": "Antiviral Agent; Clinical Trial; DAA; NS5B Polymerase Inhibitor",
"medline_ta": "Gastroenterology",
"mesh_terms": "D000998:Antiviral Agents; D015415:Biomarkers; D006528:Carcinoma, Hepatocellular; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D008103:Liver Cirrhosis; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D009520:New Zealand; D010865:Pilot Projects; D011446:Prospective Studies; D012367:RNA, Viral; D012008:Recurrence; D012254:Ribavirin; D000069474:Sofosbuvir; D013030:Spain; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D014542:Uridine Monophosphate; D019562:Viral Load",
"nlm_unique_id": "0374630",
"other_id": null,
"pages": "108-17",
"pmc": null,
"pmid": "25304641",
"pubdate": "2015-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation.",
"title_normalized": "sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis c virus infection after liver transplantation"
} | [
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"abstract": "Myeloproliferative neoplasms transformed into AML usually have a poor prognosis. We report a case of essential thrombocythemia with myelofibrosis that transformed into acute promyelocytic leukemia (APL) with both the t(15;17) translocation as well as the JAK2 V617F mutation. Clinically, this case was notable for severe differentiation syndrome despite treatment with high-dose dexamethasone. Cytokine production by differentiating APL cells was not directly abrogated by JAK2 inhibitors in vitro, suggesting that JAK2 V617F enhances the hyperinflammatory response downstream of cytokines. JAK1/2 inhibitors may therefore dampen the inflammatory cascade downstream of cytokine production, similar to glucocorticoids, and have a role in treating severe differentiation syndrome.",
"affiliations": "Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA ; MD/PhD Program.;Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.;Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR 97239, USA ; Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.;Department of Pathology, Oregon Health & Science University, Portland, OR 97239, USA.;Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR 97239, USA ; Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.;Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR 97239, USA ; Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.",
"authors": "Braun|Theodore P|TP|;Maxson|Julia E|JE|;Agarwal|Anupriya|A|;Dunlap|Jennifer|J|;Spurgeon|Stephen E|SE|;Traer|Elie|E|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.lrr.2014.12.003",
"fulltext": "\n==== Front\nLeuk Res RepLeuk Res RepLeukemia Research Reports2213-0489Elsevier S2213-0489(14)20020-310.1016/j.lrr.2014.12.003Case ReportAcute promyelocytic leukemia with JAK2 V617F and severe differentiation syndrome Braun Theodore P. bcMaxson Julia E. bAgarwal Anupriya abDunlap Jennifer dSpurgeon Stephen E. abTraer Elie traere@ohsu.eduab⁎a Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR 97239, USAb Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USAc MD/PhD Programd Department of Pathology, Oregon Health & Science University, Portland, OR 97239, USA⁎ Corresponding author. traere@ohsu.edu25 12 2014 2015 25 12 2014 4 1 8 11 16 11 2014 20 12 2014 © 2015 The Authors2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Myeloproliferative neoplasms transformed into AML usually have a poor prognosis. We report a case of essential thrombocythemia with myelofibrosis that transformed into acute promyelocytic leukemia (APL) with both the t(15;17) translocation as well as the JAK2 V617F mutation. Clinically, this case was notable for severe differentiation syndrome despite treatment with high-dose dexamethasone. Cytokine production by differentiating APL cells was not directly abrogated by JAK2 inhibitors in vitro, suggesting that JAK2 V617F enhances the hyperinflammatory response downstream of cytokines. JAK1/2 inhibitors may therefore dampen the inflammatory cascade downstream of cytokine production, similar to glucocorticoids, and have a role in treating severe differentiation syndrome.\n\nHighlights\n• Case of essential thrombocythemia transformed to acute promyelocytic leukemia.\n\n• Leukemia cells contained both t(15;17) and JAK2 V617F mutation.\n\n• Severe differentiation syndrome in response to ATRA, possibly related to JAK2 V617F.\n\n• JAK1/2 inhibitors may have clinical utility in differentiation syndrome.\n\n\n\nKeywords\nAcute promyelocytic leukemia (APL)Myeloproliferative neoplasm (MPN)Essential thrombocythemia (ET)JAK2Differentiation syndrome\n==== Body\n1 Introduction\nEssential thrombocythemia (ET) is a clonal disorder of the hematopoietic stem cell that is closely related to two other myeloproliferative neoplasms (MPNs) polycythemia vera (PV) and primary myelofibrosis (PMF). The Janus-Associated-Kinase 2 (JAK2) V617F mutation is present in the vast majority of PV patients and in 50% of patients with ET and PMF [1]. JAK2 V617F produces constitutive activation of the thrombopoietin and erythropoietin signaling pathways, driving ET and PV respectively. Over time, ET and PV can both progress to myelofibrosis [1]. Further, all three conditions can transform into acute myelogenous leukemia (AML), although this occurs most frequently in PMF [2]. Transformation carries a dismal prognosis [2] and is often associated with complex genetic changes. Transformation of ET, PV or PMF into acute promyelocytic leukemia (APL), a favorable risk leukemia characterized by the t(15;17) translocation, is exceedingly rare with only eight documented cases in the literature [3–9]. Of these, only two prior cases have been reported of ET transforming into APL with molecular documentation of t(15;17) [3,4]. We report an 83-year-old woman with a history of ET and progression to myelofibrosis, who then transformed to APL. To our knowledge, this is the first case to demonstrate co-expression of PML-RARα and JAK2 V617F by leukemic blasts. Clinically she also developed severe differentiation syndrome during induction with ATRA plus arsenic trioxide (ATO), suggesting that JAK2 signaling may augment differentiation syndrome.\n\n2 Case study\nThe patient was diagnosed with ET in 1995 and began treatment with hydroxyurea and aspirin. In 2011 she noted worsening fatigue and left lower quadrant abdominal pain. She underwent a bone marrow biopsy that revealed myelofibrosis with a JAK2 V617F allelic burden of 92% and was found to have splenomegaly. Treatment with the JAK1/2 inhibitor ruxolitinib was initiated, which resulted in a significant improvement in energy and appetite. She did well until May of 2013 when she was noted to be pancytopenic with a WBC of 2.0 ×103/mm3, hemoglobin of 8.5 mg/dL and platelets of 96×103/mm3. Concerned that her cytopenias were the result of ruxolitinib, it was discontinued; however, she remained persistently pancytopenic. A bone marrow biopsy revealed a hypercellular marrow with 70% blasts, megakaryocytic hyperplasia and grade 3/3 fibrosis. Fluorescence in-situ hybridization (FISH) confirmed the t(15;17) in 90% of cells and diagnosis of APL. A GeneTrails AML/MDS next-generation sequencing panel (Supplementary Table 1, Knight Diagnostics Lab, Portland, OR) was performed on marrow aspirate and was significant for a JAK2 V617F allelic burden of ~90%, indicating that the APL cells also contained the JAK2 V617F mutation. A FLT3 D835 mutation was also found with this panel.\n\nGiven her advanced age she was started on ATRA+arsenic trioxide (ATO) induction [10]. After two days of ATRA her WBC count began to increase rapidly and despite escalating doses of hydroxyurea her WBC count continued to rise, reaching 67.4×103/mm3 on day 6 of ATRA (Fig. 1A,B). During this time she was started on treatment-dose dexamethasone for differentiation syndrome. She developed severe abdominal pain and ultrasound demonstrated splenomegaly (15.8×6.8×13.7 cm). Despite dexamethasone, her symptoms were felt to be secondary to severe differentiation syndrome and she was given a single dose of idarubicin (12 mg/m2) for rapid cytoreduction. Her WBC count peaked on day 7 at 95.9×103/mm3. At this time she developed increasing oxygen requirements with a chest X-ray demonstrating evolving bilateral patchy opacities (Fig. 1C). Given her clinical deterioration, ATRA was held for two days but by day 9 her WBC had decreased to 27.5×103/mm3. ATRA was restarted, hydroxyurea was tapered, and on day 10 ATO (0.15 mg/kg/day) was initiated. However, despite her declining WBC count, her oxygen requirement again increased to 10 L on day 12 and she was aggressively diuresed in addition to continued dexamethasone. By day 17 she showed dramatic clinical improvement and was successfully weaned from oxygen. A repeat ultrasound at this time demonstrated a greater than 50% reduction in splenic volume (11.2×10.8×5.5 cm), suggesting that extramedullary APL cells were abundant in the spleen and the bone marrow. A bone marrow biopsy performed on day 34 revealed a morphologic complete remission and she was discharged to a rehab facility to recover. On day 47 after initiation of therapy, her peripheral blood had counts recovered with a WBC count of 29.9×103/mm3, hemoglobin of 11.0 mg/dL and platelets of 603×103/mm3, consistent with her previous ET, so she was restarted on 10 mg twice daily ruxolitinib and 81 mg aspirin. She then received four cycles of consolidation therapy with ATRA plus ATO [10]. Ruxolitinib was well tolerated during consolidation and dose reduced only when her platelet count decreased with ATO. A bone marrow biopsy after completion of consolidation revealed complete molecular remission and a return to her underlying myeloproliferative disease with grade 2/3 myelofibrosis.\n\n3 Discussion\nATRA and arsenic are both known to induce differentiation syndrome but this case was notable for its severity. Previous studies of differentiation syndrome have demonstrated that APL cells treated with ATRA secrete the chemokines CCL2 and IL-8, which in combination with chemokine production from alveolar epithelial cells, are thought to initiate a hyperinflammatory cascade in the lung [11]. While dexamethasone does not directly affect the production of CCL2 or IL-8 from APL cells, it does reduce their production in the lung and thus attenuates the clinical development of differentiation syndrome [11]. Since inflammatory cytokine signaling plays a significant role both in the pathogenesis of JAK2 V617F MPNs as well as in the development of differentiation syndrome, we postulated that robust differentiation syndrome experienced by this patient was the result of excessive inflammatory response related to her underlying JAK2 V617F mutation.\n\nTo test whether JAK2 inhibition has any direct effects on the production of cytokines by APL cells, we used ATRA to differentiate the NB-4 APL cell line in the presence or absence of ruxolitinib. Cytokine release into the media was measured over three days of ATRA-induced differentiation. There was a substantial increase in both CCL2 and IL-8 with ATRA treatment, although this was not abrogated by JAK inhibition (Fig. 2). In fact, ruxolitinib had very little effect overall on cytokine production of NB-4 cells. Therefore, CCL2 and IL-8 production by APL cells is unaffected by JAK inhibition, similar to what has been shown for dexamethasone [11]. However, there is substantial evidence that signaling downstream of cytokines is through activation of JAK2 [1]. Indeed, it is possible that the presence of JAK2 V617F in APL and non-leukemic cells enhances CCR2 and IL-8 signaling during differentiation syndrome, accelerating leukocyte extravasation and inflammatory amplification within the lungs and other organs. This suggests that JAK inhibitors may have clinical utility in attenuating the inflammatory amplification step in differentiation syndrome in a manner similar to glucocorticoids. Further studies with in vivo models of differentiation syndrome are needed to evaluate this possibility.\n\nIn summary, this case details a previously undescribed pathologic entity, the co-expression of the PML/RARα and JAK2 V617F in APL. Further, the clinical presentation with severe differentiation syndrome may be the result of this rare molecular partnership, providing a framework for future studies exploring the role of JAK2 in differentiation syndrome. In so doing, it offers the opportunity for the development of novel non-steroidal therapies in the management of differentiation syndrome.\n\nConflict of interest\nThe authors declare no conflict of interest.\n\nAuthor Contributions\nTPB, JEM and ET were responsible for experimental design, literature review, data collection, statistical analysis and manuscript writing. AA performed the cytokine analysis. JD reviewed pathology and took pictures. SES and ET cared for patient. All authors contributed to writing manuscript and reviewed before submission.\n\nAppendix A Supporting information\nSupplementary Material\n\n \n\nAcknowledgments\nThe authors would like to acknowledge the patient, and the staff involved in her care.\n\nFig. 1 Development of Severe Leukocytosis and Differentiation Syndrome. (A) Peripheral smear (40x) on day 2 of ATRA showing circulating promyelocyte with classic bi-lobed nucleus and granules and later a mixture of promyelocytes with differentiating myeloid precursors on day 7. (B) Time course of WBC count during hospitalization with demarcation of critical events. Dex=Dexamethasone, Ida=Idarubicin, ATO=Arsenic Trioxide. (C) Chest X-ray revealing bilateral patchy opacities consistent with differentiation syndrome.\n\nFig. 2 Secreted Cytokine Profile of Differentiating APL in the Presence of JAK Inhibition. NB-4 APL cells were plated at 2×105 cells were plated per well in a 12 well plate and treated with 1 μM all trans-retinoic acid (ATRA, Sigma, St. Louis, MO) and/or 10 μM ruxolitinib (Selleck Chemicals, Houston, TX) for six days with the media changed on day three. Cytokine levels were assessed in conditioned media using a multiplex magnetic bead based assay according to the manufacturer’s instructions (Life Technologies, Grand Island, NY). Values were normalized to control levels in the absence of ATRA, Log2 transformed and displayed in a heat-map format using Tree-View software.\n==== Refs\nReferences\n1 Kralovics R Passamonti F Buser AS Teo S-S Tiedt R Passweg JR A gain-of-function mutation of JAK2 in myeloproliferative disorders N Engl J Med 352 2005 1779 1790 15858187 \n2 Björkholm M Derolf AR Hultcrantz M Kristinsson SY Ekstrand C Goldin LR Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms J Clin Oncol 29 2011 2410 2415 21537037 \n3 Sato N Furukawa T Masuko M Hashimoto S Takahashi H Baba M Acute promyelocytic leukemia developing in untreated essential thrombocythemia Am J Hematol 71 2002 114 116 12353311 \n4 Mollee PN Taylor KM Williams B Taylor D Rodwell R. Long-term molecular remission in promyelocytic transformation of myeloproliferative disease Leukemia 13 1999 648 650 10214878 \n5 Kajiguchi T Simokawa T Saito M Takeyama H. Transformation of polycythemia vera to acute promyelocytic leukemia Int J Hematol 72 2000 520 521 11197225 \n6 Batlle M Fernández-Avilés F Ribera JM Millá F Granada I Gómez Espuch J Acute promyelocytic leukemia in a patient with idiopathic myelofibrosis Leukemia 13 1999 492 494 10086747 \n7 Ratti M Ghio R Casciaro S Rattenni S Boccaccio P. Acute promyelocytic leukaemia developing in essential thrombocythaemia: blastic crisis or secondary acute leukaemia? Case report Haematologica 69 1984 330 335 6432645 \n8 Sessarego M Defferrari R Dejana AM Rebuttato AM Fugazza G Salvidio E Cytogenetic analysis in essential thrombocythemia at diagnosis and at transformation. A 12-year study Cancer Genet Cytogenet 43 1989 57 65 2790773 \n9 Löfvenberg E Nordenson I Wahlin A. Cytogenetic abnormalities and leukemic transformation in hydroxyurea-treated patients with Philadelphia chromosome negative chronic myeloproliferative disease Cancer Genet Cytogenet 49 1990 57 67 2397474 \n10 Estey E Garcia-Manero G Ferrajoli A Faderl S Verstovsek S Jones D Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia Blood 107 2006 3469 3473 16373661 \n11 Luesink M Pennings JL Wissink WM Linssen PCM Muus P Pfundt R Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: triggering the differentiation syndrome Blood 114 2009 5512 5521 19828696\n\n",
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"abstract": "Carvedilol is used in the management of hypertension, ischemic heart disease, heart failure and most recently, portal hypertension. It has been associated with improved outcomes regarding variceal bleeding, hepatic decompensation and death when compared to propranolol and endoscopic band ligation. The main cause of portal hypertension is cirrhosis and therefore carvedilol is increasingly used in these patients. Due to its extensive hepatic metabolism, carvedilol is contraindicated in severe hepatic impairment. However, there are no dosage adjustments in the manufacturer's labelling for mild to moderate hepatic impairment.\nWe present a case of cardiogenic shock that occurred after carvedilol 25 mg orally was administered to a patient with cirrhosis. As there was no overdose, the diagnosis was based on clinical recognition of the toxidrome. The patient was successfully treated with glucagon 5 mg bolus followed by infusion.\nPatients with cirrhosis represent a special at-risk group for beta blocker toxicity. The typical threshold for carvedilol toxicity in overdose is 50 mg but in patients with cirrhosis this is not applicable. Nurses and physicians need to recognize the toxidrome early. Hospitals where carvedilol is used in patients with cirrhosis should have glucagon in formulary at doses to treat toxicity (bolus and infusion). Finally, dose adjustment and slow uptitration of carvedilol in cirrhosis is recommended.",
"affiliations": "Department of Internal Medicine, University of Florida College of Medicine, 4th Fl. LRC Building, 653 W 8th St, Jacksonville, Fl 32209 USA.;Department of Internal Medicine, University of Florida College of Medicine, 4th Fl. LRC Building, 653 W 8th St, Jacksonville, Fl 32209 USA.;Department of Internal Medicine, University of Florida College of Medicine, 4th Fl. LRC Building, 653 W 8th St, Jacksonville, Fl 32209 USA.;Department of Internal Medicine, University of Florida College of Medicine, 4th Fl. LRC Building, 653 W 8th St, Jacksonville, Fl 32209 USA.;Jackson Memorial Hospital, Miami, USA.;Department of Internal Medicine, University of Florida College of Medicine, 4th Fl. LRC Building, 653 W 8th St, Jacksonville, Fl 32209 USA.",
"authors": "Maharaj|Satish|S|0000-0002-2872-3011;Seegobin|Karan|K|;Perez-Downes|Julio|J|;Bajric|Belinda|B|;Chang|Simone|S|;Reddy|Pramod|P|",
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"fulltext": "\n==== Front\nClin HypertensClin HypertensClinical Hypertension2056-5909BioMed Central London 8310.1186/s40885-017-0083-zCase ReportSevere carvedilol toxicity without overdose – caution in cirrhosis http://orcid.org/0000-0002-2872-3011Maharaj Satish Satish.maharaj@jax.ufl.edu 1Seegobin Karan Karan.seegobin@jax.ufl.edu 1Perez-Downes Julio Julio.perez-downes@jax.ufl.edu 1Bajric Belinda Belinda.bajric@jax.ufl.edu 1Chang Simone simonechang@med.miami.edu 2Reddy Pramod Pramod.reddy@jax.ufl.edu 11 0000 0004 0625 1409grid.413116.0Department of Internal Medicine, University of Florida College of Medicine, 4th Fl. LRC Building, 653 W 8th St, Jacksonville, Fl 32209 USA 2 0000 0000 8525 5459grid.414905.dJackson Memorial Hospital, Miami, USA 30 11 2017 30 11 2017 2017 23 2524 10 2017 28 11 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\nCarvedilol is used in the management of hypertension, ischemic heart disease, heart failure and most recently, portal hypertension. It has been associated with improved outcomes regarding variceal bleeding, hepatic decompensation and death when compared to propranolol and endoscopic band ligation. The main cause of portal hypertension is cirrhosis and therefore carvedilol is increasingly used in these patients. Due to its extensive hepatic metabolism, carvedilol is contraindicated in severe hepatic impairment. However, there are no dosage adjustments in the manufacturer’s labelling for mild to moderate hepatic impairment.\n\nCase presentation\nWe present a case of cardiogenic shock that occurred after carvedilol 25 mg orally was administered to a patient with cirrhosis. As there was no overdose, the diagnosis was based on clinical recognition of the toxidrome. The patient was successfully treated with glucagon 5 mg bolus followed by infusion.\n\nConclusions\nPatients with cirrhosis represent a special at-risk group for beta blocker toxicity. The typical threshold for carvedilol toxicity in overdose is 50 mg but in patients with cirrhosis this is not applicable. Nurses and physicians need to recognize the toxidrome early. Hospitals where carvedilol is used in patients with cirrhosis should have glucagon in formulary at doses to treat toxicity (bolus and infusion). Finally, dose adjustment and slow uptitration of carvedilol in cirrhosis is recommended.\n\nKeywords\nBeta blockerCarvedilolCirrhosisGlucagonToxicityTreatmentissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground: Carvedilol use in patients with cirrhosis\nCarvedilol is used in the management of hypertension, ischemic heart disease, heart failure and most recently, portal hypertension. Beta blockers decrease portal hypertension and are the mainstay of pharmacologic prophylaxis for gastroesophageal varices. The original beta blockers studied were nadolol and propranolol, but carvedilol recently emerged as an alternative [1]. There is also significant evidence that carvedilol is more potent with clinical benefits. Compared with propranolol, carvedilol was found to achieve greater reduction in hepatic venous pressure gradient [2] and work in non-responders to propranolol [3]. Carvedilol has been associated with improved outcomes regarding variceal bleeding, hepatic decompensation and death when compared to propranolol and endoscopic band ligation [3]. The main cause of portal hypertension is cirrhosis and therefore carvedilol is increasingly used in these patients.\n\nCase presentation\nA 56-year-old man with liver cirrhosis (secondary to hepatitis C) presented with hematemesis. The patient did not have diabetes, ischemic heart disease or other comorbidities. He did not regularly see a primary care physician and did not take any medications prior to admission. Laboratory investigation and imaging confirmed cirrhosis, with an alanine aminotransferase (ALT) of 101 IU/L, aspartate aminotransferase (AST) of 51 IU/L, albumin of 2.9 g/dL, total bilirubin of 1.4 mg/dL and international normalized ratio (INR) of 1.4. On imaging there was slight ascites and he did not have encephalopathy on examination, with Child-Pugh score of 7. An esophagogastroduodenoscopy confirmed bleeding esophageal varices, and band ligation was performed. Post intervention, the patient had an uneventful course and 7 days after presentation carvedilol 12.5 mg twice daily orally was started. Echocardiography on admission showed cardiac function was normal with a preserved ejection fraction. The other medications being administered were rifaximin and pantoprazole, and a final dose of ceftriaxone (1 g/day for 7 days) given only as prophylaxis. The first dose of carvedilol was administered after lunch and no reaction was noted acutely. At night the second dose was given. From this point on, the heart rate and blood pressure are charted in Fig. 1. At 2 hours after administration, the blood pressure declined from 120/78 mmHg to 97/61 mmHg but the heart rate was unchanged. Throughout the night the patient remained asymptomatic but the heart rate had started to decline. The patient denied any chest pain and the overnight team excluded myocardial ischemia with cardiac biomarkers and electrocardiography.Fig. 1 Graph showing heart rate and blood pressure after carvedilol 25 mg administered\n\n\n\n\nThe following morning, 8 h after administration, the patient was hypotensive with a blood pressure of 80/45 mmHg, pulse of 51 beats/min and had a respiratory rate of 18 breaths/min. The patient was fully alert and oriented and expressed his wish to not have placement of any central venous access. A total of three liters intravenous crystalloid fluid boluses were administered but there was only a transient rise in blood pressure (Fig. 1, time 00 to 01 h). Electrocardiography and cardiac biomarkers again excluded myocardial ischemia. There was no leukocytosis, fever or tachypnea to suggest sepsis. Blood cultures demonstrated no growth. Serum biochemistry revealed normal electrolyte concentrations (K, Ca, Mg, Na) and no acute kidney injury.\n\nOn further investigation, the patient was hypothermic (33.7 °C) and hypoglycemic (serum glucose 40 g/dL) but the rest of the physical exam was unchanged. To note, the patient was not diabetic and had not received any insulin or other hypoglycemic medications. Laboratory investigations showed a stable hemoglobin and no signs of infection. Passive rewarming was started and intravenous dextrose and albumin given. Despite these measures repeat blood pressure was 69/42 and the patient began to become delirious. An electrocardiogram showed sinus bradycardia. A bolus of 5 mg intravenous glucagon was given. Within 5 min of administration the heart rate had increased to 65/min and blood pressure began to increase. This was followed by a glucagon infusion in 5% dextrose at 1 mg/h. As shown in Fig. 1, there was a steady response to treatment with clinical resolution. With a normal QT interval, the patient was pre-treated with 8 mg intravenous ondansetron to prevent vomiting associated with glucagon which did not occur. Repeat electrocardiogram during and after glucagon infusion showed normal sinus rhythm. The heart rate and blood pressure normalized and no further boluses of glucagon were required. There was concern as the nurse reported the patient had been anuric overnight. However, ultrasonography of the bladder showed that the patient was in urinary retention, which relieved with urethral catheterization. Vital signs on the following morning were blood pressure 126/56 mmHg, pulse 79 beats per minute and temperature 36.9 °C. There was no recurrence of hypoglycemia, hypothermia or urinary retention. The patient had no evidence of end organ sequelae and was discharged in stable condition.\n\nDiscussion\nPharmacokinetic considerations\nPharmacologically, carvedilol is a unique beta blocker. The formulation is a racemic mixture that forms S(−) and R(+) enantiomers which enable the drug to possess both non-selective β-adrenoreceptor antagonist and also α1-andrenoreceptor antagonist activity, respectively. Its vasodilating effect is theorized to contribute to its potency in reducing mortality and morbidity in the settings of ischemic heart disease and portal hypertension [4]. Compared to the pure β-adrenoreceptor antagonists, carvedilol’s α1-andrenoreceptor-antagonist activity may be both its strength and weakness. The vasodilating effect makes it more potent, but also presents a theoretical risk for additional hypotension in cases of overdose or supratherapeutic levels. In healthy individuals, after oral dosing, carvedilol is rapidly absorbed and undergoes extensive first-pass metabolism in the liver with a peak concentration 1 to 2 h after and subsequent hepatic metabolism [5].\n\nSafety and optimal dosing of carvedilol in patients with cirrhosis\nAs a therapeutic class the beta blockers have a good safety profile. Carvedilol has been widely used for decades, and at a dose of 25 mg daily, postmarketing surveillance has shown that it is generally well tolerated [6]. To the best of our knowledge, cardiogenic shock has not been reported with carvedilol use in therapeutic doses. Several clinical studies have investigated carvedilol in cirrhotic patients at varying doses. A summary of several studies is shown in Table 1 [2, 7–15]. Hypotensive events were noted both acutely and delayed and varied in incidence from 2.6% to 17.6%. These results imply that hemodynamic compromise can be a significant adverse effect of carvedilol at standard doses in cirrhosis.Table 1 Hypotensive events in several studies investigating carvedilol in cirrhosis\n\nStudy (n = number of patients on carvedilol)\tDaily dose of carvedilol (mg) studied\tFollow up time(s)\tIncidence of hypotension or bradycardia*\t\nHobolth et al. (21)\t3.125–25 (mean 14 ± 7)\t90 min; 92.7 ± 13.6 days\t0\t\nStanley et al. (33)\t6.25–12.5\t30.7 months (7.9–47.1)\t5 (15.2%)\t\nTripathi et al. (77)\t12.5\t26.2 ± 22.1 months\t2 (2.6%)\t\nDe et al. (18)\t12.5–25\t90 min; 7 days\t1 (5.6%)\t\nBanares et al. (14)\t25\t60 min\t0\t\nBruha et al. (36)\t25\t1 month\t0\t\nForrest et al. (16)\t25\t60 min\t0\t\nLin et al. (11)\t25\t90 min\t0\t\nStanley et al. (17)\t25\t60 mins; 28 days\t3 (17.6%)\t\nBanares et al. (26)\t6.25–50 (mean 31 ± 4)\t11.1 ± 4.1 weeks\t2 (7.7%)\t\n\n\n\nDue to its extensive hepatic metabolism, carvedilol is contraindicated in severe hepatic impairment. However, there are no dosage adjustments in the manufacturer’s labelling for mild to moderate hepatic impairment. The pharmacokinetics of carvedilol are greatly altered in cirrhosis at both hepatic and systemic levels. Hepatic blood flow and drug extraction are reduced, leading to impaired metabolism and elimination of the drug. To add to this, carvedilol is a highly protein bound drug and hypoalbuminemia in cirrhosis affects the unbound serum concentrations.\n\nDespite its widespread use in these patients, there is limited data on pharmacokinetics outside of healthy volunteers or patients with heart failure. Rasool et al. performed physiologically based pharmacokinetic modelling to simulate use in cirrhotic patients. They suggested that in these patients, to maintain drug exposure equivalent to 25 mg carvedilol in healthy individuals, the administered doses should be reduced to 12.5 mg, 6.25 mg, and 3.125 mg stratified by Child-Pugh class A, B, and C. Additionally, in liver cirrhosis the unbound systemic concentration of carvedilol increases much more in comparison to that of total systemic concentration of carvedilol [16].\n\nCarvedilol decreases portal pressure after acute and long-term administration. Some authors have suggested that the clinical benefit of carvedilol, as reflected by reduction in HVPG, is directly proportional to dosage. In the studies examined (Table 1), investigators tended to initiate therapy at daily doses of either 6.25 mg (7–9,11) or 25 mg (2,10,12–15). Studies with a protocol that initially administered 25 mg daily dosing recorded a higher incidence of bradycardia and hypotension. From these studies as well as the case presented, we can suggest that a starting dose of 25 mg daily is too large a dose in patients with cirrhosis. We recommend initiating carvedilol at low dose, 3.125 mg twice daily, with close monitoring of heart rate and blood pressure that would require home monitoring and clinic visits. Slow uptitration at regular follow up visits can then be done as the patient tolerates.\n\nCarvedilol toxidrome and treatment with glucagon\nDespite its widespread use, from our review of PubMed, ToxLine and International Pharmaceutical Abstracts, there are only two published case reports (English) of carvedilol toxicity and both of these were in the setting of overdose [17, 18]. The typical threshold for carvedilol toxicity in overdose is 50 mg [19] but in patients with cirrhosis this is not applicable. Especially in the absence of overdose, clinical recognition of the toxidrome is the key to early diagnosis leading to treatment. As in this case, the classic hallmarks of beta blocker toxidrome are hypotension and bradycardia, that can progress to cardiogenic shock and less frequently be accompanied by change in mental status, hypoglycemia or hypothermia. We were limited in this case because serum testing for carvedilol level was not available. However, the recognition of classic signs of beta blocker toxidrome and exclusion of alternative diagnoses allowed a clinical diagnosis. In practice, clinicians are unlikely to have access to carvedilol levels and prompt recognition of the toxidrome is essential to enable rapid treatment.\n\nCarvedilol is a highly lipophilic drug and mental status should be monitored closely. In carvedilol toxicity, the signs of hypoglycemia are masked and a high index of suspicion is needed. With normal mental status and a stable airway, the focus of management should be on hemodynamic stabilization. We successfully used crystalloids and albumin followed by glucagon as a high dose intravenous bolus and infusion. Atropine has been recommended by some as first line treatment but has poor results in severe beta blocker toxicity [20]. In carvedilol toxicity, it is possible to use inotropes to maintain hemodynamic support. Bouchard et al. reported a case of overdose where the patient was responsive to glucagon boluses, 2-3 mg, but this was not followed by glucagon infusion [17]. Instead a dopamine infusion was started. Despite the dopamine infusion, however, the patient had occasional hypotension and bradycardia, and glucagon boluses were still used adjunctively with good response. If inotropes are used, it is suggested to select an agent based upon specific hemodynamic and cardiodynamic monitoring. There is no one catecholamine that is superior for cardiovascular drug toxicity but catecholamines such as isoproterenol and dobutamine, that possess predominant beta receptor activity and little alpha agonist activity may decrease peripheral resistance and worsen hypotension [20].\n\nThe treatment of beta blocker toxicity continues to be an area of active investigation. In beta blocker poisoning with bradycardia and hypotension, high-dose glucagon is considered the first-line antidote [21]. Glucagon has positive inotropic and chronotropic effects. Mechanistically, glucagon activates adenyl cyclase and exerts inotropic and chronotropic effects via a pathway not mediated by the adrenergic system. As Kerns [20] points out, this property makes glucagon particularly attractive as an antidote for beta blocker toxicity by providing cAMP necessary for myocardial cell performance in the face of beta blockade.\n\nThere are no studies on glucagon use in humans and current therapy is guided by animal studies and case reports. It would be unethical to undertake a randomized clinical trial investigating treatment of beta blocker toxicity. In the five studies of animal models of beta-blocker overdose in systematic review by Bailey, glucagon increased the heart rate (at least transiently) but appeared to have no effect on mean arterial pressure [22]. In this case we observed glucagon restoring the blood pressure (Fig. 1). When glucagon is used as an antidote, an “appropriate dose” should be administered. We agree that an appropriate dose represents a bolus of 5–10 mg followed by an infusion of 1–5 mg/h, titrated based on clinical response.\n\nConclusions\nBeta blocker toxicity is usually the result of overdose. Patients with cirrhosis represent a special at-risk group that can have toxicity at standard doses. Healthcare providers need to recognize the toxidrome early. In this case reversal was achieved with intravenous glucagon as evidenced by raised cardiac output and blood pressure. Hospitals where carvedilol is used in patients with cirrhosis should have glucagon in formulary at doses to treat toxicity (bolus and infusion).\n\nAcknowledgements\nThe authors gratefully acknowledge Ms. Gretchen Kuntz (MSW, MLIS), at the University of Florida Borland Library for her assistance with literature search.\n\nFunding\nNo sources of funding are applicable to this article.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article and its supplementary files.\n\nAuthors’ contributions\nSM, BB and PR directly cared for and managed the patient and conceived the idea for this report. KS, JPD and SC performed the literature review, analyzed the existing data and contributed to the discussion. All authors contributed to the written report and approved the final version.\n\nEthics approval and consent to participate\nThis case report is published for educational purposes with the permission of the patient; written informed consent was obtained and is available. SM, BB and PR directly provided care for the patient and consent is available from the corresponding author. This was an actual clinical scenario that is retrospectively reported without any need for approval by the ethics committee.\n\nConsent for publication\nThe authors agree with the copyright and license agreements.\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. de Franchis R Baveno VI Faculty. Expanding consensus in portal hypertension: report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension J Hepatol 2015 63 3 743 752 10.1016/j.jhep.2015.05.022 26047908 \n2. Bañares R Moitinho E Matilla A García-Pagán JC Lampreave JL Piera C Abraldes JG De Diego A Albillos A Bosch J Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis Hepatology 2002 36 6 1367 1373 10.1002/hep.1840360612 12447861 \n3. Reiberger T Ulbrich G Ferlitsch A Payer BA Schwabl P Pinter M Heinisch BB Trauner M Kramer L Peck-Radosavljevic M; Vienna hepatic hemodynamic lab. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol Gut 2013 62 11 1634 1641 10.1136/gutjnl-2012-304038 23250049 \n4. Bosch J Carvedilol for portal hypertension in patients with cirrhosis Hepatology 2010 51 6 2214 2218 10.1002/hep.23689 20513005 \n5. Morgan T Clinical pharmacokinetics and pharmacodynamics of carvedilol Clin Pharmacokinet 1994 26 5 335 346 10.2165/00003088-199426050-00002 7914479 \n6. McTavish D Campoli-Richards D Sorkin EM Carvedilol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy Drugs 1993 45 2 232 235 10.2165/00003495-199345020-00006 7681374 \n7. Hobolth L Møller S Grønbæk H Roelsgaard K Bendtsen F Feldager HE Carvedilol or propranolol in portal hypertension? A randomized comparison Scand J Gastroenterol 2012 47 4 467 474 10.3109/00365521.2012.666673 22401315 \n8. Stanley AJ Dickson S Hayes PC Forrest EH Mills PR Tripathi D Leithead JA MacBeth K Smith L Gaya DR Suzuki H Young D Multicentre randomized controlled study comparing carvedilol with variceal band ligation in the prevention of variceal rebleeding J Hepatol 2014 61 5 1014 1019 10.1016/j.jhep.2014.06.015 24953021 \n9. Tripathi D Ferguson JW Kochar N Leithead JA Therapondos G McAvoy NC Stanley AJ Forrest EH Hislop WS Mills PR Hayes PC Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed Hepatology 2009 50 3 825 833 10.1002/hep.23045 19610055 \n10. De BK Das D Sen S Biswas PK Mandal SK Majumdar D Maity AK Acute and 7-day portal pressure response to carvedilol and propranolol in cirrhotics J Gastroenterol Hepatol 2002 17 2 183 189 10.1046/j.1440-1746.2002.02674.x 11966949 \n11. Bañares R Moitinho E Piqueras B Casado M García-Pagán JC de Diego A Bosch J Carvedilol, a new nonselective beta-blocker with intrinsic anti- Alpha1-adrenergic activity, has a greater portal hypotensive effect than propranolol in patients with cirrhosis Hepatology 1999 30 1 79 83 10.1002/hep.510300124 10385642 \n12. Bruha R Vitek L Petrtyl J Lenicek M Urbanek P Zelenka J Jachymova M Svestka T Kalab M Dousa M Marecek Z Effect of carvedilol on portal hypertension depends on the degree of endothelial activation and inflammatory changes Scand J Gastroenterol 2006 41 12 1454 1463 10.1080/00365520600780403 17101577 \n13. Forrest EH Bouchier IA Hayes PC Acute haemodynamic changes after oral carvedilol, a vasodilating beta-blocker, in patients with cirrhosis J Hepatol 1996 25 6 909 915 10.1016/S0168-8278(96)80296-0 9007720 \n14. Lin HC Yang YY Hou MC Huang YT Lee FY Lee SD Acute administration of carvedilol is more effective than propranolol plus isosorbide-5-mononitrate in the reduction of portal pressure in patients with viral cirrhosis Am J Gastroenterol 2004 99 1953 1958 10.1111/j.1572-0241.2004.40179.x 15447755 \n15. Stanley AJ Therapondos G Helmy A Hayes PC Acute and chronic haemodynamic and renal effects of carvedilol in patients with cirrhosis J Hepatol 1999 30 3 479 484 10.1016/S0168-8278(99)80108-1 10190732 \n16. Rasool MF Khalil F Läer S Optimizing the clinical use of Carvedilol in liver cirrhosis using a physiologically based pharmacokinetic modeling approach Eur J Drug Metab Pharmacokinet 2017 42 3 383 396 10.1007/s13318-016-0353-2 27313074 \n17. Bouchard NC, Forde J, Hoffman RS. Carvedilol overdose with quantitative confirmation. Basic Clin Pharmacol Toxicol. 2008;103(1):102–3.\n18. Hantson P Lambermont JY Simoens G Mahieu P Carvedilol overdose Acta Cardiol 1997 52 4 369 371 9381894 \n19. Wax PM Erdman AR Chyka PA Beta-blocker ingestion: an evidencebased consensus guideline for out-ofhospital management Clin Toxicol 2005 43 131 146 10.1081/CLT-62475 \n20. Kerns W II Kline J Ford MD Betablocker and calcium channel blocker toxicity Emerg Med Clin North Am 1994 12 365 390 7910555 \n21. Shepherd G Treatment of poisoning caused by beta-adrenergic and calcium-channel blockers Am J Health Syst Pharm 2006 63 19 1828 1835 10.2146/ajhp060041 16990629 \n22. Bailey B Glucagon in beta-blocker and calcium channel blocker overdoses: a systematic review J Toxicol Clin Toxicol 2003 41 5 595 602 10.1081/CLT-120023761 14514004\n\n",
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"title": "Severe carvedilol toxicity without overdose - caution in cirrhosis.",
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"abstract": "Although tyrosine kinase inhibitors markedly improve the clinical outcome of chronic myeloid leukemia (CML), blast crisis in CML (CML-BC) still has a poor prognosis. Many chromosomal abnormalities have been reported in CML-BC and may contribute to therapeutic resistance, disease progression, and prognosis. Herein, we report a rare chromosome abnormality with der(16)t(1;16)(q12;q11.2) in CML-BC. It has been demonstrated that this chromosomal abnormality is associated with disease progression and poor prognosis in other malignancies, such as Ewing sarcoma. A 70-year-old man with CML who had been treated with imatinib and dasatinib was admitted to our hospital after complaining for several weeks of fatigue and dyspnea and diagnosed with CML-BC. His tumor cells presented additional chromosomal abnormality with der(16)t(1;16)(q12;q11.2), which has never been reported in CML cases. We successfully treated him using cytotoxic agents combined with ponatinib, and this chromosome abnormality was detected via G-banding. Our patient has lived for over 8 months without any progression with ponatinib treatment alone. Although the biological function of this chromosomal abnormality remains unclear, the satellite DNA of 1q12, which induces genomic instability in other malignancies, and the loss of 16q may contribute to the disease progression of CML in this case. In conclusion, this paper is the first to report on the case of CML-BC with der(16)t(1;16)(q12;q11.2).",
"affiliations": "Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology (3rd Internal Medicine), Faculty of Medicine, Yamagata University, Yamagata, Japan.;Department of Pharmacy, Nihonkai General Hospital, Sakata, Japan.;Department of Internal Medicine, Nihonkai General Hospital, Sakata, Japan.;Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology (3rd Internal Medicine), Faculty of Medicine, Yamagata University, Yamagata, Japan.;Department of Pharmacy, Nihonkai General Hospital, Sakata, Japan.;Department of Internal Medicine, Nihonkai General Hospital, Sakata, Japan.;Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology (3rd Internal Medicine), Faculty of Medicine, Yamagata University, Yamagata, Japan.;Department of Internal Medicine, Nihonkai General Hospital, Sakata, Japan.",
"authors": "Yanagiya|Ryo|R|;Ishikawa|Daisuke|D|;Toubai|Tomomi|T|;Ichikawa|Tsubasa|T|;Kawaguchi|Naofumi|N|;Sugasawa|Kunie|K|;Ishizawa|Kenichi|K|;Saito|Soichi|S|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.1159/000509642",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 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\n10.1159/000509642\ncro-0013-1020\nCase Report\nA Rare Chromosome Abnormality with der(16)t(1;16)(q12;q11.2) in Blast Crisis of Chronic Myeloid Leukemia\nYanagiya Ryo ab* Ishikawa Daisuke c Toubai Tomomi b Ichikawa Tsubasa ab Kawaguchi Naofumi c Sugasawa Kunie b Ishizawa Kenichi a Saito Soichi b aDepartment of Neurology, Hematology, Metabolism, Endocrinology and Diabetology (3rd Internal Medicine), Faculty of Medicine, Yamagata University, Yamagata, Japan\nbDepartment of Internal Medicine, Nihonkai General Hospital, Sakata, Japan\ncDepartment of Pharmacy, Nihonkai General Hospital, Sakata, Japan\n*Ryo Yanagiya, Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology (3rd Internal Medicine), Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585 (Japan), r-yanagiya@med.id.yamagata-u.ac.jp\nMay-Aug 2020 \n27 8 2020 \n27 8 2020 \n13 2 1020 1025\n23 6 2020 24 6 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.Although tyrosine kinase inhibitors markedly improve the clinical outcome of chronic myeloid leukemia (CML), blast crisis in CML (CML-BC) still has a poor prognosis. Many chromosomal abnormalities have been reported in CML-BC and may contribute to therapeutic resistance, disease progression, and prognosis. Herein, we report a rare chromosome abnormality with der(16)t(1;16)(q12;q11.2) in CML-BC. It has been demonstrated that this chromosomal abnormality is associated with disease progression and poor prognosis in other malignancies, such as Ewing sarcoma. A 70-year-old man with CML who had been treated with imatinib and dasatinib was admitted to our hospital after complaining for several weeks of fatigue and dyspnea and diagnosed with CML-BC. His tumor cells presented additional chromosomal abnormality with der(16)t(1;16)(q12;q11.2), which has never been reported in CML cases. We successfully treated him using cytotoxic agents combined with ponatinib, and this chromosome abnormality was detected via G-banding. Our patient has lived for over 8 months without any progression with ponatinib treatment alone. Although the biological function of this chromosomal abnormality remains unclear, the satellite DNA of 1q12, which induces genomic instability in other malignancies, and the loss of 16q may contribute to the disease progression of CML in this case. In conclusion, this paper is the first to report on the case of CML-BC with der(16)t(1;16)(q12;q11.2).\n\nKeywords\nt(1;16)(q12;q11.2)Genetic instabilityChronic myeloid leukemiaBlast crisisAdditional chromosomal abnormality\n==== Body\nIntroduction\nChronic myeloid leukemia (CML) is characterized by the translocation of chromosome 9q34 Abl1 and chromosome 22q11.2 Bcr in hematopoietic stem cells [1]. Abl1 is a protooncogene that encodes a tyrosine kinase and is involved in the promotion of the cell cycle [2]. Abnormal tyrosine kinases encoded by t(9;22)(q34;q11.2) Bcr/Abl1 form a tetramer via the coiled-coil region encoded by Bcr, thereby activating Abl1-encoding tyrosine kinases permanently [3]. Activated Abl1-encoding tyrosine kinases induce disorder in the cell cycle and are responsible for the pathogenesis of chronic CML (CML-CP) [1]. Tyrosine kinase inhibitors (TKIs) inhibit the ATP-binding portion of Abl1-encoding tyrosine kinases and are capable of effectively reducing Bcr/Abl1-positive cells in CML-CP patients. There are currently several TKIs (imatinib, nilotinib, dasatinib, bosutinib, and ponatinib) available worldwide [4], and the development of these TKIs has resulted in a dramatic improvement in the prognosis of CML-CP. The 5-year overall survival (OS) of newly-diagnosed CML-CP patients who show a good response to TKIs is over 90% [5, 6]. However, patients who are refractory or intolerant to TKIs continue to show a poor prognosis [5, 6]. Blast crisis in CML (CML-BC) is characterized by excessive blast proliferation accompanied by differentiation impairment or extramedullary lesion [7] and has an extremely poor prognosis. The median OS of CML-BC patients treated with TKIs is approximately 12 months, while the median failure-free survival is around 5 months [8]. There is no standard therapeutic strategy for CML-BC. Although allogeneic hematopoietic stem cell transplantation is the only curative therapeutic option for CML-BC, the clinical outcome remains poor due to high rates of relapse and treatment-related mortality [8]. The pathogenesis of CML-BC remains unclear; however, additional chromosomal abnormalities may contribute to the progression of CML-BC [9].\n\nHerein, we report on a CML-BC patient with chromosomal abnormalities in addition to der(16)t(1;16)(q12;q11.2). Contrary to previous reports that this chromosomal abnormality is associated with a poor prognosis [10], we succeeded in controlling the patient's disease status using TKIs. This patient has not experienced any disease progression for over 8 months.\n\nCase Report/Case Presentation\nA 70-year-old man was admitted to our hospital after complaining for several weeks of fatigue and dyspnea. He was diagnosed with CML-CP 14 years ago and was initially treated with imatinib 400 mg/day. He achieved major molecular response (MMR) within a year of initiating treatment with imatinib, but decided to discontinue treatment due to economic reasons after 80 months while still with MMR. Although this patient lost MMR 4 months after discontinuing imatinib, he refused to restart treatment. Twenty-seven months after stopping imatinib, he also lost his major cytogenetic response and started treatment with dasatinib (180 mg/day). Although the patient regained MMR within 7 months of initiating treatment, he presented uncontrollable pleural effusion as a result of treatment with dasatinib and was switched onto imatinib (400 mg/day). His disease status remained well controlled for 54 months, but deteriorated gradually before being diagnosed with blast crisis in October 2019. The patient's laboratory findings at CML-BC diagnosis are shown in Table 1. The blasts in his peripheral blood (PB) were 90% and showed hypercoagulation and a high uremic acid concentration in the serum. In addition, bone marrow aspiration showed excessive blast proliferation (more than 80% of all nucleated cellular counts). Flow cytometry analysis showed that the blasts were positive for CD13, CD19, and CD10, but negative for CD33, CD14, CD11c, CD3, CD4, CD8, and cytoplasmic myeloperoxidase, which suggests B-cell phenotype (B-lymphoid BC). Real-time polymerase chain reaction (RT-PCR) for bcr/abl1 of PB showed 1.3 × 105 copies/µg RNA. As a result, the patient was diagnosed with B-lymphoid crisis. Interestingly, the patient was found to have an additional chromosome abnormality with 46,XY,t(9;22)(q34;q11.2)[3]/46,idem,der(4)t(1;4)(q12;q35)[1]/46,idem,der(16)t(1;16)(q12;q11.2),i(18)(q10)[1] in PB. The spectral karyotyping of the blasts in the PB demonstrated that all the cells (4 cells) showed reciprocal translocation of chromosomes 9 and 22. In addition, two of the 4 cells analyzed showed translocation of fragments derived from chromosomes 1 to 16 (Fig. 1). This additional chromosomal abnormality was not detected at the initial diagnosis.\n\nThe patient's symptoms quickly worsened, and he developed disseminated intravascular coagulopathy (DIC). He was started on treatment with 1 mg/kg/day of prednisolone accompanied with 24-hour continuous intravenous cytarabine 100 mg/body/day, 380 U/kg/day of recombinant thrombomodulin alfa, and transfusion with fresh frozen plasma for DIC. After cytarabine treatment, the patient's blasts in PB gradually decreased and his coagulation status improved. We decided to increase the dosage of cytarabine to 100 mg/m2/day, in addition to 50 mg/body of daunorubicin. His blasts disappeared from the PB 15 days after initiating chemotherapy. The patient was then started on ponatinib (15 mg/day). Bone marrow aspiration was performed after chemotherapy and showed a decrease in blasts (3.6% of nucleated cellular counts). Fluorescence in situ hybridization of bcr and abl1 showed that the patient achieved major cytogenetic response (fusion signal was positive for 4% of 100 assessed cells). However, G-banding of the bone marrow blasts still showed 46,XY,del(6)(q?),t(9;22)(q34;q11.2)[1]/46,XY[19]. The patient's overall condition was markedly improved and he was subsequently discharged. He continued to receive treatment with 15 mg/day of ponatinib and has not yet experienced disease progression, as of June 2020. His international scale of RT-PCR for bcr/abl1 8 months after starting ponatinib was 0.2319%. The patient achieved an optimal response at the time, according to European LeukemiaNet 2013. His laboratory findings did not show a decrease in normal hematopoiesis or excessive blast proliferation from the time of his discharge.\n\nDiscussion/Conclusion\nAccording to previous studies, increased genetic instability and incomplete repairment of deoxynucleic acids caused by Bcr/Abl1 plays an important role in generating chromosomal abnormalities in CML cells [10]. Mitelman reported that “major” and “minor” pathways of generating additional chromosomal abnormalities exist in CML cells [11]. For example, trisomy 8, i(17q), trisomy 19, and an extra Ph are generated via the “major” pathway, and about 70% of CML cases have at least one of these four chromosomal abnormalities [11]. On the other hand, −7, −17, +17, +21, ‒Y, and t(3;21)(q26;q22) were generated via the “minor” pathway, while about 15% of CML cases had at least one of these six chromosomal abnormalities [11]. Asnafi et al. reviewed the additional chromosomal abnormalities discovered in CML-BC cases between 1975 and 2017 [9] and suggested that some chromosomal abnormalities are associated with poor prognosis and poor therapeutic responses to TKIs [9]. However, the impact of these additional chromosomal abnormalities on the development of a blast crisis remains unknown and detailed investigation will be required in the future.\n\nIn our patient, der(16)t(1;16)(q12;q11.2) was identified by both G-banding and spectral karyotyping assays. There are few reports available on CML patients with this abnormal chromosome on PubMed or Atlas of Genetics and Cytogenetics in Oncology and Hematology, a database of chromosomal abnormalities in malignant tumors (http://atlasgeneticsoncology.org/; accessed June 19, 2020). This chromosomal abnormality has been reported in several types of malignancies, including breast cancer, multiple myeloma, Wilms tumor, and Ewing sarcoma (http://atlasgeneticsoncology.org/; accessed June 19, 2020) and has been associated with disease progression and poor clinical outcome [12, 13]. Although the biological function of der(16)t(1;16)(q12;q11.2) remains unclear, a previous report suggested that the translocation of 1q12 satellite DNA can mediate epigenetic perturbations and genetic instability [14]. In addition to 1q12 translocation, an unbalanced loss of chromosome 16 may also contribute to promote disease progression and a relatively poor prognosis in malignant tumors. Although the function of the unbalanced loss of 16q remains unclear, according to a previously reported retrospective analysis, both 1q gain and 16q loss, including unbalanced translocation t(1;16)(q10∼21;q10∼13), may be related to 5-year OS in cases of Ewing sarcoma [15]. In regards to the poor prognosis of der(16)t(1;16)(q12;q11.2), our patient showed relatively better responses to chemotherapy and ponatinib compared with the reported failure-free survival of CML-BC treated with TKIs [8]. Intriguingly, we found that this additional chromosomal abnormality disappeared after chemotherapy. The long-term therapeutic response will have to be carefully monitored, since this chromosomal abnormality has been previously reported as a poor prognostic factor [12, 13, 15]. In summary, this paper is the first to report on the case of a CML-BC patient with der(16)t(1;16)(q12;q11.2). Further CML cases with additional chromosomal abnormalities related to 1q or 16q, as well as abnormal chromosomes and other associated gene mutations, will need to be analyzed to improve our understanding of the pathophysiology of additional chromosomal abnormalities in CML.\n\nStatement of Ethics\nInformed consent was obtained from our patient. This study is in compliance with the ethical requirements of our institutions (Nihonkai General Hospital and Yamagata University).\n\nConflict of Interest Statement\nThe authors have no conflicts of interest to declare related to this case report.\n\nFunding Sources\nThis study did not receive any funding.\n\nAuthor Contributions\nRyo Yanagiya, Tsubasa Ichikawa, Kunie Sugasawa, and Soichi Saito treated the patients during his admission. Ryo Yanagiya and Soichi Saito selected the therapeutic strategies. Ryo Yanagiya wrote the article and has final responsibility. Soichi Saito supervised the hospital staff during the patient's admission. Daisuke Ishikawa and Naofumi Kawaguchi provided the patient and staff with pharmacological support. Tomomi Toubai and Kenichi Ishizawa supervised Ryo Yanagiya during the treatment of the patient and the writing of this article.\n\nAcknowledgment\nWe thank all staffs working in hematology and nephrology unit of Nihonkai General Hospital for their good medical, psychiatric, and social support for this patient.\n\nFig. 1 Spectral karyotyping of peripheral blasts showing the translocation of the fragment from chromosome 1 to chromosome 16 (arrow) and reciprocal translocation of chromosomes 9 and 22.\n\nTable 1 Laboratory findings at admission\n\nComplete blood cell counts\t\t\nWBC\t287,060/µL\t\nBlast\t90%\t\nSegment\t2%\t\nBand\t2%\t\nMono\t0.5%\t\nLymp\t5.5%\t\nRBC\t204×104/µL\t\nHb\t6.3 g/dL\t\nHt\t21.4%\t\nPlt\t5.6×104/µL\t\nRetic\t1.35%\t\n\t\nCoagulation\t\t\nPT\t75.1%\t\nAPTT\t26.1 s\t\nFibrinogen\t367 mg/dL\t\nFDP\t21.5 µg/dL\t\nD-dimer\t6.84 µg/dL\t\nAT III\t89%\t\n\t\nBiochemistry\t\t\nTP\t6.3 g/dL\t\nAlb\t4 g/dL\t\nT.Bil\t0.7 mg/dL\t\nAST\t26 U/L\t\nALT\t12 U/L\t\nLD\t929 U/L\t\nALP\t236 U/L\t\nγGT\t78 U/L\t\nBUN\t14.4 mg/dL\t\nCr\t0.92 mg/dL\t\nUA\t9.6 mg/dL\t\nNa\t142 mEq/L\t\nK\t4.6 mEq/L\t\nCl\t109 mEq/L\t\nCa\t8 mg/dL\t\nP\t2.1 mg/dL\t\nCRP\t8.81 mg/dL\t\nWBC, white blood cells; Mono, monocyte; Lymp, lymphocyte; RBC, red blood cells; Hb, hemoglobin; Ht, hematocrit; Plt, platelet counts; Retic, reticulocyte; PT, prothrombin time; APTT, activated partial thromboplastin time; FDP, fibrin/fibrinogen degradation products; AT III, antithrombin III; TP, total protein; Alb, albumin; T.Bil, total bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LD, lactate dehydrogenase; ALP, alkaline phosphatase; γGT, gammaglutamyl transferase; BUN, blood urea nitrogen; Cr, creatinine; UA, uric acid; CRP, C-reactive protein.\n==== Refs\nReferences\n1 Apperley JF Chronic myeloid leukaemia Lancet 2015 385 (9976) 1447 59 25484026 \n2 Goldman JM Melo JV Targeting the BCR-ABL tyrosine kinase in chronic myeloid leukemia N Engl J Med 2001 344 (14) 1084 6 11287980 \n3 McWhirter JR Galasso DL Wang JY A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins Mol Cell Biol 1993 13 (12) 7587 95 8246975 \n4 Shanmuganathan N Treatment of chronic myeloid leukemia: assessing risk, monitoring response, and optimizing outcome Leuk Lymphoma 2017 58 (12) 2799 810 28482729 \n5 Ross JE Saglio G Kantarjian HM Baccarani M Mayer J Boqué C Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial J Clin Oncol 2016 34 (20) 2333 40 27217448 \n6 Hochhaus A Saglio G Hughes TP Larson RA Kim DW Issaragrisil S Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial Leukemia 2016 30 (5) 1044 54 26837842 \n7 Vardiman JW Harris NL Brunning RD The World Health Organization (WHO) classification of the myeloid neoplasms Blood 2002 114 (5) 937 51 \n8 Jain P Kantarjian HM Ghorab A Sasaki K Jabbour EJ Gonzalez GN Prognostic Factors and Survival Outcomes in Patients With Chronic Myeloid Leukemia in Blast Phase in the Tyrosine Kinase Inhibitor Era: Cohort Study of 477 Patients Cancer 2017 123 (22) 4391 402 28743165 \n9 Asnafi AA Deris Zayeri Z Shahrabi S Zibara K Vosughi T Chronic Myeloid Leukemia With Complex Karyotypes: Prognosis and Therapeutic Approaches J Cell Physiol 2019 234 (5) 5798 806 30430567 \n10 Slupianek A Poplawski T Jozwiakowski SK Cramer K Pytel D Stoczynska E BCR/ABL stimulates WRN to promote survival and genomic instability Cancer Res 2011 71 (3) 842 51 21123451 \n11 Mitelman F The Cytogenetic Scenario of Chronic Myeloid Leukemia Leuk Lymphoma 1993 11 (Suppl 1) 11 5 8251885 \n12 Hattinger CM Rumpler S Ambros IM Strehl S Lion T Zoubek A Demonstration of the translocation der(16)t(1;16)(q12;q11.2) in interphase nuclei of Ewing tumors Genes Chromosomes Cancer 1996 17 (3) 141 50 8946192 \n13 Hattinger CM Zoubek A Ambros PF Molecular Cytogenetics in Ewing Tumors: Diagnostic and Prognostic Information Onkologie 2000 23 (5) 416 22 11441235 \n14 Fournier A McLeer-Florin A Lefebvre C Duley S Barki L Ribeyron J 1q12 chromosome translocations form aberrant heterochromatic foci associated with changes in nuclear architecture and gene expression in B cell lymphoma EMBO Mol Med 2010 2 (5) 159 71 20432501 \n15 Hattinger CM Pötschger U Tarkkanen M Squire J Zielenska M Kiuru-Kuhlefelt S Prognostic Impact of Chromosomal Aberrations in Ewing Tumours Br J Cancer 2002 86 (11) 1763 9 12087464\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "13(2)",
"journal": "Case reports in oncology",
"keywords": "Additional chromosomal abnormality; Blast crisis; Chronic myeloid leukemia; Genetic instability; t(1;16)(q12;q11.2)",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "1020-1025",
"pmc": null,
"pmid": "32999666",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "8246975;8251885;11287980;21123451;28743165;11441235;28482729;20432501;12087464;27217448;30430567;25484026;8946192;26837842;19357394",
"title": "A Rare Chromosome Abnormality with der(16)t(1;16)(q12;q11.2) in Blast Crisis of Chronic Myeloid Leukemia.",
"title_normalized": "a rare chromosome abnormality with der 16 t 1 16 q12 q11 2 in blast crisis of chronic myeloid leukemia"
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"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-270868",
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"abstract": "To describe the spectrum, treatment, and outcome of cranial nerve disorders associated with immune checkpoint inhibitor (Cn-ICI).\n\n\n\nThis nationwide retrospective cohort study on Cn-ICI (2015-2019) was conducted using the database of the French Refence Center. In addition, a systematic review of the literature (MEDLINE, Scopus, and Web of Science) for records published between 2010 and 2019 was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the search terms cranial nerve or neuropathy or palsy and immune checkpoint inhibitors.\n\n\n\nAmong 67 cases with ICI-related neurologic toxicities diagnosed in our reference center, 9 patients with Cn-ICI were identified (7 men, 78%, median age 62 years [range 26-82 years]). Patients were receiving a combination of anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed cell death 1 (PD-1)/PD-1 ligand (n = 5, 56%) or anti-PD-1 antibodies alone (n = 4, 44%). Cn-ICI involved optic (n = 3), vestibulocochlear (n = 3), abducens (n = 2), facial (n = 2), and oculomotor (n = 1) nerves. Two patients had involvement of 2 different cranial nerves. Treatment comprised corticosteroids (n = 8, 89%), ICI permanent discontinuation (n = 7, 78%), plasma exchange (n = 2, 22%), and IV immunoglobulin (n = 1, 11%). Median follow-up was 11 months (range 1-41 months). In 3 cases (33%), neurologic deficit persisted/worsened despite treatment: 2 optic and 1 vestibulocochlear. Among cases from the literature and the present series combined (n = 39), the most commonly affected cranial nerves were facial (n = 13, 33%), vestibulocochlear (n = 8, 21%), optic (n = 7, 18%), and abducens (n = 4, 10%). Trigeminal, oculomotor, and glossopharyngeal nerves were less frequently affected (total n = 7).\n\n\n\nCranial nerve disorders can complicate treatment with ICIs. Approximately one-third of the patients had persisting deficits, most frequently involving hearing and vision loss.",
"affiliations": "From the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (A.V., S.M.-C., B.J., G.P., V.R., V.D., D.P., F.D., J.H.) and Neuro-Cognition and Neuro-Ophthalmology Department (V.D., C.T.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H.), INSERM U1217/CNRS UMR5310; University Claude Bernard Lyon 1 (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H., C.T.), Université de Lyon, Lyon, France; Dermatology Department (F.S.), Centre Hospitalier de Valence; Neurology Department (M.E.), Centre Hospitalier de Libourne; Team ImpAct (C.T.), Lyon Neuroscience Research Center, INSERM U1028 CNRS UMR5292; and Neurology Department 2-Mazarin (D.P.), Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere Groupe, Hospitalier Pitie-Salpetriere et Universite Pierre et Marie Curie-Paris 6, AP-HP, France.;From the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (A.V., S.M.-C., B.J., G.P., V.R., V.D., D.P., F.D., J.H.) and Neuro-Cognition and Neuro-Ophthalmology Department (V.D., C.T.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H.), INSERM U1217/CNRS UMR5310; University Claude Bernard Lyon 1 (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H., C.T.), Université de Lyon, Lyon, France; Dermatology Department (F.S.), Centre Hospitalier de Valence; Neurology Department (M.E.), Centre Hospitalier de Libourne; Team ImpAct (C.T.), Lyon Neuroscience Research Center, INSERM U1028 CNRS UMR5292; and Neurology Department 2-Mazarin (D.P.), Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere Groupe, Hospitalier Pitie-Salpetriere et Universite Pierre et Marie Curie-Paris 6, AP-HP, France.;From the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (A.V., S.M.-C., B.J., G.P., V.R., V.D., D.P., F.D., J.H.) and Neuro-Cognition and Neuro-Ophthalmology Department (V.D., C.T.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H.), INSERM U1217/CNRS UMR5310; University Claude Bernard Lyon 1 (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H., C.T.), Université de Lyon, Lyon, France; Dermatology Department (F.S.), Centre Hospitalier de Valence; Neurology Department (M.E.), Centre Hospitalier de Libourne; Team ImpAct (C.T.), Lyon Neuroscience Research Center, INSERM U1028 CNRS UMR5292; and Neurology Department 2-Mazarin (D.P.), Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere Groupe, Hospitalier Pitie-Salpetriere et Universite Pierre et Marie Curie-Paris 6, AP-HP, France.;From the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (A.V., S.M.-C., B.J., G.P., V.R., V.D., D.P., F.D., J.H.) and Neuro-Cognition and Neuro-Ophthalmology Department (V.D., C.T.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H.), INSERM U1217/CNRS UMR5310; University Claude Bernard Lyon 1 (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H., C.T.), Université de Lyon, Lyon, France; Dermatology Department (F.S.), Centre Hospitalier de Valence; Neurology Department (M.E.), Centre Hospitalier de Libourne; Team ImpAct (C.T.), Lyon Neuroscience Research Center, INSERM U1028 CNRS UMR5292; and Neurology Department 2-Mazarin (D.P.), Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere Groupe, Hospitalier Pitie-Salpetriere et Universite Pierre et Marie Curie-Paris 6, AP-HP, France.;From the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (A.V., S.M.-C., B.J., G.P., V.R., V.D., D.P., F.D., J.H.) and Neuro-Cognition and Neuro-Ophthalmology Department (V.D., C.T.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H.), INSERM U1217/CNRS UMR5310; University Claude Bernard Lyon 1 (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H., C.T.), Université de Lyon, Lyon, France; Dermatology Department (F.S.), Centre Hospitalier de Valence; Neurology Department (M.E.), Centre Hospitalier de Libourne; Team ImpAct (C.T.), Lyon Neuroscience Research Center, INSERM U1028 CNRS UMR5292; and Neurology Department 2-Mazarin (D.P.), Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere Groupe, Hospitalier Pitie-Salpetriere et Universite Pierre et Marie Curie-Paris 6, AP-HP, France.;From the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (A.V., S.M.-C., B.J., G.P., V.R., V.D., D.P., F.D., J.H.) and Neuro-Cognition and Neuro-Ophthalmology Department (V.D., C.T.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H.), INSERM U1217/CNRS UMR5310; University Claude Bernard Lyon 1 (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H., C.T.), Université de Lyon, Lyon, France; Dermatology Department (F.S.), Centre Hospitalier de Valence; Neurology Department (M.E.), Centre Hospitalier de Libourne; Team ImpAct (C.T.), Lyon Neuroscience Research Center, INSERM U1028 CNRS UMR5292; and Neurology Department 2-Mazarin (D.P.), Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere Groupe, Hospitalier Pitie-Salpetriere et Universite Pierre et Marie Curie-Paris 6, AP-HP, France.;From the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (A.V., S.M.-C., B.J., G.P., V.R., V.D., D.P., F.D., J.H.) and Neuro-Cognition and Neuro-Ophthalmology Department (V.D., C.T.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H.), INSERM U1217/CNRS UMR5310; University Claude Bernard Lyon 1 (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H., C.T.), Université de Lyon, Lyon, France; Dermatology Department (F.S.), Centre Hospitalier de Valence; Neurology Department (M.E.), Centre Hospitalier de Libourne; Team ImpAct (C.T.), Lyon Neuroscience Research Center, INSERM U1028 CNRS UMR5292; and Neurology Department 2-Mazarin (D.P.), Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere Groupe, Hospitalier Pitie-Salpetriere et Universite Pierre et Marie Curie-Paris 6, AP-HP, France.;From the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (A.V., S.M.-C., B.J., G.P., V.R., V.D., D.P., F.D., J.H.) and Neuro-Cognition and Neuro-Ophthalmology Department (V.D., C.T.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H.), INSERM U1217/CNRS UMR5310; University Claude Bernard Lyon 1 (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H., C.T.), Université de Lyon, Lyon, France; Dermatology Department (F.S.), Centre Hospitalier de Valence; Neurology Department (M.E.), Centre Hospitalier de Libourne; Team ImpAct (C.T.), Lyon Neuroscience Research Center, INSERM U1028 CNRS UMR5292; and Neurology Department 2-Mazarin (D.P.), Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere Groupe, Hospitalier Pitie-Salpetriere et Universite Pierre et Marie Curie-Paris 6, AP-HP, France.;From the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (A.V., S.M.-C., B.J., G.P., V.R., V.D., D.P., F.D., J.H.) and Neuro-Cognition and Neuro-Ophthalmology Department (V.D., C.T.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H.), INSERM U1217/CNRS UMR5310; University Claude Bernard Lyon 1 (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H., C.T.), Université de Lyon, Lyon, France; Dermatology Department (F.S.), Centre Hospitalier de Valence; Neurology Department (M.E.), Centre Hospitalier de Libourne; Team ImpAct (C.T.), Lyon Neuroscience Research Center, INSERM U1028 CNRS UMR5292; and Neurology Department 2-Mazarin (D.P.), Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere Groupe, Hospitalier Pitie-Salpetriere et Universite Pierre et Marie Curie-Paris 6, AP-HP, France.;From the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (A.V., S.M.-C., B.J., G.P., V.R., V.D., D.P., F.D., J.H.) and Neuro-Cognition and Neuro-Ophthalmology Department (V.D., C.T.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H.), INSERM U1217/CNRS UMR5310; University Claude Bernard Lyon 1 (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H., C.T.), Université de Lyon, Lyon, France; Dermatology Department (F.S.), Centre Hospitalier de Valence; Neurology Department (M.E.), Centre Hospitalier de Libourne; Team ImpAct (C.T.), Lyon Neuroscience Research Center, INSERM U1028 CNRS UMR5292; and Neurology Department 2-Mazarin (D.P.), Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere Groupe, Hospitalier Pitie-Salpetriere et Universite Pierre et Marie Curie-Paris 6, AP-HP, France.;From the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (A.V., S.M.-C., B.J., G.P., V.R., V.D., D.P., F.D., J.H.) and Neuro-Cognition and Neuro-Ophthalmology Department (V.D., C.T.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H.), INSERM U1217/CNRS UMR5310; University Claude Bernard Lyon 1 (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H., C.T.), Université de Lyon, Lyon, France; Dermatology Department (F.S.), Centre Hospitalier de Valence; Neurology Department (M.E.), Centre Hospitalier de Libourne; Team ImpAct (C.T.), Lyon Neuroscience Research Center, INSERM U1028 CNRS UMR5292; and Neurology Department 2-Mazarin (D.P.), Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere Groupe, Hospitalier Pitie-Salpetriere et Universite Pierre et Marie Curie-Paris 6, AP-HP, France.;From the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (A.V., S.M.-C., B.J., G.P., V.R., V.D., D.P., F.D., J.H.) and Neuro-Cognition and Neuro-Ophthalmology Department (V.D., C.T.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H.), INSERM U1217/CNRS UMR5310; University Claude Bernard Lyon 1 (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H., C.T.), Université de Lyon, Lyon, France; Dermatology Department (F.S.), Centre Hospitalier de Valence; Neurology Department (M.E.), Centre Hospitalier de Libourne; Team ImpAct (C.T.), Lyon Neuroscience Research Center, INSERM U1028 CNRS UMR5292; and Neurology Department 2-Mazarin (D.P.), Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere Groupe, Hospitalier Pitie-Salpetriere et Universite Pierre et Marie Curie-Paris 6, AP-HP, France. jerome.honnorat@chu-lyon.fr.",
"authors": "Vogrig|Alberto|A|0000-0002-3652-7061;Muñiz-Castrillo|Sergio|S|;Joubert|Bastien|B|0000-0003-4631-3056;Picard|Géraldine|G|0000-0003-1282-267X;Rogemond|Véronique|V|0000-0003-2098-920X;Skowron|François|F|;Egri|Madalina|M|;Desestret|Virginie|V|0000-0001-9643-1558;Tilikete|Caroline|C|0000-0002-1452-1398;Psimaras|Dimitri|D|0000-0002-6641-288X;Ducray|François|F|0000-0002-8150-5785;Honnorat|Jérôme|J|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0000000000011340",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "96(6)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D020434:Abducens Nerve Diseases; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003389:Cranial Nerve Diseases; D005155:Facial Nerve Diseases; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D015840:Oculomotor Nerve Diseases; D009902:Optic Neuritis; D012189:Retrospective Studies; D000160:Vestibulocochlear Nerve Diseases",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "e866-e875",
"pmc": null,
"pmid": "33318162",
"pubdate": "2021-02-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D000078182:Systematic Review",
"references": null,
"title": "Cranial Nerve Disorders Associated With Immune Checkpoint Inhibitors.",
"title_normalized": "cranial nerve disorders associated with immune checkpoint inhibitors"
} | [
{
"companynumb": "FR-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-005441",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
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{
"abstract": "The mechanisms of ARONJ(anti-resorptive agents-related osteonecrosis of jaw)are not completely known. Therefore the treatment policy has been controversial between surgical and conservative approach. Recently, surgical treatment, particularly in stage 2 and 3 cases, has been increasingly reported in literature and is considered a success when oral mucosa healing is maintained without bone exposure or infection. The surgical treatment modalities were classified as follows:debridement, sequestrectomy, marginal resection(bone resection without bone defect), bone reconstruction(free flaps). The aim of this article is to consider the roll of surgical treatment for ARONJ.",
"affiliations": "Department of Oral and Maxillofacial Surgery, Tokai University, School of Medicine, Kanagawa, Japan.",
"authors": "Ota|Yoshihide|Y|",
"chemical_list": "D050071:Bone Density Conservation Agents",
"country": "Japan",
"delete": false,
"doi": "CliCa171014451452",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0917-5857",
"issue": "27(10)",
"journal": "Clinical calcium",
"keywords": null,
"medline_ta": "Clin Calcium",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D005260:Female; D006801:Humans; D008875:Middle Aged; D019651:Reconstructive Surgical Procedures",
"nlm_unique_id": "9433326",
"other_id": null,
"pages": "1445-1452",
"pmc": null,
"pmid": "28947696",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Surgical treatment for anti-resorptive agents-related osteonecrosis of jaw.",
"title_normalized": "surgical treatment for anti resorptive agents related osteonecrosis of jaw"
} | [
{
"companynumb": "PHJP2017JP035706",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALENDRONATE SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "Background: Hidradenitis suppurativa (HS) is a chronic debilitating autoinflammatory skin disease. Adalimumab is the only biologic agent available to treat HS, but lack of response is observed in some patients. Ustekinumab may be useful to treat patients with HS who do not respond to adalimumab.Objective: The objectives of this study were: (1) to retrospectively evaluate the therapeutic outcomes of ustekinumab in a multicenter series of patients with HS and (2) to assess all published scientific evidence on its utilization in patients with HS.Methods: We evaluated the therapeutic outcomes of 10 patients with HS treated with ustekinumab and conducted a systematic review of published epidemiological studies on ustekinumab-treated patients with HS.Results: In the case series, an improvement in the Physician Global Assessment score was observed in 70% (7/10) patients and an improvement in the Numerical Pain Rating Scale in 80% (8/10). In the systematic review, clinical improvement in disease severity was reported in 76% (34/45) patients and symptomatic improvement in 84% (38/45). No severe ustekinumab-related adverse event was recorded.Conclusion: These findings suggest that ustekinumab may be an effective and safe option for patients with HS who fail to respond to first-line therapies.",
"affiliations": "Hidradenitis Suppurativa Clinic, Dermatology Unit, Hospital Universitario Virgen de las Nieves, Granada, Spain.;Servicio de Dermatología, Hospital Universitario Rio Ortega, Valladolid, Spain.;Servicio de Dermatología, Hospital Universitario Rio Ortega, Valladolid, Spain.;Servicio de Dermatología, Hospital Universitario Rio Ortega, Valladolid, Spain.;Hidradenitis Suppurativa Clinic, Dermatology Unit, Hospital Universitario Virgen de las Nieves, Granada, Spain.;Hidradenitis Suppurativa Clinic, Dermatology Unit, Hospital Universitario Virgen de las Nieves, Granada, Spain.",
"authors": "Montero-Vilchez|T|T|http://orcid.org/0000-0003-4035-7955;Pozo-Román|T|T|;Sánchez-Velicia|L|L|;Vega-Gutiérrez|J|J|;Arias-Santiago|S|S|;Molina-Leyva|A|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09546634.2020.1755008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6634",
"issue": null,
"journal": "The Journal of dermatological treatment",
"keywords": "Hidradenitis suppurativa; therapy; ustekinumab",
"medline_ta": "J Dermatolog Treat",
"mesh_terms": null,
"nlm_unique_id": "8918133",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "32279593",
"pubdate": "2020-04-21",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ustekinumab in the treatment of patients with hidradenitis suppurativa: multicenter case series and systematic review.",
"title_normalized": "ustekinumab in the treatment of patients with hidradenitis suppurativa multicenter case series and systematic review"
} | [
{
"companynumb": "ES-LUPIN PHARMACEUTICALS INC.-2022-06999",
"fulfillexpeditecriteria": "2",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE"
},
"drugadditiona... |
{
"abstract": "Metformin is known for gastrointestinal side effects, but has rarely been associated with diarrhea severe enough to cause symptomatic electrolyte abnormalities and hospitalization. This case illustrates such that occurred despite multiple outpatient encounters for diarrhea. Additionally, this case highlights the importance of a comprehensive medical reconciliation as part of a thorough medical evaluation.",
"affiliations": "Medical College of Georgia at Augusta University Augusta GA USA.;Division Chief Hospital Medicine Department of Medicine Medical College of Georgia at Augusta University Augusta GA USA.",
"authors": "Sharma|Avirale|A|https://orcid.org/0000-0002-7378-0744;Walsh|David|D|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.4621",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4621\nCCR34621\nCase Report\nCase Report\nAn old friend turned foe: Metformin‐induced diarrhea with resultant symptomatic hypokalemia, hypomagnesemia, hypocalcemia, and hypophosphatemia\nSHARMA and WALSH\nSharma Avirale https://orcid.org/0000-0002-7378-0744\n1 avsharma@augusta.edu\n\nWalsh David 2\n1 Medical College of Georgia at Augusta University Augusta GA USA\n2 Division Chief Hospital Medicine Department of Medicine Medical College of Georgia at Augusta University Augusta GA USA\n* Correspondence\nAvirale Sharma, 1120 15th Street BC 1109, Augusta, GA 30912, USA.\nEmail: avsharma@augusta.edu\n\n15 8 2021\n8 2021\n9 8 10.1002/ccr3.v9.8 e0462129 6 2021\n02 2 2021\n06 7 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nMetformin is known for gastrointestinal side effects, but has rarely been associated with diarrhea severe enough to cause symptomatic electrolyte abnormalities and hospitalization. This case illustrates such that occurred despite multiple outpatient encounters for diarrhea. Additionally, this case highlights the importance of a comprehensive medical reconciliation as part of a thorough medical evaluation.\n\nMetformin is known for gastrointestinal side effects, but has rarely been associated with diarrhea severe enough to cause symptomatic electrolyte abnormalities and hospitalization. This case illustrates such that occurred despite multiple outpatient encounters for diarrhea. Additionally, this case highlights the importance of a comprehensive medical reconciliation as part of a thorough medical evaluation.\n\ndiarrhea\ndrug adverse event\nhypokalemia\nhypomagnesemia\nmedication reconciliation\nmetformin\nsource-schema-version-number2.0\ncover-dateAugust 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.5 mode:remove_FC converted:16.08.2021\nSharmaA, WalshD. An old friend turned foe: Metformin‐induced diarrhea with resultant symptomatic hypokalemia, hypomagnesemia, hypocalcemia, and hypophosphatemia. Clin Case Rep. 2021;9 :e04621. 10.1002/ccr3.4621\n==== Body\n1 INTRODUCTION\n\nMetformin is the first‐line medication for type 2 diabetes mellitus given its efficacy.1 However, it is known for gastrointestinal side effects.1 The following describes a patient who presented with severe and symptomatic hypokalemia, hypomagnesemia, hypocalcemia, and hypophosphatemia secondary to metformin‐induced diarrhea requiring hospitalization for intravenous repletion of electrolytes and close cardiac monitoring.\n\nMetformin is one of most common medications used in the treatment of type 2 diabetes mellitus, often used as the first‐line therapy to lower glycated hemoglobin (HbA1c) levels.2 As a monotherapy, it can lower HbA1c by 1.5% and has been shown to have a 36% decrease in relative risk for all‐cause mortality.2 One of the most common side effects of metformin is gastrointestinal (GI) side effects, particularly diarrhea, with up to 20% of metformin users having medication‐related diarrhea.3 A previous case report showed chronic diarrhea associated with metformin use leading to symptomatic hypomagnesemia, hypocalcemia with mild hypokalemia.4 Further descriptions in the literature are lacking. The following report describes a case with chronic metformin use leading to symptomatic and severe hypomagnesemia, hypokalemia, hypocalcemia, hypophosphatemia, potential heart‐rate corrected QT interval (QTc) prolongation, profound fatigue, and hospitalization.\n\n2 CASE HISTORY/EXAMINATION\n\nThe patient was a 54‐year‐old African American female with a past medical history of diabetes mellitus on metformin for 12 years, hypertension, breast cancer in remission, and gastroesophageal reflux disorder (GERD) who presented with lower extremity weakness, numbness, and multiple electrolyte abnormalities in the setting of undifferentiated chronic diarrhea. She was diagnosed with type 2 diabetes mellitus in 2008, where she was started on metformin, for which she reported episodes of diarrhea that began when she began taking the medication. The patient works as a nurse and reported days where she could not participate in patient care due to the diarrhea. She met with her primary care physician with these concerns. Changes were not made at that time citing the efficacy of the metformin in treating her diabetes. Over the last year, she self‐reduced her metformin 1000 mg from twice a day to once daily, which she stated significantly reduced her diarrhea. However, the patient reported to her primary care physician 5 days before coming to the emergency department (ED) for routine follow‐up and was encouraged to resume metformin 1000 mg twice a day.\n\nShe presented to the emergency department with a 1‐day history of new‐onset tingling in her arms and fingers bilaterally and muscle cramping in both of her thighs. She also described six episodes of diarrhea that occurred the day before her arrival to the ED. On interview, patient stated she has a history of diarrhea correlated with her metformin use, and recently increased her metformin dose based on her primary care physician's recommendations. Her home medications at the time of hospitalization included amlodipine, losartan, eplerenone, nadolol, albuterol, and gabapentin.\n\nOn examination, her blood pressure was 159/90 mmHg. Pertinent physical exam findings were significant for muscle tenderness of upper and lower extremities on palpation. Cardiovascular exam revealed a regular rhythm and normal rate. Lung exam was unremarkable. Neurologic exam revealed decreased sensation to light touch in the distal upper extremities and lower extremities, along with globally reduced strength in all four extremities.\n\n2.1 Investigation and treatment\n\nLaboratory data were notable for serum levels of sodium 143 mEq/L (132–146), potassium 2.5 mEq/L (3.5–5.5), chloride 101 mEq/L (99–109), bicarbonate 30 mEq/L (20–31), blood urea nitrogen 5 mg/dl (9–23), creatinine 0.48 mg/dl (0.6–1.6), glucose 170 mg/dl (74–106), HbA1c 8.4% (4–6), calcium 8.2 mg/dl (8.7–10.4), phosphorous 1.5 mg/dl (2.4–5.1), magnesium 1.2 (1.3–2.7) mg/dl, 25 Hydroxyvitamin D2 17.59 ng/ml (25–80), parathyroid hormone (PTH) 298.6 pg/ml (11.1–79.5); calcium urine 21.2 mg/dl, potassium urine 29 mEq/L, and creatinine urine 36.2 mg/dl. Electrocardiogram (EKG) demonstrated normal sinus rhythm with prolonged QTc of 534, elevated from previous baseline of 439. Analysis of serum and urine electrolytes showed a normal fractional excretion of potassium. Gastrointestinal viral and Clostridium difficile panels were performed to evaluate infectious etiologies of diarrhea, which both returned with negative results. A thorough medication reviewed was undertaken and revealed a possible association with metformin use. This medication was held. The electrolytes were repleted appropriately, with patient describing resolution of symptoms after her ions returned to reference range levels. The patient was discharged, with metformin discontinued and dapagliflozin 5 mg used as a replacement to prevent GI symptoms.\n\n2.2 Outcomes and follow‐up\n\nThe patient was ultimately switched to monotherapy with the sodium/glucose cotransporter 2 inhibitor (SGLT2) dapagliflozin with resolution of her diarrhea and electrolyte abnormalities. At follow‐up, 3 weeks later patient reported immediate resolution of her symptoms, with no diarrhea since her hospitalization, and the ability to return to her normal activities.\n\n3 DISCUSSION\n\nGiven the onset of diarrhea with the patient beginning metformin, the increase in diarrhea when the drug dose was increased, and the cessation when the metformin was replaced with dapagliflozin, the case described above is most likely suggestive of metformin directly causing severe diarrhea, hypomagnesemia, hypokalemia, hypophosphatemia, hypocalcemia, and the associated symptoms. To support this conclusion, the Naranjo algorithm5 was used to determine the likelihood of whether the adverse drug reaction was the most likely reason for these symptoms rather than another possible cause. Using the algorithm, the patient scored +1 on whether there are previous reports of severe diarrhea from metformin, +2 on diarrhea occurring after metformin was given, +1 on the stopping after metformin was discontinued, +2 on hospital work‐up determining no other causes for the chronic diarrhea, +1 diarrhea being more severe when metformin was increased, +1 on the patient having diarrhea from metformin on previous exposure for over a decade, +1 for objective evidence of ion deficiencies and QTc prolongation on EKG, for a total of 9 on the Naranjo algorithm. Based on this algorithm, a score of 9 or greater defines a definite adverse drug reaction.5\n\nDespite gastrointestinal side effects being common, severe diarrhea is a rare but reported side effect seen in literature. Svare et al.4 in 2009 reported a similar case of symptomatic hypomagnesemia. Our case additionally describes severe hypokalemia and possible prolonged QTc interval6 not seen in the case cited above. The reason for why metformin causes gastrointestinal adverse effects is a topic of ongoing research.\n\nAdverse drug events account for over 1 million ER visits and 350,000 hospitalizations per year.7 Medication reconciliation, defined as the process where the list of prescribed medications are documented and compliance is verified, is known to contribute to medication errors with up to 40% of errors being the result of medication reconciliation errors.8 Studies have been performed to assess the efficacy of electronic medication reconciliation, with one study showing that electronic medication reconciliation reduced medication discrepancy, but had no effect on adverse drug events (ADE).9 Additionally, pharmacy lead medication reconciliation teams have been shown to decrease medication discrepancies on admission and decrease adverse drug events, suggesting the benefits of an inter‐disciplinary approach to prevent adverse drug events and improve health care.10, 11 However, many places may be resource limited and unable to provide this level of support. Reasons for adverse drug reactions vary, are often multifactorial, and can include patient factors such as co‐morbidities and older age, as well as provider factors such as incorrect drug selection and regularly monitoring symptoms.12 Therefore, a thorough medical reconciliation performed on a regular basis is important to help minimize adverse drug reactions and prevent unnecessary hospitalizations. Non‐pharmacy lead randomized control trials are needed to investigate interventions that could potentially improve ADE rates.\n\nThis case serves as a reminder of the importance to continually investigate and follow‐up ongoing symptoms and review medications for adherence and side effects on a periodic basis.\n\nCONFLICT OF INTEREST\n\nNone declared.\n\nAUTHOR CONTRIBUTION\n\nAS: Helped in providing care to the patient during hospital stay. Responsible for drafting and formatting the manuscript. DW: Physician responsible for providing care to the patient during hospital stay. Responsible for drafting and formatting the manuscript. All authors participated in the research and preparation of the manuscript.\n\nACKNOWLEDGMENT\n\nPublished with written consent of the patient.\n\nDATA AVAILABILITY STATEMENT\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nREFERENCES\n\n1 StrackT. Metformin: a review. Drugs Today. 2008;44 (4 ):303‐314. 10.1358/dot.2008.44.4.1138124\n2 HolmanR. Metformin as first choice in oral diabetes treatment: the UKPDS experience. Journ Annu Diabetol Hotel Dieu. 2007;13‐20. https://pubmed.ncbi.nlm.nih.gov/18613325/ 18613325\n3 DandonaP, FonsecaV, MierA, BeckettAG. Diarrhea and metformin in a diabetic clinic. Diabetes Care. 1983;6 (5 ):472‐474. 10.2337/diacare.6.5.472 6336343\n4 SvareA. A patient presenting with symptomatic hypomagnesemia caused by metformin‐induced diarrhoea: a case report. Cases J. 2009;2 :156. 10.1186/1757-1626-2-156 19946527\n5 LiverTox: Clinical and Research Information on Drug‐Induced Liver Injury [Internet]. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases; 2012. Adverse Drug Reaction Probability Scale (Naranjo) in Drug Induced Liver Injury. https://www.ncbi.nlm.nih.gov/books/NBK548069/. Accessed May 4, 2019.\n6 VandaelE, VandenberkB, VandenbergheJ, et al. Risk factors for QTc‐prolongation: systematic review of the evidence. Int J Clin Pharm. 2017;39 :16‐25. 10.1007/s11096-016-0414-2 28012118\n7 Adverse Drug Events in Adults. Centers for Disease Control and Prevention. 2017. https://www.cdc.gov/medicationsafety/adult_adversedrugevents.html. Accessed January 28, 2021.\n8 BarnsteinerJH. Chapter 38. Medication reconciliation. In: HughesRG, ed. Patient safety and quality: An evidence‐based handbook for nurses. Rockville, MD: Agency for Healthcare Research and Quality (US); 2008. https://www.ncbi.nlm.nih.gov/books/NBK2648/\n9 TamblynR, AbrahamowiczM, BuckeridgeDL, et al. Effect of an electronic medication reconciliation intervention on adverse drug events: a cluster randomized trial. JAMA Netw Open. 2019;2 (9 ):e1910756. 10.1001/jamanetworkopen.2019.10756 31539073\n10 ManiasE, KusljicS, WuA. Interventions to reduce medication errors in adult medical and surgical settings: a systematic review. Ther Adv Drug Saf. 2020;11 :2042098620968309. 10.1177/2042098620968309 33240478\n11 MekonnenAB, McLachlanAJ, BrienJA. Effectiveness of pharmacist‐led medication reconciliation programmes on clinical outcomes at hospital transitions: a systematic review and meta‐analysis. BMJ Open. 2016;6 (2 ):e010003. 10.1136/bmjopen-2015-010003\n12 KhalilH, HuangC. Adverse drug reactions in primary care: a scoping review. BMC Health Serv Res. 2020;20 (1 ):5. 10.1186/s12913-019-4651-7 31902367\n\n",
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"issue": "9(8)",
"journal": "Clinical case reports",
"keywords": "diarrhea; drug adverse event; hypokalemia; hypomagnesemia; medication reconciliation; metformin",
"medline_ta": "Clin Case Rep",
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"title": "An old friend turned foe: Metformin-induced diarrhea with resultant symptomatic hypokalemia, hypomagnesemia, hypocalcemia, and hypophosphatemia.",
"title_normalized": "an old friend turned foe metformin induced diarrhea with resultant symptomatic hypokalemia hypomagnesemia hypocalcemia and hypophosphatemia"
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"abstract": "BACKGROUND\nProgressive multifocal leukoencephalopathy is a demyelinating disease of the central nervous system caused by the reactivation of the JC virus. This opportunistic encephalopathy mainly affects immunodepressed patients with stage III HIV infection, although in recent years it has also been found in association with treatment with immunosuppressors such as natalizumab. MRI plays an important role in both the early diagnosis and follow-up of this disease. Recently, it has been reported that hypointensities in U-fibers and cortex adjacent to white-matter lesions characteristic of the disease can be identified on T2-weighted gradient-echo and susceptibility-weighted sequences in patients with progressive multifocal leukoencephalopathy.\n\n\nOBJECTIVE\nWe aimed to analyze the presence and usefulness of cortical hypointensity on T2-weighted gradient-echo sequences in relation to the diagnosis of progressive multifocal leukoencephalopathy and to review the literature on the topic.\n\n\nMETHODS\nWe analyze three cases of progressive multifocal leukoencephalopathy seen at our center in three patients with immunosuppression of different origins: one with stage III HIV infection, one with multiple sclerosis being treated with natalizumab, and one with rheumatoid arthritis being treated with rituximab.\n\n\nRESULTS\nIn all three cases MRI showed the cortical hypointensity adjacent to the white-matter lesion in the T2-weighted gradient-echo sequence. In the patient with multiple sclerosis, this sign appeared earlier than the abnormal signal in the white matter. The patient being treated with rituximab was diagnosed postmortem and the pathology findings correlated with the MRI findings.\n\n\nCONCLUSIONS\nThe finding of cortical hypointensity on T2-weighted gradient-echo MRI sequences seems to support the diagnosis of progressive multifocal leukoencephalopathy, regardless of the type of immunosuppression, so this finding should routinely assessed in patients suspected of having this disease.",
"affiliations": "Servicio de Radiodiagnóstico, Complejo Hospitalario de Navarra, Pamplona, Navarra, España. Electronic address: paullopezsala@gmail.com.;Servicio de Radiodiagnóstico, Complejo Hospitalario de Navarra, Pamplona, Navarra, España.;Servicio de Anatomía Patológica, Complejo Hospitalario de Navarra, Pamplona, Navarra, España.;Servicio de Radiodiagnóstico, Complejo Hospitalario de Navarra, Pamplona, Navarra, España.;Servicio de Radiodiagnóstico, Complejo Hospitalario de Navarra, Pamplona, Navarra, España.",
"authors": "López Sala|P|P|;Alberdi Aldasoro|N|N|;Zelaya Huerta|M V|MV|;Bacaicoa Saralegui|M C|MC|;Cabada Giadás|T|T|",
"chemical_list": "D007155:Immunologic Factors; D000069442:Natalizumab",
"country": "Spain",
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"issue": "62(1)",
"journal": "Radiologia",
"keywords": "Agentes inmunosupresores; Esclerosis múltiple; Immunosuppressive agents; Leucoencefalopatía multifocal progresiva; Magnetic resonance imaging; Multiple sclerosis; Progressive multifocal leukoencephalopathy; Resonancia magnética",
"medline_ta": "Radiologia (Engl Ed)",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001921:Brain; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007968:Leukoencephalopathy, Progressive Multifocal; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting; D000069442:Natalizumab; D014057:Tomography, X-Ray Computed; D066127:White Matter",
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"pubdate": "2020",
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"references": null,
"title": "Cortical hypointensity in T2-weighted gradient-echo sequences in patients with progressive multifocal leukoencephalopathy.",
"title_normalized": "cortical hypointensity in t2 weighted gradient echo sequences in patients with progressive multifocal leukoencephalopathy"
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"abstract": "Coexistence of spondyloarthritis (SpA) and Takayasu's arteritis is not a common finding, but such cases have been discussed, particularly in the context of choice of therapy. Inhibition of inflammation by tumor necrosis factor inhibitors (TNFi) is a key aspect of the treatment of SpA and also positive effects of such treatment in concomitant large vessel vasculitis have been reported. However, TNFi is also associated with the possibility of initiating vasculitis. The present article based on a case study and the available literature is an attempt to discuss coexistence of these two diseases and the impact of treatment with biological drugs from the anti-TNF group in the course of SpA with Takayasu's arteritis.",
"affiliations": "Department of Internal Medicine, Sahloul Hospital, University of Sousse, Faculty of Medicine of Sousse, Tunisia.;Department of Internal Medicine, Sahloul Hospital, University of Sousse, Faculty of Medicine of Sousse, Tunisia.;Department of Internal Medicine, Sahloul Hospital, University of Sousse, Faculty of Medicine of Sousse, Tunisia.;Department of Internal Medicine, Sahloul Hospital, University of Sousse, Faculty of Medicine of Sousse, Tunisia.;Department of Internal Medicine, Sahloul Hospital, University of Sousse, Faculty of Medicine of Sousse, Tunisia.;Department of Internal Medicine, Sahloul Hospital, University of Sousse, Faculty of Medicine of Sousse, Tunisia.;Department of Internal Medicine, Sahloul Hospital, University of Sousse, Faculty of Medicine of Sousse, Tunisia.;Department of Internal Medicine, Sahloul Hospital, University of Sousse, Faculty of Medicine of Sousse, Tunisia.;Department of Internal Medicine, Sahloul Hospital, University of Sousse, Faculty of Medicine of Sousse, Tunisia.",
"authors": "Rezgui|Amel|A|;Thabet|Maissa|M|;Makki|Sahar|S|;Anoun|Jihed|J|;Hassine|Imen Ben|IB|;Karmeni|Monia|M|;Ben Fredj|Fatma|F|;Mzabi|Anis|A|;Laouani|Chedia|C|",
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"fulltext": "\n==== Front\nReumatologia\nReumatologia\nRU\nReumatologia\n0034-6233\n2084-9834\nNarodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie\n\n43206\n10.5114/reum.2021.103394\nCase-Based Review\nTakayasu’s arteritis occurring under TNF blockers in a patient with spondyloarthritis: is it an association or a paradoxical effect?\nRezgui Amel\nThabet Maissa\nMakki Sahar\nAnoun Jihed\nHassine Imen Ben\nKarmeni Monia\nBen Fredj Fatma\nMzabi Anis\nLaouani Chedia\nDepartment of Internal Medicine, Sahloul Hospital, University of Sousse, Faculty of Medicine of Sousse, Tunisia\nAddress for correspondence: Maissa Thabet, Department of Internal Medicine, Sahloul Hospital, University of Sousse, Faculty of Medicine of Sousse, Tunisia. e-mail: maissa.thabet22@gmail.com\n09 2 2021\n2021\n59 2 111114\n24 9 2020\n20 1 2021\nCopyright: © 2021 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.\nCoexistence of spondyloarthritis (SpA) and Takayasu’s arteritis is not a common finding, but such cases have been discussed, particularly in the context of choice of therapy. Inhibition of inflammation by tumor necrosis factor inhibitors (TNFi) is a key aspect of the treatment of SpA and also positive effects of such treatment in concomitant large vessel vasculitis have been reported. However, TNFi is also associated with the possibility of initiating vasculitis.\n\nThe present article based on a case study and the available literature is an attempt to discuss coexistence of these two diseases and the impact of treatment with biological drugs from the anti-TNF group in the course of SpA with Takayasu’s arteritis.\n\nankylosing spondylitis\nTakayasu’s arteritis\ntumor necrosis factor\n==== Body\nIntroduction\n\nTakayasu’s arteritis (TA) is a rare granulomatosis of large-vessel vasculitis with an unknown etiology. The association of TA and spondyloarthritis (SpA) has been reported occasionally in the literature and the authors suggested that both diseases could coexist in a single patient [1, 2].\n\nSpondyloarthritis is a wider spectrum of diseases, which contains ankylosing spondylitis, axial spondylo-arthritis, enteropathic spondyloarthritis, peripheral spondyloarthritis, psoriatic arthritis and reactive arthritis. The treatment of SpA depends on involvement of axial or peripheral joints [3].\n\nTumor necrosis factor inhibitors (TNFi) are the basic biological treatment of SpA in the cases of insufficient treatment with non-steroidal anti-inflammatory drugs (NSAID) in the course of axial involvement and disease-modifying antirheumatic drugs such as methotrexate or sulfasalazine in the case of peripheral joint involvement.\n\nUndoubtedly, the high efficacy of TNFi in the treatment of SpA was confirmed. In the case of large vessels vasculitis, such treatment was also used. In some cases its significant effectiveness was reported, but there are also contradictory observations and attention was drawn to the possibility of diagnosing e g. TA after the introduction of TNFi treatment.\n\nThe aim of this article is to draw attention to the possible coexistence of SpA and TA and to discuss the use of TNFi in such cases.\n\nObjective and methods\n\nThe aims of this case-based review were: to report a new case of TA that occurred after anti-TNF therapy in a patient with SpA and to perform a review of similar case reports (patients with TA and SpA or TA occurring under anti-TNFs).\n\nThe authors performed a systematic search of case reports or case series of patients with both TA and SpA or with TA occurring under anti-TNF in PubMed, Scopus and Google Scholar from the onset until October 2020 and using the following combination of words: ankylosing spondylitis, Takayasu’s arteritis, tumor necrosis factor. The language of the chosen articles was restricted to English. The discussion was based on the case study and a literature review.\n\nCase description\n\nA 43-year-old man presented in 2015 with inflammatory back pain for 3 years. The patient’s erythrocyte sedimentation rate (ESR) was 100 mm/hour and C-reactive protein (CRP) was 130 mg/l. Spine and pelvic MRI showed bilateral active sacroiliitis.\n\nThe diagnosis of spondyloarthritis, in its axial form, was established according to the Assessment of SpondyloArthritis International Society (ASAS) criteria.\n\nThe patient received NSAID for one year but finally without satisfactory clinical improvement according to the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) criteria and therefore was treated with adalimumab for two and a half years with complete remission.\n\nIn January 2019, the patient presented a transient ischemic attack with a normal cerebral angioscan. On admission, the patient was asymptomatic and the history gave no clue of an ongoing vasculitis. The clinical examination revealed comparable normal blood pressure values in both arms, and slightly decreased radial and pedal pulses. The pulse in the extremities was hardly discernible, with presence of a bilateral umbilical bruit, bilateral carotid bruit and a right subclavian artery bruit.\n\nThe thoracic angio-CT showed the presence of multiple significant stenoses of the supraaortic arteries (right subclavian artery (Fig. 1) and both vertebral arteries, the thoracic and abdominal aorta. The digestive tract arteries (superior and inferior mesenteric artery) and both renal arteries were also constricted (Fig. 2), with celiac trunk stenosis of 60%.\n\nFig. 1 Thoracic angio-CT showing right subclavian artery stenoses.\n\nFig. 2 Abdominal angio-CT showing superior mesenteric and renal arteries stenoses.\n\nThe laboratory examinations showed elevated markers of inflammation (CRP: 70 mg/l, ESR: 55 mm/h). The diagnosis of TA was retained and it was stage 5 according to the Tokyo 1994 classification.\n\nAdalimumab was stopped and the patient underwent a 3-day regimen of methylprednisolone (15 mg/kg/day) followed by a 1 mg/kg/day prednisone dose. Methotrexate (MTX) was maintained at the dose of 25 mg p.o. weekly. Under this treatment, a good response with normalization of the inflammatory parameters was observed.\n\nDiscussion\n\nWe have described a patient who developed active TA inflammation despite being treated with a standard regimen of anti-TNFi for SpA.\n\nAnti-TNFi therapy is highly effective for SpA and TA is usually treated with glucocorticoids, supplementing the therapy with immunosuppressive drugs such as MTX. Moreover, plasma levels of TNF-α are high in TA; thus, a large number of case series and observational studies have supported the premise that TNF inhibitors are highly effective and safe in patients with severe and refractory TA, with a prolonged sustained response [3, 4].\n\nAnti-TNFs are currently recommended for the treatment of TA in the cases of corticosteroid-dependent or corticosteroid-resistant cases despite treatment with a non-biological immunosuppressive medication [5].\n\nSome authors [6–8] reported cases of TA arising under TNFi therapy and propose a causal effect of the TNFi use on TA development. Others describe aortitis occurring under TNFi therapy [9].\n\nThe mechanism of this paradoxical side effect remains unclear and we still cannot determine the contribution of TNFi to the development of vasculitis. Nevertheless, this phenomenon might be related to immune complexes containing the drug which may be deposited on vessel walls in a disturbed immune homeostasis [6].\n\nIt is worth mentioning that paradoxical vasculitis is mainly limited to the skin, but in some cases, patients may experience the onset of an authentic systemic disease with renal, pulmonary and central and peripheral nervous system involvement [10].\n\nSome authors have suggested that prevalence of TA in SpA and SpA in TA are both higher than in the general population [1, 11]. Gudbrandsson et al. [12] reported that a Norwegian population had a prevalence of 22 cases of TA per 106 in northern Europeans. The authors also observed a high frequency of SpA and Crohn’s disease among patients with TA (7% and 8%, respectively, whereas the usual prevalence of SpA in a French population is estimated at 0.3%) [1].\n\nIn a recent study, Güzel et al. [13] enrolled 69 patients with TA. There were 14 (20.3%) patients who fulfilled the Assessment of SpondyloArthritis International Society criteria for Spondyloarthropathy.\n\nMielnik et al. [14] suggested that all epidemiological and pathological considerations lead to the hypothesis that patients with both TA and SpA diagnoses can present with extreme arterial involvement due to SpA which could be misclassified as TA.\n\nAll discussed results support an association between SpA and TA. Thus, coexistence of these diseases might be more than a coincidence, and so may be the case of our patient.\n\nHowever, Rivière et al. [1] studied 14 patients and the chronology of introduction of TNFi in SpA patients and TA diagnosis; 11 cases out of 14 did not receive anti-TNF therapy before the TA diagnosis, thus excluding an anti-TNF-α role in the development of TA. The authors suggest that TA could represent another associated disease, which may be underdiagnosed in patients with a SpA. Moreover, among the 3 patients who received anti-TNF therapy before the diagnosis of TA, all were treated with etanercept (ETN) [1], which could mean that ETN could not prevent TA in those 3 patients [1].\n\nThe occurrence of both diseases may be explained by an antigenic analogy between the aorta and the enthesis. Sherlock et al. [15] found in an animal model of SpA that the enthesopathy observed was linked with T lymphocytes (enthesis-resident), which have a double-negative phenotype, and the interleukin 23 (IL-23) receptor. This can develop in the aortic root and valve, which are structurally similar to entheses. Thus, this phenomenon could explain in part the observations of aortitis occurring during SpA evolution and could explain the association between TA and SpA.\n\nConclusions\n\nSpondyloarthritis is rarely associated with TA but this might not be a coincidence. Therefore, an exhaustive evaluation of all vessels with a clinical examination of all peripheral arterial pulses is crucial in SpA patients’ follow-up. Also the implication of treatment with TNFi in the occurrence of TA associated with SpA was also suggested.\n\nRetrospective analysis of large cohorts of patients suffering from SpA and TA may help to confirm a causative link. Also the effectiveness of TNFi treatment in such difficult cases should be more widely analyzed.\n\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n\n1 Rivière E Arnaud L Ebbo M Takayasu arteritis and spondyloarthritis: coincidence or association? A study of 14 cases J Rheumatol 2017 44 1011 1017 10.3899/jrheum.160762 28412700\n2 Ben Abdelghani K Fazaa A Ben Abdelghani Chronic inflammatory rheumatism associated with Takayasu disease Ann Vasc Surg 2013 27 353.e1 6 10.1016/j.avsg.2011.11.048\n3 Comarmond C Plaisier E Dahan K Anti TNF-alpha in refractory Takayasu’s arteritis: cases series and review of the literature Autoimmun Rev 2012 11 678 684 10.1016/j.autrev.2011.11.025 22155781\n4 Youngstein T Peters JE Hamdulay SS Serial analysis of clinical and imaging indices reveals prolonged efficacy of TNF-α and IL-6 receptor targeted therapies in refractory Takayasu arteritis Clin Exp Rheumatol 2014 32 3 Suppl 82 S11 18 24093733\n5 Clifford A Hoffman GS Recent advances in the medical management of Takayasu arteritis: an update on use of biologic therapies Curr Opin Rheumatol 2014 26 7 15 10.1097/BOR.0000000000000004 24225487\n6 Souabni L Ben Abdelghani K Jradi S Zakraoui L Takayasu’s arteritis occurring under TNF-α blockers: a new paradoxical effect? BMJ Case Rep 2014 2014 bcr2014204226 10.1136/bcr-2014-204226\n7 Mariani N So A Aubry-Rozier B Two cases of Takayasu’s arteritis occurring under anti-TNF therapy Joint Bone Spine 2013 80 211 213 10.1016/j.jbspin.2012.07.015 22999907\n8 Osman M Aaron S Noga M Yacyshyn E Takayasu’s arteritis progression on anti-TNF biologics: a case series Clin Rheumatol 2011 30 703 706 10.1007/s10067-010-1658-1 21221688\n9 Verhoeven F Bossert M Lohse-Walliser A Balblanc JC Aortitis during etanercept therapy for ankylosing spondylitis: finding the culprit Joint Bone Spine 2012 79 524 526 10.1016/j.jbspin.2012.03.006\n10 Ramos-Casals M Roberto Perez-Alvarez Diaz-Lagares C Autoimmune diseases induced by biological agents: a double-edged sword? Autoimmun Rev 2010 9 188 193 10.1016/j.autrev.2009.10.003 19854301\n11 Gan F Fei Y Li M The characteristics of patients having ankylosing spondylitis associated with Takayasu’s arteritis Clin Rheumatol 2014 33 355 358 10.1007/s10067-013-2444-7 24310108\n12 Gudbrandsson B Molberg Ø Garen T Palm Ø Prevalence, incidence and disease characteristics of Takayasu arteritis differ by ethnic background; data from a large, population based cohort resident in Southern Norway Arthritis Care Res (Hoboken) 2017 69 278 285 10.1002/acr.22931 27159262\n13 Güzel Esen S Armagan B Atas N Increased incidence of spondyloarthropathies in patients with Takayasu arteritis: a systematic clinical survey Joint Bone Spine 2019 86 497 501 10.1016/j.jbspin.2019.01.020 30735804\n14 Mielnik P Hjelle AM Nordeide JN Coexistence of Takayasu’s arteritis and ankylosing spondylitis may not be accidental – is there a need for a new subgroup in the spondyloarthritis family? Modern Rheumatology 2018 28 313 318 10.1080/14397595.2017.1341592 28718336\n15 Sherlock JP Joyce-Shaikh B Turner SP IL-23 induces spondyloarthropathy by acting on ROR-αt+ CD3+CD4–CD8– entheseal resident T cells Nat Med 2012 18 1069 1076 10.1038/nm.2817 22772566\n\n",
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"keywords": "Takayasu’s arteritis; ankylosing spondylitis; tumor necrosis factor",
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"title": "Takayasu's arteritis occurring under TNF blockers in a patient with spondyloarthritis: is it an association or a paradoxical effect?",
"title_normalized": "takayasu s arteritis occurring under tnf blockers in a patient with spondyloarthritis is it an association or a paradoxical effect"
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"abstract": "We report here a drug-drug interaction with tacrolimus in a HIV-positive patient with renal transplant, after switch from highly active antiretroviral therapy with boosted protease inhibitors to the combination bictegravir/emtricitabine/tenofovir alafenamide. Although the tacrolimus doses were adapted to take account of the pharmacokinetic interactions with protease inhibitors, a tacrolimus overdosage occurred in the patient nonetheless. Through this case report, we highlight the need to consider a sufficient timeframe of withdrawal of protease inhibitors, which induce a prolonged drug-drug interaction with tacrolimus. To conclude, we purport that the combination bictegravir/emtricitabine/tenofovir alafenamide could be an attractive alternative in the context of transplantation provided a discontinuation of boosted protease inhibitors for more than 48 hours before introducing tacrolimus.",
"affiliations": "Service de Pharmacologie Clinique et Toxicologie, CHU Besançon, Besançon, France.;Service de Pharmacologie Clinique et Toxicologie, CHU Besançon, Besançon, France.;Service de Néphrologie, Dialyse et Transplantation Rénale, CHU Besançon, Besançon, France.;Service de Néphrologie, Dialyse et Transplantation Rénale, CHU Besançon, Besançon, France.;Hôpital Nord Franche-Comté, Montbéliard, France.;Service de Virologie, CHU Besançon, Besançon, France.;Université Bourgogne Franche-Comté, Besançon, France.;Service de Pharmacologie Clinique et Toxicologie, CHU Besançon, Besançon, France.;Service de Pharmacologie Clinique et Toxicologie, CHU Besançon, Besançon, France.",
"authors": "Lagoutte-Renosi|Jennifer|J|https://orcid.org/0000-0003-2405-4778;Flammang|Mylène|M|https://orcid.org/0000-0002-4611-5757;Ducloux|Didier|D|https://orcid.org/0000-0003-3841-1211;Bamoulid|Jamal|J|https://orcid.org/0000-0002-3487-8685;Royer|Pierre-Yves|PY|;Lepiller|Quentin|Q|https://orcid.org/0000-0003-2892-4216;Clairet|Anne-Laure|AL|https://orcid.org/0000-0001-6938-6771;Davani|Siamak|S|https://orcid.org/0000-0003-0881-6947;Muret|Patrice|P|https://orcid.org/0000-0003-1347-9228",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/1120009X.2021.1940436",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-009X",
"issue": null,
"journal": "Journal of chemotherapy (Florence, Italy)",
"keywords": "Antiretroviral agents; interaction; kidney transplantation; pharmacology; tacrolimus; toxicity",
"medline_ta": "J Chemother",
"mesh_terms": null,
"nlm_unique_id": "8907348",
"other_id": null,
"pages": "1-4",
"pmc": null,
"pmid": "34180378",
"pubdate": "2021-06-26",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Bictegravir/emtricitabine/tenofovir alafenamide combination in the management of kidney transplant patients with HIV receiving immunosuppressants.",
"title_normalized": "bictegravir emtricitabine tenofovir alafenamide combination in the management of kidney transplant patients with hiv receiving immunosuppressants"
} | [
{
"companynumb": "FR-TEVA-2021-FR-1940028",
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"patient": {
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"activesubstancename": "TACROLIMUS"
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{
"abstract": "Surgery is recommended for endocarditis complicated by annular abscess or destruction of the native valve. Guidelines also recommend valvular repair over replacement for endocarditis when feasible. Guidance on management of early repair failure is not well described. (Level of Difficulty: Intermediate.).",
"affiliations": "Walter Reed National Military Medical Center, Department of Cardiology, Bethesda, Maryland, USA.;Yale New Haven Hospital, Department of Cardiac Surgery, New Haven, Connecticut, USA.;Walter Reed National Military Medical Center, Department of Cardiothoracic Surgery, Bethesda, Maryland, USA.",
"authors": "Weber|Lauren A|LA|;Geirsson|Arnar|A|;Prescher|Lindsey|L|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jaccas.2020.12.043",
"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(21)00031-0\n10.1016/j.jaccas.2020.12.043\nCase Report\nHeart Care Team/Multidisciplinary Team Live\nEarly Mitral Valve Repair Failure in the Setting of Endocarditis\nWhen to Reoperate?\nWeber Lauren A. MD lauren.a.weber3.mil@mail.mil\n@LaurenW_heartmd\na∗\nGeirsson Arnar MD b\nPrescher Lindsey DO c\na Walter Reed National Military Medical Center, Department of Cardiology, Bethesda, Maryland, USA\nb Yale New Haven Hospital, Department of Cardiac Surgery, New Haven, Connecticut, USA\nc Walter Reed National Military Medical Center, Department of Cardiothoracic Surgery, Bethesda, Maryland, USA\n∗ Address for correspondence: Dr. Lauren A. Weber, Walter Reed National Military Medical Center, Department of Cardiology, 8901 Rockville Pike, Bethesda, Maryland 20889, USA. lauren.a.weber3.mil@mail.mil@LaurenW_heartmd\n10 3 2021\n5 2021\n10 3 2021\n3 5 707711\n23 9 2020\n7 12 2020\n22 12 2020\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/).\nSurgery is recommended for endocarditis complicated by annular abscess or destruction of the native valve. Guidelines also recommend valvular repair over replacement for endocarditis when feasible. Guidance on management of early repair failure is not well described. (Level of Difficulty: Intermediate.)\n\nCentral Illustration\n\nKey Words\n\nendocarditis\nlupus\nmitral valve repair\nAbbreviations and Acronyms\n\nLV, left ventricle\nMR, mitral regurgitation\nMRI, magnetic resonance imaging\nMV, mitral valve\n==== Body\nA 41-year-old man with a history of lupus was found to have microscopic hematuria. Investigation led to the diagnosis of stage IV lupus nephritis. He underwent induction therapy with 3 days of intravenous solumedrol followed by a high-dose steroid taper and initiation of myocophenolate. His course was complicated by bacterial meningitis, which was treated with antibiotic therapy. A month later he developed streptococcal mitis bacterial endocarditis. Echocardiography was notable for a large abscess cavity adjacent to the right coronary cusp of the aortic valve, severe aortic insufficiency, and a large anterior leaflet mitral valve (MV) vegetation with evidence of perforation and severe mitral regurgitation (MR).Learning Objectives\n\n• To outline a potential management strategy for patient with early surgical valve repair failure.\n\n• Re-repair of the MV is feasible in patients where the primary repair failed due to technical factors.\n\nQuestion 1. What Would Be the Guideline Recommendations for Management of Endocarditis With This Presentation?\n\nAnswer 1. Surgery is recommended for endocarditis complicated by annular abscess or destruction of the native valve. Guidelines also recommend valvular repair over replacement for endocarditis when feasible (1). Our patient was referred for surgery. The initial surgery occurred outside of the United States and started with an attempt at repair of both the aortic and MVs. An initial attempt at aortic valve debridement was completed in addition to MV debridement with excision of the anterior leaflet vegetation. The anterior leaflet defect was repaired with autologous pericardial patch and the posterior annulus was stabilized with a running suture annuloplasty. Initial intraoperative transesophageal echocardiogram revealed persistent severe aortic insufficiency, and the decision was made to proceed with a Ross procedure. This involved removal of the infected native aortic valve and root, transitioning the native pulmonary valve and artery into the aortic position and placement of a valved homograft in the pulmonary artery position. Repeat intraoperative transesophageal echocardiography revealed persistent moderate MV regurgitation. Ultimately, due to the prolonged and additional cross-clamp time, the decision was made to accept the MR with the understanding a second surgery may be necessary. The patient recovered from his initial surgery and was transferred back to the United States as an outpatient for continued care approximately 6 weeks from the original surgery date.\n\nQuestion 2. Upon Arrival to Your Institution What Additional Diagnostic Studies Would You Obtain?\n\nAnswer 2. Because we knew the patient’s initial MV repair was unsuccessful and he was reported to have at least moderate MR, we opted to repeat transthoracic and transesophageal echocardiograms at our institution. These studies were notable for normal left ventricle (LV) size and systolic function with an LV ejection fraction of 60% to 65% in addition to confirmation of residual perforation of the anterior leaflet of the MV resulting in severe MR (Figures 1 and 2, Videos 1 to 4). Chest x-ray was unremarkable other than evidence of prior sternotomy and a peripherally inserted catheter, which was being used for antibiotic therapy (Figure 3). Electrocardiogram showed normal sinus rhythm, left ventricular hypertrophy, and early repolarization pattern (Figure 4). Coronary computed tomography also was performed for surgical planning and revealed difficult but not prohibitive retrosternal anatomy, no significant coronary artery disease, and redemonstration of the perforated anterior MV leaflet (Figure 5). Cardiac magnetic resonance imaging (MRI) would be another diagnostic consideration. The potential benefit of a cardiac MRI would be another assessment of LV systolic function and quantification of the MR. It was thought that the echo quality obtained at the patient’s presentation at our institution was sufficient and cardiac MRI was not pursued during his initial assessment.Figure 1 Transthoracic Echocardiography 4-Chamber View\n\nTransthoracic echocardiography 4-chamber view with color Doppler showing mitral regurgitation at the site of perforation in the anterior leaflet of the mitral valve.\n\nFigure 2 3-Dimensional Surgeon’s View\n\n3-dimensional surgeon’s view of the mitral valve showing anterior leaflet perforation and suture annuloplasty dehiscence.\n\nFigure 3 Chest X-Ray\n\nChest x-ray showing no acute cardiopulmonary findings, evidence of prior sternotomy, and peripherally inserted central catheter.\n\nFigure 4 Electrocardiogram\n\nElectrocardiogram showing normal sinus rhythm, left ventricular hypertrophy, and early repolarization pattern.\n\nFigure 5 Axial Cardiac Computed Tomography Image\n\nAxial cardiac computed tomography image showing a thickened anterior leaflet of the mitral valve with a central perforation and noncalcified plaque of the right coronary artery causing minimal luminal stenosis.\n\nQuestion 3. What Would Be Your Next Step in Management for This Patient?\n\nAnswer 3. Literature describing long-term outcomes of recurrent MR following a failed MV repair done for degenerative MV disease found recurrent MR was associated with increased risk of late mortality (2). Prior to returning to the United States, our patient was hypertensive with evidence of mild heart failure. He was started on carvedilol, Entresto (Novartis AG, Basel, Switzerland) (sacubitril/valsartan), spironolactone, and furosemide with resolution of his symptoms and normalization of his volume status. He was asymptomatic and off diuretic therapy when he reached our medical center. Due to the poor long-term outcomes of severe MV regurgitation, however, repeat cardiac surgery seemed prudent to avoid the consequences of severe regurgitant valvular disease. His case was presented to our Heart Team where he was classified as asymptomatic severe MR without evidence of LV dysfunction. The group acknowledged his lack of symptoms may have been related to his post-operative state and, therefore, limited exertional capacity. Given he was now several weeks out from his initial surgery and still on steroids for suppression of his lupus nephritis, the group recommended a short convalescent period to allow for partial rehabilitation and sternal wound healing before addressing the residual MR. This also allowed for further work-up and investigation into his new rheumatologic diagnoses. Initial planning included a recovery time of 3 months prior to returning to the operating room as long as the patient and left ventricular function remained stable. He was seen every 2 to 4 weeks to monitor for signs of worsening heart failure. He remained clinically stable and was able to participate in physical therapy without limitation. The patient underwent short-interval imaging with a cardiac MRI 3 months after surgery, which was notable for dilation of the LV, moderate-to-severe MR, and mildly depressed LV systolic function (left ventricular ejection fraction of 52%). At that point the patient was referred for repeat surgery.\n\nQuestion 4. Should This Patient Get a MV Replacement or a Second MV Repair?\n\nAnswer 4. MV repair has been reported to have improved preservation of LV systolic function, lower incidence of thromboembolism, hemorrhage, and endocarditis, and improved survival (3,4). Repair even in the setting of endocarditis has yielded good results out to 5 years. In a nationwide cohort study that included more than 400 patients who underwent MV repair in the setting of endocarditis, repair versus replacement yielded lower perioperative complications as well as lower rates of in-hospital and late mortality (5). Likewise, MV re-repair also has been described with good long-term results. This seems to be especially true if the reason for initial repair failure was due to technique, in which case durability of re-repair can be >90% at 10 years (4). The complexity of our patient’s valvular involvement led to prolonged surgical times negating the ability to achieve an adequate repair at the time of his initial surgery. As such, both MV replacement and MV re-repair were discussed with the patient with the understanding that the final decision would be based on the operative findings. Our operative plan was for MV repair.\n\nQuestion 5. What is the Optimal Timing for MV Re-Repair?\n\nAnswer 5. Literature discussing timing of reoperations for failed MV repairs is limited (3,4,6). The median time between the initial operation and repeat cardiac surgery in most reported cases was years. Small subgroups of patients who underwent early repeat surgery ranging anywhere from within the first 30 days of the initial operation to 3 months are included in recent literature, but the factors that prompted early repeat surgery are not well described. The most frequent indication for repeat surgery was recurrent MR and the majority of patients were symptomatic with at least New York Heart Association functional class II symptoms. There was a subgroup of 9 patients whose treatment was entirely at a single institution who needed repeat surgery due to technical failure of the initial repair. Mean delay between initial repair and repeat surgery was 5 months in that subgroup (6). Although authors have concluded that intervention for failed MV repair should not be delayed, they made no formal recommendation on how soon to pursue reintervention once initial repair failure has been identified (3,6).\n\nThere was an unintentional delay in reintervention for our case secondary to patient-driven factors and social issues. Ultimately our patient agreed to redo sternotomy 6 months after his initial surgery. Surgical findings were notable for a large perforation of the anterior leaflet of the MV that appeared to incorporate the majority of the previous pericardial patch (Figure 6). The remaining leaflet tissue surrounding the perforation was fibrotic and rigid, allowing the defect to be primarily repaired using interrupted sutures. The prior suture annuloplasty was completely dehisced. The suture was removed and replaced with a 32-mm Medtronic Simulus semirigid annuloplasty (Medtronic, Dublin, Ireland) band (model 800SC). Intraoperative transesophageal echocardiography showed no residual MR and redemonstration of competent aortic and pulmonic valves.Figure 6 Intraoperative Findings\n\nIntraoperative findings confirming a large perforation in the anterior leaflet of the mitral valve.\n\nPost-operative echocardiography performed after 7 months showed a LV ejection fraction of 49% by 3-dimensional volume, trivial MR, and no mitral stenosis. The patient recovered without further event and completed cardiac rehabilitation.\n\nQuestion 6. Should the Patient Have Undergone Repeat Cardiac Surgery Sooner?\n\nAnswer 6. We present a unique case of endocarditis in an immunosuppressed individual where the initial valve repair attempt was not successful. The need for short-interval repeat cardiothoracic surgery is uncommon and the optimal timing for reoperation in stable patients is unknown. Our goal in presenting this case is to outline our approach to the medical management and surveillance to bridge our patient to repeat surgery. In our case even a short delay (6 months) between the initial and repeat surgery resulted in mildly decreased LV systolic function. Should significant recurrent MR be discovered after MV repair, we would recommend minimizing delays to reoperation even in the setting of clinical stability.\n\nFunding Support and Author Disclosures\n\nThe identification of specific products or scientific instrumentation does not constitute endorsement or implied endorsement on the part of the author, Department of Defense, or any component agency. The views expressed in this presentation are those of the author and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or U.S. Government. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nAppendix\n\nSupplemental Video 1\n\nTransesophageal 3-D Surgeon’s View. Transesophageal 3-D surgeon’s view of the mitral valve showing anterior leaflet perforation and suture annuloplasty dehiscence.\n\nSupplemental Video 2\n\nTransesophageal With Color Doppler. Transesophageal with color doppler showing mitral regurgitation through the anterior leaflet perforation.\n\nSupplemental Video 3\n\nTransthoracic 4-Chamber View. Transthoracic 4-chamber view showing a thickened and prolapsing anterior leaflet of the mitral valve.\n\nSupplemental Video 4\n\nTransthoracic 4-Chamber View. Transthoracic 4-chamber view showing a thickened and prolapsing anterior leaflet of the mitral valve and regurgitation at the site of perforation.\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.\n\nAppendix\n\nFor supplemental videos, please see the online version of this paper.\n==== Refs\nReferences\n\n1 Nishimura R. Otto C. Bonow R. 2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease Circulation 129 2014 1\n2 Suri R. Clavel M. Schaff H. Effect of recurrent mitral regurgitation following degenerative mitral valve repair J Am Coll Cardiol 67 2016 488 498 26846946\n3 Suri R. Schaff H. Dearani J. Recurrent mitral regurgitation after repair: should the mitral valve be re-repaired? J Thorac Cardiovasc Surg 132 2006 1390 1397 17140963\n4 Dumont E. Gllinov M. Blackstone E. Reoperation after mitral valve repair for degenerative disease Ann Thorac Surg 84 2007 444 450 17643613\n5 Lee H. Cheng Y. Wu V. Nationwide cohort study of mitral valve repair vs replacement for infective endocarditis J Thorac Cardiovasc Surg 156 2018 1473 1483 29843917\n6 Aphram G. De Kerchove L. Mastrobuoni S. Re-repair of the failed mitral valve: insights into aetiology and surgical management Eur J Cardiothoracic Surg 54 2018 774 780\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2666-0849",
"issue": "3(5)",
"journal": "JACC. Case reports",
"keywords": "LV, left ventricle; MR, mitral regurgitation; MRI, magnetic resonance imaging; MV, mitral valve; endocarditis; lupus; mitral valve repair",
"medline_ta": "JACC Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101757292",
"other_id": null,
"pages": "707-711",
"pmc": null,
"pmid": "34317610",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports",
"references": "29843917;17643613;26846946;24589852;17140963;29547941",
"title": "Early Mitral Valve Repair Failure in the Setting of Endocarditis: When to Reoperate?",
"title_normalized": "early mitral valve repair failure in the setting of endocarditis when to reoperate"
} | [
{
"companynumb": "US-MYLANLABS-2021M1073830",
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"actiondrug": "5",
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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{
"abstract": "OBJECTIVE\nEverolimus is an inhibitor of mTOR, approved for treatment of advanced pancreatic neuroendocrine tumors (NETs). The purpose of this observational study was to evaluate the efficacy and safety of everolimus in treatment of progressive, advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in Taiwan.\n\n\nMETHODS\nFifty-three patients with progressive, advanced GEP-NETs who received everolimus treatment between January 2008 and August 2014 were selected. Patient characteristics, tumor features, safety profiles and treatment efficacy were retrospectively analyzed.\n\n\nRESULTS\nMean follow-up duration was 23.7 (1.2-70) months and 37 of 53 patients (69.8%) remained alive at the end of study. The one- and two-year overall survival rates were 90.5% and 75.4%, respectively. The median progression-free survival (PFS) was 18.9 (95% confidence interval; 10.9-26.8) months. Partial response was observed in 15 (28.3%) patients, 29 (54.7%) patients had stable disease and nine (17%) patients had progressive disease. Patients with World Health Organization (WHO) grade I NETs, nonfunctional tumors and liver metastasis burden <10% had significantly better PFS with everolimus treatment. Adverse events observed were stomatitis (35.8%), hyperglycemia (22.6%) and rash (18.8%). Seven (15.4%) patients experienced severe adverse events (grade 3 or more), including hyperglycemia (4.4%), anemia (4.4%), fatigue (2.2%) and elevated liver function (2.2%). One (2.2%) patient died from grade 5 interstitial pneumonitis.\n\n\nCONCLUSIONS\nEverolimus was an effective treatment for Taiwanese patients with progressive advanced GEP-NETs. Patients with nonfunctional NETs had a trend toward longer PFS, whereas patients with liver metastases burden <10% had a trend toward longer overall survival time receiving everolimus treatment.",
"affiliations": "Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.;Taipei Veterans General Hospital, Division of Hematology & Oncology- Department of Medicine, Taipei, Taiwan.;Division of Hematology-Oncology, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.;National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.;Department of Surgery, National Cheng Kung University Hospital, Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.;Chang Gung Memorial Hospital-Chiayi, Division of Hematology and Oncology- Department of Internal Medicine-, Chang Gung University College of Medicine, Chiayi, Taiwan.;Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.;Division of Hematology and Oncology, Department of Medicine, Changhua Show-Chwan Memorial Hospital, Changhua, Taiwan.;Division of Hematology-Oncology, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.;Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.",
"authors": "Liu|Chien-Ting|CT|;Chen|Ming-Huang|MH|;Chen|Jen-Shi|JS|;Chen|Li-Tzong|LT|;Shan|Yan-Shen|YS|;Lu|Chang-Hsien|CH|;Su|Yu-Li|YL|;Ku|Fan-Chen|FC|;Chou|Wen-Chi|WC|;Chen|Yen-Yang|YY|",
"chemical_list": "D000970:Antineoplastic Agents; D000068338:Everolimus",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajco.12571",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-7555",
"issue": "12(4)",
"journal": "Asia-Pacific journal of clinical oncology",
"keywords": "everolimus; gastroenteropancreatic neuroendocrine tumors; neuroendocrine tumor",
"medline_ta": "Asia Pac J Clin Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia; D000970:Antineoplastic Agents; D018450:Disease Progression; D018572:Disease-Free Survival; D003875:Drug Eruptions; D000068338:Everolimus; D005221:Fatigue; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006943:Hyperglycemia; D007414:Intestinal Neoplasms; D008113:Liver Neoplasms; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D018358:Neuroendocrine Tumors; D010190:Pancreatic Neoplasms; D012189:Retrospective Studies; D013274:Stomach Neoplasms; D013280:Stomatitis; D015996:Survival Rate; D013624:Taiwan; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101241430",
"other_id": null,
"pages": "396-402",
"pmc": null,
"pmid": "27357443",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "The efficacy and safety of everolimus for the treatment of progressive gastroenteropancreatic neuroendocrine tumors: A multi-institution observational study in Taiwan.",
"title_normalized": "the efficacy and safety of everolimus for the treatment of progressive gastroenteropancreatic neuroendocrine tumors a multi institution observational study in taiwan"
} | [
{
"companynumb": "TW-ALKEM LABORATORIES LIMITED-TW-ALKEM-2022-01846",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
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"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
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"abstract": "BACKGROUND\nDesmoid-type fibromatosis (DF) is a rare benign lesion known for its local aggressiveness. The tumor management still remains under debate. Primary head and neck (HN), represents the second most prevalently affected sitein children with DF. This study aims to analyze the specificity of HN-DF in children, focusing on long-term effects of the tumor and therapies.\n\n\nMETHODS\nThis retrospective multicenter study analyzed children treated for a HN-DF between 1993 and 2013. All medical files were reviewed and their outcomes analyzed according to the initial therapies provided.\n\n\nRESULTS\nSixteen children were selected. Mandibular and submandibular areas were the main locations (11 cases). Eight children underwent chemotherapy as first-line therapy with tumor control in 3 cases and 5 cases needing additional treatment. Six children underwent primary surgery: isolated in 3 cases and with additional treatment after tumor progression in 3 cases. A wait-and-see attitude was adopted for 2 children without any additional treatment in 1 case, and followed by additional chemotherapy in the other case. Total burden of treatment to control the disease was a biopsy (1 case), surgery (3 unique cases, 1 multiple case), surgery with chemotherapy (6 cases), and exclusive medical therapies (5 cases). Surgical postoperative sequelae were facial palsy (cases of parotid gland affection), XIth cranial nerve sacrifice or sensory impairment.\n\n\nCONCLUSIONS\nHN-DF is a local and extensive disease that is difficult to control with surgery alone. Sequelae are frequent due to the initial tumor location or therapies. Initial conservative strategies need to be discussed in a multidisciplinary way in order to try to control the disease with the minimal morbidity.",
"affiliations": "Pediatric Otolaryngology Department, Necker-Enfants Malades Hospital, Public Assistance-Hospitals of Paris, Paris, France.;Pediatric Otolaryngology Department, Necker-Enfants Malades Hospital, Public Assistance-Hospitals of Paris, Paris, France.;Pediatric Oncology Unit, Gustave-Roussy Institute, 94800, Villejuif, France.;Pathology Department, Necker-Enfants Malades Hospital, Public Assistance-Hospitals of Paris, Université Sorbonne Paris Cité, 75015, Paris, France.;Department of Pathology, Armand Trousseau Hospital, Public Assistance-Hospitals of Paris, Paris, France.;Institut D'Hématologie et D'Oncologie Pédiatrique, Centre Leon Berard, Lyon, France.;Hematology and Oncology Department, Armand Trousseau Hospital, Public Assistance-Hospitals of Paris, Paris, France.;Pediatric Ear, Nose, and Throat Department, Robert Debré Hospital, Public Assistance-Hospitals of Paris, Paris, France.;Pediatric Otolaryngology Department, Necker-Enfants Malades Hospital, Public Assistance-Hospitals of Paris, Paris, France.;Pediatric Otolaryngology Department, Necker-Enfants Malades Hospital, Public Assistance-Hospitals of Paris, Paris, France.;Pediatric Otolaryngology Department, Necker-Enfants Malades Hospital, Public Assistance-Hospitals of Paris, Paris, France.;Pediatric Otolaryngology Department, Necker-Enfants Malades Hospital, Public Assistance-Hospitals of Paris, Paris, France.;SIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), Institut Curie, PSL University, Paris, France. Electronic address: daniel.orbach@curie.fr.",
"authors": "Paul|Antoine|A|;Blouin|Marie-Julie|MJ|;Minard-Colin|Véronique|V|;Galmiche|Louise|L|;Coulomb|Aurore|A|;Corradini|Nadege|N|;Boutroux|Hélène|H|;Van den Abbeele|Thierry|T|;Leboulanger|Nicolas|N|;Denoyelle|Françoise|F|;Garabedian|Erea-Nöel|EN|;Couloigner|Vincent|V|;Orbach|Daniel|D|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.ijporl.2019.04.037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5876",
"issue": "123()",
"journal": "International journal of pediatric otorhinolaryngology",
"keywords": "Chemotherapy; Children; Desmoid fibromatosis; Neck; Surgery",
"medline_ta": "Int J Pediatr Otorhinolaryngol",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D020330:Bell Palsy; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D018450:Disease Progression; D005260:Female; D018222:Fibromatosis, Aggressive; D006258:Head and Neck Neoplasms; D006801:Humans; D007223:Infant; D008297:Male; D008339:Mandibular Neoplasms; D010306:Parotid Gland; D011183:Postoperative Complications; D012189:Retrospective Studies; D057832:Watchful Waiting",
"nlm_unique_id": "8003603",
"other_id": null,
"pages": "33-37",
"pmc": null,
"pmid": "31059930",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Desmoid-type fibromatosis of the head and neck in children: A changing situation.",
"title_normalized": "desmoid type fibromatosis of the head and neck in children a changing situation"
} | [
{
"companynumb": "FR-SHILPA MEDICARE LIMITED-SML-FR-2019-00140",
"fulfillexpeditecriteria": "2",
"occurcountry": "FR",
"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugaddition... |
{
"abstract": "Staphylococcus aureus strain sequence type (ST) 398 has emerged during the last decade, largely among persons who have contact with swine or other livestock. Although colonization with ST398 is common in livestock workers, infections are not frequently documented. We report recurrent ST398-IIa infection in an Iowa farmer in contact with swine and cattle.",
"affiliations": null,
"authors": "Wardyn|Shylo E|SE|;Stegger|Marc|M|;Price|Lance B|LB|;Smith|Tara C|TC|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.3201/eid2401.161184",
"fulltext": "\n==== Front\nEmerg Infect Dis\nEmerging Infect. Dis\nEID\nEmerging Infectious Diseases\n1080-6040\n1080-6059\nCenters for Disease Control and Prevention\n\n29260680\n16-1184\n10.3201/eid2401.161184\nResearch Letter\nResearch Letter\nWhole Genome Analysis of Recurrent Staphylococcusaureus t571/ST398 Infection in Farmer, Iowa, USA\nWhole-Genome Analysis of Recurrent Staphylococcus aureus t571/ST398 Infection in Farmer, Iowa, USA\nRecurrent S. aureus t571/ST398 infection, Iowa, USA\nWardyn Shylo E.\nStegger Marc\nPrice Lance B.\nSmith Tara C.\nUniversity of Iowa, Iowa City, Iowa, USA (S.E. Wardyn);\nStatens Serum Institut, Copenhagen, Denmark (M. Stegger);\nTranslational Genomics Research Institute, Flagstaff, Arizona, USA (L.B. Price);\nGeorge Washington University, Washington, District of Columbia, USA (L.B. Price);\nKent State University, Kent, Ohio, USA (T.C. Smith)\nAddress for correspondence: Tara C. Smith, Kent State University Epidemiology, 750 Hilltop Dr, Lowry Hall, Kent, OH 44242, USA; email: tsmit176@kent.edu\n1 2018\n24 1 153154\nStaphylococcus aureus strain sequence type (ST) 398 has emerged during the last decade, largely among persons who have contact with swine or other livestock. Although colonization with ST398 is common in livestock workers, infections are not frequently documented. We report recurrent ST398-IIa infection in an Iowa farmer in contact with swine and cattle.\n\nKeywords:\n\nmethicillin-resistant Staphylococcus aureus\nMRSA\nmethicillin-sensitive S. aureus\nMSSA\nlivestock\nswine\nantimicrobial resistance\nfarming\nfarmer\nzoonosis\nwhole-genome analysis\nsequence types\nbacteria\nIowa\nUnited States\n==== Body\nLivestock, especially swine, are a reservoir for Staphylococcus aureus sequence type 398 (ST398) (1). Carriage of this strain is primarily reported in persons with occupational exposure to livestock; however, less is known about the frequency and severity of ST398 infections, particularly in the United States, where surveillance for this organism is limited (2). We report colonization and recurrent infection with methicillin-sensitive S. aureus (MSSA), belonging to livestock clade ST398, in a farmer in Iowa, USA.\n\nA participant in a longitudinal study of rural Iowans (2) provided swab samples of his current skin infection. Swabs were cultured, and S. aureus isolates were subjected to molecular analyses as previously described (3,4). Institutional review board approval was obtained from the University of Iowa.\n\nThe 61-year-old man enrolling in the Iowa study in July 2011 reported a skin infection on his foot. He had visited a doctor the previous day and received ciprofloxacin, and noted his infection was chronic. He also reported a history of heart disease and diabetes. The participant was a farmer who raised swine (900 head × 40 years) and cattle (500 head × 10 years), and owned a dog. He reported working directly with swine and cattle ≈2 hours per day and noted that he did not use personal protective equipment such as gloves or masks. His nose and throat were colonized with MSSA ST398 that was mecA-negative, periventricular leukomalacia–negative, and staphylococcal protein A type t571. The isolate was resistant to tetracycline, trimethoprim/sulfamethoxazole, and levofloxacin. The participant’s wife was also colonized at enrollment with MSSA in her throat, showing the same molecular characteristics and susceptibility patterns as her spouse. She reported no exposure to livestock.\n\nThe isolate obtained from the participant’s first culture showed the same molecular characteristics as isolates from his nasal and throat swabs and the isolate from his second infection culture received in November 2011 (Table). He described this second infection as cellulitis: he reported draining pus, a general ill feeling, and headaches. The infection was treated empirically with ciprofloxacin, neosporin, warm compresses, and incision and drainage. Isolates from his third incident infection culture in August 2012 showed the same molecular characteristics as previous samples, but 2 different susceptibility patterns: 1 isolate was the same as previous, while another showed additional phenotypic resistance to oxacillin (MIC 4 µg/mL by broth dilution), making this a borderline-resistant S. aureus infection. Genome sequence analyses showed that this strain had not acquired a mec gene and likely had become resistant from a mutation in a penicillin-binding protein. This infection was treated with mupirocin, trimethoprim/sulfamethoxazole, ciprofloxacin, warm compresses, and drainage. \n All of the farmer’s isolates had the t571 spa type, which is common among livestock-independent (i.e., human-associated) ST398 lineages (4). S. aureus t571 strains have been isolated from an Iowa childcare worker (5), inmates from a Texas jail (6), and in community members in New York and New Jersey (7); t571 strains have been rarely isolated from Iowa livestock (8). However, whole-genome sequence analyses with 89 previously published clonal complex 398 genome data confirmed that the isolates from this case were from the livestock-associated ST398 lineage (CC398-IIa) (4).\n\nTable Details of recurrent Staphylococcus aureus t571/ST398 infection in farmer, Iowa, USA*a\n\nDate\tAntimicrobial drug resistance profile\tDescription of infection\tTreatment\t\nJuly 2011\tTET, SXT, LVX\tCellulitis\tCiprofloxacin\t\nNovember 2011\tTET, SXT, LVX\tCellulitis, draining pus, headache, ill feeling\tCiprofloxacin, Neosporin, warm compress, incision, drainage\t\nAugust 2012†\tTET, SXT, LEVO (isolate 1); OXA, TET, SXT, LVX (isolate 2)\tNone provided\tMupirocin, SXT, ciprofloxacin, \nwarm compress, drainage\t\n*All isolates were t571/ST398 and were PVL negative. Neosporin is manufactured by Johnson & Johnson (New Brunswick, NJ, USA). LEVO, levofloxacin; LVX, levofloxacin resistance to isolate 2; OXA, oxacillin; SXT, trimethoprim/sulfamethoxazole; TET, tetracycline.\n†Two isolates from this infection were tested and had different antimicrobial drug resistance profiles as noted.\n\nLongitudinal follow-up complemented with whole-genome sequence analyses showed that the participant repeatedly experienced infections by the same strain over the course of 13 months. The isolates from this patient and his wife formed a distinct clade within the ST398 global phylogeny (Technical Appendix Figure 1). In-depth genomic analyses revealed a novel ≈265,000 bp recombinant region originating from clonal complex 9, and unique to this lineage.\n\nIt is unclear whether the farmer’s recurrences arose from treatment failure, repeated acquisitions from exposure to livestock, or the result of long-term colonization and evolution. In contrast, the farmer’s wife, who was colonized by the same strain, reported no direct contact with livestock and may have become colonized by human-to-human transmission from her husband. Comparison with other strains collected as part of this (2) and other studies (9) identified closely related isolates from 3 other participants and 1 pig (Technical Appendix Figure 1) distributed throughout the state of Iowa and into western Illinois (Technical Appendix Figure 2).\n\nThis dataset does not specify whether the evolution of the borderline-resistant S. aureus phenotype took place in the patient or the livestock reservoir. The farmer was prescribed ciprofloxacin multiple times; this could have contributed to emergence of borderline oxacillin resistance (10). The farmer’s first phenotypically methicillin-resistant strain was not detected until >1 year after enrollment into this study. This case demonstrates the ability of livestock-associated S. aureus ST398 to cause repeated skin and soft tissue infections in a manner similar to community-associated strains, and the necessity to screen for MSSA and methicillin-resistant Staphylococcus aureus when studying the spread of these organisms.\n\nTechnical Appendix. Maximum-likelihood phylogenetic analysis of sequence type 398 strains based on core-genome single-nucleotide polymorphisms and locations of study participants and swine in Iowa and western Illinois, USA\n\nThis work was supported in part by the intramural research program of the National Institutes of Health (R01AI101371, LBP), National Cancer Institute (Z01-CP010119), and by the Agency for Healthcare Research and Quality (R18 HS019966, TCS).\n\nMs. Wardyn is a project manager in the Clinical Research Division at the Fred Hutchinson Cancer Research Center in Seattle, WA. Her main research interests include molecular epidemiology, disease surveillance, and patient-reported outcomes.\n\nSuggested citation for this article: Warden SE, Stegger M, Price LB, Smith TC. Whole-genome analysis of recurrent Staphylococcus aureus t571/ST398 infection in farmer, Iowa, USA. Emerg Infect Dis. 2018 Jan [date cited]. https://doi.org/10.3201/eid2401.161184\n==== Refs\nReferences\n\n1. Smith TC, Pearson N. The emergence of Staphylococcus aureus ST398. Vector Borne Zoonotic Dis. 2011;11 :327–39. 10.1089/vbz.2010.0072 20925523\n2. Wardyn SE, Forshey BM, Farina SA, Kates AE, Nair R, Quick MK, et al. Swine farming is a risk factor for infection with and high prevalence of carriage of multidrug-resistant Staphylococcus aureus. Clin Infect Dis. 2015;61 :59–66. 10.1093/cid/civ234 25931444\n3. O’Brien AM, Hanson BM, Farina SA, Wu JY, Simmering JE, Wardyn SE, et al. MRSA in conventional and alternative retail pork products. PLoS One. 2012;7 :e30092. 10.1371/journal.pone.0030092 22276147\n4. Price LB, Stegger M, Hasman H, Aziz M, Larsen J, Andersen PS, et al. Staphylococcus aureus CC398: host adaptation and emergence of methicillin resistance in livestock. MBio. 2012;3 :e00305–11. 10.1128/mBio.00305-11 22354957\n5. Moritz ED, Smith TC. Livestock-associated Staphylococcus aureus in childcare worker. Emerg Infect Dis. 2011;17 :742–4. 10.3201/eid1704101852 21470477\n6. David MZ, Siegel J, Lowy FD, Zychowski D, Taylor A, Lee CJ, et al. Asymptomatic carriage of sequence type 398, spa type t571 methicillin-susceptible Staphylococcus aureus in an urban jail: a newly emerging, transmissible pathogenic strain. J Clin Microbiol. 2013;51 :2443–7. 10.1128/JCM.01057-13 23658269\n7. Mediavilla JR, Chen L, Uhlemann AC, Hanson BM, Rosenthal M, Stanak K, et al. Methicillin-susceptible Staphylococcus aureus ST398, New York and New Jersey, USA. Emerg Infect Dis. 2012;18 :700–2. 10.3201/eid1804.111419 22469250\n8. Smith TC, Gebreyes WA, Abley MJ, Harper AL, Forshey BM, Male MJ, et al. Methicillin-resistant Staphylococcus aureus in pigs and farm workers on conventional and antibiotic-free swine farms in the USA. PLoS One. 2013;8 :e63704. 10.1371/journal.pone.0063704 23667659\n9. Smith TC, Male MJ, Harper AL, Kroeger JS, Tinkler GP, Moritz ED, et al. Methicillin-resistant Staphylococcus aureus (MRSA) strain ST398 is present in midwestern U.S. swine and swine workers. PLoS One. 2009;4 :e4258. 10.1371/journal.pone.0004258 19145257\n10. Weber SG, Gold HS, Hooper DC, Karchmer AW, Carmeli Y. Fluoroquinolones and the risk for methicillin-resistant Staphylococcus aureus in hospitalized patients. Emerg Infect Dis. 2003;9 :1415–22. 10.3201/eid0911.030284 14718085\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1080-6040",
"issue": "24(1)",
"journal": "Emerging infectious diseases",
"keywords": "Iowa; MRSA; MSSA; United States; antimicrobial resistance; bacteria; farmer; farming; livestock; methicillin-resistant Staphylococcus aureus; methicillin-sensitive S. aureus; sequence types; swine; whole-genome analysis; zoonosis",
"medline_ta": "Emerg Infect Dis",
"mesh_terms": "D000818:Animals; D000900:Anti-Bacterial Agents; D002353:Carrier State; D002417:Cattle; D000067565:Farmers; D006801:Humans; D007484:Iowa; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus; D013552:Swine",
"nlm_unique_id": "9508155",
"other_id": null,
"pages": "153-154",
"pmc": null,
"pmid": "29260680",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D052060:Research Support, N.I.H., Intramural; D016422:Letter; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "25931444;20925523;23667659;22276147;19145257;23658269;14718085;21470477;22354957;22469250",
"title": "Whole-Genome Analysis of Recurrent Staphylococcus aureus t571/ST398 Infection in Farmer, Iowa, USA.",
"title_normalized": "whole genome analysis of recurrent staphylococcus aureus t571 st398 infection in farmer iowa usa"
} | [
{
"companynumb": "US-APOTEX-2018AP005901",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "Rarely, Legionnaires' disease (LD) can progress into a slowly or nonresolving form.\n\n\n\nA nationwide retrospective study was conducted by the French National Reference Center for Legionella (2013-2017) including cases of slowly or nonresolving LD defined as persistent clinical symptoms, computed tomography (CT) scan abnormalities, and Legionella detection in lower respiratory tract specimens by culture and/or real-time (RT) polymerase chain reaction (PCR) >30 days after symptom onset.\n\n\n\nTwelve cases of community-acquired slowly or nonresolving LD were identified among 1686 cases of culture-positive LD. Median (interquartile range [IQR]) age was 63 (29-82) years. Ten (83.3%) patients had ≥1 immunosuppressive factor. Clinically, 9 patients transiently recovered before further deterioration (median [IQR] symptom-free interval, 30 [18-55] days), 3 patients had uniformly persistent symptoms (median [IQR] time, 48 [41.5-54] days). Two patients had >2 recurrences. CT scan imagery found lung abscess in 5 (41.6%) cases. Slowly or nonresolving LD was diagnosed on positive Legionella cultures (n = 10, 83.3%) at 49.5 (IQR, 33.7-79) days. Two cases were documented through positive Legionella RT PCR at 52 and 53 days (cycle threshold detection of 21.5 and 33.7, respectively). No genomic microevolution and no Legionella resistance to antibiotics were detected. The median (IQR) duration of treatment was 46.5 (21-92.5) days. Two empyema cases required thoracic surgery. At a median (IQR) follow-up of 26 (14-41.5) months, LD-attributable mortality was 16.6% (n = 2).\n\n\n\nSlowly or nonresolving LD may occur in immunocompromised patients, possibly leading to lung abscess and empyema.",
"affiliations": "Département des Maladies Infectieuses et Tropicales, Hospices Civils de Lyon, Paris, France.;Centre National de Référence des Légionelles, Institut des Agents Infectieux, Hospices Civils de Lyon, Paris, France.;Centre National de Référence des Légionelles, Institut des Agents Infectieux, Hospices Civils de Lyon, Paris, France.;Centre National de Référence des Légionelles, Institut des Agents Infectieux, Hospices Civils de Lyon, Paris, France.;Centre National de Référence des Légionelles, Institut des Agents Infectieux, Hospices Civils de Lyon, Paris, France.;Centre Hospitalier Universitaire de Grenoble, Institut de Biologie et de Pathologie, Paris, France.;Service de Radiologie, Hospices Civils de Lyon, Paris, France.;Département des Maladies Infectieuses et Tropicales, Hospices Civils de Lyon, Paris, France.;Service de Pneumologie, Hôpital St-Louis (AP-HP), Paris, France.;Centre National de Référence des Légionelles, Institut des Agents Infectieux, Hospices Civils de Lyon, Paris, France.;Département des Maladies Infectieuses et Tropicales, Hospices Civils de Lyon, Paris, France.",
"authors": "Pouderoux|Cécile|C|;Ginevra|Christophe|C|;Descours|Ghislaine|G|;Ranc|Anne-Gaëlle|AG|;Beraud|Laetitia|L|;Boisset|Sandrine|S|;Magand|Nicolas|N|;Conrad|Anne|A|;Bergeron-Lafaurie|Anne|A|;Jarraud|Sophie|S|;Ader|Florence|F|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciz538",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "70(9)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "\n Legionella\n ; Legionnaires’ disease; lung abscess; nonresolving pneumonia; slowly resolving pneumonia",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000900:Anti-Bacterial Agents; D006801:Humans; D007875:Legionella; D016952:Legionella pneumophila; D007877:Legionnaires' Disease; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1933-1940",
"pmc": null,
"pmid": "31242293",
"pubdate": "2020-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Slowly or Nonresolving Legionnaires' Disease: Case Series and Literature Review.",
"title_normalized": "slowly or nonresolving legionnaires disease case series and literature review"
} | [
{
"companynumb": null,
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": "3",
"drugadministratio... |
{
"abstract": "Pseudomembranous colitis (PMC) is classically associated with Clostridium difficile infection. We report a rare case of cytomegalovirus (CMV)-associated PMC in a 52-year-old female patient who had undergone kidney transplantation more than 20 years ago and was on low dose prednisolone and ciclosporin. She presented with an acute history of fever, lethargy, vomiting and diarrhoea on admission. Computed tomography of the abdomen showed extensive colitis, and colonoscopy revealed extensive pseudomembrane formation. Multiple tests for Clostridium difficile and other common microbiological causes of colitis were negative. CMV DNAemia and colonic biopsies confirmed the diagnosis of CMV colitis. The patient responded to prompt CMV treatment, as demonstrated by clinical, endoscopic, and histological response. While CMV is a common pathogen in the solid organ transplant population that is familiar to most transplant physicians, it may present atypically as PMC. Here, we review the literature on CMV-associated PMC and its relevance to solid organ transplant recipients. To our knowledge, this is the first reported case of CMV-associated PMC in a kidney transplant recipient.",
"affiliations": "Department of Renal Medicine, Singapore General Hospital, Singapore.;Department of Renal Medicine, Singapore General Hospital, Singapore.;Department of Anatomical Pathology, Singapore General Hospital, Singapore.;Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.;Department of Renal Medicine, Singapore General Hospital, Singapore.;Department of Renal Medicine, Singapore General Hospital, Singapore.;Department of Infectious Diseases, Singapore General Hospital, Singapore.",
"authors": "Chua|Yi Yi|YY|https://orcid.org/0000-0001-6166-1919;Ho|Quan Yao|QY|https://orcid.org/0000-0002-0884-7076;Ngo|Nye Thane|NT|https://orcid.org/0000-0003-2419-0817;Krishnamoorthy|Thinesh Lee|TL|https://orcid.org/0000-0002-5640-1079;Thangaraju|Sobhana|S|https://orcid.org/0000-0002-0758-1560;Kee|Terence|T|https://orcid.org/0000-0001-5250-855X;Wong|Hei Man|HM|https://orcid.org/0000-0003-2456-0873",
"chemical_list": "D000998:Antiviral Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13694",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "23(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "CMV; cytomegalovirus; kidney transplant; pseudomembranous colitis",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000998:Antiviral Agents; D016360:Clostridioides difficile; D003092:Colitis; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004761:Enterocolitis, Pseudomembranous; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008875:Middle Aged",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13694",
"pmc": null,
"pmid": "34288307",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Cytomegalovirus-associated pseudomembranous colitis in a kidney transplant recipient.",
"title_normalized": "cytomegalovirus associated pseudomembranous colitis in a kidney transplant recipient"
} | [
{
"companynumb": "SG-TEVA-2022-SG-2014953",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nPeople with cystic fibrosis (CF) have an increased risk of thrombosis due to acquired thrombophilia secondary to chronic systemic inflammation and central venous catheter use for treatment of pulmonary infections. The objective of this study is to determine the safety and effectiveness of a risk-stratified, venous thromboembolism (VTE) prophylaxis intervention.\n\n\nMETHODS\nThis single-center, IRB-approved, retrospective study assessed patients with CF admitted to our institution for treatment of a pulmonary exacerbation from 2017 to 2019. Data and outcomes were manually extracted from the electronic medical record and internal CF clinical database. Subject characteristics, calculated VTE risk, prophylaxis interventions prescribed, VTE incidence, and adverse events were captured.\n\n\nRESULTS\nA total of 135 CF patients had 354 admissions for pulmonary exacerbations in the time frame of the study. The majority of admissions (88.7%) were classified as moderate or high risk for VTE using the algorithm. Overall, VTE prophylaxis intervention determined by the algorithm was initiated in 36.2% of admissions. During the study period, no VTE events occurred. Four minor bleeding adverse effects were reported in patients receiving VTE chemical prophylaxis with enoxaparin (4.2%).\n\n\nCONCLUSIONS\nThis study provides the first reported outcomes following implementation of a risk-stratified VTE prophylaxis algorithm in hospitalized young people with CF. In this population at increased risk, use of risk-stratified prophylaxis was safe and effective in preventing VTE. Additional work to improve and maintain adherence to the algorithm and VTE prophylaxis interventions at our institution is planned and similar care should be considered at other pediatric CF care centers.",
"affiliations": "Department of Pharmacy, Children's Hospital Colorado, Aurora, CO, USA.;Center for Research in Outcomes for Children's Surgery, University of Colorado School of Medicine, Aurora, CO, USA; Department of Pediatrics, Section of Pediatric Pulmonary and Sleep Medicine, Children's Hospital Colorado and the University of Colorado Anschutz Medical Campus, Aurora, CO, USA.;Department of Pharmacy, Children's Hospital Colorado, Aurora, CO, USA.;Department of Pharmacy, Children's Hospital Colorado, Aurora, CO, USA.;Hemophilia & Thrombosis Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.;Hemophilia & Thrombosis Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.;Department of Pediatrics, Section of Pediatric Pulmonary and Sleep Medicine, Children's Hospital Colorado and the University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Electronic address: stacey.martiniano@childrenscolorado.org.",
"authors": "Holsteen|Page|P|;Meier|Maxene|M|;Brennan|Laney|L|;VanHorn|Tracie|T|;Kuldanek|Susan A|SA|;Wang|Michael|M|;Martiniano|Stacey L|SL|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.1016/j.thromres.2021.07.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-3848",
"issue": "206()",
"journal": "Thrombosis research",
"keywords": "Cystic fibrosis; Enoxaparin; Pediatric; Venous thromboembolism; Venous thromboembolism prophylaxis",
"medline_ta": "Thromb Res",
"mesh_terms": "D000293:Adolescent; D000465:Algorithms; D000925:Anticoagulants; D002648:Child; D003550:Cystic Fibrosis; D006801:Humans; D012189:Retrospective Studies; D054556:Venous Thromboembolism",
"nlm_unique_id": "0326377",
"other_id": null,
"pages": "36-41",
"pmc": null,
"pmid": "34399123",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety and effectiveness of a risk-stratified venous thromboembolism prophylaxis algorithm in young people with cystic fibrosis.",
"title_normalized": "safety and effectiveness of a risk stratified venous thromboembolism prophylaxis algorithm in young people with cystic fibrosis"
} | [
{
"companynumb": "US-APOTEX-2022AP008767",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "ENOXAPARIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nRanolazine is a selective inhibitor of the late inward sodium-current, approved for the treatment of chronic angina. Here, we report a case of a possibly suicidal death due to acute ranolazine overdosing. A 41-year-old woman was found unconscious by her son and was urgently admitted to the Intensive Care Unit. She had ingested an unknown amount of ranolazine tablets. Seventeen hours after admission, the patient died. An autopsy was performed 4 days post-mortem.\n\n\nMETHODS\nA routine screening analysis for drugs of abuse and medicinal drugs performed by liquid chromatography ion trap mass spectrometry on autopsy samples of biological fluids did not detect any relevant presence of toxicologically relevant compounds, but ranolazine. A quantitative analysis was then carried out by liquid chromatography- QqQ mass spectrometry in order to quantify ranolazine and its major metabolite O-desmethyl-ranolazine in biological fluids and organs.\n\n\nRESULTS\nRanolazine concentrations in biological fluids were as follows: cardiac blood, 19.5 μg/mL; femoral blood, 12.3 μg/mL; bile, 0.87 μg/mL and vitreous humor, 15.4 μg/mL. For O-desmethyl-ranolazine the concentrations in cardiac blood, femoral blood, bile and vitreous were 10.7 μg/mL; 9.6 μg/mL; 11,103 μg/mL and 11.4 μg/mL, respectively.\n\n\nCONCLUSIONS\nThe cause of death was attributed to ranolazine overdosing. To the best of our knowledge, this is the first report of a fatality associated with ranolazine, in which the postmortem distribution of ranolazine and its metabolite has been quantitatively assessed. The present study can therefore provide useful information for interpretation of the causes and mechanisms of death in ranolazine associated fatalities.",
"affiliations": "Unit of Forensic Medicine, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.;Unit of Forensic Medicine, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.;Unit of Forensic Medicine, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.;Unit of Forensic Medicine, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.;Unit of Forensic Medicine, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.",
"authors": "Gottardo|Rossella|R|;De Battisti|Zeno|Z|;Busetti|Federico|F|;Murari|Matilde|M|;Tagliaro|Franco|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkaa200",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": null,
"journal": "Journal of analytical toxicology",
"keywords": "LC-MS/MS; death; overdose; ranolazine",
"medline_ta": "J Anal Toxicol",
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"nlm_unique_id": "7705085",
"other_id": null,
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"pmid": "33382067",
"pubdate": "2020-12-31",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Fatal, Intentional Overdose of Ranolazine: Post-Mortem Distribution of Parent Drug and its Major Metabolite.",
"title_normalized": "fatal intentional overdose of ranolazine post mortem distribution of parent drug and its major metabolite"
} | [
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"companynumb": "IT-GILEAD-2021-0511719",
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"activesubstancename": "RANOLAZINE"
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"abstract": "Patients with symptoms of opiate withdrawal, after the administration of opiate antagonist by paramedics, are a common presentation in the emergency department of hospitals. Though most of opiate withdrawal symptoms are benign, rarely they can become life threatening. This case highlights how a benign opiate withdrawal symptom of hyperventilation led to severe respiratory alkalosis that degenerated into tetany and cardiac arrest. Though this patient was successfully resuscitated, it is imperative that severe withdrawal symptoms are timely identified and immediate steps are taken to prevent catastrophes. An easier way to reverse the severe opiate withdrawal symptom would be with either low dose methadone or partial opiate agonists like buprenorphine. However, if severe acid-base disorder is identified, it would be safer to electively intubate these patients for better control of their respiratory and acid-base status.",
"affiliations": "Department of Internal Medicine, Lincoln Medical and Mental Health Center, 234 East 149th Street, Bronx, NY 10451, USA.;Department of Internal Medicine, Lincoln Medical and Mental Health Center, 234 East 149th Street, Bronx, NY 10451, USA.",
"authors": "Kugasia|Irfanali R|IR|;Shabarek|Nehad|N|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1155/2014/295401",
"fulltext": "\n==== Front\nCase Rep Crit CareCase Rep Crit CareCRICCCase Reports in Critical Care2090-64202090-6439Hindawi Publishing Corporation 10.1155/2014/295401Case ReportOpiate Withdrawal Complicated by Tetany and Cardiac Arrest Kugasia Irfanali R. *Shabarek Nehad Department of Internal Medicine, Lincoln Medical and Mental Health Center, 234 East 149th Street, Bronx, NY 10451, USA*Irfanali R. Kugasia: irfanali102@gmail.comAcademic Editor: Joel Starkopf\n\n2014 15 6 2014 2014 29540114 2 2014 26 5 2014 Copyright © 2014 I. R. Kugasia and N. Shabarek.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Patients with symptoms of opiate withdrawal, after the administration of opiate antagonist by paramedics, are a common presentation in the emergency department of hospitals. Though most of opiate withdrawal symptoms are benign, rarely they can become life threatening. This case highlights how a benign opiate withdrawal symptom of hyperventilation led to severe respiratory alkalosis that degenerated into tetany and cardiac arrest. Though this patient was successfully resuscitated, it is imperative that severe withdrawal symptoms are timely identified and immediate steps are taken to prevent catastrophes. An easier way to reverse the severe opiate withdrawal symptom would be with either low dose methadone or partial opiate agonists like buprenorphine. However, if severe acid-base disorder is identified, it would be safer to electively intubate these patients for better control of their respiratory and acid-base status.\n==== Body\n1. Introductions\nWithdrawal from opiates is considered to be generally benign with the common symptoms being diaphoresis, piloerection, lacrimation, diarrhea, anxiousness, nonspecific abdominal and bodily pain sensation, and hyperventilation. It is rarely associated with life threatening complications, unlike withdrawal from benzodiazepine and alcohol which are frequently associated with life threatening complications and need close monitoring in an inpatient setting [1–3]. As a result, opiate antagonist like naloxone has been extensively and successfully used in the field and the emergency departments for diagnosing altered mental status from opiate overdose and reversing their complication of respiratory depression which is considered to be more life threatening [3–5]. However, in rare cases serious complications and fatal outcomes have been reported during opiate withdrawals, particularly in patients who are undernourished or have underlying electrolyte or cardiorespiratory abnormalities [3, 5, 6]. These complications considered to be either from direct toxic effects of naloxone or from increased catecholamine surge due to severe opiate withdrawal [4–6]. This case emphasizes the need for a cautious approach towards severe manifestations of simple opiate withdrawal symptom, like hyperventilation.\n\n2. Case\nA 54-year-old female was brought to the hospital by EMT (emergency medical team) with suspicion of opiate overdose. EMT was called by a family member after the patient was found to be less responsive and difficult to arouse. The patient received 4 mg of naloxone subcutaneously in field by the EMT which improved patient's responsiveness but pushed her into severe opiate withdrawal. In the emergency department, the patient was found to be awake, alert, and anxious. She was not oriented but was able to follow simple commands. The patient was also diaphoretic, tachypneic with respiratory rate in 30 and tachycardic with heart rate in 150 s. Lungs were clear on auscultation with good bilateral air entry. Cardiovascualr exam was unremarkable with regular rhythm good pulses present in all four extremities. Abdominal exam was also unremarkable. Neuromuscular exam showed tremulousness and muscle fasciculation in different muscle groups of the face, upper limb, and lower extremities, exacerbated deep tendon reflex and normal motor strength with severe pain on movement of left hip. The patient had a past medical history of AIDS, hepatitis C, and bipolar disorder but as per her home medication list she was not on any treatment for them. At home, the patient was on 150 mg of methadone for maintenance and oral morphine sustained release and immediate release for pain control for her recent hip fracture. The first ABG done at the time of patient's ED presentation was on a nonrebreather mask; it showed pH 7.694, PCO2 19.6 mmHg, PO2 224 mmHg, O2 saturation of 100%, and lactate of 2.97 and her initial EKG showed bigeminy with the rest of the details obscured by artifacts as seen in Figure 1. In the next 30 minutes patient's respiratory rate had decreased to 18–25 breaths per minute at which time a repeat ABG was done on room air that showed pH of 7.641, PCO2 20.3 mmHg, PO2 of 86 mmHg, and O2 saturation of 98% with lactate of 2.48. While being on telemetry, the patient had sinus tachycardia with PVCs and runs of bigeminy. The patient was subsequently deemed stable and taken for CT scan of heat and chest for further evaluation, while in CT room the patient went into generalized tetany and then into cardiac arrest with initial rhythm of ventricular tachycardia that degenerated to torsade de pointes and ventricular fibrillation. Code was run for 25 minutes, during which the patient was intubated and received 2 doses of epinephrine and 4 gm of magnesium and was shocked 3 times. She had a return of spontaneous circulation after the third shock. The patient was initially started on hypothermia protocol; however, it was abandoned as patient showed movement of extremities. The labs obtained prior to patient's cardiac arrest showed Na+ 138, K+ 3.4, Mg+ 2.0, Ca2+ 8.9, HCO3 18, and anion gap of 16; however, this sample was hemolyzed. Repeat labs obtained 30 minutes after intubation showed K+ 3.5, Ca2+ 7.6, iCa2+ 3.92, Mg+ 2.6, and HCO3 16 with anion gap of 17. EKG obtained after cardiac arrest showed sinus tachycardia. Urine toxicology obtained for the patient was positive only for methadone and opiates. Patient's serum albumin level was 2.9. The patient was extubated on day 2 and was discharged from hospital on day 8 of hospitalization.\n\n3. Discussion\nThe most important concern after giving naloxone to a patient with opiate overdose is reversal of naloxone antagonism and patient slipping back into respiratory depression from opiate overdose. This is because the half-life of naloxone action is only 20–80 minutes, much shorter than many of the opiates [2, 3]. The initial impression in this case was that patient had respiratory alkalosis from her tachypnea due to acute opiate withdrawal and this was expected to reverse as quickly as the effect of naloxone wears off. However, repeat clinical evaluation and ABG after 30 minutes did not show any major change as the patient was still breathing at 25 breaths per minute and was tachycardic to 120–140 s. So other explanations for the clinical findings were sought. The consideration of pulmonary embolism was high on the differential as the patient had recent history of hip fracture and had an A-a gradient of almost 40 mmHg on the repeat arterial blood gas. As a result, decision was made to rule it out with a chest CT which came out to be negative for pulmonary embolism or any lung pathology. CT brain was also negative for any intracranial bleed.\n\nThe cardiac arrest observed in this case can be explained by three main reasons. Firstly, it could be from naloxone itself. Pulmonary edema and cardiac arrest from ventricular fibrillation have been reported with administration of naloxone. This was mostly seen in postoperative patient to whom naloxone was given to reverse the effect of opiates and in patient who was on high dose of opiate for pain relief who had some kind of cardiac comorbidity [6, 7]. These complications were considered to be from a sudden surge in catecholamine levels and have been mostly reported within minutes of IV naloxone administration [6, 7]. Since the cardiac arrest in this case occurred almost 1 hour after the naloxone which was given subcutaneously and negative chest CT for pulmonary edema, naloxone as the cause of cardiac arrest is less likely. Secondly, the cardiac arrhythmias observed in this patient like torsades de pointes and ventricular fibrillation are found in patient with prolonged QT interval. This is commonly seen with methadone overdose. The incidence of torsades de pointes with methadone is increased when methadone overdose is associated with electrolyte abnormality especially hypokalemia [8]. The cardiac arrest in this case could be easily attributed to methadone overdose associated with some electrolyte abnormalities. However, there was no conclusive evidence of prolonged QTc. The waves in initial EKG were obscured by artifacts and repeat EKG after successful resuscitation showed a QTc of 473. Also, none of this could explain the simultaneous occurrence of tetany and cardiac arrest observed in this case. Lastly, the cardiac arrhythmia and tetany could be explained by the severe alkalemia secondary to hypocapnia from patient's hyperventilation. As per patient's initial lab and ABG, she had severe primary respiratory alkalosis with mild high anion gap metabolic acidosis which was considered to be from patient's elevated lactate level from her tachypnea. Voluntary hyperventilation in normal healthy patients has been found to be associated with severe respiratory alkalosis, increase in anion gap from lactic acidosis, and significant change in serum K+ level [9, 10]. Severe alkalemia resulting from hyperventilation and hypocapnia has been shown to cause perioral numbness, cardiac arrhythmias, seizure, and tetany [11–13]. These complications can be either due to the direct effect of alkalemia on ion gated channels controlling membrane potential or secondary to its effect on serum potassium (K+) and ionized calcium (iCa2+) levels or from combination of both [14]. Putting together these pathophysiologic effects of severe alkalemia can result in neuronal and cardiac excitability. This can explain the initial findings of muscle fasciculation and bigeminy and later the tetany, polymorphic ventricular tachycardia, and ventricular fibrillation which were observed in this patient. A simplified schematic for this mechanism is depicted in Figure 2. Also notable was the rapid improvement in patient's clinical status and EKG finding after intubation with resolution of arrhythmia and overall good patient outcome.\n\nTo avoid severe opiate withdrawals and complications, a more conservative and cautious use of naloxone is advised. Intravenous route by well-trained personnel to better titrate the naloxone dose is recommended, as at low dose naloxone can reverse the respiratory depression from opiate overdose without causing overt withdrawal from opiates [3]. With subcutaneous and intramuscular administration of naloxone, the time to peak effect and peak effect are less predictable than intravascular administration. However, once severe withdrawal symptoms are identified, immediate treatment with low dose of methadone or partial opiate agonists like buprenorphine could help in reversing some of these severe withdrawal symptoms [2, 3]. Nonetheless, with concerns of respiratory depression from opiate overdose and risk of severe alkalosis from hyperventilation, early elective intubation and sedation should be highly considered, as these would provide better control of patient's respiratory system and in turn their acid-base status.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Initial EKG showing bigeminy—showing increased cardiac muscle excitability with origination of ventricular ectopics.\n\nFigure 2 Mechanism explaining neuronal and cardiac excitability in opiate withdrawal.\n==== Refs\n1 Khantzian EJ McKenna GJ Acute toxic and withdrawal reactions associated with drug use and abuse Annals of Internal Medicine 1979 90 3 361 372 2-s2.0-0018353792 34343 \n2 Kosten TR O’Connor PG Management of drug and alcohol withdrawal The New England Journal of Medicine 2003 348 18 1786 1795 2-s2.0-0037407734 12724485 \n3 Boyer EW Management of opioid analgesic overdose The New England Journal of Medicine 2012 367 2 146 155 2-s2.0-84863649956 22784117 \n4 Yealy DM Paris PM Kaplan RM Heller MB Marini SE The safety of prehospital naloxone administration by paramedics Annals of Emergency Medicine 1990 19 8 902 905 2-s2.0-0025370002 2372173 \n5 Osterwalder JJ Naloxone-for intoxications with intravenous heroin and heroin mixtures-harmless or hazardous? A prospective clinical study Clinical Toxicology 1996 34 4 409 416 2-s2.0-0029680588 8699555 \n6 Cuss FM Colaco CB Baron JH Cardiac arrest after reversal of effects of opiates with naloxone British Medical Journal 1984 288 6414 363 364 2-s2.0-0021245457 6419929 \n7 van Dorp ELA Yassen A Dahan A Naloxone treatment in opioid addiction: the risks and benefits Expert Opinion on Drug Safety 2007 6 2 125 132 2-s2.0-33847735481 17367258 \n8 Ehret GB Voide C Gex-Fabry M Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors Archives of Internal Medicine 2006 166 12 1280 1287 2-s2.0-33745643135 16801510 \n9 Krapf R Caduff P Wagdi P Staubli M Hulter HN Plasma potassium response to acute respiratory alkalosis Kidney International 1995 47 1 217 224 2-s2.0-0028913051 7731149 \n10 Sanchez MG Finlayson DC Dynamics of serum potassium change during acute respiratory alkalosis Canadian Anaesthetists Society Journal 1978 25 6 495 498 2-s2.0-0018235318 31968 \n11 Edmondson JW Brashear RE Li TK Tetany: quantitative interrelationships between calcium and alkalosis American Journal of Physiology 1975 228 4 1082 1086 2-s2.0-0016769250 236662 \n12 Brown EB Jr. Physiological effects of hyperventilation Physiological Reviews 1953 33 4 445 471 2-s2.0-0000013369 13100065 \n13 Lawson NW Butler GH III Ray CT Alkalosis and cardiac arrhythmias Anesthesia and Analgesia 1973 52 6 951 964 2-s2.0-0015745490 4796573 \n14 Tombaugh GC Somjen GG Effects of extracellular pH on voltage-gated Na+ , K+ and Ca2+ currents in isolated rat CA1 neurons Journal of Physiology 1996 493 3 719 732 2-s2.0-0030055563 8799894\n\n",
"fulltext_license": "CC BY",
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"issue": "2014()",
"journal": "Case reports in critical care",
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"pubdate": "2014",
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"title": "Opiate withdrawal complicated by tetany and cardiac arrest.",
"title_normalized": "opiate withdrawal complicated by tetany and cardiac arrest"
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"companynumb": "US-ROXANE LABORATORIES, INC.-2016-RO-00075RO",
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"abstract": "BACKGROUND\nHLA-B*58:01 is associated with allopurinol-induced severe cutaneous adverse drug reactions (sCADR) particularly in Han Chinese, but the risk in European populations has seldom been studied.\n\n\nOBJECTIVE\nTo study the association of HLA-B*58:01 with allopurinol-induced sCADR in a Portuguese population.\n\n\nMETHODS\nWe studied 25 patients (11 male/14 female, mean age 67·4 years) with sCARD from allopurinol: 19 DRESS (drug reaction eosinophilia and systemic symptoms) and six Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). HLA was genotyped by reverse sequence-specific oligonucleotide-polymerase chain reaction and results compared statistically with a control group of 23 allopurinol-tolerant individuals and the control population.\n\n\nRESULTS\nHLA-B*58:01 was present in 16 patients with sCADR (64%) [12 DRESS (63%), four SJS/TEN (67%)], one allopurinol-tolerant individual (4%) and 63 normal controls (1·96%), with a statistically significant difference between sCADR and the two control groups. When compared with the normal population, HLA-B*58:01 was associated with a higher risk of sCADR, both DRESS [odds ratio (OR) 85·36, 95% confidence interval (CI) 32·52-224·04] and SJS/TEN (OR 99·59, 95% CI 17·91-553·72). There was no statistically different risk between these two types of CADR.\n\n\nCONCLUSIONS\nPortuguese patients with sCADR from allopurinol, both DRESS and SJS/TEN, have a high frequency of HLA-B*58:01, with an OR similar to European patients with SJS/TEN. This study also extends this association to DRESS in Europeans. The recommendation to genotype systematically before therapy is controversial, particularly when HLA-B*58:01 prevalence in the normal population is low, as in Europe. However it could be an option for patients with other risks factors.",
"affiliations": "Clinic of Dermatology, Coimbra University Hospital, Praceta Mota Pinto, P-3000-075, Coimbra, Portugal; Department of Dermatology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.",
"authors": "Gonçalo|M|M|;Coutinho|I|I|;Teixeira|V|V|;Gameiro|A R|AR|;Brites|M M|MM|;Nunes|R|R|;Martinho|A|A|",
"chemical_list": "D006074:Gout Suppressants; D015235:HLA-B Antigens; C041533:HLA-B58 antigen; D000493:Allopurinol",
"country": "England",
"delete": false,
"doi": "10.1111/bjd.12389",
"fulltext": null,
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"issn_linking": "0007-0963",
"issue": "169(3)",
"journal": "The British journal of dermatology",
"keywords": null,
"medline_ta": "Br J Dermatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000493:Allopurinol; D005260:Female; D005838:Genotype; D006074:Gout Suppressants; D015235:HLA-B Antigens; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D011174:Portugal; D011446:Prospective Studies; D012189:Retrospective Studies; D012307:Risk Factors; D013262:Stevens-Johnson Syndrome; D055815:Young Adult",
"nlm_unique_id": "0004041",
"other_id": null,
"pages": "660-5",
"pmc": null,
"pmid": "23600531",
"pubdate": "2013-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "HLA-B*58:01 is a risk factor for allopurinol-induced DRESS and Stevens-Johnson syndrome/toxic epidermal necrolysis in a Portuguese population.",
"title_normalized": "hla b 58 01 is a risk factor for allopurinol induced dress and stevens johnson syndrome toxic epidermal necrolysis in a portuguese population"
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"activesubstancename": "ALLOPURINOL"
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{
"abstract": "To synthesize the available evidence examining the efficacy and safety of levetiracetam compared with phenytoin or fosphenytoin in benzodiazepine-refractory pediatric status epilepticus.\n\n\n\nWe searched (from inception until April 27, 2020) Ovid MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials.\n\n\n\nTwo reviewers, independently and in duplicate, screened citations and manuscripts for eligible randomized controlled trials.\n\n\n\nIndependently and in duplicate, we performed data abstraction, risk of bias assessment, and certainty assessment using Grading of Recommendations, Assessment, Development, and Evaluation. We performed meta-analyses using random-effect models or, if insufficient data, presented findings narratively.\n\n\n\nWe identified seven randomized controlled trials (n = 1,575). Pooled analysis demonstrated low certainty evidence for no difference of levetiracetam on time to seizure cessation (mean difference, -3.11 min; 95% CI, -6.67 to 0.45), early seizure cessation (relative risk, 1.09, 95% CI, 0.95-1.26), or late seizure cessation (relative risk, 1.05; 95% CI, 0.93-1.18). Adverse event outcomes were limited by low event numbers. We found low certainty evidence for less respiratory depression with levetiracetam (relative risk, 0.28; 95% CI, 0.12-0.69).\n\n\n\nThe efficacy of levetiracetam is comparable with phenytoin or fosphenytoin in children with benzodiazepine-refractory status epilepticus (low certainty evidence). Levetiracetam may cause less respiratory depression. Clinicians and guideline developers should weigh safety profiles when choosing between these agents.",
"affiliations": "Department of Pediatrics, McMaster University, Hamilton, ON, Canada.;Division of Emergency Medicine, Department of Medicine, McMaster University, Hamilton, ON, Canada.;Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.;Department of Pediatrics, McMaster University, Hamilton, ON, Canada.;Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.;Department of Pediatrics, McMaster University, Hamilton, ON, Canada.;Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.",
"authors": "Klowak|Jennifer Ann|JA|;Hewitt|Mark|M|;Catenacci|Vanessa|V|;Duffett|Mark|M|;Rochwerg|Bram|B|;Jones|Kevin|K|;Choong|Karen|K|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010672:Phenytoin; C043114:fosphenytoin",
"country": "United States",
"delete": false,
"doi": "10.1097/PCC.0000000000002703",
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"issn_linking": "1529-7535",
"issue": "22(9)",
"journal": "Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies",
"keywords": null,
"medline_ta": "Pediatr Crit Care Med",
"mesh_terms": "D000927:Anticonvulsants; D002648:Child; D006801:Humans; D000077287:Levetiracetam; D010672:Phenytoin; D013226:Status Epilepticus",
"nlm_unique_id": "100954653",
"other_id": null,
"pages": "e480-e491",
"pmc": null,
"pmid": "33710073",
"pubdate": "2021-09-01",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Levetiracetam Versus Phenytoin or Fosphenytoin for Second-Line Treatment of Pediatric Status Epilepticus: A Meta-Analysis.",
"title_normalized": "levetiracetam versus phenytoin or fosphenytoin for second line treatment of pediatric status epilepticus a meta analysis"
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"abstract": "Two cases of primary distal femur osteosarcoma with subsequent metastasis to the abdomen are presented. In both cases, the development of abdominal metastasis was quickly followed by patient decline and death. A review of the literature was performed, assessing the presentation and survival of patients with osteosarcoma metastasized to the abdomen. As illustrated by the current cases and the literature review, abdominal metastasis in osteosarcoma is often a late manifestation and terminal prognostic indicator. Nonetheless, early detection and prompt intervention of this less common site of disease metastasis may improve patient care and palliative therapy.",
"affiliations": "Department of Orthopedics, Sarcoma Service, University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah, USA.;University of Miami Miller School of Medicine, Miami, Florida, USA.;Department of Orthopedic Surgery, Sarcoma Service, Rush University, Rush Medical Center, Chicago, Illinois, USA.;Department of Orthopedics, Sarcoma Service, University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah, USA.;Department of Orthopedic Surgery, University of California, Davis, UC Davis Medical Center, Sacramento, California, USA.;Department of Orthopedics, Sarcoma Service, University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah, USA.",
"authors": "Serpico|Robert|R|;Brown|Jeffrey|J|;Blank|Alan|A|;Jones|Kevin|K|;Randall|R Lor|RL|;Groundland|John|J|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000515195",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575\nS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com\n\n10.1159/000515195\ncro-0014-0647\nCase Report\nMetastasis of Osteosarcoma to the Abdomen: A Report of Two Cases and a Review of the Literature\nSerpico Robert a*\nBrown Jeffrey b\nBlank Alan c\nJones Kevin a\nRandall R. Lor d\nGroundland John a\naDepartment of Orthopedics, Sarcoma Service, University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah, USA\nbUniversity of Miami Miller School of Medicine, Miami, Florida, USA\ncDepartment of Orthopedic Surgery, Sarcoma Service, Rush University, Rush Medical Center, Chicago, Illinois, USA\ndDepartment of Orthopedic Surgery, University of California, Davis, UC Davis Medical Center, Sacramento, California, USA\n*Robert Andrew Serpico, robert.serpico@hci.utah.edu\nJan-Apr 2021\n31 3 2021\n31 3 2021\n14 1 647658\n5 2 2021\n8 2 2021\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.\nTwo cases of primary distal femur osteosarcoma with subsequent metastasis to the abdomen are presented. In both cases, the development of abdominal metastasis was quickly followed by patient decline and death. A review of the literature was performed, assessing the presentation and survival of patients with osteosarcoma metastasized to the abdomen. As illustrated by the current cases and the literature review, abdominal metastasis in osteosarcoma is often a late manifestation and terminal prognostic indicator. Nonetheless, early detection and prompt intervention of this less common site of disease metastasis may improve patient care and palliative therapy.\n\nKeywords\n\nMetastatic osteosarcoma\nAbdominal metastasis\nNonpulmonary osteosarcoma metastasis\nDistant metastasis\n==== Body\nIntroduction\n\nThis report will add value to the literature by clearly describing the clinical course 2 patients experienced with this metastatic pattern; in addition, the paper will provide practitioners and future investigators a concise, clear, and thorough review of the literature. The result of presenting these data would be an adjustment in clinical practice, whereby medical providers who manage osteosarcoma surveillance will be more attuned to abdominal manifestations of late metastasis, and they will be more prepared for the implications of that presentation on treatments and prognosis.\n\nPrimary osteosarcoma of bone is an aggressive malignancy with a metastatic pattern that favors the lungs primarily and the bones secondarily. Nonpulmonary, nonosseous metastases of osteosarcoma have been described in the literature, but the rare nature of this metastatic pattern has precluded the systematic study of these events. As presented, abdominal metastasis of osteosarcoma is often a late manifestation and terminal prognostic indicator. Nonetheless, early detection and prompt intervention of this less common site of disease may improve patient care and palliative therapy.\n\nOsteosarcoma is the most common primary bone sarcoma, with an estimated annual incidence of 800–900 patients per year in the United States [1, 2, 3]. While the historical 5-year survival rate of localized, nonmetastatic osteosarcoma at presentation improved from 15 to 67% with the development and implementation of multiagent cytotoxic chemotherapy agents in the 1970s, this rate has plateaued despite ongoing efforts [4, 5, 6, 7]. As with all sarcomas, the cause of death in patients with osteosarcoma is related to the development of metastatic disease. In osteosarcoma, the pattern of metastasis is well established, favoring the lungs in >90% of known metastatic cases, through an assumed hematogenous route [8, 9]. Nonpulmonary sites of metastasis of osteosarcoma are also well described, with metastasis to bone being the most common nonpulmonary site, occurring in approximately 5–10% of cases [9]. Nonpulmonary, nonosseous sites of metastatic osteosarcoma are considered rare, and reports of these cases are scarce in the literature. However, autopsy studies indicate that the rates of nonpulmonary, nonosseous metastasis in osteosarcoma may be higher than realized in clinical practice [8, 10]. We present 2 cases of osteosarcoma metastasizing to the abdomen and a review of the literature.\n\nCase Presentations\n\nCase 1\n\nA 10-year-old girl with no known medical issues presented to her primary care physician in October 2016 with complaints of left thigh and knee pain. The pain had been present for 1 month and was slowly getting worse. A radiograph was taken and a lesion was noted in the distal femoral metaphysis. The radiographs of the femur were concerning for an osteosarcoma, demonstrating a lytic lesion with an osseous matrix and an incomplete periosteal reaction. Immediate referral was made to an orthopedic oncologist, who saw her the next day. Magnetic resonance imagings (MRI) of the left femur was performed; the MRI correlated with the radiographs, corroborating aggressive features, including heterogeneous signal, contrast enhancement, soft tissue extension of the mass, and peritumoral edema. The patient was taken to the operating room for an open biopsy. Intraoperative pathologic assessment on frozen sections was consistent with osteosarcoma: pleomorphic spindle cells with nuclear atypia and associated osteoid. Staging was completed with computed tomography (CT) of the chest and a whole-body bone scan. The chest CT demonstrated two 1-mm nodules of indeterminate significance and the bone scan showed uptake only in the left femur. The final pathology confirmed the diagnosis of conventional osteosarcoma. The case was presented at the multidisciplinary sarcoma tumor board, and the patient began neoadjuvant chemotherapy 2 weeks after initial presentation. The multiagent cytotoxic treatment regimen proceeded according to the Children's Oncology Group AOST 0331 protocol, including doxorubicin, cisplatin, and methotrexate. The patient completed the full neoadjuvant course and was restaged with an MRI of the femur, with and without contrast, and a CT of the chest. Restaging revealed stable disease in the distal femur, albeit with a small pathologic fracture, and resolution of the two 1-mm nodules in the lungs, without development of any new nodules. Seventeen weeks after starting chemotherapy, the patient underwent local control with wide surgical resection and endoprosthetic reconstruction with a metallic distal femur replacement. Surgical pathology revealed widely negative surgical margins with >2 cm of surrounding uninvolved tissue and 90% necrosis. Chemotherapy was resumed per the AOST 0331 guidelines 3 weeks after surgery. The patient completed the course of chemotherapy 10 months after starting treatment, tolerating treatment with minimal interruptions. End-of-therapy scans were completed, revealing no observable disease on local imaging of the femur (radiographs), imaging of the lungs (CT), nor distant, nonpulmonary sites (positron emission tomography [PET]-CT).\n\nThe patient began surveillance every 3 months per the National Comprehensive Cancer Network guidelines for osteosarcoma [11]. Six months after completion of chemotherapy, 16 months after initial presentation with knee pain, the patient presented to the medical oncologist with abdominal pain. The pain had started 2 months previously and had initially been minor, so it had been treated symptomatically at home. On CT of the chest, a portion of the abdomen could be seen, revealing fluid around the spleen and liver, as well as two enlarged pericardial lymph nodes and a 2-mm nodule in the lung. Given the abdominal pain and the CT chest findings, a contrasted CT of the abdomen and pelvis was obtained by her medical oncologist. The abdominal CT demonstrated a large left lower quadrant mass (13 × 11 × 10 cm) with mineralization, a smaller adjacent mass, multiple masses throughout the abdominal cavity, and ascites (Fig. 1). Four days later, a biopsy performed in the Interventional Radiology suite confirmed the diagnosis of metastatic osteosarcoma to the abdomen. The institution's Sarcoma Tumor Board decided that the burden of disease was too extensive for surgical intervention and considered palliative radiation and/or chemotherapy. However, the symptoms rapidly declined with suspected hemorrhage of the abdominal mass, resulting in hemodynamic instability. The patient was treated with supportive measures and entered hospice care. She died of disease 1 month after diagnosis of abdominal metastasis, 3 months after the onset of abdominal pain, 19 months after initial diagnosis of her disease.\n\nCase 2\n\nAn otherwise healthy 45-year-old man sought orthopedic evaluation in December 2014 after experiencing 2 years of worsening right thigh pain. MRI at that time displayed a large, heterogeneous, contrast-enhancing lesion involving the distal right femoral metadiaphysis extending through the cortex into the anterior compartment without skip lesions. The patient was referred to a comprehensive cancer center for evaluation by a dedicated, multidisciplinary sarcoma service. An open biopsy was then performed, providing a tissue diagnosis of fibroblastic osteosarcoma. A CT of the chest and a whole-body bone scan completed the staging. The chest CT revealed two 2-mm, indeterminate nodules in the lungs, and the bone scan demonstrated radionuclide absorption at the site of the distal femoral lesion alone. Two weeks after presentation to the cancer center, the patient began neoadjuvant chemotherapy with doxorubicin, cisplatin, and high-dose methotrexate. He completed the neoadjuvant chemotherapy regimen according to the AOST 0331 protocol and had restaging studies prior to planned local control with wide surgical resection and limb salvage. No new sites of disease were noted and the lung nodules were stable. Surgical resection and endoprosthetic reconstruction with a compressive osteo-integrative device (Compress, Biomet) occurred 4 months after initial presentation. Pathologic assessment of the resected specimen revealed high-grade fibroblastic osteosarcoma with 60% necrosis. Unfortunately, malignancy-positive surgical margins were identified, and the patient underwent revision resection 1 month later; the re-resected specimen was reported to be negative for residual tumor.\n\nOn the first postoperative surveillance scans, 3 months after local control, chest CT revealed multiple new lesions throughout the lungs bilaterally, consistent with metastatic osteosarcoma. These nodules were <6 mm in dimension and were therefore not amenable to biopsy. In light of the poor necrosis rate and the patient's poor tolerance of neoadjuvant chemotherapy but the development of pulmonary nodules, the potential benefit of continuing the AOST 0331 treatment was discussed. Alternatives were explored, including gemcitabine/doxetaxol, ifosfamide/etoposide, or pazopanib. Despite the presence of concerning pulmonary nodules, the patient opted to hold on to additional medical treatments until demonstration of further progressive disease. At this same time, the patient experienced a twisting mechanism of injury to the operative extremity, resulting in failure of the connection between the compress endoprosthesis device and the host bone. This was addressed surgically with revision of the orthopedic construct, changing the Compress device to a cemented, stemmed prosthesis.\n\nEight months later, 15 months after initial presentation, the CT demonstrated enlarging nodules, now numbering 12 lesions measuring 1–2 cm, and new interstitial edema. Concurrently, a mass was noted at the distal femur surgical site, concerning for local recurrence. Both the thigh mass and the pulmonary masses were biopsied, and were histologically consistent with osteosarcoma. The patient began pazopanib treatment, having refused more aggressive medical regimens due to prior intolerance of the AOST 0331 protocol. He tolerated pazopanib well and, after 6 months of pazopanib therapy, patient underwent LLL and LUL pulmonary wedge resections without complication. Pulmonary metastatic disease continued to progress, and the patient underwent RLL and RUL wedge resections 5 months after the left. Amputation of the lower extremity had been discussed with the patient, but was delayed until the end of medical treatment in order to assess disease response. During consultation for the above knee amputation, now 27 months after presentation, the patient complained of abdominal pain. On detailed history and physical exam, it was noted that he had been having fever for 3 days to 39°C, sharp abdominal pain, nausea, loose stools, decreased appetite, and insomnia. He was admitted to the hospital and a CT of the abdomen was obtained. It revealed peritoneal thickening, ascites, small bowel obstruction, omental stippling, hepatic lesions, and bilateral adrenal nodules (Fig. 2a, b). A biopsy of the colon at the hepatic flexure showed malignant cells within the lamina propria with similar morphology to the original osteosarcoma specimen. There was no overlying epithelial dysplasia or keratin expression within the cells, arguing against a new colorectal primary tumor. Biopsy of an omental nodule demonstrated similar histologic features, confirming metastatic osteosarcoma. Abdominal symptoms were addressed with colonic stenting and palliative paracentesis, but the patient declined precipitously and ultimately developed tachycardia, lactic acidosis, and leukocytosis, succumbing to sepsis 4 weeks after onset of abdominal pain, 28 months after initially presenting with thigh pain.\n\nLiterature Review\n\nMethods\n\nA literature review was performed to identify all papers reporting on patients with primary osteosarcoma of bone with documented metastasis to the abdomen. The PubMed database was queried for abdominal metastases under the “osteosarcoma” and “osteogenic sarcoma” medical subject heading, using the keywords “metastasis,” “extra-pulmonary,” “extra-skeletal,” “gastrointestinal,” “abdomen,” “peritoneum,” stomach,” “duodenum,” “liver,” “pancreas,” “jejunum,” “ileum,” “colon,” “omentum,” and “bowel.” Papers were included if they (1) reported on human patients with primary osteosarcoma of bone with metastatic disease documented to the abdomen, (2) had complete, discernible data from initial presentation to advent of abdominal metastatic disease, and (3) were written in English. Papers with incomplete follow-up were included for assessment of presentations but excluded from the outcome/survival calculations. The exclusion criteria consisted of nonhuman subjects, patients with primary osteosarcoma of the abdomen or soft tissues, papers with incomplete data for presentation or follow-up; indiscernible data from patients with other cancers, and papers not written in English.\n\nTwo reviewers (R.S. and J.B.) read each paper for potential inclusion or exclusion. In cases of dispute, a tiebreaker (J.G.) determined the adequacy of the paper for the purposes of this review. The data from the included papers were collated on a spreadsheet, and descriptive statistics were then calculated for demographics, presentation, and outcomes.\n\nResults\n\nThe PubMed search query returned a total of 118 papers that met consideration for review. After review, 38 papers met the inclusion criteria, reporting on a total of 40 patients (Table 1) [12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49]. Including the 2 patients from this series, 42 patients with primary osteosarcoma of the bone with subsequent abdominal metastases were available for review. Descriptive statistics of the demographics, initial presentation and, outcomes of these 42 patients are presented in Table 2.\n\nTwenty-one males and 21 females are represented in this group, with a mean age of 22.1 years (Table 2). Twenty-nine patients were 21 years or younger at the time of diagnosis (69%). The majority (78.5%) had primary osteosarcoma about the knee, with 52.4% in the distal femur and 26.2% in the proximal tibia. One patient did not receive neoadjuvant chemotherapy while the rest did. Original local control was completed with amputation in 12 cases, wide resection limb salvage alone in 27 cases, and radiation combined with limb salvage surgery in 3 cases. When presenting with metastatic disease to the abdomen, 10 patients presented with intussusception (23.8%).\n\nIncomplete data for survival after diagnosis of metastatic osteosarcoma to the abdomen were noted in 10 subjects, while 8 papers did not comment on the survival of their patients at all. One patient remained alive beyond 5 years at the time of publication (62 months) [38], while 3 others were alive at their last follow-up beyond 2 years (24, 31, and 32 months) [35, 39, 44]. Of the 24 patients with known time to death, 18 died of disease within 6 months of abdominal metastases (75%), with 7 of those succumbing to disease within the month of onset of abdominal symptoms (29.2%). A Kaplan-Meier survival curve was made with the available data, demonstrating a 5-year survival of 10.9% after the diagnosis of metastatic osteosarcoma of the bone to the abdomen (Fig. 3).\n\nDiscussion\n\nPrimary osteosarcoma of bone is an aggressive malignancy with a metastatic pattern that favors the lungs primarily and the bones secondarily. Nonpulmonary, nonosseous metastases of osteosarcoma have been described in the literature, but the rare nature of this metastatic pattern has precluded the systematic study of these events. In our search of the literature, we found 38 case reports of osteosarcoma metastasis to the abdomen, of which 36 papers presented a single patient. Autopsy reports from early osteosarcoma research would, however, suggest that nonpulmonary, nonosseous metastasis of osteosarcoma is not as rare as the literature or clinical presentation may suggest [8, 9, 10]. In their report from 1975, Jeffree et al. [8] noted that the clinically evident incidence of extrapulmonary metastasis of osteosarcoma was 33% in their series, while the rate of extrapulmonary metastasis on autopsy rose, in that same group, to 83%. While these percentages include osseous as well as nonosseous metastases, they do suggest a potential within the biology of osteosarcoma to spread outside of the lungs and bones. Indeed, the literature does not include a recent, large cohort of osteosarcoma patients in which the incidence of metastatic disease to nonpulmonary, nonosseous sites has been investigated.\n\nThe case reports and review of the literature described in this paper would suggest that the development of abdominal metastasis in osteosarcoma is a poor prognostic indicator, with very limited survivability beyond 2–3 years. Twenty-four of the 42 patients found in the literature had known time to death after diagnosis of abdominal metastases. Eighteen of these patients died within 6 months of the diagnosis, with 7 of those succumbing to disease within 1 month of abdominal symptom onset. Only 1 patient survived and was followed beyond 5 years after developing abdominal metastases, while 3 others were alive at last follow-up after 2 years (alive at 24, 31, and 32 months). Caution must be used however when interpreting these findings. There may be differences in the character of the disease when it presents as acutely symptomatic in the abdomen, as it did in our cases, and disease that may be found in the asymptomatic patient on a dedicated surveillance regimen.\n\nGiven the small numbers of patients noted in the literature and the poor prognosis of patients with metastatic osteosarcoma to the abdomen, the optimal timing and extent of sarcoma surveillance screening for nonpulmonary, nonosseous osteosarcoma metastasis is not known. Currently, the National Comprehensive Cancer Network recommends that the practitioner “consider PET-CT and/or bone scan” during restaging and posttreatment surveillance of osteosarcoma, which is in addition to imaging of the primary site and the lungs [11]. Due to our experience with 2 patients in 2 years presenting with osteosarcoma metastasizing to the abdomen, we suggest evaluating posttreatment osteosarcoma surveillance patients with an appropriate screening history and physical examination, and consideration of PET-CT, if warranted by that history or physical examination.\n\nConclusion\n\nWhile the true incidence of nonpulmonary, nonosseous metastasis of osteosarcoma is not known, the scarcity of reports in the literature suggests that this is a rare event. As presented, abdominal metastasis of osteosarcoma is often a late manifestation and terminal prognostic indicator. Nonetheless, early detection and prompt intervention of this less common site of disease may improve patient care and palliative therapy.\n\nStatement of Ethics\n\nInformed written consent was obtained from the patients or their guardians for the preparation and presentation of these case reports, including associated pathology and clinical imaging.\n\nConflict of Interest Statement\n\nThere were no professional nor financial conflicts of interest between any of the authors, patients, staff involved in the production of the manuscript, nor the medical care of the patients in this case report.\n\nFunding Sources\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. No funding was provided in the development or completion of this work. None of the authors received payments or services, either directly or indirectly, from a third party in support of any aspect of this work. None of the authors has had any relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work.\n\nAuthor Contributions\n\nR. Serpico was involved in the conceptualization, methodology, validation, data curation, and writing of this paper. J. Brown was involved in the methodology, validation, formal analysis, data curation, and writing of this paper. A. Blank, K. Jones, and R.L. Randall were involved in conceptualization, methodology, validation, and writing of this paper. J. Groundland was involved in the conceptualization, methodology, validation, data curation, and writing of this paper.\n\nAcknowledgments\n\nWe would like to acknowledge Mazdak A. Khalighi, MD for assistance with assessment and description of the pathology slides, and Sarah Shaw, BS for work on data collection of the case reports and early collation of data. Finally, we would like to acknowledge and thank the patients and their families, who graciously allowed us to present their cases so that the sarcoma community may better understand this devastating disease and improve our ability to care for patients afflicted with this malignancy.\n\nFig. 1 Coronal (a) and axial (b) CT of the abdomen in a 10-year-old girl with a primary osteosarcoma of the distal femur. The abdominal mass presented 6 months after completion of chemotherapy. Subsequent biopsy confirmed the diagnosis of osteosarcoma metastasis to the peritoneal cavity. CT, computed tomography.\n\nFig. 2 a, b Coronal (a) and axial (b) CT of the abdomen and pelvis in a 45-year-old man with metastatic osteosarcoma to the lungs, abdomen, and retroperitoneal space. Note the large volume of ascites, prominent enhancement of the peritoneal surfaces, and omental caking. Nodular lesions could be seen in the liver, adrenal gland, and pericolonic gutters. c The patient's thigh resection specimen demonstrated a high-grade malignant osteoid-producing neoplasm, consistent with conventional osteosarcoma with both fibroblastic and osteoblastic features. H&E stain, ×20. d A biopsy of the colon at the hepatic flexure showed malignant cells within the lamina propria with similar morphology to the original specimen. H&E stain, ×20. There was no overlapping epithelial dysplasia or keratin expression within the cells, arguing against a new colorectal primary. Biopsy of an omental nodule showed similar histologic features. CT, computed tomography.\n\nFig. 3 Kaplan-Meier curve of survival after diagnosis of osteosarcoma metastatic to the abdomen, from the review of the literature and current cases.\n\nTable 1 Papers that met the inclusion criteria for reports of primary osteosarcoma of bone with metastases to the abdomen\n\nNumber of papers1\t\t38\t\nYear of publication\t\t1963–2017\t\nTotal number of patients\t\t40\t\nPatients per paper\tn = 1\t36\t\n\tn = 2\t2\t\n1 Does not include the current publication.\n\nTable 2 Demographics and outcomes of patients with primary osteosarcoma of bone with metastases to the abdomen, as reported in the medical literature and the current series\n\n\t\tAll patients\tPatients with metastatic disease on diagnosis\tPatients without metastatic disease on diagnosis\t\nNumber of patients\t\t42\t6\t36\t\n\t\nSex\tMale\t21\t2\t19\t\n\t\n\tFemale\t21\t4\t17\t\n\t\nAge at diagnosis (years)\tAverage\t22\t\t\t\n\t\n\tRange\t8–64\t\t\t\n\t\nSite of primary disease\tHumerus\t2\t0\t2\t\n\t\n\tPelvis\t1\t0\t1\t\n\t\n\tProximal femur\t1\t0\t1\t\n\t\n\tDistal femur\t22\t5\t17\t\n\t\n\tProximal tibia\t11\t0\t11\t\n\t\n\tDistal tibia\t0\t0\t0\t\n\t\n\tOther\t5\t1\t4\t\n\t\nSite of first documented metastasis1\tLung\t35\t5\t30\t\n\t\n\tBone\t0\t0\t0\t\n\t\n\tPeritoneum\t9\t1\t8\t\n\t\nNumber of patients with metastasis to peritoneum only\t\t7\t1\t6\t\n\t\nTime to first metastasis after initial presentation (months)\tAverage Range\t\tNA\nNA\t29.7\n6–108\t\n\t\nTime from initial diagnosis to abdominal metastasis (months)\tAverage Range\t45.1\n0–132\t29.20–48\t47.7\n14–132\t\n\t\nTime from diagnosis of abdominal metastasis to death (months)2\tAverage Range\t7.3\n1–42\t6.53–14\t7.5\n1–42\t\n\t\nTwo-year survival after diagnosis of abdominal metastasis\t\t27.2%\t\t\t\n\t\nFive-year survival after diagnosis of abdominal metastasis\t\t10.9%\t\t\t\n1 Numbers add up to 44 due to 2 patients having concurrent pulmonary and abdominal metastatic disease on follow-up.\n\n2 Time from diagnosis of abdominal disease to death excludes papers that do not provide a time to death. Four papers had a total of 4 patients who survived >2 years after abdominal metastasis (alive at 24, 31, 32, and 62 months), but these reports did not follow until time of death and are excluded from this assessment. However, all censured data are reflected in Kaplan-Meier curve calculations and the 2- and 5-year survival rates.\n==== Refs\nReferences\n\n1 Mirabello L Troisi RJ Savage SA Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program Cancer 2009 115 (7) 1531 43 19197972\n2 Damron TA Ward WG Stewart A Osteosarcoma, chondrosarcoma, and Ewing's sarcoma: National Cancer Data Base Report Clin Orthop Relat Res 2007 459 40 7 17414166\n3 Ottaviani G Jaffe N The epidemiology of osteosarcoma Cancer Treat Res 2009 152 3 13 20213383\n4 Jaffe N The potential for an improved prognosis with chemotherapy in osteogenic sarcoma Clin Orthop Relat Res 1975 113 111 8 1081438\n5 Price CH Zhuber K Salzer-Kuntschik M Salzer M Willert HG Immenkamp M Osteosarcoma in children. A study of 125 cases J Bone Joint Surg Br 1975 57 (3) 341 5 1057546\n6 Sinks LF Mindell ER Chemotherapy of osteosarcoma Clin Orthop Relat Res 1975 111 101 4\n7 Smeland S Bielack SS Whelan J Bernstein M Hogendoorn P Krailo MD Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort Eur J Cancer 2019 109 36 50 30685685\n8 Jeffree GM Price CH Sissons HA The metastatic patterns of osteosarcoma Br J Cancer 1975 32 (1) 87 107 1058038\n9 Bacci G Avella M Picci P Briccoli A Dallari D Campanacci M Metastatic patterns in osteosarcoma Tumori 1988 74 (4) 421 7 3055577\n10 Uribe-Botero G Russell WO Sutow WW Martin RG Primary osteosarcoma of bone. Clinicopathologic investigation of 243 cases, with necropsy studies in 54 Am J Clin Pathol 1977 67 (5) 427 35 266360\n11 National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology Bone Cancer 2017 2 (2017) 1 88\n12 Aarvold A Bann S Giblin V Wotherspoon A Mudan SS Osteosarcoma metastasising to the duodenum and pancreas J Bone Joint Surg Br 2007 89 (4) 542 4 17463128\n13 Abbo O Pinnagoda K Micol LA Beck-Popovic M Joseph JM Osteosarcoma metastasis causing ileo-ileal intussusception World J Surg Oncol 2013 11 (1) 188 23938137\n14 Avcu S Akdeniz H Arslan H Toprak N Unal O A case of primary vertebral osteosarcoma metastasizing to pancreas JOP 2009 10 (4) 438 40 19581752\n15 Badiu DC A rare cause of bowel obstruction: peritoneal metastases in osteosarcoma at the tibia in a young female patient with brain metastasis Case Report. Chirurgia (Bucur) 2016 111 (3) 274 8 27452942\n16 Chan HH Chan JK Ng WM Shek TW Chan FL Lace-like enhancement pattern of osteosarcoma of rib and liver metastasis in CT scans Australas Radiol 2001 45 (3) 305 8 11531753\n17 Chandramohan K Somanathan T Kusumakumary P Balagopal PG Pandey M Metastatic osteosarcoma causing intussusception J Pediatr Surg 2003 38 (10) E1 3\n18 Costa A Fustaino L Mosca F Metastatic osteosarcoma involving the colon and ileum Gastrointest Endosc 2001 54 (1) 75 11427845\n19 Costa CM de Camargo B Bagietto R Alcantra PS Chojniak R Sredni ST Abdominal recurrence of osteogenic sarcoma: a case report J Pediatr Hematol Oncol 1998 20 (3) 271 3 9628443\n20 El Ajmi M Ksantini R Chebbi F Makni A Rebai W Daghfous A Abdominal metastasis of a parosteal osteosarcoma of the femur: an unusual cause of large-bowel obstruction Acta Chir Belg 2009 109 (5) 633 4 19994810\n21 Ganguli SN Hamilton P Hanna S Morava-Protzner I Small bowel intussusception secondary to osteogenic sarcoma metastasis: case report Can Assoc Radiol J 1999 50 (3) 170 2 10405649\n22 Glass RJ Eftekhari F Kleinerman ES Jaffe N Nachman J Osteosarcoma metastatic to the pancreas in young patients Clin Radiol 1996 51 (4) 293 4 8617044\n23 Goldberg SL Fink V Goldsmith B Metastatic osteogenic sarcoma of the ileum. Intussusception and intestinal obstruction Arch Surg 1963 86 233 4 13948689\n24 Goyal S Julka PK Recurrent osteosarcoma with calcified liver metastases: uncommon development of a common disease J Cancer Res Ther 2017 13 (1) 139 41 28508848\n25 Hirota T Konno K Fujimoto T Ohta H Kato S Hara K Unusual late extrapulmonary metastasis in osteosarcoma Pediatr Hematol Oncol 1999 16 (6) 545 9 10599095\n26 Horiuchi A Watanabe Y Yoshida M Yamamoto Y Kawachi K Metastatic osteosarcoma in the jejunum with intussusception: report of a case Surg Today 2007 37 (5) 440 2 17468831\n27 Horiuchi K Susa M Mukai M Nishimoto K Suzuki Y Nakayama R Osteosarcoma with metastasis to the stomach J Orthop Sci 2010 15 (2) 265 8 20358343\n28 Hung GY Chiou T Hsieh YL Yang MH Chen WY Intestinal metastasis causing intussusception in a patient treated for osteosarcoma with history of multiple metastases: a case report Jpn J Clin Oncol 2001 31 (4) 165 7 11386464\n29 Jin P Wang W Su H Sheng JQ Osteosarcoma metastasizing to pancreas confirmed by endoscopic ultrasound-guided fine-needle aspiration Endoscopy 2014 46 (Suppl 1 UCTN) E109 10 24676813\n30 Karacalioglu O Ilgan S Kuzhan O Emer O Ozguven M Disseminated metastatic disease of osteosarcoma of the femur in the abdomen: unusual metastatic pattern on Tc-99m MDP bone scan Ann Nucl Med 2006 20 (6) 437 40 16922473\n31 Khan AS Crowe DR Trevino JM Eloubeidi MA Multiple metastases to the pancreas from primary maxillary osteosarcoma: diagnosis with EUS-guided FNA Gastrointest Endosc 2011 73 (6) 1320 2 21074764\n32 Kubo T Furuta T Johan MP Yoshizuka M Ochi M Adachi N Long-term survival after sporadic and delayed metastases of conventional osteosarcoma: a case report Medicine (Baltimore) 2017 96 (18) e6824 28471986\n33 Lasithiotakis K Petrakis I Georgiadis G Paraskakis S Chalkiadakis G Chrysos E Pancreatic resection for metastasis to the pancreas from colon and lung cancer, and osteosarcoma JOP 2010 11 (6) 593 6 21068492\n34 Lin JT Yen CC Wang WS Chiou TJ Liu JH Wu HT Case report: Unusual peritoneal spreading by metastatic osteosarcoma of the tibia Br J Radiol 2003 76 (905) 337 8 12763950\n35 Moses J Gibson N Plesec T Plautz G Kay M Soldes O Metastatic osteosarcoma to the stomach and ascending colon in a pediatric patient causing gastrointestinal hemorrhage J Pediatr Surg 2013 48 (4) e1 3\n36 Mozes M Mozes G Greiff M Sacks M Metastatic osteogenic sarcoma of small intestine with intussusception Isr J Med Sci 1988 24 (8) 426 8 3165973\n37 Onoro G Unusual sites of extrapulmonary metastases of osteosarcoma after several lines of treatment Pediatr Hematol Oncol 2011 28 (7) 604 8 21875323\n38 Overberg-Schmidt US Baumgarten E Bassir C Becker M Unger M Henze G The stomach and pulmonary interlobular space as unusual sites of osteosarcoma Pediatr Hematol Oncol 1999 16 (1) 61 6 9932275\n39 Panizo-Santos A Sola I Lozano M de Alava E Pardo J Metastatic osteosarcoma presenting as a small-bowel polyp. A case report and review of the literature Arch Pathol Lab Med 2000 124 (11) 1682 4 11079025\n40 Pirayesh E Rakhshan A Amoui M Rakhsha A Poor AS Assadi M Metastasis of femoral osteosarcoma to the abdominal wall detected on 99m Tc-MDP skeletal scintigraphy Ann Nucl Med 2013 27 (5) 478 80 23456178\n41 Rejin K Aykan OA Omer G Ensar Y Bilge B Inci A Intra-abdominal metastasis in osteosarcoma: survey and literature review Pediatr Hematol Oncol 2011 28 (7) 609 15 21875322\n42 Strauss SJ McTiernan A Whelan JS Late relapse of osteosarcoma: implications for follow-up and screening Pediatr Blood Cancer 2004 43 (6) 692 7 15390283\n43 Strong VE Shalkow J Antonescu CR Meyers P La Quaglia MP Osteosarcoma with delayed metastasis to the stomach J Pediatr Surg 2007 42 (4) 737 9 17448779\n44 Takaue Y Slopis JM Anzai T Robertson R Jaffe N Successful treatment of pulmonary and abdominal metastatic osteosarcoma Med Pediatr Oncol 1985 13 (3) 126 8 3857430\n45 Webster VJ Arons I Intussusception secondary to osteogenic sarcoma metastasis Br J Clin Pract 1987 41 (2) 628 9 3479186\n46 Westra A Schrijvers D Somville J Van Schil P Hubens G Van Oosterom A Late peritoneal metastasis in a patient with osteosarcoma Ann Oncol 1998 9 (8) 907 11 9789615\n47 Wootton-Gorges SL Stein-Wexler R West DC Metastatic osteosarcoma to the small bowel with resultant intussusception: a case report and review of the literature Pediatr Radiol 2003 33 (12) 890 2 13680015\n48 Yeh SN Lu MY Peritoneal metastasis in osteosarcoma: report of one case Acta Paediatr Taiwan 2005 46 (4) 230 4 16381339\n49 Chan RS Kumar G Vijayananthan AA Rare occurrence of bilateral breast and peritoneal metastases from osteogenic sarcoma Singapore Med J 2013 54 (3) e68 71 23546040\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "14(1)",
"journal": "Case reports in oncology",
"keywords": "Abdominal metastasis; Distant metastasis; Metastatic osteosarcoma; Nonpulmonary osteosarcoma metastasis",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "647-658",
"pmc": null,
"pmid": "33976648",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "10599095;3857430;23456178;21875323;23583157;3479186;27452942;11531753;10405649;21074764;11427845;23938137;24676813;20358343;9789615;13948689;19581752;14577092;28471986;19197972;16381339;8617044;13680015;3055577;3165973;21068492;17414166;19994810;9932275;15390283;17463128;266360;12763950;11386464;28508848;30685685;21875322;16922473;23546040;9628443;11079025;1057462;1081438;17468831;17448779;1057546;1058038;20213383",
"title": "Metastasis of Osteosarcoma to the Abdomen: A Report of Two Cases and a Review of the Literature.",
"title_normalized": "metastasis of osteosarcoma to the abdomen a report of two cases and a review of the literature"
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"companynumb": "US-PFIZER INC-202101326029",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "3... |
{
"abstract": "OBJECTIVE\nThe case of a patient who experienced bone marrow edema and pain in both feet and a compression fracture of one heel bone after several months of everolimus use is reported.\n\n\nCONCLUSIONS\nA 62-year-old woman with a grade 1 metastatic pancreatic neuroendocrine tumor (pNET) developed bilateral lower extremity edema and pain approximately 4 months after initiation of treatment with everolimus, an inhibitor of mammalian (or mechanistic) target of rapamycin (mTOR). The patient was referred for orthopedic evaluation, which resulted in diagnosis of bone marrow edema and a compression fracture of the calcaneus on the basis of magnetic resonance imaging results. The case was discussed with a clinical pharmacist, and after an in-depth analysis to rule out potential alternative causes for the patient's edema and pain, everolimus was discontinued. The patient had a full recovery from the presenting symptoms within 10 days of discontinuation of everolimus. Analysis of this case using the adverse drug reaction probability scale of Naranjo et al. yielded a score of 6, indicating a probable adverse reaction to everolimus. A hypothesized mechanism for everolimus-induced bone pain includes marrow edema and hyperemia from reduced intraosseous perfusion, which have been previously reported in association with mTOR inhibitor use.\n\n\nCONCLUSIONS\nBone marrow edema developed and a fracture occurred in a patient taking everolimus for a metastatic pNET, with complete resolution of lower extremity swelling and pain within 2 weeks of everolimus discontinuation.",
"affiliations": "University of Michigan Comprehensive Cancer Center, Ann Arbor, MI rlebovic@med.umich.edu.;University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.;Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.;Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.",
"authors": "McDevitt|Rachel Lebovic|RL|;Quinlan|Chelsey|C|;Hersberger|Katie|K|;Sahai|Vaibhav|V|",
"chemical_list": "D000970:Antineoplastic Agents; D000068338:Everolimus",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp170269",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "75(1)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": "adverse drug reaction; bone marrow edema; everolimus; toxicity",
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000970:Antineoplastic Agents; D001853:Bone Marrow; D001855:Bone Marrow Diseases; D002111:Calcaneus; D004487:Edema; D000068338:Everolimus; D005260:Female; D050815:Fractures, Compression; D006801:Humans; D008875:Middle Aged; D018358:Neuroendocrine Tumors; D010146:Pain; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "e23-e27",
"pmc": null,
"pmid": "29273609",
"pubdate": "2018-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bone marrow edema associated with everolimus.",
"title_normalized": "bone marrow edema associated with everolimus"
} | [
{
"companynumb": "PHHY2018US001969",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DULOXETINE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "A 91-year-old woman presented to the emergency department by ambulance after her family found her minimally responsive. Telemetry monitoring demonstrated episodes of non-sustained polymorphic ventricular tachycardia (PMVT) associated with significantly prolonged repolarization. Her medical history revealed that she was taking quinine or a derivative in three different forms: hydroxychloroquine, quinine sulfate (for leg cramps), and her gin mixed with tonic water (containing quinine). The present case is illustrative of classic etiologies and findings of acquired long QT syndrome, and serves as an important reminder for providers to take a complete medication history, including use of duplicative and alternative medicines and type of alcohol consumption.",
"affiliations": "Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA. etryon@salud.unm.edu.;Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.;San Juan Regional Medical Center, Farmington, NM, USA.;San Juan Regional Medical Center, Farmington, NM, USA.",
"authors": "Sheehan|Elyce T|ET|;Frizzell|Jarrod D|JD|;Gabaldon|Jude|J|;West|Michael B|MB|",
"chemical_list": "D018501:Antirheumatic Agents; D009125:Muscle Relaxants, Central; D006886:Hydroxychloroquine; D011803:Quinine",
"country": "United States",
"delete": false,
"doi": "10.1007/s11606-016-3738-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0884-8734",
"issue": "31(10)",
"journal": "Journal of general internal medicine",
"keywords": "cardiac arrhythmia; gin and tonic; prolonged QT; quinine",
"medline_ta": "J Gen Intern Med",
"mesh_terms": "D000369:Aged, 80 and over; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D002253:Carbonated Beverages; D004562:Electrocardiography; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D006886:Hydroxychloroquine; D008133:Long QT Syndrome; D009120:Muscle Cramp; D009125:Muscle Relaxants, Central; D011803:Quinine",
"nlm_unique_id": "8605834",
"other_id": null,
"pages": "1254-7",
"pmc": null,
"pmid": "27173501",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10335049;17646028;17766323;24923384;12861106;7665718;14999113;25842375;17540188;14765563;12208804;23619423",
"title": "Quinine and the ABCs of Long QT: A Patient's Misfortune with Arthritis, (Alcoholic) Beverages, and Cramps.",
"title_normalized": "quinine and the abcs of long qt a patient s misfortune with arthritis alcoholic beverages and cramps"
} | [
{
"companynumb": "US-CONCORDIA PHARMACEUTICALS INC.-GSH201610-005064",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "QUININE SULFATE"
},
... |
{
"abstract": "A nurse was accused of attempting to murder her anesthesiologist husband on two occasions by administering to him a neuromuscular blocking agent. In both episodes, urine specimens were obtained from the victim shortly after the suspected assaults. The samples were initially tested fluorometrically using Rose Bengal dye as a pairing agent. Both were presumptively positive for pancuronium. Confirmation of these results was achieved by pairing the drug with potassium iodide, extracting the complex, and submitting the extract to thin-layer chromatography (TLC) cleanup, elution at the appropriate retardation factor (Rf), and, finally, gas chromatography/mass spectrometry (GC/MS) analysis in the selected-ion monitoring mode. The two quaternary amines of pancuronium appear to undergo pyrolytic N-demethylation in the injection port to yield an entity amenable to capillary column gas chromatography. The mass spectrum of the compound consists of a base peak of m/z 322, with additional fragments of 292, 323, 338, and 397 m/z, each of which was monitored. The confirmed positive findings were instrumental in adjudicating the case.",
"affiliations": "Division of Medical-Legal Investigations and Forensic Sciences, County of Suffolk, Hauppauge, NY.",
"authors": "Briglia|E J|EJ|;Davis|P L|PL|;Katz|M|M|;Dal Cortivo|L A|LA|",
"chemical_list": "D010197:Pancuronium",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1198",
"issue": "35(6)",
"journal": "Journal of forensic sciences",
"keywords": null,
"medline_ta": "J Forensic Sci",
"mesh_terms": "D008401:Gas Chromatography-Mass Spectrometry; D006708:Homicide; D006801:Humans; D008297:Male; D010197:Pancuronium",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "1468-76",
"pmc": null,
"pmid": "2262781",
"pubdate": "1990-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Attempted murder with pancuronium.",
"title_normalized": "attempted murder with pancuronium"
} | [
{
"companynumb": "US-PFIZER INC-2021102950",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PANCURONIUM BROMIDE"
},
"drugadditional": "3",... |
{
"abstract": "The high efficacy and tolerability of biological therapies such as anti-tumour necrosis factor-alpha (TNF-α) have transformed outcomes for many inflammatory conditions. Conversely, a wide range of paradoxical reactions, including pulmonary, renal and ocular sarcoidosis secondary to TNF-α blocking agents in patients with severe psoriasis, has been reported. Sarcoid-like granulomatosis is one of these reactions, which may affect the pulmonary and cutaneous systems. Renal and ocular sarcoidosis, however, are less frequent and have unknown consequences. In this report, we present two cases of anti-TNF-α-induced sarcoidosis involving the pulmonary and renal systems.",
"affiliations": "Department of Dermatology, Barts Health NHS Trust, London, UK.;Centre for Postgraduate Medicine and Public Health, University of Hertfordshire, Hertfordshire, UK.",
"authors": "Bewley|A P|AP|https://orcid.org/0000-0003-1195-0290;Maleki|S|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/ced.14751",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0307-6938",
"issue": "46(8)",
"journal": "Clinical and experimental dermatology",
"keywords": null,
"medline_ta": "Clin Exp Dermatol",
"mesh_terms": null,
"nlm_unique_id": "7606847",
"other_id": null,
"pages": "1548-1550",
"pmc": null,
"pmid": "34021925",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Systemic sarcoidosis reactions as a result of tumour necrosis factor-alpha treatment for patients with psoriasis.",
"title_normalized": "systemic sarcoidosis reactions as a result of tumour necrosis factor alpha treatment for patients with psoriasis"
} | [
{
"companynumb": "GB-ADVANZ PHARMA-202203001730",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "4",
... |
{
"abstract": "Ocular toxicity, although uncommon, can occur with many chemotherapeutic agents. Platinum compounds have been documented to produce a variety of ocular side effects, and reports have been made of ocular toxicity with oxaliplatin. This article reports on four patients who experienced ocular symptoms while receiving oxaliplatin. The symptoms included tunnel vision and visual loss with postural changes. One patient had objective findings that included papilledema. All of the changes were reversible. Oxaliplatin will continue to be used widely, so clinicians treating patients with it must be alert for unusual toxicities such as those described in this article.",
"affiliations": "St. Vincent's Comprehensive Cancer Center, New York, NY, USA. dodea@aptiumoncology.com",
"authors": "O'Dea|Denise|D|;Handy|Catherine M|CM|;Wexler|Ann|A|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"country": "United States",
"delete": false,
"doi": "10.1188/06.CJON.227-229",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1092-1095",
"issue": "10(2)",
"journal": "Clinical journal of oncology nursing",
"keywords": null,
"medline_ta": "Clin J Oncol Nurs",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D014786:Vision Disorders",
"nlm_unique_id": "9705336",
"other_id": null,
"pages": "227-9",
"pmc": null,
"pmid": "16708705",
"pubdate": "2006-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ocular changes with oxaliplatin.",
"title_normalized": "ocular changes with oxaliplatin"
} | [
{
"companynumb": "US-PFIZER INC-2019310224",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "1",
... |
{
"abstract": "Secondary acute myeloid leukaemia complicating the natural disease course of pre-existing Philadelphia chromosome-negative myeloproliferative neoplasms (PN-MPN) is well documented and associated with treatment challenges and significant morbidity. The incidence of a T-cell malignancy developing in patients with pre-existing PN-MPN is uncommon, with one case documented in the literature. We present two cases of angioimmunoblastic T-cell lymphoma (AITL) and one case of T-cell acute lymphoblastic leukaemia (T-ALL) that developed in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), respectively. All malignancies were advanced at diagnosis and exhibited disease progression, regardless of the mutational status of the underlying ET/PMF, presence of cytogenetic abnormalities, type of T-cell neoplasm or systemic chemotherapy utilised. The median time to diagnosis of AITL or T-ALL from the onset of MPN was 4.5 years (range: 6 months-10 years). This single institutional case series demonstrates the possibility of an association between T-cell neoplasms and PN-MPNs.",
"affiliations": "Department of Internal Medicine, Houston Methodist Hospital, 6550 Fannin, Smith Tower, Ste 1101, Houston, TX 77030, USA.;Houston Methodist Cancer Center, 6445 Main Street, Outpatient Center, 24th Floor, Houston, TX 77030, USA.;Houston Methodist Hospital, Department of Pathology and Genomic Medicine, 6550 Fannin St, Houston, TX 77030, USA.;Houston Methodist Cancer Center, 6445 Main Street, Outpatient Center, 24th Floor, Houston, TX 77030, USA.;Houston Methodist Cancer Center, 6445 Main Street, Outpatient Center, 24th Floor, Houston, TX 77030, USA.;Houston Methodist Cancer Center, 6445 Main Street, Outpatient Center, 24th Floor, Houston, TX 77030, USA.",
"authors": "Burns|Ethan A|EA|;Anand|Kartik|K|;Chung|Betty|B|;Shah|Shilpan|S|;Randhawa|Jasleen K|JK|;Pingali|Sai Ravi|SR|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3332/ecancer.2020.1011",
"fulltext": "\n==== Front\nEcancermedicalscience\nEcancermedicalscience\necancermedicalscience\necancermedicalscience\n1754-6605 Cancer Intelligence \n\n10.3332/ecancer.2020.1011\ncan-14-1011\nCase Report\nThe development of T-cell malignancies in patients with pre-existing myeloproliferative neoplasms: a report of three cases\nBurns Ethan A 1* Anand Kartik 2* Chung Betty 3 Shah Shilpan 2 Randhawa Jasleen K 2 Pingali Sai Ravi 2 \n1 Department of Internal Medicine, Houston Methodist Hospital, 6550 Fannin, Smith Tower, Ste 1101, Houston, TX 77030, USA\n\n2 Houston Methodist Cancer Center, 6445 Main Street, Outpatient Center, 24th Floor, Houston, TX 77030, USA\n\n3 Houston Methodist Hospital, Department of Pathology and Genomic Medicine, 6550 Fannin St, Houston, TX 77030, USA\n\n* Equal contribution.\nCorrespondence to: Ethan A Burns Eaburns@houstonmethodist.org\n2020 \n17 2 2020 \n14 101112 9 2019 © the authors; licensee ecancermedicalscience.2020This 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.Secondary acute myeloid leukaemia complicating the natural disease course of pre-existing Philadelphia chromosome-negative myeloproliferative neoplasms (PN-MPN) is well documented and associated with treatment challenges and significant morbidity. The incidence of a T-cell malignancy developing in patients with pre-existing PN-MPN is uncommon, with one case documented in the literature. We present two cases of angioimmunoblastic T-cell lymphoma (AITL) and one case of T-cell acute lymphoblastic leukaemia (T-ALL) that developed in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), respectively. All malignancies were advanced at diagnosis and exhibited disease progression, regardless of the mutational status of the underlying ET/PMF, presence of cytogenetic abnormalities, type of T-cell neoplasm or systemic chemotherapy utilised. The median time to diagnosis of AITL or T-ALL from the onset of MPN was 4.5 years (range: 6 months–10 years). This single institutional case series demonstrates the possibility of an association between T-cell neoplasms and PN-MPNs.\n\nessential thrombocythemiaprimary myelofibrosispolycythemia veraPhiladelphia negative myeloproliferative neoplasmangioimmunoblastic T-cell lymphomaT-cell acute lymphoblastic leukaemia\n==== Body\nIntroduction\nMyeloproliferative neoplasms (MPNs) are chronic, clonal diseases defined by the overproduction of fully differentiated cells of haematopoietic origin. In 2016, the World Health Organization Revised Classification System for Haematopoietic Tumours recognised a subcategory of Philadelphia chromosome (PN)-MPN, including polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) and prefibrotic PMF [1, 2]. PN-MPNs are phenotypically driven by somatic mutations which culminate in the persistent downstream hyperactivation of the Janus Kinase (JAK)-STAT (signal transducer and activator of transcription) signal transduction pathway. The most common mutations include JAK2 V617F, calreticulin (CALR) or the thrombopoietin receptor (MPL) [3]. Wild type (triple-negative) PMF or ET is not uncommon.\n\nWhile there are similarities in the clinical, laboratory, morphologic and mutational manifestations of PN-MPNs, variations in survival and progression to leukaemic transformation necessitate an accurate diagnosis [1, 4]. The risk for leukaemic transformation in the decade following the diagnosis of a PN-MPN is 1.3% in ET [5], 2.3% in PV [6] and 10%–20% in PMF [7–9]. The lifetime cumulative incidence of a leukaemic transformation from MPN is approximately 3.8% for ET, 6.8% for PV and 14.2% for PMF [10]. While the most common haematologic malignancies following leukaemic transformation are of myeloid origin, lymphoid malignancies are seldom encountered [4]. The following three cases describe the development of T-cell neoplasms in patients with PN-MPN, a rarely reported occurrence.\n\nCases\nPatient 1\nA 78-year-old Caucasian woman with a history of pulmonary embolism and triple-negative ET diagnosed 6 months prior and treated with hydroxyurea presented to the hospital with shortness of breath and constipation.\n\nShe reported ‘B’ symptoms first noticed 1 month prior to admission. Physical examination was significant for axillary lymphadenopathy (LAD). Significant laboratory findings included hypercalcaemia of 13.6 mg/dL, acute kidney injury with admission creatinine of 2.03 mg/dL and pancytopenia. Computed Tomography (CT) showed splenomegaly (17 cm), diffuse lymphadenopathy and Positron Emission Tomography (PET) demonstrated increased uptake in the splenic and porta hepatis area. Her bone marrow biopsy found atypical lymphoid aggregates that contained a mixed population of T-cells positive for CD3, CD5 and PD1, and B-cells positive for CD20 and variably positive for PAX-5 and BCL6 (Figure 1; Table 1). Epstein Barr Virus encoded small ribonucleic acid (EBER) was highlighted in scattered, predominantly small lymphocytes. Karyotype analysis demonstrated multiple cytogenetic anomalies, with karyotype showing 47,XX,add(2)(p2),add(10)(p11.2),+add(20)(p12)[cp4]/46,XX [16] (Table 1). Excisional axillary lymph node biopsy had immunostaining positive for CD2, CD3, CD5, CD7 and CD4 PD-1, and negative for CD30 in the lesional T-cells, consistent with AITL (Figure 2; Table 1).\n\nShe received three cycles of Cyclophosphamide, Doxorubicin Hydrochloride, Etoposide, Vincristine and Prednisone (CHEOP), but repeat PET/CT indicated disease progression in the spleen and increased uptake in her cervical, supraclavicular, axillary, hilar, mediastinal, inguinal and iliac lymph nodes. She was initiated on salvage Romidepsin, Ifosfamide, Carboplatin, Etoposide (R-ICE) and completed cycle 1, 5 months following the diagnosis of AITL and 11 months following the diagnosis of ET.\n\nPatient 2\nAn 84-year-old Caucasian man with a history of congestive heart failure and ET (JAK2 V617F mutation) diagnosed 6 years prior and treated with hydroxyurea presented for evaluation of peripheral blood eosinophilia. He noted weight loss and fatigue but denied night sweats or fevers. Physical examination was notable for palpable cervical, axillary and inguinal LAD, and a diffuse macular rash. Initial laboratory findings were notable for a peripheral eosinophilia of 17.7%, peripheral monocytosis of 19.4% and lymphopenia of 12.4%. CT of his chest, abdomen and pelvis noted diffuse LAD and splenomegaly. His bone marrow biopsy showed hypercellular marrow (50%) without evidence of malignancy. Corresponding flow cytometry indicated an increased CD4:CD8 ratio of 10:1 without aberrant T-cell antigen expression or a clonal B-cell population. His axillary lymph node biopsy with immunostaining was positive for CD2, CD3, CD4, CD5, CD7, CD10 (subsets), BCL-6 and PD-1 in the lesional T-cells, consistent with AITL (Figure 3; Table 1). EBV was negative by EBER. Cytogenetic analysis demonstrated a normal male karyotype (46, XY).\n\nHis PET/CT showed increased uptake in the right cervical, infraparotid and axillary lymph nodes, right upper lobe of the lung, and spleen. He was started on Cyclophosphamide, Etoposide, Vincristine and Prednisone (CEOP); adriamycin hydrochloride was held due to his heart failure. After three cycles, repeat PET/CT showed disease progression in all involved sites. The patient ultimately requested comfort/hospice care, 4 months after the diagnosis of AITL and 6 years after the diagnosis of ET.\n\nPatient 3\nA 62-year-old African American man with a history of PMF (JAK2 V617F mutation) presented 3 years after initial diagnosis with a 30-pound weight loss, night sweats and fatigue. Physical examination revealed bilateral posterior cervical LAD. The patient had a bone marrow biopsy that indicated fibrosis with 40% cellularity, but no evidence of malignancy. Cytogenetic analysis showed 46,XY,i(17)(q10) [9]/46,idem,del(20)(q11.2q13.1) [3]. His excisional cervical lymph node biopsy immunophenotype stained positive for Tdt, CD1a, CD2, CD7, cytoplasmic CD3, CD33 and CD34, and was negative for surface CD3 and MPO in the lesional T-cells, compatible with the diagnosis of T-ALL (Figure 4; Table 1). His PET/CT showed increased uptake in the left cervical and axillary lymph nodes. He was initiated on Cyclophosphamide, Vincristine, Doxorubicin and Dexamethasone (HyperCVAD), and, after six cycles, was in complete remission.\n\nTwo months later, he developed posterior cervical and supraclavicular LAD. His CBC was significant for pancytopenia, requiring transfusions of packed red blood cells. A repeat bone marrow biopsy indicated progressive marrow fibrosis and a focal area of TdT positivity. Bone marrow flow cytometry was negative for lymphoblastic cells. The patient had a CT scan of his chest, abdomen and pelvis, which demonstrated splenomegaly (18 cm) and diffuse LAD. A core biopsy of a left cervical lymph node was consistent with relapsed T-ALL (stage IV), so the patient was started on Nelarabine and Dexamethasone. After two cycles, the patient developed a diffuse papular rash. He had a punch biopsy that showed an atypical immature cell infiltrate within the dermis. Immunochemical staining was positive for CD45, MPO, CD43 and CD68, and negative for CD3, CD5, TdT, CD20, CD34, CD117 and CD1a in the lesional cells, consistent with the diagnosis of a cutaneous myeloid sarcoma. He was transitioned to Clofarabine and Cytarabine, which was complicated by neutropenic sepsis from Escherichia Coli bacteremia and acute appendicitis after cycle 1. Ultimately, the patient requested comfort/hospice care, 3 years after being diagnosed with PMF, and 1 year following the diagnosis of T-ALL.\n\nDiscussion\nThese cases demonstrate the development of AITL and T-ALL in patients previously diagnosed with PN-MPN. This is the first case series of T-ALL or AITL arising in patients with PN-MPN, apart from one other reported case in the literature [11] (Table 1). While rarely described, these cases suggest a possible association between PN-MPN and T-cell malignancies. While the development of secondary lymphoid neoplasms remains rare, data suggest that the incidence is greater in males, in those with a JAK2 V617F mutation, and in patients with a pre-existing PN-MPN of greater than 5 years [12]. When including the other reported case with this case series, the median age was 70 years (range: 20–84 years) with a 3:1 male-to-female predominance, and a median duration of 4.5 years (range: 6 months–10 years) between the diagnosis of a PN-MPN and the development of a T-cell neoplasm (Table 1). All cases were advanced at diagnosis and exhibited rapid progression or relapse despite systemic chemotherapy and regardless of karyotype, MPN mutation and type of PN-MPN or T-cell neoplasm (Table 1).\n\nThe occurrence of a haematolymphoid malignancy following a previously diagnosed PN-MPN is uncommon. Nonetheless, clinicians should be aware that studies have demonstrated patients with PN-MPN are at increased risk of this complication. Vannucchi et al [12] reported a standardised incidence ratio (SIR) of 3.4 (95% confidence interval (95% CI): 1.9–6.2) and 12.4 (95% CI: 4.7–33.6) in patients who develop secondary chronic lymphocytic leukaemia and non-Hodgkin lymphoma compared with the general population, respectively. Furthermore, patients with PN-MPN harbouring the JAK2 V617F mutation had a SIR of 5.46 (95% CI: 2.45–12.15) of acquiring a secondary haematolymphoid malignancy [12]. In a Danish population-based cohort study, the SIR of developing a haematologic malignancy in patients with ET was 5 (95% CI: 3.5–6.9) [13]. The SIR in patients with ET was approximately equal to PV in the study and reported as 1.8 (95% CI: 1.1–2.7) and 0.6 (95% CI: 0.2–1.5) in patients with non-Hodgkin lymphoma and lymphoid leukaemia, respectively [13]. While it is well documented that haematolymphoid malignancies may lead to secondary myelofibrosis, PMF with a secondary haematolymphoid malignancy is rare and its occurrence is primarily isolated to case reports.\n\nThe pathophysiology by which a lymphoid transformation occurs in patients with PN-MPN arises has not been clearly established. However, mutations involving JAK2 V617F have been suggested as a potential contributor. There is evidence implicating lympho-myeloid progenitor cells as the cell of origin that culminates in PN-MPN [14]. The JAK-STAT pathway plays a fundamental role in lymphoid proliferation, survival and differentiation [15] and mutations have been observed in paediatric acute lymphoblastic leukaemias, adult T-cell lymphoblastic leukaemias and Hodgkin lymphoma [16, 17]. In addition, there are reported cases of the JAK2 V617F mutation in both PN-MPN as well as lymphoma cells following a lymphomatous transformation, suggestive of a causal link and mutational aetiology for the lymphomatous transformation [12]. Larsen et al [14] discovered a subpopulation of B and T lymphocytes with the JAK2 V617F mutation in a population of patients with PN-MPN, suggesting that this mutation occurs in an early stem cell with both myeloid and lymphoid differentiation potential. This may indicate that there exists a proportion of T-lymphocyte sub-clone precursors arising from a common early lympho-myeloid progenitor that harbour the mutation, creating a predisposition for eventual lymphomatous or leukaemic progression. An assessment of JAK2 mutations was not done in the malignancies in these reported cases and given that the first patient had a triple-negative ET, there may be other mutations harboured by early progenitor cells that were not assessed.\n\nPatient 1 developed AITL 6 months after the diagnosis of triple-negative ET. However, a triple-negative status does not exclude other less common genomic aberrancies [18] which may have also have contributed to the development of a secondary T-cell neoplasm. In 68 patients with previously diagnosed triple-negative ET, Zu et al [19] conducted targeted genomic sequencing and found other mutations in FLT3, SH2B3, ASXL1, ADAMTS1, TET2, TP53, EGFR, CUX1, GATA2 and MPL that may have contributed to the development of ‘triple-negative’ ET. Several of these mutations are also seen in T-cell malignancies. In T-ALL, mutations in FLT3, SH2B3 and ASXL1 have been demonstrated [20, 21], and in AITL, mutations in TET2, TP53 and GATA2 (reported in EBV-associated T-cell lymphoma) have been reported [22–24]. These were not assessed in patient 1, but may have been contributing factors to disease pathogenesis.\n\nConclusion\nThis case series demonstrates the possibility of developing T-cell neoplasms in patients with PN-MPN, independent of cytogenetic abnormalities and mutational status. Disease progression may be rapid, and disease recurrence may occur if remission is achieved. Clinicians managing patients with PN-MPN should be aware of this possibility and maintain a high index of suspicion for this potential complication when patients present with ‘B’ symptoms or new LAD. A detailed diagnostic workup should be conducted efficiently so that systemic therapy can be initiated expediently. Workup in T and B-cell malignancies that develop in patients with PN-MPN should include a mutation analysis of JAK2 V617F, CALR and MPL.\n\nAbbreviations\nMyeloproliferative neoplasm: MPN; Philadelphia Negative Myeloproliferative Neoplasm: PN-MPN; WHO: World Health Organization; Polycythemia Vera: PV; Essential Thrombocythemia: ET; Primary Myelofibrosis: PMF; Janus Kinase: JAK; Calreticulin: CALR; Thrombopoietin Receptor: MPL.\n\nConflicts of interest\nThe authors have no conflicts of interest.\n\nFunding statement\nThe authors have no financial disclosures to declare.\n\nFigure 1. Patient 1, bone marrow biopsy with AITL: (A) Focal, interstitial marrow involvement with monomorphic population of small to medium-sized lymphoid cells with moderately abundant pale eosinophilic cytoplasm, H&E, 100×. (B) PD-1, 100×. (C) EBER ISH, 400×.\nFigure 2. Patient 1, axillary lymph node with AITL: (A) Prominent vascular proliferation of high endothelial venules (HEVs) and nodal architecture effacement by a monomorphic lymphoid population, H&E, 100×. (B) Neoplastic population of follicular helper T cells with small to medium-sized nuclei and clear-to-pale cytoplasm, especially clustering adjacent to HEVs, and scattered CD30+ immunoblasts (circled, IHC not shown). H&E, 400×. (C) Increased numbers of T cells in effaced areas, especially perivascular T cells, CD3, 100x. (D) Increased numbers of neoplastic follicular helper T cells, PD-1, 100×. (E) Expanded dendritic meshwork, CD21, 100×. (F) EBER in situ hybridisation (EBER ISH) positive neoplastic T cells, 100×.\nFigure 3. Patient 2, axillary lymph node with AITL: (A) Partial nodal architecture effacement by a monomorphic lymphoid population and increased numbers of eosinophils, H&E, 100×. (B) Neoplastic population of monomorphic follicular helper T cells with small to medium-sized nuclei and clear-to-pale cytoplasm in a polymorphous background of neutrophils and increased numbers of eosinophils with scattered CD30+ immunoblasts (circled, IHC not shown), H&E, 400x. (C) Increased numbers of neoplastic helper T cells, CD4, 100×. (D) Increased numbers of neoplastic follicular T helper cells (dim) with scattered neutrophils (strong), CD10, 100x. (E) Increased numbers of neoplastic helper T cells, PD-1, 100x. (F) Expanded dendritic meshwork, CD23, 100×.\nFigure 4. Patient 3, cervical lymph node with T-ALL. (A) Relatively monomorphic infiltrate of neoplastic lymphocytes with irregularly shaped, hyperchromatic, small to medium-sized nuclei with inconspicuous nucleoli, 400x. (B) CD34-negative, (CD34-positive blood vessels as internal control), 100x. (C) CD10-negative, 100x. (D) TdT-positive (nuclear), 100x. (E) CD1a-positive, 100x. (F) Ki-67 with 80% proliferation index, 100x.\nTable 1. Characteristics of patients with MPN with secondary AITL and T-ALL.\n\tPatient 1\tPatient 2\tPatient 3\tAitchison et al [13]\t\nAge(years)/Gender/\nEthnicity\t78/Female/Caucasian\t84/Male/Caucasian\t62/Male/African American\t20/Male/Unknown\t\nMPN\tET\tET\tPMF\tPV\t\nMutation\tTriple-Negative\tJAK2 V617F\tJAK2 V617F\tUnknown\t\nTreatment\tHydroxyurea\tHydroxyurea\tErythropoietin\tUnknown\t\nTime from MPN \ndiagnosis to leukaemic transformation\t6 months\t6 years\t3 years\t10 years\t\nMalignancy\tAITL\tAITL\tT-ALL\tT-ALL\t\nDisease Stage at Diagnosis\tIV\tIV\tIV\tUnknown\t\nImmunophenotype of lesional cells\tCD2, CD3, CD5, CD7, CD4, PD-1\tCD2, CD3, CD4, CD5, CD7, with subsets expressing CD10, BCL-6, and PD-1, CD30\tTdt, CD1a, CD2, CD7 and cytoplasmic CD3, CD33 and CD34\tUnknown\t\nKaryotype\t47,XX,add(2)(p2),add(10)(p11.2),+add(20)(p12)[cp4]/46,XX [16].\t46,XY\t46,XY,i(17)(q10)[9]/46,idem,del(20)(q11.2q13.1) [3].\tUnknown\t\nBone marrow infiltration\tYes\tNo\tYes\tUnknown\t\nEBV\tPositive\tNegative\tNegative\tUnknown\t\nChemotherapy\tCHEOP, R-ICE\tCEOP\tHyperCVAD, Nelarabine, \nClofarabine and Cytarabine\tUnknown\t\nOutcome\tDisease progression, on salvage chemotherapy with R-ICE\tDisease progression, deceased\tDisease relapse within 2 months, cutaneous myeloid sarcoma, deceased\tDeceased\t\nMPN: Myeloproliferative neoplasm. ET: Essential Thrombocythemia; PV: Polycythemia Vera; PMF: Primary Myelofibrosis; AITL: Angioimmunoblastic Lymphoma; T-ALL: T-cell Acute Lymphoblastic Leukaemia; CHEOP: Cyclophosphamide, Doxorubicin hydrochloride, Etoposide, Vincristine and Prednisone; CEOP: Cyclophosphamide, Etoposide, Vincristine and Prednisone; R-ICE: Romidepsin, Ifosfamide, Carboplatin, Etoposide; HyperCVAD: Cyclophosphamide, Vincristine, Doxorubicin and Dexamethasone.\n==== Refs\nReferences\n1. Arber DA Orzai A Hasserjian R The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia Blood 2016 127 2391 2405 10.1182/blood-2016-03-643544 27069254 \n2. Barbui T Thiele J Gisslinger H The 2016 revision of WHO classification of myeloproliferative neoplasms: clinical and molecular advances Blood Rev 2016 30 6 453 459 10.1016/j.blre.2016.06.001 27341755 \n3. Nangalia J Green AR Myeloproliferative neoplasms: from origins to outcomes Blood 2017 130 2475 2483 10.1182/blood-2017-06-782037 29212804 \n4. Yogarajah M Tefferi A Leukemic transformation in myeloproliferative neoplasms. A literature review on risks, characteristics, and outcome Mayo Clin Pro 2017 92 7 1118 1128 10.1016/j.mayocp.2017.05.010 \n5. Barbui T Thiele J Passamonti F Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study J Clin Oncol 2011 29 3179 3184 10.1200/JCO.2010.34.5298 21747083 \n6. Tefferi A Rumi E Finazzi G Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study Leukemia 2013 27 1874 1881 10.1038/leu.2013.163 23739289 \n7. Abdulkarim K Girodon F Johansson P AML transformation in 56 patients with Ph- MPD in two well defined populations Eur J Haematol 2009 82 106 111 10.1111/j.1600-0609.2008.01163.x 19134023 \n8. Cervantes F Tassies D Salgado C Acute transformation in nonleukemic chronic myeloproliferative disorders: actuarial probability and main characteristics in a series of 218 patients Acta Haematol 1991 85 124 127 10.1159/000204873 2042444 \n9. Tam CS Nussenzveig RM Popat U The natural history and treatment outcome of blast phase BCR-ABL− myeloproliferative neoplasms Blood 2008 112 1628 1637 10.1182/blood-2008-02-138230 18566326 \n10. Tefferi A Guglielmelli P Larson DR Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis Blood 2014 124 16 2507 2513 quiz 2615 10.1182/blood-2014-05-579136 25037629 \n11. Aitchison R Black AJ Greaves MF Polycythaemia rubra vera transforming to acute lymphoblastic leukaemia Clin Lab Haematol 1987 9 201 204 10.1111/j.1365-2257.1987.tb01402.x 3476236 \n12. Vannucchi AM Masala G Antonioli E Increased risk of lymphoid neoplasms in patients with Philadelphia chromosome-negative myeloproliferative neoplasms Cancer Epidemiol Biomarkers Prev 2009 18 7 2068 2073 10.1158/1055-9965.EPI-09-0353 19531676 \n13. Frederiksen H Farkas DK Christiansen CF Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population based cohort study Blood 2011 118 25 6515 6120 10.1182/blood-2011-04-348755 22039256 \n14. Larsen TS Christensen JH Hasselbalch HC The JAK2 V617F mutation involves B- and T-lymphocyte lineages in a subgroup of patients with Philadelphia-chromosome negative chronic myeloproliferative disorders Br J Haematol 2007 136 5 745 751 10.1111/j.1365-2141.2007.06497.x 17313377 \n15. Murray PJ The JAK-STAT signaling pathway: input and output integration J Immunol 2007 178 5 2623 2629 10.4049/jimmunol.178.5.2623 17312100 \n16. Vainchenker W Constantinescu SN JAK/STAT signaling in hematological malignancies Oncogene 2013 32 21 2601 2613 10.1038/onc.2012.347 22869151 \n17. Roncero AM López-Nieva P Cobos-Fernández MA Contribution of JAK2 mutations to T-cell lymphoblastic lymphoma development Leukemia 2016 30 1 94 103 10.1038/leu.2015.202 26216197 \n18. Elnahass Y Mahmoud HK Mattar M Triple negative myeloproliferative neoplasms (MPNs) patients show low MPN10 score and lower grades of bone marrow fibrosis Blood 2016 128 5477 10.1182/blood.V128.22.5477.5477 \n19. Ju MK Fu RF Li HY Clinical characteristic of “triple-negative” essential thrombocythaemia patients and mutation analysis by targeted sequencing Zhongguo Shi Yan Xue Ye Xue Za Zhi 2018 26 4 1137 1145 10.7534/j.issn.1009-2137.2018.04.032 30111420 \n20. Zhang J Ding L Holmfeldt L The genetic basis of early T-cell precursor acute lymphoblastic leukaemia Nature 2012 481 7380 157 163 10.1038/nature10725 22237106 \n21. Prebet T Carbuccia N Raslova H Concomitant germ-line RUNX1 and acquired ASXL1 mutations in a T-cell acute lymphoblastic leukemia Eur J Haematol 2013 91 3 277 279 10.1111/ejh.12147 23692290 \n22. Lemonnier F Couronné L Parrens M Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters Blood 2012 120 7 1466 1469 10.1182/blood-2012-02-408542 22760778 \n23. Heavican TB Bouska A Yu J Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma Blood 2019 10.1182/blood-2018-09-872549 \n24. Cohen JI Dropulic L Hsu AP Association of GATA2 deficiency with severe primary epstein-barr virus (EBV) infection and EBV-associated cancers Clin Infect Dis 2016 1 41 7 10.1093/cid/ciw160 27169477\n\n",
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"keywords": "Philadelphia negative myeloproliferative neoplasm; T-cell acute lymphoblastic leukaemia; angioimmunoblastic T-cell lymphoma; essential thrombocythemia; polycythemia vera; primary myelofibrosis",
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"title": "The development of T-cell malignancies in patients with pre-existing myeloproliferative neoplasms: a report of three cases.",
"title_normalized": "the development of t cell malignancies in patients with pre existing myeloproliferative neoplasms a report of three cases"
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"abstract": "The authors describe bilateral and sequential pigment epithelial detachment (PED) formation in a 16-year-old girl with ABCA4-associated Stargardt's disease (STGD1). On routine examination, a new large PED was observed in the left eye with late leakage evident on fluorescein angiography suggestive of possible occult choroidal neovascularization. The lesion was therefore treated with bevacizumab, but with no involutional lesion response. Months later, a similar lesion appeared in the right eye. The authors believe this to be the first reported case of acute bilateral and sequential PED development in a patient with ABCA4-associated STGD1. Optical coherence tomography-guided morphological analysis of lesion development in ABCA4 disease with documentation of PED formation may suggest a plausible role for disruption at the level of Bruch's membrane in the pathophysiology of STGD1.",
"affiliations": "University of Florida College of Medicine, Gainesville, Florida 32610-0284, USA.",
"authors": "Cohen|Joshua|J|;Bhullar|Shaminder|S|;Kasuga|Daniel|D|;Boye|Shannon|S|;Elhalis|Hussain|H|;Kay|Christine N|CN|",
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"mesh_terms": "D018528:ATP-Binding Cassette Transporters; D000293:Adolescent; D005260:Female; D006801:Humans; D008268:Macular Degeneration; D009154:Mutation; D012163:Retinal Detachment; D000080362:Stargardt Disease",
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"title": "Retinal pigment epithelial detachment in ABCA4-associated Stargardt's disease.",
"title_normalized": "retinal pigment epithelial detachment in abca4 associated stargardt s disease"
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"abstract": "Data on the efficacy of antipsychotics as monotherapy for obsessive-compulsive disorder (OCD) are inadequate. This report presents the case of a patient with OCD that was successfully treated with risperidone as monotherapy. Assessments revealed significant reductions in OCD symptoms after risperidone treatment (4 mg/d). This report suggests the beneficial effect of risperidone for a patient with OCD comorbid with schizoaffective disorder.",
"affiliations": "Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.",
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"title": "Risperidone as monotherapy for a patient with obsessive compulsive disorder comorbid with schizoaffective disorder: a case report.",
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"abstract": "The full-mouth disinfection protocol implemented in this case can be integrated into established protocols for treating severe periodontitis in the context of a hematological malignancy, without any interference with the cancer treatment.",
"affiliations": "Department of Dentistry and Oral Surgery Keio University School of Medicine Tokyo Japan.;Department of Dentistry and Oral Surgery Keio University School of Medicine Tokyo Japan.;Department of Dentistry and Oral Surgery Keio University School of Medicine Tokyo Japan.;Department of Dentistry and Oral Surgery Keio University School of Medicine Tokyo Japan.;Department of Dentistry and Oral Surgery Keio University School of Medicine Tokyo Japan.;Department of Dentistry and Oral Surgery Keio University School of Medicine Tokyo Japan.;Division of Hematology, Department of Medicine Keio University School of Medicine Tokyo Japan.;Division of Hematology, Department of Medicine Keio University School of Medicine Tokyo Japan.;Department of Dentistry and Oral Surgery Keio University School of Medicine Tokyo Japan.",
"authors": "Morikawa|Satoru|S|https://orcid.org/0000-0001-8859-2888;Tsunoda|Kazuyuki|K|;Miyashita|Yoko|Y|;Nasu|Mana|M|;Horie|Nobuyuki|N|;Usuda|Sho|S|;Kato|Jun|J|;Mori|Takehiko|T|https://orcid.org/0000-0002-8176-4760;Nakagawa|Taneaki|T|",
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"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.3604\nCCR33604\nCase Report\nCase Reports\nManagement of generalized severe periodontitis using full‐mouth disinfection and systemic antibiotics in a leukemic patient before stem cell transplantation: A case report\nMORIKAWA et al.Morikawa Satoru https://orcid.org/0000-0001-8859-2888\n1\nmorikawa@keio.jp Tsunoda Kazuyuki \n1\n Miyashita Yoko \n1\n Nasu Mana \n1\n Horie Nobuyuki \n1\n Usuda Sho \n1\n Kato Jun \n2\n Mori Takehiko https://orcid.org/0000-0002-8176-4760\n2\n Nakagawa Taneaki \n1\n \n1 \nDepartment of Dentistry and Oral Surgery\nKeio University School of Medicine\nTokyo\nJapan\n\n\n2 \nDivision of Hematology, Department of Medicine\nKeio University School of Medicine\nTokyo\nJapan\n\n* Correspondence\n\nSatoru Morikawa, Department of Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku‐ku, Tokyo 160‐8582, Japan.\n\nEmail: morikawa@keio.jp\n\n03 12 2020 \n2 2021 \n9 2 10.1002/ccr3.v9.2644 649\n03 9 2020 24 10 2020 10 11 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nThe full‐mouth disinfection protocol implemented in this case can be integrated into established protocols for treating severe periodontitis in the context of a hematological malignancy, without any interference with the cancer treatment.\n\nThe full‐mouth disinfection protocol implemented in this case can be integrated into established protocols for treating severe periodontitis in the context of a hematological malignancy, without any interference with the cancer treatment.\n\n\nacute lymphoblastic leukemiafull‐mouth disinfectionsevere periodontitisstem cell transplantation source-schema-version-number2.0cover-dateFebruary 2021details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.7 mode:remove_FC converted:08.02.2021\n\n\nMorikawa \nS \n, \nTsunoda \nK \n, \nMiyashita \nY \n, et al. Management of generalized severe periodontitis using full‐mouth disinfection and systemic antibiotics in a leukemic patient before stem cell transplantation: A case report\n. Clin Case Rep .2021 ;9 :644 –649\n. 10.1002/ccr3.3604\n==== Body\n1 INTRODUCTION\nOral infection is a contributor to morbidity and mortality in leukemic patients. Full‐mouth disinfection, which terminates subgingival debridement within a short period, is applicable and effective in combination with antimicrobial agents in treating leukemic patients with severe periodontitis as an oral infection removal procedure prior to stem cell transplantation.\n\nHematopoietic stem cell transplantation (SCT) is a curative therapy for hematologic malignancies. Standard pretransplantation therapeutic approaches, including high‐dose chemotherapy, total body irradiation, and SCT, greatly improve the prognosis of leukemic patients. At multiple phases during SCT, patients are at risk of contracting infectious diseases due to profound and prolonged neutropenia.\n1\n The US National Cancer Institute indicated that odontogenic infection is a potential source of systemic infections that should be eliminated by dental treatment.\n2\n, \n3\n However, no definitive criteria for extraction or preservation of infected teeth that do not affect hematological treatment have been established for recipients with severe infections, including patients with hematological malignancies.\n\nHere, we present a case of acute lymphoblastic leukemia with severe periodontitis prior to SCT that was treated with a regimen involving full‐mouth disinfection (FMD).\n\n2 CASE REPORT\nA 38‐year‐old man diagnosed with acute lymphoblastic leukemia and scheduled to undergo chemotherapy, total body irradiation, and SCT was referred to our department for odontogenic infection screening. After evaluation of his clinical oral condition, dental X‐ray photographs, and the presence of periodontitis‐related bacteria by quantitative polymerase chain reaction (qPCR), a diagnosis of generalized severe periodontitis (generalized periodontitis stage IV, grade C) was made. The patient had already received intravenous antimicrobial infusion for febrile neutropenia (FN) on admission to the hospital; however, periodontitis‐related bacteria were detected (Table 1). When the leukocyte count was low, we only followed the oral hygiene instructions. To remove dental plaque and supragingival calculus, scaling procedures on the gingival margin were performed at the time of recovery from FN after induction of chemotherapy. To prevent bacteremia and septicemia after SCT, FMD was considered to remove the infectious source via completion of scaling and root planing (SRP) within the limited dental treatment window of only 1 week, covering all periodontally infected teeth (Figure 1). Before the initiation of chemotherapy, oral hygiene instructions were provided to the patient to avoid risk of infection from dental foci. In the neutropenic phase, during chemotherapy and immunosuppression, oral care was provided to reduce oral complications including oral mucositis and acute periodontitis. Since his first visit to our department, the patient was expected to develop chemotherapy‐induced FN and oral mucosal disorders. We thus provided the patient with thorough oral hygiene instructions aiming to quantitatively reduce the source of infection in the mouth. Specifically, the patient was instructed on the toothbrush Bass technique regarding the toothbrush and interdental brush cleaning methods. Oral assessments were performed based on an oral assessment guide,\n4\n and the information was shared with the physician and nurses. A nonirritating moisturizer was used for xerostomia.\n\nTABLE 1 Quantitative evaluation of periodontitis‐related bacteria in the deepest periodontal pocket of the patient\n\n\tBaseline (count)\tSeven months after FMD (count)\t\nTotal bacteria\t30 000\t<1000\t\n\nPorphyromonas gingivalis\n\t570\t<10\t\n\nTannerella forsythia\n\t1300\t<10\t\n\nTreponema denticola\n\t1100\t<10\t\n\nFusobacterium nucleatum\n\t2000\t<10\t\nJohn Wiley & Sons, LtdFIGURE 1 Treatment timeline. The patient was a 38‐year‐old male hematopoietic stem cell transplant (SCT) recipient with generalized severe periodontitis\n\nThe patient achieved complete remission following induction of chemotherapy consisting of cyclophosphamide vincristine, prednisolone, daunorubicin, and L‐asparaginase and consolidation chemotherapy consisting of doxorubicin, vincristine, and prednisolone. The myelosuppression grades of these chemotherapies were categorized as severe and moderate, respectively.\n5\n Procalcitonin (PCT) levels were measured when fever and febrile neutropenia (FN) were present. PCT was predominantly higher (7.4 ng/mL) in the presence of FN and septic shock during the first round of chemotherapy on day −116. Otherwise, the PCT was not predominant during the pretransplant oral care and at 1 month after the transplant, which is the focus of this study (Figure 1). Blood cultures were performed at the time of fever, and the only positive results between the time of admission and 1 month after transplantation were obtained from day −116 to day −111. At that time, FN and septic shock were both present, and the patient was positive for Corynebacterium striatum and Staphylococcus haemolyticus. No oral bacteria were found. Mechanical debridement for severe periodontal disease was then scheduled during the non‐neutropenic period after chemotherapy induction and consolidation. The day on which SCT was performed was designated day 0. To gain sufficient healing time of SRP for debridement of the periodontal deep pocket before SCT and to avoid reinfection from an untreated site to the treatment site in this case, we planned for FMD combined with systemic antimicrobial therapy, which could effectively be used to treat patients who had been diagnosed with generalized severe periodontitis in a short period of time.\n6\n After the first round of chemotherapy, we considered performing the procedure if the white blood cell count was normal. However, after consulting with the hematologist, we decided to schedule the consolidation chemotherapy; thus, the medical team considered the time when the consolidation chemotherapy was finished, the white blood cell and absolute neutrophil counts had recovered, there was no febrile neutropenia, and there was enough time for the wound to heal after FMD. As a result of this discussion, we treated for severe periodontitis in a short period from day −30 to day −22. FMD was performed from days −30 to −22 for debridement of all periodontal pockets by SRP with Gracey curettes. We performed SRP for tooth numbers 36, 37, 38, 46, 47, and 48 on day −30 (Federation Dentaire Internationale System); tooth numbers 14‐18 and 24‐28 on day −27; tooth numbers 31, 32, 33, 35 and from 41‐44 on day −24; and finally, tooth numbers 13, 21, 22, and 23, on day −22. During FMD, the patient was treated with sitafloxacin (100 mg/day for 14 days) to prevent bacteremia/septicemia, periodontopathic bacterial infection, and fever, which are possible adverse complications induced by FMD.\n7\n Both body temperature and C‐reactive protein (CRP) level were stable during FMD period, with a maximum body temperature of 37.0°C and maximum CRP concentration of 1.13 mg/dL (Figure 1). Allogeneic peripheral blood SCT was performed with myeloablative conditioning on day 0. The graft contained CD34+ cells at 2.66 × 106/kg. Myeloablative conditioning was based on total body irradiation at 12 Gy in six fractions on day −8 to −6, administered in combination with cytarabine 2000 mg/m2/day on days −5 to −4 and cyclophosphamide 60 mg/kg/day on days −3 to −2. In the nadir phase, the physician and nurses checked the patient's condition including oral conditions daily using the oral assessment guide to score the patient's voice, swallowing, lips, tongue, saliva, mucous membranes, gums, teeth, and dentures.\n4\n The records confirmed that there was no odontogenic infection. From day + 6, we also performed the same assessment after SCT. No acute exacerbation of periodontitis was detected. Oral mucositis was present from days + 2 to + 10. The attended hematologists and nurses shared this patient's treatment plan, the patient's condition, and oral assessment through conferences and we discussed the treatment plan with them. Seven and 13 months after FMD (6 and 12 months after SCT), the microbiological and clinical parameters of periodontitis, as demonstrated by the O’Leary plaque control record, decreased from 95% to 19%. Additionally, bleeding on probing (BOP), an indicator of periodontal inflammation (including gingivitis), decreased from 81.6% to 7.5% (Table 2). Probing depth (PD), defined as the distance from the bottom of the periodontal pocket to the gingival cuff, also improved. Deeper periodontal pockets indicate greater alveolar bone resorption. PD ≥4 mm and PD ≥7 mm significantly reduced after FMD from 98.3% to 4.6% and from 31.6% to 0%, respectively; the mean PD reduced from 6.1 to 2.5 mm (Table 2). At 13 months after FMD, gingival inflammation was effectively reduced (Figure 2 A,B), the teeth affected by severe periodontitis were preserved, alveolar bone was regenerated (Figure 2C,D), and functional occlusion was achieved without tooth extraction. Furthermore, qPCR data revealed no periodontitis‐related bacteria in the deepest periodontal pocket during the initial examination (Table 1).\n\nTABLE 2 Clinical characteristics of the patient at baseline and 13 mo after FMD\n\nCharacteristics\tBaseline\t13 mo after FMD\t\nPlaque control record (%)\t95\t19\t\nBOP (mean %)\t81.6\t7.5\t\nPD ≥4 mm (mean %)\t98.3\t4.6\t\nPD ≥7 mm (mean %)\t31.6\t0\t\nPD (mm; mean)\t6.1\t2.5\t\nAbbreviations: BOP, bleeding on probing; FMD, full‐mouth disinfection; PD, probing depth.\n\nJohn Wiley & Sons, LtdFIGURE 2 Oral evaluation and dental radiographic images. The patient was a 38‐year‐old male hematopoietic stem cell transplant (SCT) recipient with generalized severe periodontitis. A, Intraoral image at the initial visit. B, Intraoral image after SCT and full‐mouth disinfection (FMD). C, Radiographic images at the initial visit. D, Radiographic images after SCT and FMD\n\n3 DISCUSSION\nWe have demonstrated a case in which FMD was effective in treating generalized severe periodontitis without interfering with chemotherapy or SCT. Moreover, FMD effectively removed infectious sources and SRP was completed within only a few days throughout the entire jaw using antimicrobial agents. Upon re‐evaluation after SCT, we confirmed improvement of the periodontal status, bone regeneration at the resorption site, and observed no odontogenic infectious complications.\n\nFull‐mouth disinfection with systemic antimicrobial therapy was conducted on this patient for three reasons: (a) The patient was diagnosed with acute lymphoblastic leukemia, indicating immunodeficiency; (b) intensive chemotherapy, total body irradiation, and SCT were scheduled at the first visit; and (c) intensive periodontal treatment reportedly reduces the occurrence of febrile neutropenia, significantly reducing CRP levels.\n8\n Before administering the conditioning regimen preceding hematopoietic SCT, the period available for dental treatment, including tooth extraction and periodontal basic therapy, is limited due to the development of neutropenia and thrombocytopenia. Moreover, the conventional method of nonsurgical periodontal therapy consists of SRP, which involves the debridement of periodontal pockets in the jaw quadrants (Q‐SRP).\n9\n, \n10\n However, as most periodontopathic bacteria exist in periodontal pockets as well as in several other oral mucosal sites, including the saliva,\n11\n the treated periodontal pockets could be reinfected from the untreated regions\n12\n during Q‐SRP. Quirynen et al\n7\n, \n13\n suggested a one‐stage FMD protocol instead of the conventional strategy with consecutive debridement per quadrant over a 1‐2‐week interval. On the contrary, Herrera and colleagues have suggested that antimicrobials should be administered immediately after the end of debridement and that debridement should be terminated in as short a time as possible, that is, within 1 week.\n14\n Yashima et al\n15\n found that if the SRP was completed within 1 week of maintaining the effective concentration of the antimicrobial agent (azithromycin), the clinical fungicidal efficacy of SRP was comparable to that of one‐stage full‐mouth SRP. Thus, termination of SRP within 1 week under antimicrobial administration would be equivalent in clinical efficacy to SRP within 24 hours. Furthermore, in practice, SRP below the gingival margin of the entire jaw in 1 day is known to be burdensome for patients and to cause a high frequency of fever.\n7\n Therefore, we planned to complete the SRP within approximately 1 week in this case while monitoring the patient's physical condition and response on the dental chair. Systematic review and meta‐analysis\n16\n have revealed that FMD combined with systemic administration of amoxicillin and metronidazole improved the clinical and microbiological outcomes significantly and effectively. These combined periodontitis treatments have not been approved in Japan. However, in our study, we systemically administrated sitafloxacin, which has been reported as significantly effective against periodontopathic bacteria.\n17\n, \n18\n Leukemic patients with pancytopenia and hematopoietic dysfunction are often immunodeficient, with difficulty in maintaining hemostasis, which increases the risks of postoperative infection and hemorrhage. Hence, it is preferable to conduct these treatments when patients attain normal hematopoiesis after the nadir phase, in which remission induction and consolidation chemotherapy suppress tumor cells. Thus, a desirable disinfection protocol includes (a) postinduction and consolidation chemotherapy; (b) following exit from the nadir phase, administration of antibiotics in combination with oral care; and (c) completion (with epithelialization) of the indicated dental surgical treatments before pretreatment (chemotherapy and total body irradiation) for SCT. Another study showed that reduced frequency of FN coincided with periodontal treatment.\n19\n These studies clearly demonstrate the importance of periodontal management in patients with leukemia and periodontal disease.\n\nIn our case, adverse events induced by dental treatment did not occur before or after SCT. Leukemic patients with severe odontogenic infection can experience infections within the periodontal deep pockets. For instance, a prospective observational study indicated that patients with periodontal inflammation had bacteremia more often than those with healthy periodontal tissue and that bleeding on probing was related to bacteremia.\n20\n These conditions may lead to bacteremia and septicemia before and after the SCT immunodeficient phase. Moreover, previous studies have shown that periodontal disease is associated with markedly elevated hospital charges, longer hospital stays, and higher rates of infectious complications in SCT recipients.\n21\n Furthermore, significantly lower frequencies of both oral and systemic infections were observed in patients undergoing chemotherapy that completed all dental treatments compared with those who did not. However, this difference was dependent on the chemotherapy grade.\n5\n, \n22\n\n\n\nHence, dental treatment should be implemented prior to, during, and following SCT and chemotherapy. To this end, FMD can be integrated into existing protocols and regimens for hematology treatment without interfering with SCT. Furthermore, the lack of periodontitis‐related bacteria as detected by qPCR after FMD combined with systemic antimicrobial therapy suggests that FMD with systemic antimicrobial therapy may alter the oral microbiome of patients with severe periodontitis to a more desirable state.\n6\n, \n16\n However, the establishment of pre‐ and post‐SCT protocols based on individual patients’ oral condition is required to prevent oral adverse events. Overall, FMD can be performed rapidly and before SCT, providing effective oral care and improving the condition of leukemic patients with severe periodontitis.\n\nCONFLICTS OF INTEREST\nThe authors declare that they have no conflicts of interest.\n\nAUTHOR CONTRIBUTIONS\nSM: provided clinical oral care, conducted full‐mouth disinfection, collected and analyzed the data, and primarily wrote the manuscript. KT: analyzed data and revised the manuscript. YM and MN: provided clinical oral care and analyzed the data. NH and SU: provided clinical oral care and commented on the manuscript. JK: performed the SCT, clinical care, and commented on the manuscript. TM and TN: contributed to writing, reviewing, and editing the manuscript.\n\nACKNOWLEDGMENTS\nWe thank the physicians and hospital staff of the Division of Haematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan, for providing thoughtful patient care. We would also like to thank Editage (www.editage.com) for English language editing. Published with written consent of the patient.\n\nDATA AVAILABILITY STATEMENT\nThe datasets used and analyzed during this study are available from the corresponding author on reasonable request.\n==== Refs\nREFERENCES\n1 \n\nHan \nYW \n, \nWang \nX \n. Mobile microbiome: oral bacteria in extra‐oral infections and inflammation\n. J Dent Res . 2013 ;92 :485 ‐491\n.23625375 \n2 \n\nSonis \nST \n, \nWoods \nPD \n, \nWhite \nBA \n. Oral complications of cancer therapies. Pretreatment oral assessment\n. NCI Monogr . 1990 ;9 :29 ‐32\n.\n3 \n\nMaxymiw \nWG \n, \nWood \nRE \n. The role of dentistry in patients undergoing bone marrow transplantation\n. Br Dent J . 1989 ;167 (7 ):229 ‐234\n.2528979 \n4 \n\nEilers \nJ \n, \nBerger \nAM \n, \nPetersen \nMC \n. Development, testing, and application of the oral assessment guide\n. Oncol Nurs Forum . 1988 ;15 (3 ):325 ‐330\n.3287344 \n5 \n\nAkashi \nM \n, \nShibuya \nY \n, \nKusumoto \nJ \n, et al. Myelosuppression grading of chemotherapies for hematologic malignancies to facilitate communication between medical and dental staff: lessons from two cases experienced odontogenic septicemia\n. BMC Oral Health . 2013 ;13 :41 .23957921 \n6 \n\nAimetti \nM \n, \nRomano \nF \n, \nGuzzi \nN \n, \nCarnevale \nG \n. Full‐mouth disinfection and systemic antimicrobial therapy in generalized aggressive periodontitis: a randomized, placebo‐controlled trial\n. J Clin Periodontol . 2012 ;39 (3 ):284 ‐294\n.22220822 \n7 \n\nQuirynen \nM \n, \nMongardini \nC \n, \nde Soete \nM \n, et al. The role of chlorhexidine in the one‐stage full‐mouth disinfection treatment of patients with advanced adult periodontitis. Long‐term clinical and microbiological observations\n. J Clin Periodontol . 2000 ;27 (8 ):578 ‐589\n.10959784 \n8 \n\nKashiwazaki \nH \n, \nMatsushita \nT \n, \nSugita \nJ \n, et al. Professional oral health care reduces oral mucositis and febrile neutropenia in patients treated with allogeneic bone marrow transplantation\n. Support Care Cancer . 2012 ;20 :367 ‐373\n.21328006 \n9 \n\nBadersten \nA \n, \nNilveus \nR \n, \nEgelberg \nJ \n. Effect of nonsurgical periodontal therapy. I. Moderately advanced periodontitis\n. J Clin Periodontol . 1981 ;8 (1 ):57 ‐72\n.6972954 \n10 \n\nBadersten \nA \n, \nNilveus \nR \n, \nEgelberg \nJ \n. Effect of nonsurgical periodontal therapy. II. Severely advanced periodontitis\n. J Clin Periodontol . 1984 ;11 (1 ):63 ‐76\n.6363463 \n11 \n\nBeikler \nT \n, \nAbdeen \nG \n, \nSchnitzer \nS \n, et al. Microbiological shifts in intra‐ and extraoral habitats following mechanical periodontal therapy\n. J Clin Periodontol . 2004 ;31 (9 ):777 ‐783\n.15312101 \n12 \n\nvan Winkelhoff \nAJ \n, \nvan der Velden \nU \n, \nde Graaff \nJ \n. Microbial succession in recolonizing deep periodontal pockets after a single course of supra‐ and subgingival debridement\n. J Clin Periodontol . 1988 ;15 (2 ):116 ‐122\n.3279070 \n13 \n\nQuirynen \nM \n, \nBollen \nCM \n, \nVandekerckhove \nBN \n, \nDekeyser \nC \n, \nPapaioannou \nW \n, \nEyssen \nH \n. Full‐ vs. partial‐mouth disinfection in the treatment of periodontal infections: short‐term clinical and microbiological observations\n. J Dent Res . 1995 ;74 (8 ):1459 ‐1467\n.7560400 \n14 \n\nHerrera \nD \n, \nAlonso \nB \n, \nLeon \nR \n, \nRoldan \nS \n, \nSanz \nM \n. Antimicrobial therapy in periodontitis: the use of systemic antimicrobials against the subgingival biofilm\n. J Clin Periodontol . 2008 ;35 (8 Suppl ):45 ‐66\n.18724841 \n15 \n\nYashima \nA \n, \nGomi \nK \n, \nMaeda \nN \n, \nArai \nT \n. One‐stage full‐mouth versus partial‐mouth scaling and root planing during the effective half‐life of systemically administered azithromycin\n. J Periodontol . 2009 ;80 (9 ):1406 ‐1413\n.19722790 \n16 \n\nSgolastra \nF \n, \nPetrucci \nA \n, \nGatto \nR \n, \nMonaco \nA \n. Effectiveness of systemic amoxicillin/metronidazole as an adjunctive therapy to full‐mouth scaling and root planing in the treatment of aggressive periodontitis: a systematic review and meta‐analysis\n. J Periodontol . 2012 ;83 :731 ‐743\n.22050545 \n17 \n\nTomita \nS \n, \nKasai \nS \n, \nIhara \nY \n, et al. Effects of systemic administration of sitafloxacin on subgingival microflora and antimicrobial susceptibility profile in acute periodontal lesions\n. Microb Pathog . 2014 ;71–72 :1 ‐7\n.\n18 \n\nNakajima \nT \n, \nOkui \nT \n, \nMiyauchi \nS \n, et al. Effects of systemic sitafloxacin on periodontal infection control in elderly patients\n. Gerodontology . 2012 ;29 (2 ):e1024 ‐e1032\n.22616908 \n19 \n\nSoga \nY \n, \nYamasuji \nY \n, \nKudo \nC \n, et al. Febrile neutropenia and periodontitis: lessons from a case periodontal treatment in the intervals between chemotherapy cycles for leukemia reduced febrile neutropenia\n. Support Care Cancer . 2009 ;17 (5 ):581 ‐587\n.19015893 \n20 \n\nRaber‐Durlacher \nJE \n, \nLaheij \nAM \n, \nEpstein \nJB \n, et al. Periodontal status and bacteremia with oral viridans streptococci and coagulase negative staphylococci in allogeneic hematopoietic stem cell transplantation recipients: a prospective observational study\n. Support Care Cancer . 2013 ;21 (6 ):1621 ‐1627\n.23288398 \n21 \n\nAllareddy \nV \n, \nVenugopalan \nSR \n, \nEswaran \nSV \n, et al. Important impact of gingival and periodontal conditions on outcomes in SCT recipients\n. Bone Marrow Transplant . 2015 ;50 :604 ‐606\n.25599170 \n22 \n\nTsuji \nK \n, \nShibuya \nY \n, \nAkashi \nM \n, et al. Prospective study of dental intervention for hematopoietic malignancy\n. J Dent Res . 2015 ;94 :289 ‐296\n.25503612\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "9(2)",
"journal": "Clinical case reports",
"keywords": "acute lymphoblastic leukemia; full‐mouth disinfection; severe periodontitis; stem cell transplantation",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "644-649",
"pmc": null,
"pmid": "33598218",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": "23288398;22050545;19722790;23625375;22616908;18724841;15312101;7560400;6363463;2342592;6972954;19015893;25503612;25599170;10959784;3287344;2528979;24747615;23957921;21328006;22220822;3279070",
"title": "Management of generalized severe periodontitis using full-mouth disinfection and systemic antibiotics in a leukemic patient before stem cell transplantation: A case report.",
"title_normalized": "management of generalized severe periodontitis using full mouth disinfection and systemic antibiotics in a leukemic patient before stem cell transplantation a case report"
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"abstract": "BACKGROUND\nTo evaluate potential drug-drug interactions with the atypical antipsychotic lurasidone.\n\n\nMETHODS\nSeven phase I studies were conducted to investigate the effects of repeated dosing of ketoconazole, diltiazem, rifampin, or lithium on the pharmacokinetics (PK) of single oral doses of lurasidone, or the effects of repeated dosing of lurasidone on the PK of digoxin, midazolam, or the oral contraceptive norgestimate/ethinyl estradiol. Two 6-week, phase III studies included evaluation of the potential for interaction between lurasidone and lithium or valproate. Maximum serum or plasma concentration (Cmax) and area under the concentration-time curve (AUC) were calculated.\n\n\nRESULTS\nConcomitant ketoconazole administration resulted in a 6.8-fold increase in lurasidone Cmax and a 9.3-fold increase in lurasidone AUC; concomitant diltiazem administration resulted in 2.1- and 2.2-fold increases, respectively. Rifampin decreased lurasidone Cmax and AUC (one-seventh and one-fifth of lurasidone alone, respectively). Steady-state dosing with lurasidone increased Cmax and AUC0-24 (AUC from time 0 to 24 h postdose) of digoxin by 9% and 13%, respectively, and of midazolam by 21% and 44%, respectively. There were no significant interactions between lurasidone and lithium, valproate, ethinyl estradiol, or norelgestromin (the major active metabolite of norgestimate).\n\n\nCONCLUSIONS\nLurasidone PK is altered by strong cytochrome P450 (CYP) 3A4 inhibitors or inducers, and coadministration is contraindicated; whereas moderate CYP3A4 inhibitors have less effect, and lurasidone dosage restrictions are recommended. No dose adjustment for lurasidone is needed when administered with lithium or valproate. Dose adjustment is not required for lithium, valproate, digoxin (a P-glycoprotein substrate), or midazolam or oral contraceptives (CYP3A4 substrates) when coadministered with lurasidone.",
"affiliations": null,
"authors": "Chiu|Yu-Yuan|YY|;Ereshefsky|Larry|L|;Preskorn|Sheldon H|SH|;Poola|Nagaraju|N|;Loebel|Antony|A|",
"chemical_list": "D014150:Antipsychotic Agents; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D054833:Isoindoles; D018020:Lithium Compounds; D013844:Thiazoles; D051544:Cytochrome P-450 CYP3A; D004110:Diltiazem; D000069056:Lurasidone Hydrochloride; D007654:Ketoconazole; D012293:Rifampin",
"country": "Germany",
"delete": false,
"doi": null,
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"issn_linking": "0792-5077",
"issue": "29(3)",
"journal": "Drug metabolism and drug interactions",
"keywords": null,
"medline_ta": "Drug Metabol Drug Interact",
"mesh_terms": "D014150:Antipsychotic Agents; D019540:Area Under Curve; D017321:Clinical Trials, Phase I as Topic; D051544:Cytochrome P-450 CYP3A; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D004110:Diltiazem; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D054833:Isoindoles; D007654:Ketoconazole; D018020:Lithium Compounds; D000069056:Lurasidone Hydrochloride; D012293:Rifampin; D013844:Thiazoles",
"nlm_unique_id": "8904736",
"other_id": null,
"pages": "191-202",
"pmc": null,
"pmid": "24825095",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Lurasidone drug-drug interaction studies: a comprehensive review.",
"title_normalized": "lurasidone drug drug interaction studies a comprehensive review"
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"companynumb": "US-JNJFOC-20141216093",
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"activesubstancename": "LURASIDONE"
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{
"abstract": "Background. Fetal tachycardia may result from the transplacental passage of thyroid stimulating immunoglobulins in a patient with hypothyroidism secondary to ablation of Graves' disease. Case. A 32-year-old woman, gravida 4, para 2, and abortus 1, with hypothyroidism and a history of Graves' disease, presented at 23 6/7 weeks of gestation with a persistent fetal tachycardia. The treatment of the fetal tachycardia with maternally administered digoxin and Sotalol was unsuccessful. Maternal thyroid stimulating immunoglobulins were elevated, and treatment with maternally administered propylthiouracil (PTU) resulted in a normal sinus rhythm for the remainder of the pregnancy. An induction of labor was performed at 37 weeks. Four to five days after delivery, the neonate exhibited clinical signs of hyperthyroidism necessitating treatment. Conclusion. Fetal tachycardia resulting from the transplacental passage of thyroid stimulating immunoglobulins can be successfully treated with maternally administered PTU. The neonate needs to be followed up closely as clinical signs of hyperthyroidism may occur as thyroid stimulating immunoglobulins continue to circulate in the neonate, while the serum levels of PTU decline.",
"affiliations": "The Division of Maternal-Fetal Medicine, Advocate Lutheran General Hospital, Park Ridge, IL 60068, USA ; Parkside Center, 1875 W. Dempster Street, Suite 325, Park Ridge, IL 60068, USA.;The Division of Maternal-Fetal Medicine, Advocate Lutheran General Hospital, Park Ridge, IL 60068, USA ; Parkside Center, 1875 W. Dempster Street, Suite 325, Park Ridge, IL 60068, USA.;The Division of Pediatric Cardiology, Advocate Lutheran General Children's Hospital, Park Ridge, IL 60068, USA.;The Division of Maternal-Fetal Medicine, Advocate Lutheran General Hospital, Park Ridge, IL 60068, USA ; Parkside Center, 1875 W. Dempster Street, Suite 325, Park Ridge, IL 60068, USA.",
"authors": "Parilla|Barbara V|BV|;Hanif|Farhan|F|;Hasbani|Keren|K|;Iannucci|Thomas|T|0000-0003-4153-997X",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2014/968051",
"fulltext": "\n==== Front\nCase Rep Obstet GynecolCase Rep Obstet GynecolCRIOGCase Reports in Obstetrics and Gynecology2090-66842090-6692Hindawi Publishing Corporation 10.1155/2014/968051Case ReportFetal Tachycardia Treated Successfully with Maternally Administered Propylthiouracil Parilla Barbara V. \n1\n\n2\n*Hanif Farhan \n1\n\n2\nHasbani Keren \n3\nhttp://orcid.org/0000-0003-4153-997XIannucci Thomas \n1\n\n2\n1The Division of Maternal-Fetal Medicine, Advocate Lutheran General Hospital, Park Ridge, IL 60068, USA2Parkside Center, 1875 W. Dempster Street, Suite 325, Park Ridge, IL 60068, USA3The Division of Pediatric Cardiology, Advocate Lutheran General Children's Hospital, Park Ridge, IL 60068, USA*Barbara V. Parilla: barbara.parilla@advocatehealth.comAcademic Editor: Giovanni Monni\n\n2014 11 6 2014 2014 96805119 4 2014 26 5 2014 Copyright © 2014 Barbara V. Parilla et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground. Fetal tachycardia may result from the transplacental passage of thyroid stimulating immunoglobulins in a patient with hypothyroidism secondary to ablation of Graves' disease. Case. A 32-year-old woman, gravida 4, para 2, and abortus 1, with hypothyroidism and a history of Graves' disease, presented at 23 6/7 weeks of gestation with a persistent fetal tachycardia. The treatment of the fetal tachycardia with maternally administered digoxin and Sotalol was unsuccessful. Maternal thyroid stimulating immunoglobulins were elevated, and treatment with maternally administered propylthiouracil (PTU) resulted in a normal sinus rhythm for the remainder of the pregnancy. An induction of labor was performed at 37 weeks. Four to five days after delivery, the neonate exhibited clinical signs of hyperthyroidism necessitating treatment. Conclusion. Fetal tachycardia resulting from the transplacental passage of thyroid stimulating immunoglobulins can be successfully treated with maternally administered PTU. The neonate needs to be followed up closely as clinical signs of hyperthyroidism may occur as thyroid stimulating immunoglobulins continue to circulate in the neonate, while the serum levels of PTU decline.\n==== Body\n1. Introduction\n\nHypothyroidism is one of the most common disorders that affect adult women. Overt hypothyroidism occurs in 2% of female adults, and mild hypothyroidism affects approximately 2% of pregnant women and 5–17% of women older than 40 years. The most common cause of primary hypothyroidism is autoimmune thyroiditis, which increases in prevalence with age. Hypothyroidism also occurs frequently after radioiodine therapy and after surgery for hyperthyroidism, goiter, or thyroid cancer. The fetal risk of hyperthyroidism in women with a history of Graves' disease is not always appreciated, particularly in those women receiving thyroid replacement secondary to ablation or surgery. They may still be producing high levels of thyroid stimulating immunoglobulins which are able to cross the placenta and cause hyperthyroidism in the fetus [1–3]. We describe a case of fetal tachycardia secondary to the transplacental passage of thyroid stimulating antibodies, successfully treated with maternally administered PTU.\n\n2. Case\nThe patient is a 32-year-old G4P2012 admitted at 23 6/7 weeks of gestation for fetal tachycardia. The fetal heart rate was noted to be persistently between 180 and 190 beats per minute, which is shown in Figure 1. Fetal ECHO revealed a structurally normal heart, with an isolated pericardial effusion which is demonstrated in Figure 2. The patient's past medical history was significant for Graves' disease for which she underwent radioactive iodine ablation 2 years earlier. She became hypothyroid soon thereafter and has been maintained on thyroid replacement. Her current dose is 150 mcg daily. She had two prior full term vaginal deliveries without complication and one first trimester elective abortion. Her past surgical history was significant for a laparoscopic appendectomy. She denied tobacco, alcohol, or illicit drug use. On arrival to labor and delivery, the fetal tachycardia was again noted. Laboratory studies revealed a normal metabolic and thyroid profile. Stimulating thyroid antibodies were drawn but not yet available. The patient had a normal EKG. Because of the persistence of the fetal tachycardia and the pericardial effusion, the decision was made to treat the fetal tachycardia with maternally administered digoxin. Although there was suspicion that the tachycardia may be secondary to thyroid stimulating immunoglobulins (TSIs), the decision was made to start with our usual first-line drug for SVT in the absence of confirmatory results. The patient was loaded with IV digoxin and subsequently placed on an oral maintenance dose of 0.375 mg daily. She was discharged home with close follow-up.\n\nDespite having a maternal digoxin level as high as 2.5 ng/mL, the tachycardia persisted. Over the following week, she complained of increasing nausea. A maternal EKG showed nonspecific changes. The thyroid stimulating antibodies returned significantly elevated at 195% of basal activity. The digoxin was discontinued, and Sotalol 80 mg PO bid was begun. There was no significant improvement over the following few days with the fetal heart rate between 170 and 190 bpm. The Sotalol was increased to 120 mg bid. A few days later the patient complained of decreased fetal movement. A maternal EKG showed a HR of 62. The decision was then made to begin maternal PTU 100 mg three times a day for presumed fetal hyperthyroidism secondary to the transplacental crossing of maternal thyroid stimulating immunoglobulins. Within 48 hours, the fetus had a normal sinus rhythm of 150 bpm. The Sotalol was decreased to 80 mg bid and discontinued the following visit when the FHR was noted to be 140 bpm.\n\nThe pericardial effusion resolved over the next few weeks, and the fetal heart rate remained normal for the remainder of the pregnancy. She was maintained on the same dose of PTU, and her thyroid function testing remained normal.\n\nAn induction of labor was undertaken at 37 weeks of gestation for presumed fetal hyperthyroidism, which resulted in a vaginal delivery of a live born female infant, with Apgar scores of 9 and 9 after 1 and 5 minutes. The neonate appeared well and in sinus rhythm of 164 bpm. Initial thyroid labs revealed a suppressed TSH of 0.013, a normal free T4 of 1.4 ng/dL, and an elevated free T3 of 5.1 pg/mL. Although the neonate appeared clinically stable, thyroid function tests redrawn at 2 days of age were markedly abnormal, with a TSH of 0.008, free T4 > 8, free T3 > 20, and thyroid stimulating IG 372. By days 4-5 of life she was noted to be tachycardic, jittery, and with loose stools. Methimazole was started at 0.35 mcg every 8 hours. Propranolol 0.5 mg/kg/dose three times a day while being in the hospital for a HR of 180–200, which improved to a baseline of 150 bpm. The neonate was discharged home in stable condition at 1 week of age, with close follow-up. The methimazole was gradually lowered over the following few weeks based on thyroid function testing every 7–10 days. The medication was discontinued at 6 weeks of age.\n\n3. Comment\nApproximately 1 to 5 percent of mothers with hyperthyroidism caused by Graves' disease have fetuses or neonates with hyperthyroidism. Thyroid stimulating immunoglobulins cross the placental barrier and in high titers can stimulate the fetal thyroid gland, which may result in fetal hyperthyroidism [4]. The fetal thyroid gland hypertrophies and thyrotoxicosis can cause fetal tachycardia, goiter, oligohydramnios, intrauterine growth retardation, and accelerated bone maturation. Cardiac failure and hydrops may also occur with severe disease and can have deleterious effects on neural development. Most neonatal Graves' disease occurs in the setting of active Graves' hyperthyroidism in the mother. However, the disorder also can occur in infants of women with a history of Graves' hyperthyroidism treated with thyroidectomy or radioactive iodine in the past [5]. After a woman with Graves' disease undergoes one of these treatments, the risk of having an infant affected by neonatal Graves' disease falls over time, in conjunction with decreases in immunoglobulin levels. The risk of neonatal Graves' disease is generally low five years after radioactive iodine, but some mothers still have persistent elevation and will deliver babies with neonatal Graves' disease [6]. It is worth emphasizing that, in a woman with Graves' disease who has had surgery or ablation and still has elevated TSIs, the risk of fetal/neonatal Graves' disease is higher than in a woman with elevated TSIs who is taking thionamides, as the fetus is exposed only to TSIs and not to treatment.\n\nWith respect to thionamide choice in pregnancy, most clinicians now try to avoid PTU in favor of methimazole after the first trimester due to the risk of maternal agranulocytosis. Furthermore, methimazole crosses the placenta more efficiently. Measurement of maternal serum thyroid stimulating antibodies is warranted in women with active Graves' hyperthyroidism and in women with a history of Graves' disease. Serum thyroid immunoglobulin levels greater than two to three times the upper limit of normal put the fetus at risk for hyperthyroidism [7]. Therefore, fetal heart rate monitoring and serial ultrasounds to check for fetal goiter and growth should be performed when TSIs are elevated [8].\n\nMeasuring the fetal concentration of thyroid hormones when a goiter is noted is useful, as this finding can be associated with both hypothyroidism and hyperthyroidism. However, fetal tachycardia in the setting of elevated thyroid stimulating immunoglobulins has not to our knowledge been reported in association with a different etiology. Given the risks of invasive testing and the remote possibility of a different etiology, we did not pursue direct fetal thyroid testing.\n\nNeonatal hyperthyroidism may occur within 24 to 72 hours after delivery in cases of high maternal thyroid stimulating antibody titers, as the antithyroid drug concentrations decrease, while the maternally derived antibodies persist. This is what occurred in our case. Neonatal hyperthyroidism is usually a transient condition, lasting between 3 and 12 weeks as the maternal antibody clears from the infant's circulation. Treatment of the neonate with antithyroid drugs is indicated until resolution of the hyperthyroidism.\n\nIn conclusion, this is a relatively uncommon case of fetal and neonatal Graves' disease. It serves as an excellent reminder to clinicians to screen women for TSIs in early pregnancy who have either current hyperthyroid disease or hypothyroid disease secondary to ablation or surgery for Graves' disease. Clinicians should remain vigilant for fetal Graves' disease with fetal heart rate assessment and ultrasound for goiter and growth. The pediatrician caring for the neonate needs to be informed, as neonatal Graves' disease affects 2–5% of neonates born to mothers with a history of Graves' disease due to the transplacental transfer of TSIs.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Fetal tachycardia.\n\nFigure 2 Fetal pericardial effusion.\n==== Refs\n1 Skuza KA Sills IN Stene M Rapaport R Prediction of neonatal hyperthyroidism in infants born to mothers with Graves disease Journal of Pediatrics 1996 128 2 264 268 2-s2.0-0030041136 8636826 \n2 Srisupundit K Sirichotiyakul S Tongprasert F Luewan S Tongsong T Fetal therapy in fetal thyrotoxicosis: a case report Fetal Diagnosis and Therapy 2008 23 2 114 116 2-s2.0-40049093261 18033967 \n3 Yazbeck CF Sullivan SD Thyroid disorders during pregnancy Medical Clinics of North America 2012 96 2 235 256 2-s2.0-84858782840 22443973 \n4 ACOG clinical updates in women’s healthcare Thyroid Disorders 2013 12 5 \n5 Hamada N Momotani N Ishikawa N Persistent high TRAb values during pregnancy predict increased risk of neonatal hyperthyroidism following radioiodine therapy for refractory hyperthyroidism Endocrine Journal 2011 58 1 55 58 2-s2.0-79251605567 20962435 \n6 Zimmerman D Fetal and neonatal hyperthyroidism Thyroid 1999 9 7 727 733 2-s2.0-0032783726 10447021 \n7 Peleg D Cada S Peleg A Ben-Ami M The relationship between maternal serum thyroid-stimulating immunoglobulin and fetal and neonatal thyrotoxicosis Obstetrics and Gynecology 2002 99 6 1040 1043 2-s2.0-0036273792 12052596 \n8 Luton D Le Gac I Vuillard E Management of Graves' disease during pregnancy: the key role of fetal thyroid gland monitoring Journal of Clinical Endocrinology and Metabolism 2005 90 11 6093 6098 2-s2.0-27744526660 16118343\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6692",
"issue": "2014()",
"journal": "Case reports in obstetrics and gynecology",
"keywords": null,
"medline_ta": "Case Rep Obstet Gynecol",
"mesh_terms": null,
"nlm_unique_id": "101576454",
"other_id": null,
"pages": "968051",
"pmc": null,
"pmid": "25018884",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "22443973;10447021;8636826;20962435;12052596;16118343;18033967",
"title": "Fetal tachycardia treated successfully with maternally administered propylthiouracil.",
"title_normalized": "fetal tachycardia treated successfully with maternally administered propylthiouracil"
} | [
{
"companynumb": "US-BAYER-2014-112317",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "SOTALOL"
},
"drugadditional": null,
"dru... |
{
"abstract": "The treatment of chronic hypersensitivity pneumonitis (cHP) often includes systemic oral corticosteroids, but the optimal pharmacologic management remains unclear. The morbidity associated with prednisone has motivated the search for alternative therapies. We aimed to determine the effect of treatment with mycophenolate mofetil (MMF) or azathioprine (AZA) on lung function in patients with cHP.\n\n\n\nPatients with cHP treated with either MMF or AZA were retrospectively identified from four interstitial lung disease centers. Change in lung function before and after treatment initiation was analyzed using linear mixed-effects modeling (LMM), adjusting for age, sex, smoking history, and prednisone use.\n\n\n\nSeventy patients were included: 51 were treated with MMF and 19 with AZA. Median follow-up after treatment initiation was 11 months. Prior to treatment initiation, FVC and diffusion capacity of the lung for carbon monoxide (Dlco) % predicted were declining at a mean rate of 0.12% (P < .001) and 0.10% (P < .001) per month, respectively. Treatment with either MMF or AZA was not associated with improved FVC (0.5% at 1 year; P = .46) but was associated with a statistically significant improvement in Dlco of 4.2% (P < .001) after 1 year of treatment. Results were similar in the subgroup of patients treated with MMF for 1 year; the FVC increased nonsignificantly by 1.3% (P = .103) and Dlco increased by 3.9% (P < .001).\n\n\n\nTreatment with MMF or AZA is associated with improvements in Dlco in patients with cHP. Prospective randomized trials are needed to validate their effectiveness for cHP.",
"affiliations": "Department of Medicine, University of California, San Francisco, San Francisco, CA; Department of Medicine, Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada. Electronic address: julie.morisset@umontreal.ca.;Department of Medicine, University of Calgary, Calgary, AB, Canada.;Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA.;Department of Respiratory Diseases, Pontifical Catholic University of Chile, Santiago, Chile.;Department of Radiology, University of California, San Francisco, San Francisco, CA.;Department of Pathology, University of California, San Francisco, San Francisco, CA.;Department of Medicine, University of Calgary, Calgary, AB, Canada.;Department of Medicine, Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada.;Department of Medicine, Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada.;Department of Medicine, University of California, San Francisco, San Francisco, CA.;Department of Medicine, University of California, San Francisco, San Francisco, CA.;Department of Medicine and Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada.;Department of Medicine, University of California, San Francisco, San Francisco, CA.",
"authors": "Morisset|Julie|J|;Johannson|Kerri A|KA|;Vittinghoff|Eric|E|;Aravena|Carlos|C|;Elicker|Brett M|BM|;Jones|Kirk D|KD|;Fell|Charlene D|CD|;Manganas|Helene|H|;Dubé|Bruno-Pierre|BP|;Wolters|Paul J|PJ|;Collard|Harold R|HR|;Ryerson|Christopher J|CJ|;Ley|Brett|B|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D002248:Carbon Monoxide; D009173:Mycophenolic Acid; D001379:Azathioprine; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.chest.2016.10.029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "151(3)",
"journal": "Chest",
"keywords": "azathioprine; hypersensitivity pneumonitis; interstitial lung disease; mycophenolate mofetil",
"medline_ta": "Chest",
"mesh_terms": "D000368:Aged; D000542:Alveolitis, Extrinsic Allergic; D001379:Azathioprine; D002248:Carbon Monoxide; D002908:Chronic Disease; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D011241:Prednisone; D011653:Pulmonary Diffusing Capacity; D012189:Retrospective Studies; D016896:Treatment Outcome; D014797:Vital Capacity",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "619-625",
"pmc": null,
"pmid": "27816444",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "18464307;23828161;18757459;10878285;27245779;23457378;27469583;12697731;27049330;22679012;19466418;24286447;22796841;6861923;21471066;23515438;1731594;2809034;24429272;18096541;8466111;15121492;23392130",
"title": "Use of Mycophenolate Mofetil or Azathioprine for the Management of Chronic Hypersensitivity Pneumonitis.",
"title_normalized": "use of mycophenolate mofetil or azathioprine for the management of chronic hypersensitivity pneumonitis"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP007598",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drug... |
{
"abstract": "Imatinib, a synthetic tyrosine kinase inhibitor, is used as first-line therapy for chronic myeloid leukaemia. Imatinib treatment is associated with a variety of adverse effects, most of which are mild to moderate and generally abate after the first months of treatment. Cutaneous adverse reactions are often encountered in patients using imatinib. Pseudoporphyria is regularly associated with the use of medication, especially naproxen and other nonsteroidal anti-inflammatory drugs, but the list of culprits is expanding. We present a patient with imatinib-induced pseudoporphyria. Taking into account the rapidly growing use of imatinib, physicians should be aware of the possibility of imatinib-induced pseudoporphyria. Adequate photoprotection can improve treatment compliance.",
"affiliations": "Departments of Dermatology, Meander Medical Center, Amersfoort, The Netherlands.",
"authors": "Timmer-de Mik|L|L|;Kardaun|S H|SH|;Kramer|M H H|MH|;Hayes|D P|DP|;Bousema|M T|MT|",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D003561:Cytarabine; D000068877:Imatinib Mesylate",
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-2230.2008.02985.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0307-6938",
"issue": "34(6)",
"journal": "Clinical and experimental dermatology",
"keywords": null,
"medline_ta": "Clin Exp Dermatol",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D001549:Benzamides; D003561:Cytarabine; D003875:Drug Eruptions; D004359:Drug Therapy, Combination; D006801:Humans; D000068877:Imatinib Mesylate; D007951:Leukemia, Myeloid; D008297:Male; D010879:Piperazines; D011164:Porphyrias; D011743:Pyrimidines",
"nlm_unique_id": "7606847",
"other_id": null,
"pages": "705-7",
"pmc": null,
"pmid": "19077095",
"pubdate": "2009-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Imatinib-induced pseudoporphyria.",
"title_normalized": "imatinib induced pseudoporphyria"
} | [
{
"companynumb": "ES-MYLANLABS-2019M1077974",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": "3",
... |
{
"abstract": "Colorectal cancer is the third most common type of cancer worldwide, with >1 million cases diagnosed each year. Gastrointestinal bleeding is a common complication of colorectal cancer and is usually associated with the erosion and hemorrhage of the primary tumor. However, in patients who undergo a radical hemicolectomy and do not develop local recurrence, gastrointestinal bleeding may be a result of medical treatments or comorbidities. Esophageal bleeding in such patients is rare. Here, a case of severe esophageal bleeding due to anti-angiogenesis therapy with bevacizumab, and chemotherapy with the FOLFIRI regimen (irinotecan, folinic acid and 5-fluorouracil) in a patient with colorectal cancer is reported, and the possible pathogenesis of this event is analyzed based on the existing literature, in order to provide a reference for such cases.",
"affiliations": "Department of Medical Oncology, Second Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang 310009, P.R. China.;Department of Medical Oncology, Second Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang 310009, P.R. China.;Department of Medical Oncology, Second Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang 310009, P.R. China.;Department of Gastroenterology, Second Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang 310009, P.R. China.;Department of Medical Oncology, Second Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang 310009, P.R. China.",
"authors": "Shen|Hong|H|;Ye|Xian-Yun|XY|;Li|Xiao-Fen|XF|;Pan|Wen-Sheng|WS|;Yuan|Ying|Y|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2015.3742",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-1074",
"issue": "10(6)",
"journal": "Oncology letters",
"keywords": "bevacizumab; chemotherapy; colorectal cancer; esophageal bleeding",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "3660-3662",
"pmc": null,
"pmid": "26788187",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": "22504701;20865298;1870364;21543627;15175435;12098057;9152801;16427955;4536683;22209842;22776219;17442997;22468077;8996061;12903007;21525806;22862960;2783842;22898408;18408972",
"title": "Severe esophageal bleeding in colorectal cancer due to antitumor therapy: A case report.",
"title_normalized": "severe esophageal bleeding in colorectal cancer due to antitumor therapy a case report"
} | [
{
"companynumb": "CN-ACCORD-037625",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Ulcerative sarcoidosis is a rare variant of cutaneous sarcoidosis that may present as ulceration with necrotic yellow plaques on the lower extremities, face, arms, trunk, or genital area. Adalimumab, a human monoclonal anti-TNF antibody, is an emerging treatment for recalcitrant cutaneous sarcoidosis. We describe severe ulcerative sarcoidosis in a 60-year-old woman with chronic ulcerative necrobiosis lipoidica-like plaques on her left arm for over 20 years. Her condition had not responded to previous treatments with hydroxychloroquine, methotrexate, and sulfasalazine. After a four-month course of adalimumab therapy in addition to pentoxifylline and prednisone with taper, the patient had significant improvement in her skin disease.",
"affiliations": "Division of Dermatology, University of Kansas Medical Center, Kansas City, KS. arajpara@kumc.edu.",
"authors": "Vetos|Develyn|D|;Wu|Dominic J|DJ|;Downing|Malia B|MB|;Rajpara|Anand|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5070/D327654058",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "27(6)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": null,
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34387059",
"pubdate": "2021-06-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Adalimumab for treatment of severe ulcerative sarcoidosis.",
"title_normalized": "adalimumab for treatment of severe ulcerative sarcoidosis"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2022-01277",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugad... |
{
"abstract": "OBJECTIVE\nContinuous antipsychotic treatment is important in schizophrenia, and studies have shown that rates of discontinuation are high. Some studies suggest that weight gain may lead schizophrenic patients to discontinue treatment, whereas other studies show smaller effects of weight gain on medication discontinuation, and some find weight gain associated with symptom improvement. Our retrospective cohort study investigated the effect of weight change on the continued use for 1 year (persistence) of all antipsychotics, then among users of first-generation antipsychotics and second-generation antipsychotics (SGAs), and lastly subgroups of SGAs.\n\n\nMETHODS\nWe identified 2130 patients with schizophrenia starting an antipsychotic that had not used 1 in the prior year. Using multivariable logistic regression adjusted for demographic and clinical variables, we determined the odds of remaining persistent on medication among patients who either gained weight or did not gain weight in the following year.\n\n\nRESULTS\nFor all antipsychotics combined, weight change was not associated with persistence. Among SGAs, weight gain was associated with a 23% increase in the adjusted odds ratio (OR) for persistence (OR, 1.23; 95% confidence interval [CI], 1.00-1.51), whereas there was a nonsignificant decrease in the adjusted odds of persistence among first-generation antipsychotic users (OR, 0.74; 95% CI, 0.43-1.28). When SGAs were divided into subgroups (clozapine/olanzapine, risperidone/quetiapine), both had increases in the likelihood of persistence, but only the association for clozapine/olanzapine was significant at a trend level (adjusted OR, 1.46; 95% CI, 0.99-2.16).\n\n\nCONCLUSIONS\nThese findings are supportive of other research that shows weight gain does not invariably lead to medication discontinuation and may be associated with clinical improvement.",
"affiliations": "From the *Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System; †Department of Psychiatry, Boston University School of Medicine; ‡Department of Biostatistics, Boston University School of Public Health; §Harvard Medical School; and ¶Division of Aging, Brigham and Women's Hospital, Boston, MA.",
"authors": "Monnelly|Edward P|EP|;Fonda|Jennifer|J|;Gagnon|David R|DR|;Chittamooru|Subha|S|;Lawler|Elizabeth V|EV|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/JCP.0000000000000262",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-0749",
"issue": "35(1)",
"journal": "Journal of clinical psychopharmacology",
"keywords": null,
"medline_ta": "J Clin Psychopharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012559:Schizophrenia; D012565:Schizophrenic Psychology; D014481:United States; D014493:United States Department of Veterans Affairs; D014728:Veterans; D015430:Weight Gain",
"nlm_unique_id": "8109496",
"other_id": null,
"pages": "57-62",
"pmc": null,
"pmid": "25514067",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": null,
"title": "Weight gain on antipsychotic medication is associated with sustained use among veterans with schizophrenia.",
"title_normalized": "weight gain on antipsychotic medication is associated with sustained use among veterans with schizophrenia"
} | [
{
"companynumb": "US-JNJFOC-20150412931",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": null,
... |
{
"abstract": "The utility of routine transesophageal echocardiography (TEE) to exclude left atrial appendage (LAA) thrombus before atrial fibrillation (AF) ablation in patients treated with nonvitamin K oral anticoagulant (NOAC) therapy is unclear. This single-center retrospective study sought to investigate the incidence of LAA thrombus in patients undergoing routine TEE before AF ablation treated with warfarin or NOAC therapy. We included 937 routine pre-AF ablation TEE procedures performed in patients treated with warfarin (n = 517) or NOAC (n = 420). Patients were anticoagulated without interruption for at least 4 consecutive weeks before the TEE. Patients treated with warfarin had lower LAA velocity and underwent TEE earlier in the study period than those treated with NOAC (p <0.05). The incidence of LAA thrombus was higher in patients treated with warfarin (1.55%, 8 of 517) compared with patients treated with NOAC (0.24%, 1 of 420, p = 0.0473 for difference). No LAA thrombus was identified in NOAC-treated patients with a CHA2DS2-VASC score <5 and in warfarin-treated patients with a CHA2DS2-VASC score <2. TEE-related complications occurred in 3 of 937 procedures (0.3%). In conclusion, LAA thrombus is detected rarely during pre-AF ablation TEE. Treatment with an NOAC is associated with a lower incidence of pre-AF ablation LAA thrombus compared with warfarin.",
"affiliations": "Division of Cardiology, Duke University Medical Center, Durham, North Carolina.;Division of Cardiology, Duke University Medical Center, Durham, North Carolina; Duke Center for Atrial Fibrillation, Duke University Health System, Durham, North Carolina.;Division of Cardiology, Duke University Medical Center, Durham, North Carolina; Duke Center for Atrial Fibrillation, Duke University Health System, Durham, North Carolina.;Division of Cardiology, Duke University Medical Center, Durham, North Carolina; Duke Center for Atrial Fibrillation, Duke University Health System, Durham, North Carolina.;Division of Cardiology, Duke University Medical Center, Durham, North Carolina; Duke Center for Atrial Fibrillation, Duke University Health System, Durham, North Carolina.;Division of Cardiology, Duke University Medical Center, Durham, North Carolina.;Division of Cardiology, Duke University Medical Center, Durham, North Carolina.;Division of Cardiology, Duke University Medical Center, Durham, North Carolina; Duke Center for Atrial Fibrillation, Duke University Health System, Durham, North Carolina. Electronic address: brett.atwater@duke.edu.",
"authors": "Wyrembak|Joanne|J|;Campbell|Kristen B|KB|;Steinberg|Benjamin A|BA|;Bahnson|Tristram D|TD|;Daubert|James P|JP|;Velazquez|Eric J|EJ|;Samad|Zainab|Z|;Atwater|Brett D|BD|",
"chemical_list": "D000925:Anticoagulants; D003287:Contrast Media; D065427:Factor Xa Inhibitors; D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjcard.2016.12.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9149",
"issue": "119(7)",
"journal": "The American journal of cardiology",
"keywords": null,
"medline_ta": "Am J Cardiol",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D020517:Atrial Appendage; D017115:Catheter Ablation; D003287:Contrast Media; D017548:Echocardiography, Transesophageal; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D018570:Risk Assessment; D013927:Thrombosis; D014859:Warfarin",
"nlm_unique_id": "0207277",
"other_id": null,
"pages": "1017-1022",
"pmc": null,
"pmid": "28153350",
"pubdate": "2017-04-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Incidence and Predictors of Left Atrial Appendage Thrombus in Patients Treated With Nonvitamin K Oral Anticoagulants Versus Warfarin Before Catheter Ablation for Atrial Fibrillation.",
"title_normalized": "incidence and predictors of left atrial appendage thrombus in patients treated with nonvitamin k oral anticoagulants versus warfarin before catheter ablation for atrial fibrillation"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-018808",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Adolescence is a critical time of physiological, cognitive, and social development. It is also a time of increased risk-taking and vulnerability for psychopathology. White matter (WM) changes during adolescence have been better elucidated in the last decade, but how WM is impacted by psychopathology during this time remains unclear. Here, we examined the link between WM microstructure and psychopathology during adolescence. Twenty youth diagnosed with affective, attentional, and behavioral disorders (clinical sample), and 20 age-matched controls were recruited to examine group differences in WM microstructure, attentional control, and the link between them. The main results showed that clinical sample had relatively lower attentional control and fractional anisotropy (FA) in WM throughout the brain: two association tracts were identified, and many differences were found in areas rich in callosal and projection fibers. Moreover, increased FA was positively associated with attention performance in the clinical sample in structures supporting ventral WM pathways, whereas a similar link was identified in controls in dorsal WM association fibers. Overall, these results support a model of general impairment in WM microstructure combined with reliance on altered, perhaps less efficient, pathways for attentional control in youth with affective, attentional, and behavioral disorders.",
"affiliations": "Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA. andrea.shafer@nih.gov.;Department of Psychiatry, University of Alberta, Edmonton, AB, Canada.;Department of Psychiatry, University of Alberta, Edmonton, AB, Canada.;Department of Psychiatry, University of Alberta, Edmonton, AB, Canada.;Department of Educational Psychology, University of Alberta, Edmonton, AB, Canada.;Department of Psychiatry, University of Alberta, Edmonton, AB, Canada.;Department of Psychiatry, University of Alberta, Edmonton, AB, Canada.;Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada. asinghal@ualberta.ca.",
"authors": "Shafer|Andrea T|AT|http://orcid.org/0000-0003-4599-5980;Benoit|James R|JR|;Brown|Matthew R G|MRG|;Greenshaw|Andy J|AJ|;Van Vliet|K Jessica|KJ|;Vohra|Sunita|S|;Dolcos|Florin|F|;Singhal|Anthony|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s11682-019-00211-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1931-7557",
"issue": "14(2)",
"journal": "Brain imaging and behavior",
"keywords": "ADHD; Adolescent; Cognition; DTI; Emotion; Imaging; Mental health",
"medline_ta": "Brain Imaging Behav",
"mesh_terms": "D000293:Adolescent; D016880:Anisotropy; D001288:Attention; D001921:Brain; D003071:Cognition; D056324:Diffusion Tensor Imaging; D005260:Female; D006801:Humans; D008297:Male; D001523:Mental Disorders; D066127:White Matter",
"nlm_unique_id": "101300405",
"other_id": null,
"pages": "599-614",
"pmc": null,
"pmid": "31838614",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Differences in attentional control and white matter microstructure in adolescents with attentional, affective, and behavioral disorders.",
"title_normalized": "differences in attentional control and white matter microstructure in adolescents with attentional affective and behavioral disorders"
} | [
{
"companynumb": "US-OTSUKA-2020_014356",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Extraneural dissemination of primary intracranial tumours to the peritoneal cavity via ventriculoperitoneal shunts is rare, with medulloblastoma and germ-cell tumours most common and gliomas seldom implicated. This report is the first described case of a diffuse midline glioma H3 K27M-mutant disseminating to the peritoneal cavity via a shunt. A four-year-old female presented with a large solid-cystic lesion centred on the suprasellar cistern, histologically revealed to be diffuse midline glioma H3 K27M-mutant. The patient received multiple courses of radiotherapy to the primary lesion and metachronous spinal metastases, and underwent bilateral ventriculoperitoneal shunts. She presented fourteen months following diagnosis with acute hydrocephalus and massive ascites revealed to be due to histologically confirmed intra-abdominal glioma metastasis secondary to shunting. Bilateral ventriculoatrial shunts along with targeted abdominal radiotherapy and repeated ascitic drainage were performed. The patient died one month later. A literature review demonstrated that intra-abdominal glioma metastasis is an extremely rare complication of cerebrospinal fluid diversion predominantly affecting paediatric patients with high-grade lesions within the first year after diagnosis and portends poor prognosis. Predisposition to metastasis is likely associated with tumour proximity to cerebrospinal fluid spaces and tumour biology. Contraindicating shunting in the presence of an intracranial tumour cannot be endorsed but rather shunt-related metastasis should be an acknowledged risk, and not-to-be-forgotten presentation.",
"affiliations": "Neurosurgery Department, Queensland Children's Hospital, Brisbane, Queensland, Australia. Electronic address: seanchristopher.stephens@health.qld.gov.au.;Neurosurgery Department, Queensland Children's Hospital, Brisbane, Queensland, Australia.;Anatomical Pathology Department, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.;Neurosurgery Department, Queensland Children's Hospital, Brisbane, Queensland, Australia.",
"authors": "Stephens|Sean|S|;Tollesson|Gert|G|;Robertson|Thomas|T|;Campbell|Robert|R|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2019.06.043",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "67()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Diffuse midline glioma; Extraneural metastasis; Peritoneal seeding; Ventriculo-peritoneal shunt",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D001932:Brain Neoplasms; D002675:Child, Preschool; D005260:Female; D005910:Glioma; D006801:Humans; D009366:Neoplasm Seeding; D010534:Peritoneal Neoplasms; D017287:Ventriculoperitoneal Shunt",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "288-293",
"pmc": null,
"pmid": "31266714",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Diffuse midline glioma metastasis to the peritoneal cavity via ventriculo-peritoneal shunt: Case report and review of literature.",
"title_normalized": "diffuse midline glioma metastasis to the peritoneal cavity via ventriculo peritoneal shunt case report and review of literature"
} | [
{
"companynumb": "AU-APOTEX-2019AP021466",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "DISCLOSURES: No funding supported the writing of this commentary. The author has nothing to disclose.",
"affiliations": "University of Arizona College of Pharmacy, Tucson.",
"authors": "Malone|Daniel C|DC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.18553/jmcp.2020.26.12.1612a",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "26(12)",
"journal": "Journal of managed care & specialty pharmacy",
"keywords": null,
"medline_ta": "J Manag Care Spec Pharm",
"mesh_terms": "D003657:Decision Making; D003695:Delivery of Health Care; D057286:Electronic Health Records; D055317:Evidence-Based Practice; D006801:Humans",
"nlm_unique_id": "101644425",
"other_id": null,
"pages": "1612-1614",
"pmc": null,
"pmid": "33252000",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Real-world evidence enhances decision making.",
"title_normalized": "real world evidence enhances decision making"
} | [
{
"companynumb": "US-OTSUKA-2021_011618",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Primary membranous nephropathy (pMN) is less common in women of child-bearing age. The kidney risk factors to adverse maternal-fetal outcomes and the effects of pregnancy on pMN process need to be investigated.\n\n\n\nWe retrospectively screened all the patients with biopsy-proven pMN from 2008 to 2018. Any cases of pregnancy that occurred at the time of pMN diagnosis or during follow-up were included in the study. Clinical and pathological data were collected from all patients at the time of kidney biopsy and their gestational results were recorded.\n\n\n\nOf the 27 pregnancies with gestational time of 35.9 ± 4.5 weeks, 10 adverse maternal-fetal events occurred, including fetal loss (11%), preterm delivery (26%), and severe preeclampsia (15%). The kidney parameters were relatively stable with all preserved kidney function. Time-averaged urinary protein (p < 0.001) and serum albumin (p < 0.001), maximum urinary protein (p = 0.001) and minimum serum albumin (p = 0.01) before week 20, anti-phospholipase A2 receptor (PLA2R) positivity (p = 0.03), and no remission during pregnancy (p = 0.004) were risk factors to adverse maternal-fetal outcomes. Time-averaged urinary protein and serum albumin correlated with the birth weight percentile of neonates.\n\n\n\nPregnancy in pMN patients showed risks to adverse maternal-fetal events. Heavy proteinuria, especially before week 20 of gestation, severe hypoalbuminemia, positive anti-PLA2R, and no remission were risk factors to worse outcomes.",
"affiliations": "Division of Renal, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China.;Division of Renal, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China, cuizhao@bjmu.edu.cn.;Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China.;Division of Renal, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China.;Division of Renal, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China.;Division of Renal, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China.;Division of Renal, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China.;Division of Renal, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China.;Division of Renal, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China.;Division of Renal, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China.",
"authors": "Liu|Zi-Ning|ZN|;Cui|Zhao|Z|;He|Ying-Dong|YD|;Zhang|Yi-Miao|YM|;Wang|Fang|F|;Wang|Xin|X|;Meng|Li-Qiang|LQ|;Cheng|Xu-Yang|XY|;Liu|Gang|G|;Zhao|Ming-Hui|MH|",
"chemical_list": "D001323:Autoantibodies; C516360:PLA2R1 protein, human; D054507:Receptors, Phospholipase A2; D000075462:Serum Albumin, Human",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000505175",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-8095",
"issue": "51(4)",
"journal": "American journal of nephrology",
"keywords": "Membranous nephropathy; Outcomes; Phospholipase A2 receptor; Pregnancy; Risk factor",
"medline_ta": "Am J Nephrol",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D001706:Biopsy; D001724:Birth Weight; D005260:Female; D005313:Fetal Death; D050533:Glomerular Basement Membrane; D015433:Glomerulonephritis, Membranous; D006801:Humans; D008854:Microscopy, Electron; D011225:Pre-Eclampsia; D011247:Pregnancy; D047928:Premature Birth; D054507:Receptors, Phospholipase A2; D012189:Retrospective Studies; D012307:Risk Factors; D000075462:Serum Albumin, Human",
"nlm_unique_id": "8109361",
"other_id": null,
"pages": "304-317",
"pmc": null,
"pmid": "32097941",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Membranous Nephropathy in Pregnancy.",
"title_normalized": "membranous nephropathy in pregnancy"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK202005226",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MAGNESIUM SULFATE"
},
"drugadditional": n... |
{
"abstract": "There is currently no tool available to predict extreme large-for-size (LFS) syndrome, a potentially disastrous complication after adult liver transplantation (LT). We aimed to identify the risk factors for extreme LFS and to build a simple predictive model. A cohort of consecutive patients who underwent LT with full grafts in a single institution was studied. The extreme LFS was defined by the impossibility to achieve direct fascial closure, even after delayed management, associated with early allograft dysfunction or nonfunction. Computed tomography scan-based measurements of the recipient were done at the lower extremity of the xiphoid. After 424 LTs for 394 patients, extreme LFS occurred in 10 (2.4%) cases. The 90-day mortality after extreme LFS was 40.0% versus 6.5% in other patients (P = 0.003). In the extreme LFS group, the male donor-female recipient combination was more often observed (80.0% versus 17.4%; P < 0.001). The graft weight (GW)/right anteroposterior (RAP) distance ratio was predictive of extreme LFS with the highest area under the curve (area under the curve, 0.95). The optimal cutoff was 100 (sensitivity, 100%; specificity, 88%). The other ratios based on height, weight, body mass index, body surface area, and standard liver volume exhibited lower predictive performance. The final multivariate model included the male donor-female recipient combination and the GW/RAP. When the GW to RAP ratio increases from 80, 100, to 120, the probability of extreme LFS was 2.6%, 9.6%, and 29.1% in the male donor-female recipient combination, and <1%, 1.2%, and 4.5% in other combinations. In conclusion, the GW/RAP ratio predicts extreme LFS and may be helpful to avoid futile refusal for morphological reasons or to anticipate situation at risk, especially in female recipients. Liver Transplantation 23 1294-1304 2017 AASLD.",
"affiliations": "Digestive Surgery and Liver Transplantation, Hepatobiliary Center, Paul Brousse Hospital, Villejuif, France.;Digestive Surgery and Liver Transplantation, Hepatobiliary Center, Paul Brousse Hospital, Villejuif, France.;Digestive Surgery and Liver Transplantation, Hepatobiliary Center, Paul Brousse Hospital, Villejuif, France.;Digestive Surgery and Liver Transplantation, Hepatobiliary Center, Paul Brousse Hospital, Villejuif, France.;Digestive Surgery and Liver Transplantation, Hepatobiliary Center, Paul Brousse Hospital, Villejuif, France.;Digestive Surgery and Liver Transplantation, Hepatobiliary Center, Paul Brousse Hospital, Villejuif, France.;Digestive Surgery and Liver Transplantation, Hepatobiliary Center, Paul Brousse Hospital, Villejuif, France.;Digestive Surgery and Liver Transplantation, Hepatobiliary Center, Paul Brousse Hospital, Villejuif, France.;Digestive Surgery and Liver Transplantation, Hepatobiliary Center, Paul Brousse Hospital, Villejuif, France.",
"authors": "Allard|Marc-Antoine|MA|;Lopes|Felipe|F|;Frosio|Fabio|F|;Golse|Nicolas|N|;Sa Cunha|Antonio|A|;Cherqui|Daniel|D|;Castaing|Denis|D|;Adam|René|R|;Vibert|Eric|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/lt.24835",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-6465",
"issue": "23(10)",
"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": "D000293:Adolescent; D000328:Adult; D000368:Aged; D064591:Allografts; D001830:Body Surface Area; D005260:Female; D005602:France; D006085:Graft Survival; D006498:Hepatectomy; D006801:Humans; D008099:Liver; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D009929:Organ Size; D011183:Postoperative Complications; D011446:Prospective Studies; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D013577:Syndrome; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100909185",
"other_id": null,
"pages": "1294-1304",
"pmc": null,
"pmid": "28779555",
"pubdate": "2017-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Extreme large-for-size syndrome after adult liver transplantation: A model for predicting a potentially lethal complication.",
"title_normalized": "extreme large for size syndrome after adult liver transplantation a model for predicting a potentially lethal complication"
} | [
{
"companynumb": "FR-ROCHE-2006481",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nTo demonstrate the feasibility and safety of performing elective percutaneous coronary intervention (PCI) during contrast reaction producing severe hypotension.\n\n\nBACKGROUND\nThe development of profound hypotension due to a contrast reaction requires emergency treatment and usually signals procedure termination.\n\n\nRESULTS\nWe report successful completion of planned PCI with blood pressure support with vasopressors during contrast-induced hypotension in nine procedures in three patients with previously known contrast reaction causing hypotension.\n\n\nCONCLUSIONS\nThis case series provides support for the feasibility and safety of performing successful planned PCI under blood pressure support in patients with contrast reaction causing severe hypotension. A management approach for considering intervention in the setting of contrast-induced hypotension is provided.",
"affiliations": "University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;Arkansas Heart Hospital, Little Rock, Arkansas, USA.;University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.;University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.",
"authors": "Soomro|Armaghan Y|AY|;Almaddah|Nureddin|N|;Lendel|Vasili|V|;Agarwal|Shiv Kumar|SK|;Uretsky|Barry F|BF|https://orcid.org/0000-0001-9423-4702",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/ccd.29958",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1522-1946",
"issue": null,
"journal": "Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions",
"keywords": "complications; contrast reaction; percutaneous coronary intervention",
"medline_ta": "Catheter Cardiovasc Interv",
"mesh_terms": null,
"nlm_unique_id": "100884139",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34551189",
"pubdate": "2021-09-22",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Elective percutaneous coronary intervention performed during contrast-induced hypotension.",
"title_normalized": "elective percutaneous coronary intervention performed during contrast induced hypotension"
} | [
{
"companynumb": "US-GE HEALTHCARE LIFE SCIENCES-2021CSU004847",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IOHEXOL"
},
"drugadditiona... |
{
"abstract": "Shoulder arthroplasty (SA) is commonly performed in patients with rheumatoid arthritis (RA) who have been treated with long-term immunosuppressive medication. RA is associated with an increased risk of neoplasms of the immune system. A case of non-Hodgkin's lymphoma as an unexpected diagnosis after the routine pathologic examination of the soft tissues after SA was detected in a 54-year-old woman with long-standing RA and prolonged immunosuppressive therapy. Although this case does not support the cost-effectiveness of routine specimen evaluation during SA, we suggest that histological analysis of the surgical tissues is appropriate and should be performed in all patients who have been treated with prolonged immunosuppressive medication, especially RA patients as well as patients who have suspicious surgical findings.",
"affiliations": "Advanced Orthopaedic Centers, HealthSouth Medical Center, Richmond, Virginia 23294, USA.",
"authors": "Arredondo|J|J|;Worland|R L|RL|;Sinnenberg|R J|RJ|;Qureshi|G D|GD|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/s0883-5403(99)90211-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-5403",
"issue": "14(1)",
"journal": "The Journal of arthroplasty",
"keywords": null,
"medline_ta": "J Arthroplasty",
"mesh_terms": "D001172:Arthritis, Rheumatoid; D019643:Arthroplasty, Replacement; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008875:Middle Aged; D011859:Radiography; D012785:Shoulder Joint",
"nlm_unique_id": "8703515",
"other_id": null,
"pages": "108-11",
"pmc": null,
"pmid": "9926962",
"pubdate": "1999-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Non-Hodgkin's lymphoma as an unexpected diagnosis in a shoulder arthroplasty.",
"title_normalized": "non hodgkin s lymphoma as an unexpected diagnosis in a shoulder arthroplasty"
} | [
{
"companynumb": "US-PFIZER INC-2020074647",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "Patients who have overdosed on drugs commonly present to emergency departments, with only the most severe cases requiring intensive care unit (ICU) admission. Such patients typically survive hospitalisation. We studied their longer term functional outcomes and recovery patterns which have not been well described. All patients admitted to the 18-bed ICU of a university-affiliated teaching hospital following drug overdoses between 1 January 2004 and 31 December 2006 were identified. With ethical approval, we evaluated the functional outcome and recovery patterns of the surviving patients 31 months after presentation, by telephone or personal interview. These were recorded as Glasgow outcome score, Karnofsky performance index and present work status. During the three years studied, 43 patients were identified as being admitted to our ICU because of an overdose. The average age was 34 years, 72% were male and the mean APACHE II score was 16.7. Of these, 32 were discharged from hospital alive. Follow-up data was attained on all of them. At a median of 31 months follow-up, a further eight had died. Of the 24 surviving there were 13 unemployed, seven employed and four in custody. The median Glasgow outcome score of survivors was 4.5, their Karnofsky score 80. Admission to ICU for treatment of overdose is associated with a very high risk of death in both the short- and long-term. While excellent functional recovery is achievable, 16% of survivors were held in custody and 54% unemployed.",
"affiliations": "Department of Anaesthesia and Intensive Care, Mater Misericordiae University Hospital, Dublin, Ireland.",
"authors": "O'Brien|B P|BP|;Murphy|D|D|;Conrick-Martin|I|I|;Marsh|B|B|",
"chemical_list": "D000701:Analgesics, Opioid; D013287:Illicit Drugs; D003932:Heroin; D003042:Cocaine",
"country": "United States",
"delete": false,
"doi": "10.1177/0310057X0903700508",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0310-057X",
"issue": "37(5)",
"journal": "Anaesthesia and intensive care",
"keywords": null,
"medline_ta": "Anaesth Intensive Care",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000428:Alcohol Drinking; D000701:Analgesics, Opioid; D003042:Cocaine; D062787:Drug Overdose; D004651:Employment; D005260:Female; D005500:Follow-Up Studies; D023261:Glasgow Outcome Scale; D003932:Heroin; D006801:Humans; D013287:Illicit Drugs; D007362:Intensive Care Units; D017567:Karnofsky Performance Status; D008297:Male; D008875:Middle Aged; D019966:Substance-Related Disorders; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0342017",
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"abstract": "A 4-month-old infant with trisomy 21 and repaired complete atrioventricular septal defect developed endocarditis with methicillin-resistant Staphylococcus aureus in the early postoperative period. We report the successful replacement of the common atrioventricular valve with a single St. Jude mechanical prosthetic valve, along with an intraluminal pulmonary artery banding to restrict pulmonary flow.",
"affiliations": "Division of Cardiology, Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, Mich, USA.",
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"title": "Successful replacement of common atrioventricular valve with a single mechanical prosthetic valve in an infant with repaired complete atrioventricular septal defect and methicillin-resistant Staphylococcus aureus endocarditis.",
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"abstract": "This article describes a case involving the resolution of hypsarrhythmia, a generalized abnormal EEG pattern, following focal resection of a cortical tuber in a patient with tuberous sclerosis.",
"affiliations": "Department of Neuroscience Marshall University 1600 Medical Center Drive, Suite B500 Huntington 25701 West Virginia USA.;Department of Neuroscience Marshall University 1600 Medical Center Drive, Suite B500 Huntington 25701 West Virginia USA.;Department of Neuroscience Marshall University 1600 Medical Center Drive, Suite B500 Huntington 25701 West Virginia USA.",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.780CCR3780Case ReportCase ReportsNovel case of resolution of hypsarrhythmia following tuber resection in a patient with infantile spasms and tuberous sclerosis R. Marsh et al.Marsh Robert \n1\n\n2\nNichols Courtney \n1\nPayne Mary paynem@marshall.edu \n1\n1 Department of NeuroscienceMarshall University1600 Medical Center Drive, Suite B500Huntington25701West VirginiaUSA2 Present address: Department of NeurosurgeryWVU1 Medical Center Drive, Suite 4300Morgantown26506‐9183West VirginiaUSA* Correspondence\n\nMary Payne, Department of Neuroscience, Marshall University, 1600 Medical Center Drive, Suite B500, Huntington, 25701 WV, USA. Tel: 304‐691‐1787; Fax: 304‐691‐1477; E‐mail: paynem@marshall.edu\n19 4 2017 6 2017 5 6 10.1002/ccr3.2017.5.issue-6859 862 26 7 2016 18 10 2016 23 11 2016 © 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nThis article describes a case involving the resolution of hypsarrhythmia, a generalized abnormal EEG pattern, following focal resection of a cortical tuber in a patient with tuberous sclerosis.\n\nHypsarrhythmiatuber resectiontuberous sclerosis source-schema-version-number2.0component-idccr3780cover-dateJune 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.1.0 mode:remove_FC converted:05.06.2017\n==== Body\nTuberous sclerosis is an autosomal‐dominant genetic disorder caused by a mutation in either the TSC1 gene on chromosome 9q34 or the TSC2 gene on chromosome 16p13 1. Tuberous sclerosis (TS) has a characteristic triad of clinical symptoms including various cutaneous manifestations, mental retardation, and epilepsy. More than 90% of patients diagnosed with tuberous sclerosis will initially present with seizures with more than 70% presenting within the first year of life, and more than 80% will have epilepsy 1, 2, 3. These seizures can vary in both frequency and severity and can range in character from focal seizures with or without impaired consciousness to generalized convulsive seizures. EEG findings in these patients often demonstrate focal spikes correlating with focal cortical tubers. When generalized patterns are recorded, such as generalized spike and wave activity, this is thought to be secondarily generalized from a focal epileptiform region.\n\nApproximately one‐third of infants with TS will have infantile spasms 2. These infants may be diagnosed with West syndrome, which is defined by the triad of infantile spasms (IS), mental retardation, and a hypsarrhythmia pattern on EEG. The generation of hypsarrhythmia pattern in patients with tuberous sclerosis is not well understood 4. Patients diagnosed with both TS and West syndrome are known to have an overall poor prognosis including intractable seizures, abnormal EEG findings, developmental delays, lower IQs, and significant behavioral problems (including autism) 2, 5, 6, 7, 8. Even after infantile spasms resolve in these patients, studies have shown that all patients will progress to other forms of seizures, including both partial and generalized seizures 6.\n\nDue to the various long‐term effects of intractable seizures in TS, it is important to attempt to control epilepsy at a young age. Most patients with TS have intractable seizures that are refractory to antiepileptic medications 1, 2. Other treatments options include a ketogenic diet, vagal nerve stimulator, or surgery 9. Surgical treatment for seizures in tuberous sclerosis has been shown to improve seizure frequency and long‐term outcomes 1, 2, 8, 9, 10, 11. Baumgartner et al. described four patients, three of which had IS, and all underwent focal resection with dramatic improvement in seizure frequency. In this study, age at presentation ranged from 5 months to 5 years with surgical resection occurring between 5 years and adulthood. In these patients, focal resections were targeted in conjunction with focal interictal spikes. Guerreiro et al. described 12 patients with TS and intractable seizures who all showed improvement in seizure frequency and severity following focal surgical resection of epileptogenic lesions that correlated well by imaging, EEG, and clinical symptoms 1.\n\nIn this report, we present the case of a 13‐month‐old girl with tuberous sclerosis who presented with a large right frontal cortical tuber and hypsarrhythmia on EEG. EEG also showed multifocal spikes, with the majority occurring in the right frontal region. Seizures consisted of a tonic spasm with electrographic right frontal onset. Following tuber resection, interictal multifocal spikes remained and right focal spikes were still prominent. However, the EEG hypsarrhythmic pattern resolved and seizure frequency decreased.\n\nOur patient was initially diagnosed with tuberous sclerosis at birth following detection of a cardiac rhabdomyosarcoma. At that time, an EEG was performed to detect any abnormalities and found multifocal spikes. The patient began having seizures soon afterward that were initially described as staring spells, but progressed to generalized convulsive seizures. She was started on phenobarbital, which led to apparent worsening of her seizures. The patient then presented to our institution for a second opinion at 4 months of age. Levetiracetam was added at that time with only minor benefit. An MRI of the brain revealed a large right frontal cortical tuber with mass effect on the left frontal region (see MRI 1 Fig. 1). A repeat EEG carried out at 6 months of age showed hypsarrhythmia with multifocal spikes most frequent in the right frontal region (see EEG 1). Background activity consisted of high‐amplitude activity and chaotic waveforms. Seizure semiology varied, but the most consistent seizure types included complex partial seizures with staring, secondarily generalized seizures with generalized tonic clonic activity, and tonic spasms. EEG captured a tonic spasm, and its electrographic correlate consisted of right frontal low‐amplitude rhythmic spikes with rapid spread of electrographic activity to the left frontal region, then electrographic spread to the adjacent temporal and central regions. Ultimately, secondary generalization occurred (EEG 2). Vigabatrin was initiated, and the dose was increased to 150 mg/kg/day.\n\nFigure 1 Upper left: hypsarrhythmia with predominant frontal spikes, lateralized to the right. Upper right: Absence of hypsarrhythmia with right frontal slowing and right frontal sharp waves. Lower left: MRI brain showing presence of large right frontal cortical tuber. Lower right: MRI brain following tuber removal.\n\nInitially, seizure frequency and severity improved, and the EEG background was lower in amplitude with a regional differentiation and organization. However, this improvement was transient. Thus, it was decided to resect the frontal tuber. The patient's frontal tuber was resected. Pathology revealed brain tissue containing balloon cells with eosinophilic cytoplasm and dystrophic calcifications, consistent with a cortical tuber. Repeat EEG after surgery to remove the frontal tuber revealed resolution of hypsarrhythmia and appearance of regional differentiation. Another EEG was performed 7 months after surgery and again demonstrated absence of hypsarrhythmia and presence of regional organization.\n\nIn this case report, we have presented a unique case of an infant with tuberous sclerosis and West syndrome who had resolution of her interictal hypsarrhythmia pattern on EEG following surgical resection of a right frontal cortical tuber. Although other reports have described seizure improvement and even infantile spasm suppression with focal cortical tuber resection in either focal or generalized epileptiform discharges, this novel case describes resolution of hypsarrhythmia with tuber resection 7. Removal of a focal cortical tuber in an area of glucose hypometabolism seen on PET scan in patients with TS and hypsarrhythmia has previously been shown to improve seizure control and consequently resulted in improved neurological and behavioral development, but no EEG following surgery was shown to have demonstrated resolution of the hypsarrhythmia 4. A previously reported literature review of focal cortical resection in 177 patients with TS and intractable seizures showed complete resolution of seizures in 75%, with seizure onset ranging from age 1 day to 11 years and surgical resection performed between 3 months and 54 years of age 9. This review also looked at corpus callosotomy for multiple patients, showing improvement in seizure frequency, but no cases of seizure cessation following corpus callosotomy 9.\n\nEven though cortical tuber resection has been shown to decrease seizure frequency, several previous studies have questioned where the cortical tubers characteristic of TS is epileptogenic, or whether these tubers induce surrounding cortex to become epileptogenic are themselves electrically silent. Some focal cortical tubers have been shown on ECoG to be electrographically silent, while the brain cortex surrounding these tubers was the origin of epileptiform activity 3. Other focal cortical tubers have been shown on intraoperative ECoG to possess epileptiform discharges intrinsically 1. While studies still debate the precise origins of epileptiform activity in TS, these studies have still all supported the premise that surgical resection of the focal cortical tubers results in improved seizure control and enhanced developmental improvement 1, 3, 4, 9.\n\nSurgical intervention for intractable seizures in TS is primarily indicated in patients where an epileptogenic abnormality can be correlated with a single cortical tuber, imaging abnormalities, EEG findings, and clinical symptoms. Overall prognosis is also greatest in patients with little to no development or behavioral delays at time of surgery. Surgical intervention is also indicated in patients with intractable seizures whose EEG shows a pattern of secondary generalized epilepsy 1, 11.\n\nWhile infantile spasms resolve over time, all patients with TS have been shown to progress to other forms of seizures following resolution of IS 5, 6. These seizures may include tonic spasms or complex partial seizures with EEG demonstrating generalized discharges, focal spikes, or both 2, 7. The type of epilepsy that develops following IS resolution may indicate the long‐term outcome for these patients, with generalized epilepsy having a worse prognosis than localized epilepsy 6.\n\nA long‐term study of the intellectual capacity of TS patients following focal surgical tuber resection showed an objective improvement in patient's developmental age, social skills, and significant improvement in control of both seizure frequency and severity 11. By improving seizure control earlier in patients diagnosed with TS and West syndrome through focal surgical resection, we may be able to minimize developmental delays, improve social skills and behavioral issues, and avoid loss of cognitive function in these patients. In addition, patients with hypsarrhythmia often have poor long‐term outcomes in regard to seizure control and cognition. Thus, the decision to perform tuber resection should be multifactorial to include not only seizure control, but also preservation of cognitive functioning. We present a novel case of resolution of hypsarrhythmia following tuber resection, which may offer benefit to future individual patient outcome.\n\nAuthorship\nRM: is the neurosurgeon who resected frontal cortical tuber. He also contributed to writing the manuscript. CN: is a medical student who compiled the information, images, constructed the article, and performed the literature search. MP: is the neurologist who treated the patient's seizures, performed the EEG, and managed medical decision making.\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\n1 \n\nGuerreiro , M. M. \n, \nF. \nAndermann \n, \nE. \nAndermann \n, \nA. \nPalmini \n, \nP. \nHwang \n, \nH. J. \nHoffman \n, et al. 1998 \nSurgical treatment of epilepsy in tuberous sclerosis . Neurology \n51 :1263 –1269 .9818843 \n2 \n\nThiele , E. \n\n2010 \nManaging and understanding epilepsy in tuberous sclerosis complex . Epilepsia \n51 :90 –91 .20331728 \n3 \n\nMajor , P. \n, \nS. \nRakowski \n, \nM. V. \nSimon \n, \nM. L. \nCheng \n, \nE. \nEskandar \n, \nJ. \nBaron \n, et al. 2009 \nAre cortical tubers epileptogenic? Evidence from electrocorticography \nEpilepsia \n50 :147 –154 .19125835 \n4 \n\nChugani , H. T. \n, \nW. D. \nShields \n, \nD. A. \nShewmon \n, \nD. M. \nOlson \n, \nM. E. \nPhelps \n, and \nW. J. \nPeacock \n. 1990 \nInfantile spasms: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment . Ann. Neurol. \n27 :406 –413 .2353794 \n5 \n\nRiikonen , R. \n, and \nO. \nSimell \n. 1990 \nTuberous sclerosis and infantile spasms . Dev. Med. Child Neurol. \n32 :203 –209 .2155840 \n6 \n\nFukushima , K. \n, \nY. \nInoue \n, \nT. \nFujiwara \n, and \nK. \nYagi \n. 2001 \nLong‐term follow‐up study of West syndrome associated with tuberous sclerosis . Brain Dev. \n23 :698 –704 .11701281 \n7 \n\nOhmori , I. \n, \nY. \nOhtsuka \n, \nS. \nOhno \n, and \nE. \nOka \n. 1998 \nAnalysis of Ictal EEGs of Epilepsy Associated with Tuberous Sclerosis . Epilepsia \n39 :1277 –1283 .9860062 \n8 \n\nWeiner , H. L. \n, \nC. \nCarlson \n, \nE. B. \nRidgway \n, \nC. M. \nZaroff \n, \nD. \nMiles \n, \nJ. \nLaJoie \n, et al. 2006 \nEpilepsy surgery in young children with tuberous sclerosis: results of a novel approach . Pediatrics \n117 :1494 –1502 .16651302 \n9 \n\nJansen , F. E. \n, \nA. C. \nvan Huffelen \n, \nA. \nAlgra \n, and \nO. \nvan Nieuwenhuizen \n. 2007 \nEpilepsy surgery in tuberous sclerosis: a systemic review . Epilepsia \n48 :1477 –1484 .17484753 \n10 \n\nKoh , S. \n, \nP. \nJayakar \n, \nC. \nDunoyer \n, \nS. E. \nWhiting \n, \nT. J. \nResnick \n, \nL. A. \nAlvarez \n, et al. 2000 \nEpilepsy surgery in children with tuberous sclerosis complex: presurgical evaluation and outcome . Epilepsia \n41 :1206 –1213 .10999561 \n11 \n\nZaroff , C. M. \n, \nC. \nMorrison \n, \nN. \nFerraris \n, \nH. L. \nWeiner \n, \nD. K. \nMiles \n, and \nO. \nDevinsky \n. 2005 \nDevelopmental outcome of epilepsy surgery in tuberous sclerosis complex . Epileptic Disord. \n7 :321 –326 .16338674\n\n",
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"title": "Novel case of resolution of hypsarrhythmia following tuber resection in a patient with infantile spasms and tuberous sclerosis.",
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"abstract": "Purpose: To report a case of anterior uveitis in a patient under treatment with Cyclophosphamide / Bortezomid / Dexamethasone (CyBorD) protocol for Multiple Myeloma and concomitant use of Zoledronic acid.Methods: Observational case report of a 50-year-old woman presenting with acute, severe, bilateral uveitis on a medical history of Multiple Myeloma, undergoing the first cycle of CyBorD protocol, including infusion with Zoledronic acid.Results: Continuation of therapy, with parallel treatment with topical and per os steroids led to resolution of the inflammation. Three more chemotherapy cycles were performed with the same protocol including Zoledronic acid at a lower dosage and were all, uneventful.Conclusion: Our case mirrored uveitis cases with either masquerade syndrome due to Multiple Myeloma or following Zoledronic acid infusion, despite concomitant usage of Dexamethasone and Cyclophosphamide. Three consecutive rechallenges were performed without any topical prophylactic treatment and with no relapse of signs or symptoms.",
"affiliations": "Department of Ophthalmology, 251 Hellenic Airforce General Hospital, Athens, Greece.;Department of Ophthalmology, 251 Hellenic Airforce General Hospital, Athens, Greece.;Department of Ophthalmology, 251 Hellenic Airforce General Hospital, Athens, Greece.",
"authors": "Karmiris|Efthymios|E|;Vasilopoulou|Maria-Giannoula|MG|;Chalkiadaki|Evangelia|E|",
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"keywords": "Acute uveitis; anterior uveitis; masquerade syndrome; multiple myeloma; zoledronic acid",
"medline_ta": "Ocul Immunol Inflamm",
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"title": "Acute Bilateral Anterior Uveitis following Cyclophosphamide/ Bortezomid/Dexamethasone (CyBorD) Protocol in a Newly Diagnosed Multiple Myeloma Patient with Concomitant Use of Zoledronic Acid.",
"title_normalized": "acute bilateral anterior uveitis following cyclophosphamide bortezomid dexamethasone cybord protocol in a newly diagnosed multiple myeloma patient with concomitant use of zoledronic acid"
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"abstract": "Hemophagocytic lymphohistiocytosis (HLH) is a rapidly fatal condition characterized by excessive immune activation. HLH can occur as a familial or sporadic acquired disorder. Acquired HLH is more frequently found in adults and is commonly secondary to infections, malignancies, or autoimmune diseases. Diagnosing HLH is challenging because of the rare occurrence, variable presentation, and nonspecific findings of this disorder. Diagnosis of HLH can be based on the diagnostic criteria which were used in the HLH-2004 trial. Given the rarity of this disease, protocols for its treatment have developed slowly, and obtaining adequate short-term and long-term control of the disease continues to be a challenge. Conventional induction therapy for HLH is dexamethasone and etoposide (VP-16), followed by or with cyclosporine. Intrathecal methotrexate ± hydrocortisone is given to those with central nervous system disease. We are reporting a patient who was diagnosed with Epstein-Barr virus (EBV) related HLH. He achieved complete remission with rituximab alone. To our knowledge, this is the first case of an adult patient with EBV related HLH who went into remission with rituximab therapy alone, without using the conventional chemotherapy.",
"affiliations": "Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.;Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.",
"authors": "Al Asad|Omar|O|;Salam|Amir|A|;Mannem|Siva|S|;Ninan|Mary|M|0000-0002-9969-8538;Markowitz|Avi|A|0000-0001-7730-5871;Jana|Bagi|B|",
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"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi Publishing Corporation 10.1155/2015/508387Case ReportAlternative Therapy for Epstein-Barr Virus Related Hemophagocytic Lymphohistiocytosis Al Asad Omar \n*\nSalam Amir Mannem Siva http://orcid.org/0000-0002-9969-8538Ninan Mary http://orcid.org/0000-0001-7730-5871Markowitz Avi Jana Bagi Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA*Omar Al Asad: oaalasad@utmb.eduAcademic Editor: Sercan Aksoy\n\n2015 8 2 2015 2015 50838712 12 2014 24 1 2015 Copyright © 2015 Omar Al Asad et al.2015This 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.Hemophagocytic lymphohistiocytosis (HLH) is a rapidly fatal condition characterized by excessive immune activation. HLH can occur as a familial or sporadic acquired disorder. Acquired HLH is more frequently found in adults and is commonly secondary to infections, malignancies, or autoimmune diseases. Diagnosing HLH is challenging because of the rare occurrence, variable presentation, and nonspecific findings of this disorder. Diagnosis of HLH can be based on the diagnostic criteria which were used in the HLH-2004 trial. Given the rarity of this disease, protocols for its treatment have developed slowly, and obtaining adequate short-term and long-term control of the disease continues to be a challenge. Conventional induction therapy for HLH is dexamethasone and etoposide (VP-16), followed by or with cyclosporine. Intrathecal methotrexate ± hydrocortisone is given to those with central nervous system disease. We are reporting a patient who was diagnosed with Epstein-Barr virus (EBV) related HLH. He achieved complete remission with rituximab alone. To our knowledge, this is the first case of an adult patient with EBV related HLH who went into remission with rituximab therapy alone, without using the conventional chemotherapy.\n==== Body\n1. Introduction\nHemophagocytic lymphohistiocytosis (HLH) is a rapidly fatal condition characterized by fevers, hepatosplenomegaly, and cytopenias. The disease is considered to be a syndrome of excessive immune activation [1]. HLH can occur as a familial or sporadic disorder.\n\nAcquired HLH is more frequently found in adults and is commonly secondary to infections, malignancies, or autoimmune diseases.\n\nDiagnosing HLH is challenging because of the rare occurrence, variable presentation, and nonspecific findings of this disorder. Although the individual signs and symptoms of HLH may occur in a variety of clinical circumstances, the combination of these features, caused by pathologic inflammation, forms the pattern of HLH. Diagnosis of HLH can be based on the diagnostic criteria which were used in the HLH-2004 trial [2, 3] as follows:\n\n\nA. molecular diagnosis consistent with HLH: pathologic mutations of PRF1, UNC13D, Munc18-2, Rab27a, STX11, SH2D1A, or BIRC4, or\n\n\nB. five of the 8 criteria listed below which are fulfilled:fever ≥ 38.5°C;\n\nsplenomegaly;\n\ncytopenias (affecting at least 2 of 3 lineages in the peripheral blood);\n\n\n hemoglobin < 9 g/dL (in infants < 4 weeks: hemoglobin < 10 g/dL),\n\n\n platelets < 100 × 103/mL,\n\n neutrophils < 1 × 103/mL;\n\n\n\n\n\n\n\nhypertriglyceridemia (fasting, >2.9 mmol/L) and/or hypofibrinogenemia (<4.4 mmol/L);\n\nhemophagocytosis in bone marrow, spleen, lymph nodes, or liver;\n\nlow or absent NK-cell activity;\n\nferritin > 1124 mmol/L;\n\nelevated sCD25 (α-chain of sIL-2 receptor).\n\n\n\n\nGiven the rarity of this disease, protocols for its treatment have developed slowly, and obtaining adequate short-term and long-term control of the disease continues to be a challenge.\n\nEBV is the most frequent infection associated with HLH [2]. Because it can eliminate EBV-infected B cells, rituximab may be a beneficial addition to other therapies in patients with progressive EBV-HLH [4]. We present in this report a case of a patient who was diagnosed with HLH after meeting the diagnostic criteria according to HLH-2004. He achieved complete remission with rituximab alone, weekly for 4 doses.\n\n2. Case Report\nA 52-year-old male presented to the hospital with 2 months of fevers of up to 40 degrees Celsius, weakness, and a 15 kg weight loss over 6 months. His past medical history was notable for a cadaveric renal transplant of over 20 years for which he had been on immunosuppressant therapy, mycophenolate, sirolimus, and prednisone. On admission, he was found to have profound anemia with hemoglobin of 4.9 g/dL, a platelet count of 50,000/uL, and ferritin above 22470 mmol/L. He also had elevated liver transaminases fluctuating between 100 and 200 mmol/L. A bone marrow biopsy was performed to look for other causes of his cytopenias such as infectious infiltration; he was found to have hemophagocytosis involving 50% of the histiocytes (Figure 1). Further workup revealed a triglyceride level of 9.04 mmol/L, LDH of 2000 mmol/L, and a soluble IL-2 level of 23,690 pg/mL. Given his history of being on immunosuppressants, an infectious workup for opportunistic infections was investigated upon admission to the hospital. All microbiological cultures were negative. However, he was later found to have profound Epstein-Barr virus infection with 9,380,000 copies/mL in his peripheral blood, as well as EBV positivity in his cerebrospinal fluid. CT of chest, abdomen, and pelvis did not show masses or lymphadenopathy, so we ruled out posttransplant lymphoproliferative disorder. The diagnosis of HLH was made as he met the diagnostic criteria: fever, hemophagocytosis on bone marrow biopsy, elevated ferritin, cytopenias, hypertriglyceridemia, and high soluble IL-2 level.\n\nThe patient's outpatient immunosuppressants were held. He was begun on dexamethasone 10 mg/m2/day according to the HLH-94 protocol [2]. After being on therapy for 3 days, his fevers and cytopenias did not improve. Due to his abnormal kidney and liver function, we did not start conventional chemotherapy (etoposide) [2] and gave him instead rituximab weekly for the EBV infection (375 mg/m2 intravenously). This was based on the knowledge regarding the relationship between EBV infections and HLH [2].\n\nWithin one week following the first dose, his fevers, cytopenias, liver function tests, and inflammatory markers improved significantly. He was given his second dose of rituximab in the hospital setting and discharged safely to continue his third and fourth doses of rituximab in the outpatient setting. During 3-month follow-up period, the patient remained in complete remission. His counts normalized with the exception of his hemoglobin, as he remained mildly anemic due to his transplanted kidney failure and the initiation of dialysis. EBV viral load was checked 7 weeks after finishing treatment, and it was undetectable (Figure 2).\n\n3. Discussion\nThe goal of therapy for patients with HLH is to suppress life-threatening uncontrolled inflammatory reaction. Conventional induction therapy for HLH is dexamethasone and etoposide (VP-16), followed by or with cyclosporine. Intrathecal methotrexate ± hydrocortisone is given to those with central nervous system disease [2, 5].\n\nThere have been studies on the treatment of Epstein-Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemoimmunotherapeutic regimens. These studies demonstrated that rituximab-containing regimens significantly reduce EBV load and signs of inflammation [6, 7].\n\nTo our knowledge, this is the first case of an adult patient with EBV related HLH who went into remission with rituximab therapy alone. On review of the literature, we did find a case in which an adolescent with Crohn's disease was treated with rituximab and had good response [8]. Some case reports also showed the effectiveness of rituximab alone in treating HLH secondary to different triggers other than EBV [9, 10].\n\nRituximab is chimeric monoclonal antibody against the protein CD20. By targeting CD-20 positive B-cells, rituximab decreases the load of the causative pathogen (EBV), which in turn decreases the EBV-induced hyperactive immune response.\n\nIn conclusion, rituximab is a potential alternative treatment for EBV related HLH patients who are not fit for conventional chemotherapy with etoposide. Further clinical trials are warranted on rituximab as a sole treatment.\n\nConsent\nThe patient described in the case report has given his informed consent for the case report to be published.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 The histiocyte in the center of this picture appears “stuffed” with engulfed erythrocyte precursors.\n\nFigure 2 Trend of hemoglobin and markers of disease severity before and after starting rituximab.\n==== Refs\n1 Janka G. Hemophagocytic lymphohistiocytosis: when the immune system runs amok Klinische Padiatrie 2009 221 5 278 285 10.1055/s-0029-1237386 2-s2.0-77949704386 19707989 \n2 Jordan M. B. Allen C. E. Weitzman S. Filipovich A. H. McClain K. L. How I treat hemophagocytic lymphohistiocytosis Blood 2011 118 15 4041 4052 10.1182/blood-2011-03-278127 2-s2.0-80054109736 21828139 \n3 Henter J.-I. Horne A. Aricó M. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis Pediatric Blood and Cancer 2007 48 2 124 131 10.1002/pbc.21039 2-s2.0-33845619137 16937360 \n4 Milone M. C. Tsai D. E. Hodinka R. L. Treatment of primary Epstein-Barr virus infection in patients with X-linked lymphoproliferative disease using B-cell-directed therapy Blood 2005 105 3 994 996 10.1182/blood-2004-07-2965 2-s2.0-12844253028 15494422 \n5 Trottestam H. Horne A. Aricò M. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol Blood 2011 118 17 4577 4584 10.1182/blood-2011-06-356261 2-s2.0-80055079785 21900192 \n6 Chellapandian D. Das R. Zelley K. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens British Journal of Haematology 2013 162 3 376 382 10.1111/bjh.12386 2-s2.0-84880319443 23692048 \n7 Balamuth N. J. Nichols K. E. Paessler M. Teachey D. T. Use of rituximab in conjunction with immunosuppressive chemotherapy as a novel therapy for Epstein Barr virus-associated hemophagocytic lymphohistiocytosis Journal of Pediatric Hematology/Oncology 2007 29 8 569 573 10.1097/MPH.0b013e3180f61be3 2-s2.0-34548406426 17762500 \n8 Fitzgerald M. P. Armstrong L. Hague R. Russell R. K. A case of EBV driven haemophagocytic lymphohistiocytosis complicating a teenage Crohn's disease patient on azathioprine, successfully treated with rituximab Journal of Crohn's and Colitis 2013 7 4 314 317 10.1016/j.crohns.2012.05.002 2-s2.0-84875255740 \n9 So M. W. Koo B. S. Kim Y. J. Kim Y.-G. Lee C.-K. Yoo B. Successful rituximab treatment of refractory hemophagocytic lymphohistiocytosis and autoimmune hemolytic anemia associated with systemic lupus erythematosus Modern Rheumatology 2013 10.1007/s10165-013-0838-7 2-s2.0-84873391329 \n10 Sano T. Sakai H. Takimoto K. Ohno H. Rituximab alone was effective for the treatment of a diffuse large B-cell lymphoma associated with hemophagocytic syndrome International Journal of Clinical Oncology 2007 12 1 59 62 10.1007/s10147-006-0627-9 2-s2.0-33947537946 17380444\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2015()",
"journal": "Case reports in oncological medicine",
"keywords": null,
"medline_ta": "Case Rep Oncol Med",
"mesh_terms": null,
"nlm_unique_id": "101581035",
"other_id": null,
"pages": "508387",
"pmc": null,
"pmid": "25737788",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "16937360;17762500;15494422;17380444;22640698;19707989;21828139;23692048;21900192;24517558",
"title": "Alternative therapy for epstein-barr virus related hemophagocytic lymphohistiocytosis.",
"title_normalized": "alternative therapy for epstein barr virus related hemophagocytic lymphohistiocytosis"
} | [
{
"companynumb": "PHHY2015US034475",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "Neuroleptic malignant syndrome (NMS) is a rare, serious complication caused by neuroleptic medications. It is characterized by rigidity, hyperthermia, tachycardia, leukocytosis, and an elevated creatine kinase (CK). We present a case of a 50-year-old male who underwent bilateral total hip replacements and subsequently developed NMS. This condition is typically triggered by the sudden introduction, omission, or change in dose of a neuroleptic; in contrast with previous case reports of post-surgical NMS, however, no such trigger was identifiable for our patient. Moreover, this is the first reported case of NMS after single-stage bilateral hip arthroplasty. Consequently, by presenting this case report we hope to make clinicians aware of the possibility of NMS occurring after hip arthroplasty in any patient taking longterm neuroleptics.",
"affiliations": null,
"authors": "Halim|Usman|U|;Ajwani|Sanil|S|;Lovell|Martyn|M|",
"chemical_list": "D014150:Antipsychotic Agents; D001843:Bone Cements",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2328-4633",
"issue": "75(4)",
"journal": "Bulletin of the Hospital for Joint Disease (2013)",
"keywords": null,
"medline_ta": "Bull Hosp Jt Dis (2013)",
"mesh_terms": "D014150:Antipsychotic Agents; D019644:Arthroplasty, Replacement, Hip; D001843:Bone Cements; D003866:Depressive Disorder; D006801:Humans; D008297:Male; D008875:Middle Aged; D009459:Neuroleptic Malignant Syndrome; D015207:Osteoarthritis, Hip; D011183:Postoperative Complications",
"nlm_unique_id": "101614130",
"other_id": null,
"pages": "286-288",
"pmc": null,
"pmid": "29151017",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neuroleptic Malignant Syndrome Following Bilateral Cemented Total Hip Replacements.",
"title_normalized": "neuroleptic malignant syndrome following bilateral cemented total hip replacements"
} | [
{
"companynumb": "GB-TEVA-2018-GB-877214",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "Effective treatment of systolic hypertension in elderly patients remains a major therapeutic challenge. A multicenter, double-blind, randomized controlled trial with sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, was conducted to determine its effects versus olmesartan (angiotensin receptor blocker) on central aortic pressures, in elderly patients (aged ≥60 years) with systolic hypertension and pulse pressure >60 mm Hg, indicative of arterial stiffness. Patients (n=454; mean age, 67.7 years; mean seated systolic blood pressure, 158.6 mm Hg; mean seated pulse pressure, 69.7 mm Hg) were randomized to receive once-daily sacubitril/valsartan 200 mg or olmesartan 20 mg, force titrated to double the initial doses after 4 weeks, before primary assessment at 12 weeks. The study extended double-blind treatment for 12 to 52 weeks, during which amlodipine (2.5-5 mg) and subsequently hydrochlorothiazide (6.25-25 mg) were added-on for patients not achieving blood pressure target (<140/90). At week 12, sacubitril/valsartan reduced central aortic systolic pressure (primary assessment) greater than olmesartan by -3.7 mm Hg (P=0.010), further corroborated by secondary assessments at week 12 (central aortic pulse pressure, -2.4 mm Hg, P<0.012; mean 24-hour ambulatory brachial systolic blood pressure and central aortic systolic pressure, -4.1 mm Hg and -3.6 mm Hg, respectively, both P<0.001). Differences in 24-hour ambulatory pressures were pronounced during sleep. After 52 weeks, blood pressure parameters were similar between treatments (P<0.002); however, more patients required add-on antihypertensive therapy with olmesartan (47%) versus sacubitril/valsartan (32%; P<0.002). Both treatments were equally well tolerated. The PARAMETER study (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Measuring Arterial Stiffness in the Elderly), for the first time, demonstrated superiority of sacubitril/valsartan versus olmesartan in reducing clinic and ambulatory central aortic and brachial pressures in elderly patients with systolic hypertension and stiff arteries.",
"affiliations": "From the Department of Cardiovascular Sciences, University College London (UCL), United Kingdom (B.W.); National Institute for Health Research, University College London Hospitals Biomedical Research Centre, United Kingdom (B.W.); Department of Cardiology, University of Cardiff, Wales, United Kingdom (J.R.C.); Jichi Medical School, Tochigi, Japan (K.K.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.H.Z., W.G.); Novartis Pharma AG, Basel, Switzerland (P.C.B.); Beijing Novartis Pharma Co, Ltd, Shanghai, China (Q.W.). bryan.williams@ucl.ac.uk.;From the Department of Cardiovascular Sciences, University College London (UCL), United Kingdom (B.W.); National Institute for Health Research, University College London Hospitals Biomedical Research Centre, United Kingdom (B.W.); Department of Cardiology, University of Cardiff, Wales, United Kingdom (J.R.C.); Jichi Medical School, Tochigi, Japan (K.K.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.H.Z., W.G.); Novartis Pharma AG, Basel, Switzerland (P.C.B.); Beijing Novartis Pharma Co, Ltd, Shanghai, China (Q.W.).;From the Department of Cardiovascular Sciences, University College London (UCL), United Kingdom (B.W.); National Institute for Health Research, University College London Hospitals Biomedical Research Centre, United Kingdom (B.W.); Department of Cardiology, University of Cardiff, Wales, United Kingdom (J.R.C.); Jichi Medical School, Tochigi, Japan (K.K.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.H.Z., W.G.); Novartis Pharma AG, Basel, Switzerland (P.C.B.); Beijing Novartis Pharma Co, Ltd, Shanghai, China (Q.W.).;From the Department of Cardiovascular Sciences, University College London (UCL), United Kingdom (B.W.); National Institute for Health Research, University College London Hospitals Biomedical Research Centre, United Kingdom (B.W.); Department of Cardiology, University of Cardiff, Wales, United Kingdom (J.R.C.); Jichi Medical School, Tochigi, Japan (K.K.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.H.Z., W.G.); Novartis Pharma AG, Basel, Switzerland (P.C.B.); Beijing Novartis Pharma Co, Ltd, Shanghai, China (Q.W.).;From the Department of Cardiovascular Sciences, University College London (UCL), United Kingdom (B.W.); National Institute for Health Research, University College London Hospitals Biomedical Research Centre, United Kingdom (B.W.); Department of Cardiology, University of Cardiff, Wales, United Kingdom (J.R.C.); Jichi Medical School, Tochigi, Japan (K.K.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.H.Z., W.G.); Novartis Pharma AG, Basel, Switzerland (P.C.B.); Beijing Novartis Pharma Co, Ltd, Shanghai, China (Q.W.).;From the Department of Cardiovascular Sciences, University College London (UCL), United Kingdom (B.W.); National Institute for Health Research, University College London Hospitals Biomedical Research Centre, United Kingdom (B.W.); Department of Cardiology, University of Cardiff, Wales, United Kingdom (J.R.C.); Jichi Medical School, Tochigi, Japan (K.K.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.H.Z., W.G.); Novartis Pharma AG, Basel, Switzerland (P.C.B.); Beijing Novartis Pharma Co, Ltd, Shanghai, China (Q.W.).;From the Department of Cardiovascular Sciences, University College London (UCL), United Kingdom (B.W.); National Institute for Health Research, University College London Hospitals Biomedical Research Centre, United Kingdom (B.W.); Department of Cardiology, University of Cardiff, Wales, United Kingdom (J.R.C.); Jichi Medical School, Tochigi, Japan (K.K.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (D.H.Z., W.G.); Novartis Pharma AG, Basel, Switzerland (P.C.B.); Beijing Novartis Pharma Co, Ltd, Shanghai, China (Q.W.).",
"authors": "Williams|Bryan|B|;Cockcroft|John R|JR|;Kario|Kazuomi|K|;Zappe|Dion H|DH|;Brunel|Patrick C|PC|;Wang|Qian|Q|;Guo|Weinong|W|",
"chemical_list": "D000613:Aminobutyrates; D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D007093:Imidazoles; D013777:Tetrazoles; D000068756:Valsartan; C437965:olmesartan; C549068:sacubitril and valsartan sodium hydrate drug combination",
"country": "United States",
"delete": false,
"doi": "10.1161/HYPERTENSIONAHA.116.08556",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0194-911X",
"issue": "69(3)",
"journal": "Hypertension (Dallas, Tex. : 1979)",
"keywords": "central pressure; elderly; sacubitril/valsartan; systolic hypertension",
"medline_ta": "Hypertension",
"mesh_terms": "D000368:Aged; D000613:Aminobutyrates; D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D006439:Hemodynamics; D006801:Humans; D006973:Hypertension; D007093:Imidazoles; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013599:Systole; D013777:Tetrazoles; D013997:Time Factors; D016896:Treatment Outcome; D000068756:Valsartan",
"nlm_unique_id": "7906255",
"other_id": null,
"pages": "411-420",
"pmc": null,
"pmid": "28093466",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Effects of Sacubitril/Valsartan Versus Olmesartan on Central Hemodynamics in the Elderly With Systolic Hypertension: The PARAMETER Study.",
"title_normalized": "effects of sacubitril valsartan versus olmesartan on central hemodynamics in the elderly with systolic hypertension the parameter study"
} | [
{
"companynumb": "GB-DSJP-DSU-2018-100275",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE\\OLMESARTAN MEDOXOMIL"
},
"... |
{
"abstract": "Patients with recent-onset atrial fibrillation commonly undergo immediate restoration of sinus rhythm by pharmacologic or electrical cardioversion. However, whether immediate restoration of sinus rhythm is necessary is not known, since atrial fibrillation often terminates spontaneously.\n\n\n\nIn a multicenter, randomized, open-label, noninferiority trial, we randomly assigned patients with hemodynamically stable, recent-onset (<36 hours), symptomatic atrial fibrillation in the emergency department to be treated with a wait-and-see approach (delayed-cardioversion group) or early cardioversion. The wait-and-see approach involved initial treatment with rate-control medication only and delayed cardioversion if the atrial fibrillation did not resolve within 48 hours. The primary end point was the presence of sinus rhythm at 4 weeks. Noninferiority would be shown if the lower limit of the 95% confidence interval for the between-group difference in the primary end point in percentage points was more than -10.\n\n\n\nThe presence of sinus rhythm at 4 weeks occurred in 193 of 212 patients (91%) in the delayed-cardioversion group and in 202 of 215 (94%) in the early-cardioversion group (between-group difference, -2.9 percentage points; 95% confidence interval [CI], -8.2 to 2.2; P = 0.005 for noninferiority). In the delayed-cardioversion group, conversion to sinus rhythm within 48 hours occurred spontaneously in 150 of 218 patients (69%) and after delayed cardioversion in 61 patients (28%). In the early-cardioversion group, conversion to sinus rhythm occurred spontaneously before the initiation of cardioversion in 36 of 219 patients (16%) and after cardioversion in 171 patients (78%). Among the patients who completed remote monitoring during 4 weeks of follow-up, a recurrence of atrial fibrillation occurred in 49 of 164 patients (30%) in the delayed-cardioversion group and in 50 of 171 (29%) in the early-cardioversion group. Within 4 weeks after randomization, cardiovascular complications occurred in 10 patients and 8 patients, respectively.\n\n\n\nIn patients presenting to the emergency department with recent-onset, symptomatic atrial fibrillation, a wait-and-see approach was noninferior to early cardioversion in achieving a return to sinus rhythm at 4 weeks. (Funded by the Netherlands Organization for Health Research and Development and others; RACE 7 ACWAS ClinicalTrials.gov number, NCT02248753.).",
"affiliations": "From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.;From the Departments of Cardiology (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.) and Clinical Epidemiology and Medical Technology Assessment (B.A.B.E.), the Cardiovascular Research Institute Maastricht (N.A.H.A.P., E.A.M.P.D., J.G.L.M.L., H.J.G.M.C.), Maastricht University Medical Center, Maastricht, VieCuri Medical Center Noord-Limburg, Venlo (J.G.M.), Zuyderland Medical Center, Heerlen (T.L.), Elisabeth-TweeSteden Hospital, Tilburg (J.W.), Diakonessen Hospital, Utrecht (J.J.J.B.), University of Groningen, Groningen (M.R., I.C.V.G.), VU University Medical Center Amsterdam (O.K.) and Academic Medical Center (J.G.P.T), Amsterdam, Medical Spectrum Twente, Enschede (J.M.V.O.), Amphia Hospital, Breda (M.A.), Antonius Hospital, Sneek (A.O.), Alrijne Hospital, Leiderdorp (C.J.K.), St. Antonius Hospital, Nieuwegein (V.F.V.D.), Haga Teaching Hospital, The Hague (H.R.), St. Franciscus Gasthuis, Rotterdam (A.L.), and Catharina Hospital, Eindhoven (L.R.D) - all in the Netherlands.",
"authors": "Pluymaekers|Nikki A H A|NAHA|0000-0002-9663-6315;Dudink|Elton A M P|EAMP|0000-0003-4572-3969;Luermans|Justin G L M|JGLM|;Meeder|Joan G|JG|0000-0003-3261-9361;Lenderink|Timo|T|;Widdershoven|Jos|J|;Bucx|Jeroen J J|JJJ|;Rienstra|Michiel|M|;Kamp|Otto|O|;Van Opstal|Jurren M|JM|;Alings|Marco|M|;Oomen|Anton|A|;Kirchhof|Charles J|CJ|;Van Dijk|Vincent F|VF|;Ramanna|Hemanth|H|;Liem|Anho|A|;Dekker|Lukas R|LR|;Essers|Brigitte A B|BAB|;Tijssen|Jan G P|JGP|;Van Gelder|Isabelle C|IC|;Crijns|Harry J G M|HJGM|;|||",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D004077:Digoxin",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa1900353",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "380(16)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D000368:Aged; D000889:Anti-Arrhythmia Agents; D001281:Atrial Fibrillation; D002121:Calcium Channel Blockers; D004077:Digoxin; D004554:Electric Countershock; D004636:Emergency Service, Hospital; D005260:Female; D006339:Heart Rate; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D012008:Recurrence; D061665:Time-to-Treatment; D016896:Treatment Outcome",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "1499-1508",
"pmc": null,
"pmid": "30883054",
"pubdate": "2019-04-18",
"publication_types": "D000073843:Equivalence Trial; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Early or Delayed Cardioversion in Recent-Onset Atrial Fibrillation.",
"title_normalized": "early or delayed cardioversion in recent onset atrial fibrillation"
} | [
{
"companynumb": "NL-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-014240",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "To identify clinicopathological characteristics, treatment patterns, clinical outcomes and prognostic factors in patients with vulvar melanoma (VM).\n\n\n\nThis retrospective multicentre cohort study included 198 women with VM treated in eight cancer centres in the Netherlands and UK between 1990 and 2017. Clinicopathological features, treatment, recurrence, and survival data were collected. Overall and recurrence-free survival was estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariable Cox regression analysis.\n\n\n\nThe majority of patients (75.8%) had localized disease at diagnosis. VM was significantly associated with high-risk clinicopathological features, including age, tumour thickness, ulceration, positive resection margins and involved lymph nodes. Overall survival was 48% (95% CI 40-56%) and 31% (95% CI 23-39%) after 2 and 5 years respectively and did not improve in patients diagnosed after 2010 compared to patients diagnosed between 1990 and 2009. Recurrence occurred in 66.7% of patients, of which two-third was non-local. In multivariable analysis, age and tumour size were independent prognostic factors for worse survival. Prognostic factors for recurrence were tumour size and tumour type. Only the minority of patients were treated with immuno- or targeted therapy.\n\n\n\nOur results show that even clinically early-stage VM is an aggressive disease associated with poor clinical outcome due to distant metastases. Further investigation into the genomic landscape and the immune microenvironment in VM may pave the way to novel therapies to improve clinical outcomes in these aggressive tumours. Clinical trials with immunotherapy or targeted therapy in patients with high-risk, advanced or metastatic disease are highly needed.",
"affiliations": "Department of Gynaecology, Leiden University Medical Centre, Leiden, the Netherlands. Electronic address: f.l.boer@lumc.nl.;Department of Gynaecology Oncology, Radboud University Medical Centre, the Netherlands.;Department of Biomedical Data Sciences, Leiden University Medical Centre, the Netherlands.;Department of Medical Oncology, Leiden University Medical Centre, Leiden, the Netherlands.;Department of Gynaecology, Leiden University Medical Centre, Leiden, the Netherlands.;Department of Gynaecology, Derriford hospital NHS Trust, Plymouth, United Kingdom.;Department of Gynaecology Oncology, Centre for Gynaecologic Oncology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek, the Netherlands.;Department of Gynaecology Oncology, Erasmus MC Cancer Institute, Erasmus Medical Centre, the Netherlands.;Department of Gynaecology Oncology, Amsterdam University Medical Centre, the Netherlands.;Department of Gynaecology Oncology, Radboud University Medical Centre, the Netherlands.;Department of Gynaecology, Royal Cornwall hospital NHS trust, Truro, United Kingdom.;Department of Gynaecology, Leiden University Medical Centre, Leiden, the Netherlands.",
"authors": "Boer|Florine L|FL|;Ten Eikelder|Mieke L G|MLG|;van Geloven|Nan|N|;Kapiteijn|Ellen H|EH|;Gaarenstroom|Katja N|KN|;Hughes|Geoff|G|;Nooij|Linda S|LS|;Jozwiak|Marta|M|;Tjiong|Ming Y|MY|;de Hullu|Joanne M A|JMA|;Galaal|Khadra|K|;van Poelgeest|Mariette I E|MIE|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ygyno.2021.01.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-8258",
"issue": "161(1)",
"journal": "Gynecologic oncology",
"keywords": "Prognostic factors; Recurrence; Survival; Treatment; Vulvar melanoma",
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000368:Aged; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008545:Melanoma; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D009426:Netherlands; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D006113:United Kingdom; D014846:Vulvar Neoplasms",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "202-210",
"pmc": null,
"pmid": "33514483",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Evaluation of treatment, prognostic factors, and survival in 198 vulvar melanoma patients: Implications for clinical practice.",
"title_normalized": "evaluation of treatment prognostic factors and survival in 198 vulvar melanoma patients implications for clinical practice"
} | [
{
"companynumb": "NVSC2021NL021421",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo evaluate the long-term safety and effectiveness of tocilizumab (TCZ) for the treatment of rheumatoid arthritis (RA) in a real-world clinical setting in Taiwan.\n\n\nMETHODS\nAll refractory RA patients who initiated intravenous TCZ between August 2012 and March 2015 were enrolled. Data on patient characteristics, drug safety and effectiveness were collected.\n\n\nRESULTS\nA total of 114 RA patients were recruited. Despite the majority of them (93%) had previous biologic failure, 43.75% of the patients were able to reach ACR50 after one year. Serious adverse events commonly found were bacterial pneumonia (4.24/100 patient-years) followed by cellulitis (2.12/100 patient-years). Twenty-three patients had old or latent TB infections, 11 patients had chronic hepatitis B. During the 3 years follow-up, none of them had reactivation of TB, or hepatitis B with concomitant use of isoniazid prophylaxis or pre-emptive antiviral treatment.\n\n\nCONCLUSIONS\nIn this 3-year real-world study on RA patients of Taiwan, we found a good long-term effectiveness and similar safety profiles for the TCZ treatment. With prophylactic strategy for latent TB and pre-emptive antiviral treatment for HBV carriers, the risk of reactivation of latent TB and HBV may be reassured.",
"affiliations": "Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.;Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan; Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.;Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.;Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan; Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.;Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan; Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan; Institute of Biomedical Science and Ron Hsing Research Center for Translational Medicine, National Chung-Hsing University, Taichung, Taiwan.;Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.;Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan; Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address: ysanne@vghtc.gov.tw.",
"authors": "Lin|Ching-Tsai|CT|;Huang|Wen-Nan|WN|;Hsieh|Chia-Wei|CW|;Chen|Yi-Ming|YM|;Chen|Der-Yuan|DY|;Hsieh|Tsu-Yi|TY|;Chen|Yi-Hsing|YH|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.1016/j.jmii.2017.04.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1684-1182",
"issue": "52(1)",
"journal": "Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi",
"keywords": "Hepatitis B; Rheumatoid arthritis; Safety and effectiveness; Tocilizumab; Tuberculosis",
"medline_ta": "J Microbiol Immunol Infect",
"mesh_terms": "D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D002648:Child; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D012720:Severity of Illness Index; D013624:Taiwan; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100956211",
"other_id": null,
"pages": "141-150",
"pmc": null,
"pmid": "28734675",
"pubdate": "2019-02",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Safety and effectiveness of tocilizumab in treating patients with rheumatoid arthritis - A three-year study in Taiwan.",
"title_normalized": "safety and effectiveness of tocilizumab in treating patients with rheumatoid arthritis a three year study in taiwan"
} | [
{
"companynumb": "TW-ROCHE-1978043",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOCILIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "OBJECTIVE\nStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) associated with the use of nonsteroidal antiinflammatory drugs (NSAIDs) are described.\n\n\nCONCLUSIONS\nA search of the English- language medical literature was conducted to identify studies and cases of SJS and TEN associated with NSAIDs and cyclooxygenase-2-selective NSAIDs available in the United States. Several epidemiologic studies, case reports, and case series involving SJS and TEN associated with NSAIDs were identified. Of the available NSAIDs, oxicam derivatives appeared to have the greatest association with SJS and TEN. The relative risks reported with other NSAIDs are much lower. The risk with cyclooxygenase-2-selective NSAIDs and meloxicam is less clear, since all were introduced after the completion of the epidemiologic studies. SJS or TEN from NSAIDs and cyclooxygenase-2-selective NSAIDs appears to affect the same patient population as other medications that cause SJS or TEN. The risk of SJS or TEN caused by NSAIDs is extremely low (less than 2 per 1 million users per week for oxicam derivatives, less than 1 per 1 million users per week for other NSAIDs, and 6 cases per 1 million person-years for celecoxib). Aspirin is not typically associated with SJS or TEN. Of the other salicylates, SJS or TEN has only been reported with diflunisal.\n\n\nCONCLUSIONS\nThe risk of SJS or TEN in patients receiving NSAIDs is extremely low; older patients, women, and patients within the first month of treatment initiation appear to have the greatest risk. Health care providers and patients should be aware of the signs and symptoms of SJS and TEN.",
"affiliations": "College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA. kward@uri.edu",
"authors": "Ward|Kristina E|KE|;Archambault|Raoul|R|;Mersfelder|Tracey L|TL|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp080603",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "67(3)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D000367:Age Factors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D005260:Female; D006801:Humans; D008297:Male; D012307:Risk Factors; D012737:Sex Factors; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "206-13",
"pmc": null,
"pmid": "20101062",
"pubdate": "2010-02-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Severe adverse skin reactions to nonsteroidal antiinflammatory drugs: A review of the literature.",
"title_normalized": "severe adverse skin reactions to nonsteroidal antiinflammatory drugs a review of the literature"
} | [
{
"companynumb": "FR-AUROBINDO-AUR-APL-2020-052712",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nCryptosporidium spp. is a ubiquitous parasite affecting humans as well as domestic and wild vertebrates, causing diarrhea in both immunocompetent and immunocompromised hosts worldwide. Its transmission occurs primarily by the fecal-oral route. In humans, C. parvum and C. hominis are the most prevalent species, whereas immunocompetent and immunocompromised individuals can also be infected by other zoonotic species. Renal transplant patients are prone to develop cryptosporidiosis, which can induce severe and life-threatening diarrhea.\n\n\nMETHODS\nWe report here a series of nearly concomitant cases of acute symptomatic cryptosporidiosis in three renal transplant patients attending the Strasbourg University Hospital Nephrology Unit. The clinical presentation was persistent diarrhea and acute renal failure. The diagnosis was confirmed by microscopic stool examination using a modified Ziehl-Neelsen staining method and species identification by molecular tools. All patients were treated with nitazoxanide and recovered from diarrhea after 14 days of therapy.\n\n\nCONCLUSIONS\nGenotypic species identification was not consistent with an epidemic context, thus underlining the need for genotyping to monitor at risk patients.",
"affiliations": "Laboratoire de Parasitologie et de Mycologie Médicale, Plateau Technique de Microbiologie, Hôpitaux Universitaires de Strasbourg, 1 place de l'Hôpital, BP 426, F-67091, Strasbourg cedex, France. jbrunet@unistra.fr.;Laboratoire de Parasitologie et de Mycologie Médicale, Plateau Technique de Microbiologie, Hôpitaux Universitaires de Strasbourg, 1 place de l'Hôpital, BP 426, F-67091, Strasbourg cedex, France.;Laboratoire de Parasitologie et de Mycologie Médicale, Plateau Technique de Microbiologie, Hôpitaux Universitaires de Strasbourg, 1 place de l'Hôpital, BP 426, F-67091, Strasbourg cedex, France.;Laboratoire de Parasitologie et de Mycologie, Plateau Technique de Biologie du CHU Dijon, 2 rue Angélique Ducoudray, BP 37013, F-21070, Dijon cedex, France.;Laboratoire de Parasitologie et de Mycologie, Plateau Technique de Biologie du CHU Dijon, 2 rue Angélique Ducoudray, BP 37013, F-21070, Dijon cedex, France.;Laboratoire de Parasitologie et de Mycologie, Plateau Technique de Biologie du CHU Dijon, 2 rue Angélique Ducoudray, BP 37013, F-21070, Dijon cedex, France.;Département de Néphrologie et Transplantation, Hôpitaux Universitaires de Strasbourg, 1 place de l'Hôpital, BP 426, F-67091, Strasbourg cedex, France.;Département de Néphrologie et Transplantation, Hôpitaux Universitaires de Strasbourg, 1 place de l'Hôpital, BP 426, F-67091, Strasbourg cedex, France.;Département de Néphrologie et Transplantation, Hôpitaux Universitaires de Strasbourg, 1 place de l'Hôpital, BP 426, F-67091, Strasbourg cedex, France.;Département de Néphrologie et Transplantation, Hôpitaux Universitaires de Strasbourg, 1 place de l'Hôpital, BP 426, F-67091, Strasbourg cedex, France.;Laboratoire de Parasitologie et de Mycologie Médicale, Plateau Technique de Microbiologie, Hôpitaux Universitaires de Strasbourg, 1 place de l'Hôpital, BP 426, F-67091, Strasbourg cedex, France.;Laboratoire de Parasitologie-Mycologie, EA 3800, Centre Hospitalier Universitaire, Université de Rouen, 1, rue de Germont, F-76031, Rouen, France.;Laboratoire de Parasitologie et de Mycologie Médicale, Plateau Technique de Microbiologie, Hôpitaux Universitaires de Strasbourg, 1 place de l'Hôpital, BP 426, F-67091, Strasbourg cedex, France.;Laboratoire de Parasitologie-Mycologie, EA 3800, Centre Hospitalier Universitaire, Université de Rouen, 1, rue de Germont, F-76031, Rouen, France.;Laboratoire de Parasitologie et de Mycologie Médicale, Plateau Technique de Microbiologie, Hôpitaux Universitaires de Strasbourg, 1 place de l'Hôpital, BP 426, F-67091, Strasbourg cedex, France.",
"authors": "Brunet|J|J|;Lemoine|J P|JP|;Pesson|B|B|;Valot|S|S|;Sautour|M|M|;Dalle|F|F|;Muller|C|C|;Borni-Duval|C|C|;Caillard|S|S|;Moulin|B|B|;Pfaff|A W|AW|;Razakandrainibe|R|R|;Abou-Bacar|A|A|;Favennec|L|L|;Candolfi|E|E|",
"chemical_list": "D003049:Coccidiostats; D009574:Nitro Compounds; D013844:Thiazoles; C041747:nitazoxanide",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-016-1661-5",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 166110.1186/s12879-016-1661-5Case ReportRuling out nosocomial transmission of Cryptosporidium in a renal transplantation unit: case report Brunet J. jbrunet@unistra.fr 12Lemoine J. P. jean-philippe.lemoine@etu.unistra.fr 1Pesson B. bernard.pesson@wanadoo.fr 1Valot S. stephane.valot@chu-dijon.fr 3Sautour M. marc.sautour@u-bourgogne.fr 34Dalle F. Frederic.Dalle@u-bourgogne.fr 34Muller C. Clotilde.muller@chru-strasbourg.fr 5Borni-Duval C. Claire.borniduval@chru-strasbourg.fr 5Caillard S. Sophie.caillard@chru-strasbourg.fr 5Moulin B. bmoulin@mac.com 5Pfaff A. W. pfaff@unistra.fr 12Razakandrainibe R. romy.razakandrainibe@univ-rouen.fr 6Abou-Bacar A. aboubacar@unistra.fr 1Favennec L. Loic.Favennec@chu-rouen.fr> 6Candolfi E. candolfi@unistra.fr 121 Laboratoire de Parasitologie et de Mycologie Médicale, Plateau Technique de Microbiologie, Hôpitaux Universitaires de Strasbourg, 1 place de l’Hôpital, BP 426, F-67091 Strasbourg cedex, France 2 Institut de Parasitologie et Pathologie Tropicale, EA 7292, Fédération de Médecine Translationnelle, Université de Strasbourg, 3 rue Koeberlé, F-67000 Strasbourg, France 3 Laboratoire de Parasitologie et de Mycologie, Plateau Technique de Biologie du CHU Dijon, 2 rue Angélique Ducoudray, BP 37013, F-21070 Dijon cedex, France 4 UMR 1347, Université de Bourgogne, 17 rue de Sully, F-21000 Dijon, France 5 Département de Néphrologie et Transplantation, Hôpitaux Universitaires de Strasbourg, 1 place de l’Hôpital, BP 426, F-67091 Strasbourg cedex, France 6 Laboratoire de Parasitologie-Mycologie, EA 3800, Centre Hospitalier Universitaire, Université de Rouen, 1, rue de Germont, F-76031 Rouen, France 2 8 2016 2 8 2016 2016 16 3631 7 2015 8 6 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nCryptosporidium spp. is a ubiquitous parasite affecting humans as well as domestic and wild vertebrates, causing diarrhea in both immunocompetent and immunocompromised hosts worldwide. Its transmission occurs primarily by the fecal-oral route. In humans, C. parvum and C. hominis are the most prevalent species, whereas immunocompetent and immunocompromised individuals can also be infected by other zoonotic species. Renal transplant patients are prone to develop cryptosporidiosis, which can induce severe and life-threatening diarrhea.\n\nCase presentation\nWe report here a series of nearly concomitant cases of acute symptomatic cryptosporidiosis in three renal transplant patients attending the Strasbourg University Hospital Nephrology Unit. The clinical presentation was persistent diarrhea and acute renal failure. The diagnosis was confirmed by microscopic stool examination using a modified Ziehl-Neelsen staining method and species identification by molecular tools. All patients were treated with nitazoxanide and recovered from diarrhea after 14 days of therapy.\n\nConclusion\nGenotypic species identification was not consistent with an epidemic context, thus underlining the need for genotyping to monitor at risk patients.\n\nKeywords\nCryptosporidiumRenal transplantZoonotic speciesGenotypic species identificationCase reportissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nThe coccidian protozoan Cryptosporidium spp. is an intestinal parasite and a significant cause of enteric disease in humans and numerous other vertebrates worldwide. Cryptosporidiosis is the most common zoonotic cause of human parasitic diarrhea (i.e., 60 % of epidemic cases linked to waterborne and 2–6 % of cases involving severe diarrhea worldwide), especially in immunocompromised individuals and young children [1]. The latter is notably the case in developing countries, where this parasite ranks second in the causes of death in children under 2 years [1, 2]. The prevalence of Cryptosporidium in stools of immucompetent persons was found to be lower in high-income countries than in developing regions [3]. Infection occurs by oocyst-stage ingestion via contaminated drinking water, food or recreational waters, as well as by direct or indirect human-to-human or animal-to-human contact [4]. In France, 407 cases of cryptosporidiosis were diagnosed between 2006 and 2009 [5]. A study conducted by the Strasbourg University Hospital between 2011 and 2013 detected Cryptosporidium spp. in 2.4 % of stools in which parasites have been detected out of a total of 6515 analyzed stools [6]. Over the past 20 years, three cryptosporidiosis outbreaks have been reported in France [5]. Other documented cases are linked to outdoor activity, swimming pools, day-care centers, and travel [3, 7]. Cryptosporidiosis can spread also among hospitalized patients and hospital staff and nosocomial outbreak of Cryptosporidium have been described. Source of infection could be contaminated water or contact with the hands of infected people [8, 9].\n\nThe increasing frequency of human cryptosporidiosis outbreaks raises relevant public health and economic concerns [10–12]. Human cases are commonly due to two species: C. hominis, which primarily infects humans, and C. parvum, which infects both humans and animals. Occasional infections by other species/genotypes, such as C. felis, C. meleagridis, C. canis or chipmunk and rabbit genotypes have been primarily reported in immunodeficient patients [5]. C. hominis and the zoonotic Cryptosporidium species are associated with a variety of clinical manifestations in humans [13].\n\nThe severity and duration of human Cryptosporidium infections are linked to the host’s immune status [14]. Immunocompetent patients experience self-limiting disease, while in immunosuppressed patients, especially those with T-cell deficiency, cryptosporidiosis is often chronic and severe with risks of extra-intestinal disease development [15].\n\nIn renal transplant patients, post-transplant cryptosporidiosis with diarrhea is a frequent complication [16]. In France, 69.3 % of clinically apparent cryptosporidiosis cases reported from 2006 to 2009 involved immunocompromised patients and 16.5 % of them were reported in patients who had received solid-organ or stem-cell transplants [5]. One report from a pediatric renal transplant unit demonstrated that infections were the primary cause of diarrhea, with Cryptosporidium spp. diagnosed in 11 % of 199 cases [3].\n\nWe report here three Cryptosporidium spp. infections with acute diarrhea and abdominal pain, observed almost simultaneously in three renal transplant patients who were subject to species genotyping in order to investigate a potential epidemic context in an outpatient nephrology unit.\n\nCase presentation\nThe three cases were diagnosed in the outpatient unit of the Nephrology Department at Strasbourg University Hospital, France.\n\nClinical histories\nPatient #1 was a 60-year-old man who underwent transplantation at the age of 52 for chronic renal failure due to polycystic kidney disease. He initially received immunosuppressive treatment, consisting of tacrolimus (4 mg/day), mycophenolate mofetil (MMF) (1 g x 2/day), and prednisone (7.5 mg/day). Eight years after renal transplantation, he presented with watery diarrhea, nausea and vomiting starting 15 days before consulting (September 25th, 2014). Physical examination revealed asthenia, weight loss (6Kg), hypotension, dry mouth, and acute renal failure (glomerular filtration rate [GFR]: 30 ml/min/1.73 m2). The patient reported no recent travel or contact with swimming pool water, non-drinking water or farm animals, but admitted to own a dog. No other family member experienced diarrhea.\n\nPatient #2 was a 64-year-old man of Malian origin who had lived in France for 40 years and undergone transplantation at the age of 62 for chronic renal failure secondary to glomerulonephritis. Immunosuppressive treatment consisted of tacrolimus (7 mg x 2/day), MMF (750 mg x 2/day), and prednisone (10 mg/day). Two years and 4 months following renal transplantation, he presented with watery diarrhea and abdominal pain lasting for 15–20 days (starting September 26th, 2014). Physical examination revealed weight loss (13Kg), esophageal pain, and acute renal failure (GFR: 36 mL/min/1.73 m2). The patient also presented leucopenia and neutropenia, initially attributed to an overdose of tacrolimus. He reported no previous contact with non-drinking water, swimming pool water or farm animals, but had travelled to Mali for 2 months shortly before the onset of diarrhea. No other person of his family experienced diarrhea.\n\nPatient #3 was a 34-year-old man of Kosovar origin who underwent transplantation aged 24-year-old for an undetermined reason. Acute transplant rejection 2 years later led to a second transplantation in September, 2014. Immunosuppressive treatment consisted of tacrolimus (6 mg x 2/day), MMF (750 mg x 2/day), and prednisone (25 mg/day). Ten days following the second renal transplantation (September 21th, 2014), the patient exhibited watery diarrhea and abdominal pain. Physical examination indicated weight loss (10Kg) and acute renal failure (GFR: 16 ml/min/1.73 m2). The patient, who reported no contact with non-drinking water, swimming pool water or farm animals, had travelled to Kosovo for 1 month before transplantation. His 2-year-old daughter also presented with diarrhea from an unknown cause that lasted for 3 days. No stool analyses were done for the daughter.\n\nParasitological investigations\nFor all three patients, stool examinations performed at the first consultation revealed the presence of Cryptosporidium oocysts, using a modified Ziehl-Neelsen staining method (5–10 oocysts/slide, >100 oocysts/slide, and 1–5 oocysts/slide for cases #1, #2, and #3, respectively). All stool samples were negative for the bacteria Clostridium difficile, Salmonella, Shigella but also for rotavirus and norovirus, and for parasites Giardia and microsporidia.\n\nDNA was extracted from the stool samples using a NucliSENS easyMAG device (bioMérieux, Marcy l’Etoile, France) [17]. Briefly, it consisted of adding 400 mg of stool samples to 1 mL of NucliSENS lysis buffer in a tube containing ceramic beads (lysing matrix D; MP Biomedicals, Illkirch, France), disrupted in a FastPrep-24 grinder (MP Biomedicals) at maximum power for 1 min. After 10 min of incubation at room temperature to ensure complete lysis, the tubes were centrifuged at 10,000 × g for 10 min and extraction was performed with 250 μL of supernatant. Elution was performed at 70 °C with 100 μL of elution buffer. An in-house real-time polymerase chain reaction (PCR) assay was set up to enable the detection and identification of the most common Cryptosporidium species/genotypes [18]. To this end, we used a single reaction tube with fluorescence-labelled probes for the real-time detection of Cryptosporidium, in addition to melting curve analyses of PCR products to differentiate between the Cryptosporidium species/genotypes. We conducted the amplification of a 258 bp DNA fragment located in the 18S ribosomal ribonucleic acid (rRNA) gene (GenBank accession n°L16996; positions 80 to 337) using the following primers: Cry80F: 5’-GTTAAACTGCRAATGGCT-3’; Cry337R: 5’-CGTCATTGCCACGGTA-3’. The CryAnch-labelled hybridization probe (5’-CCGTCTAAAGCTGATAGGTCAGAAACTTGAATG-fluorescein-3’) hybridizes in a region that is conserved among all Cryptosporidium species and the CrySens labelled hybridization probe (5’-LCRed640-GTCACATTAATTGTGATCCGTAAAG-3’) hybridizes in a polymorphic region (nucleotides 260 to 264) with various mismatches. Thermocycling and fluorescence detection were performed by means of a LightCycler 2.0 system (Roche Diagnostics) in a final volume of 20 μL, using a Roche LC Faststart DNA Master HYPROBE (Roche Diagnostics) with 0.5 μM of each primer, 0.2 μM of hybridization probe, 0.5U of UNG (Roche Diagnostics), and 5 μL of extracted DNA. After applying 95 °C for 10 min, amplification was commenced consisting of 50 cycles of 10-sec denaturation at 95 °C, 15 sec of annealing at 50 °C (with a touchdown protocol beginning at 60 °C), and 15 sec of elongation at 72 °C. The fluorescent signal (640 nm) was detected following the annealing step of each cycle. Species/genotypes differentiation was based on differences in the melting temperatures of the PCR-probe complexes, which were determined based on the extent of complementation of the probes to the target strand of the PCR product. For the melting curve analysis, a quick denaturation step was performed at 95 °C followed by a 30-sec annealing step from 45 °C to 80 °C (ramp-up rate: 0.1 °C/s), with continuous detection throughout the ramp up. The technique was validated using Cryptosporidium DNA of a stool collection already characterized at the genus level and positive controls for C. parvum and C. hominis [12].\n\nThe five predominant human pathogenic Cryptosporidium species were identified based on their melting curve profiles (61.9 °C, 53.8 °C, 48.8 °C, 56.7 °C, and 51.8 °C for C. parvum, C. hominis, C. felis, C. meleagridis, and C. canis, respectively). Given that C. cuniculus, an emergent human species, possesses the same melting curve profile as that of C. hominis, with both species exhibiting the same DNA sequence at the hybridization probe locus, all isolates identified as C. hominis were then sequenced to differentiate C. hominis from C. cuniculus.\n\nFor sub-genotyping analysis, DNA samples were subjected to amplification of an 850-bp fragment of the gp60 gene using a nested PCR method [19]. The total volume of PCR mixture was 50 μL, containing 5 μL of DNA for the primary PCR or 5 μL of the primary PCR products, primers (outer primers: AL3531 and AL3535; inner primers: AL3432 and AL3534) at a concentration of 0.4 μM, 0.2 mM deoxyribonucleotide triphosphate mix, and 1.25U of DreamTaq DNA polymerase. Each PCR reaction was subjected to 40 cycles of 30s denaturation at 95 °C, 60s annealing at 55 °C, and 60s extension at 72 °C, with an initial 5 min denaturation at 95 °C and a final 10 min extension at 72 °C. PCR products were visualized by electrophoresis on an ethidium bromide stained 2 % agarose gel electrophoresis. Amplicons were purified and sequenced in both directions with the forward and reverse primers used in the secondary PCR at a concentration of 0.32 μM. Sequencing was performed using a BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, USA) and an ABI PRISM 3100 Genetic Analyzer® (Applied Biosystems, USA). We analyzed the quality of the generated electrophoregrams from each strand using 4Peaks software and compared them with those available in the GenBank database using the basic local alignment search tool. Subtype assignment was based on the number of trinucleotide repeats (TCA, TCG or TCT) in the coding for serine [20].\n\nResults\nFor Patient #1, genotyping revealed a C. felis infection. For Patient #2, genotyping revealed C. hominis sub-genotype IaA13. For Patient #3, the C. parvum sub-genotype IIaA13G1R2 was identified.\n\nTreatment\nAll three patients were treated with nitazoxanide (500 mg x 2/day for 14 days). For Patient #1, the stools tested negative 2 weeks after treatment initiation, with no recurrence of diarrhea observed 4 months after the first episode. For Patient #2, a reduction of tacrolimus was initiated and the diarrhea regressed 8 days after treatment initiation, although 3 months after therapy was started, his stools still tested positive. A second administration of nitazoxanide was thus prescribed and we requested a stool sample from his daughter for testing. One month after the second treatment course, his stools were tested negative for Cryptosporidium oocysts. For Patient #3, tacrolimus was also reduced and his diarrhea was regressing 1 month after treatment initiation. Four months after the second treatment course, his stools were tested negative for Cryptosporidium oocysts.\n\nConclusions\nWe report here a series of nearly concomitant cases of acute symptomatic cryptosporidiosis in three renal transplant patients attending the same outpatient unit of a Nephrology Department. The patients’ consultations records in the Nephrology department showed that they could have been in contact in July 2014. This possibility of contact before the onset of symptoms suggesting a possible nosocomial infection requires a genotyping to explore this hypothesis. In these patients, Cryptosporidium species and gp60 genotypes, which were determined to document a possible outbreak, provided no evidence of nosocomial transmission.\n\nAs our report demonstrates, the detection of three different Cryptosporidium species in three cryptosporidiosis patients excluded the possibility of nosocomial transmission in the Nephrology unit, where renal transplant patients frequently consult and come into contact with each other. Our findings highlight the risk of symptomatic cryptosporidiosis in immunosuppressed renal transplant patients. In 2014, nine out of ten patients with cryptosporidiosis diagnosed by the medical Parasitology and Mycology laboratory of the Strasbourg University Hospital were renal transplant patients (unpublished data). In a pediatric renal transplantation unit, Cryptosporidium spp. was confirmed as the principal cause of diarrhea in patients between 6 months and 12 years of age following transplantation. In Poland and India, the prevalence of Cryptosporidium spp. in renal transplant patients was reported to be 18.8 and 20 %, respectively [21, 22]. Cryptosporidium spp. infections were more commonly associated with profuse watery diarrhea in solid-organ recipients than in immunocompetent patients [21, 23, 24]. Our patients undergoing combined immunosuppressive therapies exhibited watery diarrhea for several weeks before consulting, suggesting that the prevalence of Cryptosporidium spp. infections is probably underestimated in renal transplant units where screening of patients with diarrhea is not routinely performed. In all three of our patients, the symptoms completely resolved within 8 days to 1 month, in line with previous reports of slower recovery duration compared to immunocompetent patients in whom diarrhea symptoms usually cease after 10 to 15 days without treatment [3, 16]. Considering the role of immunosuppression in the appearance and persistence of cryptosporidiosis, we opted to reduce the immunosuppressive regimen in two of our patients, which, in association with the anticryptosporidial agent, could prove an effective method in reducing both duration and severity of symptoms [3, 12, 25].\n\nC. felis cryptosporidiosis (patient #1) is rarely diagnosed in France (4.8 % of all cases between 2006 and 2009 vs., 54 % for C. parvum and 36 % for C. hominis) [5]. No contact with cats was reported, in agreement with previous reports showing that cat ownership is not a significant risk factor for C. felis infection and that C. felis host specificity is not very strict, since it was observed in cats, cattle and humans, thus rendering it often difficult to determine the source of infection [5, 26, 27].\n\nC. hominis infection observed in Patient #2, is prevalent worldwide, and especially in developing areas, with similar incidences to those of C. parvum infection in most European countries, but less frequently reported than C. parvum infection in France and the Middle-East area [20, 24–29]. Travel-related cryptosporidiosis and small family outbreaks have been frequently associated with C. hominis infection, consistent with the onset of symptoms during our patient’s trip to Africa [5]. To the best of our knowledge, human cases of the C. hominis IaA13 sub-genotype have only been reported in Australia, but reports of the C. hominis genotypes present in Africa are scarce [30].\n\nC. parvum, the predominant species in French cryptosporidiosis patients, was detected in Patient #3 [5]. The C. parvum IIaA13G1R2 genotype had previously been reported in Sweden and Germany with no identification of the mode of contamination [31].\n\nOur findings confirm the need to consider cryptosporidiosis as a significant cause of acute persistent watery diarrhea in immunocompromised kidney transplanted patients. In hospitals or day-care centers, renal transplant patients should be informed in order to minimize risk of infection by handwashing and avoiding contact with young pets, infected people and swimming pools. Moreover, in renal transplant unit, patient with prolonged diarrhea should be tested for Cryptosporidium and isolated [14, 15]. Risk of diarrhea due to Cryptosporidium being high for kidney transplant patients, species identification by molecular biology is important. First, to eliminate a possible nosocomial infection in patients who will be often in contact during consultations in the nephrology department; second, to determine the source of contamination (notably animal) and eliminate it to prevent any subsequent recontamination.\n\nAbbreviations\nMMF, mycophenolate mofetil; GFR, glomerular filtration rate; PCR, polymerase chain reaction; rRNA, ribosomal ribonucleic acid\n\nThe authors wish to thank the following contributors: ANOFEL Cryptosporidium National Network: Accoceberry I CHU Bordeaux, Agnamey P CHU Amiens, Angoulvant A CHU Bicêtre Paris, Aubert D CHU Amiens, Belkhadi G CHU St Antoine, Paris., Berry A. CHU Toulouse, Blanchet D CHU Cayenne, Bonhomme J CHU Caen, Botterel F CHU Creteil, Bougnoux ME CHU Necker, Paris, Brunet J CHU Strasbourg, Buffet P CHU Pitié, Paris, Dalle F CHU Dijon, Dannaoui E HEGP, Paris., Darde ML CHU Limoges, De Gentile L.CHU Angers, Debourgogne A. CHU Nancy, Debruyne M (Cerba, Paris), Degeilh B CHU Rennes, Demar M CHU Cayenne, Desbois N CHU Fort de France, Desoubeaux G CHU Tours, Delaunay P CHU Nice, Flori P CHU St Etienne, Gargala G CHU Rouen, Goubard A Biomnis Paris, Grenouillet F CHU Besancon, Hamane S CHU St Louis, Paris, Houze S CHU Bichat, Paris, Jamet D CHU Brest, Kapel N CHU Pitié, Paris, Labbe F CH Le Havre, Lemeteil D Lab. St Valéry en Caux, Magne D CHU St Antoine Paris, Marty P CHU Nice, Menotti J CHU St Louis, Paris, Million L CHU Besançon, Morelle C CHU Montpellier, Morio F CHU Nantes, Murat LB CHU Grenoble, Nevez G CHU Brest, Nicolas M CHU Guadeloupe, Poirier P CHU Clermont-Ferrand, Rabodonirina M CHU Lyon, Rodier MH CHU Poitiers, Sautour M CHU Dijon, Thellier M CHU Pitié, Paris, Totet A CHU Amiens, Valentin A CHU Toulouse, Villena I CHU Reims, and Yera H CHU Cochin, Paris.\n\nFunding\nNo funding was obtain for this study.\n\nAvailability of data and materials\nAll the data supporting your findings is contained within the manuscript.\n\nAuthors’ contributions\nJB, BP, LF, EC were responsible for data analysis, management of data and wrote the manuscript. JPL, MS, FD, AWP, RR, AA helped in manuscript revision. SV, CM, CBD, SC, BM conducted clinical investigation and helped in manuscript revision. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nConsent of each patient was obtained for the clinical data presented in this article.\n\nEthics approval and consent to participate\nNot Applicable.\n==== Refs\nReferences\n1. Baldursson S Karanis P Waterborne transmission of protozoan parasites: review of worldwide outbreaks - an update 2004–2010 Water Res 2011 45 6603 6614 10.1016/j.watres.2011.10.013 22048017 \n2. Kotloff KL Nataro JP Blackwelder WC Nasrin D Farag TH Panchalingam S Wu Y Sow SO Sur D Breiman RF Faruque AS Zaidi AK Saha D Alonso PL Tamboura B Sanogo D Onwuchekwa U Manna B Ramamurthy T Kanungo S Ochieng JB Omore R Oundo JO Hossain A Das SK Ahmed S Qureshi S Quadri F Adegbola RA Antonio M Hossain MJ Akinsola A Mandomando I Nhampossa T Acacio S Biswas K O’Reilly CE Mintz ED Berkeley LY Muhsen K Sommerfelt H Robins Browne RM Levine MM Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case–control study Lancet 2013 382 209 222 10.1016/S0140-6736(13)60844-2 23680352 \n3. Checkley W White AC Jr Jaganath D Arrowood MJ Chalmers RM Chen XM Fayer R Griffiths JK Guerrant RL Hedstrom L Huston CD Kotloff KL Kang G Mead JR Miller M Petri WA Jr Priest JW Roos DS Striepen B Thompson RC Ward HD Van Voorhis WA Xiao L Zhu G Houpt ER A review of the global burden, novel diagnostics, therapeutics, and vaccine targets for cryptosporidium Lancet Infect Dis 2015 15 85 94 10.1016/S1473-3099(14)70772-8 25278220 \n4. Fayer R Morgan U Upton SJ Epidemiology of Cryptosporidium : transmission, detection and identification Int J Parasitol 2000 30 1305 1322 10.1016/S0020-7519(00)00135-1 11113257 \n5. Network ACN Laboratory-based surveillance for Cryptosporidium in France, 2006–2009 Euro Surveill 2010 15 19642 20739000 \n6. Pesson B Brunet J Abou Bacar A Pfaff A Zuccala C Candolfi E Coprologie parasitaire : bilan des examens au CHU de Strasbourg de 2011 à 2013 Feuillets de Biologie 2015 324 33 40 \n7. Colussi O Rouen A Seksik P Cosnes J Beaugerie L Sokol H Acute cryptosporidiosis as a cause of sudden recurrence of digestive symptoms in patients with Crohn’s disease J Crohns Colitis 2010 4 669 670 10.1016/j.crohns.2010.05.008 21122578 \n8. Feng Y Wang L Duan L Gomez-Puerta LA Zhang L Zhao W Hu J Zhang N Xiao L Extended outbreak of cryptosporidiosis in a pediatric hospital, China Emerg Infect Dis 2012 18 312 314 10.3201/eid1802.110666 22305484 \n9. Bruce BB Blass MA Blumberg HM Lennox JL del Rio C Horsburgh CR Jr Risk of Cryptosporidium parvum transmission between hospital roommates Clin Infect Dis 2000 31 947 950 10.1086/318147 11049775 \n10. MacKenzie WR Schell WL Blair KA Addiss DG Peterson DE Hoxie NJ Kazmierczak JJ Davis JP Massive outbreak of waterborne cryptosporidium infection in Milwaukee, Wisconsin: recurrence of illness and risk of secondary transmission Clin Infect Dis 1995 21 57 62 10.1093/clinids/21.1.57 7578760 \n11. Roefer P Monscvitz JT Rexing DJ The Las Vegas cryptosporidiosis outbreak JAWWA 1996 88 95 106 \n12. Dalle F Roz P Dautin G Di-Palma M Kohli E Sire-Bidault C Fleischmann MG Gallay A Carbonel S Bon F Tillier C Beaudeau P Bonnin A Molecular characterization of isolates of waterborne Cryptosporidium spp. collected during an outbreak of gastroenteritis in South Burgundy, France J Clin Microbiol 2003 41 2690 2693 10.1128/JCM.41.6.2690-2693.2003 12791906 \n13. Xiao L Feng Y Zoonotic cryptosporidiosis FEMS Immunol Med Microbiol 2008 52 309 323 10.1111/j.1574-695X.2008.00377.x 18205803 \n14. Hunter PR Nichols G Epidemiology and clinical features of Cryptosporidium infection in immunocompromised patients Clin Microbiol Rev 2002 15 145 154 10.1128/CMR.15.1.145-154.2002 11781272 \n15. Chalmers RM Davies AP Minireview: clinical cryptosporidiosis Exp Parasitol 2010 124 138 146 10.1016/j.exppara.2009.02.003 19545516 \n16. Aulagnon F Scemla A DeWolf S Legendre C Zuber J Diarrhea after kidney transplantation: a new look at a frequent symptom Transplantation 2014 98 806 816 10.1097/TP.0000000000000335 25073040 \n17. Mary C Chapey E Dutoit E Guyot K Hasseine L Jeddi F Menotti J Paraud C Pomares C Rabodonirina M Rieux A Derouin F ANOFEL Cryptosporidium National Network. Multicentric evaluation of a new real-time PCR assay for quantification of Cryptosporidium spp. and identification of Cryptosporidium parvum and Cryptosporidium hominis J Clin Microbiol 2013 51 2556 2563 10.1128/JCM.03458-12 23720792 \n18. Limor JR Lal AA Xiao L Detection and differentiation of Cryptosporidium parasites that are pathogenic for humans by real-time PCR J Clin Microbiol 2002 40 2335 2338 10.1128/JCM.40.7.2335-2338.2002 12089244 \n19. Alves M Xiao L Sulaiman I Lal AA Matos O Antunes F Subgenotype analysis of Cryptosporidium isolates from humans, cattle and zoo ruminants in Portugal J Clin Microbiol 2003 41 2744 2747 10.1128/JCM.41.6.2744-2747.2003 12791920 \n20. Sulaiman IM Hira PR Zhou L Al-Ali FM Al-Shelahi FA Shweiki HM Iqbal J Khalid N Xiao L Unique endemicity of cryptosporidiosis in children in Kuwait J Clin Microbiol 2005 43 2805 9 10.1128/JCM.43.6.2805-2809.2005 15956401 \n21. Ok UZ Cirit M Uner A Ok E Akcicek F Basci A Ozcel MA Cryptosporidiosis and blastocystosis in renal transplant recipients Nephron 1997 75 171 4 10.1159/000189527 9041537 \n22. Udgiri N Minz M Kashyap R Heer M Gupta CS Mohandas K Minz RW Malla N Intestinal cryptosporidiasis in living related renal transplant recipients Transplant Proc 2004 36 2128 9 10.1016/j.transproceed.2004.08.107 15518772 \n23. Arslan H Inci EK Azap OK Karakayali H Torgay A Haberal M Etiologic agents of diarrhea in solid organ recipients Transpl Infect Dis 2007 9 270 5 10.1111/j.1399-3062.2007.00237.x 17511817 \n24. Raja K Abbas Z Hassan SM Luck NH Aziz T Mubarak M Prevalence of cryptosporidiosis in renal transplant recipients presenting with acute diarrhea at a single center in Pakistan J Nephropathol 2014 3 127 31 25374881 \n25. Collinet-Adler S Ward HD Cryptosporidiosis: environmental, therapeutic, and preventive challenges Eur J Clin Microbiol Infect Dis 2010 29 927 35 10.1007/s10096-010-0960-9 20521158 \n26. Glaser CA Safrin S Reingold A Newman TB Association between Cryptosporidium infection and animal exposure in HIV-infected individuals J Acquir Immune Defic Syndr Hum Retrovirol 1998 17 79 82 10.1097/00042560-199801010-00012 9436763 \n27. Guyot K Follet-Dumoulin A Lelievre E Sarfati C Rabodonirina M Nevez G Cailliez JC Camus D Cei-Cas E Molecular characterization ofCryptosporidium isolates obtained from humans in France J Clin Microbiol 2001 39 3472 80 10.1128/JCM.39.10.3472-3480.2001 11574558 \n28. Gatei W Das P Dutta P Sen A Cama V Lal AA Xiao L Multilocus sequence typing and genetic structure of Cryptosporidium hominis from children in Kolkata India. Infect Genet Evol 2007 7 197 205 10.1016/j.meegid.2006.08.006 17010677 \n29. Zintl A Ezzaty-Mirashemi M Chalmers RM Elwin K Mulcahy G Lucy FE DE Waal T Longitudinal and spatial distribution of GP60 subtypes in human cryptosporidiosis cases in Ireland Epidemiol Infect 2011 139 1945 55 10.1017/S0950268810002992 21281547 \n30. Waldron LS Dimeski B Beggs PJ Ferrari BC Power ML Molecular epidemiology, spatiotemporal analysis, and ecology of sporadic human cryptosporidiosis in Australia Appl Environ Microbiol 2011 77 7757 65 10.1128/AEM.00615-11 21908628 \n31. Silverlås C Bosaeus-Reineck H Näslund K Björkman C Is there a need for improved Cryptosporidium diagnostics in Swedish calves? Int J Parasitol 2013 43 155 61 10.1016/j.ijpara.2012.10.009 23142404\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "16()",
"journal": "BMC infectious diseases",
"keywords": "Case report; Cryptosporidium; Genotypic species identification; Renal transplant; Zoonotic species",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000818:Animals; D003049:Coccidiostats; D003428:Cross Infection; D003457:Cryptosporidiosis; D003458:Cryptosporidium; D003967:Diarrhea; D005243:Feces; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009574:Nitro Compounds; D013844:Thiazoles",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "363",
"pmc": null,
"pmid": "27484187",
"pubdate": "2016-08-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15956401;11049775;21908628;18205803;21281547;21122578;23680352;25073040;12791906;12791920;19545516;23720792;12089244;25278220;11781272;20739000;11113257;17010677;15518772;22048017;22305484;7578760;17511817;11574558;9436763;23142404;9041537;25374881;20521158",
"title": "Ruling out nosocomial transmission of Cryptosporidium in a renal transplantation unit: case report.",
"title_normalized": "ruling out nosocomial transmission of cryptosporidium in a renal transplantation unit case report"
} | [
{
"companynumb": "PHHY2016FR129547",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Immune checkpoint inhibitor and chimeric antigen receptor T-cell therapies are associated with a unique spectrum of complications termed immune-related adverse events (irAEs). The abdomen is the most frequent site of severe irAEs that require hospitalization with life-threatening consequences. Most abdominal irAEs such as enterocolitis, hepatitis, cholangiopathy, cholecystitis, pancreatitis, adrenalitis, and sarcoid-like reaction are initially detected on imaging such as ultrasonography (US), CT, MRI and fusion 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT during routine surveillance of cancer therapy. Early recognition and diagnosis of irAEs and immediate management with cessation of immune modulator cancer therapy and institution of immunosuppressive therapy are necessary to avert morbidity and mortality. Diagnosis of irAEs is confirmed by tissue sampling or by follow-up imaging demonstrating resolution. Abdominal radiologists reviewing imaging on patients being treated with anti-cancer immunomodulators should be familiar with the imaging manifestations of irAEs.",
"affiliations": "Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.;Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.;Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.;Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.;Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.;Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.",
"authors": "Anderson|Mark A|MA|https://orcid.org/0000-0002-6144-9093;Kurra|Vikram|V|;Bradley|William|W|;Kilcoyne|Aoife|A|;Mojtahed|Amirkasra|A|;Lee|Susanna I|SI|",
"chemical_list": "D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18",
"country": "England",
"delete": false,
"doi": "10.1259/bjr.20200663",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1285",
"issue": "94(1118)",
"journal": "The British journal of radiology",
"keywords": null,
"medline_ta": "Br J Radiol",
"mesh_terms": "D004066:Digestive System Diseases; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007167:Immunotherapy; D008279:Magnetic Resonance Imaging; D009369:Neoplasms; D000072078:Positron Emission Tomography Computed Tomography; D019275:Radiopharmaceuticals; D014057:Tomography, X-Ray Computed; D014463:Ultrasonography",
"nlm_unique_id": "0373125",
"other_id": null,
"pages": "20200663",
"pmc": null,
"pmid": "33112648",
"pubdate": "2021-02-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "27113507;30528964;25320738;27864215;25763727;10903686;31791986;19097774;23060594;24610577;28631096;23471977;28106152;30891590;27920706;16710025;26282644;31345627;20525992;21918050;27009942;19426218;29703758;28317087;27141885;29442540;25034862;22658127;28076863;17366705;26765102;23408334;30286224;24590637;30457485;32297899;23400564;26922661;28913619;30197906;28031822;22109345;29081991;27857838;29763666;29603856;28476244;25891304;30106351;28189263;24778161;27085692;27998967;30464684;25610749;31321613;22493370;26034866;20004617;23718569;29113194;31584861;16227604;29162153;23341990;29320654;28124291;26027431;30790009;23724867;26867901;27282937;26164177;32451672;22437870;22614989;30228268;27818005;29131763;28096717;31187535;29698933;10715339;8208972;30612580;26100356;29226781;32334270;19587352",
"title": "Abdominal immune-related adverse events: detection on ultrasonography, CT, MRI and 18F-Fluorodeoxyglucose positron emission tomography.",
"title_normalized": "abdominal immune related adverse events detection on ultrasonography ct mri and 18f fluorodeoxyglucose positron emission tomography"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-137738",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "Chronic granulomatous disease (CGD) is a rare immunodeficiency disorder with genetic defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in phagocytes, leading to recurrent severe infections and granuloma formation. Genitourinary involvement, including obstructive granulomas, infections, nephrotoxicity of anti-infective agents, and amyloidosis, is frequently observed in patients with CGD, whereas the clinical and pathological details of the less commonly reported glomerular disease remain obscure. Here, we report the case of a patient with CGD who developed rapidly progressive IgA vasculitis-associated nephritis (IgAVN) and review the literature on biopsy-proven glomerular diseases in patients with CGD. A 22-year-old male patient with CGD developed rapidly progressive glomerulonephritis (RPGN) following peripheral purpura and was diagnosed with crescentic IgAVN based on the renal biopsy evaluation. There was no evidence of active infections, and he received pulse intravenous methylprednisolone followed by oral prednisolone. His renal function returned to normal within 4 weeks, and his proteinuria and microhematuria finally resolved. The present case and literature review indicate that IgAVN and IgA nephropathy with RPGN are the most common causes of glomerular disease in patients with CGD. Clinicians should be aware of the possibility of these diseases as causes of RPGN in CGD, because delays in diagnosis and appropriate treatment may affect renal outcomes.",
"affiliations": "Department of Nephrology and Dialysis, Hyogo Prefectural Amagasaki General Medical Center, 2-17-77 Higashinaniwa-cho, Amagasaki, Hyogo, 660-8550, Japan. maritana196@gmail.com.;Department of Nephrology and Dialysis, Hyogo Prefectural Amagasaki General Medical Center, 2-17-77 Higashinaniwa-cho, Amagasaki, Hyogo, 660-8550, Japan.;Department of Nephrology and Dialysis, Hyogo Prefectural Amagasaki General Medical Center, 2-17-77 Higashinaniwa-cho, Amagasaki, Hyogo, 660-8550, Japan.;Department of Nephrology and Dialysis, Hyogo Prefectural Amagasaki General Medical Center, 2-17-77 Higashinaniwa-cho, Amagasaki, Hyogo, 660-8550, Japan.;Department of Nephrology and Dialysis, Hyogo Prefectural Amagasaki General Medical Center, 2-17-77 Higashinaniwa-cho, Amagasaki, Hyogo, 660-8550, Japan.;Hasui Pediatric Clinic, Osaka, Japan.;Department of Nephrology and Dialysis, Hyogo Prefectural Amagasaki General Medical Center, 2-17-77 Higashinaniwa-cho, Amagasaki, Hyogo, 660-8550, Japan.",
"authors": "Tanaka|Mari|M|0000-0003-2187-1406;Taniguchi|Keisuke|K|;Miki|Sho|S|;Iwanari|Sachio|S|;Ikeda|Masaki|M|;Hasui|Masafumi|M|;Takeoka|Hiroya|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-021-00586-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "10(4)",
"journal": "CEN case reports",
"keywords": "Autoimmune disease; Chronic granulomatous disease (CGD); Glomerulonephritis; Immunoglobulin A (IgA); Kidney biopsy; Treatment",
"medline_ta": "CEN Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "461-467",
"pmc": null,
"pmid": "33683583",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": "24985400;21326171;31522454;23302723;18823651;29329643;10530081;16468977;29746679;23386289;1569675;16078034;30898864;4191616;19478457;3984721;24398680;25688001;1984766;12495290;31316952;495232;2044603;27514771",
"title": "Rapidly progressive IgA vasculitis-associated nephritis successfully treated with immunosuppressive therapy in an adolescent with chronic granulomatous disease.",
"title_normalized": "rapidly progressive iga vasculitis associated nephritis successfully treated with immunosuppressive therapy in an adolescent with chronic granulomatous disease"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2021-24421",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
... |
{
"abstract": "BACKGROUND\nRegenerative endodontic therapy is currently used to treat immature permanent teeth with necrotic pulp and/or apical periodontitis. However, mature teeth with necrotic pulp and apical periodontitis have also been treated using regenerative endodontic therapy. The treatment resulted in resolution of apical periodontitis, regression of clinical signs and symptoms but no apparent thickening of the canal walls, and/or continued root development. A recent study in an animal model showed that the tissues formed in the canals of mature teeth with apical periodontitis after regenerative endodontic therapy were cementumlike, bonelike, and periodontal ligament-like tissue with numerous blood vessels. These tissues are similar to the tissues observed in immature permanent teeth with apical periodontitis after regenerative endodontic therapy.\n\n\nMETHODS\nA 23-year-old woman had a history of traumatic injury to her upper anterior teeth when she was 8 years old. Subsequently, #8 developed pulp necrosis and an acute apical abscess and #7 symptomatic apical periodontitis. The apex of #8 was slightly open, and the apex of #7 was completely formed. Instead of nonsurgical root canal therapy, regenerative endodontic therapy was attempted, including complete chemomechanical debridement on #8 and #7. This was based on the premise that filling of disinfected root canals with the host's biological vital tissue might be better than filling with foreign materials.\n\n\nRESULTS\nAfter regenerative endodontic therapy of #8 and #7, there was radiographic evidence of periapical osseous healing and regression of clinical signs and symptoms. The pulp cavity of #8 decreased in size, and the apex closed. The pulp cavity of #7 appeared to be obliterated by mineralized tissue. These indicated ingrowth of new vital tissue into the chemomechanically debrided canals.\n\n\nCONCLUSIONS\nRegenerative endodontic therapy of mature teeth with apical periodontitis and apical abscess can result in the regression of clinical signs and/or symptoms and healing of apical periodontitis but no apparent thickening of the canal walls or continued root development. Filling of the disinfected canals with the host's vital tissue may be better than with foreign materials because vital tissue has innate and adaptive immune defense mechanisms.",
"affiliations": "Department of Endodontics, Faculty of Dentistry, University of Benghazi, Benghazi, Libya.;Department of Endodontics, College of Dentistry, New York University, New York, New York.;Department of Endodontics, College of Dentistry, New York University, New York, New York.;Department of Endodontics, College of Dentistry, New York University, New York, New York. Electronic address: lml7@nyu.edu.;Private Practice, Rome, Italy.",
"authors": "Saoud|Tarek Mohamed A|TM|;Sigurdsson|Asgeir|A|;Rosenberg|Paul A|PA|;Lin|Louis M|LM|;Ricucci|Domenico|D|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008768:Methylmethacrylates; D015035:Zinc Oxide-Eugenol Cement; D008795:Metronidazole; D002939:Ciprofloxacin; C031667:IRM cement; D008911:Minocycline",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0099-2399",
"issue": "40(12)",
"journal": "Journal of endodontics",
"keywords": "Apical periodontitis; mature teeth; necrotic pulp; regenerative endodontic therapy; root canal therapy; vital tissue",
"medline_ta": "J Endod",
"mesh_terms": "D000900:Anti-Bacterial Agents; D056624:Apexification; D001777:Blood Coagulation; D002939:Ciprofloxacin; D003790:Dental Pulp Necrosis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008768:Methylmethacrylates; D008795:Metronidazole; D008911:Minocycline; D010347:Patient Care Planning; D010482:Periapical Abscess; D010485:Periapical Periodontitis; D012038:Regeneration; D018915:Root Canal Preparation; D012390:Root Canal Therapy; D055815:Young Adult; D015035:Zinc Oxide-Eugenol Cement",
"nlm_unique_id": "7511484",
"other_id": null,
"pages": "2081-6",
"pmc": null,
"pmid": "25292168",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment of a large cystlike inflammatory periapical lesion associated with mature necrotic teeth using regenerative endodontic therapy.",
"title_normalized": "treatment of a large cystlike inflammatory periapical lesion associated with mature necrotic teeth using regenerative endodontic therapy"
} | [
{
"companynumb": "US-BAYER-2017-134302",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE"
},
"druga... |
{
"abstract": "The risk of liver injury in patients with atrial fibrillation (AF) using nonvitamin K antagonist oral anticoagulants (NOACs) has not been previously examined using liver function tests as the primary outcome in the real-world setting. This study assessed the association between NOACs (dabigatran, rivaroxaban, and apixaban) and warfarin and the risk of liver injury, as defined by laboratory tests.\n\n\n\nPatients newly diagnosed with AF and prescribed NOACs or warfarin between 2010 and 2016, identified using the Hong Kong Clinical Database and Reporting System, were matched on age, sex, health status scores, comorbidities, and medications by propensity score on a 1:1 ratio. Risk of liver injury, defined as laboratory test values >3 times the upper limit of normal of alanine aminotransferase or aspartate aminotransferase and >2 times the upper limit of normal of total bilirubin, was compared between NOAC and warfarin users using Cox proportional hazards regression.\n\n\n\nAfter propensity score matching, 13,698 patients were included, of which 141 (2.1%) NOAC users and 232 (3.4%) warfarin users developed liver injury. The hazard ratio (HR) for NOAC vs warfarin users was 0.71 (95% confidence interval: 0.58-0.89). When comparing individual NOACs, only dabigatran (hazard ratio: 0.63; 95% confidence interval: 0.48-0.82) was associated with a lower risk of liver injury.\n\n\n\nAmong patients with AF, NOACs as a group, and dabigatran alone were associated with a significantly lower risk of laboratory-based liver injury when compared with warfarin. However, liver injury occurs more frequently in real-world practice than in NOAC randomized controlled trials.",
"affiliations": "Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.;Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.;Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.;Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.;Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Victoria, Australia.;Department of Medicine, The University of Hong Kong, Hong Kong SAR, China.;Department of Cardiology, University Hospital Geelong and Deakin University, Geelong, Victoria, Australia.;Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.;Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.;Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.;Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.",
"authors": "Zhao|Jiaxi|J|;Blais|Joseph E|JE|;Chui|Celine S L|CSL|;Suh|In-Hye|IH|;Chen|Esa Y H|EYH|;Seto|Wai-Kay|WK|;Mok|Michael T|MT|;Yan|Vincent K C|VKC|;Lau|Wallis C Y|WCY|;Wong|Ian C K|ICK|;Chan|Esther W|EW|",
"chemical_list": "D000925:Anticoagulants; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D014859:Warfarin; D000069552:Rivaroxaban; D000069604:Dabigatran",
"country": "United States",
"delete": false,
"doi": "10.14309/ajg.0000000000000678",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9270",
"issue": "115(9)",
"journal": "The American journal of gastroenterology",
"keywords": null,
"medline_ta": "Am J Gastroenterol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D056486:Chemical and Drug Induced Liver Injury; D015331:Cohort Studies; D000069604:Dabigatran; D016208:Databases, Factual; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D057216:Propensity Score; D011720:Pyrazoles; D011728:Pyridones; D012306:Risk; D000069552:Rivaroxaban; D014859:Warfarin",
"nlm_unique_id": "0421030",
"other_id": null,
"pages": "1513-1524",
"pmc": null,
"pmid": "32467502",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Association Between Nonvitamin K Antagonist Oral Anticoagulants or Warfarin and Liver Injury: A Cohort Study.",
"title_normalized": "association between nonvitamin k antagonist oral anticoagulants or warfarin and liver injury a cohort study"
} | [
{
"companynumb": "GB-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-028811",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Obsessive-compulsive disorder (OCD) is a chronic psychiatric condition that is associated with considerable morbidity, and ~90% of individuals with OCD have another psychiatric comorbidity. Patients with comorbid OCD and body dysmorphic disorder (BDD) have limited insight and poor psychosocial function, respond poorly to drug treatment, and have an increased risk of suicide. Modified electroconvulsive therapy (ECT) has been attempted to improve symptoms of OCD when drug treatment does not have a satisfactory effect. This report describes a patient who had OCD comorbid with BDD that was successfully treated with modified ECT. Although the mechanism of its effect is unclear, modified ECT may be an alternative treatment for patients with comorbid OCD and BDD. Its efficacy and mechanism of action require further investigation in a large sample of patients with these comorbid disorders.",
"affiliations": "Institute of Mental Health, Tianjin Anding Hospital, Tianjin, China.;Institute of Mental Health, Tianjin Anding Hospital, Tianjin, China.",
"authors": "Ma|Xiaoyan|X|;Li|Ranli|R|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fpsyt.2021.706506",
"fulltext": "\n==== Front\nFront Psychiatry\nFront Psychiatry\nFront. Psychiatry\nFrontiers in Psychiatry\n1664-0640\nFrontiers Media S.A.\n\n10.3389/fpsyt.2021.706506\nPsychiatry\nCase Report\nCase Report: Effect of Electroconvulsive Therapy on Obsessive-Compulsive Disorder Comorbid With Body Dysmorphic Disorder\nMa Xiaoyan *\n\nLi Ranli\nInstitute of Mental Health, Tianjin Anding Hospital, Tianjin, China\nEdited by: Rafael Christophe Freire, Queen's University, Canada\n\nReviewed by: Casimiro Cabrera Abreu, Queens University, Canada; Elisabetta Filomena Buonaguro, University of Naples Federico II, Italy\n\n*Correspondence: Xiaoyan Ma ma_xiaoyan81@126.com\nThis article was submitted to Mood and Anxiety Disorders, a section of the journal Frontiers in Psychiatry\n\n02 8 2021\n2021\n12 70650625 5 2021\n08 7 2021\nCopyright © 2021 Ma and Li.\n2021\nMa and Li\nhttps://creativecommons.org/licenses/by/4.0/ This 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.\nObsessive-compulsive disorder (OCD) is a chronic psychiatric condition that is associated with considerable morbidity, and ~90% of individuals with OCD have another psychiatric comorbidity. Patients with comorbid OCD and body dysmorphic disorder (BDD) have limited insight and poor psychosocial function, respond poorly to drug treatment, and have an increased risk of suicide. Modified electroconvulsive therapy (ECT) has been attempted to improve symptoms of OCD when drug treatment does not have a satisfactory effect. This report describes a patient who had OCD comorbid with BDD that was successfully treated with modified ECT. Although the mechanism of its effect is unclear, modified ECT may be an alternative treatment for patients with comorbid OCD and BDD. Its efficacy and mechanism of action require further investigation in a large sample of patients with these comorbid disorders.\n\nobsessive compulsive disorder\nmorbidity\nbody dysmorphic disorder\nmodified electroconvulsive therapy\nfunctional impairment\n==== Body\nIntroduction\n\nObsessive compulsive disorder (OCD) is a chronic psychiatric condition characterized by obsessive thinking, compulsive behaviors, and excessive anxiety, and is associated with considerable morbidity and economic and social burden. The obsessions and compulsions that are the hallmark of this disorder consume much time and energy and create significant functional impairment and distress (1). Approximately 3% of the general population experience OCD at some point in their lifetime (2). Moreover, epidemiological studies have found that up to 90% of individuals with OCD have a comorbid psychiatric disorder.\n\nBody dysmorphic disorder (BDD) is a psychiatric condition characterized by a preoccupation with a perceived defect in appearance that is slight and not noticed by others. Individuals with BDD usually have poor insight and become preoccupied with the perceived physical defect. BDD is classified as an “Obsessive-Compulsive and Related Disorder” in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. OCD and BDD often coexist, sharing common genetic and environmental risk factors and clinical features and having a similar sociodemographic profile. Patients with OCD and BDD respond poorly to drug treatment and are at increased risk of suicide.\n\nSelective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT) are the recommended first-line interventions for OCD. However, even after conventional treatment ~30–40% of patients have persistent symptoms and ongoing dysfunction (3). Patients who fail to respond to first-line pharmacological treatments and/or CBT are considered to have refractory OCD. Second-line combination, augmented, and switching strategies have been devised to customize treatment but have a limited effect on symptoms. When these strategies fail, non-pharmacological treatments may be effective.\n\nInvasive treatments, including anterior capsulotomy, cingulotomy by thermal radiofrequency/gamma knife ablation, and deep brain stimulation, are effective therapeutic alternatives for refractory OCD, with response rates ranging from 10 to 80% (4–6). Non-invasive treatments, including transcranial magnetic stimulation and electroconvulsive therapy (ECT), have been investigated for their value in the treatment of refractory OCD. All the above-mentioned treatments have some degree of efficacy in OCD but the results of the relevant studies have been inconsistent. As yet, there is still no effective treatment for OCD, particularly for patients with complicated clinical symptoms comorbid with another psychiatric disorder. ECT is a personalized approach that holds promise as a treatment for this type of psychiatric comorbidity. Although a few reports have suggested that ECT is effective in patients with severe OCD (7, 8), the evidence is insufficient and ECT is still not recommended for OCD in the treatment guidelines (9). ECT still plays a role in the treatment of certain psychiatric disorders, particularly when the symptoms are severe and life-threatening (10, 11). Here, we report a case of OCD comorbid with BDD that was successfully treated with modified ECT.\n\nCase Report\n\nAn 18-year-old male high school student with an established diagnosis of OCD presented in our department accompanied by his parents after cutting off a small piece of his nose with scissors. A year and a half earlier, he had decided that his nose was ugly and started picking and prodding his nose repeatedly until it was bleeding and painful. Psychiatric treatment had been sought nearly a year before the current presentation. At that time, he was started on fluvoxamine 200 mg twice daily for 12 weeks and then in combination with CBT for a further 12 weeks. However, his symptoms worsened and he was spending increasing amounts of time picking at his nose. The fluvoxamine was switched to fluoxetine, another SSRI, which was started at a dose of 20 mg and increased gradually to 50 mg over 2 weeks, and then combined with aripiprazole 10 mg/day and alprazolam 0.8 mg/day for 12 weeks. However, the patient continued to pick at his nose.\n\nOn admission, the patient was unstable, irritable, and still repeatedly picking at his injured nose, despite being aware that he should not be doing so. He was in severe pain but still repeatedly checking his nose in a mirror. He was in obvious distress with low mood, even though he knew rationally there was nothing abnormal about his nose. On examination, he met the ICD-10 diagnostic criteria for comorbid OCD and BDD. In view of the poor efficacy of the first-line and second-line treatments, we opted for a non-pharmacological treatment in this patient.\n\nECT has been used successfully as a treatment for mood and psychotic disorders. Although there is no mention of ECT as a treatment modality for OCD in the guidelines (9), there are a few reports of ECT being an effective treatment for severe OCD. After a full assessment of the severity of the patient's condition and the risk of self-injury, ECT was considered as a treatment for this patient. A thorough physical examination (including measurement of blood pressure, heart rate, and respiratory function and a neurological assessment), laboratory investigations (including hematology and biochemistry), and chest radiography revealed no obvious abnormalities. Written informed consent to treatment with modified ECT under general anesthesia was obtained from the patient after he had been provided with a detailed explanation about the course of treatment and the potential risks.\n\nModified ECT was performed using a Thymatron System IV (America Somatics LLC, Lake Bluff, IL, USA). All doses of psychotropic drugs were reduced, fluoxetine and aripiprazole was reduced to 40mg and 5 mg/d, respectively, on the day before modified ECT. Alprazolam was discontinued the day before modified ECT. The patient was fasted for at least 8 h before ECT, and his temperature, weight, and blood pressure were measured 30min before treatment. The modified ECT procedure is performed as follows. After venipuncture with a 20–30-cm plastic needle, 10ml of 25% glucose solution are injected to confirm successful puncture. The following agents are then injected sequentially: atropine sulfate 0.5–1.0mg, diluted to 2 ml with water for injection; etomidate 0.2–0.3mg/kg, administered intravenously until loss of the eyelash reflex; 100% pure oxygen with pressure ventilation at a frequency of 20–30 tt/m, until the recovery of spontaneous breathing; and succinylcholine chloride (2mM; 100mg in glycerin) diluted to 5ml with water for injection. Approximately 30–60 s after intravenous injection of succinylcholine chloride 0.8–1mg/kg, when fasciculations in the muscle fibers of the face and limbs have stopped, a muscle relaxant is administered. Mask ventilation is used throughout the procedure with careful monitoring for airway patency and reflux aspiration and insertion of an oral protector. Frontotemporal electrodes are then placed on both sides. The stimulation parameters are as follows: charge, 101.1 millicoulombs; pulse width, 0.5 ms; frequency, 20Hz; current intensity, 0.9A; and stimulus duration, 5.6 s. A voltage of 110 V is then applied for 2–3 s. Mask ventilation was used until spontaneous respiration resumes. Finally, airway patency and thoracic movements are assessed and aspiration and auscultation are performed. Spontaneous respiration usually resumes within 5–10min, after which the intravenous needle is removed.\n\nOur patient underwent 12 sessions of modified ECT over 3 weeks with a maximum of three sessions per week and a minimum interval between sessions of 48 h. Seizure monitoring included two-lead electroencephalography (EEG) and oximetry. The two-lead EEG electrodes were placed on the left and right frontopolar points and over the ipsilateral mastoid processes (FP1-A1 and FP2-A2 according to the International 10Y20 system). The patient did not report any adverse reactions, such as dizziness or headache, after the sessions.\n\nPsychiatric symptoms were assessed using the Hamilton Anxiety Scale (HAM-A), Hamilton Depression Scale (HAM-D), and Yale Brown Obsessive Compulsive Scale (Y-BOCS) before and 2 and 4 weeks after completion of the course of modified ECT. Before treatment, the HAM-A, HAM-D, and Y-BOCS scores were 25, 14, and 26, respectively. After 2 weeks of treatment, there was a marked decrease in the frequency of nose-picking. The HAM-A, HAM-D, and Y-BOCS scores decreased to 17, 9, and 19, respectively, after 2 weeks of treatment and to 14, 6, and 10 at 4 weeks. At the end of the treatment course, the patient's clinical symptoms were significantly improved. Although he remained anxious about having what he perceived to be an unattractive nose, he stopped picking at it.\n\nDiscussion\n\nPatients with comorbid OCD-BDD have high morbidity, limited insight, and poor psychosocial outcomes (12, 13). Moreover, rates of anxiety, schizotypal features, and suicidal ideation have been reported to be higher in patients with comorbid OCD-BDD than in those with BDD or OCD alone (13, 14).\n\nAlthough ECT is not recommended in the treatment guidelines for OCD, case reports indicate that it may be an effective therapy for OCD. ECT has been confirmed to be an effective treatment for depression (15) and for OCD (16). Our patient had a diagnosis of comorbid OCD and BDD. His condition continued to deteriorate on first-line therapy to the point that he sustained a self-inflicted injury. Antipsychotic medication was added without noticeable improvement in symptoms. However, after ~2 weeks of treatment with modified ECT, there was a marked improvement in his mood, and after 12 treatment sessions, the patient stopped picking at his nose and felt less anxious than before treatment.\n\nECT has been reported to be effective in the treatment of comorbid OCD and depression and has shown promise in the treatment of both refractory OCD (17) and severe OCD (18). Conventional OCD treatments and augmentation strategies were unsuccessful in our patient, but when combined with ECT, his symptoms improved significantly, suggesting that ECT may be effective in the treatment of comorbid OCD and BDD. According to previous reports, the beneficial effect of ECT is transient (19, 20). Our patient was discharged in remission but without any follow-up. Although it is unknown whether the favorable effect of modified ECT was transient or not in this patient, our experience in this case demonstrates that ECT may be a treatment option for OCD with comorbid BDD. However, a large-scale clinical study is needed to confirm the efficacy of ECT in patients with comorbid OCD and BDD.\n\nThe mechanism underlying the effect of ECT in patients with OCD remains unclear. Neuroimaging studies over the past two decades have found a close association between OCD and dysfunction in certain brain regions, including the orbitofrontal cortex, anterior cingulate cortex, dorsolateral prefrontal cortex, basal ganglia, caudate nucleus, and amygdala. However, circuit dysfunction is an underlying neural mechanism rather than a specific regional abnormality, as confirmed by biological and neuroimaging evidence. Dysfunction in the cortico-striatal-thalamo-cortical circuitry is strongly associated with OCD pathology. However, recent research shows that the pathological mechanism of OCD is complex and that the comorbidity rate is high regardless of subtype of OCD. Indeed, large epidemiological studies have shown that comorbidity rates in patients with OCD are generally higher than those in the general population. These comorbid psychiatric disorders add more challenges in terms of treatment. Depression is the most common comorbidity in patients with OCD, with a lifetime prevalence of 40–70% (12). Both depression and OCD are characterized by a chronic and/or recurrent course, leading to a profound deterioration in psychosocial functioning. Patients with OCD that is comorbid with another psychiatric condition have functional impairment and poor quality of life that responds particularly poorly to psychological and pharmacological treatments.\n\nBDD is a psychiatric disorder characterized by a distressing preoccupation with a perceived defect in appearance and often coexists with OCD. A genetic study found common traits in OCD and BDD due to a 64% overlap in the genes associated with these two disorders (21). The risk of comorbid OCD and BDD is three times higher than that of OCD and BDD alone. Comorbidity may play a key role in refractory OCD in that patients with similar comorbidities might share similar important characteristics related to etiology/pathophysiology and the course of illness. Grouping patients based on their comorbidity may be a useful strategy for reducing clinical heterogeneity.\n\nThe main limitation of this report is that it is based on an isolated case and therefore cannot confirm the efficacy of modified ECT for OCD comorbid with BDD. Accumulation of more cases is needed to clarify both the pathological and etiological mechanisms of OCD. Large-scale studies are needed in the future to confirm whether or not ECT has a therapeutic effect in OCD comorbid with BDD, and if so, the mechanism involved. Another limitation may be that the patient was discharged without follow-up and the implications in terms of the durability of the beneficial effect seen.\n\nConclusion\n\nComorbid BDD played an important role in this patient's lack of response to SSRIs and CBT as first-line therapies for OCD. Combination, augmentation, and switching strategies also achieved little improvement. Modified ECT was added to treat both the OCD and the BDD. Findings from biological research point to “circuit dysfunction” as the underlying neural mechanism for OCD rather than a specific regional abnormality. Aberrant function in the cortico-striatal-thalamo-cortical circuitry is strongly associated with the pathology of OCD. The therapeutic effect in our case suggested that modified ECT may be a good treatment option in patients with OCD and comorbid BDD. However, a clinical study in a larger sample is needed to confirm its efficacy in patients with this type of comorbidity and to elucidate the mechanism underlying its effect.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Medical ethics committee of Tianjin Anding Hospital. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nXM wrote the first draft of the manuscript. All authors contributed to the conception and design of this manuscript, manuscript revision, and approved the submitted version.\n\nConflict of Interest\n\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\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nThanks to Professor Chuanjun Zhuo for his advice and help in the article writing.\n\nAbbreviations\n\nBDD body dysmorphic disorder\n\nCBT cognitive behavioral therapy\n\nECT electroconvulsive therapy\n\nEEG electroencephalography\n\nHAM-A hamilton anxiety scale\n\nHAM-D hamilton depression scale\n\nSSRIs selective serotonin reuptake inhibitors\n\nY-BOCS yale brown obsessive compulsive scale.\n\nFunding. This research was supported by a grant from the Tianjin Key Clinical Discipline Construction Project (ADYKHT2020007).\n==== Refs\nReferences\n\n1. Marazziti D Avella MT Basile L Mucci F Dell'Osso L . Pharmacokinetics of serotonergic drugs: focus on OCD. Expert Opin Drug Metab Toxicol. (2019) 15 :261–73. 10.1080/17425255.2019.1584611 30793987\n2. Ruscio AM Stein DJ Chiu WT Kessler RC . The epidemiology of obsessive-compulsive disorder in the national comorbidity survey replication. Mol Psychiatry. (2010) 15 :53–63. 10.1038/mp.2008.94 18725912\n3. Pallanti S Quercioli L . Treatment-refractory obsessive–compulsive disorder: methodological issues, operational definitions and therapeutic lines. Prog Neuropsychopharmacol Biol Psychiatry. (2006) 30 :400–12. 10.1016/j.pnpbp.2005.11.028 16503369\n4. Batistuzzo MC Hoexter MQ Taub A Gentil AF Cesar RC Joaquim MA . Visuospatial memory improvement after gamma ventral capsulotomy in treatment refractory obsessive–compulsive disorder patients. Neuropsychopharmacology. (2015) 40 :1837–45. 10.1038/npp.2015.33 25645373\n5. Fitzgerald PB Segrave RA . Deep brain stimulation in mental health: review of evidence for clinical efficacy. Aust N Z J Psychiatry. (2015) 49 :979–93. 10.1177/0004867415598011 26246408\n6. Taub A Lopes AC Fuentes D D'Alcante CC de Mathis ME Canteras MM . Neuropsychological outcome of ventral capsular/ventral striatal gamma capsulotomy for refractory obsessive-compulsive disorder: a pilot study. J Neuropsychiatry Clin Neurosci. (2009) 21 :393–7. 10.1176/jnp.2009.21.4.393 19996247\n7. D'Urso G Mantovani A Barbarulo AM Labruna L Muscettola G . Brain-behavior relationship in a case of successful ECT for drug refractory catatonic OCD. J ECT. (2012) 28 :190–3. 10.1097/YCT.0b013e3182542649 22569374\n8. Liu X Cui H Wei Q Wang Y Wang K Wang C . Electroconvulsive therapy on severe obsessive-compulsive disorder comorbid depressive symptoms. Psychiatry Investig. (2014) 11 :210–3. 10.4306/pi.2014.11.2.210 24843380\n9. Koran LM Hanna GL Hollander E Nestadt G Simpson HB American Psychiatric Association. Practice guideline for the treatment of patients with obsessive-compulsive disorder. Am J Psychiatry. (2007) 164 :5–53.17849776\n10. Besse M Methfessel I Simon A Wille C Zilles D . Electroconvulsive therapy in incapable patients refusing treatment: prevalence, effectiveness, and associated factors. J ECT. (2019) 35 :161–4. 10.1097/YCT.0000000000000572 30720549\n11. Pinna M Manchia M Oppo R Scano F Pillai G Loche AP . Clinical and biological predictors of response to electroconvulsive therapy (ECT): a review. Neurosci Lett. (2018) 669 :32–42. 10.1016/j.neulet.2016.10.047 27793702\n12. Eskander N Limbana T Khan F . Psychiatric comorbidities and the risk of suicide in obsessive–compulsive and body dysmorphic disorder. Cureus. (2020) 12 :e9805. 10.7759/cureus.9805 32953317\n13. Lochner C Fineberg NA Zohar J van Ameringen M Juven-Wetzler A Altamura AC . Comorbidity in obsessive-compulsive disorder (OCD): A report from the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS). Compr Psychiatry. (2014) 55 :1513–9. 10.1016/j.comppsych.2014.05.020 25011690\n14. Bowen R Rahman H Dong LY Khalaj S Baetz M Peters E . Suicidality in people with obsessive-compulsive symptoms or personality traits. Front Psychiatry. (2018) 9 :747. 10.3389/fpsyt.2018.00747 30692943\n15. Hermida AP Glass OM Shafi H McDonald WM . Electroconvulsive therapy in depression: current practice and future direction. Psychiatr Clin North Am. (2018) 41 :341–53. 10.1016/j.psc.2018.04.001 30098649\n16. Saglam T Aksoy Poyraz C Poyraz BÇ Tosun M . Successful use of electroconvulsive therapy in a patient with anorexia nervosa and severe acute-onset obsessive-compulsive disorder. Int J Eat Disord. (2018) 51 :1026–8. 10.1002/eat.22923 30051497\n17. Chiu CH Yang WC Lin CH . Electroconvulsive therapy in treatment-resistant obsessive–compulsive disorder comorbid with major depressive disorder: a series of 3 cases. J ECT. (2020) 36 :e34–5. 10.1097/YCT.0000000000000660 31977581\n18. Fukuchi T Okada Y Katayama H Nishijima K Kato S Netsu S . A case of pregnant woman with severe obsessive-compulsive disorder successfully treated by modified-electroconvulsive therapy. Seishin Shinkeigaku Zasshi. (2003) 105 :927–32.14560648\n19. Khanna S Gangadhar BN Sinha V Rajendra PN Channabasavanna SM . Electroconvulsive therapy in obsessive-compulsive disorder. Convuls Ther. (1988) 4 :314–20.11940981\n20. Rapinesi C Kotzalidis GD Ferracuti S Sani G Girardi P Del Casale A . Brain stimulation in obsessive-compulsive disorder (OCD): A systematic review. Curr Neuropharmacol. (2019) 17 :787–807. 10.2174/1570159X17666190409142555 30963971\n21. Monzani B Rijsdijk F Iervolino AC Anson M Cherkas L Mataix-Cols D . Evidence for a genetic overlap between body dysmorphic concerns and obsessive-compulsive symptoms in an adult female community twin sample. Am J Med Genet B Neuropsychiatr Genet. (2012) 159B :376–82. 10.1002/ajmg.b.32040 22434544\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-0640",
"issue": "12()",
"journal": "Frontiers in psychiatry",
"keywords": "body dysmorphic disorder; functional impairment; modified electroconvulsive therapy; morbidity; obsessive compulsive disorder",
"medline_ta": "Front Psychiatry",
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"pmid": "34408682",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "26246408;25011690;30051497;22569374;30793987;31977581;25645373;19996247;18725912;27793702;17849776;22434544;14560648;30692943;30098649;32953317;30963971;11940981;16503369;24843380;30720549",
"title": "Case Report: Effect of Electroconvulsive Therapy on Obsessive-Compulsive Disorder Comorbid With Body Dysmorphic Disorder.",
"title_normalized": "case report effect of electroconvulsive therapy on obsessive compulsive disorder comorbid with body dysmorphic disorder"
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"abstract": "Objective: To examine patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) who receive sequential treatment with somatostatin analogs. Materials and Methods: This retrospective chart review examined lanreotide depot/autogel tolerability and efficacy among GEP-NET patients who received lanreotide after octreotide long-acting release (LAR) at Tufts University Medical Center. Information obtained included background patient characteristics, dosing, adverse events (AEs), radiologic response, and biochemical markers. Results: Patients (n = 16; 43-81 years; mean age, 64.25 years; 11 female) with nonfunctional, low-grade GEP-NETs receiving octreotide LAR 30-60 mg were transitioned to lanreotide because of patient decision (n = 6), disease progression (n = 6), AEs (n = 2), poor tolerance (n = 1), and injection discomfort/pain (n = 1). Lanreotide doses started at 120 mg (n = 13), 90 mg (n = 1), or 60 mg (n = 2); 8 patients received concomitant therapies, mostly liver-directed (radiofrequency ablation/radioembolization). AEs associated with lanreotide experienced by ≥2 patients were fatigue, diarrhea, nausea, hypertension, pancreatic enzyme deficiency, and hyperglycemia. Radiologic treatment responses of the combination of lanreotide with other therapeutic modalities included complete response (n = 1), partial response (n = 5), and stable disease (n = 9). One patient had radiologic progression. Serum serotonin and chromogranin levels decreased, but urinary 5-hydroxyindoleacetic acid levels appeared relatively unchanged. Conclusion: Among post-octreotide GEP-NET patients, including those with disease progression or poor octreotide tolerance, lanreotide alone or with concomitant therapies was well tolerated and associated with radiologic responses.",
"affiliations": "Department of Medical Oncology, Tufts Cancer Center-Tufts Medical Center, Boston, Massachusetts.;Department of Medical Oncology, Tufts Cancer Center-Tufts Medical Center, Boston, Massachusetts.;Department of Medical Oncology, Tufts Cancer Center-Tufts Medical Center, Boston, Massachusetts.;Department of Pathology, Tufts Cancer Center-Tufts Medical Center, Boston, Massachusetts.;Department of Medical Oncology, Tufts Cancer Center-Tufts Medical Center, Boston, Massachusetts.;Department of Invasive Radiology, Tufts Cancer Center-Tufts Medical Center, Boston, Massachusetts.",
"authors": "Saif|Muhammad Wasif|MW|;Fu|Julie|J|;Smith|Melissa H|MH|;Weinstein|Barbara|B|;Relias|Valerie|V|;Daly|Kevin P|KP|",
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"doi": "10.1089/pancan.2018.0013",
"fulltext": "\n==== Front\nJ Pancreat CancerJ Pancreat CancerpancanJournal of Pancreatic Cancer2475-3246Mary Ann Liebert, Inc., publishers 140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA 10.1089/pancan.2018.001310.1089/pancan.2018.0013Original ArticleTreatment with Lanreotide Depot Following Octreotide Long-Acting Release Among Patients with Gastroenteropancreatic Neuroendocrine Tumors Saif Muhammad Wasif 1,*Fu Julie 1Smith Melissa H. 1Weinstein Barbara 2Relias Valerie 1Daly Kevin P. 31 Department of Medical Oncology, Tufts Cancer Center–Tufts Medical Center, Boston, Massachusetts.2 Department of Pathology, Tufts Cancer Center–Tufts Medical Center, Boston, Massachusetts.3 Department of Invasive Radiology, Tufts Cancer Center–Tufts Medical Center, Boston, Massachusetts.A portion of these results were presented at the North American Neuroendocrine Tumor Society Symposium, September 30–October 1, 2016, Jackson, WY. Poster 146.\n\n* Address correspondence to: Muhammad Wasif Saif, MD, Department of Medical Oncology, Tufts Cancer Center–Tufts Medical Center, 800 Washington Street, Box 245, Boston, MA 02111, wsaif@tuftsmedicalcenter.org01 10 2018 2018 01 10 2018 4 1 64 71 © Muhammad Wasif Saif et al. 2018; Published by Mary Ann Liebert, Inc.2018This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract\nObjective: To examine patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) who receive sequential treatment with somatostatin analogs.\n\nMaterials and Methods: This retrospective chart review examined lanreotide depot/autogel tolerability and efficacy among GEP-NET patients who received lanreotide after octreotide long-acting release (LAR) at Tufts University Medical Center. Information obtained included background patient characteristics, dosing, adverse events (AEs), radiologic response, and biochemical markers.\n\nResults: Patients (n = 16; 43–81 years; mean age, 64.25 years; 11 female) with nonfunctional, low-grade GEP-NETs receiving octreotide LAR 30–60 mg were transitioned to lanreotide because of patient decision (n = 6), disease progression (n = 6), AEs (n = 2), poor tolerance (n = 1), and injection discomfort/pain (n = 1). Lanreotide doses started at 120 mg (n = 13), 90 mg (n = 1), or 60 mg (n = 2); 8 patients received concomitant therapies, mostly liver-directed (radiofrequency ablation/radioembolization). AEs associated with lanreotide experienced by ≥2 patients were fatigue, diarrhea, nausea, hypertension, pancreatic enzyme deficiency, and hyperglycemia. Radiologic treatment responses of the combination of lanreotide with other therapeutic modalities included complete response (n = 1), partial response (n = 5), and stable disease (n = 9). One patient had radiologic progression. Serum serotonin and chromogranin levels decreased, but urinary 5-hydroxyindoleacetic acid levels appeared relatively unchanged.\n\nConclusion: Among post-octreotide GEP-NET patients, including those with disease progression or poor octreotide tolerance, lanreotide alone or with concomitant therapies was well tolerated and associated with radiologic responses.\n\nKeywords: \nchromograningastroenteropancreatic neuroendocrine tumorslanreotide depotoctreotide long-acting release\n==== Body\nIntroduction\nThe incidence of neuroendocrine tumors (NETs) has increased markedly in the United States over the past several decades. The U.S. Surveillance, Epidemiology, and End Results (SEER) database, for example, shows a 6.4-fold increase in NETs from 1973 to 2012 (1.09–6.98 per 100,000 persons).1 For gastroenteropancreatic neuroendocrine tumors (GEP-NETs), the overall incidence was 3.56 per 100,000 persons between 2000 and 2012. Across all NET patients, median overall survival was the highest for NETs in the appendix (>30 years) and rectum (24.6 years), while NETs in the pancreas showed the lowest median survival (3.6 years).1\n\nEvaluation of somatostatin receptor expression in human tissues is complicated by the fact that there are five receptor subtypes (SSTR1–SSTR5).2 Only a limited number of studies have comprehensively investigated the expression of all five of the SSTR subtypes, and thus knowledge regarding the correlation of their expression with clinical outcomes in NET is incomplete.3\n\nAn assessment of SSTR receptor subtypes in NETs revealed that 51% of cases highly expressed SSTR2, 47% SSTR1, 43% SSTR5, 36% SSTR4, and 23% SSTR3.3 A high expression of both SSTR1 and SSTR2 was found more frequently in pancreatic NETs and small intestinal NETs than in other NETs.3 It is important to note that octreotide and lanreotide, both of which are synthetic somatostatin analogs (SSAs), primarily bind to SSTR2 and SSTR5.3\n\nThe randomized, double-blind, placebo-controlled Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors (CLARINET) was the largest trial and one of the few trials conducted to compare long-acting lanreotide depot/autogel (n = 101, hereafter referred to as lanreotide) with placebo (n = 103) among patients with primary NETs in the pancreas, midgut, or hindgut.4 Progression-free survival (PFS) was the primary efficacy end-point of CLARINET. There was significantly prolonged PFS among patients treated with lanreotide (median PFS not reached vs. 18.0 months; p < 0.001; hazard ratio for progression/death for lanreotide vs. placebo, 0.47; 95% confidence interval [CI], 0.30–0.73).4 The estimated rates of PFS at 24 months were 65.1% (95% CI, 54.0–74.1) versus 33.0% (95% CI, 23.0–43.3) for the lanreotide and placebo groups, respectively. A greater number of patients in the placebo group (n = 58) than the lanreotide group (n = 30) had centrally assessed disease progression events. Two patients from each of the groups died. The most commonly reported treatment-related adverse events (AEs; >10% of patients) were diarrhea (26% in lanreotide group and 9% in placebo group) and abdominal pain (14% in lanreotide group and 2% in placebo group). A follow-up of CLARINET published 2 years later further demonstrated the long-term safety and tolerability of lanreotide.5\n\nThe treatment goals of NETs include suppressing tumor growth and controlling the symptoms of carcinoid syndrome.6 The primary objective of the Evaluating Lanreotide Efficacy and Safety as a Carcinoid-syndrome Treatment (ELECT) study was to determine whether there was a clinically meaningful difference between lanreotide (n = 59) and placebo (n = 56) groups in the use of daily short-acting subcutaneous rescue octreotide as a correlate of improved symptom control.6 Inclusion criteria were carcinoid (neuroendocrine) tumor or one on an unknown location with liver metastasis and a history of carcinoid syndrome. The adjusted mean (95% CI) percentage of days of rescue octreotide use during the 16-week double-blind phase was significantly lower in the lanreotide group (33.7% [25.0–42.4]) than the placebo group (48.5% [39.6–57.4]), with a between-group absolute difference of −14.8% (95% CI, −26.8 to −2.8; p = 0.017). From baseline to week 12, global health status/quality of life, gastrointestinal symptoms, and endocrine symptoms all improved among lanreotide-treated patients, while the placebo group experienced lesser improvements or no changes (95% CIs for adjusted treatment differences were wide and favored the lanreotide group). Excluding diarrhea and flushing, which were assessed separately in this study, no AE occurred in >9% of patients, and few AEs were serious (n = 2 [3.4%] for lanreotide vs. n = 5 [8.8%] for placebo).6 These results indicate that treatment with lanreotide could reduce the number of days that treatment with rescue octreotide is required.\n\nDespite the fact that primary treatment for metastatic NETs often includes SSAs,7,8 the tolerability of sequential use of SSAs for GEP-NETs, including octreotide followed by lanreotide, has not been studied in depth. Although octreotide is not approved by the U.S. Food and Drug Administration (FDA) for treatment of GEP-NETs,9 a few studies have been conducted to measure the safety and efficacy of treatment for NETs. One of these was a randomized, placebo-controlled study that included patients with metastatic midgut NETs. The results showed that octreotide long-acting release (LAR; n = 42) stabilized tumor growth, prolonged time to tumor progression, and improved long-term survival compared with placebo (n = 43).10\n\nLanreotide 120 mg administered as a deep subcutaneous injection is approved by the FDA for treatment of GEP-NETs in patients with unresectable, well- or moderately-differentiated, locally-advanced, or metastatic GEP-NETs to improve PFS.11 Recently (September 2017), the same dosage was approved by the FDA for the treatment of carcinoid syndrome in adults to reduce the frequency of short-acting SSA rescue therapy.11 The objectives of this case series included assessing the safety, tolerability, and efficacy of lanreotide in patients with various GEP-NETs who were previously treated with octreotide LAR.\n\nMaterials and Methods\nStudy design\nInstitutional Review Board (IRB) approval was granted before the initiation of this retrospective chart review that was conducted at the Tufts University Medical Center. The procedures followed in this study were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki. Included patients had NETs and received lanreotide following octreotide LAR.\n\nEach patient was evaluated by an oncologist or their nurse every 4 weeks before receiving subsequent lanreotide injections. All patients received deep subcutaneous injections of lanreotide, with the exception of one individual who received one injection of lanreotide by intramuscular route.\n\nAssessments and outcome measures\nThe information obtained from patient charts included demographic data, tumor stage/grade, SSA treatment/dose, AEs, radiologic response, and baseline/current levels of biochemical markers (chromogranin A [CgA], urinary 5-hydroxyindoleacetic acid [5-HIAA; primary metabolite of serotonin], serotonin, gastrin, pancreatic polypeptide, and adrenocorticotropic hormone). Treatment response, assessed radiologically, was defined as complete response (CR), partial response (PR), stable disease (SD), and disease control rate (CR+PR+SD).12–14\n\nRadiologic imaging, including computed tomography scans of the abdomen, pelvis, and chest, were performed every 3 months, and patients who underwent liver-directed therapy also received dedicated magnetic resonance imaging (MRI) along with an additional MRI scan within 8–12 weeks of the procedure. An octreotide scan was performed only at baseline and 6–12 months later to confirm disease progression and/or response. Serologic tumor markers were evaluated at each visit, and 5-HIAA was collected in 24-h urine samples every 3–6 months.\n\nResults\nPatient characteristics\nA total of 16 patients (11 female, 5 male; age range, 43–81 years; mean age, 64.3 years) with nonfunctional and low-grade NETs were included in this retrospective chart review (Table 1). The primary tumor locations are presented in Table 1 and included 9 intestinal, 4 pancreatic, and 3 unknown. The locations of metastatic sites, along with stage (all of which are III or IV) and histology, are also presented in Table 1. Each of the 16 patients had been receiving octreotide LAR 30–60 mg for a median duration of 6.5 months (range 3–36 months) and were transitioned to lanreotide because of patient decision (n = 6), disease progression (n = 6), AEs (n = 2), poor tolerance (n = 1), and injection discomfort/pain (n = 1; Table 2). The starting doses of lanreotide were 120 mg (n = 13), 90 mg (n = 1), or 60 mg (n = 2) every 28 days, based on renal dysfunction. At the time the results reported here were quantified, the median number of lanreotide cycles was 5.23 (range 2–10); however, all but 1 patient is still receiving lanreotide. Concomitant therapies were noted in 8 of 16 patients, including radiofrequency ablation (n = 3), yttrium-90 transarterial radioembolization (Y90 TARE; n = 1), chemotherapy (n = 1), surgery (n = 1), chemotherapy+Y90 TARE (n = 1), and chemotherapy+surgery (n = 1; Table 3).\n\nTable 1. Baseline and Demographic Information (N = 16)\n\nPatient\tGender/age (years)\tPrimary tumor location\tMetastatic site(s)\tGrade\tStage (I–IV)\tHistologya\tMitotic index (10 HPF)\tKi-67 (%)\t\n 1\tM, 81\tDuodenum\tLiver, mesentery\tG1\tIV\tWell-differentiated NET\t<2\t3\t\n 2\tF, 68\tAntrum of stomach\tN/A\tG1\tIII\tWell-differentiated NET\t<2\t5\t\n 3\tM, 69\tIleocecum\tRight inguinal LN, liver\tG2\tIV\tModerately-differentiated, intermediate-grade NET\t8–10\t3–4\t\n 4\tM, 81\tMesenteric mass (primary unknown)\tAbdominal LN\tG1\tIII\tWell-differentiated NET, positive immunohistochemical stains for synaptophysin, chromogranin-A, serotonin, and negative for TTF-1\t<2\t7\t\n 5\tF, 72\tIleum\tLN, liver\tG2\tIV\tWell- to moderately-differentiated NET\t10\t<10\t\n 6\tF, 56\tUnknown\tLiver\tG1\tIV\tWell-differentiated NET, positive immunohistochemical stains for synaptophysin, chromogranin-A, and negative for TTF-1, CK7, CK20, CDX2\t6–8\t8\t\n 7\tF, 75\tMediastinal LN (primary unknown)\tHilar LN\tG2\tIV\tModerately-differentiated NET, positive immunohistochemical stains for synaptophysin, chromogranin-A, serotonin, and negative for TTF-1, CK7, VIP, S-100, CK20, CDX2, CK5/6, p63, napsin-A\t14–15\t26\t\n 8\tM, 78\tPancreas\tLiver, spleen\tG2\tIV\tModerately-differentiated NET\t5–6\t15\t\n 9\tF, 60\tIleocecal\tLiver\tG2\tIV\tModerately-differentiated NET\t8\t16\t\n10\tF, 53\tPancreas\tLiver\tG1\tIV\tACTH-producing pancreatic NET complicated by Cushing's syndrome\t8\tN/A\t\n11\tF, 64\tGastric\tLiver, spleen, bone, lung\tG2\tIV\tModerately-differentiated NET\t4\t10\t\n12\tF, 61\tPancreas\tPeritoneum\tG1\tIV\tWell-differentiated NET\t1\tN/A\t\n13\tM, 47\tIleum\tLiver, colon\tG1–G2\tIV\tWell- to moderately-differentiated NET\t12\t16\t\n14\tF, 43\tGastric\tLiver\tG2\tIV\tModerately-differentiated NET\t3\t3\t\n15\tF, 56\tPancreas\tLiver, LN\tG1–G2\tIV\tWell- to moderately-differentiated NET\t6\t13\t\n16\tF, 64\tAppendix\tPeritoneum, LN\tG2\tIV\tModerately-differentiated NET\t<2\t4\t\na Poorly, moderately, or well differentiated.\n\nACTH, adrenocorticotropic hormone; CDX2, caudal-type home box transcription factor 2; CK, cytokeratin; G, grade; HPF, high-power field; LN, lymph nodes; N/A, not assessed; NET, neuroendocrine tumor; TTF-1, thyroid transcription factor-1; VIP, vasoactive intestinal peptide.\n\nTable 2. Octreotide to Lanreotide Depot: Rationale and Dosing\n\nPatient\tLast octreotide dose (mg IM)\tReason for transitioning to lanreotide\tLanreotide starting/current dose (mg SQ)\tTotal lanreotide doses\t\n 1\t30\tPatient decision\t120\t9\t\n 2\t30\tPatient decision\t120\t5\t\n 3\t30\tPatient decision\t120\t8\t\n 4\t30\tPatient decision\t60a\t8\t\n 5\t30 to >40\tIncreased serologic marker+new liver lesion\t120\t8\t\n 6\t30\tPatient decision\t120\t3b\t\n 7\t40\tDiarrhea and abdominal pain\t120\t2 (stopped)c\t\n 8\t30 to >40\tProgressive disease (liver)\t120\t3\t\n 9d\t20\tCost, GI pain, nausea\t120\t10\t\n10\t20\tRadiologic and serologic disease progression\t90a\t5\t\n11\t30 to >60\tGI upset, bone progression (stable liver)\t120\t3\t\n12\t40\tSerologic marker\t120\t3\t\n13\t20 to >40\tPatient decision\t120\t5\t\n14\t30\tIntolerance, low muscle mass (anorexia)\t120\t3\t\n15\tUnknown\tSerologic progression\t120\t3\t\n16\t30\tButtock pain\t60a\t6\t\na Patients No. 4 and No. 10 were successfully escalated to full dose without any adverse events, and patient No. 16 had dose escalated to 90 mg but not beyond because kidney function remained moderately impaired due to diabetic nephropathy.\n\nb Past intolerance to octreotide-associated diarrhea.\n\nc Patient received 1 dose at Roswell Park Cancer Center (Buffalo, NY) and an unknown number of additional doses administrated by a healthcare professional located closer to the patient's residence.\n\nd Received 1 inadvertent misadministration of lanreotide depot by IM route instead of SQ route.\n\nGI, gastrointestinal; IM, intramuscular, SQ, subcutaneous.\n\nTable 3. Biomarkers, Concurrent Treatments, Radiologic Response, and Serologic Markers\n\nPatient\tCgAa (nmol/L)\t5-HIAAb (μmol/day)\t5-HTc (nmol/L)\tRequired concurrent treatment?\tRadiologic response\tOther serologic markers\t\n 1\tLevel at lanreotide initiation\t30\tN/A\t431.3\tNo\tSD\tGastrin level reduced (<100 ng/L)d\t\nCurrent\t39\tN/A\t448.3\t\n 2\tLevel at lanreotide initiation\t43\tN/A\tN/A\tNo\tSD\tGastrin level reduced (239–76 ng/L)d\t\nCurrent\t15\tN/A\tN/A\t\n3\tLevel at lanreotide initiation\t7\tN/A\t2116.8\tRFA\tPR\tNone\t\nCurrent\t<5\tN/A\t1509.6\t\n4\tLevel at lanreotide initiation\t224\tN/A\t2451.6\tNo\tSD\tNone\t\nCurrent\t112\tN/A\t584.5\t\n5\tLevel at lanreotide initiation\t18\t25.1\t3893.1\tY90 TARE\tPR\tNone\t\nCurrent\t14\t18.8\t3024.8\t\n6\tLevel at lanreotide initiation\t366\t29.8\t505.1\tNo\tSD\tNone\t\nCurrent\t224\t20.4\t402.9\t\n7\tLevel at lanreotide initiation\t168\tN/A\t<56.8\tNo\tSD\tNone\t\nCurrent\t122\tN/A\t<56.8\t\n8\tLevel at lanreotide initiation\t2555\tN/A\t3961.2\tCAPTEM and Y90 TARE\tPR\tNone\t\nCurrent\t204\tN/A\t505.1\t\n9\tLevel at lanreotide initiation\t172\tN/A\t317.8\tDebulking surgery\tSD\tNone\t\nCurrent\t29\tN/A\t431.3\t\n10\tLevel at lanreotide initiation\t30\tN/A\t1163.4\tNo\tSD\tACTH-producing tumor normalized; PPP reduced by 50% (1221–610 ng/L)e\t\nCurrent\t<5\tN/A\t1140.7\t\n11\tLevel at lanreotide initiation\t382\t45.5\t4523.0\tCAPTEM, sunitinib\tPD\tNone\t\nCurrent\t160\t16.2\t1957.9\t\n12\tLevel at lanreotide initiation\t67\tN/A\t1004.5\t5-FU, irinotecan, debulking surgery\tCR\tPPP reduced by >50% (1100–430 ng/L)e\t\nCurrent\t>5\tN/A\t862.6\t\n13\tLevel at lanreotide initiation\t93\t36.1\t7320.8\tRFA\tPR\tNone\t\nCurrent\t>5\t21.4\t1163.4\t\n14\tLevel at lanreotide initiation\t21\t17.3\t3637.7\tRFA\tPR\tNone\t\nCurrent\t18\t66.9\t164.6\t\n15\tLevel at lanreotide initiation\t735\t120.3\t317.8\tNo\tSD\tNone\t\nCurrent\t440\t83.7\t187.3\t\n16\tLevel at lanreotide initiation\t382\tN/A\t1339.3\tNo\tSD\tNone\t\nCurrent\t78\tN/A\t38.6\t\na CgA target level, 0–5.0 nmol/L.\n\nb 5-HIAA target level, 0–77.9 μmol/day.\n\nc 5-HT target level, 119.2–1821.7 nmol/L.\n\nd Gastrin normal range, 0–100 ng/L.\n\ne PPP normal range, 70–430 ng/L.\n\n5-FU, 5-fluorouracil; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, serotonin; CAPTEM, capecitabine+temozolomide; CgA, chromogranin A; CR, complete response; G1, grade 1; PD, progressive disease; PPP, pancreatic polypeptide; PR, partial response; RFA, radiofrequency ablation; SD, stable disease; TARE, transarterial radioembolization; Y90, yttrium-90.\n\nAdverse events\nDuring the observation period, AEs affected 11 of the patients; gastrointestinal AEs (diarrhea, nausea, constipation, and abdominal pain) were the most common (n = 6) and were considered to be associated with lanreotide (Table 4). Other AEs experienced by more than 1 individual included fatigue (n = 3), hypertension (n = 2), hyperglycemia (n = 2), and pancreatic exocrine enzyme deficiency (n = 2).\n\nTable 4. Adverse Events\n\nPatient\tAdverse events/grade (CTCAEv4.0)\t\n 1\tG1 fatigue\t\n 2\tNone\t\n 3\tG2 hypertension\t\n 4\tNone\t\n 5\tG2 pancreatic exocrine enzyme deficiency, G1 weight lossa, G1 headache\t\n 6\tNone\t\n 7\tG1 tremor, G2 hyperglycemia, G1 fatigue, G2 nausea, G1 blurred vision\t\n 8\tG1 nausea, G1 abdominal pain\t\n 9\tG1 diarrhea, G1 hypertension\t\n10\tNone\t\n11\tG1 diarrhea\t\n12\tNone\t\n13\tG1 diarrhea, G2 pancreatic exocrine enzyme deficiency, G3 hyperglycemia\t\n14\tG1 pruritus (no rash)\t\n15\tG1 fatigue\t\n16\tG1 constipation, G1 alopecia\t\na Possibly related to pancreatic exocrine enzyme deficiency.\n\nCTCAEv.4.0, Common Terminology Criteria for Adverse Events, version 4.0; G, grade 1.\n\nTumor response\nRadiologic treatment responses of the combination of lanreotide with other therapeutic modalities were CR (n = 1), PR (n = 5), or progressive disease (n = 1). Overall disease control (a combination of CR+PR+SD) was achieved in 15 of 16 patients (93.8%) at the end of the study. Five patients achieved PR; however, it is important to note that all of these patents also received concomitant liver-directed treatment: radiofrequency ablation (RFA) in 3 patients and Y90 TARE in 2 patients. One patient had no evidence of disease after surgical resection (CR). In addition to these patients, 9 others still had SD at the end of the study period.\n\nBiochemical response\nNumerical decreases in CgA levels after initiation of lanreotide treatment were observed in 15 of 16 patients (range of CgA levels changed from 7–2555 nmol/L at baseline to <5–440 nmol/L after treatment; Table 3). Urinary 5-HIAA values, available for 7 patients, ranged from 17.3–120.3 μmol/day at baseline to 16.2–83.7 μmol/day after treatment. Serum serotonin ranged from <56.8–7320.8 nmol/L at baseline to <56.8–3024.8nmol/L following initiation of lanreotide. Decreases in other serologic markers were noted in 4 patients, including gastrin (n = 2), pancreatic polypeptide (n = 1), and pancreatic polypeptide and adrenocorticotropic hormone (n = 1).\n\nDiscussion\nThis retrospective analysis reports the safety, tolerability, and efficacy of lanreotide in patients with various GEP-NETs who were previously treated with octreotide LAR. Lanreotide was well tolerated among these patients, including those who experienced disease progression or lack of tolerance on octreotide LAR. As a part of multidisciplinary management of these patents, many of them received concomitant treatment with other modalities, especially liver-directed therapy. Overall disease control (a combination of CR+PR+SD) was >90% in our study, including CR in 6%, PR in 31%, and SD in 56%. One patient had no evidence of disease after surgical resection (CR), while the patients with PR had received concurrent liver-directed therapy as described in the Results section. In 2016, Phan et al. reported on tumor response in the CLARINET study of lanreotide depot versus placebo in patients with metastatic GEP-NETs. Among 110 patients who were on the lanreotide arm, 2 patients achieved a PR and 65 demonstrated SD (44/103 patients receiving placebo).15\n\nThe most common AEs reported in these patients were consistent with those reported in previous studies of lanreotide.4,5 These results also noted the use of lanreotide in a patient with moderate renal dysfunction. In this patient, lanreotide was started at 60 mg and was titrated up to a maximum tolerated dose of 90 mg. This is noteworthy because dose adjustments of lanreotide depot for moderate renal impairment are currently only recommended for acromegaly patients.11\n\nThe outcomes of this study also demonstrated best tumor response of SD, PR, or CR in all but 1 patient during lanreotide treatment. Of note is that this case series included a small number of patients with GEP-NETs, which is a limitation, as is the retrospective nature of the analysis. Also, half of the patients (8/16) were receiving concomitant therapies, mostly liver-directed therapies, including radiofrequency ablation and transarterial radioembolization. Several patients received concomitant chemotherapy. Among these patients, gastrointestinal AEs, including diarrhea, were either absent or reported as low grade despite receiving concomitant chemotherapy containing capecitabine or irinotecan, 2 of the well-known systemic cytotoxic agents associated with dose-limiting toxicities, including diarrhea.\n\nFollowing sequencing from octreotide to lanreotide, reductions in the levels of CgA were observed in 15 of 16 patients, with the most substantial reductions occurring among those who had the greatest levels before treatment with lanreotide. Currently, CgA, which can be identified in patients with GEP-NETs by immunohistochemistry, is widely used as a neuroendocrine marker, especially among patients with well-differentiated NETs.16–18 Despite its utility, the use of CgA has some limitations, including a lack of international standardization.16 In addition, recent research has raised a question of whether CgA acts more effectively as a diagnostic biomarker than as a method for identifying the risk of metastasis.17 However, the results of a pharmacokinetic/pharmacodynamics model analysis using CLARINET data suggest that change in CgA over time is a relevant covariate/predictor of PFS in GEP-NETs among patients who are either untreated or treatment-naive18; similar findings have been reported elsewhere.12\n\nThe efficacy of utilizing 5-HIAA as a prognostic marker among individuals with GEP-NETs has not been definitively established. Several studies have concluded that increased levels of urinary 5-HIAA can be associated with decreases in survival.19,20 However, a multivariate analysis published in 2016 indicated that there is no prognostic value for 5-HIAA.21 These confounding results clearly indicate that additional research regarding prognostic markers is still needed.\n\nThe prescribing information of lanreotide produced in 2014 includes renal dose adjustments for acromegaly,11 which should be considered when treating patients. Specifically, acromegaly patients with moderate to severe renal impairment should receive an initial dose of 60 mg by deep subcutaneous injection every 4 weeks for 3 months, followed by dose adjustments, as described for non–renal-impaired patients. It is stated that caution should be used when considering an extended dosing interval for acromegaly, including 120 mg every 6 or 8 weeks, among patients with moderate or severe renal impairment. However, no dose adjustments are recommended for mild to moderate renal impairment in patients with GEP-NETs, and currently there are no data available for dosing recommendations in GEP-NET patients with severe renal impairment.\n\nAdditional studies not only provide information pertaining to severe renal impairment but also help define efficacy and safety in patients who were previously treated with octreotide or another SSA. We are currently conducting a retrospective medical chart review that is designed to include data obtained from ∼100 patients (ClinicalTrials.gov number NCT03112694). The objectives of that retrospective analysis include evaluating the efficacy and safety of lanreotide in a real-world setting, providing additional information on lanreotide efficacy and safety following treatment with octreotide, assessing both quality of life and patient satisfaction, and identifying the reasons why patients transitioned from octreotide to lanreotide.\n\nIn summary, treatment with lanreotide was well tolerated among patients with GEP-NETs when given alone or in combination with other treatment modalities, including radioembolization, radiofrequency ablation, and chemotherapy. Dose escalation was also well tolerated in a patient with moderate renal dysfunction. To our knowledge, results from this retrospective analysis also documented for the first time a clinical, biochemical, and radiological benefit of transitioning patients with GEP-NETs from one SSA (octreotide LAR) to another (lanreotide).\n\nAcknowledgments\nIRB approval for this study was provided by the Tufts University Medical Center, and data were acquired, analyzed, and interpreted by the authors, who are all employees of the Tufts Medical Center. The authors thank Sarah Mizne, PharmD, and Aric Fader, PhD, of MedVal Scientific Information Services, LLC, for medical writing and editorial assistance. This article was prepared according to the International Society for Medical Publication Professionals' “Good Publication Practice for Communicating Company-Sponsored Medical Research: The GPP3 Guidelines” and the International Committee of Medical Journal Editors' “Uniform Requirements for Manuscripts Submitted to Biomedical Journals.”\n\nFunding\nIpsen Biopharmaceuticals, Inc. provided support for editorial assistance to MedVal Scientific Information Services, LLC. Aside from procuring editorial support, Ipsen did not contribute to the study conduct or reporting of results. The authors retain full responsibility for the concept, analysis, and all content in the final version for submission.\n\nAuthor Disclosure Statement\nM.W.S.: speakers' bureau, Ipsen Biopharmaceuticals; research funding, Ipsen Biopharmaceuticals. J.F., M.H.S., B.W., and K.P.D.: nothing to disclose. V.R.: speakers' bureau, AbbVie, Genentech.\n\nAbbreviation Used\n5-HIAA5-hydroxyindoleacetic acid\n\nAEadverse event\n\nCgAchromogranin A\n\nCIconfidence interval\n\nCLARINETControlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors\n\nCRcomplete response\n\nFDAFood and Drug Administration\n\nGEP-NETsgastroenteropancreatic neuroendocrine tumors\n\nLARlong-acting release\n\nMRImagnetic resonance imaging\n\nNETsneuroendocrine tumors\n\nPFSprogression-free survival\n\nPRpartial response\n\nSDstable disease\n\nSSAssomatostatin analogs\n\nY90 TAREyttrium-90 tranarterial radioembolization\n\n\nCite this article as: Saif MW, Fu J, Smith MH, Weinstein B, Relias V, Daly KP (2018) Treatment with lanreotide depot following octreotide long-acting release among patients with gastroenteropancreatic neuroendocrine tumors, Journal of Pancreatic Cancer 4:1, 64–71, DOI: 10.1089/pancan.2018.0013.\n==== Refs\nReferences\n1 Dasari A , Shen C , Halperin D , et al. \nTrends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States . JAMA Oncol . 2017 ;3 :1335 –1342 28448665 \n2 Reubi JC , Schonbrunn A \nIlluminating somatostatin analog action at neuroendocrine tumor receptors . Trends Pharmacol Sci . 2013 ;34 :676 –688 24183675 \n3 Qian ZR , Li T , Ter-Minassian M , et al. \nAssociation between somatostatin receptor expression and clinical outcomes in neuroendocrine tumors . Pancreas . 2016 ;45 :1386 –1393 27622342 \n4 Caplin ME , Pavel M , Ćwikła JB , et al. \nLanreotide in metastatic enteropancreatic neuroendocrine tumors . N Engl J Med . 2014 ;371 :224 –233 25014687 \n5 Caplin ME , Pavel M , Ćwikła JB , et al. \nAnti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: The CLARINET open-label extension study . Endocr Relat Cancer . 2016 ;23 :191 –199 26743120 \n6 Vinik AI , Wolin EM , Liyanage N , et al. \nEvaluation of lanreotide depot/autogel efficacy and safety as a carcinoid syndrome treatment (ELECT): A randomized, double-blind, placebo-controlled trial . Endocr Pract . 2016 ;22 :1068 –1080 27214300 \n7 Cives M , Strosberg J \nThe expanding role of somatostatin analogs in gastroenteropancreatic and lung neuroendocrine tumors . Drugs . 2015 ;75 :847 –858 25911185 \n8 Saif MW \nLanreotide for the treatment of gastroenteropancreatic neuroendocrine tumors . Expert Opin Pharmacother . 2016 ;17 :443 –456 26635177 \n9 Sandostatin LAR® Depot (Octreotide Acetate for Injectable Suspension) . Novartis Pharmaceuticals Corp. : East Hanover, NJ , 2014 \n10 Rinke A , Müller HH , Schade-Brittinger C , et al. \nPlacebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID Study Group . J Clin Oncol . 2009 ;27 :4656 –4663 19704057 \n11 Somatuline® Depot (lanreotide) Injection [Prescribing Information] . Ipsen Biopharmaceuticals, Inc. : Basking Ridge, NJ ; 2017 \n12 Bajetta E , Procopio G , Catena L , et al. \nLanreotide autogel every 6 weeks compared with Lanreotide microparticles every 3 weeks in patients with well differentiated neuroendocrine tumors: A Phase III Study . Cancer . 2006 ;107 :2474 –2481 17054107 \n13 Bajetta E , Zilembo N , Di Bartolomeo M , et al. \nTreatment of metastatic carcinoids and other neuroendocrine tumors with recombinant interferon-alpha-2a. A study by the Italian Trials in Medical Oncology Group . Cancer . 1993 ;72 :3099 –3105 7693327 \n14 Eisenhauer EA , Therasse P , Bogaerts J , et al. \nNew response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) . Eur J Cancer . 2009 ;45 :228 –247 19097774 \n15 Korse CM , Taal BG , Vincent A , et al. \nChoice of tumour markers in patients with neuroendocrine tumours is dependent on the histological grade. A marker study of Chromogranin A, Neuron specific enolase, Progastrin-releasing peptide and cytokeratin fragments . Eur J Cancer . 2012 ;48 :662 –671 21945100 \n16 Phan AT , Dasari A , Liyanage N , et al. \nTumor response in the CLARINET study of lanreotide depot vs. placebo in patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) . J Clin Oncol . 2016 ;34 :434 –434 \n17 Tang C , Gong L , Zou W , et al. \nMultivariate analysis of metastasisrelated risk factors for patients with gastroenteropancreatic neuroendocrine tumors based on clinicopathological and endoscopic features . Oncol Rep . 2016 ;36 :3343 –3352 27748940 \n18 Buil-Bruna N , Dehez M , Manon A , et al. \nEstablishing the quantitative relationship between lanreotide autogel®, chromogranin A, and progression-free survival in patients with nonfunctioning gastroenteropancreatic neuroendocrine tumors . AAPS J . 2016 ;18 :703 –712 \n19 Formica V , Wotherspoon A , Cunningham D , et al. \nThe prognostic role of WHO classification, urinary 5-hydroxyindoleacetic acid and liver function tests in metastatic neuroendocrine carcinomas of the gastroenteropancreatic tract . Br J Cancer . 2007 ;96 :1178 –1182 17406366 \n20 van der Horst-Schrivers AN , Post WJ , Kema IP , et al. \nPersistent low urinary excretion of 5-HIAA is a marker for favourable survival during follow-up in patients with disseminated midgut carcinoid tumours . Eur J Cancer . 2007 ;43 :2651 –2657 17825550 \n21 Zandee WT , Kamp K , van Adrichem RC , et al. \nLimited value for urinary 5-HIAA excretion as prognostic marker in gastrointestinal neuroendocrine tumours . Eur J Endocrinol . 2016 ;175 :361 –366 27491374\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2475-3246",
"issue": "4(1)",
"journal": "Journal of pancreatic cancer",
"keywords": "chromogranin; gastroenteropancreatic neuroendocrine tumors; lanreotide depot; octreotide long-acting release",
"medline_ta": "J Pancreat Cancer",
"mesh_terms": null,
"nlm_unique_id": "101703452",
"other_id": null,
"pages": "64-71",
"pmc": null,
"pmid": "30788459",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "17054107;17406366;17825550;19097774;19704057;21945100;24183675;25014687;25911185;26635177;26743120;26908127;27214300;27491374;27622342;27748940;28448665;7693327",
"title": "Treatment with Lanreotide Depot Following Octreotide Long-Acting Release Among Patients with Gastroenteropancreatic Neuroendocrine Tumors.",
"title_normalized": "treatment with lanreotide depot following octreotide long acting release among patients with gastroenteropancreatic neuroendocrine tumors"
} | [
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"companynumb": "US-IPSEN BIOPHARMACEUTICALS, INC.-2018-18908",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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"abstract": "While many studies have examined environmental risk factors for autism spectrum disorder (ASD), much of the research focus has been on prenatal or perinatal factors. Yet, the postnatal environment may affect the risk of ASD as well.\nTo determine whether a set of five postnatal variables are associated with ASD. These variables are: acetaminophen exposure, antibiotic exposure, incidence of ear infection, decreased duration of breastfeeding, and decreased consumption of oral vitamin D drops.\nAn Internet-based survey was conducted. Participants were parents living in the USA with at least one biological child between 3 and 12 years of age. Potential participants were informed about the survey via postings on social media, websites, and listservs and were offered an opportunity to participate in a raffle as well. Participants were also recruited through the Interactive Autism Network.\nThere were 1,741 completed survey responses. After exclusions, there remained 1,001 responses associated with children with ASD (cases) and 514 responses associated with children who do not have ASD (controls). In this data set, doses of postnatal acetaminophen (adjusted odds ratio [aOR] 1.016, CI: 1.003-1.032, p=0.026), courses of postnatal antibiotics (aOR 1.103, CI: 1.046-1.168, p<0.001), incidence of postnatal ear infection (aOR 1.137, CI: 1.046-1.236, p=0.003), and decreased duration of breastfeeding (aOR 0.948, CI: 0.932-0.965, p<0.001) are all associated with ASD when adjusted for eight demographic variables. A weak association between oral vitamin D drop exposure and ASD was also found when adjusted for breastfeeding and demographics (aOR 1.025, CI: 0.995-1.056, p=0.102).\nThis study adds to evidence that postnatal acetaminophen use, postnatal antibiotic use, incidence of ear infection, and early weaning are associated with an increased risk of ASD. It also finds that postnatal oral vitamin D drops are weakly associated with ASD when adjusted for breastfeeding and demographics.",
"affiliations": "Interdisciplinary Center for Innovative Theory and Empirics (INCITE), Columbia University, New York, NY, USA.;Independent Contractor, Waterloo, ON, Canada.",
"authors": "Bittker|Seth Scott|SS|;Bell|Kathleen Roberta|KR|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/NDT.S158811",
"fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNeuropsychiatric Disease and TreatmentNeuropsychiatric Disease and Treatment1176-63281178-2021Dove Medical Press 10.2147/NDT.S158811ndt-14-1399Original ResearchAcetaminophen, antibiotics, ear infection, breastfeeding, vitamin D drops, and autism: an epidemiological study Bittker Seth Scott 1Bell Kathleen Roberta 2\n1 Interdisciplinary Center for Innovative Theory and Empirics (INCITE), Columbia University, New York, NY, USA\n2 Independent Contractor, Waterloo, ON, CanadaCorrespondence: Seth Scott Bittker, 17 Edmond Street, Darien, CT 06820, USA, Tel +212 203 6550, Email sbittker@yahoo.com2018 31 5 2018 14 1399 1414 © 2018 Bittker and Bell. This work is published and licensed by Dove Medical Press Limited2018The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Background\nWhile many studies have examined environmental risk factors for autism spectrum disorder (ASD), much of the research focus has been on prenatal or perinatal factors. Yet, the postnatal environment may affect the risk of ASD as well.\n\nObjective\nTo determine whether a set of five postnatal variables are associated with ASD. These variables are: acetaminophen exposure, antibiotic exposure, incidence of ear infection, decreased duration of breastfeeding, and decreased consumption of oral vitamin D drops.\n\nMaterials and methods\nAn Internet-based survey was conducted. Participants were parents living in the USA with at least one biological child between 3 and 12 years of age. Potential participants were informed about the survey via postings on social media, websites, and listservs and were offered an opportunity to participate in a raffle as well. Participants were also recruited through the Interactive Autism Network.\n\nResults\nThere were 1,741 completed survey responses. After exclusions, there remained 1,001 responses associated with children with ASD (cases) and 514 responses associated with children who do not have ASD (controls). In this data set, doses of postnatal acetaminophen (adjusted odds ratio [aOR] 1.016, CI: 1.003–1.032, p=0.026), courses of postnatal antibiotics (aOR 1.103, CI: 1.046–1.168, p<0.001), incidence of postnatal ear infection (aOR 1.137, CI: 1.046–1.236, p=0.003), and decreased duration of breastfeeding (aOR 0.948, CI: 0.932–0.965, p<0.001) are all associated with ASD when adjusted for eight demographic variables. A weak association between oral vitamin D drop exposure and ASD was also found when adjusted for breastfeeding and demographics (aOR 1.025, CI: 0.995–1.056, p=0.102).\n\nConclusion\nThis study adds to evidence that postnatal acetaminophen use, postnatal antibiotic use, incidence of ear infection, and early weaning are associated with an increased risk of ASD. It also finds that postnatal oral vitamin D drops are weakly associated with ASD when adjusted for breastfeeding and demographics.\n\nVideo abstract\n\n\n\nKeywords\nASDfolateepidemiologyrisk factorpostnatal\n==== Body\nPlain language summary\nIn order to determine whether certain factors are associated with autism spectrum disorder (ASD), we conducted an Internet survey among parents whose children have ASD and parents whose children do not have ASD. Based on the response from this survey, we find that increased use of acetaminophen among children under 2 years, increased use of antibiotics among children under 2 years, increased cases of ear infection among children under 2 years, and early weaning are associated with ASD. These results account for the associations with demographic variables. In addition, we find a weak association between consumption of oral vitamin D drops and ASD when accounting for associations with breastfeeding and demographics.\n\nIntroduction\nAutism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted and repetitive behaviors and deficits in social communication.1 Evidence suggests that both genetic and environmental factors are involved in its etiology.2 While many studies have been conducted to examine possible environmental risk factors for ASD, much of the research focus has been on prenatal or perinatal factors.3–5 Yet other studies have found that some infants with seemingly normal or near-normal development in early infancy later regress into ASD.6,7 This suggests that postnatal factors may be of some importance as well.\n\nSome potential postnatal risk factors that have been considered are decreased breastfeeding,8 antibiotic exposure,9 ear infection,10 acetaminophen exposure,11 and decreased vitamin D consumption.12 With respect to breastfeeding, some studies have found that longer duration of breastfeeding is associated with decreased risk of ASD,8,13,14 but one large study found no such effect.15 With respect to antibiotics, prenatal maternal exposure has been found to be associated with ASD.16 Separately, there have been anecdotal reports of regression into ASD following postnatal antibiotic exposure.17 Two small case–control studies, one with 24 controls and the other with 11 controls, found an association between postnatal antibiotics and ASD.9,18 With respect to ear infection, three small case–control studies found an association with ASD,9,10,19 but one large case–control study found the opposite.20 With respect to acetaminophen, a case–control study using Danish medical records found that prenatal exposure is associated with ASD21 and a small case–control survey study found that postnatal exposure is associated with ASD.11 A recent review summarized evidence that postnatal exposure may be a risk factor for ASD and concluded that a rigorous study examining whether it increases the risk is urgently needed.22 With respect to postnatal oral vitamin D exposure, some have inferred that it may reduce the risk based on a variety of arguments,12,23,24 but others have suggested that excessive multivitamin consumption in general during infancy may increase the risk,25 and one of the authors of this study has offered some epidemiological evidence that postnatal oral vitamin D is unlikely to decrease the risk.26\n\nTherefore, with respect to these potential postnatal risk factors for ASD, it would appear the effects of duration of breastfeeding, ear infection, and oral vitamin D supplementation are unsettled. Postnatal antibiotics have been found to be associated with ASD in two small studies, and postnatal acetaminophen has been found be associated with ASD in one small study that has yet to be replicated. The present study was designed to examine these potential factors.\n\nMaterials and methods\nQuestionnaire\nA survey was constructed using Qualtrics software. Participants were to be biological parents of children who were born and resided in the USA, and at least one child of each participant was to be between 3 and 12 years of age. The survey had between 22 and 25 multiple-choice questions, depending upon whether the participant had a child with ASD. Each participant with a child with ASD was asked questions regarding the participant’s youngest child with ASD. Each participant whose children did not have ASD was asked questions regarding the participant’s youngest child between 3 and 12 years of age.\n\nMost questions on postnatal exposures were focused on the first 2 years of life. Five questions had an “Other” answer with a textbox to permit entry of additional information. For example, one question asked of ASD parents was, “Does your child have a known genetic syndrome?” The set of non-exclusive multiple-choice answers included “Fragile X”, “Rett Syndrome”, “Tuberous Sclerosis”, “None”, and an “Other” box where participants could enter other genetic conditions.\n\nEthics\nThis study was approved by the Institutional Review Board of Columbia University Medical School. All participants whose responses were used in this study completed an electronic informed consent, which served as the first question in the survey.\n\nRecruitment\nPotential participants were informed via postings, listservs, and landing pages that the investigators were conducting a short Internet-based research survey. Participants were also offered the opportunity to enter a raffle for a $50 gift card. To increase participation, especially among parents of children who do not have ASD, participants were encouraged to share the survey with friends whose children do not appear to have ASD. A thank you landing page that appeared upon completion of the survey included buttons for sharing the survey on Facebook and for sending an email about the survey to friends.\n\nPosts or emails about the survey were sent to the members of 216 different groups (Table S1) as follows: 32 Autism Society of America chapters, 160 other ASD-related groups, 20 general parenting groups, and 4 other groups. This was done with the permission and often the direct involvement of the leadership of each group. Of these groups, 196 were Facebook groups, 18 were listservs, and 2 were websites.\n\nSome participants were recruited with the assistance of the Interactive Autism Network (IAN) Research Database at the Kennedy Krieger Institute, Baltimore, MD, which is a partnership of Kennedy Krieger Institute and the Simons Foundation and is approved by the Johns Hopkins Medicine Institutional Review Board. The IAN Research Database has been clinically validated,27,28 as well as verified by a review of parent- and professional-provided medical records,29 and participants must have received a professional diagnosis of ASD.\n\nTo decrease the likelihood of bias, groups with strongly held views on the etiology of ASD were not targeted for recruitment. Nor were groups where vitamin supplementation was a theme. The survey was referred to as “Developmental Factors Survey”, and the specific factors being examined were not disclosed in any of the recruitment materials. To decrease the likelihood of survey fraud, the IP addresses of participants were recorded and participants were asked to provide their email addresses.\n\nExclusions\nAfter the data were collected, case and control groups were determined. Only responses from biological parents residing in the USA who answered the survey questions regarding a child between 3 and 12 years of age were included. Responses were then separated into ASD and non-ASD buckets. The ASD bucket as defined in this step included responses associated with children who have ASD, autism, Asperger’s, or pervasive developmental disorder-not otherwise specified according to the survey respondent. While the latter three diagnoses are no longer used, older children may have been diagnosed with these conditions before 2014.30\n\nThe following were excluded from the ASD bucket: those not diagnosed by a professional and those with a genetic condition of high penetrance for ASD. As this study is focused on potential postnatal risk factors, if a child’s diagnosis could be attributed to a known genetic factor, which is by the nature of genetics a prenatal factor, exclusion of these individuals from the case set is justified.\n\nOne of the questions in the survey was whether the child has attention-deficit/hyperactivity disorder, attention deficit disorder, sensory processing disorder, apraxia, or some other neurologic condition. Often, some symptoms of these disorders are present in those with ASD31–33 and some of these disorders appear to share some common genetic risk factors with ASD.34,35 Likewise, it seems conceivable that they may share some non-genetic risk factors with ASD as well. Therefore, survey responses on children with any of these four conditions were excluded from the control group.\n\nConstruction of variables\nAn initial set of raw binary categorical variables was constructed based on the specific answers to eight questions from the survey. For example, one question in the survey was on breastfeeding duration, and five binary categorical variables were constructed from the five answers to this question.\n\nUsing data from these same eight questions, a second distinct set of seven scaled exposure variables was constructed to represent magnitudes of exposure by associating a number with each answer of each of the questions of interest. These seven scaled exposure variables are: breastfeeding (months), antibiotic (courses), ear infection (number), acetaminophen (doses), ibuprofen (doses), vitamin D drop (months × dose), and folate (binary).\n\nFor example, the discrete answers to a question on the number of courses of antibiotics provided up to the second birthday were: “None”, “1”, “2–3”, “4–7”, “8–15”, “16+”, and “I’m not sure”. Each answer was associated with the number corresponding to the lower bound in the respective range. Specifically, the corresponding numbers for these answers were 0, 1, 2, 4, 8, 16, and not available (NA). This correspondence was used to construct the scaled antibiotic variable.\n\nWhile there were two questions related to vitamin D drops in the survey (one for duration and the other for dose), a single cumulative vitamin D drop exposure variable was included among the seven scaled variables used in most analyses to parsimoniously represent vitamin D drop exposure. Specifically, it was defined as a vitamin D drop duration variable multiplied by a vitamin D drop dose variable.\n\nSome research on prenatal folate suggests that maternal supplementation around the time of conception is associated with a decreased risk of ASD.36–38 Thus, the folate variable was defined to be a binary categorical variable, with a value of 1 if the respondent indicated that the biological mother used prenatal folate for the entire pregnancy or just the first trimester and a value of 0 otherwise.\n\nEight demographic variables were also constructed. Some were scaled variables such as education where the answers were assigned to ordinal numbers. Others were binary categorical variables such as ethnicity, where “White (non-Hispanic)” was associated with 0 and all other ethnicities were associated with 1.\n\nTwo additional scaled exposure variables were defined. One was a low-granularity antibiotic variable. The antibiotic question on the survey included six answers with ranges. The ear infection variable included four answers with ranges. Thus, the original antibiotic variable provides data with greater granularity than the ear infection variable. The low-granularity antibiotic variable was constructed to provide data at comparable granularity. Specifically, the top three ranges for antibiotics were assigned to a single value for this variable.\n\nThe other scaled exposure variable was a crude total oral vitamin D variable, which was constructed to represent the average amount of oral vitamin D consumed in the first 18 months of life from vitamin D drops, breast milk, infant formula, and cow’s milk. It was calculated using answers from survey questions and data from the literature, and was normalized to 400 International Units (IU) per day, which is the Recommended Dietary Allowance for oral vitamin D for those <1 year old.39\n\nBreast milk, infant formula, and cow’s milk average about 45 IU of vitamin D per liter,40 450 IU of vitamin D per liter,41 and 500 IU of vitamin D per liter,42 respectively. The latter two fluids have more vitamin D because they are highly fortified.41,42 This variable assumed each infant received one of these primary sources of sustenance at any given time during its development. The primary source of sustenance for each month of development was determined by the answer to the breastfeeding question in the survey. For months 1 through 12, those who were not breastfed during that month were assumed to receive infant formula. After 12 months, those who were not breastfed for that time were assumed to receive cow’s milk. The daily exposure to the primary source of sustenance in any given month was assumed to be 600 mL, which is generally consistent with the literature on consumption of breast milk and infant formula.43,44\n\nDetails on the encoding of the scaled exposure variables and the encoding of the demographic variables are provided in Tables S2 and S3, respectively.\n\nStatistical analysis\nAnalyses were run using the R statistical package. Crude Wald odds ratios (ORs) and CIs were computed for each of the binary categorical variables. Pearson’s correlations between each pair of the seven scaled exposure variables were calculated.\n\nA consistent set of covariates was determined objectively for most logistic regressions using the following procedure. A candidate set of covariates was defined to be the set of eight demographic variables. For each of the seven scaled exposure variables, a minimal set of covariates was selected from this candidate set of covariates, using Akaike information criterion (AIC) for a logistic regression of the scaled exposure variable in question against the outcome of ASD. AIC is a measure of relative model quality.45 The superset of covariates obtained from these seven minimal sets defined the consistent set of covariates to be used in most analyses.\n\nLogistic regressions were run to compute ORs and adjusted odds ratios (aORs) for the seven scaled exposure variables using a consistent set of covariates. In addition, six models, each of which included pairs of potentially related variables, were constructed: 1) Antibiotic/Ear infection; 2) Low-granularity antibiotic/Ear infection; 3) Acetaminophen/Ibuprofen, an Analgesic model; 4) Breastfeeding/Vitamin D drops; 5) Breastfeeding/Vitamin D drops excluding cases with ASD siblings; and 6) Breastfeeding/Total vitamin D.\n\nAn additional analysis was run on prenatal folate, where the underlying data set was enlarged to include those with genetic conditions of high penetrance for ASD.\n\nSeparately, a multifactor ASD risk model was constructed. Candidate variables for inclusion in this model consisted of the seven scaled exposure variables and the eight demographic variables previously described. Variable selection for this model was determined objectively using AIC.45\n\nResults\nCases and controls\nThe survey was opened to participants on April 5, 2017 and was closed on May 29, 2017. There were 1,741 completed survey responses.\n\nFollowing the procedure described in the “Materials and methods” section, the raw responses were pared down to case and control groups as shown in Figure 1. Through the “Other” textbox on the genetic syndrome question, some respondents indicated that genetic testing was planned or that the child had a common single-nucleotide polymorphism such as MTHFR. As these answers do not qualify as known genetic conditions of high penetrance for ASD, these responses were not excluded from the case set. After exclusions, 1,515 responses were included in the primary case–control analyses: 1,001 cases and 514 controls.\n\nDemographics\nTable 1 provides the demographic characteristics of the participants. Case children were on average 1.8 years older than controls, were much more likely to be male than controls, and were somewhat more ethnically diverse than controls. There was proportionally greater representation in the South among cases than controls and, conversely, proportionally less case representation in the Midwest than controls. Case biological mothers were on average 1.2 years younger than control biological mothers at the birth of the child and were somewhat less educated than control biological mothers. The survey respondents for both cases and controls were overwhelmingly biological mothers.\n\nOf the groups targeted, the greatest number of responses was generated by IAN. The “How did you hear about the survey?” question did not have an explicit answer for IAN, but many who learned about the survey through IAN selected “Other” and filled in “IAN” or some variant in a textbox. Due to the large number of participants who did this, these responses have been separated from the residual “Other” responses in Table 1.\n\nORs and aORs\nWald ORs for the set of categorical variables constructed from the raw survey responses are reported in Table 2. Six of the eight questions highlighted in this table have categorical variables with statistically significant associations with ASD. An alternative set of dose-dependent Wald ORs relative to no exposure were computed on the categorical variables and are reported in Table S4.\n\nCorrelations were computed between each pair of the seven scaled exposure variables and are shown in Table 3, with n’s and p-values in Tables S5 and S6, respectively. Many questions in the survey included an “I’m not sure” answer, or other answers that conveyed limited information. Thus, some variables had missing data. Pairwise deletion was used when computing correlations.\n\nThe consistent set of covariates was found to include all eight of the candidate covariates as all eight were included in the minimal sets of covariates for some of the seven scaled exposure variables based on AIC. The eight covariates are: gender, age of the child, ethnicity, Midwest, South, maternal education, age of the mother at the time of birth of the child, and relationship to the child. The latter two variables were not present in some of the minimal sets.\n\nFour of the seven scaled exposure variables were found to have statistically significant associations with ASD when adjusted for the eight covariates (Table 4). These four are: duration of breastfeeding, doses of postnatal antibiotics, doses of postnatal acetaminophen, and incidence of ear infection. Analogous results, where gender is not a covariate, are shown in Table S7.\n\nAdditional analyses were run to determine whether excluding the covariate for relationship or the covariate for age of the mother would impact the results. Excluding either of these covariates was found to have only minor effects.\n\nSpecialized general linear models\nThe Antibiotic/Ear infection model shows that only the antibiotic variable is statistically significant when included in a joint model with ear infection. The Low-granularity antibiotic/Ear infection model shows that the same is true of the low-granularity antibiotic variable in a joint model with ear infection. Similarly, the Analgesic model shows that the association between acetaminophen and ASD is weak but still present, while any relationship between ibuprofen and ASD is no longer evident in a joint model. Both the Breastfeeding/Vitamin D drop models show that when breastfeeding is included in a model, increased oral vitamin D drop exposure is weakly associated with ASD. Likewise, the Breastfeeding/Total oral vitamin D model shows that when breastfeeding is included, increased total oral vitamin D exposure is weakly associated with ASD. Statistics on these paired variable models as well as the Folate only model with additional genetic conditions are shown in Table 5. Results for analogous models, where gender is not a covariate, are shown in Table S8.\n\nMultifactor model\nUsing AIC as the criterion for variable inclusion, the resulting multifactor risk model consists of the variables for breastfeeding, antibiotics, vitamin D drops, gender, and five other covariates. Table 6 provides statistics on this model.\n\nDiscussion\nDemographics\nWhile there is a high concentration of males among case children, this is expected as male gender is a significant risk factor for ASD.46 In contrast, the male to female ratio among control children is unremarkable.\n\nThe age difference between case and control children can be explained by the survey design. Case parents were asked questions about their youngest biological child with ASD, while control parents were asked questions about their youngest biological child between 3 and 12 years of age. Hence, some case parents would have had a younger child between 3 and 12 years. In addition ASD is often diagnosed late.47 Thus, based on these two observations, one would expect that case children would be somewhat older than control children, which is what was found.\n\nWhile control biological mothers were better educated than case biological mothers in aggregate, both were better educated than the female adult population of the USA between 25 and 54 years of age.48\n\nThe emphasis on friend recruitment of controls appears to have been effective. As Table 1 indicates, 73.3% of control respondents were friends of other respondents, while only 16.0% of cases were friends of other respondents. Studies that rely on friend recruitment of controls often result in control groups that are marginally less ethnically diverse and somewhat better educated than cases.49 Thus, it is not surprising that this pattern holds in this data set as well.\n\nPotential bias\nOne type of bias that may have affected results in this study is self-selection bias. This is sometimes called nonresponse bias, and it comes about from differences between those who choose to participate in a study and those who do not.50 A relevant question is whether this effect resulted in systematic bias in the answers to the exposure questions in this survey. The beliefs of parents of children with ASD regarding causes of ASD are not homogeneous.51–53 About 13% of parents of children with ASD consider vaccines to be the major cause of ASD.51 Since none of the questions in this survey relate to vaccines, this survey is unlikely to have been of exceptional interest to these parents. About 55% of parents of children with ASD believe that genetics is the major cause of ASD.51 It seems likely that this survey would not have been of exceptional interest to most of these parents either. However, some parents whose children have ASD view environmental variables excluding vaccines as potentially significant risk factors.51–53 It seems likely that the survey may have been of exceptional interest to some of these parents. Thus, it seems plausible that such parents participated disproportionately.\n\nIt also seems plausible that the views of parents on potential risk factors may have been partly informed by their experiences in the development of their own children. For example, a mother of a child with ASD who did not breastfeed and who later became superficially aware of some of the existing research on potential benefits of breastfeeding might be more inclined to believe that early weaning could be a risk factor for ASD. This is a form of confirmation bias.\n\nIf this led to systematic bias on the answers to exposure questions, then it seems probable that this would tend to bias results toward aggregate participant views on whether the variables examined are likely to be causative. As many participants were highly educated, and there is some existing medical literature related to many of the variables examined in the study, it seems plausible that the survey results could be biased toward what the existing medical literature suggests is the general direction or hypothesized direction of association of each of the potential risk factors with ASD. For example, as previously mentioned, some medical literature suggests that breastfeeding may be protective.8,13,14 Hence, the survey results could be biased in this direction. Such an effect could bias results in favor of associations between ASD and early weaning,8,13,14 incidence of ear infection,9,10,19 use of acetaminophen,11,22 and use of antibiotics.9,18 Relatedly, some of the existing literature seems to suggest that prenatal folate and postnatal oral vitamin D could be protective.12,23,24,36–38 However, the results from this study show no association between prenatal folate and the risk of ASD, and the results suggest that postnatal oral vitamin D is weakly associated with increased risk of ASD. Thus, it would seem either this type of confirmation bias did not significantly affect the direction of the associations found in this study or its effects vary significantly per variable.\n\nEncouraging friends of participants to participate in a study is known as snowball sampling.54 Thus, by construction, this study made use of snowball sampling in obtaining some of its case participants and in obtaining the majority of its control participants. Snowball sampling has been used in a number of epidemiological studies on ASD.11,55–57 While snowball sampling has the possibility of inducing biases in a sample,58 some research suggests that in practice, this concern may be overstated.59–61 A key question in this study is whether the reliance on snowball sampling for much of the control group induced systematic bias in the answers to the exposure questions. As many of the control participants were social media friends of cases, it seems likely that some of the control participants had some exposures among the variables under consideration in common with the case participants who referred them. Such a scenario would tend to make control responses more similar to case responses than they would have been with a purely random sample for controls. While this scenario could decrease the strength of some of the associations found, it seems unlikely that it would change the direction of such associations.\n\nAs this study is retrospective, the recall of participants is a key consideration. As one might expect, some participants selected the “I’m not sure” answer to some of the questions. This was especially common for the questions related to doses of acetaminophen, ibuprofen, vitamin D drops, and, to a lesser extent, courses of antibiotics. Cases selected this answer much more frequently than controls for each of these questions. For example, for the question on the number of doses of acetaminophen provided up to age two, 17.8% of cases selected “I’m not sure” compared to 9.9% of controls. As previously noted, case children were on average 1.8 years older than controls. Thus, one would expect case participants to be more likely than control participants to select the “I’m not sure” answer. A relevant question is whether this differential in recall affected the ORs and aORs.\n\nThe question on number of doses of acetaminophen included answers, “None”, “1–3”, “4–15”, “16–63”, “64+”, and “I’m not sure”. If a participant never provided acetaminophen to her child, or perhaps provided it just once due to a high fever or some other novel event, it seems probable that the participant would be able to recall this fact when taking the survey. If the participant provided acetaminophen frequently to her child for more mundane aches and pains, it seems more likely that the participant would not be able to recall the number of doses. This inference is consistent with research on memory formation, which shows that recall for novel events is superior to recall for common events.62 Thus, it seems likely that children of respondents who selected the “I’m not sure” answer on average received more doses of acetaminophen than children of respondents who did not select this answer. As mentioned, a greater proportion of case participants selected “I’m not sure” than controls. This suggests that exposure of case children to acetaminophen in this survey may have been underestimated relative to controls, which means that the ORs and aORs for acetaminophen may have been underestimated as well. The same is true of the other dose-dependent variables in this study.\n\nUnits\nNumeric values for ORs, aORs, and CIs are dependent on the units in which the underlying variable is measured.63 For example, the variables for breastfeeding and cumulative vitamin D drop exposure were measured in units of months and months per normalized dose, respectively. If these variables were annualized, the ORs, aORs, and CIs would be greater in magnitude. Relatedly, while the aOR and CI for the total vitamin D drop variable may seem unusually large in nominal terms, this variable was defined in units of a normalized dose of oral vitamin D per day. If this variable were instead represented in units of IUs of oral vitamin D per day, then the aOR and CI would be much smaller in magnitude.\n\nGender as a covariate\nWhile the main analyses in this study used gender as a covariate, and its selection as a covariate was based on objective criteria, there are reasons why analyses excluding gender may also be relevant. First, as previously highlighted, existing research shows gender is a significant risk factor for ASD,46 and the results from the multifactor risk model (Table 6) confirm this. Hence, if another variable has a gender-specific effect on risk, the inclusion of gender as a covariate may diminish or possibly obscure an association of that variable with ASD due to interaction effects. Second, based on the survey design, none of the biological children of each of the control respondents had ASD. Data on gender of the siblings of each control child were not collected, and it seems plausible that there may be correlation of some of the exposure variables under consideration among siblings in the same family. Thus, the gender-specific nature of some of the control observations may be somewhat overstated, as only one gender was represented per control family, but none of the children in any of the control families had ASD. For these reasons, readers may wish to peruse results in Tables S6 and S7, where gender was not included as a covariate.\n\nBreastfeeding\nBreastfeeding durations for controls in this study were somewhat longer than those seen in other national surveys. For example, the Centers for Disease Control found that 30.7% of infants born in 2013 were breastfed for 12 months or more.64 This study found that 37.7% of controls were breastfed for >12 months. The biological mothers of controls in this study were more highly educated, and based on the ethnicities of control children, less ethnically diverse than the national population.48,65 These characteristics are associated with increased duration of breastfeeding.66 Thus, the breastfeeding durations for controls in this study are about what one would expect given the demographics of the control population.\n\nIn this data set, longer duration of breastfeeding is associated with decreased risk of ASD when adjusted for any of the other variables. This finding was robust across all models examined. This finding is also consistent with many, but not all, of the existing studies on breastfeeding and ASD.8,13–15\n\nThis finding could conceivably reflect correlated variables that are not examined in this study. For example, decreased breastfeeding could reflect an insufficiently developed suckling reflex in the infant or an inability to breastfeed due to poor maternal health. Both could plausibly decrease the number of those who were ever breastfed among cases. However, for those in which breastfeeding was successfully initiated, it seems neither of these factors would lead to appreciably shorter duration. Thus, it appears neither of these factors could explain the significant differences between cases and controls in the longer duration categorical breastfeeding variables from Table 2.\n\nAlternatively, this breastfeeding finding may reflect some protective effect of breast milk. For example, breast milk contains each of the following: bifidobacteria,67 lysozyme,68 lipoxins,69 glutathione,70 and anti-inflammatory cytokines.71 Literature suggests that relative to controls, children with ASD in aggregate have lower levels or bifidobacteria and lysozyme in the digestive tract,72 decreased levels of lipoxin A4 and glutathione in plasma,73–75 and increased levels of inflammatory cytokines in plasma.76 Therefore, a number of possible components of breast milk could plausibly be connected to these results on breastfeeding and ASD.\n\nEar infection and antibiotics\nTable 2 shows that ORs for categorical variables for ear infection incidence increase monotonically with the number of incidents of ear infection. In other words, the raw data suggest ear infection is associated with increased risk of ASD. Table 4 shows that increased incidence of ear infection is associated with ASD (aOR 1.137, CI: 1.046–1.236, p=0.003).\n\nThree smaller studies have previously found such an association between ear infection and ASD.9,10,19 However, a large study based on medical charts recorded prior to diagnosis found that those with ASD had fewer ear infections than controls.20 This study based on charts had an unusually high percentage of controls with at least one ear infection during the first 2 years of life. It also found the following: 1) marginally higher rates of hospitalization for ear infection among those later diagnosed with ASD, 2) higher rates of infection during the first 30 days of life among those diagnosed with ASD, and 3) marginal overrepresentation of those with 13 or more infections among those with ASD. These data suggest that this Rosen et al20 study might have obtained a different result if the focus had been on ear infections that are unusually severe, persistent, or in the very young. Therefore, the authors would not disregard the findings in the present study and the three smaller studies on an association between ear infection and ASD based solely on the Rosen et al study.\n\nTable 2 shows that ORs for categorical variables for antibiotic use increase monotonically with the number of courses. Table 4 shows that increased exposure to postnatal antibiotics is associated with ASD (aOR 1.103, CI: 1.046–1.168, p<0.001). Two smaller studies have previously found such an association, one of which also found an association with ear infection.9,18\n\nAntibiotics and ear infection are correlated variables. The correlation coefficient in Table 3 is 0.64. This is expected, as antibiotics are often used as a treatment for ear infection.77 A natural question is whether one of these variables is causative, while the other is merely associated due to correlation.\n\nStatistics for the Antibiotic/Ear infection model in Table 5 provide one way of examining this question. While the antibiotic variable has a statistically significant association with ASD in this model, the ear infection variable has no meaningful association with ASD. An analogous result holds in the Low-granularity antibiotic/Ear infection model where the antibiotic variable is expressed with a granularity that is comparable to that of the ear infection variable.\n\nSimilarly, the objective criteria used in constructing the multifactor model result in inclusion of the antibiotic variable and dropping of the ear infection variable. These results suggest that the antibiotic variable is the more significant of the two. Plausibly, the association of ear infection with ASD could be primarily a result of antibiotic use being correlated with ear infection.\n\nIf the association between antibiotics and ASD is fundamental, this may reflect the effect of antibiotics on the microbiome. Specifically, antibiotic use in childhood is associated with increased microbiome depletion and bacterial dysbiosis,78,79 and children with ASD are more prone to microbiome depletion and bacterial dysbiosis.72,80\n\nAcetaminophen and ibuprofen\nAs Table 2 shows, never being exposed to postnatal acetaminophen is associated with decreased risk of ASD (OR 0.652, CI: 0.432–0.986, p=0.041) and being exposed to 64+ doses of postnatal acetaminophen is associated with increased risk of ASD (OR 3.743, CI: 1.298–10.793, p=0.009). In addition, as Table 4 shows, increased exposure to postnatal acetaminophen, in general, is associated with increased risk of ASD (aOR 1.016, CI: 1.003–1.032, p=0.026). In contrast, the analogous relationships between ibuprofen and ASD are much weaker. The correlation coefficient between acetaminophen and ibuprofen is 0.72, which shows they are correlated. This is not surprising as they are both analgesics. However, the Analgesic model showed that the association between acetaminophen and ASD is weakened but still present when ibuprofen is included as a confounding variable. No such association is evident between ibuprofen and ASD when acetaminophen is included as a confounding variable. In other words, the association between postnatal acetaminophen and ASD is much stronger than the association between ibuprofen and ASD, and the latter weak association could come about solely from ibuprofen use being correlated with acetaminophen use.\n\nAs neither analgesic variable is included in the multifactor model, one cannot preclude the possibility that the association between acetaminophen and ASD is due to correlation with other variables. Specifically, from Table 3, acetaminophen use is correlated with antibiotic use. However, the statistically significant and distinct pattern of association exhibited by the categorical acetaminophen variables and the relative strength of the association of the scaled acetaminophen variable with ASD relative to the scaled ibuprofen variable suggest that the association with ASD is not merely due to its correlation with antibiotic use.\n\nThe present study replicates findings from a small survey study on postnatal acetaminophen use and ASD.11 Some existing literature has already explored why acetaminophen exposure could be a risk factor for ASD.11,22,81 In this context, the authors wish to highlight that children with ASD in aggregate are likely to metabolize acetaminophen less efficiently than unaffected children. In young children, sulfation is the primary pathway for the metabolism of acetaminophen,82 and the antioxidant glutathione is critical for detoxifying a residual by-product.83,84 Relatedly, research on acetaminophen in animal models suggests that acetaminophen has greater toxicity in those where any of the following are in short supply: sulfate, cysteine, S-adenosyl methionine, or glutathione.85–89 In children with ASD, the levels of free sulfate,74,75 cysteine,74,75,90,91\nS-adenosyl methionine,74,75,90,91 and reduced glutathione74,75,90,91 in plasma are on average significantly lower than in controls. Hence, children with ASD as a group would appear to be particularly prone to acetaminophen toxicity.\n\nVitamin D drops\nThe “No vitamin D drop” variable (OR 1.475, CI: 1.165–1.866, p=0.001) in Table 2 suggests that providing no vitamin D drops is associated with increased risk of ASD. Yet, there are hints in the “3 months or less vitamin D drop” variable (OR 0.646, CI: 0.474–0.879, p=0.005) and the “Less than standard dose” (OR 0.376, CI: 0.178–0.793, p=0.008) variable that shorter duration of exposure and lower doses are associated with decreased risk of ASD.\n\nThe unadjusted OR in Table 4 for the cumulative postnatal vitamin D drop variable (OR 0.982, CI: 0.959–1.006, p=0.132) would seem to suggest that increased exposure to vitamin D drops is weakly associated with decreased risk of ASD. However, control mothers were better educated on average than case mothers, and those with higher education tended to use oral vitamin D drops. In addition, cases in this study were somewhat older than controls, and older children were somewhat less likely to have been exposed to oral vitamin D drops. Thus, once one adjusts for confounding variables, the association between vitamin D drops and ASD no longer points in the direction of decreased risk.\n\nTable 3 shows that the correlation between vitamin D drops and breastfeeding is 0.25. In the USA, vitamin D drops are recommended for children who are breastfed, since infant formula is already fortified with vitamin D.92 Thus, it is expected that these variables would be correlated. Yet, there does not appear to be any associated reduction in ASD risk due to vitamin D drop use. In models that include vitamin D drops, breastfeeding, and demographic variables, the vitamin D drop variable is weakly associated with increased risk of ASD. Specifically, in the multifactor model, where the AIC results in the inclusion of the cumulative vitamin D drop exposure variable, it is weakly associated with ASD (aOR 1.026, CI: 0.996–1.057, p=0.093).\n\nThis weak association goes in the opposite direction of that hypothesized by most researchers who have considered vitamin D supplementation in the context of ASD.12,23,24 It seems conceivable that a parent who has multiple children with ASD might have provided vitamin D drops to a younger child with ASD, following the diagnosis of an older child, if the parent was exposed to media suggesting that vitamin D might have a prophylactic effect on the development of ASD. This scenario would tend to bias the results toward case use of vitamin D drops. This scenario is also plausible, since as early as 2008, some literature hypothesized that vitamin D deficiency could be a risk factor for ASD.93 To test whether this media effect could be significant in this data set, the specialized general linear model for breastfeeding and vitamin D drops excluding those with multiple ASD children was constructed as previously described. The association between vitamin D drops and ASD under this model was comparable to the model without this exclusion. Therefore, the weak association between vitamin D drop use and ASD does not appear to be due to a media effect.\n\nOne might wonder whether such a relationship would hold if other sources of postnatal oral vitamin D were included in an analysis. This was tested using the Breastfeeding/Total vitamin D model. Based on p-values from Table 5, the association between total oral vitamin D and ASD was marginally stronger than the association between vitamin D drops and ASD.\n\nThus, vitamin D drops as well as modeled total oral vitamin D consumed were both weakly associated with ASD in this sample when adjusted for breastfeeding. While none of these results are statistically significant using a 0.05 threshold, analogous results for both vitamin D drops and total vitamin D are statistically significant if gender is not included as a covariate (Table S8). These results seem to support Zhou et al’s work suggesting that excessive nutrient intake may be a risk factor for ASD.25 Specifically, these results suggest that excessive postnatal oral vitamin D exposure may be a risk factor for ASD.\n\nPrenatal folate\nUnlike other variables in this study, prenatal folate could plausibly affect genetic risk for ASD if taken prior to conception. Therefore, exclusion of those with genetic conditions of high penetrance for ASD from the case set for analysis on prenatal folate seems unjustified. The Folate including genetic conditions model addresses this (Table 5). Yet, statistics on the folate variable in this model are similar to the statistics on the folate variable with genetic conditions excluded (Table 4). None of the folate variables in Tables 2, 4, and 5 have p-values or CIs that would suggest a firm relationship between prenatal folate and risk of ASD.\n\nA number of studies have found that prenatal folate supplementation is associated with a decreased risk of ASD,36–38,94 and other studies have found that prenatal folate attenuates the effect of other risk factors for ASD.95,96 However, other studies, which in aggregate have received much less attention, have found that prenatal folate supplementation may not affect the risk of ASD,97,98 may be associated with an increased risk of ASD,99 may be associated with a decreased risk of ASD when included in a multivitamin but increased risk of ASD when consumed separately,100 or may be associated with an increased risk of ASD at high levels of supplementation and a decreased risk of ASD at moderate levels of supplementation.101\n\nGiven the varied and conflicting results in the literature, it is not surprising that the present study found no firm relationship between prenatal folate and the risk of ASD. Three additional considerations are relevant when evaluating this result. First, there was a single question in the survey on prenatal folate, and no data were collected on prenatal folate consumption prior to conception. Each of the studies that found that prenatal folate reduces the risk of ASD included some analysis of supplementation prior to conception.36–38,94 Second, the biological mothers in the present study appear to be somewhat better educated on average than those in at least three of the studies that found that prenatal folate reduces risk.36,37,94\nTable 3 in the present study shows that prenatal folate use in this data set is correlated with higher education. Thus, there may be less variability in use of prenatal folate in this sample with higher average education than there were in some of the prior studies. Third, while fortification of some foods with folic acid is mandatory in the USA, it is not mandatory in three of the countries where studies found that prenatal folate reduces risk.36,38,94,102 Hence, a study relying on a data set from the USA like the present one is less likely to find supplementation is beneficial than those based on data sets from countries where food fortification is not mandatory.\n\nWhile there are already many studies on prenatal folate and ASD in literature, this study adds to evidence that prenatal folate supplementation has no significant effect on the risk of ASD in some populations. However, the results of this study are not inconsistent with the possibility that prenatal folate supplementation may reduce the risk of ASD if consumed prior to conception, in moderate doses only, by those in a less-educated demographic, or by those who do not consume foods fortified with folate.\n\nStrengths and limitations\nSome limitations of this study arose from its reliance on data from an Internet survey. While efforts have been made to limit bias in this study and some of the analysis above suggests that any bias in the results was limited, the raw data collected from the survey were essentially unverified beyond what could be gleaned from the participants’ answers. For example, only children whose parents indicated that a diagnosis was made by a professional were included in the case group, but whether such a diagnosis was actually made by a professional for a particular child was not independently verified. Relatedly, there was no uniformity in the type or methodology of diagnosis among case participants.\n\nSeparately, as previously noted, there are some material differences between case and control group demographics in this study. For example, the case and control groups differed in aggregate on gender distribution, mean age of child, maternal education, and, to a lesser extent, ethnicity. While most of the key statistical measures used in this study were adjusted to account for differences in these variables and others, it would be desirable if the aggregate demographic characteristics of the case and control groups had greater similarity.\n\nWhile using an Internet survey to build the underlying data set led to some of the study’s limitations, this approach was also responsible for some of its strengths. For example, a relatively large sample size was obtained. Few ASD survey studies have as many participants as this one has, and this is especially true of postnatal ASD risk factor studies. Relatedly, a large and diverse set of groups were used in recruitment for this study, and participants came from all regions of the USA. Therefore, the results of this study do not have the limitation of potentially only applying to children who were seen at a particular medical center or to children whose parents are members of a particular organization. In addition, using an Internet survey to collect the data for this study minimized the probability of some types of bias associated with personal interactions. For example, data sets assembled via personal interviews have risks of bias associated with inconsistencies in interviewer technique or interviewer subjectivity.\n\nConclusion\nThis study adds to the evidence that increased duration of breastfeeding is associated with a decreased risk of ASD (aOR 0.948, CI: 0.932–0.949, p<0.001). It finds that postnatal acetaminophen (aOR 1.016, CI: 1.003–1.032, p=0.026), postnatal antibiotics (aOR 1.103, CI: 1.046–1.168, p<0.001), and incidence of ear infection (aOR 1.137, CI: 1.046–1.236, p=0.003) are associated with an increased risk of ASD. While associations with each of these three latter variables and the risk of ASD appear in the literature, this study serves as replication. This study also finds that cumulative oral vitamin D drop exposure is weakly associated with increased risk of ASD when adjusted for breastfeeding and demographics (aOR 1.025, CI: 0.995–1.056, p=0.102). An analogous result holds for modeled total oral vitamin D as well.\n\nAcknowledgments\nWe benefited from the facilities, resources, administrative, institutional, and research support provided by the Columbia University’s Interdisciplinary Center for Innovative Theory and Empirics (INCITE). We are especially grateful to Peter Bearman of INCITE for his thoughtful suggestions on the design of the questionnaire and drafts of this paper. We are also grateful to the 1,741 parents who took the time to participate in this study, as well as the administrators, executive directors, and presidents of various groups who graciously permitted the survey to be highlighted through their media. We are also grateful to the Interactive Autism Network (IAN) for its generous assistance with subject recruitment, and we wish to express our gratitude to the following people: Michael Falco of INCITE, Dr Kiely Law of IAN, and Dr Alison Marvin of IAN.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Flow chart for participant inclusion.\n\nAbbreviations: ADD, attention-deficit disorder; ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; PDD-NOS, pervasive developmental disorder–not otherwise specified; SPD, sensory processing disorder.\n\nTable 1 Demographics\n\nVariable\tCases\tControls\t\nn\t1,001\t514\t\nAge of child (mean, SD)\t7.3 (2.9)\t5.5 (2.6)\t\nGender of child – male (n, %)\t801 (80.0)\t268 (52.1)\t\nEthnicity of child (n, %)\t\t\t\n White (non-Hispanic)\t773 (77.2)\t438 (85.2)\t\n Hispanic/Latino\t104 (10.4)\t30 (5.8)\t\n African American/Black\t39 (3.9)\t5 (1.0)\t\n Asian\t19 (1.9)\t11 (2.1)\t\n Other\t66 (6.6)\t30 (5.8)\t\nRegions of the USA (n, %)\t\t\t\n Northeast\t180 (18.0)\t103 (20.0)\t\n Midwest\t240 (24.0)\t176 (34.2)\t\n South\t362 (36.2)\t108 (21.0)\t\n West\t219 (21.9)\t127 (24.7)\t\nMaternal age at birth of child (mean, SD)\t30.0 (5.6)\t31.2 (4.6)\t\nMaternal education (n, %)\t\t\t\n Grade school or some high school\t10 (1.0)\t6 (1.2)\t\n High school\t80 (8.0)\t22 (4.3)\t\n Some college\t272 (27.2)\t72 (14.0)\t\n Bachelor’s or associate’s degree\t394 (39.4)\t208 (40.5)\t\n Graduate or professional degree\t244 (24.4)\t206 (40.1)\t\n I’m not sure\t1 (0.1)\t–\t\nRelationship to the child (n, %)\t\t\t\n Biological mother\t978 (97.7)\t497 (96.7)\t\n Biological father\t21 (2.1)\t15 (2.9)\t\n NA\t2 (0.2)\t2 (0.4)\t\nHow did (the participant) hear about this survey? (n, %)\t\t\t\n Autism Society of America chapter\t92 (9.2)\t7 (1.4)\t\n Autism or Asperger’s related group\t443 (44.3)\t24 (4.7)\t\n Apraxia, ADHD, ADD, or SPD related group\t14 (1.4)\t4 (0.8)\t\n General interest parenting group\t145 (14.5)\t86 (16.7)\t\n Friend\t160 (16.0)\t377 (73.3)\t\n Other\t147 (14.7)\t16 (3.1)\t\n Interactive Autism Network\t111 (11.1)\t–\t\n Remaining other\t36 (3.6)\t–\t\nNote: %, Percentage of cases or controls.\n\nAbbreviations: ADD, attention-deficit disorder; ADHD, attention-deficit/hyperactivity disorder; NA, not available; SPD, sensory processing disorder.\n\nTable 2 Categorical variables and ORs\n\nQuestiona/variable\tCases\n\tControls\n\tOR\t95% CI\tp-value\t\nn (%)\tn (%)\t\nDuration of breastfeeding?\t\t\t\t\t\t\n Never breastfed\t234 (23.4)\t70 (13.6)\t1.935\t1.446–2.590\t<0.0001*\t\n 3 months or less\t277 (27.7)\t80 (15.6)\t2.076\t1.575–2.735\t<0.0001*\t\n >3 months and up to 6 months\t118 (11.8)\t66 (12.8)\t0.907\t0.657–1.252\t0.5527\t\n >6 months and up to 12 months\t155 (15.5)\t90 (17.5)\t0.863\t0.649–1.147\t0.3107\t\n >12 months\t217 (21.7)\t208 (40.5)\t0.407\t0.323–0.513\t<0.0001*\t\nCourses of antibiotics up to second birthday?\t\t\t\t\t\t\n None\t194 (19.4)\t141 (27.4)\t0.667\t0.519–0.858\t0.0015*\t\n 1\t174 (17.4)\t132 (25.7)\t0.638\t0.492–0.826\t0.0006*\t\n 2–3\t282 (28.2)\t133 (25.9)\t1.196\t0.938–1.526\t0.1483\t\n 4–7\t181 (18.1)\t64 (12.5)\t1.642\t1.206–2.236\t0.0015*\t\n 8–15\t71 (7.1)\t19 (3.7)\t2.086\t1.242–3.504\t0.0046*\t\n 16+\t18 (1.8)\t4 (0.8)\t2.440\t0.821–7.249\t0.0975\t\n I’m not sure\t81 (8.1)\t21 (4.1)\t–\t–\t–\t\nEar infections up to second birthday?\t\t\t\t\t\t\n None\t341 (34.1)\t230 (44.7)\t0.644\t0.517–0.802\t0.0001*\t\n 1\t179 (17.9)\t115 (22.4)\t0.764\t0.587–0.994\t0.0446*\t\n 2–3\t208 (20.8)\t76 (14.8)\t1.533\t1.149–2.044\t0.0035*\t\n >3 or persistent\t246 (24.6)\t84 (16.3)\t1.694\t1.286–2.230\t0.0002*\t\n I’m not sure\t27 (2.7)\t9 (1.8)\t–\t–\t–\t\nDoses of acetaminophen up to second birthday?\t\t\t\t\t\t\n None\t54 (5.4)\t45 (8.8)\t0.652\t0.432–0.986\t0.0414*\t\n 1–3\t174 (17.4)\t91 (17.7)\t1.096\t0.825–1.456\t0.5266\t\n 4–15\t378 (37.8)\t216 (42.0)\t0.971\t0.773–1.220\t0.8029\t\n 16–63\t191 (19.1)\t107 (20.8)\t1.006\t0.768–1.317\t0.9682\t\n 64+\t26 (2.6)\t4 (0.8)\t3.743\t1.298–10.793\t0.0089*\t\n I’m not sure\t178 (17.8)\t51 (9.9)\t–\t–\t–\t\nDoses of ibuprofen up to second birthday?\t\t\t\t\t\t\n None\t185 (18.5)\t115 (22.4)\t0.898\t0.687–1.172\t0.4279\t\n 1–3\t167 (16.7)\t91 (17.7)\t1.064\t0.800–1.415\t0.6716\t\n 4–15\t304 (30.4)\t180 (35.0)\t0.947\t0.749–1.197\t0.6495\t\n 16–63\t141 (14.1)\t74 (14.4)\t1.110\t0.816–1.510\t0.5067\t\n 64+\t17 (1.7)\t6 (1.2)\t1.635\t0.640–4.177\t0.2993\t\n I’m not sure\t187 (18.7)\t48 (9.3)\t–\t–\t–\t\nDuration of vitamin D drops as a baby?\t\t\t\t\t\t\n No vitamin D drops\t642 (64.1)\t307 (59.7)\t1.475\t1.165–1.866\t0.0012*\t\n 3 months or less\t108 (10.8)\t85 (16.5)\t0.646\t0.474–0.879\t0.0053*\t\n >3 months and up to 6 months\t62 (6.2)\t44 (8.6)\t0.746\t0.498–1.117\t0.1534\t\n >6 months and up to 12 months\t50 (5.0)\t30 (5.8)\t0.898\t0.563–1.432\t0.6499\t\n >12 months\t31 (3.1)\t18 (3.5)\t0.931\t0.515–1.682\t0.8128\t\n I’m not sure\t108 (10.8)\t30 (5.8)\t–\t–\t–\t\nDosage of vitamin D drops as a baby?\t\t\t\t\t\t\n No vitamin D drops\t641 (64.0)\t308 (59.9)\t1.489\t1.173–1.891\t0.0010*\t\n Less than the standard dose\t12 (1.2)\t17 (3.3)\t0.376\t0.178–0.793\t0.0077*\t\n About the standard dose\t220 (22.0)\t149 (29.0)\t0.738\t0.577–0.945\t0.0156*\t\n More than the standard dose\t7 (0.7)\t5 (1.0)\t0.760\t0.240–2.408\t0.6401\t\n I’m not sure\t121 (12.1)\t35 (6.8)\t–\t–\t–\t\nPrenatal folate supplementation?\t\t\t\t\t\t\n Yes, for the entire or nearly entire pregnancy\t788 (78.7)\t421 (81.9)\t0.849\t0.634–1.137\t0.2718\t\n Yes, during the first trimester\t55 (5.5)\t29 (5.6)\t0.985\t0.620–1.566\t0.9489\t\n Yes, after the first trimester\t45 (4.5)\t15 (2.9)\t1.587\t0.876–2.876\t0.1249\t\n No\t72 (7.2)\t34 (6.6)\t1.109\t0.726–1.693\t0.6318\t\n I’m not sure\t41 (4.1)\t15 (2.9)\t–\t–\t–\t\nNotes:\n\na Questions in this table were edited for brevity.\n\n* p-values <0.05.\n\nAbbreviation: OR, Wald Odds Ratio.\n\nTable 3 Correlationa matrix\n\nVariable\tASD\tBreastfeed\tAntibiotic\tEar infection\tAcetaminophen\tIbuprofen\tVitamin D drop\tFolate\t\nASD\t1.00\t\t\t\t\t\t\t\t\nBreastfeed\t−0.22\t1.00\t\t\t\t\t\t\t\nAntibiotic\t0.13\t−0.15\t1.00\t\t\t\t\t\t\nEar infection\t0.13\t−0.14\t0.64\t1.00\t\t\t\t\t\nAcetaminophen\t0.07\t−0.07\t0.38\t0.25\t1.00\t\t\t\t\nIbuprofen\t0.04\t−0.02\t0.34\t0.24\t0.72\t1.00\t\t\t\nVitamin D drop\t−0.04\t0.25\t−0.03\t−0.09\t0.01\t0.02\t1.00\t\t\nFolate\t−0.04\t0.05\t−0.01\t−0.02\t−0.01\t−0.02\t0.09\t1.00\t\nNote:\n\na Regression coefficients computed by Pearson’s correlations with pairwise deletions.\n\nAbbreviation: ASD, autism spectrum disorder.\n\nTable 4 ORs and aORs\n\nVariable\tMean loading\n\tUnadjusted\n\tAdjusted for demographics\n\t\nCases\tControls\tOR\t95% CI\tp-value\taORa\t95% CI\tp-value\t\nBreastfeeding (months)\t7.30\t10.62\t0.935\t0.920–0.949\t<0.0001*\t0.948\t0.932–0.965\t<0.0001*\t\nAntibiotic (courses)\t2.52\t1.77\t1.138\t1.083–1.201\t<0.0001*\t1.103\t1.046–1.168\t0.0004*\t\nEar infection (number)\t1.62\t1.19\t1.208\t1.123–1.301\t<0.0001*\t1.137\t1.046–1.236\t0.0026*\t\nAcetaminophen (doses)\t7.78\t6.31\t1.015\t1.003–1.028\t0.018*\t1.016\t1.003–1.032\t0.0259*\t\nIbuprofen (doses)\t5.81\t5.11\t1.008\t0.996–1.021\t0.210\t1.012\t0.998–1.027\t0.1106\t\nVitamin D drops (months × dose)\t2.01\t2.41\t0.982\t0.959–1.006\t0.132\t1.006\t0.979–1.035\t0.6654\t\nFolate first trimester (binary)\t0.88\t0.90\t0.785\t0.547–1.110\t0.177\t1.054\t0.703–1.566\t0.7956\t\nNotes:\n\na Covariates for the aORs are gender, age of the child, ethnicity, Midwest, South, maternal education, age of the mother at the birth of the child, and relationship.\n\n* p-values <0.05.\n\nAbbreviations: aOR, adjusted odds ratio; OR, odds ratio.\n\nTable 5 Specialized general linear models\n\nModel\tn\tVariable\taORa\t95% CI\tp-value\t\nAntibiotic/Ear infection\t1,388\tAntibiotic (courses)\t1.080\t1.009–1.162\t0.0322*\t\nEar infection (number)\t1.055\t0.942–1.180\t0.3546\t\nLow-granularity antibiotic/Ear infection\t1,388\tLow-granularity antibiotic (courses)\t1.177\t1.023–1.356\t0.0239*\t\nEar infection (number)\t1.013\t0.884–1.160\t0.8548\t\nAnalgesic\t1,257\tAcetaminophen (doses)\t1.018\t0.998–1.039\t0.0892\t\nIbuprofen (doses)\t1.000\t0.979–1.020\t0.9701\t\nBreastfeeding/Vitamin D drops\t1,327\tBreastfeeding (months)\t0.948\t0.930–0.966\t<0.0001*\t\nVit D drop (months × dose)\t1.025\t0.995–1.056\t0.1024\t\nBreastfeeding/Vitamin D drops excluding >1 ASD child\t1,208\tBreastfeeding (months)\t0.949\t0.930–0.968\t<0.0001*\t\nVit D drop (months × dose)\t1.025\t0.994–1.057\t0.1144\t\nBreastfeeding/Total vitamin D\t1,327\tBreastfeeding (months)\t0.963\t0.941–0.986\t0.0016*\t\nTotal oral D (norm dose)\t1.562\t0.928–2.664\t0.0970\t\nFolate including genetic conditions\t1,505\tFolate first trimester (binary)\t1.077\t0.719–1.596\t0.7144\t\nNotes:\n\na Covariates for aORs are gender, age of the child, ethnicity, Midwest, South, maternal education, age of the mother at the birth of the child, and relationship.\n\n* p-values <0.05.\n\nAbbreviations: aOR, adjusted odds ratio; norm, normalized.\n\nTable 6 Multifactor modela\n\nVariable\taORa\t95% CI\tp-value\t\nBreastfeeding (months)\t0.954\t0.935–0.973\t<0.0001*\t\nAntibiotic (courses)\t1.083\t1.023–1.151\t0.0076*\t\nVitamin D drops (months × dose)\t1.026\t0.996–1.057\t0.0928\t\nGender (male)\t3.951\t2.983–5.260\t<0.0001*\t\nNotes:\n\na Covariates are age of the child, ethnicity, maternal education, Midwest, and South (n=1,244).\n\n* p-values <0.05.\n\nAbbreviation: aOR, adjusted odds ratio.\n==== Refs\nReferences\n1 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 5th ed Arlington, Virginia American Psychiatric Association 2013 \n2 Wender CLA Veenstra-VanderWeele J Challenge and potential for research on gene-environment interactions in autism spectrum disorder Tolan PH Leventhal BL Gene-Environment Transactions in Developmental Psychopathology 2017 2 157 176 Available from: https://books.google.com/books?isbn=3319492276 Accessed March 22, 2018 \n3 Lyall K Schmidt RJ Hertz-Picciotto I Maternal lifestyle and environmental risk factors for autism spectrum disorders Int J Epidemiol 2014 43 2 443 464 24518932 \n4 Wang C Geng H Liu W Zhang G Prenatal, perinatal, and postnatal factors associated with autism: a meta-analysis Medicine (Baltimore) 2017 96 18 e6696 28471964 \n5 Mandy W Lai MC Annual Research Review: the role of the environment in the developmental psychopathology of autism spectrum condition J Child Psychol Psychiatry 2016 57 3 271 292 26782158 \n6 Williams K Brignell A Prior M Bartak L Roberts J Regression in autism spectrum disorders J Paediatr Child Health 2015 51 1 61 64 25586846 \n7 Jones W Klin A Attention to eyes is present but in decline in 2–6-month-old infants later diagnosed with autism Nature 2013 504 7480 427 431 24196715 \n8 Boucher O Julvez J Guxens M Association between breastfeeding duration and cognitive development, autistic traits and ADHD symptoms: a multicenter study in Spain Pediatr Res 2017 81 3 434 442 27846197 \n9 Niehus R Lord C Early medical history of children with autism spectrum disorders J Dev Behav Pediatr 2006 27 2 Suppl S120 S127 16685178 \n10 Jeans LM Santos RM Laxman DJ McBride BA Dyer WJ Early predictors of ASD in young children using a nationally representative data set J Early Interv 2013 35 4 303 331 \n11 Schultz ST Klonoff-Cohen HS Wingard DL Akshoomoff NA Macera CA Ji M Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey Autism 2008 12 3 293 307 18445737 \n12 Cannell JJ Autism, will vitamin D treat core symptoms? Med Hypotheses 2013 81 2 195 198 23725905 \n13 Al-Farsi YM Al-Sharbati MM Waly MI Effect of suboptimal breast-feeding on occurrence of autism: a case-control study Nutrition 2012 28 7–8 e27 e32 22541054 \n14 Schultz ST Klonoff-Cohen HS Wingard DL Akshoomoff NA Macera CA Ji M Bacher C Breastfeeding, infant formula supplementation, and Autistic Disorder: the results of a parent survey Int Breastfeeding J 2006 1 16 \n15 Husk JS Keim SA Breastfeeding and autism spectrum disorder in the national survey of children’s health Epidemiology 2015 26 4 451 457 25872161 \n16 Atladóttir HÓ Henriksen TB Schendel DE Parner ET Autism after infection, febrile episodes, and antibiotic use during pregnancy: an exploratory study Pediatrics 2012 130 6 e1447 e1454 23147969 \n17 Sandler RH Finegold SM Bolte ER Short-term benefit from oral vancomycin treatment of regressive-onset autism J Child Neurol 2000 15 7 429 435 10921511 \n18 Adams JB Romdalvik J Ramanujam VM Legator MS Mercury, lead, and zinc in baby teeth of children with autism versus controls J Toxicol Environ Health A 2007 70 12 1046 1051 17497416 \n19 Konstantareas MM Homatidis S Ear infections in autistic and normal children J Autism Dev Disord 1987 17 4 585 594 3680158 \n20 Rosen NJ Yoshida CK Croen LA Infection in the first 2 years of life and autism spectrum disorders Pediatrics 2007 119 1 e61 e69 17200260 \n21 Liew Z Ritz B Virk J Olsen J Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood: a Danish national birth cohort study Autism Res 2016 9 9 951 958 26688372 \n22 Parker W Hornik CD Bilbo S The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism J Int Med Res 2017 45 2 407 438 28415925 \n23 Patrick RP Ames BN Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism FASEB J 2014 28 6 2398 2413 24558199 \n24 Mostafa GA Al-Ayadhi LY Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity J Neuroinflammation 2012 17 9 201 \n25 Zhou SS Zhou YM Li D Ma Q Early infant exposure to excess multivitamin: a risk factor for autism? Autism Res Treat 2013 963697 23533752 \n26 Bittker S Oral vitamin D, infants, toddlers, and autism in the United States: 1980 to 2010 J Autism (Herbert) 2015 2 1 \n27 Lee H Marvin AR Watson T Accuracy of phenotyping of autistic children based on Internet implemented parent report Am J of Med Genet 2010 153B 6 1119 1126 20552678 \n28 Marvin AR Law PA Law JK Non-verbal children with ASD (NV-ASD): validating a registry and characterizing a population Presentation at the International Meeting for Autism Research Atlanta, GA 2014 Available from: https://insar.confex.com/insar/2014/web-program/Paper16978.html Accessed March 22, 2018 \n29 Daniels AM Rosenberg RE Anderson C Law JK Marvin AR Law PA Verification of parent-report of child autism spectrum disorder diagnosis to a web-based autism registry J Autism Dev Disord 2012 42 2 257 265 21468770 \n30 Hazen EP McDougle CJ Volkmar FR Changes in the diagnostic criteria for autism in DSM-5: controversies and concerns J Clin Psychiatry 2013 74 7 739 740 23945452 \n31 Sinzig J Morsch D Bruning N Schmidt MH Lehmkuhl G Inhibition, flexibility, working memory and planning in autism spectrum disorders with and without comorbid ADHD-symptoms Child Adolesc Psychiatry Ment Health 2008 2 1 4 18237439 \n32 Lane AE Young RL Baker AE Angley MT Sensory processing subtypes in autism: association with adaptive behavior J Autism Dev Disord 2010 40 1 112 122 19644746 \n33 Tierney C Mayes S Lohs SR Black A Gisin E Veglia M How valid is the checklist for autism spectrum disorder when a child has apraxia of speech? J Dev Behav Pediatr 2015 36 8 569 574 26114615 \n34 Rommelse NN Franke B Geurts HM Hartman CA Buitelaar JK Shared heritability of attention-deficit/hyperactivity disorder and autism spectrum disorder Euro Child Adolesc Psychiatry 2010 19 3 281 295 \n35 Baranek GT Roberts JE David FJ Developmental trajectories and correlates of sensory processing in young boys with fragile X syndrome Phys Occup Ther Pediatr 2008 28 1 79 98 18399048 \n36 Surén P Roth C Bresnahan M Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children JAMA 2013 309 6 570 577 23403681 \n37 Schmidt RJ Hansen RL Hartiala J Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism Epidemiology 2011 22 4 476 485 21610500 \n38 Steenweg-de Graaff J Ghassabian A Jaddoe VW Tiemeier H Roza SJ Folate concentrations during pregnancy and autistic traits in the offspring. The Generation R Study Eur J Public Health 2015 25 3 431 433 25085472 \n39 Ross AC Taylor CL Yaktine AL Del Valle HB Dietary Reference Intakes for Calcium and Vitamin D Washington, DC National Academies Press 2011 \n40 Reeve LE Chesney RW DeLuca HF Vitamin D of human milk: identification of biologically active forms Am J Clin Nutr 1982 36 1 122 126 7091022 \n41 Pehrsson PR Lemar LE Patterson K Yand Exler J Vitamin D and Selected Fatty Acids in U.S. Infant Formulas USDA 2008 Available from: https://www.ars.usda.gov/ARSUserFiles/80400525/Articles/NDBC33_InfForm.pdf Accessed March 1, 2018 \n42 Patterson KY Phillips KM Horst RL Vitamin D content and variability in fluid milks from a US Department of Agriculture nationwide sampling to update values in the National Nutrient Database for Standard Reference J Dairy Sci 2010 93 5082 5090 20965322 \n43 Picciano MF Calkins EJ Garrick JR Deering RH Milk and mineral intakes of breastfed infants Acta Paediatr Scand 1981 70 189 194 7234402 \n44 Bonuck K Avraham SB Hearst M Kahn R Hyden C Is overweight at 12 months associated with differences in eating behaviour or dietary intake among children selected for inappropriate bottle use? Matern Child Nutr 2014 10 234 244 23556429 \n45 Bozdogan H Model selection and Akaike’s Information Criterion (AIC): the general theory and its analytical extensions Psychometrika 1987 52 3 345 370 \n46 Fombonne E Epidemiology of autistic disorder and other pervasive developmental disorders J Clin Psychiatry 2005 66 Suppl 10 3 8 \n47 Daniels AM Mandell DS Explaining differences in age at autism spectrum disorder diagnosis: a critical review Autism 2014 18 5 583 597 23787411 \n48 US Census Bureau Educational Attainment of the Population 18 Years and Over, by Age, Sex, Race, and Hispanic Origin for 2016 Available from: https://www.census.gov/data/tables/2016/demo/education-attainment/cps-detailed-tables.html Accessed March 1, 2018 \n49 Bunin GR Vardhanabhuti S Lin A Anschuetz GL Mitra N Practical and analytical aspects of using friend controls in case-control studies: experience from a case-control study of childhood cancer Paediatr Perinat Epidemiol 2011 25 5 402 412 21819422 \n50 Chubak J Boudreau DM Wirtz HS McKnight B Weiss NS Threats to validity of nonrandomized studies of postdiagnosis exposures on cancer recurrence and survival J Natl Cancer Inst 2013 105 19 1456 1462 23940288 \n51 Fischbach RL Harris MJ Ballan MS Fischbach GD Link BG Is there concordance in attitudes and beliefs between parents and scientists about autism spectrum disorder? Autism 2015 20 3 353 363 26014839 \n52 Russell G Kelly S Golding J A qualitative analysis of lay beliefs about the aetiology and prevalence of autistic spectrum disorders Child Care Health Dev 2009 36 3 431 436 19735265 \n53 Mercer L Creighton S Holden JJ Lewis ME Parental perspectives on the causes of an autism spectrum disorder in their children J Genet Couns 2006 15 1 41 50 16547798 \n54 Morgan DL The SAGE Encyclopedia of Qualitative Research Methods Thousand Oaks, CA, USA SAGE Publications, Inc 2008 816 817 \n55 Cath DC Ran N Smit JH van Balkom AJ Comijs HC Symptom overlap between autism spectrum disorder, generalized social anxiety disorder and obsessive-compulsive disorder in adults: a preliminary case-controlled study Psychopathology 2008 41 2 101 110 18033980 \n56 Heffernan KS Columna L Russo N Brief report: physical activity, body mass index and arterial stiffness in children with autism spectrum disorder: preliminary findings J Autism Dev Disord 2018 48 2 625 631 29119519 \n57 Martins Y Young RL Robson DC Feeding and eating behaviors in children with autism and typically developing children J Autism Dev Disord 2008 38 10 1878 1887 18483843 \n58 Atkinson R Flint J Encyclopedia of Social Science Research Methods Thousand Oaks, CA, USA SAGE Publications, Inc 2004 1044 1045 \n59 Etter JF Perneger TV Snowball sampling by mail: application to a survey of smokers in the general population Int J Epidemiol 2000 29 1 43 48 10750602 \n60 Gyarmathy VA Johnston LG Caplinskiene I Caplinskas S Latkin CA A simulative comparison of respondent driven sampling with incentivized snowball sampling–the “strudel effect” Drug Alcohol Depend 2014 135 71 77 24360650 \n61 Lopes CS Rodrigues LC Sichieri R The lack of selection bias in a snowball sampled case-control study on drug abuse Int J Epidemiol 1996 25 6 1267 1270 9027534 \n62 Ranganath C Rainer G Neural mechanisms for detecting and remembering novel events Nat Rev Neurosci 2003 4 3 193 202 12612632 \n63 Pepe MS Janes H Longton G Leisenring W Newcomb P Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker Am J Epidemiol 2004 159 9 882 890 15105181 \n64 Center for Disease Control Breastfeeding Report Card Progressing Toward National Breastfeeding Goals United States 2016 Available from: https://www.cdc.gov/breastfeeding/pdf/2016breastfeedingreportcard.pdf Accessed March 1, 2018 \n65 US Census Bureau Quick Facts United States Available from: https://www.census.gov/quickfacts/ Accessed March 1, 2018 \n66 Thulier D Mercer J Variables associated with breastfeeding duration J Obstet Gynecol Neonatal Nurs 2009 38 3 259 268 \n67 Grönlund MM Gueimonde M Laitinen K Maternal breast-milk and intestinal bifidobacteria guide the compositional development of the Bifidobacterium microbiota in infants at risk of allergic disease Clin Exp Allergy 2007 37 12 1764 1772 17941914 \n68 Lönnerdal B Bioactive proteins in human milk: health, nutrition, and implications for infant formulas J Pediatr 2016 173 Suppl S4 S9 27234410 \n69 Weiss GA Troxler H Klinke G Rogler D Braegger C Hersberger M High levels of anti-inflammatory and pro-resolving lipid mediators lipoxins and resolvins and declining docosahexaenoic acid levels in human milk during the first month of lactation Lipids Health Dis 2013 12 89 23767972 \n70 Ankrah NA Appiah-Opong R Dzokoto C Human breastmilk storage and the glutathione content J Trop Pediatr 2000 46 2 111 113 10822938 \n71 Field CJ The immunological components of human milk and their effect on immune development in infants J Nutr 2005 135 1 1 4 15623823 \n72 Adams JB Johansen LJ Powell LD Quig D Rubin RA Gastrointestinal flora and gastrointestinal status in children with autism–comparisons to typical children and correlation with autism severity BMC Gastroenterol 2011 11 22 21410934 \n73 Yan CL Zhang J Hou Y Decreased plasma levels of lipoxin A4 in children with autism spectrum disorders Neuroreport 2015 26 6 341 345 25714424 \n74 Adams JB Audhya T McDonough-Means S Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity Nutr Metab 2011 8 1 34 \n75 Geier DA Kern JK Garver CR Adams JB Audhya T Geier MR A prospective study of transsulfuration biomarkers in autistic disorders Neurochem Res 2008 34 2 386 393 18612812 \n76 Ashwood P Krakowiak P Hertz-Picciotto I Hansen R Pessah I Van de Water J Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome Brain Behav Immun 2011 25 1 40 45 20705131 \n77 Del Mar C Glasziou P Hayem M Are antibiotics indicated as initial treatment for children with acute otitis media? A meta-analysis BMJ 1997 314 7093 1526 1529 9183201 \n78 Yassour M Vatanen T Siljander H Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability Sci Transl Med 2016 8 343 343ra81 \n79 Korpela K Salonen A Virta LJ Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children Nat Commun 2016 7 10410 26811868 \n80 Wang L Christophersen CT Sorich MJ Gerber JP Angley MT Conlon MA Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism J Appl Environ Microbiol 2011 77 18 6718 6721 \n81 Ghanizadeh A Acetaminophen may mediate oxidative stress and neurotoxicity in autism Med Hypotheses 2012 78 2 351 22154541 \n82 Jiang XL Zhao P Barrett JS Lesko LJ Schmidt S Application of physiologically based pharmacokinetic modeling to predict acetaminophen metabolism and pharmacokinetics in children CPT Pharmacometrics Syst Pharmacol 2013 2 e80 24132164 \n83 Mazaleuskaya LL Sangkuhl K Thorn CF FitzGerald GA Altman RB Klein TE PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses Pharmacogenet Genomics 2015 25 8 416 426 26049587 \n84 Linden CH Rumack BH Acetaminophen overdose Emerg Med Clin North Am 1984 2 1 103 119 6394298 \n85 Gregus Z Kim HJ Madhu C Liu Y Rozman P Klaassen CD Sulfation of acetaminophen and acetaminophen-induced alterations in sulfate and 3′-phosphoadenosine 5′-phosphosulfate homeostasis in rats with deficient dietary intake of sulfur Drug Metab Dispos 1994 22 5 725 730 7835224 \n86 Price VF Jollow DJ Effects of sulfur-amino acid-deficient diets on acetaminophen metabolism and hepatotoxicity in rats Toxicol Appl Pharmacol 1989 101 2 356 369 2815088 \n87 Lauterburg BH Corcoran GB Mitchell JR Mechanism of action of N-acetylcysteine in the protection against the hepatotoxicity of acetaminophen in rats in vivo J Clin Invest 1983 71 4 980 991 6833497 \n88 Terneus MV Kiningham KK Carpenter AB Sullivan SB Valentovic MA Comparison of S-Adenosyl-L-methionine and N-acetylcysteine protective effects on acetaminophen hepatic toxicity J Pharmacol Exp Ther 2007 320 1 99 107 17065366 \n89 Zhao P Kalhorn TF Slattery JT Selective mitochondrial glutathione depletion by ethanol enhances acetaminophen toxicity in rat liver Hepatology (Baltimore, Md) 2002 36 2 326 335 \n90 James SJ Cutler P Melnyk S Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism Am J Clin Nutr 2004 80 6 1611 1617 15585776 \n91 Melnyk S Fuchs GJ Schulz E Metabolic imbalance associated with methylation dysregulation and oxidative damage in children with autism J Autism Dev Disord 2012 42 3 367 377 21519954 \n92 Wagner CL Greer FR American Academy of Pediatrics Section on Breastfeeding American Academy of Pediatrics Committee on Nutrition Prevention of rickets and vitamin D deficiency in infants, children, and adolescents Pediatrics 2008 122 5 1142 1152 18977996 \n93 Cannell JJ Autism and vitamin D Med Hypotheses 2008 70 4 750 759 17920208 \n94 Levine SZ Kodesh A Viktorin A Association of maternal use of folic acid and multivitamin supplements in the periods before and during pregnancy with the risk of autism spectrum disorder in offspring JAMA Psychiatry 2018 75 2 176 184 29299606 \n95 Goodrich AJ Volk HE Tancredi DJ Joint effects of prenatal air pollutant exposure and maternal folic acid supplementation on risk of autism spectrum disorder Autism Res 2018 11 1 69 80 29120534 \n96 Bjørk M Riedel B Spigset O Association of folic acid supplementation during pregnancy with the risk of autistic traits in children exposed to antiepileptic drugs in utero JAMA Neurol 2018 75 2 160 168 29279889 \n97 Virk J Liew Z Olsen J Nohr EA Catov JM Ritz B Preconceptional and prenatal supplementary folic acid and multivitamin intake and autism spectrum disorders Autism 2016 20 6 710 718 26408631 \n98 Strøm M Granström C Lyall K Ascherio A Olsen SF Research Letter: folic acid supplementation and intake of folate in pregnancy in relation to offspring risk of autism spectrum disorder Psychol Med 2018 48 6 1048 1054 28946926 \n99 DeSoto MC Hitlan R Synthetic folic acid supplementation during pregnancy may increase the risk of developing autism J Pediatr Biochem 2012 2 251 261 \n100 DeVilbiss EA Magnusson C Gardner RM Antenatal nutritional supplementation and autism spectrum disorders in the Stockholm youth cohort: population based cohort study BMJ 2017 359 j4273 28978695 \n101 Raghavan R Riley AW Volk H Maternal multivitamin intake, plasma folate and vitamin B12 levels and autism spectrum disorder risk in offspring Paediatr Perina Epidemiol 2018 32 1 100 111 \n102 EUROCAT World map of countries having mandatory fortification of food with folic acid Available from: http://www.eurocat-network.eu/content/EUROCAT-Folic-Acid-Map.pdf Accessed March 22, 2018\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6328",
"issue": "14()",
"journal": "Neuropsychiatric disease and treatment",
"keywords": "ASD; epidemiology; folate; postnatal; risk factor",
"medline_ta": "Neuropsychiatr Dis Treat",
"mesh_terms": null,
"nlm_unique_id": "101240304",
"other_id": null,
"pages": "1399-1414",
"pmc": null,
"pmid": "29910617",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "18977996;20705131;16978397;26014839;26408631;17920208;26049587;26782158;9183201;21819422;23147969;17497416;10822938;23787411;10750602;6833497;7835224;23940288;21784919;7234402;6394298;20148275;27234410;16401144;24132164;17200260;19735265;29279889;25872161;22154541;24196715;18033980;18237439;29299606;29120534;28415925;17065366;15105181;25714424;3680158;21519954;23533752;18399048;9027534;15585776;19538614;26811868;7091022;10921511;25085472;23556429;17941914;16547798;29119519;12612632;12143040;22541054;23403681;21651783;18612812;26114615;19644746;28471964;23945452;2815088;24558199;21468770;16685178;28978695;27846197;26688372;24518932;27306663;20552678;23767972;18445737;20965322;21410934;22898564;28946926;18483843;15623823;24360650;21610500;25586846;23725905",
"title": "Acetaminophen, antibiotics, ear infection, breastfeeding, vitamin D drops, and autism: an epidemiological study.",
"title_normalized": "acetaminophen antibiotics ear infection breastfeeding vitamin d drops and autism an epidemiological study"
} | [
{
"companynumb": "US-JNJFOC-20180713808",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
"d... |
{
"abstract": "BACKGROUND\nThis prospective, open-label phase II study assessed the impact of liver-directed therapy with selective internal radiation therapy (SIRT) and systemic chemotherapy on progression-free survival (PFS) in liver-dominant metastatic pancreatic adenocarcinoma.\n\n\nMETHODS\nPatients received yttrium-90-labelled ((90)Y) resin microspheres (SIR-Spheres; Sirtex Medical Limited, Sydney, Australia) as a single procedure on day 2 of the first weekly cycle of 5-fluorouracil (5FU; 600 mg/m(2)) with the option to switch to gemcitabine (1000 mg/m(2)) after 8 weeks of 5FU. Statistical analysis was conducted using Microsoft Excel (Microsoft Corporation, Redmond, Washington, USA). The primary endpoint of the study was PFS in the liver, with a median of ≥ 16 weeks defined as the threshold for clinical significance. PFS and overall survival (OS) were summarised by the Kaplan-Meier method using non-parametric estimates of the survivor function.\n\n\nRESULTS\nFourteen eligible patients were enrolled; ten had primary tumour in situ and eight had liver-only metastases. Patients received a median (90)Y activity of 1.1 GBq and 8 weekly doses of 5FU; seven patients received a median of two doses of gemcitabine. Disease control in the liver was 93% (two confirmed partial responses [PR], one unconfirmed PR, ten stable disease). Median reduction in cancer antigen 19-9 was 72%. Median PFS was 5.2 months in the liver, which met the primary endpoint of the study, and 4.4 months at any site. PFS was prolonged in those with a resected primary compared with patients with primary in situ (median 7.8 vs. 3.4 months; p = 0.017). Median OS was 5.5 months overall and 13.6 months in patients with a resected primary. Grade 3/4 adverse events occurred in eight (57%) patients during days 0-60. There was one sudden death and another patient who died from possible treatment-related liver failure 7.0 months after SIRT.\n\n\nCONCLUSIONS\nSIRT and chemotherapy appears to be an effective treatment for liver metastases from pancreatic cancer, likely to be of most benefit in selected patients with a resected primary tumour and liver only disease. Significant toxicity was observed and the safety of this approach in patients with metastatic pancreatic cancer will need to be confirmed in subsequent studies. Further study is warranted with SIRT and modern chemotherapies.\n\n\nBACKGROUND\nACTRN12606000015549.",
"affiliations": "Department of Medical Oncology, Royal Melbourne Hospital, Grattan Street, Parkville, VIC, 3050, Australia. Peter.Gibbs@mh.org.au.;Department of Medical Oncology, Western Hospital, Melbourne, Australia. Coung.Do@wh.org.au.;Department of Medical Oncology, Royal Melbourne Hospital, Grattan Street, Parkville, VIC, 3050, Australia. Lara.Lipton@wh.org.au.;Sirtex Medical Limited, Sydney, Australia. dcade@sirtex.com.;Sirtex Medical Limited, Sydney, Australia. mtapner@sirtex.com.;Perth Radiological Clinic, Mount Hospital, Perth, Australia. dpri3807@bigpond.net.au.;Mount Nuclear Medicine, Mount Hospital, Perth, Australia. gbower@isotope.com.au.;Department of Radiology, Royal Melbourne Hospital, Melbourne, Australia. Richard.Dowling@mh.org.au.;Department of Nuclear Medicine, Royal Melbourne Hospital, Melbourne, Australia. Mia.Lichtenstein@mh.org.au.;Perth Oncology, Mount Hospital, Perth, Australia. gvh@perthoncology.com.au.",
"authors": "Gibbs|Peter|P|;Do|Cuong|C|;Lipton|Lara|L|;Cade|David N|DN|;Tapner|Michael J|MJ|;Price|David|D|;Bower|Geoff D|GD|;Dowling|Richard|R|;Lichtenstein|Meir|M|;van Hazel|Guy A|GA|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D015021:Yttrium Radioisotopes; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-015-1822-8",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 26503593182210.1186/s12885-015-1822-8Research ArticlePhase II trial of selective internal radiation therapy and systemic chemotherapy for liver-predominant metastases from pancreatic adenocarcinoma Gibbs Peter +61 3 9342 4269Peter.Gibbs@mh.org.au 12Do Cuong Coung.Do@wh.org.au 2Lipton Lara Lara.Lipton@wh.org.au 12Cade David N. dcade@sirtex.com 3Tapner Michael J. mtapner@sirtex.com 3Price David dpri3807@bigpond.net.au 4Bower Geoff D. gbower@isotope.com.au 5Dowling Richard Richard.Dowling@mh.org.au 6Lichtenstein Meir Mia.Lichtenstein@mh.org.au 7van Hazel Guy A. gvh@perthoncology.com.au 81 Department of Medical Oncology, Royal Melbourne Hospital, Grattan Street, Parkville, VIC 3050 Australia 2 Department of Medical Oncology, Western Hospital, Melbourne, Australia 3 Sirtex Medical Limited, Sydney, Australia 4 Perth Radiological Clinic, Mount Hospital, Perth, Australia 5 Mount Nuclear Medicine, Mount Hospital, Perth, Australia 6 Department of Radiology, Royal Melbourne Hospital, Melbourne, Australia 7 Department of Nuclear Medicine, Royal Melbourne Hospital, Melbourne, Australia 8 Perth Oncology, Mount Hospital, Perth, Australia 26 10 2015 26 10 2015 2015 15 80225 2 2014 16 10 2015 © Gibbs et al. 2015Open 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\nThis prospective, open-label phase II study assessed the impact of liver-directed therapy with selective internal radiation therapy (SIRT) and systemic chemotherapy on progression-free survival (PFS) in liver-dominant metastatic pancreatic adenocarcinoma.\n\nMethods\nPatients received yttrium-90-labelled (90Y) resin microspheres (SIR-Spheres; Sirtex Medical Limited, Sydney, Australia) as a single procedure on day 2 of the first weekly cycle of 5-fluorouracil (5FU; 600 mg/m2) with the option to switch to gemcitabine (1000 mg/m2) after 8 weeks of 5FU. Statistical analysis was conducted using Microsoft Excel (Microsoft Corporation, Redmond, Washington, USA). The primary endpoint of the study was PFS in the liver, with a median of ≥16 weeks defined as the threshold for clinical significance. PFS and overall survival (OS) were summarised by the Kaplan-Meier method using non-parametric estimates of the survivor function.\n\nResults\nFourteen eligible patients were enrolled; ten had primary tumour in situ and eight had liver-only metastases. Patients received a median 90Y activity of 1.1 GBq and 8 weekly doses of 5FU; seven patients received a median of two doses of gemcitabine. Disease control in the liver was 93 % (two confirmed partial responses [PR], one unconfirmed PR, ten stable disease). Median reduction in cancer antigen 19–9 was 72 %. Median PFS was 5.2 months in the liver, which met the primary endpoint of the study, and 4.4 months at any site. PFS was prolonged in those with a resected primary compared with patients with primary in situ (median 7.8 vs. 3.4 months; p = 0.017). Median OS was 5.5 months overall and 13.6 months in patients with a resected primary. Grade 3/4 adverse events occurred in eight (57 %) patients during days 0–60. There was one sudden death and another patient who died from possible treatment-related liver failure 7.0 months after SIRT.\n\nConclusions\nSIRT and chemotherapy appears to be an effective treatment for liver metastases from pancreatic cancer, likely to be of most benefit in selected patients with a resected primary tumour and liver only disease. Significant toxicity was observed and the safety of this approach in patients with metastatic pancreatic cancer will need to be confirmed in subsequent studies. Further study is warranted with SIRT and modern chemotherapies.\n\nTrial registration\n\nACTRN12606000015549\n\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s12885-015-1822-8) contains supplementary material, which is available to authorized users.\n\nKeywords\nAdvancedLiverMetastasesPancreasRadioembolizationSIRTissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nPancreatic cancer is the fourth leading cause of cancer-related deaths in the USA and the fifth leading cause of cancer deaths in Europe with the incidence continuing to rise [1, 2]. The majority of patients have locally advanced and/or metastatic disease at presentation, resulting in a dismal 5-year survival rate of less than 5 % [3]. At the time that this study was conducted, gemcitabine was the most widely used systemic treatment for metastatic pancreatic cancer. In a phase III study, gemcitabine had a modest survival benefit of 5.6 months compared with 4.4 months for 5-fluorouracil (5FU) [4], and so the rationale for treatment with gemcitabine was primarily the alleviation of disease-related symptoms rather than extending overall survival (OS) [4]. Since then, the landmark European PRODIGE-4 trial with combined chemotherapy with folinic acid, fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) has extended the OS of patients with metastatic pancreatic cancer beyond 10 months (11.1 months vs. 6.8 months with gemcitabine) [5]. However, despite improvements in the control of locally advanced and metastatic disease with FOLFIRINOX [5–7], a recent published multicentre evaluation showed that Zapproximately one-third of patients were hospitalised due to adverse events [8] and it remains uncertain how widely this regimen will be used in the routine management of pancreatic cancer.\n\nLiver metastases are a dominant cause of treatment failure in pancreatic cancer, occurring in 25–53 % of patients even after loco-regional control with chemo-radiation and surgical resection [9]. For patients with advanced disease, the PRODIGE-4 trial showed hepatic metastases and declining liver function (defined by albumin levels <3.5 g/dL) remain independent adverse prognostic factors for OS [5]. Consequently, liver-directed therapies, which improve disease control in the liver, may be of value in extending OS when combined with systemic chemotherapy.\n\nSelective internal radiation therapy (SIRT) with yttrium-90 (90Y)-labelled microspheres is a loco-regional treatment, which has been evaluated in patients with hepatocellular carcinoma [10–12], as well as liver-dominant neuroendocrine tumours [13, 14], colorectal cancer (CRC) [15–18] and breast cancer [19–21]. To date, however, there have been very limited published data on SIRT in pancreatic cancer [22, 23]. Following the positive experience with SIRT in these primary and secondary hepatic neoplasms, we conducted a prospective study to assess whether SIRT, combined with 5FU, would extend PFS in the liver, and consequently OS, in patients with liver-only or liver-dominant advanced pancreatic cancer.\n\nMethods\nStudy design\nThis was a prospective, open-label, multicentre, phase II trial to assess the safety and efficacy of SIRT combined with 5FU in patients with recently diagnosed liver-dominant metastases from pancreatic adenocarcinoma. Enrolled patients were to have liver metastases as the dominant clinical issue and the site of disease that threatened the patient’s life. This criterion was created with the expectation that enrolled patients would have bulky liver metastases, and small volume or no extra-hepatic disease.\n\nPatients received SIRT using 90Y-resin microspheres (SIR-Spheres; Sirtex Medical Limited, Sydney, Australia) as a single procedure, 2 days after the first bolus injection of 5FU 600 mg/m2 (administered once weekly). Patients with on-going response could continue to receive chemotherapy for 16 weeks, until disease progression or unacceptable toxicity. At the time the protocol was written the standard treatment options for metastatic pancreatic cancer were gemcitabine and 5FU. Given the safety data for the combination of 5FU and SIRT and in order to avoid the well-documented radiosensitising effects of gemcitabine [24, 25] initial therapy was with 5FU alone, Investigators had the option after 8 weeks of 5FU to switch patients to gemcitabine 1000 mg/m2 (given weekly for 7 weeks followed by a 1-week rest, and thereafter weekly for 3 weeks, every 4 weeks) provided that the patient had not progressed on or experienced unacceptable toxicity from gemcitabine previously.\n\nThe principal aim of the study was to evaluate hepatic disease control, using PFS in the liver as the primary endpoint. The combination of SIRT and chemotherapy would be considered to be of clinical significance if the median PFS in the liver was ≥16 weeks. This was based on data from a study of 5FU alone, where more than 70 % of patients had disease progression by 2 months [4], suggesting that if median PFS in the liver was more than twice this it would suggest significant impact from the addition of SIRT. The secondary endpoints were: safety and toxicity, PFS at any site, best objective response rate in the liver and at any site, site of disease progression and OS.\n\nThe study conformed to the World Medical Association Declaration of Helsinki and the Australian National Health and Medical Research Council statement on human experimentation. Prior approval of the study protocol was received from each institute’s Human Research Ethics Committee (Melbourne Health Ethics Committee study 2006.124 and Mount Hospital Ethics Committee study EC35.3).\n\nPatients\nPatients were enrolled at two centres (Mount Medical Centre, Perth, Australia; Western Hospital, Melbourne, Australia) between October 2006 and November 2009. All patients were fully informed of the nature of the trial and signed an informed consent document.\n\nPatients were included in the study if they were 18 years of age or older, with a life expectancy of ≥2 months without any active treatment, had a World Health Organization (WHO) performance status of 0 or 1, and a diagnosis of pancreatic adenocarcinoma. At the time of inclusion, the liver had to be the dominant site of disease, impacting on patients’ health-related quality of life and/or survival; low-volume extra-hepatic metastases and/or an intact primary cancer were permitted. Previous chemotherapy, either as adjuvant treatment or first-line therapy for metastatic disease was permitted. All laboratory parameters had to be within the defined limits for the safe delivery of SIRT, i.e. neutrophil count >1.5 × 109/L; platelets >100 × 109/L; creatinine <150 μmol/L; bilirubin ≤1 × upper limit of normal (ULN); albumin ≥3 g/dL. Female patients were either postmenopausal, sterile, or if sexually active using an acceptable method of contraception. Male patients, if sexually active (and not surgically sterile) and having a pre-menopausal partner, were required to use an acceptable method of contraception.\n\nPatients were excluded with evidence of ascites, cirrhosis or portal hypertension (as determined by clinical or radiological assessment), occlusion of the main portal vein, central nervous system metastases, prior radiotherapy that included the liver in the treatment field, prior treatment with an investigational agent within 30 days of SIRT, or evidence of any concurrent condition that, in the opinion of the investigator, would render the patient ineligible for treatment according to this protocol.\n\nAssessment and data handling\nAll baseline assessments were carried out within 29 days of enrolment, including serum cancer antigen 19-9 (CA19-9), and computed tomography (CT) or magnetic resonance imaging (MRI) to assess the extent of disease in the abdomen and chest. The percentage tumour burden within the liver was determined using the baseline CT/MRI scan, utilising validated tumour volumetry software (MeVis Distant Services, Bremen, Germany). Patients underwent a baseline hepatic angiogram to map the vascular anatomy of the liver. Technetium-99 m macroaggregated albumin was used as a surrogate for 90Y-resin microspheres during the pre-treatment planning to determine the presence and magnitude of arterio-venous shunting to the lungs so that the lung radiation exposure could be kept within safe limits (<25 Gy) and the activity of 90Y administered was adjusted accordingly [25]. The calculated activity of 90Y to be implanted was determined from tables provided by the manufacturer, based on a modification of the Body Surface Area formula and adjusted for the extent of lung shunting for each patient (see Additional file 1).\n\nPost-SIRT, patients were evaluated every 4 weeks and tumour response was assessed every 8 weeks until disease progression in the liver according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.0. Complete response or partial response (PR) of liver metastases were confirmed by a further CT scan performed after 4 weeks. Patients were analysed according to the presence or absence of the primary tumour in situ and the presence or absence of extra-hepatic metastases.\n\nPFS in the liver was defined as the interval between trial entry and the date of tumour progression (based on RECIST) or death, whichever occurred sooner. OS was defined as the interval between enrolment and the date of death.\n\nAdverse events were recorded from consent until 30 days after the last dose of protocol chemotherapy was administered. At the time of their occurrence, the causal relationship between the adverse events and the protocol therapy was recorded by the investigator. All adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Adverse events are presented according to time of occurrence: from enrolment up to day 60 or beyond day 60.\n\nStatistical analysis was conducted using Microsoft Excel (Microsoft Corporation, Redmond, Washington, USA). PFS and OS was summarised by the Kaplan-Meier method using nonparametric estimates of the survivor function.\n\nResults\nBaseline characteristics and treatment\nFifteen patients were enrolled and received protocol therapy. One patient was excluded from the analysis after the histopathology report confirmed retrospectively that the liver lesion was derived from a pancreatic neuroendocrine tumour. Patient and disease characteristics for the remaining 14 patients are detailed in Table 1. Patients entered the study a median of 13 days after diagnosis of metastatic pancreatic cancer. Most patients had a good performance status, either WHO 0 (71 %) or 1 (29 %). The primary cancer was in situ in ten patients (71 %); six of these patients had liver-only metastases, and four had extrahepatic disease/metastases (EHD). The primary tumour had been resected in four patients (two with liver-only disease; two with EHD). Three patients had received prior chemotherapy (three received gemcitabine, two 5FU, one carboplatin); all three had liver-only metastases, two with a resected primary. The tumour burden in the liver varied between 1 and 37 % of the liver volume (mean 14 %), with bilobar involvement in all patients.Table 1 Baseline patient and disease characteristics\n\nCharacteristics\tPatients\t\nNumber\tPercentage\t\nGender\tMale\t6\t43 %\t\nFemale\t8\t57 %\t\nAge, years; median (range)\t62 (48–76)\t\nWHO performance status\t0\t10\t71 %\t\n1\t4\t29 %\t\nTime from diagnosis of metastatic pancreas cancer to trial entry, adays; median (range)\t13 (5–434)\t\nCancer stage at diagnosis\tTX\t4\t29 %\t\nT2\t6\t43 %\t\nT3\t2\t14 %\t\nT4\t2\t14 %\t\nPrimary tumour in situ\tYes\t10\t71 %\t\nNo\t4\t29 %\t\nMetastases\tLiver only\t8\t57 %\t\nLiver and lung\t2\t14.5 %\t\nLiver and lymph nodes\t2\t14.5 %\t\nLiver, lung and lymph nodes\t1\t7 %\t\nLiver, lung, lymph nodes, soft tissue\t1\t7 %\t\nNumber of metastatic sites; median (range)\t3 (1–5)\t\nCA19-9, bU/mL; median (range)\t3480 (33–280,000)\t\n>ULN\t13\t93 %\t\nPrior lines of chemotherapy for metastatic disease\t0\t13\t93 %\t\n1\t1\t7 %\t\naTrial entry defined as day of informed consent\n\nbN = 13 patients with elevated CA19-9 baseline levels (ULN 37 U/mL)\n\n\n\nAll patients received SIRT 2 days after the first weekly dose of 5FU. The median prescribed and administered activity of 90Y-resin microspheres was 1.1 GBq (range 0.7–2.0 GBq). 90Y-resin microspheres were administered by selective injection to left and right hepatic arteries except in one patient who did not receive SIRT in the right lobe due to an unfavourable hepatic arterial anatomy that precluded catheter access. Median follow-up from study entry was 5.9 months (range 1.4–16.2 months). Patients received a median of 8 weekly doses of 5FU (median 600 mg/m2; range 350–638 mg/m2). Seven patients (50 %), one of whom had progressive disease, received a median of 2 doses (range 2–10) of gemcitabine (median 1000 mg/m2; range, 600–1000 mg/m2), an average of 3.7 months (range 2.1–8.1 months) after the start of 5FU.\n\nAdverse events\nAdverse events are listed in Table 2A and B. The majority of adverse events occurred during the first 60 days of therapy.Table 2 Adverse events. Adverse events (by NCI-CTCAE v.3 grade) recorded up to 60 days after the start of protocol therapy, from 61 days onwards and across the whole study period (n = 14) \n\nCategory/event\tDay 1 to 60 (n = 14)\tDay 61 onwards (n = 12)\tDay 1 to last assessment (n = 14)\t\n\tGrade 1–2\tGrade ≥3\tGrade 1–2\tGrade ≥3\tGrade 1–2\tGrade ≥3\t\nA.\t\t\t\t\t\t\t\nGastrointestinal\t\t\t\t\t\t\t\n Nausea\t10\t0\t4\t1\t10\t1\t\n Vomiting\t7\t0\t1\t0\t8\t0\t\n Anorexia\t5\t0\t5\t2\t6\t2\t\n Diarrhoea\t4\t0\t1\t1\t4\t1\t\n Stomatitis\t1\t0\t2\t0\t2\t0\t\n Mucositis\t2\t0\t0\t0\t2\t0\t\n Constipation\t2\t0\t1\t0\t2\t0\t\nPain\t\t\t\t\t\t\t\n Abdominal pain\t2\t0\t1\t0\t3\t0\t\n Pain (non-abdominal)\t0\t1\t0\t0\t0\t1\t\nConstitutional Symptoms\t\t\t\t\t\t\t\n Fatigue\t6\t2\t5\t5\t4\t6\t\n Fever\t3\t0\t0\t0\t3\t0\t\nHepatobiliary/Pancreas\t\t\t\t\t\t\t\n Ascites\t0\t1\t0\t3\t0\t3\t\n Jaundice\t0\t0\t0\t1\t0\t1\t\n Liver failure\t0\t0\t0\t1\t0\t1\t\nNeurology\t\t\t\t\t\t\t\n Neuropathy\t3\t0\t1\t0\t3\t0\t\nPulmonary/Upper Respiratory\t\t\t\t\t\t\t\n Dyspnoea\t1\t1\t1\t1\t1\t1\t\n Bruising\t1\t0\t2\t0\t2\t0\t\n Pneumonia\t0\t1\t1\t0\t0\t1\t\nVascular\t\t\t\t\t\t\t\n Pulmonary embolism\t0\t1\t0\t0\t0\t1\t\n Deep vein thrombosis\t0\t1\t0\t1\t0\t1\t\nDermatology/Skin\t\t\t\t\t\t\t\n Dry skin/cracked skin\t1\t1\t0\t1\t1\t1\t\nHaemorrhage/Bleeding\t\t\t\t\t\t\t\n Epistaxis\t1\t0\t2\t0\t2\t0\t\nOcular/Visual\t\t\t\t\t\t\t\n Epiphora\t3\t0\t3\t0\t3\t0\t\nB.\t\t\t\t\t\t\t\nBiochemical/Laboratory\t\t\t\t\t\t\t\n Hyperbilirubinemia\t5\t3\t2\t6\t4\t7\t\n Albumin\t9\t1\t8\t1\t11\t1\t\n Alkaline phosphatase\t4\t1\t8\t0\t8\t1\t\n Alanine transaminase\t8\t0\t5\t0\t10\t0\t\n Aspartate aminotransferase\t3\t0\t5\t0\t6\t0\t\nBlood/Bone Marrow\t\t\t\t\t\t\t\n Haemoglobin\t7\t0\t3\t0\t8\t0\t\n Platelets\t4\t2\t5\t2\t4\t4\t\n Leukocytes\t8\t1\t2\t0\t8\t1\t\n Neutrophils\t2\t2\t1\t1\t2\t2\t\nA) Any grade 1–2 treatment-related adverse clinical events occurring in >10 % of patients and all grade 3–4 treatment-related adverse clinical events. B) All-cause laboratory events\n\n\n\nEarly events (days 0–60): grade 3/4 adverse clinical and/or laboratory events occurred in 8 (57 %) patients during this period. Nine patients (64 %) had no grade 3 or higher treatment-related clinical adverse events, and there was no grade 3 or 4 abdominal pain, nausea, vomiting or diarrhoea during this period. Two patients (14 %) developed grade 3 fatigue which may have been treatment-related. Grade 3 biochemical toxicities were observed in two patients (14 %) and significant haematological events in four patients (28 %): grade 3 neutropenia (two patients; 14 %) and grade 3 thrombocytopenia (two patients; 14 %).\n\nLater events (after 60 days): six patients (50 %) had grade 3 or higher treatment-related clinical adverse events, four of whom had switched to gemcitabine, with biochemical toxicities reported in six patients (50 %, three on gemcitabine) and hematologic events in three patients (25 %, all on gemcitabine).\n\nDeath without documented progression occurred in two patients. The first patient died suddenly 1.5 months after study entry and within 28 days of SIRT; the patient had no adverse events greater than grade 1 severity, laboratory tests were within normal limits but CA19-9 had increased by 293 % from baseline. At enrolment, this patient had a T4 primary tumour in situ with metastases to the liver, lungs and lymph nodes. The second patient, who died 7.0 months after study entry, presented with liver-only metastases following prior resection of a T2 primary cancer. The patient died from hepatic failure, considered to possibly be due to radioembolization-induced liver disease (REILD), although the role of prior gemcitabine and herbal remedies prior to protocol therapy should also be considered. The patient had also received external beam radiotherapy (45 Gy in 25 fractions) to the pancreas.\n\nTreatment response and survival\nIndividual best response within the liver (according to RECIST) is presented in the waterfall plot together with the tumour characteristics and CA19-9 response (Fig. 1). A PR in the liver was recorded in three patients (21 %) (2 confirmed; 1 unconfirmed) and stable disease (SD) in ten patients (71 %), giving a liver disease control rate of 93 %. CT scans of a patient with a partial response are shown in Fig. 2. Best response (at all sites) was 1 PR (7 %), SD in nine patients (64 %) and progression in four patients (29 %). Median reduction in CA19-9 was 72 %. Switching to gemcitabine did not appear to contribute to the initial response.Fig. 1 Percentage change from baseline in the sum of index lesions in the liver. Waterfall plot of percentage change from baseline in the sum of index lesions in the liver, with pancreatic lesion response, CA19-9 response and tumour characteristics. § Patients switching protocol chemotherapy to gemcitabine 2.1–8.1 months after the start of 5FU (red asterisk); † Tumour response by RECIST v1.0 (change while on 5FU in blue; change while on gemcitabine in red); nm: non-measurable disease; ‡ baseline value < ULN (excluded from analysis of mean change in CA19-9)\n\n\n\nThe median liver PFS was 5.2 months (range 1.4–17.7 months), which exceeded the pre-specified threshold for clinical significance, and 4.4 months (range 1.4–16.3 months) at any site (Fig. 3). The median time to progression in the liver was derived by per protocol follow-up scans on all patients until progression of liver metastases, including patients who had progressed outside the liver as the first site of progression and may have commenced a second line of chemotherapy. PFS at any site was shorter in patients with advanced primary tumour in situ compared with those who had their primary tumour resected (median 3.4 vs. 7.8 months; p = 0.017; Fig. 4). Two patients with liver-only metastases and a resected primary had an overall PFS of 16.3 and 7.0 months, respectively.Fig. 2 Tumour response in a patient with liver-only metastases from primary pancreatic adenocarcinoma. a Contrast-enhanced CT scan prior to SIRT + 5FU. b) Follow-up contrast-enhanced CT scan 3 months post-SIRT + 5FU, and prior to gemcitabine, demonstrates a partial response (40 % reduction in hepatic tumour burden), as assessed according to RECIST v1.0\n\nFig. 3 Kaplan-Meier analysis of PFS and OS. 3) PFS in the liver and at any site. 4) PFS at any site stratified by the presence or absence of the primary tumour in situ. 5) OS. 6) OS stratified by the presence or absence of the primary tumour in situ. 7) OS stratified by the presence of liver-only metastases or liver plus EHD\n\n\n\nThe first site of progression is listed in Table 3. The liver was the first site of progression in two patients: one with new lesions at 6.5 months and one with progression of existing liver lesions at 8.5 months after enrolment. Three patients (21 %) deteriorated clinically without documented evidence of disease progression. Two patients (13 %) were withdrawn from study treatment due to adverse events: one with grade 2 nausea/vomiting 3.6 months after study entry and 1 week after commencing gemcitabine, and the other with obstructive jaundice and ascites, at 2.7 months post-enrolment and 2 weeks after switching to gemcitabine.Table 3 Site of first progression (n = 14)\n\nLocation of first progression\tPatients\t\nNumber\tPercentage\t\nDocumented progression on CT\t\n Liver\t2\t20\t\n Lung\t2\t13\t\n Lymph node\t1\t7\t\n Peritoneum\t1\t7\t\n Pleural effusion\t1\t7\t\nNo progression documented\t\n Clinical deterioration\t3\t20\t\n Death without progression\t2\t13\t\n Withdrawn due to adverse events\t2\t13\t\n\n\nMedian OS was 5.5 months (range 1.4–19.5 months) for the entire cohort (Fig. 5) and 12.2 months (range 7.0–17.7 months) for patients with disease confined to the liver. Unplanned subgroup analysis revealed significantly longer survival in patients whose primary tumour had been resected (n = 4; median 13.6 vs. 4.2 months; p = 0.015; Fig. 6). For patients with liver-only metastases (n = 8), median survival was 6.6 months (range 3.6–17.7 months; Fig. 7). Where patients had EHD (n = 6), the median survival was 4.6 months (range 1.4–19.5 months). A summary of the characteristics of patients alive after 12 months is shown in Table 4.Table 4 Characteristics of patients who survived greater than 12 months\n\nPatient\tStage at diagnosisa\tStatus of primary tumour\tSite of metastases\tPFS in the liver (months)\tPFS (months)\tSurvival (months)\tSite of first disease progression\t\nPatient 1\tTx\tPrimary in situ\tLiver only\t6.5\t6.5\t16.2\tLiver\t\nPatient 2\tT2\tPrior resection\tLiver only\t17.7\t16.3\t17.7\tPleural effusion\t\nPatient 3\tT3\tPrior resection\tLiver and lymph nodes\t8.5\t8.5\t19.5\tLiver\t\naAccording to United Network for Organ Sharing staging criteria\n\n\n\nDiscussion\nMetastatic pancreatic cancer carries a very poor prognosis. Progress has been frustratingly slow with numerous agents in combination with gemcitabine demonstrating promise in phase II studies, but minimal impact on OS in subsequent phase III randomised trials. Limited benefit has been demonstrated with the addition of oxaliplatin [26], cisplatin [27], capecitabine [28, 29], cetuximab [30], bevacizumab [31] or erlotinib [32] to gemcitabine. A recent study demonstrated a significant improvement in OS with FOLFIRINOX, but uncertainty remains as to whether this can be safely achieved in routine clinical practice [5].\n\nIn this first prospective study of the safety and efficacy of SIRT in advanced pancreatic cancer, 5FU rather than gemcitabine was administered concomitantly with 90Y-resin microspheres, thereby circumventing any potential adverse events associated with gemcitabine radiosensitisation of non-target tissue. Overall, the spectrum of adverse events in this study associated with SIRT (characterised by mild-to-moderate abdominal pain, nausea, and transient changes in liver function) and 5FU (neutropenia and thrombocytopenia) were similar to those reported in several previous trials in patients with liver metastases from CRC, in which this combination has been demonstrated to be safe [15, 16]. The incidence of grade 3/4 haematological toxicities (14 %) was consistent with the past experience with SIRT and 5FU [15, 16]. Patients who received gemcitabine no sooner than 8 weeks post-SIRT experienced a similar rate of adverse events as would be expected from gemcitabine therapy alone [4], without any evidence of REILD [33]; suggesting that gemcitabine can safely be given after SIRT.\n\nIn this study, one responding patient on 5FU developed signs suggestive of REILD and died at 7.0 months after treatment. REILD is defined as jaundice and ascites in the absence of tumour progression or bile duct obstruction commencing within 8 weeks of SIRT [33], so this event occurred well outside that window. Both rising bilirubin levels (from grade 2 on day 39 to grade 4 on day 102) and elevated alkaline phosphatase levels (which were greater than grade 1 from day 116 onwards) are recognised hallmarks of REILD [33]; although the clinical picture in this patient was complicated by use of herbal remedies [34] and gemcitabine pre-SIRT, which may have contributed to liver failure in this case as may have disease progression. The sudden death observed in one other patient was considered unlikely to be related to SIRT as sudden deaths on SIRT have not previously been reported, and the only likely cause of treatment related death (liver failure) is usually of slow onset with clinical and laboratory signs evident well in advance of patients dying.\n\nTumour response within the liver was encouraging, with 21 % of patients (three out of 14) achieving a confirmed or unconfirmed PR and 71 % (ten out of 14) achieving SD, by RECIST criteria, for a disease control rate of 93 %. As shown in Fig. 1, the size of the liver lesions diminished in all but one of the 13 patients who had post-SIRT imaging at 8 weeks intervals and no patient had progressive disease within the liver on initial follow-up CT imaging. With limited radiological response on gemcitabine, it would seem reasonable to conclude that the recorded response was largely due to the protocol treatment rather than subsequent gemcitabine.\n\nThe imaging results are also corroborated by the decline in CA19-9 observed in 12 of 13 patients with an elevated CA19-9 at baseline, including all but one of those with EHD. Similar to the experience in SIRT-treated CRC liver metastases [35, 36], the decline in tumour marker was rapid and appeared to predict later CT response and PFS.\n\nThe results of our phase II study compare favourably to a time to progression in the randomised controlled trial by Burris et al. of 0.9 months for 5FU alone, and 2.3 months for gemcitabine and response rate with 5FU alone of 0 and 19 % SD. Subsequently Cunningham et al. has recorded small incremental improvements in PFS with gemcitabine combined with capecitabine compared with gemcitabine alone (5.3 vs. 3.8 months), which have been accompanied by a small survival benefit (6.2 vs. 7.1 months) [29]. The median PFS reported for patients treated with FOLFIRINOX in the recent randomised study was 6.4 months [5]. Significantly however, the studies by Cunningham et al. [28] and that of Burris et al. [4] included many patients with locally advanced disease (29 and 26 % of patients, respectively), for whom the median PFS would be expected to be superior, whereas the current study and the FOLFIRINOX study only included patients with metastatic disease.\n\nAs expected for a liver-directed therapy, studies of SIRT in patients with CRC have demonstrated better outcomes in patients with disease confined to the liver [18, 37]. In the current trial, outcomes likewise appeared related to extent of disease outside the liver, with the best results seen in the two patients with liver-only disease (OS of 7.0 and 17.7 months) and the worst outcomes in the four patients with an intact primary and liver metastases plus EHD (median OS of 4.2 months). These results suggest that further studies of SIRT in pancreatic cancer liver metastases should be confined to the population of patients with liver-only disease who have had their primary lesion resected or who have well-controlled primary disease. These analyses should not be used to select patients for treatment outside of clinical trials, as SIRT remains an experimental treatment option in this disease type.\n\nConclusions\nThe data obtained from this study of the combination of SIRT and 5FU in the treatment of liver metastases from primary pancreatic cancer demonstrated evidence of effective disease control of liver metastases from pancreatic adenocarcinoma, with a disease control rate of 93 % and a liver PFS of 5.2 months. However, the combination of SIRT and 5FU resulted in a toxicity profile that was significant and the safety of this approach in patients with metastatic pancreatic cancer will need to be confirmed in subsequent studies. This combination of therapy is likely to be of most benefit in selected patients with a resected primary tumour and liver only disease. Ultimately though, randomised trials will be needed to prove the role of SIRT in combination with chemotherapy in metastatic pancreatic cancer, and to define the patients who will most benefit from this treatment. Strategies combining SIRT with gemcitabine are likely to be limited by the doses of gemcitabine that could be given safely with SIRT, without compromising its systemic activity. Several studies in CRC have demonstrated that SIRT can be safely combined with FOLFOX [15–17] and with irinotecan [38], suggesting that initial cycles with FOLFOX or irinotecan might be an attractive strategy.\n\nHuman research and ethics committees approval\nThis study was approved by the ethics committees of Melbourne Health, Parkville, Australia (for patients enrolled at Western Hospital) and Mount Hospital, Perth, Australia (for patients enrolled at Mount Hospital)\n\nAdditional file\n\nAdditional file 1: Dosimetry tables for\n90Y-resin microspheres. The following tables (Table S1A to S1C) provided by Sirtex Medical Limited, Sydney, Australia were used in this phase II study to guide the dosimetry for 90Y-resin microspheres (SIR-Spheres). The tables, based a modification of the Body Surface Area (BSA) formula, calculated the activity in gigabecquerels (GBq) of 90Y which was to be implanted determined from the BSA and percentage tumour involvement of whole liver for each patient. Three tables were provided so that the implanted activity of 90Y could be further adjusted for each patient according to extent of lung shunting (0–10 %; 11–15 %; 16–20 %). The tables provide a more user-friendly method for calculating the dosimetry for 90Y-resin microspheres, while at the same including slight modifications to the dosing, in order to improve the safety of this procedure in patients with either a very low (<10 %) or high (>60 %) tumour volume in the liver. (DOCX 43 kb)\n\n\n\n\nAbbreviations\n5FU5-fluorouracil\n\nYYttrium-90\n\nCA19-9Cancer antigen 19–9\n\nCRCColorectal cancer\n\nCTComputed tomography\n\nEHDExtrahepatic disease/metastases\n\nFOLFIRINOXFolinic acid, fluorouracil, irinotecan, oxaliplatin\n\nFOLFOXFolinic acid, fluorouracil, oxaliplatin\n\nmCRCMetastatic colorectal cancer\n\nMRIMagnetic resonance imaging\n\nNCI-CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events\n\nOSOverall survival\n\nPFSProgression-free survival\n\nPRPartial response\n\nRECISTResponse Evaluation Criteria In Solid Tumours\n\nREILDRadioembolization-induced liver disease\n\nSDStable disease\n\nSIRTSelective internal radiation therapy\n\nULNUpper limit of normal\n\nWHOWorld Health Organization\n\nCompeting interests\n\nPG and GVH have received honoraria from SIRTEX for participation in advisory boards and for presentations. DC and MT are employees of Sirtex Medical Limited. The remaining authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nPG conceived of the study, and participated in its design and co-ordination and drafted the manuscript. CD assisted in analysis of data and in drafting the manuscript. LL recruited patients to the study and reviewed the manuscript, DC assisted in study design, analysis and manuscript preparation. MT assisted in study design, analysis and manuscript preparation, DP was involved in delivery of study treatment and reviewed the manuscript, GB was involved in delivery of study treatment and reviewed the manuscript, RD was involved in delivery of study treatment and reviewed the manuscript, ML was involved in delivery of study treatment and reviewed the manuscript, GVH participated in study design, recruited patients and reviewed the manuscript.\n\nAcknowledgements\nThis study was supported by SIRTEX Medical. The authors would like to thank Rae Hobbs for her help in editing this manuscript, funding for which was provided by Sirtex Medical Ltd.\n==== Refs\nReferences\n1. Pancreatic Action Support Network: the alarming rise of pancreatic cancer deaths in the United States: why we need to stem the tide. http://www.pancan.org/section_research/reports/pdf/incidence_report_2012.pdf.\n2. World health Organization. Estimated cancer incidence, mortality, prevalence and disability-adjusted life years (DALYs) worldwide in 2008. GLOBOCAN (International Agency for Research on Cancer). 2008. http://globocan.iarc.fr/.\n3. Jemal A Siegel R Xu J Ward E Cancer statistics, 2010 CA Cancer J Clin 2010 60 277 300 10.3322/caac.20073 20610543 \n4. Burris HA Moore MJ Andersen J Green MR Rothenberg ML Modiano MR Improvements in survival and clinical benefit with gemcitabine as first line therapy for patients with advanced pancreas cancer J Clin Oncol 1997 15 2403 2413 9196156 \n5. Conroy T Desseigne F Ychou M Bouché O Guimbaud R Bécouarn Y FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer N Engl J Med 2011 364 1817 1825 10.1056/NEJMoa1011923 21561347 \n6. Lorgis V Chauffert B Gentil J Ghiringhelli F Influence of localization of primary tumor on effectiveness of 5-Fluorouracil/leucovorin combined with irinotecan and oxaliplatin (FOLFIRINOX) in patients with metastatic pancreatic adenocarcinoma: a retrospective study Anticancer Res 2012 32 4125 4130 22993372 \n7. Hosein PJ Macintyre J Kawamura C Maldonado JC Ernani V Loaiza-Bonilla A A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma BMC Cancer 2012 12 199 10.1186/1471-2407-12-199 22642850 \n8. Peddi PF Lubner S McWilliams R Tan BR Picus J Sorscher SM Multi-institutional experience with FOLFIRINOX in pancreatic adenocarcinoma JOP 2012 13 497 501 22964956 \n9. Evans DB Abbruzzese JL Willett CG DeVita VT Jr Hellman S Rosenberg SA Cancer of the pancreas Cancer: principles and practice of oncology 2001 6 Philadelphia Lippincott Williams & Wilkins 1126 1161 \n10. Sangro B Carpanese L Cianni R Golfieri R Gasparini D Ezziddin S Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation Hepatology 2011 54 868 878 10.1002/hep.24451 21618574 \n11. Salem R Lewandowski RJ Mulcahy MF Riaz A Ryu RK Ibrahim S Radioembolization for hepatocellular carcinoma using yttrium-90 microspheres: a comprehensive report of long-term outcomes Gastroenterology 2010 138 52 64 10.1053/j.gastro.2009.09.006 19766639 \n12. Sangro B Iñarrairaegui M Bilbao JI Radioembolisation for hepatocellular carcinoma J Hepatol 2012 56 464 473 10.1016/j.jhep.2011.07.012 21816126 \n13. Kennedy AS Dezarn WA McNeillie P Coldwell D Nutting C Carter D Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90 Y-microspheres: early results in 148 patients Am J Clin Oncol 2008 31 271 279 10.1097/COC.0b013e31815e4557 18525307 \n14. King J Quinn R Glenn DM Janssen J Tong D Liaw W Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases Cancer 2008 113 921 929 10.1002/cncr.23685 18618495 \n15. Hendlisz A Van den Eynde M Peeters M Maleux G Lambert B Vannoote J Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy J Clin Oncol 2010 28 3687 3694 10.1200/JCO.2010.28.5643 20567019 \n16. Van Hazel G Blackwell A Anderson J Price D Moroz P Bower G Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer J Surg Oncol 2004 88 78 85 10.1002/jso.20141 15499601 \n17. Kosmider S Tan TH Yip D Dowling R Lichtenstein M Gibbs P Radioembolization in combination with systemic chemotherapy as first-line therapy for liver metastases from colorectal cancer J Vasc Interv Radiol 2011 22 780 786 10.1016/j.jvir.2011.02.023 21515072 \n18. Sharma RA Van Hazel GA Morgan B Berry DP Blanshard K Price D Radioembolization of liver metastases from colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil, and leucovorin chemotherapy J Clin Oncol 2007 25 1099 1106 10.1200/JCO.2006.08.7916 17369573 \n19. Coldwell DM Kennedy AS Nutting CW Use of yttrium-90 microspheres in the treatment of unresectable hepatic metastases from breast cancer Int J Radiat Oncol Biol Phys 2007 69 800 804 10.1016/j.ijrobp.2007.03.056 17524567 \n20. Jakobs TF Hoffmann RT Fischer T Stemmler HJ Tatsch K La Fougere C Radioembolization in patients with hepatic metastases from breast cancer J Vasc Interv Radiol 2008 19 683 690 10.1016/j.jvir.2008.01.009 18440456 \n21. Bangash AK Atassi B Kaklamani V Rhee TK Yu M Lewandowski RJ 90 Y radioembolization of metastatic breast cancer to the liver: toxicity, imaging response, survival J Vasc Interv Radiol 2007 18 621 628 10.1016/j.jvir.2007.02.019 17494843 \n22. Cao C Yan TD Morris DL Bester L Radioembolization with yttrium-90 microspheres for pancreatic cancer liver metastases: results from a pilot study Tumori 2010 96 955 958 21388058 \n23. Gulec SA Wheeler J Pennington K Hall M Bruetman D Westbrook C Chemotherapy with Yttrium-90 microsphere selective internal radiation treatment and selective external radiation treatment in patients with metastatic pancreatic cancer J Interven Oncol 2009 2 84 92 \n24. Kornek GV Pötter R Selzer E Schratter A Ulrich-Pur H Rogy M Combined radiochemotherapy of locally advanced unresectable pancreatic adenocarcinoma with mitomycin C plus 24-hour continuous infusional gemcitabine Int J Radiat Oncol Biol Phys 2001 49 665 671 10.1016/S0360-3016(00)01388-2 11172947 \n25. de Lange SM van Groeningen CJ Meijer OW Cuesta MA Langendijk JA van Riel JM Gemcitabine-radiotherapy in patients with locally advanced pancreatic cancer Eur J Cancer 2002 38 1212 1217 10.1016/S0959-8049(02)00076-X 12044508 \n26. Louvet C Labianca R Hammel P Lledo G Zampino MG André T Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial J Clin Oncol 2005 23 3509 3516 10.1200/JCO.2005.06.023 15908661 \n27. Colucci G Labianca R Di Costanzo F Gebbia V Cartenì G Massidda B Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study J Clin Oncol 2010 28 1645 1651 10.1200/JCO.2009.25.4433 20194854 \n28. Herrmann R Bodoky G Ruhstaller T Glimelius B Bajetta E Schüller J Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group J Clin Oncol 2007 25 2212 2217 10.1200/JCO.2006.09.0886 17538165 \n29. Cunningham D Chau I Stocken DD Valle JW Smith D Steward W Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer J Clin Oncol 2009 27 5513 5518 10.1200/JCO.2009.24.2446 19858379 \n30. Philip PA Benedetti J Corless CL Wong R O’Reilly EM Flynn PJ Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205 J Clin Oncol 2010 28 3605 3610 10.1200/JCO.2009.25.7550 20606093 \n31. Kindler HL Niedzwiecki D Hollis D Sutherland S Schrag D Hurwitz H Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303) J Clin Oncol 2010 28 3617 3622 10.1200/JCO.2010.28.1386 20606091 \n32. Moore MJ Goldstein D Hamm J Figer A Hecht JR Gallinger S Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group J Clin Oncol 2007 25 1960 1966 10.1200/JCO.2006.07.9525 17452677 \n33. Sangro B Gil-Alzugaray B Rodriguez J Sola I Martinez-Cuesta A Viudez A Liver disease induced by radioembolization of liver tumors: description and possible risk factors Cancer 2008 112 1538 1546 10.1002/cncr.23339 18260156 \n34. Whiting PW Clouston A Kerlin P Black cohosh and other herbal remedies associated with acute hepatitis MJA 2002 177 432 435 \n35. Jakobs TF Hoffmann RT Dehm K Trumm C Stemmler HJ Tatsch K Hepatic yttrium-90 radioembolization of chemotherapy-refractory colorectal cancer liver metastases J Vasc Interv Radiol 2008 19 1187 1195 10.1016/j.jvir.2008.05.013 18656012 \n36. Gray BN Burton MA Kelleher DK Anderson J Klemp P Selective internal radiation (SIR) therapy for treatment of liver metastases: measurement of response rate J Surg Oncol 1989 42 192 196 10.1002/jso.2930420313 2811384 \n37. Nace GW Steel JL Amesur N Zajko A Nastasi BE Joyce J Yttrium-90 radioembolization for colorectal cancer liver metastases: a single institution experience Int J Surg Oncol 2011 2011 571261 22312513 \n38. van Hazel GA Pavlakis N Goldstein D Olver IN Tapner MJ Price D Treatment of fluorouracil-refractory patients with liver metastases from colorectal cancer by using Yttrium-90 resin microspheres plus concomitant systemic irinotecan chemotherapy J Clin Oncol 2009 27 4089 4095 10.1200/JCO.2008.20.8116 19652069\n\n",
"fulltext_license": "CC BY",
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"mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D003131:Combined Modality Therapy; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D011446:Prospective Studies; D015021:Yttrium Radioisotopes",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "802",
"pmc": null,
"pmid": "26503593",
"pubdate": "2015-10-26",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "21618574;12381254;22993372;20606093;20194854;21816126;21561347;12044508;18525307;20610543;21515072;17369573;15499601;20567019;21388058;22312513;17524567;18618495;22642850;11172947;2811384;19652069;18440456;20606091;19858379;18260156;22964956;19766639;17538165;15908661;18656012;17452677;17494843;9196156",
"title": "Phase II trial of selective internal radiation therapy and systemic chemotherapy for liver-predominant metastases from pancreatic adenocarcinoma.",
"title_normalized": "phase ii trial of selective internal radiation therapy and systemic chemotherapy for liver predominant metastases from pancreatic adenocarcinoma"
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"abstract": "Pemetrexed is a key anticancer agent for treatment of advanced non-small cell lung cancer (NSCLC). Pemetrexed is generally well tolerated, but individual-patient differences exist in severity of adverse events. Our study aimed to characterize the adverse events of pemetrexed that result in discontinuation of chemotherapy and to identify risk factors associated with those adverse events. We retrospectively studied the incidence of adverse events in 257 patients with NSCLC who received pemetrexed (P) with or without bevacizumab (B) and/or carboplatin (C): P, PB, CP, or CPB. Patients whose chemotherapy was discontinued were divided into two groups according to adverse events and disease progression. Grade 2/3 nausea, fatigue with P and PB, and rash with CP and CPB occurred more frequent in the adverse events group than in the disease progression group. Multivariate analysis indicated that grade 2/3 nausea [odds ratio (OR) 9.94; 95% confidence interval (CI) 1.46-67.37; p = 0.01] and fatigue (OR 10.62; CI 1.60-70.20; p = 0.01) with P or PB, and rash (OR 6.12; CI 1.34-27.88; p = 0.01) with CP or CPB, were independent risk factors for discontinuation of chemotherapy. Administration of dexamethasone at doses less than 4 mg after the day of pemetrexed administration was associated with nausea following P or PB (OR 11.08; 95% CI 1.02-119.95; p = 0.04). Grade 2/3 nausea and fatigue with P or PB, and rash with CP or CPB, were associated with discontinuation of chemotherapy.",
"affiliations": "Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, 849-8501, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, 849-8501, Japan. sueokan@cc.saga-u.ac.jp.;Division of Respiratory Medicine, Saga-Ken Medical Centre Koseikan, Saga, Japan.;Division of Medical Oncology, Saga-Ken Medical Centre Koseikan, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, 849-8501, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, 849-8501, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, 849-8501, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, 849-8501, Japan.;Department of Pharmacy, Saga-Ken Medical Centre Koseikan, Saga, Japan.;Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, 849-8501, Japan.",
"authors": "Miyahara|Tsuyoshi|T|;Sueoka-Aragane|Naoko|N|http://orcid.org/0000-0002-7428-9068;Iwanaga|Kentaro|K|;Ureshino|Norio|N|;Komiya|Kazutoshi|K|;Nakamura|Tomomi|T|;Nakashima|Chiho|C|;Abe|Tomonori|T|;Matsunaga|Hisashi|H|;Kimura|Shinya|S|",
"chemical_list": "D000068437:Pemetrexed",
"country": "United States",
"delete": false,
"doi": "10.1007/s12032-017-1053-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1357-0560",
"issue": "34(12)",
"journal": "Medical oncology (Northwood, London, England)",
"keywords": "Dexamethasone; Discontinuation of chemotherapy; Non-hematological toxicity; Non-small cell lung cancer; Pemetrexed",
"medline_ta": "Med Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D005221:Fatigue; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009325:Nausea; D000068437:Pemetrexed; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "9435512",
"other_id": null,
"pages": "195",
"pmc": null,
"pmid": "29124473",
"pubdate": "2017-11-09",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "19841321;21850416;12479273;18506025;28158216;26521826;21947834;15117980;18358737;26081252;27286996;17473654;1711156;27185838;16182899;26235582;18181887;27239238;9533527;10683005;22341744;25559804;24991206;23775961",
"title": "Severity and predictive factors of adverse events in pemetrexed-containing chemotherapy for non-small cell lung cancer.",
"title_normalized": "severity and predictive factors of adverse events in pemetrexed containing chemotherapy for non small cell lung cancer"
} | [
{
"companynumb": "JP-ROCHE-2036501",
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"activesubstancename": "CARBOPLATIN"
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{
"abstract": "Tuberculous pyomyositis is a rare clinical entity with serious consequences if a diagnosis is not established early. A 53-year-old female with a past medical history of sarcoidosis and pulmonary fibrosis presented from an outside hospital with persistent fevers and a rash. She had been hospitalized multiple times at an outside hospital without any improvement in her symptoms. On examination, she was noted to have a large area of left upper lower extremity (LUE) tenderness with superimposed erythema. Laboratory data revealed a white blood cell count of 22,300. Computed tomography (CT) scans of the LUE, chest, and left lower extremity (LLE) showed multiple intramuscular abscesses in those regions without evidence of osteomyelitis. Subsequent drainage of the abscesses and resulting cultures revealed Mycobacterium tuberculosis. The patient was started on therapy with rifampin, isoniazid, pyrazinamide, and ethambutol. However, the patient developed hepatitis on these agents and subsequently went into septic shock with multiorgan failure. Care was eventually withdrawn as a result of a poor prognosis. This case illustrates the severe consequences of TB pyomyositis if not diagnosed promptly. While tuberculosis is uncommon in the United States, it should be an important consideration in the differential diagnosis of immunocompromised patients.",
"affiliations": "UPMC Montefiore Hospital, N-715, 200 Lothrop Street, Pittsburgh, PA 15213, USA.",
"authors": "Krishnasamy|Vikram|V|;Joseph|Matthew|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2013/126952",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIM.MEDICINECase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2013/126952Case ReportTuberculous Pyomyositis: A Rare but Serious Diagnosis 0000-0002-1203-3198Krishnasamy Vikram *Joseph Matthew UPMC Montefiore Hospital, N-715, 200 Lothrop Street, Pittsburgh, PA 15213, USA*Vikram Krishnasamy: vikram.p.krishnasamy@gmail.comAcademic Editor: Stephen A. Klotz\n\n2013 24 3 2013 2013 12695220 12 2012 28 2 2013 Copyright © 2013 V. Krishnasamy and M. Joseph.2013This 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.Tuberculous pyomyositis is a rare clinical entity with serious consequences if a diagnosis is not established early. A 53-year-old female with a past medical history of sarcoidosis and pulmonary fibrosis presented from an outside hospital with persistent fevers and a rash. She had been hospitalized multiple times at an outside hospital without any improvement in her symptoms. On examination, she was noted to have a large area of left upper lower extremity (LUE) tenderness with superimposed erythema. Laboratory data revealed a white blood cell count of 22,300. Computed tomography (CT) scans of the LUE, chest, and left lower extremity (LLE) showed multiple intramuscular abscesses in those regions without evidence of osteomyelitis. Subsequent drainage of the abscesses and resulting cultures revealed Mycobacterium tuberculosis. The patient was started on therapy with rifampin, isoniazid, pyrazinamide, and ethambutol. However, the patient developed hepatitis on these agents and subsequently went into septic shock with multiorgan failure. Care was eventually withdrawn as a result of a poor prognosis. This case illustrates the severe consequences of TB pyomyositis if not diagnosed promptly. While tuberculosis is uncommon in the United States, it should be an important consideration in the differential diagnosis of immunocompromised patients.\n==== Body\n1. Case Presentation\nThe patient is a 53-year-old Caucasian female with a history of sarcoidosis and pulmonary fibrosis on chronic glucocorticoids who presented to the hospital with a 6–8 month history of progressive pain, erythema, and edema on the left scapula, biceps, and groin. The symptoms started with a burning sensation over her left scapula. Her husband noted at the time that she had a furuncular lesion in the area. Of note, there was no prior trauma to the area. The lesion subsequently progressed in size and pain, and she then developed fevers, chills, and a home recorded temperature of 102°F. She also progressed to left medial arm pain, swelling, and redness as well as left leg erythema and pain. On review of systems, she endorsed subjective fevers, chills, and night sweats; a two-month history of blurry vision; baseline dyspnea on supplemental oxygen use of 4 liters by nasal cannula; and a recent sinus infection. She denied any cough, wheezes, chest pain, palpitations, nausea, vomiting, abdominal pain, or dysuria. She was hospitalized multiple times at an outside hospital (OSH) where she received vancomycin, meropenem, and doxycycline. Due to progression of her illness despite treatment, she was subsequently transferred to our hospital.\n\nHer past medical history included sarcoidosis and pulmonary fibrosis for which she was on 10 mg bid of prednisone for about one year. Her only surgical history was a cholecystectomy. Her medications prior to admission included fentanyl, prednisone, furosemide, fluoxetine, metoprolol, and ferrous sulfate. Significant allergies included sulfa and penicillins both of which caused hives. She had a 10-pack-year history of tobacco use, but her last cigarette was 25 years ago. Her past occupation was a secretary, but she was retired at the time of presentation. She currently resides with her husband in a house located in a wooded area of western Pennsylvania. Her travel history was as far north as New York and as far south as South Carolina. There was no recent travel history. She has 3 pets: 2 dogs and 1 cat. There was no significant family history of tuberculosis. It is unknown if she ever had a tuberculin skin test. \n\nOn initial physical exam, the patient had a temperature of 36.2°C, blood pressure of 110/62 mmHg, pulse of 78 beats/min, respiratory rate of 18 breaths/min, and an oxygen saturation of 98% on 4 liters of supplemental nasal oxygen. She was toxic appearing, and in pain. Her pupils were equal, round, and reactive to light. Extraocular movements were also intact. The neck was supple, without thyromegaly or jugular venous distension. Her lungs were clear to auscultation bilaterally, and on cardiac exam, she had regular heart sounds. The abdomen was soft, nontender, nondistended, and without hepatosplenomegaly. On her left upper back, she had a well-defined boggy area of tissue which was mildly erythematous and tender to palpation. Within the boggy area was a 5 mm hollow, circular ulceration without fluctuance or purulence (Figure 1). On her left arm, she had erythema, purpura, and induration which were painful to palpation. On her LLE, she had 2+ pitting edema and erythema extending from the groin to the foot. There was no cervical, axillary, epitrochlear, or inguinal lymphadenopathy. \n\nInitial laboratory values are summarized in Table 1.\n\n2. Hospital Course \nThe patient was admitted to the general medicine service and started on empiric broad spectrum antibiotics. CT scans of the left arm and left leg revealed multiple subcutaneous and intramuscular abscesses in the region of the left shoulder, left arm, and left chest wall without evidence of osteomyelitis (Figure 2). A large intramuscular abscess in the anterior compartment of the left thigh approximately 12 cm in diameter was also found. A subsequent CT of the chest, abdomen, and pelvis demonstrated ground glass opacities in the right upper lung and bilateral lower lungs, centrilobular nodules, a right upper lobe calcified granuloma, prominent paratracheal and anteroposterior window lymph nodes, steatosis of the liver, and parts of the fluid collections in the thigh as noted above. She was started on empiric antibiotic therapy with vancomycin, ceftriaxone, and metronidazole pending drainage of the sample with cultures and sensitivities. She then developed a rash on vancomycin and was switched to linezolid. \n\n Interventional radiology was consulted to biopsy the affected areas. Multiple attempts were made in the back, left arm, and left inguinal region with the only successful aspiration from the left inguinal region. The other sites failed due to the thickness of the aspirate. The aspirate showed acid-fast bacilli on smear and subsequently Mycobacterium tuberculosis (MTB) on hospital day 14 via DNA probe. At that time, empiric antibiotics were stopped, and quadruple antituberculin therapy was initiated with isoniazid/pyridoxine, rifampin, pyrazinamide, and ethambutol. \n\nConcurrently, given the ground glass opacities and lack of cough or sputum production by the patient, pulmonology was consulted for bronchoscopy and bronchoalveolar lavage (BAL) to rule out pulmonary tuberculosis. One month after bronchoscopy, the culture from the BAL turned positive for MTB. \n\nThere were concerns about the patient's potential wound healing given the degree of tissue involved as well as chronic steroid use. As a result, surgical debridement was deferred. Unfortunately, on hospital day 28, the patient developed elevated liver function tests (LFTs) necessitating cessation of rifampin, isoniazid, and pyrazinamide. Moxifloxacin was added as a second-line agent. Once her LFTs normalized, rifampin was added. However, several days later, the patient developed fevers and diarrhea. She was found to be hypotensive with a systolic blood pressure in the 70s and was transferred to the intensive care unit. She was started on vasopressors for septic shock, intubated for respiratory failure, and started on continuous renal replacement therapy for acute kidney injury. Over the ensuing days, given her overall poor prognosis, care was deescalated and the patient died. \n\n3. Discussion\nPyomyositis is a purulent infection of muscle that is generally the result of hematogenous spread [1]. Typically, the infection is known to occur in the tropics in otherwise healthy individuals with no comorbidities. Those afflicted in more temperate regions tend to have severe underlying comorbidities or are immunocompromised in some way [2]. \n\nThe most common organisms implicated in pyomyositis include Staphylococcus aureus as well as, increasingly, MRSA. Group A streptococci are also common with gram-negative bacilli and pneumococci, with non-group A streptococci occurring less often [2]. There have also been instances of mycobacterial-induced pyomyositis [3]. \n\nTypical presentations of pyomyositis involve fever and pain localized to a muscle group, generally the lower extremities [2]. The infection usually progresses in three stages. Stage one tends to be characterized by fever, muscle pain, and swelling. Since this is an early stage, an abscess may not yet be apparent, and very few patients present at this stage. Stage two is where most patients present and occurs 10–21 days after initial symptoms begin. It is characterized by fever, muscle tenderness, and leukocytosis. Aspiration of the area will yield purulent material. Finally, stage three is the most severe and is accompanied by systemic toxicity. As a result, patients can develop complications of bacteremia [4]. One study showed a mortality rate that reached ten percent [5]. \n\nDiagnosis is typically made by radiography, predominantly by CT, and culture data [6]. MRI may also be helpful, especially in tuberculous pyomyositis [7, 8]. Because pyomyositis arises from hematologic spread, cultures, both from blood and drainage specimens, are extremely useful for determining appropriate antibiotic use [1, 2]. \n\nTreatment is dependent on the stage of the disease with stage 1 able to be treated by antibiotics. Stages 2-3 require both drainage as well as antibiotic treatment. Drainage is typically CT guided, but in the face of extensive disease, surgical intervention may be a necessity [4]. \n\nInitial empiric antibiotic therapy is generally directed against staphylococci and streptococci and typically includes MRSA coverage in those who have previous infections, risk factors, or systemic toxicity. If an individual is immunocompromised, antibiotic coverage should be broad, covering gram positive and negative as well as anaerobic organisms [2, 4]. For suspected mycobacterial disease, treatment is the same as pulmonary tuberculosis. Duration of treatment is variable depending on the complications and organisms involved, with mycobacteria requiring longer treatment courses [9]. \n\nWhile tuberculosis itself is common around the world, extrapulmonary manifestations tend to be less common. A study by Wang et al. in 2003 demonstrated that 1.8% of culture positive TB cases (21/1153) in Taiwan were TB myositis cases. However, many of these cases had other manifestations of TB, unlike our patient [3]. The difficulty of diagnosis in our patient stems from her immunocompromised state and the lack of other symptoms of tuberculosis. Isolated presentations of TB as myositis are rare and not widely reported in the literature. \n\n4. Conclusion\nTuberculous pyomyositis should be considered in the differential diagnosis of immunosuppressed patients with fevers and myalgias.\n\nAcknowledgments\nThe authors are deeply indebted to the patient and her family. \n\nFigure 1 Focal area of involvement on posterior chest wall.\n\nFigure 2 Multiple abscesses in the left upper extremity and chest wall.\n\nTable 1 Laboratory values at presentation to the outside hospital and at presentation to our hospital.\n\nLaboratory values\tPresentation to OSH\tPresentation to our hospital\t\nSodium (136–146 mMol/L)\t122\t133\t\nPotassium (3.5–5 mMol/L)\t4.1\t4.3\t\nChloride (98–107 mMol/L)\t80\t93\t\n\nBicarbonate (21–31 mMol/L)\t33.3\t31\t\nBUN (8–26 mg/dL)\t16\t12\t\nCreatinine (0.5–1.4 mg/dL)\t0.79\t0.8\t\nTotal protein (6.3–7.7 g/dL)\t5.6\t4.7\t\nAlbumin (3.4–5 g/dL)\t2.4\t2\t\nCalcium (8.4–10.2 mg/dL)\t8.2\t \t\nTotal bilirubin (0.3–1.5 mg/dL)\t0.8\t0.5\t\nAST (15–41 IU/L)\t26\t28\t\nALT (14–52 IU/L)\t36\t23\t\nAlkaline phosphatase (38–126 IU/L)\t120\t101\t\nWBC (3.8–10.6 × 109/L) \t22,300\t12,100\t\nHemoglobin (11.6–14.6 g/dL)\t12.4\t10.3\t\nMCV (82.6–97.4 fL)\t86.2\t85.3\t\nPlatelets (156–359 × 109/L) \t406\t295\t\nESR (0–40 mm/hr) \t \t39\t\nCRP (<0.748 mg/dL)\t \t15.7\t\nINR (0.8–1.2)\t \t1.1\n==== Refs\n1 Stevens DL Bisno AL Chambers HF Practice guidelines for the diagnosis and management of skin and soft-tissue infections Clinical Infectious Diseases 2005 41 10 1373 1406 16231249 \n2 Crum NF Bacterial pyomyositis in the United States American Journal of Medicine 2004 117 6 420 428 2-s2.0-5444222892 15380499 \n3 Wang JY Lee LN Hsueh PR Tuberculous myositis: a rare but existing clinical entity Rheumatology 2003 42 7 836 840 12826705 \n4 Chukwuma Chiedozi L Pyomyositis. Review of 205 cases in 112 patients American Journal of Surgery 1979 137 2 255 259 2-s2.0-0018408248 426186 \n5 Sharma A Kumar S Wanchu A Clinical characteristics and predictors of mortality in 67 patients with primary pyomyositis: a study from North India Clinical Rheumatology 2010 29 1 45 51 2-s2.0-72949117251 19763666 \n6 Struk DW Munk PL Lee MJ Ho SGF Worsley DF Imaging of soft tissue infections Radiologic Clinics of North America 2001 39 2 277 303 11316360 \n7 Soler R Rodríguez E Remuiñán C Santos M MRI of musculoskeletal extraspinal tuberculosis Journal of Computer Assisted Tomography 2001 25 2 177 183 11242210 \n8 Kim JY Park YH Choi KH Park SH Lee HY MRI of tuberculous pyomyositis Journal of Computer Assisted Tomography 1999 23 3 454 457 2-s2.0-0344223325 10348455 \n9 Bass JB Jr. Faren LS Hopewell PC Jacobs RF Treatment of tuberculosis and tuberculosis infection in adults and children American Review of Respiratory Disease 1986 134 2 355 363 3527010\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2013()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "126952",
"pmc": null,
"pmid": "23634147",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": "11316360;3527010;11242210;15380499;10348455;426186;16231249;12826705;19763666",
"title": "Tuberculous pyomyositis: a rare but serious diagnosis.",
"title_normalized": "tuberculous pyomyositis a rare but serious diagnosis"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-16-02221",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"dr... |
{
"abstract": "A 71-year-old male patient began FOLFOX6 plus panitumumab treatment for unresectable recurrent rectal cancer. He developed thrombocytopenia after 2 courses of treatment and therefore a platelet transfusion was performed. The day after transfusion, the patient developed jaundice and hematuria. His lactate dehydrogenase levels had increased and a peripheral blood smear review revealed the presence of schistocytes. Anti-ADAMTS13 antibodies were present, and there was a reduction in ADAMTS13 activity. The patient was diagnosed with thrombotic thrombocytopenic purpura and treated with a plasma exchange. The day after the plasma exchange, his clinical condition rapidly worsened and he died. Thrombocytopenia due to chemotherapy often appears as myelosuppression. If conditions such as jaundice, indirect bilirubinemia, or hematuria appear during the course of chemotherapy, this condition must be considered as a differential diagnosis.",
"affiliations": "Dept. of Surgery, Noshiro Public Welfare Medical Center.",
"authors": "Kato|Kuniyuki|K|;Michishita|Yoshihiro|Y|;Oyama|Kenichi|K|;Hatano|Yoshiaki|Y|;Nozawa|Tatsuru|T|;Ishibashi|Masahisa|M|;Konda|Ryuichiro|R|;Sasaki|Akira|A|",
"chemical_list": "D000911:Antibodies, Monoclonal; D009944:Organoplatinum Compounds; D000077544:Panitumumab; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "43(1)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; D000368:Aged; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D018450:Disease Progression; D017809:Fatal Outcome; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D009944:Organoplatinum Compounds; D000077544:Panitumumab; D010951:Plasma Exchange; D011697:Purpura, Thrombotic Thrombocytopenic; D012004:Rectal Neoplasms; D012008:Recurrence",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "133-6",
"pmc": null,
"pmid": "26809542",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Thrombotic Thrombocytopenic Purpura in a Patient Undergoing FOLFOX6 plus Panitumumab Therapy for Unresectable Recurrent Rectal Cancer with a Rapidly Progressive Course.",
"title_normalized": "a case of thrombotic thrombocytopenic purpura in a patient undergoing folfox6 plus panitumumab therapy for unresectable recurrent rectal cancer with a rapidly progressive course"
} | [
{
"companynumb": "JP-ACTAVIS-2016-08516",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
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"activesubstancename": "OXALIPLATIN"
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... |
{
"abstract": "Objectives: Extrapyramidal symptoms (EPS) are a common adverse effect of antipsychotics. However, there are case reports describing EPS following treatment with antidepressants. It is not fully understood how antidepressants cause EPS, but a serotonergic input to dopaminergic pathways is a probable mechanism of action.Methods: Data from a multicenter drug-surveillance programme (AMSP, 'drug safety in psychiatry') which systemically documents severe drug reactions during psychiatric inpatient admissions, were reviewed to assess for EPS associated with antidepressant treatment. We identified 15 such cases, which were studied to detect similarities and to characterise risk factors.Results: We report on 15 patients with EPS following antidepressant-therapy between 1994 and 2016. EPS frequently occurred with selective serotonin reuptake inhibitor (SSRI) treatment alone (7/15 cases) or concomitant SSRI treatment (6/15 cases). EPS were most frequent with escitalopram-treatment (5 cases). The most common EPS was atypical dyskinesia (6/15 cases) followed by akathisia (4/15 cases). The mean age of onset for EPS was 54.93 years (SD 17.9). EPS occurred at any dosage and equally often in men and women.Conclusions: Our results highlight the possibility of EPS as an important, although uncommon, adverse effect of antidepressants. Clinicians should beware of this adverse effect and monitor early warning signs carefully.",
"affiliations": "Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria.;Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria.;Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria.;Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria.;Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria.;Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany.;Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.;Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.;Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany.;Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland.;Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.",
"authors": "Mörkl|Sabrina|S|0000-0001-5034-6358;Seltenreich|Daniel|D|;Letmaier|Martin|M|;Bengesser|Susanne|S|0000-0001-8012-908X;Wurm|Walter|W|;Grohmann|Renate|R|;Bleich|Stefan|S|;Toto|Sermin|S|;Stübner|Susanne|S|0000-0003-4734-1198;Butler|Mary I|MI|;Kasper|Siegfried|S|0000-0001-8278-191X",
"chemical_list": "D000928:Antidepressive Agents; D017367:Serotonin Uptake Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1080/15622975.2019.1648871",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1562-2975",
"issue": "21(4)",
"journal": "The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry",
"keywords": "AMSP; Antidepressants; EPS; drug surveillance; extrapyramidal symptoms",
"medline_ta": "World J Biol Psychiatry",
"mesh_terms": "D000928:Antidepressive Agents; D001480:Basal Ganglia Diseases; D005260:Female; D006801:Humans; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D011358:Product Surveillance, Postmarketing; D017367:Serotonin Uptake Inhibitors",
"nlm_unique_id": "101120023",
"other_id": null,
"pages": "308-316",
"pmc": null,
"pmid": "31347932",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Extrapyramidal reactions following treatment with antidepressants: Results of the AMSP multinational drug surveillance programme.",
"title_normalized": "extrapyramidal reactions following treatment with antidepressants results of the amsp multinational drug surveillance programme"
} | [
{
"companynumb": "AT-TEVA-2020-AT-1802669",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "BACKGROUND\nThere are multiple case reports in the literature describing an association between fingolimod and cutaneous neoplasms.\n\n\nOBJECTIVE\nInvestigate and report a case of a primary mediastinal large B-cell lymphoma in a patient on fingolimod for Relapsing-Remitting Multiple Sclerosis (RRMS).\n\n\nMETHODS\nCase Report.\n\n\nRESULTS\nThe patient developed a primary mediastinal large B-cell lymphoma after seven years of treatment with fingolimod. The patient is currently in complete remission after cessation of treatment, surgical resection, chemotherapy, and radiation therapy.\n\n\nCONCLUSIONS\nThis case report highlights the first primary mediastinal large B-cell lymphoma associated with fingolimod treatment. It should be considered a rare, but potential adverse effect of fingolimod.",
"affiliations": "College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address: jachacko@uams.edu.;Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Arkansas Pathology Associates PA, Little Rock, AR, USA.;College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Hematology/Oncology Division, CHI St. Vincent Infirmary, Little Rock, AR, USA.;College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.",
"authors": "Chacko|Joseph A|JA|;Strati|Paolo|P|;Stout|Paul W|PW|;Archer|Robert L|RL|;Baltz|Brad P|BP|;Chacko|Joseph G|JG|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2021.102776",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "49()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "CD30; Fingolimod; Lymphoma; Multiple sclerosis; Primary mediastinal large B-cell lymphoma",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D000328:Adult; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents; D016393:Lymphoma, B-Cell; D009103:Multiple Sclerosis; D020529:Multiple Sclerosis, Relapsing-Remitting",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "102776",
"pmc": null,
"pmid": "33508568",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Primary mediastinal large B-cell lymphoma in a patient on Fingolimod for relapsing-remitting multiple sclerosis.",
"title_normalized": "primary mediastinal large b cell lymphoma in a patient on fingolimod for relapsing remitting multiple sclerosis"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-299817",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FINGOLIMOD"
},
"drug... |
{
"abstract": "Here we report a case of a 63-year-old male diagnosed with recurrent depressive disorder and current episode of severe depression with psychotic symptoms, developed hyponatremia soon after addition of olanzapine and increasing the dose of escitalopram. A possible causality association was established with olanzapine, and the possible etiological reasons of this clinically significant risk were discussed.",
"affiliations": "Department of Psychiatry, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India.;Department of Medicine, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India.;Department of Psychiatry, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India.",
"authors": "Bakhla|Ajay Kumar|AK|;Guria|Rishi Tuhin|RT|;Kumar|Abhishek|A|",
"chemical_list": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000077152:Olanzapine",
"country": "India",
"delete": false,
"doi": "10.4103/0253-7613.135961",
"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-46-44110.4103/0253-7613.135961Drug WatchA suspected case of olanzapine induced hyponatremia Bakhla Ajay Kumar Guria Rishi Tuhin 1Kumar Abhishek 2Department of Psychiatry, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India1 Department of Medicine, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India2 Department of Psychiatry, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, IndiaCorrespondence to: Dr. Ajay Kumar Bakhla, E-mail: ajaybakhla@gmail.comJul-Aug 2014 46 4 441 442 13 9 2013 31 1 2014 20 5 2014 Copyright: © Indian Journal of Pharmacology2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Here we report a case of a 63-year-old male diagnosed with recurrent depressive disorder and current episode of severe depression with psychotic symptoms, developed hyponatremia soon after addition of olanzapine and increasing the dose of escitalopram. A possible causality association was established with olanzapine, and the possible etiological reasons of this clinically significant risk were discussed.\n\nKEY WORDS\nAntipsychoticescitalopramhyponatremiaolanzapine\n==== Body\nIntroduction\nOlanzapine is a commonly used atypical antipsychotic used in patients having psychotic symptoms. A Medline search revealed a report of olanzapine-induced hyponatremia,[1] and three such cases have been reported at a Dutch pharmacovigilance centre.[2] Hyponatremia has also been reported with other typical and atypical antipsychotics.[345] A systemic review by Meulendijks et al.[3] included four studies and 91 publications containing case reports and case series of antipsychotic-induced hyponatremia. They found that the number of case reports of hyponatremia involving typical and atypical antipsychotics was 58 and 10 respectively, from 1974 to 2003. They also concluded that antipsychotic-induced hyponatremia did not seem to be associated with age or gender and was not dose dependent.\n\nCase Report\nA 63-year-old Hindu male, smoker and a known case of prostate enlargement was diagnosed with recurrent depressive disorder, for which he was on escitalopram 5 mg/day for last two years. Around two months back, he complained of unsatisfactory night sleep, feeling low, and experiencing referential ideas with elementary auditory hallucinations. The current exacerbation was categorized as severe depression with psychotic symptoms as per ICD-10 (DCR).[6] The dose of escitalopram was increased to 10 mg/day and olanzapine 5 mg/day was added. After two weeks, his sleep pattern was restored, symptoms abated and patient was better for about a month. He then developed symptoms of mild anorexia, nausea, mild weakness, and occasional muscle cramps. After 10 days, abrupt exacerbation of excessive weakness, lethargy, muscle cramps, unsteady gait, fleeting disorientation, and urinary retention developed, and the patient was admitted.\n\nHis physical examination revealed mild pallor, tachycardia, normal blood pressure, moderate dehydration, and disorientation of time and place. His respiratory system and abdominal examination was unremarkable and his Glasgow Coma Scale was 11. His blood investigations revealed Serum sodium was 118 mmol/l, Serum potassium was 3.5 mmol/l, and total leucocyte count was 12,100/cmm with 78% neutrophils. Thyroid-stimulating hormone, hemoglobin, albumin, and bicarbonate levels; liver and renal function; and lipid profile were normal.\n\nHe was treated with oral fluid restriction, stopping olanzapine and starting antibiotics. In view of lack of signs and symptoms of fluid overload, it was considered as probable case of normovolemic hyponatremia and 3% NaCl was used initially as the correcting fluid. Initially, rapid correction was done to achieve full consciousness. It was done over 4 hours keeping in mind maximum desired correction of 8–10 mmol/l/day. After 4 hours, the patient became alert and regained his sensorium. Later, correction was done using free water restriction, normal saline, and oral salt supplement, and by serially measuring blood Na+ regularly every 6 hours.\n\nHis symptoms and general condition improved over the next two days and serum sodium level reached 138 mmol/l. Patient was discharged on third day and he was told to continue escitalopram 10 mg. Olanzapine or any other antipsychotic was not restarted as his mental status examination did not revealing any psychotic psychopathology at that point of time. The patient and guardians were educated about the risk of hyponatremia, importance of diet and fluid intake habits, and early warning signs, and about quitting smoking. On subsequent three follow ups, he was maintaining well, and his serum electrolyte estimation was within normal range. His depressive psychopathology was better, and no psychotic symptoms appeared. A “possible” causal relation between the drug and adverse event was established by the WHO-UMC scale (WHO)[7] and Naranjo algorithm.[8] Written informed consent has been obtained from the patient for publication of this case report.\n\nDiscussion\nThe exact estimate about incidence of hyponatremia induced by antipsychotics is currently not available but many antipsychotics like chlorpromazine, fluphenazine, haloperidol, flupenthixol, trifluoperazine, thioridazine, amisulpride, and risperidone have been implicated.[34] It has been suggested that the inhibitory effect of dopamine on release of anti-diuretic hormone (ADH) is blocked by D2 receptor antagonism.[9] This may be the possible mechanism for the causation of hyponatremia by all D2 receptor antagonists including olanzapine. The exception is clozapine, which has been found to have a beneficial effect on polydipsic behavior and development of hyponatremia, which may be attributed to its lower binding affinity to D2 receptors.[10] Other contributory factors like old age, diet, salt intake, smoking, original psychopathology like psychogenic polydipsia, diabetes, other comorbid conditions, and side effects of antipsychotics or concurrent medications such as dryness of mouth may also play a role.[11]\n\nIn this case, the temporal relationship suggests olanzapine as the causative molecule, but it is difficult to pinpoint the offending medication. All serotonin reuptake inhibitors including escitalopram are also known for causing hyponatremia, and the patient was on escitalopram for two years without any problems. With the worsening of the disease, the dose of escitalopram was increased and at the same time, olanzapine was also initiated. Hence, the causality may be attributed to the combined effect to both of these drugs. However, escitalopram was restarted with no further episodes of hyponatremia suggesting a stronger possibility of causal relation with olanzapine. There may be involvement of other possible non-pharmacological factors like water and salt intake pattern and some infection as evidenced by leucocytosis.\n\nOlanzapine may be responsible for hyponatremia in vulnerable people, which may be the product of a combination of factors. Clinicians need to be cautious when prescribing psychotrophic drugs especially to elderly patients. Emphasis should also be laid on the education of patients and their family members regarding early identification of hyponatremia.\n\nSource of Support: Nil\n\nConflict of Interest: No\n==== Refs\n1 Dudeja SJ McCormick M Dudeja RK Olanzapine induced hyponatremia Ulster Med J 2010 79 104 5 21116433 \n2 Lareb The Netherlands Pharmacovigilance Centre. Olanzapine and hyponatraemia 2006 Last accessed 2013 Aug 03 Holland Hertogenbosch Available from: \nhttp://www.lareb.nl/Signalen/kwb_2006_1_olanz \n3 Meulendijks D Mannesse CK Jansen PA van Marum RJ Egberts TC Antipsychotic-induced hyponatraemia: A systematic review of the published evidence Drug Saf 2010 33 101 14 20082537 \n4 Collins A Anderson J SIADH induced by two atypical antipsychotics Int J Geriatr Psychiatry 2000 15 282 3 10713589 \n5 Chiang CL Lin YH Hsieh MH Olanzapine-induced hyponatremia in a patient with autism J Child Adolesc Psychopharmacol 2013 23 699 700 24261660 \n6 World Health Organization Classification of Mental and Behavioural Disorders 1994 Last accessed 2013 Aug 07 10th ed Chapter 5 Geneva World Health Organization The ICD-10 Available from: \nhttp://www.who.int/classifications/icd \n7 The use of the WHO-UMC system for standardized case causality assessment [monograph on the Internet] 2005 Last accessed 2013 Aug 21 Uppsala The Uppsala Monitoring Centre Available from: \nhttp://who-umc.org/Graphics/24734.pdf \n8 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508 \n9 Yamaguchi K Hama H Adachi C Inhibitory role of periventricular dopaminergic mechanisms in hemorrhage induced vasopressin secretion in conscious rats Brain Res 1990 513 335 8 2350705 \n10 Bersani G Pesaresi L Orlandi V Gherardelli S Pancheri P Atypical antipsychotics and polydipsia: A cause or a treatment? Hum Psychopharmacol 2007 22 103 7 17335101 \n11 Siegler EL Tamres D Berlin JA Allen-Taylor L Strom BL Risk factors for the development of hyponatremia in psychiatric inpatients Arch Intern Med 1995 155 953 7 7726704\n\n",
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"abstract": "Mycosis fungoides, along with Sezary syndrome, is the most common subtype of cutaneous T-cell lymphoma. In this report, we present a patient with advanced-stage mycosis fungoides, who after successful treatment of methicillin-resistant Staphylococcus aureus bacteremia had prolonged disease control off systemic therapy. While this may have been due to single-agent gemcitabine, which can result in long remission, we hypothesize that our patient's durable response was in part due to the immune response elicited after treatment of her severe infection.",
"affiliations": "Division of Regenerative Medicine, Department of Medicine, UC San Diego, Moores Cancer Center, San Diego, CA, USA.;Department of Radiation Oncology, Duke University, Durham, NC, USA.;Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.",
"authors": "Heyman|Benjamin|B|https://orcid.org/0000-0001-6707-0861;Kelsey|Chris R|CR|;Beaven|Anne|A|",
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"fulltext": "\n==== Front\nCase Rep HematolCase Rep HematolCRIHEMCase Reports in Hematology2090-65602090-6579Hindawi 10.1155/2019/1507014Case ReportDurable Control of Mycosis Fungoides after Sepsis: “Coley's Toxin?” Case Report and Review of the Literature https://orcid.org/0000-0001-6707-0861Heyman Benjamin bheyman@ucsd.edu\n1\nKelsey Chris R. \n2\nBeaven Anne \n3\n\n1Division of Regenerative Medicine, Department of Medicine, UC San Diego, Moores Cancer Center, San Diego, CA, USA\n2Department of Radiation Oncology, Duke University, Durham, NC, USA\n3Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USAAcademic Editor: Masayuki Nagasawa\n\n2019 4 8 2019 2019 150701415 3 2019 16 7 2019 Copyright © 2019 Benjamin Heyman et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Mycosis fungoides, along with Sezary syndrome, is the most common subtype of cutaneous T-cell lymphoma. In this report, we present a patient with advanced-stage mycosis fungoides, who after successful treatment of methicillin-resistant Staphylococcus aureus bacteremia had prolonged disease control off systemic therapy. While this may have been due to single-agent gemcitabine, which can result in long remission, we hypothesize that our patient's durable response was in part due to the immune response elicited after treatment of her severe infection.\n==== Body\n1. Introduction\nCutaneous T-cell lymphomas (CTCL) are a heterogeneous group of extranodal hematologic malignancies with diverse biology and clinical presentations. Mycosis fungoides (MF) is the most common subtype of CTCL, comprising approximately 50% of CTCLs [1]. Sezary syndrome (SS) is the leukemic form of MF, characterized by circulating abnormal α/β T lymphocytes with immunophenotype of memory cells, but with aberrant expression of common T-cell markers: CD3dim, CD4+, CD45RO+, CCR4+, CD2−, CD5−, CD7−, and CD8− [2]. Patients present with persistent and progressive plaques, patches, cutaneous tumors, or erythroderma at isolated or multiple sites [3]. Sezary syndrome consists of an erythrodermic skin presentation in addition to leukemic involvement of MF [4]. Prognosis for early-stage disease MF is excellent, with normal survival for stage Ia. In contrast, patients with stage IV MF at diagnosis have a median OS of 1.5 years [5]. Currently, optimal treatment for MF is controversial as remissions are rare and are usually not durable [6]. We report a case of a patient with advanced-stage MF who after receiving a course of gemcitabine was hospitalized with sepsis and cervical diskitis, treated with antibiotics, and subsequently experienced a durable treatment-free remission of her CTCL after infection clearance.\n\n2. Case\nA 61-year-old African American woman with a past medical history of C6-7 spinal stenosis complained of a pruritic rash that began on her face one year prior. The rash appeared raised and erythematous and contained plaques and patches. Despite treatment with topical steroids and emollients, these lesions evolved into cutaneous tumors and spread to encompass >50% of her body surface. The largest tumor was located on her forehead and measured 5 cm (Figure 1(a)). Biopsy of a back lesion demonstrated a pandermal infiltrate of lymphocytes with epidermotropism and pautrier microabscesses in the epidermis. Immunohistochemical stains were positive for CD3, CD4, BF1, CD5, and CD45RA. T-cell clonality studies revealed a monoclonal T-cell receptor (TCR) gene rearrangement for the TCR-γ chain. A Sezary preparation demonstrated 73% of abnormal lymphocytes in the blood. Peripheral blood flow cytometry revealed that CD4+/CD7− cells comprised 46% of lymphocytes, CD4+/CD26− cells comprised 74% of lymphocytes, and the CD4+/CD8+ ratio was 18 : 1. CT scans demonstrated bilateral axillary and inguinal lymphadenopathy up to 2.9 × 2.5 cm in size, and node biopsy confirmed MF involvement ISCL/EORTC classification N3. Thus, at diagnosis, she had stage IVa (T3N3M0B2) disease.\n\nInitial therapy consisted of interferon-α and concomitant total skin electron beam therapy (EBT) (36 Gy). The patient's nodules and tumors on her face, trunk, and back resolved; however, she continued to have significant pruritus and progressive lymphadenopathy (Figure 1(b)). Interferon was poorly tolerated; therefore, the treatment was changed to oral etoposide (50 mg/day). This resulted in temporary stabilization of her systemic disease. However, after four months, she had worsening cutaneous lesions and lymphadenopathy. She was subsequently started on single-agent gemcitabine. Initially, a dose of 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle was planned, but it was decreased to 750 mg/m2 every other week starting with cycle 3 due to neutropenia. She completed 13 cycles of gemcitabine with improvement in her cutaneous disease, as she was now found to have lichenification of the arms, abdomen, and lower extremities but continued cracking of hands and feet and she still suffered from pruritus.\n\nAfter completing the 13th cycle, the patient presented to the emergency department with fever, hypotension, and new left-sided hemiparesis. She was diagnosed with sepsis, secondary to methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. She was not neutropenic. Magnetic resonance imaging (MRI) of her spine revealed T2-hyperintense abnormalities involving the C5–C7 vertebral bodies and the C5-6 and C6-7 disc interspaces, concerning for cord edema/myelomalacia (Figure 2). She subsequently underwent an anterior cervical discectomy and fusion at C6-C7, from which cultures grew MRSA, confirming C6-7 diskitis. After surgery and completion of intravenous antibiotics, she was transitioned to a suppressive antibiotic regimen (rifampin and sulfamethoxazole/trimethoprim). With treatment of the infection and prolonged physical therapy, she regained almost complete use of her left side.\n\nFollowing discharge, she was seen in follow-up where cutaneous physical exam revealed hyperkeratosis of upper and lower extremities, hypopigmentation of her face without any tumors, and 1 cm bilateral axillary lymphadenopathy. Further systemic treatment of her CTCL was held due to poor performance status, recent severe infection, and low burden of cutaneous disease. The patient was started on narrow-band ultraviolet light therapy for one month, but this was discontinued due to excellent skin symptom control with topical moisturizers. Eighteen months after the MRSA infection, she continued to have very mild cutaneous symptoms off systemic therapy. A Sezary preparation of her peripheral blood revealed 4% abnormal lymphocytes, and peripheral blood flow cytometry revealed CD4+/CD7− T cells comprised 2.12% of lymphocytes, CD4+/CD26− T cells comprised 1.88% of lymphocytes, and the CD4 : CD8 ratio of the T cells was 1.24 : 1. Restaging computed tomography (CT) scan demonstrated significantly decreased lymphadenopathy, with a left axillary lymph node now measuring 1.2 cm, which decreased from 2.9 cm at diagnosis. There was no evidence of disease progression until 33 months after her infection. At that time, the patient presented with new facial nodules on her left cheek and right forehead, concerning for relapse. Sezary preparation and peripheral blood flow cytometry were still negative for disease. A restaging CT scan revealed stable lymphadenopathy. She received focal RT (4 Gy × 2 to 8 Gy) to her nose, left cheek, and right temple, resulting in complete resolution of her nodules. After the completion of EBT, she has remained off further systemic therapy, which is now 46 months after gemcitabine was stopped for the development of MRSA bacteremia (Figure 1(c)).\n\n3. Discussion\nWe present a patient who was diagnosed with advanced-stage MF and had a durable response off systemic treatment following a prolonged course of gemcitabine followed by MRSA bacteremia and cervical diskitis. The natural history of advanced-stage MF is of relapsing disease with remissions that are rarely durable. For patients with advanced-stage MF, there is no standard of care. Initial treatment for most patients requires both systemic and skin-directed therapies. Initial systemic therapies for advanced-stage MF include interferons, methotrexate, histone deacetylase inhibitors (romidepsin and vorinostat), brentuximab vedotin, psoralen and ultraviolet A, or single-agent cytotoxic chemotherapy [3]. Common chemotherapies include pegylated liposomal doxorubicin, pralatrexate, or gemcitabine [3].\n\nGemcitabine is a pyrimidine antimetabolite that inhibits DNA synthesis by blocking DNA polymerase and ribonucleotide reductase [7]. Our patient received 13 cycles of gemcitabine because of her aggressive initial presentation, failure to respond to initial therapies, improvement in symptoms, and lack of serious side effects until her infection. Zinzani et al. conducted a phase II clinical trial of single-agent gemcitabine in patients with relapsed or refractory (R/R) CTCLs, of which 30 patients had MF [8]. In patients with MF, the CR rate (CRR) was 10% and the partial response rate (PRR) was 60% [8]. For patients who obtained a CR, responses were ongoing at 6–22 months. Those with partial responses (PR) had a median duration of response ranging from 6 to 10 months [8]. A long-term updated analysis of 39 patients with R/R T-cell lymphoma treated with single-agent gemcitabine demonstrated an ORR of 48% and a CRR of 16%, in the 19 patients who had MF [9]. In the three patients with MF who developed CRs, responses were durable with remissions lasting 10, 18, and 120 months [9]. Lastly, Duvic et al. conducted a phase II clinical trial of single-agent gemcitabine in 33 patients with R/R cutaneous T-cell lymphomas, of which 8 patients were treated off protocol [10]. Thirty-one patients in the study had the diagnosis of MF, with 28 having advanced-stage disease. The ORR for protocol patients was 68%, with a CRR of 12%. The median duration of response for protocol patients achieving a PR was 4.1 months. The estimated median 3-year overall survival was 20.4 months [10]. Thus, single-agent gemcitabine can be effective in some patients, and, although rare, it can produce long-term remissions.\n\nIt is possible that our patient's durable response was due to single-agent gemcitabine; however, there is only one reported remission in the literature lasting >2 years. Therefore, we hypothesize that the immune response stimulated by her bacterial sepsis/diskitis may have contributed to the prolonged disease control. This idea was first proposed by William B. Coley in the early 1900s when he demonstrated that the exposure to bacteria/bacterial toxins hindered tumor growth. “Coley's toxins” were heat-killed combinations of Streptococcus pyogenes and Serratia marcescens that Dr. Coley injected into patients with advanced malignancies [11]. He reported that in 80% of the cases, for which no alternative treatment was available, survival was >5 years. Coley found that fever induction was the best predictor of patient response. The mechanism of action of “Coley's toxins” is not completely understood, but it is thought that the infection-stimulated tumor regression occurred because of an innate immune response, leading to increased expression of tumor necrosis factor (TNF), interferons, and other cytokines [11].\n\nAlthough “Coley's toxin” never became part of standard care, cancer immunotherapy is a burgeoning area of research and, in the form of interferon alpha, has been a part of MF treatment for many years. Interferon alpha (IFN) was the first cancer immunomodulating agent approved by the FDA, in 1986, for use in hairy cell leukemia. Although not an FDA indication, it is an effective MF treatment with reports of objective responses in over 70% of patients [12, 13].\n\nSince Coley's time, research has moved away from using bacterial vaccines to induce an antitumor response to the development of drugs that more specifically target tumor-immune cell interactions. These immunomodulating drugs target immune system checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1). A phase I trial of the anti-PD-1 monoclonal antibody, nivolumab, reported that in 13 patients with MF, the ORR was 15%, with a median progression-free survival (PFS) of 10 months [14]. A phase II trial of a similar agent, pembrolizumab, reported an ORR of 38% with one CR in 24 patients with MF. The one-year PFS was 69%, suggesting that checkpoint inhibitors may lead to durable responses in MF [15]. Currently, pembrolizumab in combination with radiotherapy is being investigated as a way to enhance the abscopal effect for the treatment of patients with R/R MF (NCT03385226).\n\n4. Conclusion\nWe present data on a patient with advanced MF who had unusually prolonged disease control after single-agent gemcitabine with subsequent MRSA bacteremia and diskitis. Forty-six months after her infection, she has had excellent control of her disease without any systemic therapy since single-agent gemcitabine was stopped. Patients who receive single-agent gemcitabine typically do not achieve such impressive durable control of disease. Therefore, we suspect that her prolonged response was secondary to the severe bacterial infection, resulting in an antitumor immunity similar to Coley's toxin. Currently, there is a lack of reported cases in the literature regarding the role of infection and immune system stimulation on disease outcome in MF. Further reporting and investigation are required to better understand its role and significance in MF.\n\nConflicts of Interest\nThe authors have no conflicts of interest to disclose.\n\nAuthors' Contributions\nDr. Heyman conceived the idea for this work and wrote the manuscript. Drs. Beaven and Kelsey conceived the idea for this work, helped write the manuscript, provided critical feedback, edited, and contributed to the final manuscript.\n\nFigure 1 Photograph of cutaneous disease burden at diagnosis (a), after initial radiation therapy (b), and presently (c).\n\nFigure 2 MRI of cervical spine demonstrating epidural abscess from MRSA.\n==== Refs\n1 Criscione V. D. Weinstock M. A. Incidence of cutaneous T-cell lymphoma in the United States, 1973–2002 Archives of Dermatology 2007 143 7 854 859 10.1001/archderm.143.7.854 2-s2.0-34447558598 17638728 \n2 Yawalkar N. Ferenczi K. Jones D. A. Profound loss of T-cell receptor repertoire complexity in cutaneous T-cell lymphoma Blood 2003 102 12 4059 4066 10.1182/blood-2003-04-1044 2-s2.0-0345257351 12829591 \n3 Foss F. M. Girardi M. Mycosis fungoides and sezary syndrome Hematology/Oncology Clinics of North America 2017 31 2 297 315 10.1016/j.hoc.2016.11.008 2-s2.0-85015748358 28340880 \n4 Virmani P. Hwang S. H. Hastings J. G. Systemic therapy for cutaneous T-cell lymphoma: who, when, what, and why? Expert Review of Hematology 2017 10 2 111 121 10.1080/17474086.2017.1270201 2-s2.0-85011422419 27998183 \n5 Kim Y. H. Liu H. L. Mraz-Gernhard S. Varghese A. Hoppe R. T. Long-term outcome of 525 patients with mycosis fungoides and Sézary syndrome: clinical prognostic factors and risk for disease progression Archives of Dermatology 2003 139 7 857 866 10.1001/archderm.139.7.857 2-s2.0-0042964834 12873880 \n6 Quaglino P. Maule M. Prince H. M. Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the cutaneous lymphoma international consortium Annals of Oncology 2017 28 10 2517 2525 10.1093/annonc/mdx352 2-s2.0-85030534328 28961843 \n7 Plunkett W. Huang P. Xu Y. Z. Heinemann V. Grunewald R. Gandhi V. Gemcitabine: metabolism, mechanisms of action, and self-potentiation Seminars in Oncology 1995 22 3 10 \n8 Zinzani P. L. Baliva G. Magagnoli M. Gemcitabine treatment in pretreated cutaneous T-cell lymphoma: experience in 44 patients Journal of Clinical Oncology 2000 18 13 2603 2606 10.1200/jco.2000.18.13.2603 2-s2.0-0033934870 10893292 \n9 Zinzani P. L. Venturini F. Stefoni V. Gemcitabine as single agent in pretreated T-cell lymphoma patients: evaluation of the long-term outcome Annals of Oncology 2010 21 4 860 863 10.1093/annonc/mdp508 2-s2.0-77951964918 19887465 \n10 Duvic M. Talpur R. Wen S. Kurzrock R. David C. L. Apisarnthanarax N. Phase II evaluation of gemcitabine monotherapy for cutaneous T-cell lymphoma Clinical Lymphoma and Myeloma 2006 7 1 51 58 10.3816/clm.2006.n.039 2-s2.0-33748320723 16879770 \n11 Hoption Cann S. A. van Netten J. P. van Netten C. Dr William Coley and tumour regression: a place in history or in the future Postgraduate Medical Journal 2003 79 938 672 680 14707241 \n12 Papa G. Tura S. Mandelli F. Is interferon alpha in cutaneous T-cell lymphoma a treatment of choice? British Journal of Haematology 1991 79 s1 48 51 10.1111/j.1365-2141.1991.tb08119.x 2-s2.0-0025937507 1931709 \n13 Rupoli S. Goteri G. Pulini S. Long-term experience with low-dose interferon-alpha and PUVA in the management of early mycosis fungoides European Journal of Haematology 2005 75 2 136 145 10.1111/j.1600-0609.2005.00497.x 2-s2.0-22444448736 16000130 \n14 Lesokhin A. M. Ansell S. M. Armand P. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study Journal of Clinical Oncology 2016 34 23 2698 2704 10.1200/jco.2015.65.9789 2-s2.0-84979240618 27269947 \n15 Khodadoust M. Rook A. H. Porcu P. Pembrolizumab for treatment of relapsed/refractory mycosis fungoides and sezary syndrome: clinical efficacy in a citn multicenter phase 2 study Blood 2016 128 p. 181\n\n",
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"title": "Durable Control of Mycosis Fungoides after Sepsis: \"Coley's Toxin?\" Case Report and Review of the Literature.",
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"abstract": "Hungry Bone Syndrome (HBS) refers to rapid, profound, and prolonged hypocalcemia associated with hypophosphatemia and hypomagnesemia occurring in patients with increased bone turnover after successful management of the underlying disorder. We describe a male patient with primary hyperparathyroidism (PHPT), in whom HBS was diagnosed 6 months after parathyroidectomy. Histopathologic examination revealed an atypical parathyroid adenoma (APA), while immunohistochemistry showed cell proliferation index Ki-67 10% and overexpression of cyclin D1 (>90%). Preoperative treatment with vitamin D3 had normalized 25OHD and alkaline phosphatase levels, reflected in an improvement in bone turnover prior to surgery. Postoperative treatment for HBS with alfacalcidol, calcium, vitamin D3 and magnesium was administered for a long period. This treatment prevented severe postoperative hypocalcemia and he was discharged two days later. Preoperative cinacalcet treatment did not reduce hypercalcemia implying that the tumor had lack of calciumsensing receptors (CaSR). In conclusion, preoperative restoration of low 25OHD levels is essential for prevention of HBS. Postoperative treatment with active metabolites of vitamin D must be initiated as early as possible, in order to prevent or minimize the development of HBS, and to reduce the duration of hospitalization.",
"affiliations": "Department of Endocrinology, Metropolitan General Hospital, Athens, Greece.;Department of Endocrine Surgery, Hygeia Hospitals Group, Athens, Greece.;Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.;Department of Endocrinology and Diabetes and Department of Medical Research, 251 Hellenic Air Force General Hospital, Athens, Greece.",
"authors": "Florakis|Dimos|D|;Karakozis|Stavros|S|;Tseleni-Balafouta|Sophia|S|;Makras|Polyzois|P|",
"chemical_list": "D050071:Bone Density Conservation Agents; D000077264:Calcium-Regulating Hormones and Agents; D006887:Hydroxycholecalciferols; D002762:Cholecalciferol; D008274:Magnesium; D002118:Calcium; D000069449:Cinacalcet; C008088:alfacalcidol",
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"fulltext": "\n==== Front\nJ Musculoskelet Neuronal InteractJ Musculoskelet Neuronal InteractJournal of Musculoskeletal & Neuronal Interactions1108-7161International Society of Musculoskeletal and Neuronal Interactions Greece 31475947JMNI-19-379Case ReportLessons learned from the management of Hungry Bone Syndrome following the removal of an Atypical Parathyroid Adenoma Florakis Dimos 1Karakozis Stavros 2Tseleni-Balafouta Sophia 3Makras Polyzois 41 Department of Endocrinology, Metropolitan General Hospital, Athens, Greece2 Department of Endocrine Surgery, Hygeia Hospitals Group, Athens, Greece3 Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece4 Department of Endocrinology and Diabetes and Department of Medical Research, 251 Hellenic Air Force General Hospital, Athens, GreeceCorresponding author: Dimos Florakis MD, PhD, Ypsilantou 54, Halandri 15232, Athens, Greece E-mail: florakid@otenet.gr2019 19 3 379 384 03 5 2019 Copyright: © Journal of Musculoskeletal and Neuronal Interactions2019This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 4.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Hungry Bone Syndrome (HBS) refers to rapid, profound, and prolonged hypocalcemia associated with hypophosphatemia and hypomagnesemia occurring in patients with increased bone turnover after successful management of the underlying disorder. We describe a male patient with primary hyperparathyroidism (PHPT), in whom HBS was diagnosed 6 months after parathyroidectomy. Histopathologic examination revealed an atypical parathyroid adenoma (APA), while immunohistochemistry showed cell proliferation index Ki-67 10% and overexpression of cyclin D1 (>90%). Preoperative treatment with vitamin D3 had normalized 25OHD and alkaline phosphatase levels, reflected in an improvement in bone turnover prior to surgery. Postoperative treatment for HBS with alfacalcidol, calcium, vitamin D3 and magnesium was administered for a long period. This treatment prevented severe postoperative hypocalcemia and he was discharged two days later. Preoperative cinacalcet treatment did not reduce hypercalcemia implying that the tumor had lack of calcium-sensing receptors (CaSR). In conclusion, preoperative restoration of low 25OHD levels is essential for prevention of HBS. Postoperative treatment with active metabolites of vitamin D must be initiated as early as possible, in order to prevent or minimize the development of HBS, and to reduce the duration of hospitalization.\n\nHungry Bone SyndromeAtypical Parathyroid AdenomaKi-67 IndexVitamin D3Alfacalcidol\n==== Body\nIntroduction\nHungry Bone Syndrome (HBS) is usually a complication of successful parathyroidectomy for severe primary hyperparathyroidism (PHPT) which is associated with preoperative high bone turnover. HBS is characterized by profound and prolonged hypocalcemia (corrected serum calcium <8.5 mg/dL), hypophosphatemia and hypomagnesemia[1]. The abrupt postoperative removal of the high circulating levels of PTH (parathyroid hormone) results in an increased influx of calcium into the skeleton in order to meet the needs of the rebound bone formation, while bone resorption is arrested. Postoperatively, HBS is characterized by elevated PTH levels in patients with severe PHPT, whereas HBS is quite rare in patients with mild PHPT[2]. The most common diagnoses associated with HBS are PHPT and secondary or tertiary hyperparathyroidism after parathyroidectomy, in patients with end-stage renal disease receiving renal replacement therapy or with a functioning renal transplant[3]. Another diagnosis sometimes associated with usually a mild form of HBS is severe thyrotoxicosis associated with high bone turnover in which hypocalcaemia may occur in up to 46% of patients, while HBS may last for up to 3 months after the initiation of hyperthyroidism treatment (surgical or medical)[4,5]. In contrast to HBS due to PHPT, hypocalcaemia that arises following treatment for hyperthyroidism is associated with appropriate increase of PTH levels[1]. Less frequent causes of HBS are parathyroid cancer (PC)[6,7] and metastatic prostate cancer[8]. Bone metastases from prostate cancer are predominantly osteoblastic and commonly cause increased levels of PTH as calcium is transferred from serum into the osteoblast-rich neoplastic environment[8].\n\nNowadays, HBS rarely involves skeletal manifestations such as brown tumors and osteitis fibrosa cystica, whereas fragility fractures due to severe osteoporosis are more likely to be occurred. HBS develops postoperatively in up to 13% of patients with PHPT, although this figure varies among centers[1].\n\nThe duration of the syndrome has been defined as the time needed for bone remineralization and normalization of bone turnover markers, as well as the time required for normalization of serum calcium following successful parathyroidectomy[1]. In addition, improvement or normalization of bone mineral density (BMD) is considered to be a criterion for resolution of HBS[9], and several studies adopting this notion have reported that HBS may last from 4.5 to 16 months[9]. Nevertheless, there is as yet no consensus on a definition of disease duration for HBS.\n\nWe herein describe a case of PHPT without severe skeletal findings, in which HBS was diagnosed 6 months after the surgical excision of an atypical parathyroid adenoma (APA).\n\nCase presentation\nA 44-year-old Caucasian male presented with a history of arthralgia and myalgia for several months. Medical history of nephrolithiasis was reported.\n\nThe initial laboratory results were as follows: corrected serum calcium 12.26 mg/dL (normal range 8.6-10.2), phosphate levels 1.9 mg/dL (normal range 2.5-4.5), magnesium levels 1.7 mg/dL (normal range 1.6-2.6) and alkaline phosphatase levels (ALP) 1015 U/L (normal range 50-290). The elevated PTH levels of 1131 pg/mL (normal range 15-65) together with hypercalcaemia confirmed the diagnosis of PHPT, despite low levels of 25OHD and 1,25(OH)2D of 8 ng/mL (sufficiency >20) and 18 pg/mL (normal range 18-65), respectively. Hypercalciuria (485 mg/24 hours) was also found (Table 1).\n\nTable 1 Laboratory findings preoperatively (Preop) and postoperatively (Postop).\n\n\tPreop\tPreop cinacalcet vitamin D3 magnesium\tPostop 48 h\tPostop 6m vitamin D3 calcium magnesium without alfacalcidol HBS b\tPostop 8m alfacalcidol vitamin D3 calcium magnesium\tPost 20m alendronate alfacalcidol vitamin D3 calcium magnesium\tPostop 4 years without treatment\tReference values\t\nCorrected Calcium serum a\t12.26\t12.36\t8.64\t8.06\t9.04\t8.94\t8.76\t8.6 - 10.2\t\nCalcium serum (mg/dL)\t12.5\t12.6\t8.8\t8.3\t9.2\t9.1\t9.0\t8.6 - 10.2\t\nAlbumin serum (mg/dL)\t4.3\t4.3\t4.2\t4.3\t4.2\t4.2\t4.3\t3.5 - 5.5\t\nPhosphate serum (mg/dL)\t1.9\t1.6\t3.6\t2.4\t2.7\t3.2\t1.8\t2.5 - 4.5\t\nMagnesium serum (mg/dL)\t1.7\t\t\t1.8\t\t\t1.8\t1.6 - 2.6\t\nCreatinine serum (mg/dL)\t0.9\t\t\t1.0\t\t\t1.0\t0.4 - 1.09\t\nAlkaline phosphatase (ALP) (U/L)\t1015\t275\t\t123\t\t68\t73\t50 - 290\t\n24-hour urine calcium (mg/24h)\t485\t\t\t37\t218\t\t208\t100 - 300\t\n24-hour urine creatinine (mg/24h)\t1356\t\t\t\t1655\t\t1645\t1040- 2300\t\n25OHD (ng/mL)\t8\t27\t\t31\t\t\t15.2\t> 20 ng/mL\t\n1,25 (OH)2 D (pg/mL)\t18\t\t\t\t25\t\t26.3\t18 - 65\t\nPTH (pg/mL)\t1131\t1315\t34\t120\t60\t62\t102\t15 - 65\t\nTSH (µUI/mL)\t1.87\t\t\t2.6\t\t\t\t0.36 - 4.94\t\na Corrected calcium\nwith albumin using the following formula: calcium measured + 0.8 (4 - albumin measured).\n\nb HBS: Hungry bone syndrome.\n\nSkeletal X-rays of the hip-pelvis and lumbar spine showed diffuse osteopenia without any skeletal fractures. The initial dual energy X-ray absorptiometry (DXA) scan confirmed BMD below the expected range for age[10] [left neck Z-score -4.28] (Table 2). Technetium-99m-pertechnetate whole-body scan did not reveal any skeletal lesion.\n\nTable 2 Dual energy X-ray absorptiometry (DXA) values preoperatively and postoperatively.\n\n\tPreoperative\tPostoperative 12m a\tPostoperative 36m\t\n Left Femoral Neck\t\t\n BMD (g/cm2)\t0.443\t0.706\t0.746\t\n Z-score\t- 4.28\t- 2.3\t- 1.9\t\n Right Femoral Neck\t\t\n BMD (g/cm2)\tn/a\t0.773\t0.812\t\n Z-score\t\t- 1.8\t- 1.4\t\n Lumbar L1-L4\t\t\n BMD (g/cm2)\tn/a\t1.059\t1.116\t\n Z-score\t\t- 1.3\t- 0.8\t\nOsteoporosis is diagnosed when BMD is below the expected range for age (Z-score < -2.0)\n\na Treatment with alendronate was given for 1 year after postoperative DXA at 12 months\n\nNeck ultrasonography showed a hypoechogenic mass measuring 2.6 x 3.6 cm with a well-defined margin posterior to the right lobe of the thyroid gland, without signs of blood flow (Figure 1a, b). [99]Tc-sestamibi scintigraphy revealed persistence of the radionucleotide in the right posterior parathyroid gland, but with extension of the radionucleotide to the upper right mediastinum (Figure 1c). Therefore, neck MRI was performed and a large mass with cystic degeneration measuring 8.7 x 4.6 cm was found posterior to the right thyroid lobe extending to the right mediastinum, while shifting the trachea and the esophagus to the left (Figure 1d).\n\nFigure 1 Neck ultrasonoraphy (a, b): Hypoechogenic mass measuring 2.6 x 3.6 cm with well-defined margin posterior to the right lobe of the thyroid gland without signs of blood flow. 99Tc-sestamibi scintigraphy (c): Persistence of the radionuclide material in the right posterior parathyroid gland with extension of the radionuclide material in the upper right mediastinum. Neck MRI (d): A large mass with cystic degeneration measuring 8.7 x 4.6 cm posterior to the right thyroid lobe extending to the right mediastinum with trachea and esophagus shift to the left. (e): Atypical parathyroid adenoma. HE 250X. (f): Overexpression of the proliferation index Ki67 (MIB 1). Immunohistochemistry 250X.\n\nA diagnosis of PHPT due to a large parathyroid tumor was established. Preoperative treatment with cinacalcet 30 mg b.i.d. was initiated with a daily dose of 2000 IU vitamin D3 (cholecalciferol) and 243 mg of magnesium, in order to control the hypercalcemia and correct the low levels of 25OHD and magnesium, respectively. Nevertheless, corrected serum calcium levels remained increased at 12.36 mg/dL, while 25OHD levels were partially corrected to 15 ng/mL. Daily doses of cinacalcet and vitamin D3 were subsequently increased to 60 mg t.i.d. and 4000 IU, respectively, resulting in correction of 25OHD and ALP levels, although hypercalcemia persisted (Table 1). Subsequently, cinacalcet treatment was ceased due to the unresolved hypercalcaemia, while the vitamin D3 daily dose was reduced to 2000 IU, since 25OHD levels had increased to 27 ng/mL. Bisphosphonates were not used preoperatively.\n\nTotal surgical excision of the tumor was performed without any surgical complications. Postoperatively the patient had asymptomatic hypocalcaemia (corrected serum calcium 7.34 mg/dL) with inappropriately normal PTH levels of 34 pg/ml, confirming successful parathyroidectomy (Table 1). Alfacalcidol 1mcg and calcium carbonate 4 gr daily were initiated with concomitant use of 1600 IU vitamin D3 and 243 mg magnesium. The patient was discharged two days after surgery with corrected serum calcium concentration at 8.64 mg/dl, while calcium carbonate dose was reduced to 2 grams.\n\nHistopathological examination revealed a tumor weighing 22 grams and measuring 7.2 x 4.5 x 2.7 cm. The parathyroid neoplasm consisted of solid and cystic areas with fibrosis and partial capsular invasion, however, without extensive local infiltration or metastasis. Immunohistochemistry showed increased expression of cyclin D1 (>90%) and cell proliferation Ki-67 index (with MIB 1 antibody) was 10%. The tumor was classified as an APA[11] (Figure 1e, f).\n\nSix months later, PTH levels were increased with low levels of calcium, phosphate and magnesium, and normal levels of 25OHD and ALP (Table 1). The patient’s treatment included calcium carbonate/D3 tablets of 1000mg/880 IU twice per day and 243 mg of magnesium, whereas alfacalcidol had been ceased 2 months previously. HBS was diagnosed and alfacalcidol 1mcg was recommended, with concomitant use of calcium carbonate/D3 and magnesium. PTH and calcium levels were normalized, after 2 months (Table 1).\n\nTwelve months following parathyroidectomy, DXA showed a significant increase of 59.4% in the left femoral neck BMD (Table 2). As BMD, in the left femoral neck, was still below the expected range for age [left neck Z-score -2.3], alendronate 70 mg weekly was administered for 12 months as additional treatment together with alfacalcidol, calcium carbonate, cholecalciferol, and magnesium. Six months later, serum levels of corrected calcium, phosphate, ALP and PTH were normalized (Table 1). Three years after parathyroidectomy, a new DXA showed a further increase of BMD in all skeletal sites: lumbar spine (+5.4%); left hip (+5.7%) and of the right hip (+5.0%), indicating a positive effect of alendronate treatment and parathyroidectomy (Table 2). It was therefore decided that no additional treatment was required.\n\nSix months later (4 years postoperatively), PTH was once again increased to 102 pg/mL with low levels of phosphate, magnesium, and 25OHD, while corrected calcium levels were low normal at 8.76 mg/dL (Table 1).\n\nSecondary hyperparathyroidism (sHPT) due to vitamin D deficiency seemed as the most possible diagnosis, although persistent of HBS was a less likely option, and treatment with alfacalcidol, calcium, vitamin D3 and magnesium was recommended. Additional treatment with alendronate was not considered necessary as BMD values were within the expected range for age (Table 2).\n\nDiscussion\nHypocalcemia following successful parathyroidectomy is usually transient, lasting less than a week, since the associated PHPT bone disease is frequently mild and the remaining normal parathyroid glands recover rapidly, even after long-term suppression by the hyperfunctioning parathyroid adenoma[12,13].\n\nΙn patients with PHPT and preoperative high rates of bone turnover, a successful parathyroidectomy limits osteoclastic resorption, which in turn decreases the activation frequency of new remodeling sites and remodeling space, leading to a consequent gain of bone mass. This mechanism in combination with the homeostatic increase of bone formation which corrects the PHPT-induced bone deficits, is believed to be the etiology of the rapid, severe and prolonged hypocalcemia that occurs in HBS[1]. In addition, hypophosphataemia in HBS is probably due to an increase in bone uptake that facilitates matrix remineralization[14,15]. Magnesium levels after parathyroidectomy may decrease secondary to increased bone mineralization, especially in patients with PTH-related bone disease, such as osteitis fibrosa[16]. In our case, magnesium level was low normal preoperatively and remained low normal postoperatively, despite supplementation for a long period. Hypomagnesemia in PHPT is an uncommon finding. It has been shown that few patients with PHPT have high urinary magnesium output, indicating a defect in renal magnesium retention[16].\n\nPHPT-related bone disease, such as brown tumors or osteitis fibrosa and skeletal fractures, is of considerable importance for the development of HBS, as it has been reported in 25-90% of patients with skeletal involvement compared with 0-6% of patients without skeletal involvement[1]. It is of interest that our patient developed HBS without any of the above skeletal findings or fracture. Another interesting point is the young age of our patient, since older age at the time of HBS diagnosis is considered as an additional risk factor for the development of the syndrome[1].\n\nLow preoperative 25OHD has been also proposed as an important factor that increases the risk for HBS[2]. In PHPT, vitamin D insufficiency is more common than in the general population[2]. Low 25OHD levels in PHPT patients, have been associated with greater severity of disease, higher bone turnover and BMD reduction, more severe postoperative hypocalcemia, and higher overall PTH levels[2]. A randomized study, showed that daily high-dose vitamin D supplementation of 2800 IU for 6 months preoperatively and 6 months postoperatively is a safe way to improves vitamin D status in PHPT patients, without increasing plasma or urinary calcium[2]. In addition, preoperative treatment with vitamin D3 reduced bone resorption and was followed by postoperative reduction of PTH and ALP levels, confirming that preoperative vitamin D3 supplementation may decrease the likelihood of development of HBS[2]. In our case, the preoperative vitamin D3 treatment normalized 25OHD and ALP levels, reflecting a possible improvement of bone turnover prior to surgery. Treatment with alfacalcidol and calcium was initiated immediately after parathyroidectomy, with concomitant use of cholecalciferol and magnesium. This treatment course prevented severe postoperative hypocalcemia, and the patient was discharged two days later, without the need for an intravenous calcium infusion. A case report has been published with a patient presenting protracted and severe HBS requiring 3 months of intravenous calcium supplementation, whereas the patient received ergocalciferol and calcitriol, before and after parathyroidectomy[9]. The authors reported that 25OHD levels never reached a value above 30 ng/ml, despite the administration of ergocalciferol, and this underlines the importance of 25OHD levels normalization with cholecalciferol.\n\nPostoperative treatment with active metabolites of vitamin D with concomitant use of calcium and cholecalciferol are considered mandatory and need to be initiated as early possible in order to prevent or ameliorate HBS. Several case reports of patients with HBS have described the difficulties involved in the postoperative management of hypocalcemia whenever the treatment consists solely of calcium plus ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) without concomitant use of vitamin D active metabolites[6,9].\n\nIn our case, the preoperative hypercalcemia was not adequately controlled even with high-dose cinacalcet treatment, this arousing speculation that the tumor lacked expression of the calcium sensing receptor (CaSR). Cinacalcet is a calcimimetic agent which directly lowers PTH levels by increasing the sensitivity of the CaSR to extracellular calcium. Immunohistochemical studies have shown that global loss of CaSR staining in parathyroid tumors is a diagnostic marker for PC[17]. However, in our case study the histopathologic diagnosis of an APA was established, because the tumor exhibited some features of a parathyroid carcinoma such as fibrosis and partial capsular invasion but had lack of unequivocal invasive growth and metastasis. APA may be considered tumor of uncertain malignant potential, and most patients with APA have a benign clinical course[11].\n\nMost of the bone loss in PHPT patients is reversible after parathyroidectomy. In a case series of patients with HBS, parathyroidectomy improved femoral neck BMD scores from 35% to 131% 1 year after successful surgery. In addition, case reports showed an increase in BMD of the lumbar spine of 27% to 63% 1 year after parathyroidectomy[1].\n\nPreoperative treatment with bisphosphonates in HBS is controversial. A retrospective case series of 46 patients with severe bone disease, who were treated with zoledronate preoperatively, showed a low frequency of postoperative HBS of only 4%[18]. In contrast, other case reports using bisphosphonates prior to surgery demonstrated no such effect[19]. The aim of the preoperative bisphosphonate treatment is to reduce bone turnover by inhibition of osteoclast bone resorption, and to decrease the activation frequency of remodeling space, thus resulting in refilling of remodeling space and increasing mineralization of the bone. However, short-term preoperative bisphosphonate treatment may exacerbate postoperative hypocalcemia by reducing bone resorption, without allowing time for a coupled decrease in bone formation. In our case, alendronate was given for 1 year, postoperatively, when the DXA has showed that BMD was still below the expected range for age.\n\nIn our patient high PTH levels with low normal calcium, phosphate, and suboptimal 25OHD levels were measured 4 years after parathyroidectomy, concomitantly with normal BMD, ALP, and 24-hour urine calcium levels (Table 1). Postoperative treatment included alendronate for 1 year and cholecalciferol, alfacalcidol and magnesium for more than 3 years. Secondary hyperparathyroidism (sHPT) due to vitamin D deficiency may be considered as the most likely diagnosis in our case. However, in sHPT the increases of serum PTH associated with vitamin D deficiency are usually within the high normal reference range[20]. In a large vitamin D study, it was determined that the negative relationship between serum PTH and serum 25(OH)D was significant only when serum 25(OH)D was lower than 12 ng/ml[21]. Furthermore, high PTH levels occurs in only 10% to 33% of people with vitamin D insufficiency[22]. In our case report, the high PTH levels in correlation with the lack of hypocalcemia and the normal 24-hour urine calcium levels indicate that HBS could be an alternative, less possible, diagnosis. Unfortunately, there are no available data regarding the postoperative use of bisphosphonates after parathyroidectomy, for the prevention or amelioration of HBS. However, it may be speculated that the postoperative treatment with alendronate for 1 year maintained low normal calcium levels by decreasing calcium influx to the bone, and thus masking the presentation of HBS while making sHPT the most acceptable diagnosis in our case.\n\nConclusion\nPreoperative restoration of 25OHD levels is essential for prevention of HBS, though only vitamin D3 preparations are recommended, since vitamin D2 preparations have much lower efficiency in restoring vitamin D levels[23]. Postoperative treatment with active metabolites of vitamin D, must be initiated as early as possible in order to prevent the development of HBS, and to reduce the duration of hospitalization. Magnesium supplementation is also important for the prevention and treatment of HBS, given that hypocalcemia is very difficult to resolve if there is concomitant hypomagnesemia. Data on the management of HBS are limited, while clinical guidelines and consensus regarding the precise definition and management of the syndrome are as yet lacking.\n\nThe authors have no conflict of interest.\n\nEdited by: G. Lyritis\n==== Refs\nReferences\n1 Witteveen JE van Thiel S Romijn JA Hamdy NA Hungry bone syndrome:still a challenge in the post-operative management of primary hyperparathyroidism:a systematic review of the literature Eur J Endocrinol 2013 168 3 45 53 \n2 Rolighed L Rejnmark L Sikjaer T Vitamin D Treatment in Primary Hyperparathyroidism:A Randomized Placebo Controlled Trial JCEM 2014 99 3 1072 80 24423366 \n3 Latus J Roesel M Fritz P Incidence of and risk factors for hungry bone disease in 84 patients with secondary hyperparathyroidism Int J Nephrol Renovasc Dis 2013 6 131 37 23882155 \n4 See AC Soo KC Hypocalcaemia following thyroidectomy for thyrotoxicosis Br J Surg 1997 84 1 95 7 9043468 \n5 Grieff M The hungry bone syndrome after medical treatment of thyrotoxicosis Ann Intern Med 2003 139 8 706 7 14568870 \n6 Kwang-Min Kim Joon-Beom Park Keum-Seok Bae Hungry bone syndrome after parathyroidectomy of a minimally invasive parathyroid carcinoma JKSS 2011 81 5 344 49 22148128 \n7 Rathi MS Ajjan R Orme SM A case of parathyroid carcinoma with severe hungry bone syndrome and review of literature Exp Clin Endocrinol Diabetes 2008 116 487 490 18095236 \n8 Rizzo C Vella S Cachia MJ Refractory hypocalcaemia complicating metastatic prostatic carcinoma BMJ Case Rep 2015 doi:10.1136/bcr-2015-210003 \n9 Óscar Alfredo Juárez-León Miguel Ángel Gómez-Sámano Daniel Cuevas-Ramos Atypical Parathyroid Adenoma Complicated with Protracted Hungry Bone Syndrome after Surgery:A Case Report and Literature Review Case Reports in Endocrinology 2015 757951 1 8 \n10 The International Society for Clinical Densitometry (2015) Official Positions of the International Society for Clinical Densitometry last access 15 Dec. 2018 www.iscd.org \n11 DeLellis RA Arnold A Bilezikian JP Eng C Lloyd RV Osamura RY Klöppel G Rosai J WHO Classification of tumours of the parathyroid glands WHO Classification of tumours of endocrine organs 2017 Lyon IARC Press 146 158 \n12 Makras P Anastasilakis AD Bone disease in primary hyperparathyroidism Metabolism 2018 80 57 65 29051042 \n13 Mosekilde L Primary hyperparathyroidism and the skeleton Clin Endocr 2008 69 1 1 19 18167138 \n14 Dunlay R Hruska K PTH receptor coupling to phospholipase C is an alternate pathway of signal transduction in bone and kidney Am J Physiol 1990 258 2 223 31 \n15 Brasier AR Nussbaum SR Hungry bone syndrome:clinical and biochemical predictors of its occurrence after parathyroid surgery Am J Med 1988 84 654 60 3400660 \n16 Sutton RAL Plasma Magnesium Concentration in Primary Hyperparathyroidism BMJ 1970 1 5695 529 33 5436362 \n17 Erickson LA Mete O Immunohistochemistry in Diagnostic Parathyroid Pathology Endocr Pathol 2018 29 2 113 29 29626276 \n18 Malabu UH Founda MA Primary hyperparathyroidism in Saudi Arabia:a review of 46 cases Med J Malaysia 2007 62 5 394 97 18705474 \n19 Agarwal G Mishra SK Kar DK Recovery pattern of patients with osteitis fibrosa cystica in primary hyperparathyroidism after successful parathyroidectomy Surgery 2002 132 6 1075 83 12490858 \n20 Lips P Vitamin D deficiency and secondary hyperparathyroidism in the elderly:consequences for bone loss and fractures and therapeutic implications Endocr Rev 2001 22 4 477 501 11493580 \n21 Ooms ME Lips P Roos JC Vitamin D status and sex hormone binding globulin:determinants of bone turnover and bone mineral density in elderly women J Bone Miner Res 1995 10 1177 1184 8585420 \n22 Hansen KE Johnson RE Chambers KR Treatment of vitamin D insufficiency in postmenopausal women:a randomized clinical trial JAMA Intern Med 2015 175 1612 21 26237520 \n23 Shieh A Chun RF Ma C Effects of High-Dose Vitamin D2 Versus D3 on Total and Free 25-Hydroxyvitamin D and Markers of Calcium Balance JCEM 2016 101 8 3070 8 27192696\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1108-7161",
"issue": "19(3)",
"journal": "Journal of musculoskeletal & neuronal interactions",
"keywords": "Alfacalcidol; Atypical Parathyroid Adenoma; Hungry Bone Syndrome; Ki-67 Index; Vitamin D3",
"medline_ta": "J Musculoskelet Neuronal Interact",
"mesh_terms": "D000236:Adenoma; D000328:Adult; D050071:Bone Density Conservation Agents; D002118:Calcium; D000077264:Calcium-Regulating Hormones and Agents; D002762:Cholecalciferol; D000069449:Cinacalcet; D006801:Humans; D006887:Hydroxycholecalciferols; D006961:Hyperparathyroidism; D006996:Hypocalcemia; D017674:Hypophosphatemia; D008274:Magnesium; D008297:Male; D010282:Parathyroid Neoplasms; D016105:Parathyroidectomy; D011183:Postoperative Complications; D013577:Syndrome",
"nlm_unique_id": "101084496",
"other_id": null,
"pages": "379-384",
"pmc": null,
"pmid": "31475947",
"pubdate": "2019-09-01",
"publication_types": "D002363:Case Reports",
"references": "11493580;12490858;14568870;18095236;18167138;18705474;2155534;22148128;23152439;23882155;24423366;26123464;26237520;26640724;27192696;29051042;29626276;3400660;5436362;8585420;9043468",
"title": "Lessons learned from the management of Hungry Bone Syndrome following the removal of an Atypical Parathyroid Adenoma.",
"title_normalized": "lessons learned from the management of hungry bone syndrome following the removal of an atypical parathyroid adenoma"
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"abstract": "An elderly male was admitted to the Department of Neurology for slowly progressive dysarthria and right-sided atactic hemiparesis. Magnetic resonance imaging (MRI) revealed a small contrast-enhanced focus of malignant glioma in the left parietal lobe - with the growth pattern of cerebral gliomatosis - involving the whole left cerebral hemisphere, the corpus callosum, and spreading into the right frontal hemisphere. Diagnostic biopsy was deferred until the exclusion of other possible causes of the brain lesion. A follow-up brain MRI was planned in 6 weeks. In the interim, the patient was treated with dexamethasone, with mild improvement of the neurological symptoms. He was discharged home with a date for a follow-up brain MRI. One week later, the patient was readmitted due to a deterioration of speech and severe respiratory distress. The repeat brain MRI showed regression of contrast enhancement and no progression of the diffuse growth. Laboratory tests demonstrated tracheal candidiasis, invasive aspergillosis, and disseminated strongyloidiasis, including the brain. The patient rapidly deteriorated and died 11 days after the 2nd admission. The autopsy confirmed a small focus of glioblastoma in the left parietal lobe with the diffuse growth pattern of cerebral gliomatosis, laryngeal candidiasis, diffuse alveolar damage, with angioinvasive aspergillosis in the lungs and heart, and disseminated strongyloidiasis.",
"affiliations": null,
"authors": "Car|Milan|M|;Šteblaj|Simona|S|;Mitrovič|Goran|G|;Dolenc-Stražar|Zvezdana|Z|;Popović|Mara|M|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D003907:Dexamethasone",
"country": "Germany",
"delete": false,
"doi": "10.5414/NP301167",
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"issn_linking": "0722-5091",
"issue": "38(4)",
"journal": "Clinical neuropathology",
"keywords": null,
"medline_ta": "Clin Neuropathol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D001344:Autopsy; D001706:Biopsy; D001932:Brain Neoplasms; D003907:Dexamethasone; D005909:Glioblastoma; D005910:Glioma; D006801:Humans; D007154:Immune System Diseases; D008279:Magnetic Resonance Imaging; D008297:Male; D018302:Neoplasms, Neuroepithelial",
"nlm_unique_id": "8214420",
"other_id": null,
"pages": "189-194",
"pmc": null,
"pmid": "30964431",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Corticosteroid-induced immunodeficiency in a patient with gliomatosis cerebri: Are corticosteroids indicated in all brain tumors?",
"title_normalized": "corticosteroid induced immunodeficiency in a patient with gliomatosis cerebri are corticosteroids indicated in all brain tumors"
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"companynumb": "SI-BAUSCH-BL-2019-013632",
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"abstract": "Invasive pulmonary aspergillosis (IPA) is a life-threatening condition that usually occurs in immunocompromised hosts. However, according to recent reports it can affect immunocompetent hosts with severe influenza infection due to viral-dependent disruption of respiratory immune defenses. We present the case of a 61-year-old Caucasian man admitted to the Emergency Department with respiratory failure and fever, who was diagnosed with H1N1 influenza and IPA. Because of his poor general conditions, he was treated with a double antifungal scheme, although this lies outside the suggested treatment guidelines. This choice turned out to be extremely effective. He was discharged after one month and his clinical conditions showed rapid improvement, with nearly complete normalization of the radiological pattern in three months. IPA remains a life-threatening condition, even in immunocompetent hosts, and should therefore always be suspected; if necessary, a combined treatment should rapidly be started. We report this case as the interest in influenza-associated IPA is high, both due to the clinical severity of this condition, which is treatable if identified early, and the emerging importance of respiratory infections caused by viruses belonging to the SARS family, such as SARS-CoV-2.",
"affiliations": "Infectious Diseases Unit, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy.;Infectious Diseases Unit, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy.;Infectious Diseases Unit, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy.;Infectious Diseases Unit, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy.;Infectious Diseases Unit, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy.",
"authors": "Saccaro|Luigi Francesco|LF|;Galfo|Valentina|V|;Ferranti|Simone|S|;Russo|Alessandro|A|;Menichetti|Francesco|F|",
"chemical_list": "D000935:Antifungal Agents",
"country": "Italy",
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"issn_linking": "1124-9390",
"issue": "28(2)",
"journal": "Le infezioni in medicina",
"keywords": null,
"medline_ta": "Infez Med",
"mesh_terms": "D000935:Antifungal Agents; D060085:Coinfection; D004359:Drug Therapy, Combination; D006801:Humans; D007121:Immunocompetence; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human; D055744:Invasive Pulmonary Aspergillosis; D008297:Male; D008875:Middle Aged; D012131:Respiratory Insufficiency; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9613961",
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"pages": "263-267",
"pmc": null,
"pmid": "32487793",
"pubdate": "2020-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe respiratory failure in an immunocompetent host with invasive pulmonary aspergillosis and H1N1 influenza.",
"title_normalized": "severe respiratory failure in an immunocompetent host with invasive pulmonary aspergillosis and h1n1 influenza"
} | [
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"abstract": "•First case of NACT in cervical embryonal RMS•Second case occurring in pregnancy•Histological review outlining diagnostic difficulties.",
"affiliations": "Registrar in Obstetrics and Gynecology, Christchurch Women's Hospital, Private Bag 4711, Christchurch 8140, New Zealand.;Department of Obstetrics and Gynecogoly, New Zealand.;Christchurch Women's Hospital, University of Otago, New Zealand.;Christchurch Women's Hospital, University of Otago, New Zealand.;Canterbury Health Laboratories, New Zealand.;Pathology Registrar at Canterbury Health Laboratories, New Zealand.;Christchurch Women's Hospital, University of Otago, New Zealand.",
"authors": "Taghavi|Katayoun|K|;Sykes|Peter|P|;Innes|Carrie|C|;Gibbs|David|D|;Hunter|Lauree|L|;McBurnie|Wendy|W|;Simcock|Bryony|B|",
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"doi": "10.1016/j.gore.2015.04.001",
"fulltext": "\n==== Front\nGynecol Oncol RepGynecol Oncol RepGynecologic Oncology Reports2352-5789Elsevier S2352-5789(15)00027-210.1016/j.gore.2015.04.001Case ReportWrong place at the wrong time: A case of cervical embryonal rhabdomyosarcoma in pregnancy Taghavi Katayoun katayoun.taghavi@gmail.coma⁎Sykes Peter bInnes Carrie cGibbs David cHunter Lauree dMcBurnie Wendy eSimcock Bryony ca Registrar in Obstetrics and Gynecology, Christchurch Women's Hospital, Private Bag 4711, Christchurch 8140, New Zealandb Department of Obstetrics and Gynecogoly, New Zealandc Christchurch Women's Hospital, University of Otago, New Zealandd Canterbury Health Laboratories, New Zealande Pathology Registrar at Canterbury Health Laboratories, New Zealand⁎ Corresponding author. Fax: + 64 3 364 4331. katayoun.taghavi@gmail.com18 4 2015 4 2015 18 4 2015 12 77 79 9 2 2015 12 4 2015 © 2015 The Authors2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• First case of NACT in cervical embryonal RMS\n\n• Second case occurring in pregnancy\n\n• Histological review outlining diagnostic difficulties\n\n\n\nKeywords\nEmbryonal rhabdomyosarcomaBotryoid typeCervical cancerCancer in PregnancyNeoadjuvent chemotherapyPathology\n==== Body\nIntroduction\nCancer affects approximately 1 in 1000 pregnancies and is expected to become increasingly common. The most frequently diagnosed cancers in pregnancy include breast cancer, cervical cancer, melanoma, lymphoma and leukaemia (Meseci et al., 2014). Cervical cancer makes up approximately 25% of cancers diagnosed in pregnancy (Meseci et al., 2014). Nevertheless, the literature to inform evidence-based practice in this situation remains limited. The management approach in many circumstances is extrapolated from case studies involving non-pregnant women.\n\nThere are many factors which may be associated with this alarming trend including; delaying pregnancy into later reproductive years, the potential influence that pregnancy has on tumour growth, and the increased likelihood of diagnosis associated with increased interaction with health services (Meseci et al., 2014).\n\nThe most common subtypes of cervical cancer are squamous cell carcinoma and adenocarcinoma, making up approximately 95% of cases (Behtash et al., 2003). More rare varieties include small cell, glassy cell, neuroendocrine types, melanoma and lymphoma (Behtash et al., 2003). Embryonal rhabdomyosarcoma (RMS) is extremely rare. We present the second reported case in pregnancy, and describe management of a FIGO 1B1 tumour in pregnancy where a delivery delay was desired. The chemotherapy used pertains to the recommended regime for RMS which is mostly extrapolated from paediatric evidence (Zeisler et al., 1998, Brand et al., 1987). It is the 38th reported case of cervical cancer in pregnancy where neoadjuvent chemotherapy (NACT) has been adopted in order to achieve foetal lung maturity. It is the first case of RMS in pregnancy where NACT has been used.\n\nCase\nA 36 year old, with a history of spotting since 13 weeks, presented at 20 weeks of gestation with heavy bleeding and passing “grape-like” tissue. On examination she had a 4 cm exophytic lesion on her cervix which was very friable. Abdominal ultrasound scan was normal and showed no extension of the cervical lesion. Examination under anaesthetic was performed with excision of the mass under spinal anaesthesia. A histological diagnosis of cervical embryonal rhabdomyosarcoma (botryoides) was made (Fig. 2).\n\nWith a normal cervical smear history prior six months before the above diagnosis, she had been referred for review of a large cervical polyp. At this time, the lesion appeared clinically and histologically benign (Fig. 1). However, when reviewed again at the time of diagnosis, this was also noted to be embryonal rhabdomyosarcoma. Her obstetric history included two previous caesarean sections (her children now aged four and one), a previous termination of pregnancy for an anencephalic baby, and one first trimester miscarriage.\n\nStaging investigations, MRI and CXR, performed at 24 weeks showed no evidence of metastatic disease. Multi-disciplinary-team review panel recommended, six rounds of chemotherapy starting antenatally with vincristine (1.4 mg m− 2), adriamycin (0.75 mg m− 2), and cyclophosphamide (1500 mg m− 2). During each round, these three medications were administered within 2 days and there were 21 days between each round of chemotherapy. Delivery with caesarean, radical hysterectomy and nodal clearance were performed at 34 weeks. The final histology showed no residual tumour. Chemotherapy was subsequently continued.\n\nAntenatally, our patient was seen weekly, with alternating obstetric and gynae-oncology reviews. Fortnightly growth scans were performed and weekly biophysical profiles during the period of antenatal chemotherapy. No significant foetal or maternal complications were encountered antenatally. Post-operatively, after the 4th round of chemotherapy she was admitted with mild neutropenia and a pelvic vault collection that was drained. She also suffered a transient period of moderate short term memory impairment. All of these issues resolved and the patient has remained free from disease to date. Her child had no significant neonatal complications and all developmental milestones have been met to 2 years follow-up.\n\nDiscussion\nThe case represents the second case of embryonal rhabdomyosarcoma (RMS) in pregnancy. In another recently described case, a FIGO stage 1A embryonal RMS was diagnosed at 30 weeks of gestation. Interestingly, there was a delay in diagnosis in this case too as a polyp noted at 6 weeks was initially thought benign (Meseci et al., 2014). In this case the decision was made to delay treatment until foetal lung maturity was achieved at 34 weeks. Then, a caesarean section with radical hysterectomy, pelvic para-aortic lymphadenectomy was performed and adjuvant chemotherapy subsequently commenced.\n\nRMS is extremely rare in absolute numbers and is classically seen in infants or young children. In this age group, it accounts for 4–6% of malignancies (Zeisler et al., 1998, Behtash et al., 2003). The mean age at diagnosis is two years and 90% of cases will occur prior to the age of five (Singhal et al., 1990). A recent case series of all documented cases reports 8 cases in women of reproductive age. RMS is classified into three sub-types: embryonal, alveolar and pleomorphic (Behtash et al., 2003). RMS can arise anywhere, the most common locations being the head and neck (40%), the genitourinary tract (25%) and the extremities (20%) (Dehner et al., 2012). A subtype of the embryonal category is botryoides (which describes the grossly polypoid “grape like” appearance) first described by Pfannensteil in 1892 (Zeisler et al., 1998). The botryoid subtype is generally found in the vagina during early childhood, the cervix in adolescence and in the uterus during postmenopausal years (Dehner et al., 2012, Zeisler et al., 1998, Behtash et al., 2003, Brand et al., 1987, Daya and Scully, 1988).\n\nDiagnosis can be very complicated. Pathological findings in the early stages of disease may be obscure and a high level of suspicion is required to guide investigations. The microscopic findings in embryonal RMS are relatively consistent irrespective of the organ involved. Including ours, five cases of cervical disease have encountered a delay in diagnosis (Zeisler et al., 1998, Behtash et al., 2003, Garrett et al., 2013). No clear diagnostic features in the early stage of disease have been described in the literature (Garrett et al., 2013). A foci of increased cellularity, indicative of neoplasm, may be the only distinguishing feature and lead to the observed delay in diagnosis (Dehner et al., 2012, Singhal et al., 1990, Zeisler et al., 1998). The differential diagnosis for polypoid spindle cell lesions of the cervix in adult women can be broad and includes endometriosis, cervical or endometrial polyps, adenofribroma, adenosarcoma, mesodermal polyps, small cell carcinoma and lymphoma. Distinguishing features would include rhabdomyoblasts of varying differentiations (which may be dispersed with loose myxoid stroma) and a cambium layer. Cartilaginous differentiation is also a feature in many cases.\n\nHistopathological features associated with poor prognosis include deep myometrial invasion, lymphatic invasion and focal alveolar pattern (Singhal et al., 1990). Data regarding cytogenetics and heritability of the disease is limited and may comprise a rare cluster of inheritable soft tissue malignancies called the Li-Fraumeni syndrome (Mousavi and Akhavan, 2010). Only one case of embryonal RMS has been cytogenetically analysed (Palazzo et al., 1993). Cervical embryonal RMS has been reported in sisters at age 15 and 17 respectively (Mousavi and Akhavan, 2010). Unfortunately genetic information from these cases is not available. The significance of these findings on their own is limited but it does highlight the importance of having new cases genetically examined. Furthermore, in the evolving landscape of cancer medicine, individualising treatment based on cytogenetics is increasingly relevant.\n\nTreatment of RMS has evolved considerably over the past several decades. Management of the disease in adults is guided by the paediatric literature and recommendations developed by The Soft Tissue Sarcoma Committee of the Children's Oncology Group (Zeisler et al., 1998). They suggest complete excision for localized disease. If not feasible, an initial diagnostic biopsy followed by NACT, then definitive local therapy is suggested, however, there are no cases of this in the adult cohort. Using combined modality therapy, 70–90% of patients with localized RMS achieve cure. Radiation therapy can enhance local control in patients with residual microscopic or gross disease following surgery.\n\nAll reported cases of embryonal RMS in the literature have been managed with primary surgery and subsequent chemotherapy/radiotherapy (Dehner et al., 2012, Singhal et al., 1990, Zeisler et al., 1998, Behtash et al., 2003, Brand et al., 1987, Daya and Scully, 1988, Garrett et al., 2013, Mousavi and Akhavan, 2010). Management in pregnancy is challenging as deliberate delay raises concerns for maternal morbidity, especially when the diagnosis occurs in the first and second trimester. The principles guiding care include the evaluation of tumour size and stage, nodal status, gestation, parental wishes regarding the pregnancy, and histological subtype. This is the first time that NACT has been used and our case suggests good maternal and foetal outcomes. NACT followed by radical hysterectomy has emerged in recent years as an alternative to allow foetal lung maturation in pregnancy (Pettersson et al., 2010). 37 cases of NACT have been described in women with cervical cancer in pregnancy who have FIGO stage > 1B1. The advantages of this approach include the opportunity to evaluate the efficacy of the drugs after each cycle, a reduction of the tumour burden to make it operable, and the theoretical treatment of nodal micrometastasis (Pettersson et al., 2010).\n\nEvaluation of the efficacy and safety of NACT in pregnancy is not easy for several reasons but primarily due to the limited number of cases reported in the literature. The cases described to date predominantly involve squamous cell carcinoma and adenocarcinoma (n = 29 78%) (Yousefi et al., 2013). Most cases used single therapy cisplatin with good effect and safety (Yousefi et al., 2013). The chemotherapy regime of paclitaxel, ifosfamide and cisplatin is not recommended due to the nephrotoxic effect of ifosfamide on the foetus (Yousefi et al., 2013). Seven cases used the combination of cisplatin and paclitaxel, and in one case this combination was associated with a severe allergic reaction leading to the onset of pre-term labour (Yousefi et al., 2013). The regime used in our case looked at the use of vincristine, dactinomycin and cyclophosphamide. These drugs have been extensively studied in animals but human data is sparse. Fewer than 10 cases describe the use of each of these medications in pregnancy and this limited data suggests that in the second and third trimesters there is a reduced likelihood of congenital malformations (Kirshon et al., 1988, Nicholson, 1968). Associated problems may include craniofacial dysmorphisms, growth restriction, pancytopenia or foetal demise (Kirshon et al., 1988, Nicholson, 1968).\n\nIn considering delivery delay, the effect of pregnancy on the tumour and progression of disease is of fundamental importance. To date there is no evidence that pregnancy itself worsens the prognosis for patients (Pettersson et al., 2010). Many studies show no significant difference in survival between pregnant and non-pregnant women who are matched by age stage and histopathology (Pettersson et al., 2010). There is growing evidence for the use of NACT as an option for women with invasive cervical cancer who do not wish to sacrifice their pregnancy (Yousefi et al., 2013). Therefore, management in a multi-disciplinary team is required with comprehensive counselling regarding the full spectrum of management options. Particular care and monitoring are required when FIGO stage 1B2 or higher occurs to ensure that there is a favourable response to treatment and no signs of progression. Our case is the 38th case where NACT has been used and the first case of embryonal RMS in pregnancy. The results have been most promising.\n\nConflict of interest statement\nThe authors declare there is no conflict of interest.\n\nConsent\nInformed written consent was obtained from the patient for publication of this report and the accompanying images. A copy of the written consent is available for review of the editor in chief of this journal on request.\n\nFig. 1 First cervical polyp, early disease: under low power, high power and myogenin stain.\n\nFig. 2 EUA biopsies — 4 cm exophyitic lesion now visible on examination: low, medium and high power, desmin staining.\n==== Refs\nReferences\nBehtash N. Mousavi A. Tehranian A. Khanafshar N. Hanjani P. Embryonal rhabdomyosarcoma of the uterine cervix: case report and review of the literature Gynecol. Oncol. 91 2003 452 455 14599884 \nBrand E. Berek J.S. Nieberg R.K. Hacker N.F. Rhabdomyosarcoma of the uterine cervix. Sarcoma botryoides Cancer 60 1987 1552 1560 3621128 \nDaya D.A. Scully R.E. Sarcoma botryoides of the uterine cervix in young women: a clinicopathological study of 13 cases Gynecol. Oncol. 29 1988 290 304 3278956 \nDehner L.P. Jarzembowski J.A. Hill D.A. Embryonal rhabdomyosarcoma of the uterine cervix: a report of 14 cases and a discussion of its unusual clinicopathological associations Mod. Pathol. 25 2012 602 614 22157934 \nGarrett L.A. Harmon D.C. Schorge J.O. Embryonal rhabdomyosarcoma of the uterine corpus J. Clin. Oncol. 31 2013 e48 e50 23248250 \nKirshon B. Wasserstrum N. Willis R. Herman G.E. McCabe E.R. Teratogenic effects of first-trimester cyclophosphamide therapy Obstet. Gynecol. 72 1988 462 464 3136412 \nMeseci E. Onculoglu C. Ince U. Teomete M. Eser S.K. Demirkiran F. Embryonal rhabdomyosarcoma of the uterine cervix in a pregnant woman Taiwan. J. Obstet. Gynecol. 53 2014 423 425 25286807 \nMousavi A. Akhavan S. Sarcoma botryoides (embryonal rhabdomyosarcoma) of the uterine cervix in sisters J. Gynecol. Oncol. 21 2010 273 275 21278891 \nNicholson H.O. Cytotoxic drugs in pregnancy. Review of reported cases J. Obstet. Gynaecol. Br. Commonw. 75 1968 307 312 4868587 \nPalazzo J.P. Gibas Z. Dunton C.J. Talerman A. Cytogenetic study of botryoid rhabdomyosarcoma of the uterine cervix Virchows Arch. A Pathol. Anat. Histopathol. 422 1993 87 91 8438559 \nPettersson B.F. Andersson S. Hellman K. Hellstrom A.C. Invasive carcinoma of the uterine cervix associated with pregnancy: 90 years of experience Cancer 116 2010 2343 2349 20209612 \nSinghal S. Sharma S. De S. Kumar L. Chander S. Rath G.K. Adult embryonal rhabdomyosarcoma of the vagina complicating pregnancy: a case report and review of the literature Asia Oceania J. Obstet. Gynaecol. 16 1990 301 306 2099725 \nYousefi Z. Hoshyar A.H. Kadkhodayan S. Hasanzade M. Kalantari M.R. Mottaghi M. Neoadjuvant chemotherapy and radical surgery in locally advanced cervical cancer during pregnancy: case report and review of literature Oman Med. J. 28 2013 60 62 23386949 \nZeisler H. Mayerhofer K. Joura E.A. Bancher-Todesca D. Kainz C. Breitenecker G. Embryonal rhabdomyosarcoma of the uterine cervix: case report and review of the literature Gynecol. Oncol. 69 1998 78 83 9571003\n\n",
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"keywords": "Botryoid type; Cancer in Pregnancy; Cervical cancer; Embryonal rhabdomyosarcoma; Neoadjuvent chemotherapy; Pathology",
"medline_ta": "Gynecol Oncol Rep",
"mesh_terms": null,
"nlm_unique_id": "101652231",
"other_id": null,
"pages": "77-9",
"pmc": null,
"pmid": "26076166",
"pubdate": "2015-04",
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"title": "Wrong place at the wrong time: A case of cervical embryonal rhabdomyosarcoma in pregnancy.",
"title_normalized": "wrong place at the wrong time a case of cervical embryonal rhabdomyosarcoma in pregnancy"
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"abstract": "Acute compartment syndrome is a limb-threatening condition often associated with high-energy injury. We present the case of a man who sustained compartment syndrome secondary to an atraumatic tear in the gastrocnemius muscle and the complications which arose in his treatment due to his being on rivaroxaban.",
"affiliations": "Trauma and Orthopaedic Department, Addenbrooke's Hospital, Cambridge, UK.;Trauma and Orthopaedic Department, Addenbrooke's Hospital, Cambridge, UK.",
"authors": "Phillips|Georgina Stefanie Anne|GSA|http://orcid.org/0000-0002-6160-3951;McDonnell|Stephen Martin|SM|",
"chemical_list": "D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban",
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"keywords": "drug therapy related to surgery; haematology (drugs and medicines); orthopaedic and trauma surgery; trauma; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D003161:Compartment Syndromes; D003937:Diagnosis, Differential; D065427:Factor Xa Inhibitors; D000071938:Fasciotomy; D006489:Hemostatic Techniques; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal; D019106:Postoperative Hemorrhage; D011655:Pulmonary Embolism; D000069552:Rivaroxaban",
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"title": "Compartment syndrome secondary to an atraumatic gastrocnemius tear in a patient on NOACs: presentation and complications of treatment.",
"title_normalized": "compartment syndrome secondary to an atraumatic gastrocnemius tear in a patient on noacs presentation and complications of treatment"
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"abstract": "Clostridioides (Clostridium) difficile infection (CDI) is a leading cause of antibiotics-associated diarrhoea. Faecal microbiota transplantation (FMT) is effective for recurrent CDI and may be provided as a home treatment to frail, older people.\n\n\n\nWe present four consecutive patients with recurrent CDI, treated at home using nasojejunal tube-delivered or encapsulated donor faeces. The primary outcome was combined clinical resolution and a negative CD toxin test 8 weeks post-treatment.\n\n\n\nAll four patients had severe CDI and all improved clinically following one FMT. Sustained resolution following one FMT was observed in one patient. Two patients had recurrence and received a second FMT using capsules; both achieved resolution. One patient who had recurrence declined from further FMT due to fear of relapse and was established on long-term vancomycin. No adverse events related to FMT were observed.\n\n\n\nFrail older people may benefit from FMT. Home treatment is a viable option and may be considered both for clinical cure and for palliation.",
"affiliations": "Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark.;Department of Geriatrics, Aarhus University Hospital, Aarhus N, Denmark.;Department of Geriatrics, Aarhus University Hospital, Aarhus N, Denmark.;Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark.;Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark.",
"authors": "Jørgensen|Simon Mark Dahl|SMD|;Rubak|Tone Maria Mørck|TMM|;Damsgaard|Else Marie|EM|;Dahlerup|Jens Frederik|JF|;Hvas|Christian Lodberg|CL|",
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"doi": "10.1093/ageing/afaa073",
"fulltext": "\n==== Front\nAge Ageing\nAge Ageing\nageing\nAge and Ageing\n0002-0729 1468-2834 Oxford University Press \n\n10.1093/ageing/afaa073\nafaa073\nAcademicSubjects/MED00280\nShort Report\nFaecal microbiota transplantation as a home therapy to frail older people\nJørgensen Simon Mark Dahl 1 Rubak Tone Maria Mørck 2 Damsgaard Else Marie 2 Dahlerup Jens Frederik 1 http://orcid.org/0000-0001-7973-7184Hvas Christian Lodberg 1 1 \nDepartment of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark\n2 \nDepartment of Geriatrics, Aarhus University Hospital, Aarhus N, Denmark\nAddress correspondence to: Christian L. Hvas, Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus N, Denmark. Tel: (+45) 7845 3800; Fax: (+45) 7846 2820. Email: christian.hvas@auh.rm.dk\n11 2020 \n04 5 2020 \n04 5 2020 \n49 6 1093 1096\n15 9 2019 15 3 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of the British Geriatrics Society.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\n\nClostridioides (Clostridium) difficile infection (CDI) is a leading cause of antibiotics-associated diarrhoea. Faecal microbiota transplantation (FMT) is effective for recurrent CDI and may be provided as a home treatment to frail, older people.\n\nMethods\nWe present four consecutive patients with recurrent CDI, treated at home using nasojejunal tube-delivered or encapsulated donor faeces. The primary outcome was combined clinical resolution and a negative CD toxin test 8 weeks post-treatment.\n\nResults\nAll four patients had severe CDI and all improved clinically following one FMT. Sustained resolution following one FMT was observed in one patient. Two patients had recurrence and received a second FMT using capsules; both achieved resolution. One patient who had recurrence declined from further FMT due to fear of relapse and was established on long-term vancomycin. No adverse events related to FMT were observed.\n\nConclusion\nFrail older people may benefit from FMT. Home treatment is a viable option and may be considered both for clinical cure and for palliation.\n\nfaecal microbiota transplantationClostridioides (Clostridium) difficile infectionfrailtyolder peopleInnovation Fund Denmark10.13039/1000127748056-00006B\n==== Body\nKey points\nFrail older people with recurrent C. difficile infection have high morbidity and mortality.\n\nFaecal microbiota transplantation (FMT) may be administered in the patient’s home.\n\nFMT which is offered to older people may be life-saving or palliative.\n\nIntroduction\n\nClostridioides (formerly Clostridium) difficile infection (CDI) is the leading cause of antibiotics-associated diarrhoea and a major health burden [1,2]. Disease severity ranges from mild persistent diarrhoea to life-threatening toxic megacolon and death [3]. From 2000 to 10, CDI incidence has doubled to 700,000 annual cases in Europe and the United States with a concurrent rise in hospitalizations, costs and deaths [2,4–6].\n\nOlder people are particularly prone to acquire CDI. Risk factors such as antibiotics exposure, high age and comorbidity are common in geriatric patients [1,2]. More than 90% of all CDI-attributable deaths occur among comorbid, frail older patients and their risk of severe CDI is increased 3-fold [2,7]. Recurrence develops in 20% following standard vancomycin treatment, and 12% suffer refractory disease, posing a therapeutic challenge [2,8].\n\nFaecal microbiota transplantation (FMT) is a new and effective therapy for recurrent CDI with cure rates > 90% [9,10]. It is recommended for recurrent CDI and may be a rescue treatment for refractory or severe CDI [11]. In recent years, FMT has undergone drastic technical improvements, enabling widespread access to the treatment [12]. Thorough donor screening and application protocols have been implemented [13,14] and ensure safety and sustainability of the service. By convention, FMT requires hospital attendance. Frail older patients who are too weak to tolerate transportation for treatment may therefore be withheld treatment.\n\nSpecialised geriatric teams that provide patient-tailored geriatric care in the patients’ homes have been implemented in most community settings to accommodate the needs of frail older patients. The implementation of acute geriatric teams has reduced admission rates and mortality [15], and it enables risk stratification of the patients. Geriatric teams may successfully handle home treatments such as FMT.\n\nHere, we report our experience with providing FMT as a home treatment in a nursing home setting in four critically ill, geriatric patients with CDI.\n\nMethods\nThis was a single-centre clinical collaboration between the specialised geriatric team and an established FMT programme [13] at a teaching university hospital.\n\nThe geriatric team comprised a geriatrician and a trained geriatric homecare nurse. All patients were assessed at the first home visit following discharge, using the Multidimensional Prognostic Index (MPI) as a cumulative frailty assessment [16]. We used the MPI to describe the patients’ frailty level as low, moderate or severe. The MPI is based on subscores from eight domains, i.e. social status, medication, activities of daily living, mobility, cognitive status, risk of pressure sores, morbidity and nutritional risk. Each domain is assigned a score between 0 and 1 with different lowest and highest scores, leading to different domain weights. The MPI is calculated as the mean of the domain subscores. Three levels of MPI are identified according to validated cut-offs for the risk of mortality: values from 0 to 0.33 are considered as low, 0.34 to 0.66 as moderate and 0.67 to 1.0 as severe [17]. A Danish version of the MPI was translated and validated from the English version.\n\nCDI was identified by the geriatric team during post-discharge visits. Patients with unresolving diarrhoea, defined as three or more liquid stools per day, had stool samples taken for intestinal pathogens and a single-test algorithm polymerase chain reaction test for C. difficile toxin A, toxin B, or binary toxin. In patients with a positive C. difficile toxin test, antibiotic treatment was initiated. The CDI severity was evaluated according to clinical guidelines [3] and was considered refractory if the diarrhoea persisted or worsened beyond 6 days of antibiotic treatment.\n\nAt our institution, an FMT programme has been implemented since 2014 [13,18]. FMT was carried out using either nasojejunal tube delivery or glycerol-based enterocapsules with frozen-thawed, single donor faeces from thoroughly screened healthy blood donors [19]. FMT for nasojejunal tube delivery was processed as previously described [13] with ~50 g of crude donor faeces being processed into a 200 ml solution stored in a 500 ml cryobag (CryoMACS®, Miltenyi Biotec, Bergisch Gladbach, Germany). For the encapsulated FMT, ~21–25 g of crude donor faeces was diluted with sterile saline and glycerol, concentrated during a three-step centrifugation protocol and dispersed into double-coated, acid-resistant enterocapsules (Capsugel® VcapsTM size 0 og 00, Lonza Biopharmaceuticals, Colmar, France).\n\nDelivery mode for each FMT was decided according to the clinical state of the patient. Patients deemed too frail to swallow capsules or with signs of gastroparesis were offered FMT by nasojejunal tube delivery, and encapsulated FMT was offered in all other cases. The nasojejunal tube delivery required tube insertion the day prior to the treatment, overnight fasting and radiologic imaging verification of intestinal position. Radiologic verification of intestinal tube placement was performed in the patient’s home by an outgoing X-ray service. FMT required 6-hour fasting and cessation of proton pump inhibitors for 2 days. With nasojejunal delivery, the faecal solution was instilled at ambient temperature over 10 min. With encapsulated delivery, the 30 enterocapsules were ingested orally over 30 min with apple juice, acidic with a pH of 3 to prevent gastric capsule dissolution.\n\nPatients were evaluated Week 1 and 8 following treatment, and the primary outcome was clinical resolution of diarrhoea with a negative C. difficile toxin test at Week 8. All patients were monitored closely the days following FMT, for clinical improvement and potential adverse reactions. All patients gave written informed consent to the treatment and to presentation of their treatment course. This study was carried out as a part of the observational cohort study, Fecal Microbiota Transplantation (FMT) for Clostridium difficile (CEFTA), registered at www.ClinicalTrials.gov (study identifier NCT03712722).\n\nResults\nFour consecutive older patients who were admitted to a nursery home and developed CDI received a patient-tailored home FMT regimen. All had severe comorbidities and were rated as severely frail (Table 1). In two patients, FMT was indicated by treatment-refractory primary CDI with rapid clinical deterioration. In the other two, the indication was recurrence of CDI with severe disease defined as abdominal pain, leukocytosis and hypoalbuminaemia. In all four, the joint evaluation by the geriatric team was that the infection was imminently life-threatening.\n\nTable 1 Patient characteristics in four frail older patients who received FMT as a home treatment. The MPI is a cumulative frailty assessment tool validated in a Danish department of geriatrics, and individual scores were converted to low, moderate or severe degree of frailty\n\nNo.\tGender, age\tPrevious history\tIncident\tFrailty level\tAntibiotics before CDI\tInitial CDI presentation\tClinical course following FMT\t\n1\tFemale 85 years\tAtrial fibrillation, hypothyroidism, upper gastrointestinal bleeding\tChest pain and fever, cholangitis\tSevere\tPiperacillin-tazobactam, ciprofloxacin, cefuroxim, pivmecillinam\tSevere, C. difficile toxin A/B, initial resolution. Recurrence within 1 week, severe CDI with abdominal pain, refractory to vancomycin\tTube-delivered FMT with complete recovery and negative C. difficile test\t\n2\tFemale 93 years\tHypertension, atrial fibrillation, recent stroke\tFall with rhabdomyolysis\tSevere\tCefuroxim, pivmecillinam\tSevere, C. difficile toxin A/B, refractory to metronidazole and vancomycin, with general deterioration. Severe bradycardia, but pacemaker implantation not possible due to CDI\tTube-delivered FMT with instant improvement. Pacemaker inserted. Recurrence following prophylactic antibiotics. Second FMT delivered by capsules, complete recovery\t\n3\tMale 88 years\tAtrial fibrillation, biological aortic valve, ischaemic heart disease\tFall and wound infection\tSevere\tDicloxacillin, penicillin, cefuroxim, meropenem, trimopan\tSevere, C. difficile toxin A/B, initial resolution with metronidazole. Recurrence after 2 weeks, rapid decline despite vancomycin\tTube-delivered FMT with clinical resolution. Recurrence after 2 months, vancomycin no effect. Capsule FMT for refractory CDI with complete recovery\t\n4\tFemale 92 years\tHypertension, diabetes mellitus, polymyalgia, renal failure\tFall with rhabdomyolysis, hip fracture\tSevere\tPiperacillin-tazobactam\tSevere, C. difficile toxin A/B, no effect of vancomycin, deterioration with immobilisaiton, anorexia, confusion, leukocytosis\tTube-delivered FMT, complete recovery. Recurrence following pivmecillinam for UTI, improvement with vancomycin. Feared further recurrences, established on long-term vancomycin\t\nAll patients experienced marked clinical improvements in the days following their FMT, with increased mobility and arousal and normalisation of bowel habits. Sustained resolution at Week 8 following one FMT was observed in one of four patients. Two patients received antibiotics and had CDI recurrence. They both received a second FMT using capsules and achieved resolution. One patient with recurrence declined further FMT due to fear of another relapse, and because she tolerated vancomycin she was prescribed long-term vancomycin treatment. No adverse events related to FMT were observed during follow-up.\n\nThe clinical courses of the four patients are summarised in Table 1.\n\nDiscussion\nIn this study, we present four cases of severely ill, older patients who were successfully treated with FMT in their homes as a life-saving therapy for refractory or recurrent CDI. All four patients were weakened to a degree where they could not tolerate hospitalisation. Our results provide the proof of principle how current FMT programmes may collaborate with specialised geriatric teams to extend their reach to those most in need.\n\nOlder patients are particularly vulnerable to CDI. As illustrated here, older people with CDI rapidly and progressively lose function with affection of multiple organs. CDI should be suspected on broad indications, and vancomycin treatment should be started promptly and according to published guidelines [11]. Our results are in accordance with a previous study demonstrating that the high effect of FMT also applies to the geriatric population with recurrent CDI [7]. Importantly, the present paradigm only to use FMT for patients with their third or fourth recurrence is problematic in this population because not all older patients survive their first recurrence or even their initial CDI. All patients in the present study showed a marked and immediate clinical improvement following their first FMT. A crude evaluation of bowel habits and C. difficile toxin tests may be insufficient to identify the overall effect of providing FMT to this population. The results and the limited number of patients call for further clinical trials, and we suggest that future studies in older people include validated indices of general performance and function, such as the MPI and muscle strength parameters such as hand grip strength.\n\nIn the present study, we used FMT delivered by capsules or tube. Both methods have pros and cons. Although tube delivery requires tube insertion and X-ray control, capsule ingestion requires intact gastric emptying. Treatment effects are similar with the two methods [20], but a higher load of donor faeces may be applied using tube delivery. This may be relevant in patients with a high risk of relapse, e.g. those with liver cirrhosis or anaemia [10,21]. In each patient, a risk-benefit balance should guide a joint treatment decision. Particular attention should be paid to patients with refractory disease, i.e. those who do not improve clinically with vancomycin. The optimal treatment regimen for these patients remains to be determined, but it may include early FMT [14]. It also underpins that only patients who respond well to vancomycin should be considered for long-term maintenance treatment.\n\nIn conclusion, home treatment with FMT may successfully be provided to frail older patients with CDI who cannot tolerate hospital admission. Patient assessment and monitoring from a specialised geriatric team and collaboration with an FMT centre enable a balanced treatment approach that may be both life-saving and cost-effective.\n\nDeclaration of Conflicts of Interest\nNone.\n\nFunding\nThe study was in part funded by Innovation Fund Denmark (grant no. 8056-00006B). The funder was not involved in study design, data collection, analysis of data, manuscript drafting or submission.\n==== Refs\nReferences\n1. \nBauer MP , Notermans DW , Benthem BH van et al. Clostridium difficile infection in Europe: a hospital-based survey\n. Lancet 2011 ; 377 : 63 –73\n.21084111 \n2. \nLessa FC , Mu Y , Bamberg WM et al. Burden of Clostridium difficile infection in the United States\n. N Engl J Med 2015 ; 372 : 825 –34\n.25714160 \n3. \nSurawicz CM , Brandt LJ , Binion DG et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections\n. Am J Gastroenterol 2013 ; 108 : 478 –98\n.23439232 \n4. \nLeffler DA , Lamont JT \nClostridium difficile infection\n. N Engl J Med 2015 ; 372 : 1539 –48\n.25875259 \n5. \nMagill SS , O'Leary E , Janelle SJ et al. Changes in prevalence of health care-associated infections in U.S. hospitals\n. N Engl J Med 2018 ; 379 : 1732 –44\n.30380384 \n6. \nEuropean Centre for Disease Prevention and Control \nHealthcare-associated infections: Clostridium difficile infections In: ECDC. Annual Epidemiological Report for 2016 . Stockholm :\nECDC , 2018 .\n7. \nGirotra M , Garg S , Anand R et al. Fecal microbiota transplantation for recurrent Clostridium difficile infection in the old: long-term outcomes and microbiota changes\n. Dig Dis Sci 2016 ; 61 : 3007 –15\n.27447476 \n8. \nHenrich TJ , Krakower D , Bitton A et al. Clinical risk factors for severe Clostridium difficile-associated disease\n. Emerg Infect Dis 2009 ; 15 : 415 –22\n.19239754 \n9. \nNood E van, Vrieze A , Nieuwdorp M et al. Duodenal infusion of donor feces for recurrent Clostridium difficile\n. N Engl J Med 2013 ; 368 : 407 –15\n.23323867 \n10. \nHvas CL , Jørgensen SMD , Jørgensen SP et al. Fecal microbiota transplantation is superior to fidaxomicin for treatment of recurrent Clostridium difficile infection\n. Gastroenterology 2019 ; 156 : 1324 –32\n.30610862 \n11. \nMcDonald LC , Gerding DN , Johnson S et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)\n. Clin Infect Dis 2018 ; 66 : 987 –94\n.29562266 \n12. \nAllegretti JR , Kassam Z , Fischer M et al. Risk factors for gastrointestinal symptoms following successful eradication of Clostridium difficile by fecal microbiota transplantation (FMT)\n. J Clin Gastroenterol 2019 ; 53 : e405 –8\n.30882536 \n13. \nJørgensen SMD , Hansen MM , Erikstrup C et al. Faecal microbiota transplantation: establishment of a clinical application framework\n. Eur J Gastroenterol Hepatol 2017 ; 29 : 36 –45\n.27556687 \n14. \nMullish BH , Quraishi MN , Segal JP et al. The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridium difficile infection and other potential indications: joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines\n. Gut 2018 ; 67 : 1920 –41\n.30154172 \n15. \nPedersen LH , Gregersen M , Barat I et al. Early geriatric follow-up after discharge reduces mortality among patients living in their own home. A randomised controlled trial\n. Eur Ger Med 2016 ; 8 : 330 –6\n.\n16. \nPilotto A , Ferrucci L , Franceschi M et al. Development and validation of a Multidimensional Prognostic Index for one-year mortality from comprehensive geriatric assessment in hospitalized older patients\n. Rejuvenation Res 2008 ; 11 : 151 –61\n.18173367 \n17. \nVolpato S , Bazzano S , Fontana A et al. Multidimensional Prognostic Index predicts mortality and length of stay during hospitalization in the older patients: a multicenter prospective study\n. J Gerontol A Biol Sci Med Sci 2015 ; 70 : 325 –31\n.25209253 \n18. \nJørgensen SMD , Hvas CL , Dahlerup JF et al. Banking feces: a new frontier for public blood banks?\n Transfusion 2019 ; 59 : 2776 –82\n.31241182 \n19. \nJørgensen SMD , Erikstrup C , Dinh KM et al. Recruitment of feces donors among blood donors: results from an observational cohort study\n. Gut Microbes 2018 ; 9 : 540 –50\n.29617178 \n20. \nKao D , Roach B , Silva M et al. Effect of oral capsule- vs colonoscopy-delivered fecal microbiota transplantation on recurrent Clostridium difficile infection: a randomized clinical trial\n. Jama 2017 ; 318 : 1985 –93\n.29183074 \n21. \nPringle PL , Soto MT , Chung RT et al. Patients with cirrhosis require more fecal microbiota capsules to cure refractory and recurrent Clostridium difficile infections\n. Clin Gastroenterol Hepatol 2019 ; 17 : 791 –3\n.29859984\n\n",
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"issn_linking": "0002-0729",
"issue": "49(6)",
"journal": "Age and ageing",
"keywords": "\n Clostridioides (Clostridium) difficile infection; faecal microbiota transplantation; frailty; older people",
"medline_ta": "Age Ageing",
"mesh_terms": "D000368:Aged; D016360:Clostridioides difficile; D003015:Clostridium Infections; D000069467:Fecal Microbiota Transplantation; D016330:Frail Elderly; D006801:Humans; D012008:Recurrence; D016896:Treatment Outcome",
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"pubdate": "2020-10-23",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Faecal microbiota transplantation as a home therapy to frail older people.",
"title_normalized": "faecal microbiota transplantation as a home therapy to frail older people"
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"abstract": "BACKGROUND\nTuberculosis (TB) reactivation has been increasingly identified following immune checkpoint inhibitor (ICI) therapy for cancer patients. However there has been no report on TB reactivation in the gastrointestinal tract. In the report, we describe a patient who developed TB ileitis after pembrolizumab for her metastatic nasopharyngeal carcinoma (NPC). Rechallenge with pembrolizumab after its temporary interruption together with anti-TB therapy produced continuous tumor response but without further TB reactivation.\n\n\nMETHODS\nA 29-year-old lady with metastatic NPC involving the cervical nodes, lungs and bones started pembrolizumab after failure to multiple lines of chemotherapy. She complained of sudden onset of abdominal pain, vomiting and bloody diarrhea with mucus 21 months after pembrolizumab. Colonoscopy revealed terminal ileitis with multiple caseating granulomas with Langerhan cells. Serum interferon gamma release assay was strongly positive. She was treated with anti-TB medication and was later rechallenged with pembrolizumab for her progressive lung metastases without further TB relapse while her lung metastases were brought under control again.\n\n\nCONCLUSIONS\nTo date, this is the first gastrointestinal TB reactivation after ICI therapy for cancer. Guidelines to screen for TB before initiation of ICIs in endemic areas should be established.",
"affiliations": "Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.;Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.;Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.;Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.;Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.;Department of Pathology, Queen Mary Hospital, Hong Kong, China.;Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.;Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.;Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.;Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.;Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.;Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.;Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.;Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. vhflee@hku.hk.",
"authors": "Lau|Kin-Sang|KS|;Cheung|Ben Man-Fei|BM|;Lam|Ka-On|KO|;Chan|Sum-Yin|SY|;Lam|Ka-Ming|KM|;Yeung|Chun-Fai|CF|;Hung|Ivan Fan-Ngai|IF|;Kwong|Dora Lai-Wan|DL|;Tong|Chi-Chung|CC|;Leung|To-Wai|TW|;Luk|Mai-Yee|MY|;Lee|Anne Wing-Mui|AW|;Yuen|Kwok-Keung|KK|;Lee|Victor Ho-Fun|VH|http://orcid.org/0000-0002-6283-978X",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000082082:Immune Checkpoint Inhibitors; C582435:pembrolizumab",
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"doi": "10.1186/s12879-021-06845-7",
"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect Dis\nBMC Infectious Diseases\n1471-2334\nBioMed Central London\n\n6845\n10.1186/s12879-021-06845-7\nCase Report\nTuberculosis reactivation at ileum following immune checkpoint inhibition with pembrolizumab for metastatic nasopharyngeal carcinoma: a case report\nLau Kin-Sang 1\nCheung Ben Man-Fei 1\nLam Ka-On 1\nChan Sum-Yin 1\nLam Ka-Ming 1\nYeung Chun-Fai 2\nHung Ivan Fan-Ngai 3\nKwong Dora Lai-Wan 1\nTong Chi-Chung 1\nLeung To-Wai 1\nLuk Mai-Yee 1\nLee Anne Wing-Mui 1\nYuen Kwok-Keung 1\nhttp://orcid.org/0000-0002-6283-978X\nLee Victor Ho-Fun vhflee@hku.hk\n\n1\n1 grid.194645.b 0000000121742757 Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China\n2 grid.415550.0 0000 0004 1764 4144 Department of Pathology, Queen Mary Hospital, Hong Kong, China\n3 grid.194645.b 0000000121742757 Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China\n10 11 2021\n10 11 2021\n2021\n21 114818 1 2021\n4 11 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nTuberculosis (TB) reactivation has been increasingly identified following immune checkpoint inhibitor (ICI) therapy for cancer patients. However there has been no report on TB reactivation in the gastrointestinal tract. In the report, we describe a patient who developed TB ileitis after pembrolizumab for her metastatic nasopharyngeal carcinoma (NPC). Rechallenge with pembrolizumab after its temporary interruption together with anti-TB therapy produced continuous tumor response but without further TB reactivation.\n\nCase presentation\n\nA 29-year-old lady with metastatic NPC involving the cervical nodes, lungs and bones started pembrolizumab after failure to multiple lines of chemotherapy. She complained of sudden onset of abdominal pain, vomiting and bloody diarrhea with mucus 21 months after pembrolizumab. Colonoscopy revealed terminal ileitis with multiple caseating granulomas with Langerhan cells. Serum interferon gamma release assay was strongly positive. She was treated with anti-TB medication and was later rechallenged with pembrolizumab for her progressive lung metastases without further TB relapse while her lung metastases were brought under control again.\n\nConclusion\n\nTo date, this is the first gastrointestinal TB reactivation after ICI therapy for cancer. Guidelines to screen for TB before initiation of ICIs in endemic areas should be established.\n\nKeywords\n\nNasopharyngeal carcinoma\nImmune checkpoint inhibitors\nTuberculosis reactivation\nIGRA\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nImmune checkpoint inhibitors (ICI) against programmed death-(ligand)1 (PD-(L)1) and cytotoxic T-lymphocyte-associated antigen 4 have gained increasing popularity for various malignancies [1]. Despite improvement in progressive-free survival and overall survival particularly in melanoma and lung cancer, immune-related adverse events (irAE) have also been increasingly reported [2]. There has a dozen of case reports of tuberculosis (TB) reactivation after ICI therapy so far, including two patients who developed pulmonary TB reactivation during ICI therapy for their metastatic nasopharyngeal carcinoma (NPC) [3–15]. However, the incidence of TB reactivation after ICI therapy is western countries is exceedingly rare [16]. Here, we report a patient with metastatic NPC who developed TB ileitis during pembrolizumab therapy and was subsequently treated with a full course of anti-TB antibiotics with temporary ICI interruption. She was successfully re-challenged with pembrolizumab during anti-TB treatment, with her tumours still in continuous response. Various strategies on identifying latent TB infection before initiation of anti-TB prophylaxis are proposed.\n\nCase presentation\n\nA 29-year-old lady was diagnosed with metastatic NPC with cervical nodal, lung and bone metastases in December 2014. Her disease progressed despite multiple lines of chemotherapy including gemcitabine and cisplatin (3 cycles from December 2014 to March 2015)cisplatin plus 5-fluorouracil (1 cycle in April 2015) which was changed to docetaxel plus cisplatin because of 5-fluorouracil allergy (3 cycles from April 2015 to June 2015), gemcitabine and carboplatin (6 cycles from November 2015 to March 2016) capecitabine (6 cycles from April 2016 to August 2016), and metronomic cyclophosphamide (from August 2016 to September 2016). Radical chemoradiation with cisplatin was given to her progressive neck nodes in July 2015. Her lung metastases later further progressed resulting in mild dyspnea and her plasma Epstein-Barr virus (EBV) deoxyribonucleic acid (DNA) rose from 4919 to 119,125 copies/ml (Fig. 1a). Pembrolizumab, an anti-PD-1 inhibitor was considered owing to very limited further treatment options. Her archived neck lymph node specimens sent for PD-L1 expression with immunohistochemical staining revealed that the tumor proportion score was 100 and the combined positive score was 101, indicating that a promising response to ICI was expected. She denied any past medical history of tuberculosis. She then received pembrolizumab at 2 mg/kg every three weeks since September 2016. Her dyspnea and lung metastases improved and reduced in number dramatically after only two cycles of pembrolizumab, accompanied by a slump of EBV DNA to 83 copies/ml (Fig. 1b). She experienced mild irAEs with hypocortisolism and hypothyroidism which were effectively managed with hormone replacement therapy. In May 2018, she presented with a sudden onset of severe, colicky and localized right lower abdominal pain, projectile vomiting and bloody diarrhea with mucus, and persistent fever (temperature > 38.6 degrees Celsius). Initially immune-related enteritis/colitis was suspected and pembrolizumab was suspended. Positron emission tomography with integrated computed tomography (PET-CT) of the abdomen showed terminal ileitis with multiple enlarged mesenteric lymph nodes Colonoscopy was performed and the inflamed terminal ileum was biopsied, which exhibited multiple caseating granulomas with Langerhan cells, compatible with tuberculous ileitis (microscopic images captured by Nikon model DS-FI3 attached to Nikon Eclipse Ni microscope viewed by Application DS-L4 Viewer Software Ver1.2.0) (Fig. 2a). Otherwise, the pathology did not show any features of inflammatory bowel disease or immune-related enteritis. Though Ziehl–Neelsen stain did not identify any acid-fast bacilli, polymerase chain reaction test for TB of the ileal biopsy and interferon gamma release assay (IGRA) with QuantiFERON TB Gold Plus were both strongly positive. She immediately received anti-TB medication including rifampicin, ethambutol, pyrazinamide and isoniazid for 1 year following our microbiologist’s suggestion. Her terminal ileitis and the enlarged mesenteric lymphadenitis resolved in the follow-up PET-CT scan 9 months later. Colonoscopy performed 15 months after the last one confirmed complete resolution of her ileitis (Fig. 2b).Fig. 1 Serial positron emission tomography with integrated computed tomography images showing response to lung metastases before and after pembrolizumzb treatment, interruption and rechallenge during and after anti-tuberculosis (TB) therapy. a Multiple bilateral lung metastases before pembrolizumab treatment. b Marked reduction in size and number of lung metastases after pembrolizumab treatment. c Enlarging lung metastases after pembrolizumab interruption due to TB reactivation. d Tumour shrinkage after re-challenge with pembrolizumab\n\nFig. 2 Ileal biopsies of our patient who developed tuberculosis (TB) reactivation after pembrolizumab and resolution after anti-TB therapy (image resolution 2880 × 2048 without additonal processing made). a TB ileitis with small well-formed caseating granulomas after pembrolizumab. b Resolution of TB ileitis after initiation of anti-TB medication and pembrolizumb interruption\n\nHowever, her lung metastases worsened again 7 months after anti-TB treatment (Fig. 1c), concurrent with an elevated plasma EBV DNA of 2826 copies/ml following pembrolizumab interruption. In light of her current progressive metastases and the prior extraordinary response to pembrolizumab, she was re-challenged with pembrolizumab in December 2018 together with her anti-TB treatment. PET-CT scan 5 months later showed promising tumour shrinkage (Fig. 1d). She is still receiving pembrolizumab with no evidence of TB relapse or other irAE.\n\nDiscussion and conclusions\n\nNPC, which is highly associated with EBV infection, is endemic in southern China including Hong Kong with an incidence of more than 20.0 per 100,000 [17]. Platinum-based chemotherapy is the standard first-line treatment for recurrent/metastatic NPC. Unfortunately, almost all patients relapse despite an initial response to chemotherapy. ICI alone, or in combination with systemic chemotherapy has established itself as an efficacious first- and second-line treatment in recurrent/metastatic head and neck squamous cell carcinoma. However, its role in recurrent/metastatic NPC is less defined. The phase I KEYNOTE-028 trial revealed an objective response of 26.3% with pembrolizumab [18]. Tumor response was highly correlated with PD-L1 expression in tumor cells.\n\nMeanwhile, TB is also a notifiable and endemic disease in Hong Kong, with the notification rate of 54.0 per 100,000 population in 2019 [19], compared to 2.8 per 100,000 in the United States. It may remain latent for years or even decades. Containment of TB in its latent state is achieved through the surveillance of TB-directed CD4 + and CD8 + T cells [20], which happen to be the targets of ICIs. Indeed, the pathophysiology of TB reactivation following ICI therapy is complex and poorly understood, which involves both innate and acquired immune responses [15]. On one hand, exposure to TB leads to increased PD-1 and PD-L1 expression on natural killer (NK) cells of the innate system, resulting in release of interferon-γ (IFNγ) and cell lysis. Subsequent binding of PD-1 to PD-L1 and PD-L2 might inhibit further activation of NK cells, which prevents further tissue damage brought by inflammation. On the other hand, TB can also use the acquired immune response to avoid the host immune response by preventing IFNγ release and inhibiting CD8 + cell cytotoxicity via increased PD-1 expression. PD-1/PD-L1 inhibition by ICI, was shown in vitro to enhance CD8 + cell cytotoxicity against IFNγ-activated macrophages, leading to TB reactivation.\n\nThere have been some reports of TB reactivation following ICI therapy [3–15]. Intriguingly, patients in these reports who developed TB reactivation were those whose tumors also responded well to ICIs. It is postulated that TB reactivation which symbolizes an exaggerated immune response in the host might also predict a favorable tumor response to ICI therapy, though further studies are warranted to confirm such correlation.\n\nA recent retrospective review using the US Food and Drug Administration Adverse Events Reporting System revealed that TB infection was only seen in 0.1% of patients after PD-1/PD-L1 therapy [16]. That said, the incidence would be much higher in TB-endemic regions. While international and local guidelines on screening TB before initiation of biological agents including anti-tumor necrosis factor-α (TNFα) for several chronic inflammatory diseases like rheumatoid arthritis have been published [21, 22], consensus on routine screening for TB before ICI therapy for cancer patients is still lacking. Chest radiograph and tuberculin test are recommended screening tools in these guidelines before anti-TNFα therapy. However, they may not be sensitive to diagnose acute/latent TB infection in cancer patients who are often immunocompromised and are also the high-risk groups more susceptible to TB reactivation after ICI therapy [23].\n\nIGRA by detecting IFNγ released by T cells exposed to TB antigens, has been found more sensitive than the traditional methods to diagnose acute and latent TB, even in immunocompromised patients [24, 25]. New generations of IGRA were found even more sensitive than their earlier generations [24, 25]. Hopefully, international recommendations on TB screening with accurate and reliable methods before ICI initiation for cancer patients can be proposed and implemented routinely in TB-endemic regions.\n\nIn conclusion, we report the first gastrointestinal TB reactivation following ICI therapy for metastatic NPC. Accurate TB screening methods should be considered for latent TB infection before ICI therapy for cancer patients.\n\nAbbreviations\n\nDNA Deoxyribonucleic acid\n\nEBV Epstein–Barr virus\n\nICI Immune checkpoint inhibitors\n\nIFNγ Interferon-γ\n\nIGRA Interferon gamma release assay\n\nirAE Immune-related adverse events\n\nNK Natural killer\n\nNPC Nasopharyngeal carcinoma\n\nPD-1 Programmed death-1\n\nPD-L1 Programmed death-(ligand)1\n\nPET-CT Positron emission tomography with integrated computed tomography\n\nTB Tuberculosis\n\nTNFα Tumour necrosis factor-α\n\nAcknowledgements\n\nNot applicable.\n\nAuthors' contributions\n\nKSL, BMFC, CFY and VHFL were major contributors in writing this manuscript. KSL, BMCF, KOL, SYC, KM Lam, CFY, IFNH, DLWK, CCT, TWL, MYL, AWML, KKY and VHFL participated in the diagnosis and treatment of the patient, conceptualized the study, and acquired and interpreted the study data. VHFL conceived the study and oversaw the manuscript. All authors read and approved the final manuscript.\n\nFunding\n\nThere was no funding for this study.\n\nAvailability of data and materials\n\nThe datasets analyzed during the current study are not publicly available due to patient privacy concerns but are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nThe patient provided a written informed consent for the personal and clinical details along with any identifying images to be published in this study.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nKin-Sang Lau and Ben Man-Fei Cheung contributed equally to this manuscript\n==== Refs\nReferences\n\n1. Sunshine J Taube JM PD-1/PD-L1 inhibitors Curr pin Pharmacol 2015 23 32 38 10.1016/j.coph.2015.05.011\n2. Michot JM Bigenwald C Champiat S Collins M Carbonnel F Postel-Vinay S Immune-related adverse events with immune checkpoint blockade: a comprehensive review Eur J Cancer 2016 54 139 148 10.1016/j.ejca.2015.11.016 26765102\n3. 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 4 519 520 10.3109/0284186X.2015.1125017 26754959\n4. Chu YC Fang KC Chen HC Yeh YC Tseng CN 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 8 e111 e114 10.1016/j.jtho.2017.03.012 28748816\n5. Fujita K Uchida N Horimoto K Hashimoto M Nakatani K Moriyoshi K Two cases of cavitary lung cancer with concomitant chronic infectious disease Respir Med Case Rep 2018 24 122 124 29977778\n6. 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 3 216 218 10.1016/j.cmi.2017.12.003 29269089\n7. 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 8 1127 1128 10.1080/0284186X.2018.1433877 29384034\n8. 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 OncoTargets Ther 2018 11 7423 7427 10.2147/OTT.S178246\n9. 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 1 54 58 10.1016/j.jiac.2018.06.016 30055859\n10. Tsai CC Chen JH Wang YC Chang FY Re-activation of pulmonary tuberculosis during anti-programmed death-1 (PD-1) treatment QJM 2019 112 1 41 42 10.1093/qjmed/hcy243 30351391\n11. van Eeden R Rapoport BL Smit T Anderson R Tuberculosis infection in a patient treated with nivolumab for non-small cell lung cancer: case report and literature review Front Oncol 2019 9 659 10.3389/fonc.2019.00659 31396484\n12. Inthasot V Bruyneel M Muylle I Ninane V Severe pulmonary infections complicating nivolumab treatment for lung cancer: a report of two cases Acta Clin Belg 2020 75 4 308 310 10.1080/17843286.2019.1629078 31179880\n13. Barber DL Sakai S Kudchadkar RR Fling SP Day TA Vergara JA Tuberculosis following PD-1 blockade for cancer immunotherapy Sci Transl Med. 2019 11 475 eaat2702 10.1126/scitranslmed.aat2702 30651320\n14. Song JS Jeffery CC Laryngeal tuberculosis in a patient on avelumab for metastatic nasopharyngeal carcinoma J Immunother 2020 43 7 222 223 10.1097/CJI.0000000000000324 32780576\n15. Langan EA Graetz V Allerheiligen J Zillikens D Rupp J Terheyden P Immune checkpoint inhibitors and tuberculosis: an old disease in a new context Lancet Oncol 2020 21 1 e55 65 10.1016/S1470-2045(19)30674-6 31908308\n16. Anand K Sahu G Burns E Ensor A Ensor J Pingali SR Mycobacterial infections due to PD-1 and PD-L1 checkpoint inhibitors ESMO Open. 2020 5 4 e000866 10.1136/esmoopen-2020-000866 32817069\n17. Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2018 68 6 394 424 10.3322/caac.21492 30207593\n18. Hsu C Lee SH Ejadi S Even C Cohen RB Le Tourneau C Safety and antitumor activity of pembrolizumab in patients with programmed death-ligand 1-positive nasopharyngeal carcinoma: results of the KEYNOTE-028 study J Clin Oncol 2017 35 36 4050 4056 10.1200/JCO.2017.73.3675 28837405\n19. Centre for Health Protection. Notification & death rate of tuberculosis (all forms), 1947-2019. Available from: https://www.chp.gov.hk/en/statistics/data/10/26/43/88.html. Assessed 30 Dec 2020.\n20. O'Garra A Redford PS McNab FW Bloom CI Wilkinson RJ Berry MP The immune response in tuberculosis Annu Rev Immunol 2013 31 475 527 10.1146/annurev-immunol-032712-095939 23516984\n21. British Thoracic Society Standards of Care Committee BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-alpha treatment Thorax 2005 60 10 800 805 10.1136/thx.2005.046797 16055611\n22. Wang PH Lin CH Chang TH Wu CS Chest roentgenography is complementary to interferon-gamma release assay in latent tuberculosis infection screening of rheumatic patients BMC Pulm Med 2020 20 1 232 10.1186/s12890-020-01274-9 32867745\n23. Kim EY Lim JE Jung JY Son JY Lee KJ Yoon YW Performance of the tuberculin skin test and interferon-gamma release assay for detection of tuberculosis infection in immunocompromised patients in a BCG-vaccinated population BMC Infect Dis 2009 9 207 10.1186/1471-2334-9-207 20003535\n24. Della Bella C Spinicci M Alnwaisri HFM Bartalesi F Tapinassi S Mencarini J LIOFeronTB/LTBI: A novel and reliable test for LTBI and tuberculosis Int J Infect Dis 2020 91 177 181 10.1016/j.ijid.2019.12.012 31877486\n25. Sotgiu G Saderi L Petruccioli E Aliberti S Piana A Petrone L QuantiFERON TB Gold Plus for the diagnosis of tuberculosis: a systematic review and meta-analysis J Infect 2019 79 5 444 453 10.1016/j.jinf.2019.08.018 31473271\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "21(1)",
"journal": "BMC infectious diseases",
"keywords": "IGRA; Immune checkpoint inhibitors; Nasopharyngeal carcinoma; Tuberculosis reactivation",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D006801:Humans; D007082:Ileum; D000082082:Immune Checkpoint Inhibitors; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms; D009364:Neoplasm Recurrence, Local; D014376:Tuberculosis",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "1148",
"pmc": null,
"pmid": "34758746",
"pubdate": "2021-11-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31908308;29977778;29269089;31396484;26765102;30351391;20003535;32780576;30651320;28837405;28748816;30207593;29384034;32867745;23516984;31877486;30425530;32817069;26754959;16055611;31473271;30055859;26047524;31179880",
"title": "Tuberculosis reactivation at ileum following immune checkpoint inhibition with pembrolizumab for metastatic nasopharyngeal carcinoma: a case report.",
"title_normalized": "tuberculosis reactivation at ileum following immune checkpoint inhibition with pembrolizumab for metastatic nasopharyngeal carcinoma a case report"
} | [
{
"companynumb": "HK-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-325045",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
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{
"abstract": "BACKGROUND\nLimited data are available regarding the 95% effective dose (ED95 ) of remifentanil to prevent the cough response during emergence from general anesthesia in children.\n\n\nMETHODS\nThis study included 40 patients aged 3-12 years who underwent elective tonsillectomy with or without adenoidectomy. A predetermined remifentanil dose was infused continuously with desflurane during surgery and was continued until extubation. In the emergence period, the cough response during awake extubation was assessed to determine the remifentanil dose for the next patient. The first patient received remifentanil at the rate of 0.01 μg·kg(-1) ·min(-1) , and subsequent patients received a 0.01 μg·kg(-1) ·min(-1) higher dose than the previous patient if there was more than moderate coughing detected, and the patient after those with less than mild coughing received either the same dose (95% probability) or a 0.01 μg·kg(-1) ·min(-1) lower dose (5% probability) using the biased coin design. Times to extubation and adverse events were recorded. The ED95 was calculated using the maximum-likelihood estimation.\n\n\nRESULTS\nThe ED95 of remifentanil for preventing coughing during extubation was 0.060 μg·kg(-1) ·min(-1) (95% confidence interval, 0.037-0.068). There was moderate coughing in all groups receiving 0.01-0.06 μg·kg(-1) ·min(-1) of remifentanil, but no cough response occurred in the group receiving remifentanil 0.07 μg·kg(-1) ·min(-1) . Time to extubation was weakly correlated with remifentanil infusion rate (r = 0.331). One patient who received remifentanil 0.07 μg·kg(-1) ·min(-1) showed desaturation over 5 s immediately after extubation, but recovered after receiving 100% oxygen.\n\n\nCONCLUSIONS\nThe ED95 of the continuous remifentanil infusion rate was 0.060 μg·kg(-1) ·min(-1) to prevent the cough response during extubation in children after tonsillectomy.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Chung-Ang University Hospital, Seoul, Korea.",
"authors": "Park|Yong-Hee|YH|;Chung|Eun-Jin|EJ|;Lee|Ji-Hyun|JH|;Kim|Jin-Tae|JT|;Kim|Chong-Sung|CS|;Kim|Hee-Soo|HS|",
"chemical_list": "D018686:Anesthetics, Intravenous; D010880:Piperidines; D000077208:Remifentanil",
"country": "France",
"delete": false,
"doi": "10.1111/pan.12616",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1155-5645",
"issue": "25(6)",
"journal": "Paediatric anaesthesia",
"keywords": "children; coughing; remifentanil; tonsillectomy",
"medline_ta": "Paediatr Anaesth",
"mesh_terms": "D000233:Adenoidectomy; D060666:Airway Extubation; D018686:Anesthetics, Intravenous; D002648:Child; D002675:Child, Preschool; D003371:Cough; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D010880:Piperidines; D000077208:Remifentanil; D014068:Tonsillectomy",
"nlm_unique_id": "9206575",
"other_id": null,
"pages": "567-72",
"pmc": null,
"pmid": "25559991",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Determination of the 95% effective dose of remifentanil for the prevention of coughing during extubation in children undergoing tonsillectomy (with or without adenoidectomy).",
"title_normalized": "determination of the 95 effective dose of remifentanil for the prevention of coughing during extubation in children undergoing tonsillectomy with or without adenoidectomy"
} | [
{
"companynumb": "KR-BAXTER-2015BAX029719",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "REMIFENTANIL"
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"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nMacrophage activation syndrome (MAS) or reactive hemophagocytic lymphohistiocytosis (HLH) refers to a set of clinical symptoms caused by the excessive activation and proliferation of macrophages. It was linked with autoimmune disease such as systemic-onset juvenile rheumatoid arthritis, systemic lupus erythematosus, rheumatoid arthritis, and dermatomyositis, etc. Herein we report a case of myasthenia gravis (MG) with concurrent cytomegalovirus (CMV) infection developed MAS.\n\n\nMETHODS\nA 31-year-old female with history of MG for 2 years under stable control with azathioprine and prednisolone. She presented with persistent high fever for 2 weeks after an upper respiratory infection. Lab data revealed pancytopenia, elevated triglyceride, ferritin and C-reactive protein (CRP). A bone marrow aspiration confirmed hemophagocytosis. Investigation for occult infection revealed her plasma was positive for CMV IgG and IgM, and high for CMV viral load. She was then treated with 5 sessions of plasmapheresis and pulse steroid. Azathioprine was discontinued and replaced with cyclosporine. Gancylovir was given for her concurrent CMV infection. After 2 weeks of treatment, her fever gradually subsided, and her blood cell count, hepatobiliary enzymes, ferritin and CRP have returned to normal range. She was discharged in good recovery.\n\n\nCONCLUSIONS\nMAS is a rare complication of systemic autoimmune disease with poor prognosis, which may be precipitated by concurrent infection. Early recognition of this syndrome and prompt immune modulation therapy is crucial for successful treatment.",
"affiliations": "Department of Neurology, Shin Kong Wu Ho- Su Memorial Hospital.;Department of Neurology, Shin Kong Wu Ho- Su Memorial Hospital.;Department of Neurology, Shin Kong Wu Ho- Su Memorial Hospital.",
"authors": "Huang|Nai-Hsin|NH|;Lien|Li-Ming|LM|;Chen|Wen-Hung|WH|",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1028-768X",
"issue": "29(4)()",
"journal": "Acta neurologica Taiwanica",
"keywords": "Macrophage activation syndrome; cytomegalovirus; hemophagocytic lymphohistiocytosis; myasthenia gravis; myasthenia gravis plasmpaheresis.",
"medline_ta": "Acta Neurol Taiwan",
"mesh_terms": "D000328:Adult; D003586:Cytomegalovirus Infections; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D051359:Lymphohistiocytosis, Hemophagocytic; D055501:Macrophage Activation Syndrome; D009157:Myasthenia Gravis",
"nlm_unique_id": "9815355",
"other_id": null,
"pages": "114-118",
"pmc": null,
"pmid": "34018170",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Macrophage Activation Syndrome in a Case of Myasthenia Gravis with Concurrent Cytomegalovirus Infection.",
"title_normalized": "macrophage activation syndrome in a case of myasthenia gravis with concurrent cytomegalovirus infection"
} | [
{
"companynumb": "US-AMNEAL PHARMACEUTICALS-2021-AMRX-01306",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditio... |
{
"abstract": "Plasmablastic lymphoma (PBL) clinical descriptions are scarce from sub-Saharan Africa (SSA) where both HIV and EBV are highly endemic. We identified 12 patients with pathologically confirmed PBL from a prospective cohort in Lilongwe, Malawi. Median age was 46 (range 26-71), seven (58%) were male, and six (50%) were HIV-positive. Eight patients were treated with CHOP and four with a modified EPOCH regimen. One-year overall survival was 56% (95% CI 24-79%), without clear differences based on HIV status. PBL occurs in Malawi in HIV-positive and HIV-negative individuals and can be treated successfully with curative intent, even in a low-resource setting in SSA.",
"affiliations": "UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi.;UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi.;UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi.;UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi.;UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi.;UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi.;UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi.;UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi.;4Kamuzu Central Hospital, Lilongwe, Malawi.;UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi.;UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi.;UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi.;UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi.;UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi.;UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi.;UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi.;2University of North Carolina, Chapel Hill, USA.;2University of North Carolina, Chapel Hill, USA.;UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi.",
"authors": "Zuze|Takondwa|T|;Painschab|Matthew S|MS|;Seguin|Ryan|R|;Kudowa|Evarista|E|;Kaimila|Bongani|B|;Kasonkanji|Edwards|E|;Tomoka|Tamiwe|T|;Dhungel|Bal Mukunda|BM|;Mulenga|Maurice|M|;Chikasema|Maria|M|;Tewete|Blessings|B|;Ntangwanika|Asekanadziwa|A|;Chiyoyola|Sarah|S|;Chimzimu|Fred|F|;Kampani|Coxcilly|C|;Krysiak|Robert|R|;Montgomery|Nathan D|ND|;Fedoriw|Yuri|Y|;Gopal|Satish|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13027-018-0195-4",
"fulltext": "\n==== Front\nInfect Agent CancerInfect. Agents CancerInfectious Agents and Cancer1750-9378BioMed Central London 19510.1186/s13027-018-0195-4Short ReportPlasmablastic lymphoma in Malawi Zuze Takondwa tzuze@unclilongwe.org 1Painschab Matthew S. Matthew.Painschab@unchealth.unc.edu 12Seguin Ryan rseguin@live.unc.edu 12Kudowa Evarista ekudowa@unclilongwe.org 1Kaimila Bongani bkaimila@unclilongwe.org 1Kasonkanji Edwards ekasonkanji@unclilongwe.org 1Tomoka Tamiwe ttomoka@unclilongwe.org 13Dhungel Bal Mukunda drbmdhungel@gmail.com 12Mulenga Maurice mauricemulenga1@gmail.com 4Chikasema Maria mchikasema@unclilongwe.org 1Tewete Blessings btewete@unclilongwe.org 1Ntangwanika Asekanadziwa antangwanika@unclilongwe.org 1Chiyoyola Sarah schiyoyola@unclilongwe.org 1Chimzimu Fred fchimzimu@unclilongwe.org 1Kampani Coxcilly ckampani@unclilongwe.org 1Krysiak Robert robert_krysiak@med.unc.edu 12Montgomery Nathan D. Nathan.Montgomery@unchealth.unc.edu 2Fedoriw Yuri Yuri.Fedoriw@unchealth.unc.edu 2Gopal Satish +265 1 758 491satish_gopal@med.unc.edu 1231 UNC Project-Malawi, Private Bag, A-104 Lilongwe, Malawi 2 0000 0001 1034 1720grid.410711.2University of North Carolina, Chapel Hill, USA 3 0000 0001 2113 2211grid.10595.38University of Malawi College of Medicine, Blantyre, Malawi 4 0000 0004 0521 7778grid.414941.dKamuzu Central Hospital, Lilongwe, Malawi 28 6 2018 28 6 2018 2018 13 2223 5 2018 22 6 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Plasmablastic lymphoma (PBL) clinical descriptions are scarce from sub-Saharan Africa (SSA) where both HIV and EBV are highly endemic. We identified 12 patients with pathologically confirmed PBL from a prospective cohort in Lilongwe, Malawi. Median age was 46 (range 26–71), seven (58%) were male, and six (50%) were HIV-positive. Eight patients were treated with CHOP and four with a modified EPOCH regimen. One-year overall survival was 56% (95% CI 24–79%), without clear differences based on HIV status. PBL occurs in Malawi in HIV-positive and HIV-negative individuals and can be treated successfully with curative intent, even in a low-resource setting in SSA.\n\nKeywords\nPlasmablastic lymphomaHIVEBVEPOCHSub-Saharan Africahttp://dx.doi.org/10.13039/100000002National Institutes of HealthK01TW009488R21CA180815U54CA190152Gopal Satish Medical Education Partnership InitiativeU2GPS001965Gopal Satish http://dx.doi.org/10.13039/100008615Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel HillP30CA016086Gopal Satish issue-copyright-statement© The Author(s) 2018\n==== Body\nIntroduction\nPlasmablastic lymphoma (PBL) is an aggressive non-Hodgkin lymphoma (NHL) subtype associated with human immunodeficiency virus (HIV) infection [1], constituting 2% of all HIV-associated lymphomas [2]. Despite strong association with HIV, PBL is also seen in HIV-negative patients [3, 4]. Epstein-Barr virus (EBV) increases plasmablasts in blood and lymph nodes in the presence or absence of HIV, and may play a direct role in PBL development [5].\n\nDespite high prevalence of HIV infection in sub-Saharan Africa (SSA), PBL descriptions from the region are scarce. We describe characteristics, treatment, and outcomes of PBL patients enrolled in a prospective, observational cohort in Malawi. This is among the first detailed clinical descriptions of this unique and aggressive NHL subtype from SSA, where HIV and EBV are endemic.\n\nMethods\nWe identified patients with PBL enrolled in the prospective Kamuzu Central Hospital Lymphoma Study between May 2013 and May 2017 in Lilongwe, Malawi. PBL diagnoses were histologically and immunophenotypically confirmed, and underwent subsequent secondary review in the United States [6]. All cases were positive for CD138 and negative for CD20 with Ki67 > 90%.\n\nFollowing diagnosis, all patients underwent standardized clinical, laboratory, and radiologic assessments as previously described [7]. Before August 2016, patients were treated with CHOP (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 day 1, and prednisone 40 mg/m2 days 1–5; 21 day cycles). After August 2016, patients received a modified EPOCH regimen (etoposide 50 mg/m2, vincristine 0.4 mg/m2, and doxorubicin 10 mg/m2 days 1–4, prednisone 60 mg/m2 days 1–5, and cyclophosphamide 750 mg/m2 day 1; 21-day cycles). Because the local clinical environment does not allow safe administration of 24-h continuous infusions, 24-h doses of etoposide, vincristine, and doxorubicin were instead administered over 6–8 h on successive days. Hematopoietic growth factors were not available. All HIV-infected patients received antiretroviral therapy (ART) concurrent with chemotherapy.\n\nCohort characteristics were summarized using simple descriptive statistics. Patients were followed until death or administrative censoring on September 30, 2017. Adverse events were reported using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Kaplan-Meier methods were used to estimate overall survival (OS). Analyses were conducted using Stata version 14.1 (College Station, Texas).\n\nResults\nOf 183 adults with pathologically confirmed NHL during the study period, we identified 12 patients with PBL (Table 1). Median age was 46 years (range 26–71), seven (58%) were male, and six (50%) were HIV-positive. Of HIV-positive patients, three were diagnosed with HIV prior to PBL diagnosis, and had been on ART for 6, 10, and 14 months. Among HIV-positive patients, median CD4 cell count was 147 cell/μL (range 9–460) and three (50%) had suppressed HIV RNA < 400 copies/mL at PBL diagnosis. Of seven patients whose tumors were tested for EBV-encoded RNA (EBER) by in situ hybridization, five (71%) were positive: 3/3 HIV-positive, 2/4 HIV-negative. All patients had a primary site of disease in the head and neck. Nine (75%) patients had Ann Arbor stage I/II disease. Median lactate dehydrogenase was 339 IU/L (range 186–2522 IU/L, upper limit of normal 250 IU/L).Table 1 Baseline characteristics of plasmablastic lymphoma patients from the Kamuzu Central Hospital Lymphoma Cohort study\n\n\tTotal (n = 12)\tHIV+ (n = 6)\tHIV- (n = 6)\t\nAge, years, median (range)\t46 (26–71)\t39 (30–60)\t53 (26–71)\t\nMale sex, n (%)\t7 (58)\t2 (33)\t5 (83)\t\nLargest tumor location head and neck, n (%)\t12 (100)\t6 (100)\t6 (100)\t\nCNS involvement, n (%)\t1 (8)\t0 (0)\t1 (17)\t\nBone marrow involvement, n (%)\t3 (25)\t2 (33)\t1 (17)\t\nLargest diameter of mass, cm, median (range)\t10 (3–22)\t8 (3–15)\t11 (10–22)\t\nAnn Arbor stage I/II, n (%)\t9 (75)\t6 (100)\t3 (50)\t\nPerformance score ≥ 2, n (%)\t1 (8)\t0 (0)\t1 (17)\t\nWhite blood cells, 103/uL, median (range)\t4.6 (2.7–14.9)\t11.6 (6.2–12.5)\t6.1 (2.7–14.9)\t\nAbsolute neutrophils, 103/uL, median (range)\t2.74 (0.92–10.6)\t2.55 (0.9–4.07)\t2.48 (1.3–10.6)\t\nHemoglobin, g/dL, median (range)\t11 (6.2–14.9)\t11.6 (6.2–12.5)\t10.9 (10.1–14.9)\t\nPlatelets, 103/uL, median (range)\t206 (103–666)\t210 (176–666)\t233 (103–458)\t\nLactate dehydrogenase (LDH), IU/L, median (range)a\t338 (186–2522)\t328 (240–2522)\t226 (186–1803)\t\nCD4 count, cells/μL, median (range)\t―\t147 (9–460)\t―\t\nHIV RNA < 400 copies/mL, n (%)\t―\t3 (50)\t―\t\nEBER expression n (%)\t5 (71)\t3 (100)\t2 (50)\t\nAbbreviations: CNS Central nervous system, EBV Epstein Barr virus, EBER EBV encoded RNA, ECOG PS Eastern oncology cooperative group performance status, HIV human immunodeficiency virus, LDH lactate dehydrogenase\n\naLDH normal range = 0–250 IU/L\n\n\n\nEight patients were treated with CHOP for a median of six cycles (range 1–8). Four patients received the modified EPOCH regimen for a median of five cycles (range 2–6). All patients receiving EPOCH and 50% of CHOP recipients experienced treatment delay due to grade 3/4 neutropenia and one CHOP recipient experienced delay due to grade 3 anemia. Overall, five (42%) patients achieved a complete response (CR) after chemotherapy [CHOP 2/8 (25%); EPOCH 3/4 (75%)]. Both patients who achieved CR after CHOP relapsed 4 months after treatment completion.\n\nAs of September 30, 2017, vital status was known for all patients and median follow-up was 13 months (range 1–35) among patients still alive. One-year OS was 56% (95% CI 24–79%, Fig. 1). No differences were observed between HIV-positive patients (1-year OS 67, 95% CI 19–90%) and HIV-negative patients (1-year OS 42, 95% CI 6–77%, p = 0.53). Of seven deaths, one was due to neutropenic sepsis and six due to lymphoma progression.Fig. 1 Overall survival of plasmablastic lymphoma patients in Lilongwe stratified by HIV status. No difference was found between HIV+ and HIV- patients by log-rank test\n\n\n\nDiscussion\nIn resource-rich settings, PBL is a rare lymphoma subtype with poor outcomes [8, 9]. The current National Comprehensive Cancer Network guidelines recommend intensive chemotherapy regimens such as dose-adjusted EPOCH, hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with cytarabine, methotrexate), or CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, methotrexate alternating with ifosfamide, etoposide, cytarabine). Consolidative high-dose chemotherapy and autologous stem cell rescue in first remission is also recommended by some [10]. Ongoing studies in high-income countries are attempting to investigate anti-myeloma agents (bortezomib, daratumumab, etc.) added to aggressive NHL chemotherapy regimens to improve outcomes, based on plasmacytic differentiation of PBL tumor cells [11, 12]. Conversely, other studies have demonstrated similar or worse results after intensive chemotherapy regimens compared with CHOP due to excess treatment-related complications [10, 13].\n\nUpon first recognition of PBL in Malawi, and due to supportive care constraints, we initially treated participants with CHOP resulting in a 25% CR rate, with nearly all patients dying of progressive disease rather than treatment-related complications. Given these poor outcomes, we intensified our approach to a modified EPOCH regimen adapted as required by clinic infrastructure, resulting in a 75% CR rate, although follow-up time for this more recently treated group is limited. Nevertheless, this experience illustrates that even in a resource-limited country, sustained investments in cancer diagnostic and treatment capabilities can lead to recognition of new tumor types, foundational understanding of outcomes using standard approaches, and evidence-based adjustment of therapeutic approaches.\n\nHIV-positive and HIV-negative patients with PBL have different clinical and pathologic characteristics, including better response to chemotherapy in HIV-positive patients [14]. HIV-positive PBL patients are younger, predominantly male, and have more frequent oral involvement. HIV-positive PBL cases have significantly higher expression of CD20, CD56, and EBER compared with HIV-negative PBL. HIV-positive patients with PBL have also been reported to have better survival than HIV-negative patients with PBL [14]. We found no difference in OS between HIV-positive and HIV-negative patients, although our sample size is small and trends in OS by HIV status were similar to those described in high-income countries.\n\nPrevious studies have indicated that PBL is closely associated with EBV infection. A metanalysis of PBL cases demonstrated EBV by in situ hybridization in 75% of HIV-infected cases and 50% of HIV-uninfected cases [9]. Similarly, our findings confirmed EBV presence in 3/3 HIV-positive cases but only 2/4 HIV-negative cases.\n\nStrengths of our study include its prospective longitudinal nature, no loss to follow-up, standardized treatment, and pathologic confirmation using immunohistochemistry and telepathology consultation, all of which are not common in studies of lymphoproliferative disorders in SSA. Limitations are small sample size and relatively short follow-up. Ongoing enrollment and long-term follow-up will allow better understanding of prognostic factors and outcomes.\n\nIn conclusion, PBL occurs in SSA and may be underdiagnosed in many settings. Further study is needed to identify best treatment approaches, but our early experience suggests treatment intensification might lead to better outcomes for this population even in highly resource-limited environments.\n\nAbbreviations\nCD4Positive for cluster of differentiation 4\n\nCHOPCyclophosphamide, doxorubicin, vincristine, and prednisone\n\nEBEREpstein-Barr virus-encoded RNA\n\nEBVEpstein Barr virus\n\nEPOCHEtoposide, prednisone, vincristine, cyclophosphamide and doxorubicin\n\nHIVHuman immunodeficiency virus\n\nOSOverall survival\n\nPBLPlasmablastic lymphoma\n\nAcknowledgements\nWe wish to thank patients and their families for participating in this study. We also thank Wiza Kumwenda for developing the study database, our pathology team and the University of North Carolina Translational Pathology Laboratory for performing additional stains.\n\nFunding\nThis work was supported by grants from the National Institutes of Health (K01TW009488, R21CA180815, and U54CA190152 to S.G.), the Medical Education Partnership Initiative (U2GPS001965), and the Lineberger Comprehensive Cancer Center (P30CA016086).\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nTZ performed research, analyzed data, and wrote the manuscript; MSP and RS wrote the manuscript; EK analyzed the data; BK, EK, TT, BMD, MM, MC, BT, SC, AN, FC, CK, RK, NDM, YF performed research; SG designed the study, performed research, and wrote the manuscript. All authors approved the manuscript for submission.\n\nEthics approval and consent to participate\nAll patients provided written informed consent for participation in the Kamuzu Central Hospital Lymphoma Study, which was approved by the Malawi National Health Sciences Research Committee (1107) and University of North Carolina Biomedical Institutional Review Board (12–2255).\n\nConsent for publication\nNot applicable\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. STEIN & H. Plasmablastic lymphoma: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues; 2008. p. 256–7. https://ci.nii.ac.jp/naid/10027382444/ Accessed 8 Feb 2018\n2. Carbone A AIDS-related non-Hodgkin’s lymphomas: from pathology and molecular pathogenesis to treatment Hum Pathol 2002 33 392 404 10.1053/hupa.2002.124723 12055673 \n3. Han X Duan M Hu L Zhou D Zhang W Plasmablastic lymphoma: review of 60 Chinese cases and prognosis analysis Medicine 2017 96 e5981 10.1097/MD.0000000000005981 28248855 \n4. Choi S-Y Cho Y-A Hong S-D Lee J-I Hong S-P Yoon H-J Plasmablastic lymphoma of the oral cavity in a human immunodeficiency virus-negative patient: a case report with literature review Oral Surg Oral Med Oral Pathol Oral Radiol 2014 117 e115 e120 10.1016/j.oooo.2013.04.017 23791544 \n5. Ferrazzo K Mesquita R Aburad A Nunes F de Sousa S EBV detection in HIV-related oral plasmablastic lymphoma Oral Dis 2007 13 564 569 10.1111/j.1601-0825.2006.01336.x 17944673 \n6. Tomoka T Montgomery ND Powers E Dhungel BM Morgan EA Mulenga M Gopal S Fedoriw Y Lymphoma and pathology in sub-Saharan Africa Clin Lab Med 2018 38 91 100 10.1016/j.cll.2017.10.007 29412887 \n7. Gopal S Fedoriw Y Kaimila B Montgomery ND Kasonkanji E Moses A Nyasosela R Mzumara S Varela C Chikasema M Makwakwa V Itimu S Tomoka T Kamiza S Dhungel BM Chimzimu F Kampani C Krysiak R Richards KL Shea TC CHOP chemotherapy for aggressive non-Hodgkin lymphoma with and without HIV in the antiretroviral therapy era in Malawi PLoS One 2016 11 e0150445 10.1371/journal.pone.0150445 26934054 \n8. Loghavi S Alayed K Aladily TN Zuo Z Ng S-B Tang G Hu S Yin CC Miranda RN Medeiros LJ Khoury JD Stage, age, and EBV status impact outcomes of plasmablastic lymphoma patients: a clinicopathologic analysis of 61 patients J Hematol Oncol 2015 8 65 10.1186/s13045-015-0163-z 26055271 \n9. Morscio J Dierickx D Nijs J Verhoef G Bittoun E Vanoeteren X Wlodarska I Sagaert X Tousseyn T Clinicopathologic comparison of Plasmablastic lymphoma in HIV-positive, immunocompetent, and posttransplant patients Am J Surg Pathol 2014 38 875 886 10.1097/PAS.0000000000000234 24832164 \n10. Castillo JJ Bibas M Miranda RN Review article the biology and treatment of plasmablastic lymphoma Blood 2015 125 2323 2331 10.1182/blood-2014-10-567479 25636338 \n11. Guerrero-Garcia TA Mogollon RJ Castillo JJ Bortezomib in plasmablastic lymphoma: a glimpse of hope for a hard-to-treat disease Leuk Res 2017 62 12 16 10.1016/j.leukres.2017.09.020 28963907 \n12. Castillo JJ Reagan JL Sikov WM Winer ES Bortezomib in combination with infusional dose-adjusted EPOCH for the treatment of plasmablastic lymphoma Br J Haematol 2015 169 352 355 10.1111/bjh.13300 25612847 \n13. Castillo JJ Reagan JL Plasmablastic lymphoma: a systematic review TheScientificWorldJournal 2011 11 687 696 10.1100/tsw.2011.59 21442146 \n14. Castillo JJ Winer ES Stachurski D Perez K Jabbour M Milani C Colvin G Butera JN Clinical and pathological differences between human immunodeficiency virus-positive and human immunodeficiency virus-negative patients with plasmablastic lymphoma Leuk Lymphoma 2010 51 2047 2053 10.3109/10428194.2010.516040 20919850\n\n",
"fulltext_license": "CC BY",
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"issue": "13()",
"journal": "Infectious agents and cancer",
"keywords": "EBV; EPOCH; HIV; Plasmablastic lymphoma; Sub-Saharan Africa",
"medline_ta": "Infect Agent Cancer",
"mesh_terms": null,
"nlm_unique_id": "101276559",
"other_id": null,
"pages": "22",
"pmc": null,
"pmid": "29988350",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
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"title": "Plasmablastic lymphoma in Malawi.",
"title_normalized": "plasmablastic lymphoma in malawi"
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"abstract": "The effects of daily administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) to eight normal volunteers donating granulocytes for neutropenic relatives undergoing marrow transplantation were studied. Granulocyte donors consisted of seven marrow donors (5 syngeneic, 2 HLA identical) and one haploidentical son who had not donated marrow. All donors were administered daily rhG-CSF at a mean dose of 5 micrograms/kg/d (range 3.5 to 6.0) for a mean of 11.75 days (range 9 to 14 days), and granulocytes were collected a mean of 7.6 times (range 4 to 12). RhG-CSF was well tolerated and only minor side effects were observed. All donors became anemic from marrow donation and the removal of red blood cells during the collection procedures. Red blood cell transfusions were not given. All donors had a decrease in platelet counts and the magnitude of the decrement appeared to be greater than in historical donors. This was due in part to increased removal of platelets with the collection product, but a direct effect of rhG-CSF on platelet production cannot be excluded. The mean precollection granulocyte level was 29.6 x 10(9)/L (range 11.8 to 79.8), which was a 10-fold increase over baseline. The mean number of granulocytes collected was 41.6 x 10(9) (range 1.3 to 144.1), which was a six-fold increase over historical donors not receiving rhG-CSF. The mean granulocyte level 24 hours after transfusion into neutropenic recipients was 0.95 x 10(9)/L (median 0.57 and range .06 to 9.47). This study indicates that rhG-CSF is safe to administer to normal individuals, significantly improves the quantity of granulocytes collected, and results in significant circulating levels of granulocytes in neutropenic recipients. Further studies to evaluate rhG-CSF in normal granulocyte donors are warranted.",
"affiliations": "Fred Hutchinson Cancer Research Center, Seattle, WA 98104.",
"authors": "Bensinger|W I|WI|;Price|T H|TH|;Dale|D C|DC|;Appelbaum|F R|FR|;Clift|R|R|;Lilleby|K|K|;Williams|B|B|;Storb|R|R|;Thomas|E D|ED|;Buckner|C D|CD|",
"chemical_list": "D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor",
"country": "United States",
"delete": false,
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"issn_linking": "0006-4971",
"issue": "81(7)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000328:Adult; D001782:Blood Donors; D004334:Drug Administration Schedule; D004551:Elbow Joint; D004911:Erythrocyte Volume; D005260:Female; D005269:Femur; D016179:Granulocyte Colony-Stimulating Factor; D006098:Granulocytes; D006801:Humans; D007937:Leukapheresis; D007958:Leukocyte Count; D008297:Male; D010146:Pain; D011994:Recombinant Proteins",
"nlm_unique_id": "7603509",
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"pages": "1883-8",
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"pubdate": "1993-04-01",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "The effects of daily recombinant human granulocyte colony-stimulating factor administration on normal granulocyte donors undergoing leukapheresis.",
"title_normalized": "the effects of daily recombinant human granulocyte colony stimulating factor administration on normal granulocyte donors undergoing leukapheresis"
} | [
{
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... |
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