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"abstract": "Purpose of the article: Clozapine is the only evidence based treatment for treatment-resistant schizophrenia. Constipation is a well known side effect of clozapine treatment. The aims of this study are to describe the prevalence of constipation and ileus during clozapine treatment of patients with schizophrenia in Iceland and to assess the concomitant use of medication that can cause constipation, and laxatives used to treat constipation.\n\n\nMETHODS\nWe identified 188 patients treated with clozapine by searching the electronic health records of Landspitali, the National University Hospital, during the study period 1.1.1998 - 21.11.2014. Cases of constipation and ileus were identified using an electronic search with keywords related to ileus in the patients' electronic health records. Detailed medication use was available for 154 patients that used clozapine for at least one year.\n\n\nRESULTS\nFour out of 188 patients were diagnosed with ileus that resulted in admission to hospital. Two of these required a permanent stoma as a consequence of their ileus. Laxatives were prescribed for 24 out of 154 patients (15.4%) while on clozapine. In total 40.9% of the patients either had laxatives prescribed or had constipation documented in the medical records. Apart from clozapine, other medications known to cause constipation were prescribed to 28 out of 154 patients (18.2%).\n\n\nCONCLUSIONS\nConstipation is a common problem during clozapine treatment which can progress to full-blown ileus which can be fatal. Clinicians need to monitor signs of constipation during treatment with clozapine and respond to it with lifestyle advice and laxative treatment.",
"affiliations": "a Faculty of Medicine, School of Health Sciences , University of Reykjavik, Iceland.;c Institute of Psychiatry, Psychology and Neuroscience , King's College London , UK.;a Faculty of Medicine, School of Health Sciences , University of Reykjavik, Iceland.",
"authors": "Ingimarsson|Oddur|O|;MacCabe|James H|JH|;Sigurdsson|Engilbert|E|",
"chemical_list": "D014150:Antipsychotic Agents; D054368:Laxatives; D003024:Clozapine",
"country": "England",
"delete": false,
"doi": "10.1080/08039488.2018.1517189",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0803-9488",
"issue": "72(7)",
"journal": "Nordic journal of psychiatry",
"keywords": "clozapine; constipation; ileus; laxatives; schizophrenia",
"medline_ta": "Nord J Psychiatry",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D015331:Cohort Studies; D003248:Constipation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007055:Iceland; D045823:Ileus; D054368:Laxatives; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D012189:Retrospective Studies; D012559:Schizophrenia; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100927567",
"other_id": null,
"pages": "497-500",
"pmc": null,
"pmid": "30348045",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Constipation, ileus and medication use during clozapine treatment in patients with schizophrenia in Iceland.",
"title_normalized": "constipation ileus and medication use during clozapine treatment in patients with schizophrenia in iceland"
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"companynumb": "IS-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-288291",
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"activesubstancename": "CLOZAPINE"
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"abstract": "Despite the widespread use of statins and ezetimibe to decrease low-density lipoprotein cholesterol (LDL-C) levels and associated atherosclerotic cardiovascular disease (ASCVD), many patients do not achieve adequate LDL-C lowering as per the recommended American College of Cardiology (ACC)/American Heart Association (AHA) and European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines and demonstrate residual cardiovascular risk. The introduction of proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors in 2015 was a promising addition to hypercholesterolemia therapies, but their cost and subcutaneous administration has limited their use, and therefore, new affordable and patient friendly treatment strategies are crucial to help reduce ASCVD risk. Bempedoic acid, a drug currently under investigation, is a small molecule that has been shown to upregulate LDL receptors, decrease LDL-C, and reduce atherosclerotic plaque formation in hypercholesterolemic patients. Furthermore, bempedoic acid is a prodrug that becomes activated by an enzyme expressed primarily in the liver, allowing it to avoid the potential myotoxicity associated with statin therapy. The purpose of this review is to summarize the major clinical studies evaluating bempedoic acid and describe its potential addition to currently approved lipid-lowering therapies.",
"affiliations": "East Coast Institute for Research, Jacksonville, FL, USA.;East Coast Institute for Research, Jacksonville, FL, USA.;East Coast Institute for Research, Jacksonville, FL, USA.;Northeast Florida Endocrine and Diabetes Associates, Jacksonville, FL, USA.;Baker-Gilmour Cardiovascular Institute, Jacksonville, FL, USA.;East Coast Institute for Research, Jacksonville, FL, USA.;East Coast Institute for Research, Jacksonville, FL, USA. rebecca.goldfaden@ecirmed.com.",
"authors": "Niman|Stephanie|S|;Rana|Khyatiben|K|;Reid|Jessica|J|;Sheikh-Ali|Mae|M|;Lewis|Todd|T|;Choksi|Rushab R|RR|;Goldfaden|Rebecca F|RF|",
"chemical_list": "D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D003998:Dicarboxylic Acids; D004338:Drug Combinations; D005227:Fatty Acids; D011973:Receptors, LDL; C581236:8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid; D000069438:Ezetimibe",
"country": "New Zealand",
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"doi": "10.1007/s40256-020-00399-w",
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"issn_linking": "1175-3277",
"issue": "20(6)",
"journal": "American journal of cardiovascular drugs : drugs, devices, and other interventions",
"keywords": null,
"medline_ta": "Am J Cardiovasc Drugs",
"mesh_terms": "D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D003998:Dicarboxylic Acids; D004338:Drug Combinations; D050171:Dyslipidemias; D000069438:Ezetimibe; D005227:Fatty Acids; D006801:Humans; D006937:Hypercholesterolemia; D006938:Hyperlipoproteinemia Type II; D016032:Randomized Controlled Trials as Topic; D011973:Receptors, LDL",
"nlm_unique_id": "100967755",
"other_id": null,
"pages": "535-548",
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"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "A Review of the Efficacy and Tolerability of Bempedoic Acid in the Treatment of Hypercholesterolemia.",
"title_normalized": "a review of the efficacy and tolerability of bempedoic acid in the treatment of hypercholesterolemia"
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"abstract": "Tumor lysis syndrome (TLS) is a fatal complication of chemotherapy treatment. It is rarely seen in the treatment of solid tumors particularly in breast cancer. We presented the case of a chemo-naïve 58-year-old Caucasian woman who developed tumor lysis syndrome (TLS) after a single treatment dose of gemcitabine for metastatic breast cancer. Despite optimal management, the patient clinically deteriorates and is referred to inpatient hospice. Although targeted chemotherapy options have become increasingly effective, physicians should be aware of the rare, yet often fatal complications of TLS. Similarly, physicians should be able to quickly recognize the development of TLS to ensure swift and effective prophylaxis or treatment.",
"affiliations": "Internal Medicine, Seton Hall University, Hackensack Meridian School of Medicine, Trenton, USA.;Internal Medicine, Drexel University College of Medicine, Philadelphia, USA.;Internal Medicine, Seton Hall University / Hackensack Meridian School of Medicine, Trenton, USA.",
"authors": "Aslam|Hafiz M|HM|;Zhi|Cassandra|C|;Wallach|Sara L|SL|",
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"country": "United States",
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"doi": "10.7759/cureus.4024",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.4024Internal MedicineNephrologyOncologyTumor Lysis Syndrome: A Rare Complication of Chemotherapy for Metastatic Breast Cancer Muacevic Alexander Adler John R Aslam Hafiz M 1Zhi Cassandra 2Wallach Sara L 3\n1 \nInternal Medicine, Seton Hall University, Hackensack Meridian School of Medicine, Trenton, USA \n2 \nInternal Medicine, Drexel University College of Medicine, Philadelphia, USA \n3 \nInternal Medicine, Seton Hall University / Hackensack Meridian School of Medicine, Trenton, USA \nHafiz M. Aslam muhammadaslamsaleem@hotmail.com7 2 2019 2 2019 11 2 e40243 1 2019 6 2 2019 Copyright © 2019, Aslam et al.2019Aslam 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/17079-tumor-lysis-syndrome-a-rare-complication-of-chemotherapy-for-metastatic-breast-cancerTumor lysis syndrome (TLS) is a fatal complication of chemotherapy treatment. It is rarely seen in the treatment of solid tumors particularly in breast cancer. We presented the case of a chemo-naïve 58-year-old Caucasian woman who developed tumor lysis syndrome (TLS) after a single treatment dose of gemcitabine for metastatic breast cancer. Despite optimal management, the patient clinically deteriorates and is referred to inpatient hospice. Although targeted chemotherapy options have become increasingly effective, physicians should be aware of the rare, yet often fatal complications of TLS. Similarly, physicians should be able to quickly recognize the development of TLS to ensure swift and effective prophylaxis or treatment.\n\nsolid tumorstumor lysis syndromechemotherapyThe 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\nTumor lysis syndrome (TLS) is defined as an oncologic emergency, characterized by massive tumor cell lysis and the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation. It is often seen as a result of chemotherapy treatment of lymphomas and T-cell acute lymphoblastic leukemias [1]. In one report, the incidence of TLS in AML was found to be around 17 percent. The incidence of TLS in solid tumors is very rare and is mostly described in case reports [1]. TLS is rarely observed in solid tumors such as breast cancer. In this report, we have described a rare case of TLS that occurred after a single treatment of gemcitabine, which only rarely causes TLS in solid tumors, in the context of metastatic breast cancer in a chemo-naïve patient [1] .\n\nCase presentation\nA 58-year-old Caucasian woman was admitted to our hospital with complaints of generalized weakness, lethargy, anorexia, and weight loss. She was diagnosed with metastatic breast cancer 17 days prior to this admission. She also had a past medical history of treated hypertension and chronic back pain. Before this admission, she had complained of a breast lump in the previous year but never got it examined. The primary breast tumor was found on ultrasound to be approximately 4 cm by 5 cm and was found to be an invasive, poorly differentiated, ductal carcinoma with extensive necrosis. It had no expression of the hormone receptors, estrogen, and progesterone and was human epidermal growth factor 2 (HER2) positive. At the time of presentation, the cancer was advanced with innumerable hepatic metastases and multiple bilateral pulmonary metastases. There was also a small-moderate right pleural effusion. It had spread to the spine, causing a bony lytic lesion at the T9 vertebrae. On physical examination, she also had jaundice of the skin and mild splenomegaly, likely secondary to extensive liver disease.\n\nThe patient had undergone the planned chemotherapy four days prior, which was a treatment of gemcitabine 1600 mg. Gemcitabine has long been shown to be an effective agent in the treatment of metastatic breast cancer [2]. A Port-A-Cath had been placed successfully without any complications two days before the first chemotherapy treatment. On this present admission, her blood tests showed high uric acid levels (18.2 mg/dL), hyperphosphatemia (6.7 mg/dL), hyperkalemia (5.4 mmol/L), calcium (9.6 mg/dL), increased creatinine (3.38 mg/dL) and decreased glomerular filtration rate (14 mL/min). Nephrologists were consulted and they recognized this as TLS. It was recommended to give the patient vigorous intravenous (IV) fluid hydration with normal saline at 125 cc/hr as well as transfuse packed red blood cells to maintain the hemoglobin levels above 8 g/dL. Allopurinol 100 mg three times a day was also given. Hematologists/oncologists were consulted and they recommended chemotherapy treatment to be on hold for now until the patient’s labs become more stable.\n\nBy day two of admission, the patient appeared jaundiced and lethargic but was still alert and oriented. Her blood tests showed high uric acid levels (15.1 mg/dL), hyperphosphatemia (6.1 mg/dL), potassium (4.7 mmol/L), calcium (9.0 mg/dL), increased creatinine (2.69 mg/dL), and decreased glomerular filtration rate (18 mL/min). Rasburicase was not started at this time because it was not readily available at the current medical facility. Over the course of the next few days, the patient’s platelet count continued to drop, likely due to the initial chemotherapy treatment. The creatinine levels remained elevated, and the patient’s bilirubin and other liver function enzymes continued to rise, making the option of chemotherapy less feasible.\n\nBy day six of admission, the patient’s blood tests showed high uric acid levels (11.1 mg/dL), potassium (4.0 mmol/L), calcium (8.7 mg/dL), increased creatinine (2.71 mg/dL), and decreased glomerular filtration rate (18 mL/min). On examination, clinical deterioration was evident and the patient appeared even more lethargic and sleepy. She was difficult to wake with verbal stimuli.\n\nDespite optimal management, by day seven of admission, she was drowsy and minimally responsive and had a slow response to any stimuli. At times, she could not open her eyes. At this time, it was decided by the patient, husband, and daughter that the patient would have a ‘do not resuscitate’ order and would be transferred to inpatient hospice when stable.\n\nDiscussion\nOnly a few published cases of TLS developing in patients with breast cancer either due to underreporting or rarity are available. Moreover, the reason why TLS is rarely seen in solid tumors is currently unclear. TLS is more likely to happen in more indolent proliferations such as that seen in leukemias or lymphomas [3]. In a report evaluating the presence of TLS in breast cancer patients, it was found that in the few cases that have been published, most of the patients had metastatic breast adenocarcinomas. The age of the patients ranged from 31 to 94 years, with the average age being 54.1 years. The majority of these patients had a baseline increase in LDH as well as a baseline increase in uric acid levels [4].\n\nTLS is diagnosed both clinically and through laboratory values. The Cairo-Bishop definition was proposed in 2004, which provides specific criteria for the diagnosis of TLS [5]. Clinically, the symptoms associated with TLS reflect the metabolic abnormalities. Symptoms include nausea, vomiting, diarrhea, anorexia, lethargy, hematuria, heart failure, cardiac dysrhythmias, seizures, muscle cramps, tetany, syncope, and possible sudden death [6]. Clinical TLS is defined as laboratory TLS plus one or more of the following: increased serum creatinine concentration (>1.5 times the upper limit of normal, cardiac arrhythmia/sudden death, or seizures). TLS can also be confirmed through laboratory values. Laboratory TLS is defined as two or more abnormal serum values, as shown in Table 1, presenting within three days before or seven days after chemotherapy treatment [5]. Based on these definitions, the patient, in this case, can be diagnosed with TLS both in terms of laboratory TLS and clinical TLS.\n\nTable 1 Cairo-Bishop definition of laboratory tumor lysis syndrome \nNOTE: Two or more laboratory changes within three days before or seven days after cytotoxic therapy.\n\n\nElement\n\t\nValue\n\t\nChange from baseline\n\t\n\nUric acid\n\t\n≥476 micromol/L (8 mg/dL)\n\t\n25% increase\n\t\n\nPotassium\n\t\n≥6.0 mmol/L (or 6 mEq/L)\n\t\n25% increase\n\t\n\nPhosphorus\n\t\n≥2.1 mmol/L (6.5 mg/dL) for children or ≥1.45 mmol/L (4.5 mg/dL) for adults\n\t\n25% increase\n\t\n\nCalcium\n\t\n< 1.75 mmol/L (7mg/ dL)\n\t\n25% decrease\n\t\nThe prevalence of TLS occurring after chemotherapy with solid tumors is rare but may be underreported in many patients [7]. In recent years, there have been a few case reports about TLS developing in patients with breast cancer. For example, in 2012 and 2014, two studies were conducted that reviewed modern literature on TLS in solid tumors and included 100 and 120 patients with solid tumors complicated with TLS, respectively [1,8]. A literature search for metastatic breast cancer treated with gemcitabine, as in this case, complicated by TLS, showed only one or two cases prior to this present case [9]. This again indicated either the rarity of TLS occurring with the treatment of solid tumors or its underreporting and underrecognition.\n\nMost patients who received chemotherapy treatment for solid tumors did not develop TLS. A strong risk factor for TLS is the patients’ health status. This includes the presence of hypotension, dehydration, acidic urine, oliguria, and nephropathy [10]. Certain medications may be additional risk factors for TLS due to their side effects of increasing uric acid levels in the body. These are shown in Table 2. The patient discussed in this case was not on any of these substances. Lastly, additional risk factors for TLS include the tumor’s size and expansion. For example, bulky tumors with wide metastatic dispersal and bone marrow involvement would put a patient at a higher risk [10]. In the present case, the patient had large primary breast cancer with numerous metastatic tumors to the liver, lungs, and spine, putting her at higher risk for the development of TLS.\n\nTable 2 Medications/drugs that can increase the risk of tumor lysis syndrome by increasing uric acid levels in the body \n\nMedications:\n\t\n\nAlcohol\n\t\nDiazoxide\n\t\nMethyldopa\n\t\n\nAscorbic acid\n\t\nDiuretics (Thiazide)\n\t\nNicotinic acid\n\t\n\nAspirin\n\t\nEpinephrine\n\t\nPyrazinamide\n\t\n\nCaffeine\n\t\nEthambutol\n\t\nPhenothiazines\n\t\n\nCisplatin\n\t\nLevodopa\n\t\nTheophylline\n\t\nProphylaxis with rasburicase or allopurinol is often initiated for patients with lymphomas or acute leukemias for prevention of TLS [6]. In a phase III trial comparing the use of rasburicase with allopurinol, 280 patients with hematologic malignancies at risk for TLS were assigned to be prophylaxed with rasburicase (0.2 mg/kg daily), rasburicase (0.2 mg/kg daily), and oral allopurinol (300 mg daily), or allopurinol alone (300 mg daily). The results showed that both rasburicase groups were superior to allopurinol alone in controlling serum uric acid levels. Rasburicase and allopurinol together were shown to contribute to a higher control of uric acid levels rather than rasburicase alone. However, this result was not statistically significant (p = 0.06) [11]. Rasburicase has been seen to be a more effective way of reducing hyperuricemia and has thus begun to replace allopurinol as prophylaxis. Because the incidence of TLS with solid tumors is less common, prophylaxis is often not done. Patients who develop TLS during chemotherapy should receive intensive supportive care with continuous cardiac monitoring and measurement of electrolytes and creatinine and uric acid levels every four to six hours. It is also important to treat specific electrolyte abnormalities, to administer rasburicase at 0.2 mg/kg, and to wash out obstructing uric acid crystals with fluids with or without a loop diuretic [1]. It should be noted that patients with solid tumors at a higher risk for TLS could also benefit from prophylaxis with rasburicase or allopurinol\n\nConclusions\nIn this report, we describe one of the first literature-documented cases of TLS in a patient diagnosed with metastatic breast cancer as a result of a single dose of gemcitabine treatment. Although TLS is not an extremely common outcome resulting from chemotherapy treatment in patients with solid tumors, it is important for physicians to recognize patients who may be at a higher risk of developing TLS. Proper knowledge of the prevalence and outcomes is important for physicians to help recognize and prevent potentially fatal outcomes. Physicians should be aware of the clinical and laboratory diagnostic criteria of TLS as well as the options for management of TLS.\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 Tumor lysis syndrome: prevention and treatment 12 2018 2018 https://www.uptodate.com/contents/tumor-lysis-syndrome-prevention-and-treatment \n2 Tumor lysis syndrome following trastuzumab and pertuzumab for metastatic breast cancer: a case report J Med Case Rep Baudon C Duhoux F Sinapi I Canon JL 1 4 10 2016 26758705 \n3 Tumor lysis syndrome in solid tumors: an up to date review of the literature Rare Tumors Mirrakhimov A Ali A Khan M Barbaryan A 5389 6 2014 25002953 \n4 Tumor lysis syndrome: definition, pathogenesis, clinical manifestations, etiology and risk factors 12 2018 2018 https://www.uptodate.com/contents/tumor-lysis-syndrome-definition-pathogenesis-clinical-manifestations-etiology-and-risk-factors \n5 Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review J Clin Oncol Coiffier B Altman A Pui C Younes A Cairo MS 708 28 2012 \n6 Tumor lysis syndrome in solid tumors Support Cancer Ther Mott FE Esana A Chakmakjian C Herrington JD 188 191 2 2005 18628171 \n7 An unusual presentation of tumor lysis syndrome in a patient with advanced gastric adenocarcinoma: case report and literature review Case Rep Med Vodopivec D Rubio J Fornoni A Lenz O 1 12 2012 2012 \n8 Gemcitabine-induced tumor lysis syndrome caused by recurrent breast cancer in a patient without hemodialysis Gan To Kagaku Ryoho Kawaguchi U Hattori M Kohno N Kaise H Iwata H 1529 1532 40 2013 https://www.ncbi.nlm.nih.gov/pubmed/24231708 24231708 \n9 Recognizing and managing the expanded risk of tumor lysis syndrome in hematologic and solic malignancies J Hematol Oncol McBride A Westervelt P 1 11 5 2012 22272800 \n10 Control of plasma uric acid in adults at risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone--results of a multicenter phase III study J Clin Oncol Cortes J Moore J Maziarz R 4207 28 2010 20713865 \n11 Acute tumor lysis syndrome in solid tumors--a case report and review of the literature Cancer Chemother Pharmacol Baeksgaard L Sorensen J 187 192 51 2003 https://www.ncbi.nlm.nih.gov/pubmed/12655435 12655435\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "11(2)",
"journal": "Cureus",
"keywords": "chemotherapy; solid tumors; tumor lysis syndrome",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e4024",
"pmc": null,
"pmid": "31007982",
"pubdate": "2019-02-07",
"publication_types": "D002363:Case Reports",
"references": "12655435;18509186;18628171;20713865;22685470;23237230;24231708;25002953;27312594",
"title": "Tumor Lysis Syndrome: A Rare Complication of Chemotherapy for Metastatic Breast Cancer.",
"title_normalized": "tumor lysis syndrome a rare complication of chemotherapy for metastatic breast cancer"
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"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
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"abstract": "BACKGROUND\nSome guidelines suggest that poor performance status (PS) is a contraindication to 1st line chemotherapy. Poor PS is a known adverse prognostic factor in advanced epithelial ovarian cancer (EOC). We show in this retrospective analysis that 1st line chemotherapy in this patient group is not only safe but is associated with good outcomes.\n\n\nMETHODS\nA retrospective review of 114 patients with stage III/IV EOC, who presented with a PS ≥3 at diagnosis and treated as inpatients with upfront platinum-based chemotherapy between 2000 and 2013, at the Royal Marsden Hospital, was conducted. The association between clinical parameters and the likelihood of completion of chemotherapy and overall survival (OS) was assessed.\n\n\nRESULTS\n66% of patients completed ≥6cycles of platinum-based chemotherapy. Prognostic factors for completion of chemotherapy were improvement of PS during hospital stay (p<0.001) and doublet-chemotherapy with carboplatin/paclitaxel compared to single-agent carboplatin (p=0.004). A negative trend for completion of treatment was seen for patients with low albumin (<25g/l) and low CA125 levels at baseline. The median OS for all patients was 13.1months (95% CI: 10.4-15.8) and 21.2months (95% CI: 16.5-25.8) for those who completed 6cycles of chemotherapy.\n\n\nCONCLUSIONS\nUpfront platinum-based chemotherapy is feasible, beneficial and tolerable for the majority of patients with advanced EOC and poor PS. Guidelines suggesting that best supportive care is the preferred option for poor PS patients with solid tumours should be revised to exclude those with advanced EOC. An aggressive approach utilising neoadjuvant carboplatin plus paclitaxel should be regarded as standard of care.",
"affiliations": "Gynaecology Unit, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, United Kingdom.;Gynaecology Unit, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, United Kingdom.;Gynaecology Unit, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, United Kingdom.;Gynaecology Unit, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, United Kingdom.;Department of Statistics, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom.;Gynaecology Unit, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, United Kingdom.;Gynaecology Unit, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, United Kingdom.;Gynaecology Unit, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, United Kingdom.;Gynaecology Unit, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, United Kingdom.;Gynaecology Unit, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, United Kingdom. Electronic address: susana.banerjee@rmh.nhs.uk.",
"authors": "Seifert|Heike|H|;Georgiou|Alexandros|A|;Alexander|Helen|H|;McLachlan|Jennifer|J|;Bodla|Shankar|S|;Kaye|Stan|S|;Barton|Desmond|D|;Nobbenhuis|Marielle|M|;Gore|Martin|M|;Banerjee|Susana|S|",
"chemical_list": "D016190:Carboplatin; D017239:Paclitaxel",
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"issue": "139(2)",
"journal": "Gynecologic oncology",
"keywords": "Advanced epithelial ovarian cancer; First line chemotherapy; Poor performance status; Prognostic markers",
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D000077216:Carcinoma, Ovarian Epithelial; D015331:Cohort Studies; D005185:Fallopian Tube Neoplasms; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D018297:Neoplasms, Cystic, Mucinous, and Serous; D009375:Neoplasms, Glandular and Epithelial; D010051:Ovarian Neoplasms; D017239:Paclitaxel; D010534:Peritoneal Neoplasms; D011379:Prognosis; D012189:Retrospective Studies; D012720:Severity of Illness Index; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "216-20",
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"pmid": "26318078",
"pubdate": "2015-11",
"publication_types": "D000068397:Clinical Study; D016428:Journal Article",
"references": null,
"title": "Poor performance status (PS) is an indication for an aggressive approach to neoadjuvant chemotherapy in patients with advanced epithelial ovarian cancer (EOC).",
"title_normalized": "poor performance status ps is an indication for an aggressive approach to neoadjuvant chemotherapy in patients with advanced epithelial ovarian cancer eoc"
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... |
{
"abstract": "Sedation/anesthesia is critical to cardiac catheterization in the pediatric/congenital heart patient. We sought to identify current sedation/anesthesia practices, the serious adverse event rate related to airway, sedation, or anesthesia, and the rate of intra-procedural conversion from procedural sedation to the use of assisted ventilation or an artificial airway. Data from 13,611 patients who underwent catheterization at eight institutions were prospectively collected from 2007 to 2010. Ninety-four (0.69 %) serious sedation/airway-related adverse events occurred; events were more likely to occur in smaller patients (<4 kg, OR 4.4, 95 % CI 2.3-8.2, p < 0.001), patients with non-cardiac comorbidities (OR 1.7, 95 % CI 1.1-26, p < 0.01), and patients with low mixed venous oxygen saturation (OR 2.3, 95 % CI 1.4-3.6, p < 0.001). Nine thousand three hundred and seventy-nine (69 %) patients were initially managed with general endotracheal anesthesia, LMA, or tracheostomy, whereas 4232 (31 %) were managed with procedural sedation without an artificial airway, of which 75 (1.77 %) patients were converted to assisted ventilation/general anesthesia. Young age (<12 months, OR 5.2, 95 % CI 2.3-11.4, p < 0.001), higher-risk procedure (category 4, OR 10.1, 95 % CI 6.5-15.6, p < 0.001), and continuous pressor/inotrope requirement (OR 11.0, 95 % CI 8.6-14.0, p < 0.001) were independently associated with conversion. Cardiac catheterization in pediatric/congenital patients was associated with a low rate of serious sedation/airway-related adverse events. Smaller patients with non-cardiac comorbidities or low mixed venous oxygen saturation may be at higher risk. Patients under 1 year of age, undergoing high-risk procedures, or requiring continuous pressor/inotrope support may be at higher risk of requiring conversion from procedural sedation to assisted ventilation/general anesthesia.",
"affiliations": "Methodist DeBakey Heart and Vascular Center, 6550 Fannin St, Smith Tower, Suite 1901, Houston, TX, 77030, USA. clin@tmhs.org.;Children's Hospital of Philadelphia, Philadelphia, PA, USA.;St. Louis Children's Hospital, St. Louis, MO, USA.;Children's Hospital Boston, Boston, MA, USA.;Children's Hospital of Wisconsin, Milwaukee, WI, USA.;St. Louis Children's Hospital, St. Louis, MO, USA.;Oregon Health Sciences University, Portland, OR, USA.;Children's Hospital Boston, Boston, MA, USA.;Children's Hospital Boston, Boston, MA, USA.;Children's Hospital Boston, Boston, MA, USA.;Morgan Stanley Children's Hospital, New York, NY, USA.;Rady Children's Hospital, San Diego, CA, USA.;Cincinnati Children's Hospital, Cincinnati, OH, USA.;Cincinnati Children's Hospital, Cincinnati, OH, USA.;Nationwide Children's Hospital, Columbus, OH, USA.;Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.;St. Louis Children's Hospital, St. Louis, MO, USA.;Children's Hospital Boston, Boston, MA, USA.",
"authors": "Lin|C Huie|CH|;Desai|Sanyukta|S|;Nicolas|Ramzi|R|;Gauvreau|Kimberlee|K|;Foerster|Susan|S|;Sharma|Anshuman|A|;Armsby|Laurie|L|;Marshall|Audrey C|AC|;Odegard|Kirsten|K|;DiNardo|James|J|;Vincent|Julie|J|;El-Said|Howaida|H|;Spaeth|James|J|;Goldstein|Bryan|B|;Holzer|Ralf|R|;Kreutzer|Jackie|J|;Balzer|David|D|;Bergersen|Lisa|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s00246-015-1167-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-0643",
"issue": "36(7)",
"journal": "Pediatric cardiology",
"keywords": "Anesthesia; Angioplasty; Catheterization; Congenital; Heart defects; Pediatrics",
"medline_ta": "Pediatr Cardiol",
"mesh_terms": "D000293:Adolescent; D000768:Anesthesia, General; D006328:Cardiac Catheterization; D002648:Child; D002675:Child, Preschool; D016292:Conscious Sedation; D005260:Female; D006330:Heart Defects, Congenital; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D015999:Multivariate Analysis; D010372:Pediatrics; D011446:Prospective Studies; D012720:Severity of Illness Index",
"nlm_unique_id": "8003849",
"other_id": null,
"pages": "1363-75",
"pmc": null,
"pmid": "25991570",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "17142550;6427531;18337600;15172773;21310103;21939947;22560979;19885913;11176085;23900744;2029444;12545318;19041130;23749445;10208959;17171905;20103543;10589618",
"title": "Sedation and Anesthesia in Pediatric and Congenital Cardiac Catheterization: A Prospective Multicenter Experience.",
"title_normalized": "sedation and anesthesia in pediatric and congenital cardiac catheterization a prospective multicenter experience"
} | [
{
"companynumb": "US-TEVA-603469USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": null,
"drug... |
{
"abstract": "BACKGROUND\nPost varicella angiopathy (PVA) is an underdiagnosed but potentially severe disease in both pediatric and adult settings. No guidelines are available for the medical and neurosurgical management of this condition. We report the first pediatric case with headache and PVA who was treated with surgical revascularization before the onset of ischemic events.\n\n\nMETHODS\nThis case report was conducted via retrospective chart review. A literature review was also completed, in order to identify previously described PVA undergone to revascularization.\n\n\nRESULTS\nWe report on a 9-year-old boy presenting with a long history of headache and PVA involving the distal left middle cerebral artery. The arterial lesion rapidly worsened over a 10 months' period with formation of focal moyamoya-like collaterals, despite an adequate intravenous antiviral treatment. The pattern of headaches significantly changed with a clear left-side lateralization and a \"re-build-up\" phenomenon on EEG. The patient was treated with left superficial temporal artery - middle cerebral artery (STA-MCA) bypass and encephalo-duro-arterio-myo-pericranial-synangiosis. This combined treatment resulted in an immediate and persistent improvement of brain perfusion, accompanied by prompt resolution of neurological symptoms. Two cases who presented with Suzuki stage III (unilateral or bilateral) moyamoya PVA and recurrent strokes or transient ischemic attacks despite adequate pharmacological prophylaxis have been surgically treated using both indirect and direct revascularization technique. The outcome was good in both cases.\n\n\nCONCLUSIONS\nSurgical revascularization may have a role in the treatment of PVA and may prevent stroke. Given the lack of standardized treatment algorithms, individualized regimens should be formulated on a case-specific basis.",
"affiliations": "Child Neuropsychiatry Unit, APSS Ospedale S. Chiara, Trento, Italy.;Dipartimento di Neuroscienze, riabilitazione, oftalmologia, genetica e scienze materno-infantili (DINOGMI) Università di Genova, Genoa, Italy; Autoinflammatory Diseases and Immunodeficiencies Center, IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Physical Medicine and Rehabilitation Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Dipartimento di Neuroscienze, riabilitazione, oftalmologia, genetica e scienze materno-infantili (DINOGMI) Università di Genova, Genoa, Italy; Medical Genetic Unit,IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Neurosurgery Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Physical Medicine and Rehabilitation Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy. Electronic address: martabertamino@gaslini.org.;Neurosurgery Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.",
"authors": "Iodice|Alessandro|A|;Signa|Sara|S|;Severino|Mariasavina|M|;Tortora|Domenico|D|;Zanetti|Alice|A|;Amico|Giulia|G|;Piatelli|Gianluca|G|;Bertamino|Marta|M|;Pavanello|Marco|M|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.braindev.2021.07.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0387-7604",
"issue": "43(10)",
"journal": "Brain & development",
"keywords": "Antiviral treatment; Focal cerebral arteriopathy; Pediatric stroke; Post varicella angiopathy; Revascularization",
"medline_ta": "Brain Dev",
"mesh_terms": null,
"nlm_unique_id": "7909235",
"other_id": null,
"pages": "1051-1056",
"pmc": null,
"pmid": "34332825",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Combined medical therapy and neurosurgical revascularization preventing stroke in post-varicella angiopathy: Case report and review of literature.",
"title_normalized": "combined medical therapy and neurosurgical revascularization preventing stroke in post varicella angiopathy case report and review of literature"
} | [
{
"companynumb": "IT-MYLANLABS-2022M1018854",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
"drugadditional": "3",
... |
{
"abstract": "Objectives This article aims to clarify the long-term outcomes of patients with squamous cell carcinoma of the temporal bone who underwent concomitant chemoradiotherapy (CCRT). Design and Setting The study design was a retrospective chart review. Patients and Methods From December 2001 to June 2014, 23 patients with cancer of the temporal bone who were treated by CCRT at the Tohoku University Hospital and the Iwate Medical University Hospital were enrolled in this study. For advanced cancer of the temporal bone, a modified docetaxel, cisplatin, and 5-fluorouracil (TPF) regimen was used for CCRT. The long-term outcomes, including prognoses and late complications, were analyzed after CCRT of patients with cancers of the temporal bone. Results The main long-term complications were stenosis of the external auditory canal and conductive hearing loss. No harmful late complications were observed in these patients. Disease-specific survival rates were 84.9% for all patients, 100% for patients of stage I, II, and III ( n = 10), and 75.5% for patients of stage IV ( n = 13) at 5 years. Conclusions Our study showed that CCRT is an effective treatment choice for squamous cell carcinoma of the temporal bone. Furthermore, CCRT using the TPF regimen is a safe and effective initial treatment for patients with advanced cancers of the temporal bone.",
"affiliations": "Department of Head and Neck Surgery, Iwate Medical University Hospital, Iwate Medical University, Morioka, Japan.;Department of Head and Neck Surgery, Iwate Medical University Hospital, Iwate Medical University, Morioka, Japan.;Department of Head and Neck Surgery, Iwate Medical University Hospital, Iwate Medical University, Morioka, Japan.;Department of Otolaryngology-Head and Neck Surgery, Tohoku University Hospital, Tohoku University, Sendai, Japan.;Department of Otolaryngology-Head and Neck Surgery, Tohoku University Hospital, Tohoku University, Sendai, Japan.;Department of Radiation Oncology, Iwate Medical University Hospital, Iwate Medical University, Morioka, Japan.",
"authors": "Shiga|Kiyoto|K|;Katagiri|Katsunori|K|;Saitoh|Daisuke|D|;Ogawa|Takenori|T|;Higashi|Kenjiro|K|;Ariga|Hisanori|H|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0038-1651522",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2193-634X",
"issue": "79(Suppl 4)",
"journal": "Journal of neurological surgery. Part B, Skull base",
"keywords": "adverse events; chemoradiotherapy; complications; external auditory canal; long-term prognosis; squamous cell carcinoma",
"medline_ta": "J Neurol Surg B Skull Base",
"mesh_terms": null,
"nlm_unique_id": "101580780",
"other_id": null,
"pages": "S316-S321",
"pmc": null,
"pmid": "30210984",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": "10768432;10884498;2396807;17960012;17960013;25995093;24692266;17972507;28180041;17547996;22451818;5902519;8134137;15900997;27466887;24436889;16406396",
"title": "Long-Term Outcomes of Patients with Squamous Cell Carcinoma of the Temporal Bone after Concomitant Chemoradiotherapy.",
"title_normalized": "long term outcomes of patients with squamous cell carcinoma of the temporal bone after concomitant chemoradiotherapy"
} | [
{
"companynumb": "PHHY2018JP137718",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nTramadol use is largely considered safe. However, several lethal cases of tramadol intoxication were reported, suggesting an underestimated toxicity. We report for a tramadol overdose case in combination with other central nervous system depressants, leading to refractory shock requiring extracorporeal life support.\n\n\nMETHODS\nA 33-year-old man was admitted in our intensive care unit for drug intoxication with coma, seizures, and hypotension without signs of heart failure. A few hours later, he developed a ventricular tachycardia, followed by a brief cardiac arrest in asystole with refractory shock requiring an extracorporeal life support, vasopressors, and hemofiltration. With this aggressive support, his overall status gradually improved. Repeated echocardiography showed an improvement in the cardiac function. The patient was weaned off extracorporeal life support on day eight and discharged on day 12. On admission, a urine analysis, using gas chromatography-mass spectrometry, showed high peaks of tramadol and desmethyltramadol with the presence of hydroxyzine, gabapentine, and clonazepam. The tramadol blood concentration measured by the high-performance liquid chromatography method-diode array detector was 23.9 mg/L, much higher than many previously reported fatal overdoses. No other drugs with potential cardiac toxicity, such as beta-blockers, calcium antagonists, antiarrythmic, antidepressants, meprobamate, or other xenobiotics were detected.\n\n\nCONCLUSIONS\nThis case illustrates that tramadol overdose may cause refractory shock and asystole when taken in combination with CNS depressants, and reminds all physicians to be vigilant with regard to the potential toxic effects of tramadol.",
"affiliations": "Department of Medical Intensive Care, Caen University Hospital, Caen Cedex, France. daubin-c@chu-caen.fr",
"authors": "Daubin|Cédric|C|;Quentin|Charlotte|C|;Goullé|Jean-Pierre|JP|;Guillotin|Damien|D|;Lehoux|Philippe|P|;Lepage|Olivier|O|;Charbonneau|Pierre|P|",
"chemical_list": "D000701:Analgesics, Opioid; D002492:Central Nervous System Depressants; D014147:Tramadol",
"country": "England",
"delete": false,
"doi": "10.1080/15563650701438847",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "45(8)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D002492:Central Nervous System Depressants; D062787:Drug Overdose; D006323:Heart Arrest; D006801:Humans; D008297:Male; D012769:Shock; D014147:Tramadol",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "961-4",
"pmc": null,
"pmid": "17852155",
"pubdate": "2007-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Refractory shock and asystole related to tramadol overdose.",
"title_normalized": "refractory shock and asystole related to tramadol overdose"
} | [
{
"companynumb": "FR-ROCHE-2417859",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": "1",
"druga... |
{
"abstract": "BACKGROUND\nProgrammed cell death protein 1 (PD-1) and its ligand, PD-L1, have shown great promise in clinical practice and have been incorporated into standard management of NSCLC. Pneumonitis is a serious autoimmune toxicity associated with the use of anti-PD-1/PD-L1 antibodies, resulting in significant morbidity and mortality.\n\n\nMETHODS\nWe described the case of a 73-year-old woman with no history of smoking developing exertional dyspnea four months after taking Pembrolizumab.\n\n\nRESULTS\nHigh resolution contrast CT scan (HRCT) presented a unilateral \"crazy paving\" pattern, and bronchoalveolar lavage (BAL) an important lymphocytosis (20% of total cell count). The patient reached clinical stability after the administration of systemic steroids (2mg\\Kg\\die) and was discharged with long term oxygen therapy.\n\n\nCONCLUSIONS\nPulmonary toxicity is frequent when using PD-1 inhibitors, resulting in significant morbidity and mortality, often leading to the discontinuation of therapy. Clinical presentation is usually protean and HRCT pattern is nonspecific. This is the first case presenting a \"crazy paving\" pattern associated with BAL lymphocytosis.\n\n\nCONCLUSIONS\nOncologists, pulmonologists, radiologists and general practitioners have to consider PD-1 and PD-L1 inhibitor pneumonitis as a potentially disabling and fatal event.",
"affiliations": "Depertment of Internal Medicine, Istituto Figlie di San Camillo, Cremona, Italy.;Depertment of Internal Medicine, Istituto Figlie di San Camillo, Cremona, Italy.;Depertment of Internal Medicine, Istituto Figlie di San Camillo, Cremona, Italy.;Depertment of Internal Medicine, Istituto Figlie di San Camillo, Cremona, Italy.",
"authors": "Marvisi|Maurizio|M|;Ramponi|Sara|S|;Balzarini|Laura|L|;Mancini|Chiara|C|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574886314666190312115648",
"fulltext": "\n==== Front\nCurr Drug SafCurr Drug SafCDSCurrent Drug Safety1574-88632212-3911Bentham Science Publishers CDS-14-24210.2174/1574886314666190312115648ArticleA “Crazy Paving” Pattern on CT Scan in a Patient Treated with Pembrolizumab Marvisi Maurizio 1*Ramponi Sara 1Balzarini Laura 1Mancini Chiara 11 Depertment of Internal Medicine, Istituto Figlie di San Camillo, Cremona, Italy* Address correspondence to this author at the Depertment of Internal Medicine, Istituto Figlie di San Camillo, Cremona, Italy; Tel: +390372421459; Fax: +390372421256; E-mail: mmarvis@alice.it11 2019 11 2019 14 3 242 245 14 1 2019 28 2 2019 05 3 2019 © 2019 Bentham Science Publishers2019 This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.Background:\nProgrammed cell death protein 1 (PD-1) and its ligand, PD-L1, have shown great promise in clinical practice and have been incorporated into standard management of NSCLC. Pneumonitis is a serious autoimmune toxicity associated with the use of anti-PD-1/PD-L1 antibodies, resulting in significant morbidity and mortality.\n\nMethods:\nWe described the case of a 73-year-old woman with no history of smoking developing exertional dyspnea four months after taking Pembrolizumab.\n\nResults:\nHigh resolution contrast CT scan (HRCT) presented a unilateral “crazy paving” pattern, and bronchoalveolar lavage (BAL) an important lymphocytosis (20% of total cell count). The patient reached clinical stability after the administration of systemic steroids (2mg\\Kg\\die) and was discharged with long term oxygen therapy.\n\nDiscussion:\nPulmonary toxicity is frequent when using PD-1 inhibitors, resulting in significant morbidity and mortality, often leading to the discontinuation of therapy. Clinical presentation is usually protean and HRCT pattern is nonspecific. This is the first case presenting a “crazy paving” pattern associated with BAL lymphocytosis.\n\nConclusion:\nOncologists, pulmonologists, radiologists and general practitioners have to consider PD-1 and PD-L1 inhibitor pneumonitis as a potentially disabling and fatal event.\n\nKeywords\nPembrolizimabPD-1 inhibitorspulmonary toxicitypneumonitisNSCLCICIsHRCT\n==== Body\n1 INTRODUCTION\nNon-Small Cell Lung Cancer (NSCLC) is a common disease with a high mortality rate and poor response to cytotoxic therapy. In recent years, immunotherapeutic agents that target immune checkpoint pathways have shown great promise in clinical practice and have been incorporated into the standard managementof NSCLC [1]. These immunotherapies block the function of Immune Checkpoints (ICIs), thereby promoting T cell-mediated antitumor responses. Optimal T-cell activation requires two signals. The first signal involves the interaction between the T-Cell Receptor (TCR) and its cognate peptide-major histocompatibility complex molecule expressed on antigen presenting cells (APCs). The second co-stimulatory signal comprises CD28, which is constitutively expressed on T cells, binding to B7 ligands expressed on professional APCs. Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an ICI that bears structural similarity to CD28, and it is upregulated on activated T cells and constitutively expressed on regulatory T cells. CTLA-4 competes with CD28 for binding to the B7 ligands, and it inhibits T cell–mediated immune responses. Other ICIs belonging to theCD28/B7 superfamily have been identified, and they include programmed cell death protein 1 (PD-1) and its ligand, PD-L1. Monoclonal antibodies targeting CTLA-4 (ipilimumab, tremelimumab), PD-1 (nivolumab, pembrolizumab), and PD-L1 (durvalumab, atezolizumab, avelumab) have been designed to block the function of these immune checkpoints, resulting in enhanced antitumoral responses. ICIs can cause a spectrum of toxicities mediated by their immunologic mechanism of action, including thyroiditis, colitis, myocarditis, inflammatory arthritis, hypophysitis and others [2, 3]. Pneumonitis is a serious autoimmune toxicity associated with the use of anti-PD-1/PD-L1 antibodies, resulting in significant morbidity and mortality rates, often resulting in the discontinuation of therapy [4]. In a recent meta- analysis of all published clinical trials of PD-1 and PD-L1 inhibitor therapy, the overall incidence of pneumonitis in the PD-1 inhibitor group was 3.6% and in the PD-L1 inhibitor group 1.3% [5].\n\n2 CLINICAL PRESENTATION\nA 73-year-old woman with no history of smoking was admitted to the hospital in October 2018 for severe weakness and dyspnea on minimal exertion. The symptoms appeared a couple of months ago and worsened in the last two weeks.\n\nShe had received a diagnosis of NSCLC (adenocarcinoma: EGFR, ALK, ROS1, MET, KRAS, BRAF, WILD Type, PDL1 5%) 18 months before. She had no comorbidities and was not taking any drug. The CT- scan and PET-CT scan showed a lesion 7.5 cm in diameter on the superior segment of the upper left lobe and 3 metastatic nodules in the right lung with an enlargement of the hilar lymph nodes (T4N2M1) She began neoadjuvant chemotherapy (June 2017) with Carbo/pemetrexed (pemetrexed 500 mg/m2 and carboplatin AUC 5 mg/mL per min) for 4 cycles and then continued with pemetrexed. The thoracic surgeon re-evaluated the patient but ruled out the possibility of radical surgical treatment. In April 2018 a CT scan showed an increased size in the principal lesions and the appearance of a new lesion in the right lung. At the end of April, she started a second line therapy with Pembrolizumab at a dose of 2\\mg\\Kg die every 3 weeks. Four months later she began to experience dyspnea during exertion. Chest X-ray, spirometry (curve\\volume curve), echocardiography and exercise test were normal. The patient first came to our attention at the beginning of October; on that occasion we performed a blood gas analysis at rest (pH 7.38, PaO2 66 mmHg, PaCO2 38 mmHg) and a global spirometry including carbon monoxide diffusing capacity (DLco)showing a significant reduction (60% of that predicted). Physical examination highlighted the presence of fine crackles at the end of inspiration in the left lower lobe. The blood exams showed a normal value of ESR (7 mm) and CRP (0.5mg\\L), and a minimal increase in LDH (800 U\\l). High resolution contrast tomography highlighted the presence of diffuse parenchymal opacity with “air bronchogram” resembling organizing pneumonia (OP) at the upper lung lobes and widespread thickening of the interlobular interstitium, the so-called “crazy paving” pattern, in the left lower lobe (Figs. 1 and 2). In a few days her clinical condition worsened. Arterial blood gas value at rest was: PaO2 44 mmHg, PaCO3 32 mmHg, pH 7.50, HCO3- 16 mEq\\L. Bronchoscopy with bronchoalveolar lavage (BAL) was negative for infections (viral, fungal, bacterial and Pneumocystis jirovecii). The BAL pattern showed a mild lymphocytosis (20% of total cell count) with a normal CD4\\CD8 ratio. A diagnosis of checkpoint inhibitor pneumonitis was made considering the close relationship between starting pembrolizumab and symptoms appearing, the CT scan pattern, and the BAL data: mild lymphocytosis with normal T Helper\\suppressor ratio and the negative results for infection. Pembrolizumab was stopped and steroid therapy (2 mg\\Kg die) was started. The patient gained clinical stability after a week and was discharged with long term oxygen therapy (4\\l\\min at rest and 5\\l\\min walking).\n\n3 DISCUSSION\nAn expanding body of evidence supports the efficacy of ICIs in a variety of tumor types. In NSCLC, anti PD-1 /PD-L1 ICIs have been studied in the first line, maintenance and second-line setting [1, 3]. The incidence of pneumonitis has been evaluated in large clinical trials and in meta-analyses. Khunger et al. showed an overall incidence of all-grade pneumonitis in the PD-1 inhibitor group of 3.6% and in the PD-L1 inhibitor group of 1.3%. The use of PD-1 and PD-L1 inhibitors in the first line setting was associated with a significantly higher incidence of all-grade pneumonitis compared with previously treated patients [4, 5]. Khunger et al. hypothesized that the lower incidence of pneumonitis in PD-L1 inhibitors could be due to the sparing of PD-1/programmed death-ligand 2 (PD-L2) interaction with PD-L1 inhibitors, which might be an important player in mediating immune tolerance in the lungs [5]. There were seven deaths attributed to pneumonitis, all in patients who had been treated with PD-1 inhibitors. Across all the trials, no clear relationship between the occurrence of pneumonitis and treatment duration or dose level was noted. Six out of these seven patients were former smokers, and three were treated with radiation therapy prior to PD-1/PD-L1 inhibitor therapy. In patients with underlying pulmonary pathologies, such as COPD, interstitial lung diseases, and lung cancer often resulting from smoking exposure, early diagnosis of pneumonitis is challenging, and failure to recognize the symptoms and signs of pneumonitis could lead to poor outcomes [1, 5]. The time to onset of symptoms from drug administration can be quite variable. Naidoo and coworkers reported a median time to onset of symptoms of 2.8 months. [6] Suresh et al suggest that more severe grades of pneumonitis tend to occur within 100 to 200 days of therapy initiation. [1] Chest CT scan (HRCT) is the imaging modality of choice for diagnosis. Nishino at al reviewed imaging from 20 cases and reported an Organizing Pneumonia (OP) pattern in 65% of cases, followed by nonspecific interstitial pneumonia (NSIP) in 15% of cases. [7] The role of bronchoscopy is currently unknown. The vast majority of patients undergo bronchoscopy to rule out infections. However, studies examining the utility of BAL are sparse. [1] Recently, Leroy et al. published a report of 3 cases of patients with metastatic melanoma and lung metastasis. They developed pulmonary toxicities with an NSIP- OP pattern on TC scan and BAL data showed a mild lymphocytosis (ranging from 22-35%). The management strategy is based on corticosteroid therapy. Current guidelines recommend a dose of 1 mg\\kg\\die of prednisone, and 2-4 mg\\Kg\\die for higher grade pneumonitis. Patients who remain without clinical improvement after 72 hours of therapy are considered steroid refractory. In these cases infliximab, IV Immunoglobulin, and tocilizumab may play a key role [8-10]. Our case has some peculiarities. The first clinical manifestation appeared 4 months after the start of therapy and worsened progressively in a couple of months. The only clinical manifestation was dyspnea on minimal exertion accompanied by oxygen desaturation. High-resolution contrast tomography described a unilateral “crazy paving” pattern that is the hallmark of this case. Interesting was BAL data showing considerable lymphocytosis with a normal CD4\\CD8 ratio. Systemic steroids were useful in gaining clinical and radiological stability.\n\nCONCLUSION\nTo conclude, pneumonitis induced by ICIs, and in particular PD-1 inhibitors, is frequent in everyday clinical practice. Given the nonspecific pattern on presentation, vigilant attention to respiratory symptoms is required for early detection of pulmonary involvement. Pulmonologists, oncologists, radiologists and general practitioners have to consider this important and potentially fatal adverse event. Unilateral “crazy paving” on HRCT and lymphocytosis in BAL may be useful tools.\n\nACKNOWLEDGEMENTS\nDeclared none.\n\nETHICS APPROVAL AND CONSENT TO PARTICIPATE\nNot applicable.\n\nHUMAN AND ANIMAL RIGHTS\nNot applicable.\n\nCONSENT FOR PUBLICATION\nNot applicable.\n\nSTANDARD FOR REPORTING\nThe CARE guidelines and methodologies were followed in this study.\n\nFUNDING\nNone.\n\nCONFLICT OF INTEREST\nThe authors declare no conflict of interest, financial or otherwise.\n\nFig. (1) HRCT, duffuse parenchimal opacities with air bronchogram at the upper lobes.\n\nFig. (2) HRCT, widespread thickening of the interlobular interstitium (crazy paving pattern) in the lower lobe.\n==== Refs\nREFERENCES\n1 Suresh K. Naidoo J. Ting Lin C. Immune checkpoint immunotherapy for non-small cell lung cancer. Chest 2018 154 1416 1423 30189190 \n2 Morgensztern D. Herbst R.S. Nivolumab and pembrolizumab for non-small cell lung cancer. Clin. Cancer Res. 2016 22 3713 3717 27252413 \n3 Pardoll D.M. The blockade of immune check points in cancer immunotherapy. Nat. Rev. Cancer 2012 12 252 264 22437870 \n4 Nishino M. Giobbie-Hurder A. Fatabu H. Incidence of programmed cell death 1 inhibitor related pneumonitis in patents with advance cancer: A systematic review and meta-analysis. JAMA Oncol. 2016 2 1607 1616 27540850 \n5 Khunger M. Rakshit S. Pasupuleti V. Incidence of pneumonitis with use of PD-1 and PD-L1 inhibitors in non-small cell lung cancer: A systematic review and meta-analysis of clinical trials. Chest 2017 152 271 281 28499515 \n6 Naidoo J. Page D.B. Li B.T. Pneumonitis in patients treated with PD-1 and PD-L1 therapy. J. Clin. Oncol. 2017 35 709 717 27646942 \n7 Nishino M. Ramaya N.H. Award M.M. PD-1 inhibitor related pneumonitis in advance cancer patients: Radiographic pattern and clinical course. Clin. Cancer Res. 2016 22 6051 6060 27535979 \n8 Leroy V. Templier C. Faivre J-B. Pembrolizumab-induced pneumonitis. ERJ Open Res. 2017 3 00081 02016 28480216 \n9 Trotti A Colevas A.D. Setser A. Patients reported outcomes and the evolution of adverse events report in oncology. J. Clin. Oncol. 2007 25 5121 5127 17991931 \n10 Puzanov I. Diab A. Abdallah K. Management toxicities associated with immune check point inhibitors consensus recommendations from the Society of Immunotherapy of cancer toxicity management working group. J. Immunother. Cancer 2017 5 95 29162153\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1574-8863",
"issue": "14(3)",
"journal": "Current drug safety",
"keywords": "HRCT; ICIs; NSCLC; PD-1 inhibitors; Pembrolizimab; pneumonitis; pulmonary toxicity.",
"medline_ta": "Curr Drug Saf",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D006801:Humans; D008171:Lung Diseases; D008175:Lung Neoplasms; D061026:Programmed Cell Death 1 Receptor; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101270895",
"other_id": null,
"pages": "242-245",
"pmc": null,
"pmid": "30864509",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "30189190;27252413;17991931;28499515;27535979;27540850;29162153;28480216;22437870;27646942",
"title": "A \"Crazy Paving\" Pattern on CT Scan in a Patient Treated with Pembrolizumab.",
"title_normalized": "a crazy paving pattern on ct scan in a patient treated with pembrolizumab"
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"abstract": "BACKGROUND\nConstitutional mismatch repair deficiency syndrome results from bi-allelic inheritance of mutations affecting the key DNA mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. Individuals with bi-allelic mutations have a dysfunctional mismatch repair system from birth; as a result, constitutional mismatch repair deficiency syndrome is characterised by early onset malignancies. Fewer than 150 cases have been reported in the literature over the past 20 years. This is the first report of the founder PMS2 mutation - NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11 and its associated cancers in this family.\n\n\nMETHODS\nThe proband is 30 years old and is alive today. She is of Pakistani ethnic origin and a product of consanguinity. She initially presented aged 24 with painless bleeding per-rectum from colorectal polyps and was referred to clinical genetics. Clinical examination revealed two café-au-lait lesions, lichen planus, and a dermoid cyst. Her sister had been diagnosed in childhood with an aggressive brain tumour followed by colorectal cancer. During follow up, the proband developed 37 colorectal adenomatous polyps, synchronous ovarian and endometrial adenocarcinomas, and ultimately a metachronous gastric adenocarcinoma. DNA sequencing of peripheral lymphocytes revealed a bi-allelic inheritance of the PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11. Ovarian tumour tissue demonstrated low microsatellite instability. To date, she has had a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and a total gastrectomy. Aspirin and oestrogen-only hormone replacement therapy provide some chemoprophylaxis and manage postmenopausal symptoms, respectively. An 18-monthly colonoscopy surveillance programme has led to the excision of three high-grade dysplastic colorectal tubular adenomatous polyps. The proband's family pedigree displays multiple relatives with cancers including a likely case of 'true' Turcot syndrome.\n\n\nCONCLUSIONS\nConstitutional mismatch repair deficiency syndrome should be considered in patients who present with early onset cancer, a strong family history of cancer, and cutaneous features resembling neurofibromatosis type I. Immunohistochemistry analysis of tumour and normal tissue is sensitive and specific for identifying patients with mismatch repair deficiency and should direct DNA sequencing of lymphocytic tissue to establish a diagnosis. Microsatellite instability status appears to be of little value in identifying patients who may have constitutional mismatch repair deficiency syndrome.",
"affiliations": "The University of Manchester, Oxford Road, Manchester, M13 9PT, UK.;Clinical Research Fellow, Division of Molecular & Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, Fifth Floor - Research, St Mary's Hospital, University of Manchester, Oxford Road, Manchester, M13 9WL, UK. neilryan@nhs.net.;Gynaecological Oncology, Division of Molecular & Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, Fifth Floor - Research, St Mary's Hospital, University of Manchester, Oxford Road, Manchester, M13 9WL, UK.;Medical Genetics and Cancer Epidemiology, Genomic Medicine, Manchester Academic Health Science Centre, The University of Manchester, Oxford Road, Manchester, M13 9WL, UK.",
"authors": "Ramchander|N C|NC|;Ryan|N A J|NA|http://orcid.org/0000-0003-3117-3257;Crosbie|E J|EJ|;Evans|D G|DG|",
"chemical_list": "D004247:DNA; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2",
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"fulltext": "\n==== Front\nBMC Med GenetBMC Med. GenetBMC Medical Genetics1471-2350BioMed Central London 39110.1186/s12881-017-0391-xCase ReportHomozygous germ-line mutation of the PMS2 mismatch repair gene: a unique case report of constitutional mismatch repair deficiency (CMMRD) Ramchander N. C. neal.ramchander@student.manchester.ac.uk 1http://orcid.org/0000-0003-3117-3257Ryan N. A. J. +44 (0)161 701 19119neilryan@nhs.net 2Crosbie E. J. emma.crosbie@manchester.ac.uk 34Evans D. G. gareth.evans@manchester.ac.uk 561 grid.5379.8The University of Manchester, Oxford Road, Manchester, M13 9PT UK 2 grid.5379.8Clinical Research Fellow, Division of Molecular & Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, Fifth Floor - Research, St Mary’s Hospital, University of Manchester, Oxford Road, Manchester, M13 9WL UK 3 grid.5379.8Gynaecological Oncology, Division of Molecular & Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, Fifth Floor - Research, St Mary’s Hospital, University of Manchester, Oxford Road, Manchester, M13 9WL UK 4 grid.411037.0Department of Obstetrics and Gynaecology, Manchester, Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK 5 grid.5379.8Medical Genetics and Cancer Epidemiology, Genomic Medicine, Manchester Academic Health Science Centre, The University of Manchester, Oxford Road, Manchester, M13 9WL UK 6 grid.416523.7Central Manchester University Hospitals NHS Foundation Trust, Saint Mary’s Hospital, Oxford Road, Manchester, M13 9WL UK 5 4 2017 5 4 2017 2017 18 4015 10 2016 6 3 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\nConstitutional mismatch repair deficiency syndrome results from bi-allelic inheritance of mutations affecting the key DNA mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. Individuals with bi-allelic mutations have a dysfunctional mismatch repair system from birth; as a result, constitutional mismatch repair deficiency syndrome is characterised by early onset malignancies. Fewer than 150 cases have been reported in the literature over the past 20 years. This is the first report of the founder PMS2 mutation - NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11 and its associated cancers in this family.\n\nCase presentation\nThe proband is 30 years old and is alive today. She is of Pakistani ethnic origin and a product of consanguinity. She initially presented aged 24 with painless bleeding per-rectum from colorectal polyps and was referred to clinical genetics. Clinical examination revealed two café-au-lait lesions, lichen planus, and a dermoid cyst. Her sister had been diagnosed in childhood with an aggressive brain tumour followed by colorectal cancer. During follow up, the proband developed 37 colorectal adenomatous polyps, synchronous ovarian and endometrial adenocarcinomas, and ultimately a metachronous gastric adenocarcinoma. DNA sequencing of peripheral lymphocytes revealed a bi-allelic inheritance of the PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11. Ovarian tumour tissue demonstrated low microsatellite instability. To date, she has had a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and a total gastrectomy. Aspirin and oestrogen-only hormone replacement therapy provide some chemoprophylaxis and manage postmenopausal symptoms, respectively. An 18-monthly colonoscopy surveillance programme has led to the excision of three high-grade dysplastic colorectal tubular adenomatous polyps. The proband’s family pedigree displays multiple relatives with cancers including a likely case of ‘true’ Turcot syndrome.\n\nConclusions\nConstitutional mismatch repair deficiency syndrome should be considered in patients who present with early onset cancer, a strong family history of cancer, and cutaneous features resembling neurofibromatosis type I. Immunohistochemistry analysis of tumour and normal tissue is sensitive and specific for identifying patients with mismatch repair deficiency and should direct DNA sequencing of lymphocytic tissue to establish a diagnosis. Microsatellite instability status appears to be of little value in identifying patients who may have constitutional mismatch repair deficiency syndrome.\n\nKeywords\nConstitutional mismatch repair deficiencyCMMRDMismatch repairMMRPMS2Lynch syndromeTurcot syndromehttp://dx.doi.org/10.13039/501100000265Medical Research CouncilMR/M018431/1http://dx.doi.org/10.13039/501100000272National Institute for Health ResearchNIHR-CS-012-009NF-SI-0513-10076issue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nMismatch repair (MMR) proteins maintain genomic stability [1]. Four of these proteins are pivotal to DNA mismatch repair: MLH1, MSH2, MSH6 and PMS2. Mismatch repair involves the recognition and correction of single DNA base-base mismatches and insertion-deletion loops (IDL’s) that arise during cellular replication, preventing these mutations from persisting in daughter cells [2].\n\nLynch syndrome (formerly known as hereditary nonpolyposis colorectal cancer or HNPCC) is an autosomal dominant cancer predisposition syndrome with a variable penetrance; it results from the inheritance of a heterozygous mutation affecting one of the key mismatch repair genes: MLH1, MSH2, MSH6, or PMS2 [3–5]. The loss of the wild-type allele leads to MMR deficiency, and a hyper-mutated phenotype. The repetitive coding sequences of microsatellites are particularly susceptible to acquiring insertions and deletions of nucleotide bases during cellular replication, which result in frameshift mutations. Mismatch repair deficiency promotes the persistence of these frameshift mutations in daughter cells, measured as microsatellite instability (MSI). Microsatellite instability-high (MSI-H) tumours are characteristic of Lynch syndrome associated colorectal cancer (CRC) [6]. A severe variant of Lynch syndrome is constitutional mismatch repair deficiency (CMMRD), which results from bi-allelic inheritance of an MMR gene mutation [7, 8]. With it comes a poor prognosis; over 50% of patients develop malignant brain tumours, over 30% develop haematological malignancies, and 40% develop digestive tract tumours, all at very young ages [9]. The most frequent cancers observed in CMMRD are brain gliomas, non-Hodgkin’s lymphomas and CRC’s, with an average age at diagnosis of 9.5 years, 5 years, and 16 years, respectively [10]. The cancer spectrum in CMMRD appears to be related to the gene mutated; homozygous carriers of MSH6 and PMS2 mutations develop brain tumours in the first decade of life [10]. Importantly, over 40% of individuals homozygous for a PMS2 mutation develop second primary malignancies. This is in contrast to the 22% of individuals homozygous for MLH1/MSH2 mutations that develop second primary malignancies [10]. This difference may be because individuals with homozygous PMS2 mutations often survive their first malignancy, unlike their MLH1/MSH2 counterparts who develop aggressive haematological malignancies at an average age of 2.5 years. Café-au-lait (CAL) lesions are the most common dermatological manifestation of individuals with CMMRD [11]. Consanguinity of the parents and/or homozygosity for a founder mutation is observed in over 50% of reported cases of CMMRD.\n\nCase presentation\nThe proband is a 30-year-old female of Pakistani ethnic origin and a product of consanguinity; her parents are distant cousins. Her family pedigree is depicted in Fig. 1. The prominent feature was that a sister (III:1) had developed a high-grade parietal lobe astrocytoma aged 10 years but died from a metastatic primary adenocarcinoma of the caecum aged 20 years. The proband (III:3) presented aged 24 years, with painless bleeding per-rectum (PR) and iron deficiency anaemia. This was investigated by colonoscopy at which 10 colonic tubullo-villous adenomatous polyps with low-grade dysplasia were excised. Further clinical investigation was prompted by her unusual presentation. On examination, she had two distinct CAL lesions, one on her right arm and one on her left leg. Both CAL lesions had irregular edges with foci of hypopigmentation within areas of hyperpigmentation (Fig. 2). She also had widespread lichen planus mostly concentrated to her lower limbs, and a dermoid cyst on her left lower back.Fig. 1 Family pedigree for the familial PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11, of a family of Pakistani ethnic origin living in the UK. The proband (III:3, arrow), is homozygous for this PMS2 mutation. She presented with café-au-lait lesions, lichen planus, a dermoid cyst, and bleeding per-rectum. She has developed 37 benign colorectal adenomatous polyps to date. She has developed ovarian and endometrial cancer (both at age 26) and gastric cancer (age 28). III:1 developed a parietal lobe astrocytoma (age 10) and a caecal adenocarcinoma of which she died (age 20); her mutation status is unknown, however III:1’s history is representative of true Turcot syndrome. III:9 died of a brain tumour (age 17); her mutation status is unknown. III:5 has declined genetic testing for the time being. II:5 and II:6, II:7 and II:8, II:11 and II:12 are distant cousins\n\n\nFig. 2 Photograph of the proband’s left leg showing café-au-lait lesions on a background of lichen planus\n\n\n\n\nInitial investigations were for MUTYH associated polyposis (MAP) and Lynch syndrome given the early age of onset of polyps, dermatological manifestations, and very early onset family history of CRC. Direct sequencing of lymphocytic tissue for MUTYH did not reveal any mutations. All tissue analyses performed are summarised in Table 1. Initial immunohistochemistry (IHC) analysis was deemed inconclusive for Lynch syndrome due to perceived poor technical quality of PMS2 staining; there was universal absence of PMS2 antibody uptake in tumour and control tissue.Table 1 Molecular analysis of polypoid and cancerous tumour tissue resected from the proband\n\nMismatch repair protein immunohistochemistry\t\nColorectal polypoid tissue\t• >80% positivity for MLH1, MSH2 and MSH6\n• Inconclusive result for PMS2 (reported poor technical quality of staining)\t\nOvarian tumour tissue\t• >80% positivity for MLH1, MSH2, MSH6\n• 0% positivity for PMS2. In addition, there was 0% positivity for PMS2 expression in control tissue\t\nCancer tumour characteristics\t\nOvarian tumour tissue\t• Positive for CK7, PAX-8 and ER\n• MSI low\t\nGastric tumour tissue\t• Positive for CK7, CDX2 with focal positivity for CX20\n• Negative expression of ER, PR, WT1, PAX8 and GCDFP15\n• There was no evidence of loss of E-cadherin expression\t\nMolecular characteristics of the colorectal polypoid tissue, ovarian cancer tumour tissue, and gastric cancer tumour tissue resected from the proband. Initial colorectal polypoid tissue analysis was deemed inconclusive due to perceived poor technical quality of the staining due to universally absent uptake of the PMS2 antibody\n\n\n\n\nA pelvic ultrasound scan was performed later that year when the patient reported symptoms of bloating. This revealed malignant-looking bilateral ovarian cysts. Bilateral ovarian cystectomy revealed grade 1/grade 2 endometrioid adenocarcinomas affecting both ovaries. Peritoneal washings demonstrated the presence of adenocarcinoma cells. The proband’s tumour phenotype is summarised in Table 2. Immunohistochemistry was repeated on ovarian tissue; 0% tumour positivity and 0% control positivity for PMS2 was established. Microsatellite instability analysis demonstrated the ovarian tumour to be microsatellite instability-low (MSI-L). Sanger dye terminator sequencing of lymphocytic tissue identified that the proband was homozygous for the PMS2 founder mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11, and a diagnosis of CMMRD was made (Fig. 3). The described PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) leads to a downstream stop codon at the 94th amino acid, creating a truncated protein. Given the lack of protein expression on IHC, it is likely that truncation leads to nonsense mediated decay with no protein product. The variant has been seen twice on the Exome Aggregation Consortium (ExAc) with a frequency of 0.0000165, which represents 2 of 30,610 individuals tested.Table 2 Cancer tumour tissue histology and the management of malignancies in the proband\n\nYear\tProband’s age\tLocation\tTumour histology\tStage (Grade)\tManagement\t\nAug. 2012\t26y9m\tOvaries\tEndometrioid adenocarcinoma\tFIGO Stage 1c (Grade 2)\tTotal abdominal hysterectomy with bilateral salpingo-oophorectomy\t\nOct. 2012\t26y10m\tUterus\tEndometrioid adenocarcinoma\tFIGO 2009 Stage 1a (Grade 1)\tTotal abdominal hysterectomy with bilateral salpingo-oophorectomy\t\nDec. 2013\t28y0m\tStomach\tGastric Adenocarcinoma\tT3N2M0 (Grade 3)\tTotal gastrectomy with neoadjuvant chemotherapy\t\nThe proband has developed multiple malignancies since first presenting at age 24. Her first malignancy (ovarian cancer) was diagnosed less than three years after initial presentation. Despite presenting with bleeding PR, the patient has not yet developed colorectal cancer. Aggressive surgical management was used for her gynaecological malignancies, and a combination of neoadjuvant chemotherapy and surgery was used for her gastric malignancy\n\n\nFig. 3 Sanger sequence of the proband’s peripheral lymphocytes showing PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11. Arrow points to homozygous loss of cytosine at the 1500 frame\n\n\n\n\nThe proband underwent full staging surgery with a total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), and partial omentectomy. No residual ovarian disease was present, which corresponds to an International Federation of Gynecology and Obstetrics FIGO Stage 1c (Grade 2) endometrioid adenocarcinoma of the ovary. An incidental, synchronous FIGO Stage 1a (Grade 1) endometrioid adenocarcinoma of the endometrium was identified during routine post operative histological examination of the uterus. Adjuvant chemotherapy was not used.\n\nThe proband was then initiated on an 18-monthly colonoscopy-surveillance program and advised to take daily aspirin (75mg-150mg) for chemoprevention against MSI-H CRC. In total, the proband has had 37 adenomatous large bowel polyps excised; three of these were high-grade dysplastic tubular adenomatous polyps of the rectosigmoid that were identified and excised as part of her surveillance programme following diagnosis. She was also initiated on oestrogen-only hormone replacement therapy (HRT) following unsuccessful vasomotor menopausal treatment with venlafaxine.\n\nThe following year she developed nausea and vomiting, and as a result, an urgent oesophago-gastro-duodenoscopy was performed. Gastric biopsy revealed a poorly differentiated adenocarcinoma in the body of the stomach and confirmed it was a primary tumour that did not represent recurrence (Table 1). She was treated with neoadjuvant chemotherapy followed by total gastrectomy and completion of omentectomy, with the excision of 0.5 cm of the lower oesophagus and 1.3 cm of the duodenum. This revealed a poorly differentiated primary gastric adenocarcinoma (T3N2M0) with diffuse widespread infiltration through the muscularis propria into the subserosal tissue. Four lymph nodes showed evidence of metastatic adenocarcinoma.\n\nImmunohistochemistry analysis for MLH1, MSH2, MSH6 and PMS2 was performed on 4μm formalin fixed, paraffin embedded tissue sections using the automated Ventana BenchMark ULTRA IHC/ISH Staining Module (Ventana Co., Tucson, AZ, United States) together with the OptiView, 3′ diaminobenzidine (DAB) version 5 detection system (Ventana Co., Tucson, AZ, United States). 0% staining intensity for an MMR protein was regarded as negative expression of that protein.\n\nMicrosatellite instability analysis was performed on ovarian tumour tissue using the Promega MSI analysis system v1.2 (Wisconsin, United States). The MSI Analysis System includes fluorescently labelled primers for co-amplification of seven markers including five mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27) and two pentanucleotide repeat markers (Penta C and Penta D). The mononucleotide markers were used for MSI determination, and the pentanucleotide markers were used to detect potential sample mix-ups and/or contamination. In addition, control lymphocytic tissue from the proband was analysed using the same platform.\n\nPeripheral lymphocytes were utilised for genetic sequencing. Mutations in the MUTYH (formerly known as MYH) and MMR genes were searched for using dye terminator Sanger sequencing on ABI Genetic Analysis of the exon regions of the coding sequences. Sequence analysis of exons 2, 4, 6, 7, 13 and 14 of the MUTYH gene was used to detect common Indian and Pakistani mutations (p.Tyr104Ter and p.Glu480Ter) and common European mutations (p.Tyr179Cys and p.Glu396Asp). The reference sequence for the MUTYH gene was NM_001128425.1. All 19 exons in MLH1, 16 exons in MSH2 and 10 exons in MSH6 were sequenced in both directions. Analysis of mutations in the PMS2 exon coding sequence was complicated by presence of multiple pseudogenes corresponding to exons 1–5 of PMS2 and a single large pseudogene encompassing exons 9 and 11–15 of PMS2. Exon 11 particularly had a high homology to the pseudogene. Long range PCR was performed first to amplify PMS2 (and not the pseudogene PMS2CL) prior to Sanger sequencing. Multiple ligation dependent probe amplification (MLPA) was used to detect dosage abnormalities in exons 1–11 of PMS2 using kit P008-B1 [MRC-Holland]. Due to gene conversion and technical issues, analysis of exons 13–15 was not performed. The reference sequence for PMS2 was NM_000535.5.\n\nTissue analysis results are summarised in Table 1. Of note, the initial IHC staining of polypoid tissue and non-malignant control tissue was deemed inconclusive due to absent uptake of the PMS2 antibody in both the polypoid tissue and control tissue; this was attributed to poor technical quality of the staining. This delayed diagnosis until subsequent IHC analysis of the ovarian tumour, which established 0% immunopositivity for PMS2 in tumour tissue and control tissue. This prompted DNA sequencing of lymphocytic tissue, resulting in diagnosis of the proband as homozygous for the founder PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11.\n\nDiscussion\nHere we present the rare case of a young woman with CMMRD, a severe variant of Lynch syndrome. The proband presented in her twenties with PR bleeding, went on to develop multiple gynaecological malignancies, and ultimately, an advanced primary gastric tumour. Both of these cancer types are rare amongst individuals with CMMRD; the later represents the first reported gastric malignancy in a confirmed case of CMMRD. CMMRD is rare and poses both a diagnostic and managerial challenge. It is interesting to note the delay in onset of disease in this individual. One may speculate that this results from retained PMS2 function despite the mutation. The complete loss of protein expression on IHC suggests that this explanation is unlikely. In addition, pathological mutations identified in distal exons indicate the structural functionality of PMS2 lies beyond exon 11. Both of these observations would support nonsense decay of PMS2 consequent to the reported mutation.\n\nA review of 146 cases of CMMRD conducted by Wimmer et al. concluded that PMS2 mutations were responsible for 60% of cases, with the remaining being MLH1, MSH2 and MSH6 mutations; this is in contrast to Lynch syndrome, where heterozygous MLH1 and MSH2 mutations are responsible for the majority of cases [10]. In CMMRD, MLH1/MSH2 mutations carry a worse prognosis compared to MSH6/PMS2 mutations; individuals with MSH6 or PMS2 mutations often survive their first malignancy and develop secondary malignancies, as was the case in the proband. Heterozygous PMS2 mutations appear to display an attenuated Lynch syndrome phenotype. This is reflected not only by the later age of onset of cancer, but also by the lower penetrance of cancer [12]. A potential explanation for this could be the partial compensation of absent PMS2 by MLH3, which can form a functional heterodimeric protein with MLH1 that has mismatch repair capacity [5]. Neither of the proband’s parents have a history of cancer, reflecting this attenuated phenotype. This presents a diagnostic challenge and highlights the difficulty in identifying familial PMS2 mutations. Several features in the history alluded to a severe inherited cancer predisposition. This included the family history of childhood malignancies, parental consanguinity, early presentation of the patient and the presence of cutaneous signs resembling neurofibromatosis type I (NF-1). The identification of the proband’s homozygous PMS2 mutation status has led to the diagnosis of several family members with Lynch syndrome (Fig. 1).\n\nBakry et al. report that immunohistochemistry of tumour tissue and intratumoural normal tissue is 100% sensitive in detecting MMR deficiency resulting from bi-allelic gene inactivation in CMMRD [8]. Therefore, in cases of early onset cancer, with a history of consanguinity and cutaneous features resembling NF-1, Durno et al. propose performing IHC for MMR proteins on tumour and normal tissue; abnormal IHC in both tumour and normal tissue should alert to CMMRD, and relevant DNA sequencing should follow [11]. Microsatellite instability is the molecular hallmark of Lynch syndrome associated tumours, and hence MSI status is part of the revised Bethesda guidelines for identifying Lynch syndrome [6, 13]. Microsatellite instability status in CMMRD, however, has been reported as neither sensitive nor specific; particularly in extra-intestinal tumours [8]. This suggests it is less reliable as an assessment tool for CMMRD than it is for Lynch syndrome. In the proband, therefore, the fact that her ovarian tumour was MSI-L did not prevent escalation of investigation for MMR deficiency to include genetic sequencing.\n\nAnother diagnostic challenge arises from the presentation individuals with CMMRD: often with CAL lesions, which raises the differential of NF-1. Neurofibromatosis type I is an autosomal dominant condition, and a clinical diagnosis can be made using the National Institute of Health (NIH) criteria [14]. Whilst other features of NF-1 are observed in patients with CMMRD, such as Lisch nodules, plexiform neurofibromas and axillary freckling, they rarely meet the diagnostic criteria [15]. The proband did not meet these criteria. The CAL lesions observed in the proband displayed diffuse borders with areas of hypopigmentation within lesions of hyperpigmentation, as reported elsewhere in the CMMRD literature [10]. This is in contrast to the homogenous, well-demarcated CAL lesions observed in NF-1 [14, 16, 17].\n\nLooking to other reported cases of CMMRD, brain tumours have been observed in 53% of cases [9]. Gliomas are the most common, and present in the first decade of life. Other brain tumours include supratentorial neuroectodermal tumours and meduloblastomas. III:1 developed a parietal lobe astrocytoma aged 10 followed by CRC aged 20. Genetic testing was never performed, however her history strongly reflects PMS2 mutation homozygosity. It is interesting to note that III:1’s history could be representative of ‘true’ Turcot syndrome. Brain tumour polyposis syndrome (BTPS) is defined by a combination of synchronous or metasynchronous brain and colonic neoplasms [18–20]. BTPS is divided into type 1 and type 2. The distinctions between BTPS type 1 and BTPS type 2 lie in their modes of inheritance and tumour phenotypes. BTPS type 1 refers to autosomal recessive inheritance of MMR gene mutations with the development of Lynch syndrome and the childhood (<20 years) onset of brain glial tumours (glioblastomas or astrocytomas). BTPS type 1 is in keeping with McKusick’s original description of Turcot syndrome and with a CMMRD spectrum disease [21, 22]. BTPS type 2 refers to autosomal dominant inheritance of APC gene mutations with the development of Familial Adenomatous Polyposis (FAP), and the development of brain medulloblastomas [20]. The authors suggest that a diagnosis of Turcot syndrome be restricted to patients with homozygous loss of MMR, that is CMMRD, and not in those with heterozygous loss of MMR or FAP with neurological tumours.\n\nThe management of CMMRD individuals is without a solid evidence base. The effectiveness of chemotherapy in patients with MSI-H Lynch syndrome associated tumours is unknown; there is some evidence that these tumours are less responsive to 5-fluorouracil based chemotherapy [23, 24]. Importantly, there is also the possibility of accelerated mutagenesis and the development of second malignancies when CMMRD cells are exposed to alkylating agents [25]. Our patient was not treated with adjuvant chemotherapy. This was in light of the uncertain benefit of such treatment in CMMRD and the risk of accelerated tumourigenesis. The patient did however receive neoadjuvant chemotherapy preceding her gastrectomy.\n\nAnother important aspect of the proband’s management was the decision to start her on oestrogen-only HRT. This was to reduce the symptoms of menopause, as well as protect against the development of CRC and osteoporosis. The proband was also advised to take daily aspirin. This has been shown to reduce the incidence of CRC in Lynch syndrome [26]. Further clarity is required regarding its efficacy in CMMRD patients, as the molecular mechanism of aspirin in preventing colorectal cancer is attributed to its suppressive effect of an MSI phenotype, via a nitric oxide mediated genetic selection that enhanced apoptosis of cells undergoing MSI [27].\n\nA wide tumour phenotype is observed in CMMRD as well as a variable age of tumour onset. The age-dependent levels of mitotic activity in local tissue could explain this. Tissue with increased mitotic activity, combined with an inability to correct accumulating DNA mismatches and IDL’s, is predisposed to tumourigenesis. This wide tumour spectrum complicates the implementation of an effective, comprehensive surveillance program. Screening should target the most common cancers observed in CMMRD patients for that age group. The European Consortium provided screening guidance for the management of individuals with CMMRD [9]. The routine colonoscopy surveillance of patients with Lynch syndrome has reduced CRC-mortality by over 60% [28]. To improve sensitivity, it is recommended to combine chromoscopy with colonoscopy [29, 30]. The European Consortium recommend annual video-capsule endoscopy (VCE) and ileocolonoscopy for patients with CMMRD to identify small and large bowel cancer [9]. Patients with CMMRD who have multiple colorectal adenomas are recommended a shorter screening interval of 6 months. The proband is currently on an 18-monthly colonoscopy and VCE-screening program, in keeping with the standard UK Lynch syndrome protocol [31]. An annual or 6-monthly colonoscopy program was not utilised due to the absence of a robust evidence base and the difficulty of the bowel prep following her gastrectomy. Her surveillance program has resulted in the identification and excision of three adenomatous polyps with high-grade dysplasia, and so in the proband, surveillance has been successful.\n\nPsychosocial support is central to providing holistic care for patients, as well as the families of patients, with CMMRD. This can improve familial uptake of diagnostic testing and compliance with surveillance programs [32]. The use of a multidisciplinary team throughout the proband and her family’s care has therefore been, and continues to be, vital.\n\nConclusions\nIn conclusion, the proband is part of the novel CMMRD cohort described over the last 20 years; we describe here for the first time her family’s PMS2 mutation. She is unique within this cohort in that she did not develop a childhood malignancy, but rather presented in the third decade of her life with rectal bleeding. Even more interesting is that further investigation did not reveal cancer. Her primary tumours were bilateral ovarian endometrioid adenocarcinomas. Her gastric malignancy was a metachronous tumour unrelated to her endometrial and ovarian tumours and represents the first of its kind in the CMMRD literature. Constitutional mismatch repair deficiency is a poorly described cancer predisposition syndrome. We have outlined the diagnosis and treatment of this case, which highlights the complexity of diagnosing CMMRD. The proposed guidelines by Durno et al. for identifying patients at risk of having CMMRD, along with the European consortium’s proposed guidelines on surveillance in CMMRD, are therefore invaluable resources and should be used to direct the diagnosis and management of individuals with CMMRD [9, 11].\n\nAbbreviations\nBSOBilateral salpingo-oophorectomy\n\nBTPSBrain tumour polyposis syndrome\n\nCALCafé-au-lait lesion\n\nCMMRDConstitutional mismatch repair deficiency\n\nCRCColorectal cancer\n\nFIGOInternational Federation of Gynaecology Oncology\n\nHRTHormone replacement therapy\n\nIDLInsertion-deletion loop\n\nIHCImmunohistochemistry\n\nMAPMUTYH associated polyposis\n\nMMRMismatch repair\n\nMSIMicrosatellite instability\n\nMSI-HMicrosatellite instability-high\n\nMSI-LMicrosatellite instability-low\n\nNF-1Neurofibromatosis type 1\n\nPRPer-rectum\n\nTAHTotal abdominal hysterectomy\n\nVCEVideo capsule endoscopy\n\nAcknowledgements\nThe authors would like to thank Dr. Lindsay Helen, clinical scientist at the Leeds Genetics Laboratory and Dr. Andrew Wallace, clinical scientist at St Mary’s Hospital Manchester.\n\nFunding\nNR is an MRC Doctoral Research Fellow (MR/M018431/1). EJC is a National Institute for Health Research (NIHR) Clinician Scientist (NIHR-CS-012-009) and DGE is an NIHR Senior Investigator (NF-SI-0513-10076). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.\n\nAvailability of data and materials\nThe datasets generated and/or analysed during the current study are not publicly available due to patient confidentiality.\n\nAuthors’ contribution\nNCR produced a first draft of this manuscript. All authors contributed extensively to the writing of the final manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the signed consent form was sent to the Editor-in-Chief of BMC Medical Genetics ahead of publication.\n\nEthics approval and consent to participate\nThe interventions presented in this report are inline with standard of care. The individual has given their consent for their case, clinical investigations and images to be published. The consent form is available.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Kolodner RD Marsischky GT Eukaryotic DNA mismatch repair Curr Opin Genet Dev 1999 9 1 89 96 10.1016/S0959-437X(99)80013-6 10072354 \n2. Kunkel TA Erie DA DNA Mismatch Repair Annu Rev Biochem 2005 74 1 681 710 10.1146/annurev.biochem.74.082803.133243 15952900 \n3. Warthin AS Heredity With Reference To Carcinoma: As Shown By the Study of the Cases Examined in the Pathological Laboratory of the University of Michigan, 1895-1913 Arch Intern Med 1913 12 5 546 55 10.1001/archinte.1913.00070050063006 \n4. Douglas JA Gruber SB Meister KA Bonner J Watson P Krush AJ History and molecular genetics of Lynch syndrome in family G: a century later JAMA 2005 294 17 2195 202 10.1001/jama.294.17.2195 16264161 \n5. Li G Mechanisms and functions of DNA mismatch repair Cell Res 2008 18 1 85 98 10.1038/cr.2007.115 18157157 \n6. Lynch HT Hitchins MP Shaw TG Lynch JF Roy H Hereditary Colorectal Cancer Arch Intern Med 2010 348 10 15 43 \n7. Ricciardone MD Ozçelik T Cevher B Ozdağ H Tuncer M Gürgey A Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1 Cancer Res 1999 59 2 290 3 9927033 \n8. Bakry D Aronson M Durno C Rimawi H Farah R Alharbi QK Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency consortium Eur J Cancer 2014 50 5 987 96 10.1016/j.ejca.2013.12.005 24440087 \n9. Vasen HF Ghorbanoghli Z Bourdeaut F Cabaret O Caron O Duval A Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D) J Med Genet 2014 51 5 283 93 10.1136/jmedgenet-2013-102238 24556086 \n10. Wimmer K Kratz CP Vasen HF Caron O Colas C Entz-Werle N Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium “care for CMMRD” (C4CMMRD) J Med Genet 2014 51 6 355 65 10.1136/jmedgenet-2014-102284 24737826 \n11. Durno CA Sherman PM Aronson M Malkin D Hawkins C Bakry D Phenotypic and genotypic characterisation of biallelic mismatch repair deficiency (BMMR-D) syndrome Eur J Cancer 2015 51 8 977 83 10.1016/j.ejca.2015.02.008 25883011 \n12. Hendriks YMC Jagmohan-Changur S Van Der Klift HM Morreau H Van Puijenbroek M Tops C Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome) Gastroenterology 2006 130 2 312 22 10.1053/j.gastro.2005.10.052 16472587 \n13. Umar A Boland CR Terdiman JP Syngal S de la Chapelle A Rüschoff J Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability J Natl Cancer Inst 2004 96 4 261 8 10.1093/jnci/djh034 14970275 \n14. Boyd KP Korf BR Theos A Neurofibromatosis type 1 J Am Acad Dermatol 2009 61 1 1 14 10.1016/j.jaad.2008.12.051 19539839 \n15. Gallinger S Aronson M Shayan K Ratcliffe EM Gerstle JT Parkin PC Gastrointestinal Cancers and Neurofibromatosis Type 1 Features in Children with a Germline Homozygous MLH1 Mutation Gastroenterology 2004 126 2 576 85 10.1053/j.gastro.2003.11.008 14762794 \n16. De Vos M Hayward BE Picton S Sheridan E Bonthron DT Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome Am J Hum Genet 2004 74 5 954 64 10.1086/420796 15077197 \n17. Wimmer K Etzler J Constitutional mismatch repair-deficiency syndrome: Have we so far seen only the tip of an iceberg? Hum Genet 2008 124 2 105 22 10.1007/s00439-008-0542-4 18709565 \n18. Turcot J Després J Pierre F Malignant tumors of the central nervous system associated with familial polyposis of the colon Dis Colon Rectum 1959 2 5 465 8 10.1007/BF02616938 13839882 \n19. Itoh H Ohsato K Yao T Iida M Watanabe H Turcot’s syndrome and its mode of inheritance Gut 1979 20 5 414 9 10.1136/gut.20.5.414 223949 \n20. Paraf F Jothy S Van Meir EG Brain tumor-polyposis syndrome: Two genetic diseases? J Clin Oncol 1997 15 7 2744 58 10.1200/JCO.1997.15.7.2744 9215849 \n21. McKusick V Genetic factors in intestinal polyposis JAMA 1962 182 271 7 10.1001/jama.1962.03050420047012 13932116 \n22. Hamilton SR Liu B Parsons RE Papadopoulos N Jen J Powell SM The Molecular Basis of Turcot’s Syndrome N Engl J Med 1995 332 13 839 47 10.1056/NEJM199503303321302 7661930 \n23. Carethers JM Chauhan DP Fink D Nebel S Bresalier RS Howell SB Mismatch repair proficiency and in vitro response to 5-fluorouracil Gastroenterology 1999 117 1 123 31 10.1016/S0016-5085(99)70558-5 10381918 \n24. Vasen HF Moslein G Alonso A Bernstein I Bertario L Blanco I Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer) J Med Genet 2007 44 6 353 62 10.1136/jmg.2007.048991 17327285 \n25. Hunter C Smith R Cahill DP Stephens P Stevens C Teague J A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy Cancer Res 2006 66 8 3987 91 10.1158/0008-5472.CAN-06-0127 16618716 \n26. Burn J Gerdes AM MacRae F Mecklin JP Moeslein G Olschwang S Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: An analysis from the CAPP2 randomised controlled trial Lancet 2011 378 9809 2081 7 10.1016/S0140-6736(11)61049-0 22036019 \n27. McIlhatton MA Tyler J Burkholder S Ruschoff J Rigas B Kopelovich L Nitric oxide-donating aspirin derivatives suppress microsatellite instability in mismatch repair-deficient and hereditary nonpolyposis colorectal cancer cells Cancer Res 2007 67 22 10966 75 10.1158/0008-5472.CAN-07-2562 18006842 \n28. Järvinen HJ Aarnio M Mustonen H Aktan-Collan K Aaltonen LA Peltomäki P Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer Gastroenterology 2000 118 5 829 34 10.1016/S0016-5085(00)70168-5 10784581 \n29. Rondagh EJA Gulikers S Gómez-García EB Vanlingen Y Detisch Y Winkens B Nonpolypoid colorectal neoplasms: A challenge in endoscopic surveillance of patients with Lynch syndrome Endoscopy 2013 45 4 257 64 10.1055/s-0032-1326195 23440588 \n30. Niv Y Moeslein G Vasen HF Karner-Hanusch J Lubinsky J Gasche C Quality of colonoscopy in Lynch syndrome Endosc Int open 2014 2 4 252 5 10.1055/s-0034-1377920 \n31. Vasen HF Blanco I Aktan-Collan K Gopie JP Alonso A Aretz S Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts Gut 2013 62 6 812 23 10.1136/gutjnl-2012-304356 23408351 \n32. Watson M Lloyd S Davidson J Meyer L Eeles R Ebbs S The impact of genetic counselling on risk perception and mental health in women with a family history of breast cancer Br J Cancer 1999 79 5–6 868 74 10.1038/sj.bjc.6690139 10070883\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2350",
"issue": "18(1)",
"journal": "BMC medical genetics",
"keywords": "CMMRD; Constitutional mismatch repair deficiency; Lynch syndrome; MMR; Mismatch repair; PMS2; Turcot syndrome",
"medline_ta": "BMC Med Genet",
"mesh_terms": "D000328:Adult; D001483:Base Sequence; D001932:Brain Neoplasms; D015179:Colorectal Neoplasms; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis; D004247:DNA; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006720:Homozygote; D006801:Humans; D000070976:Mismatch Repair Endonuclease PMS2; D009386:Neoplastic Syndromes, Hereditary; D010375:Pedigree",
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"pubdate": "2017-04-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Homozygous germ-line mutation of the PMS2 mismatch repair gene: a unique case report of constitutional mismatch repair deficiency (CMMRD).",
"title_normalized": "homozygous germ line mutation of the pms2 mismatch repair gene a unique case report of constitutional mismatch repair deficiency cmmrd"
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"abstract": "Fixed drug eruption (FDE) is a type of drug-induced cutaneous disorder that characteristically presents with recurrence of similar lesion at the same skin or mucosal site as a result of systemic exposure to a drug. Paracetamol is commonly prescribed analgesic-antipyretic agent in all age group of patients. FDE due to paracetamol is not very common but it is well reported in literature for all age groups. We report a case of a 7-year-old male with FDE due to paracetamol involving upper eyelid and presenting as an eyelid skin necrosis.",
"affiliations": "Department of Pediatrics, Dr Shroff's Charity Eye Hospital, New Delhi, India.;Oculoplasty and Ocular Oncology Services, Dr Shroff's Charity Eye Hospital, New Delhi, India.;Ocular Pathology and Laboratory Services, Dr Shroff's Charity Eye Hospital, New Delhi, India.;Department of Pediatrics, Dr Shroff's Charity Eye Hospital, New Delhi, India.",
"authors": "Kimmatkaar|Prajakta|P|;Das|Sima|S|;Gandhi|Arpan|A|;Taneja|Vidya|V|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen",
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"fulltext": "\n==== Front\nIndian J OphthalmolIndian J OphthalmolIJOIndian Journal of Ophthalmology0301-47381998-3689Medknow Publications & Media Pvt Ltd India 30355885IJO-66-162710.4103/ijo.IJO_448_18Case ReportsParacetamol-induced fixed drug eruption presenting as eyelid skin necrosis Kimmatkaar Prajakta Das Sima 1Gandhi Arpan 2Taneja Vidya Department of Pediatrics, Dr Shroff's Charity Eye Hospital, New Delhi, India1 Oculoplasty and Ocular Oncology Services, Dr Shroff's Charity Eye Hospital, New Delhi, India2 Ocular Pathology and Laboratory Services, Dr Shroff's Charity Eye Hospital, New Delhi, IndiaCorrespondence to: Dr. Sima Das, 128 Ankur Apartments, 7 I P Extension, Patparganj, New Delhi - 110 092, India. E-mail: contactsima@gmail.com11 2018 66 11 1627 1629 05 4 2018 25 6 2018 Copyright: © 2018 Indian Journal of Ophthalmology2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Fixed drug eruption (FDE) is a type of drug-induced cutaneous disorder that characteristically presents with recurrence of similar lesion at the same skin or mucosal site as a result of systemic exposure to a drug. Paracetamol is commonly prescribed analgesic-antipyretic agent in all age group of patients. FDE due to paracetamol is not very common but it is well reported in literature for all age groups. We report a case of a 7-year-old male with FDE due to paracetamol involving upper eyelid and presenting as an eyelid skin necrosis.\n\nEyelidfixed drug eruption (FDE)necrosisparacetamol\n==== Body\nFixed drug eruption (FDE) is commonly seen in children and adolescent age groups. It is defined as a cutaneous drug eruption that recurs at the same site upon administration of the same drug and heals with residual hyperpigmentation. The residual hyperpigmentation serves as an indicator of site recognition.[1] Missing the diagnosis of FDE can lead to recurrent eruptions when the offending drug is readministered.[2] Isolated involvement of the eyelid and periocular skin in FDE is rare. Paracetamol is a readily available over the counter antipyretic and is generally well tolerated at recommended dose. Its cutaneous adverse effects are rare, varying from mild pruritis to severe form of rash as in Stevens–Johnson syndrome and even fatal toxic epidermal necrolysis.[34]\n\nCase Report\nA 7-year-old male child presented with history of painful left upper eyelid swelling with overlying skin excoriation and ulceration of 3 days duration. There was history of associated fever that was treated with antipyretics. On examination he had left upper eyelid erythema and edema causing mild ptosis along with a well-defined area of bluish-purple discoloration of the lateral upper eyelid skin [Fig. 1]. His visual acuity was 20/20 in both eyes and anterior and posterior segments were normal. Ocular movements were full and free. Diagnosis of left eye pre-septal cellulites was made and he was prescribed oral antibiotics. After 3 days there was no improvement in the eyelid swelling and erythema and there was sloughing of the lateral eyelid skin epidermis and the underlying dermis appeared necrotic. A provisional diagnosis of eyelid skin necrotizing fasciitis was made, secondary to preseptal cellulitis. Scrapping from necrotic eyelid skin tissue was sent for microscopy and culture the reports of which were negative.\n\nFigure 1 Edema, erythema, bluish skin discoloration, and necrosis of the epidermis of the left upper eyelid skin after ingestion of paracetamol\n\nOn further enquiry, parents gave history of similar episode of eyelid swelling associated with fever in the past. It subsided on its own after the resolution of the fever. The febrile episodes were treated with paracetamol each time. In view of similar chronological events in each febrile episode and same site of recurrence of the lesion and absence of any other associated systemic illness, possibility of FDE due to antipyretic paracetamol was thought of. Using Naranjo ADR probability scale and WHO-UMC causality system, casual relationship between paracetamol intake and FDE was established.[56] Allergy screening test by serum radioimmunoassay was done and that showed allergy to paracetamol. Paracetamol was discontinued and parents were counselled to avoid use of it for any febrile episodes in future. The eyelid skin lesion healed with hyperpigmentation [Fig. 2].\n\nFigure 2 Healed eyelid skin lesion with hyperpigmentation after discontinuation of paracetamol\n\nDiscussion\nParacetamol is a widely used over the counter analgesic-antipyretic agent and known to have safety profile with very low incidence of side effects. Toxic eruptions induced by paracetamol are rare and usually of the fixed pigmenting type.[3] Paracetamol induced FDE is reported in less than 1.5% of all cases of FDEs.[34] The reactions can present as maculopapular rash, cellulites like reaction, bullous reaction, or pigmenting type.[2378] The pigmenting FDE, usually manifests as round or oval, sharply demarcated erythematous or edematous plaques located on the lip, hip, sacrum, leg, hand, face, oral mucosa, and genitalia.[9] In our case, FDE due to paracetamol is fixed pigmenting type and involved the left upper eyelid and simulated preseptal cellulitis and eyelid skin necrosis. Based on these findings, a provisional diagnosis of necrotizing fasciitis of the eyelid was made and microbiological evaluation of the skin scrapping was done to rule out any infective etiology.\n\nOcular involvement in FDE has been reported rarely in literature. Rubegni et al. have reported a case of generalized FDE from nimesulide with ocular involvement.[10] The ocular symptoms of conjunctival edema and injection were associated with an erythematous plaque over lower eyelid. The generalized skin rash developed within hours of onset of ocular symptoms and the diagnosis was established on skin biopsy and patch test.\n\nIn our patient, similar eyelid involvement had happened with prior exposure to paracetamol without any associated systemic manifestations. The casual relationship with paracetamol was established using Naranjo ADR probability scale (score of +7) and WHO-UMC causality system.[5611] Parents did not give consent for a skin test or drug challenge test and the drug allergy was confirmed by allergy test using serum specific radio immunoassay that showed allergy to paracetamol.\n\nThe erythematous patches or plaques of FDE gradually fade with residual hyperpigmentation. In our case FDE started with left upper lid swelling, erythema, and skin necrosis that healed with residual hyperpigmentation after discontinuation of paracetamol.\n\nFDE may also follow a site-specific eruption pattern. For example, trimethoprim-sulfamethoxazole has been shown to favor the genital region, especially in males and naproxen and the oxicams involve the lips, dipyrone on trunk and extremities.[9] To the best of our knowledge, paracetamol causing site specific FDE has not been reported.\n\nConclusion\nIn conclusion, we report a case of paracetamol-induced FDE involving upper eyelid presenting as eyelid skin necrosis. Paracetamol is widely prescribed by clinicians and is available as over the counter drug. FDE with isolated eyelid involvement will often present to the ophthalmologist and the clinician should be aware of this clinical appearance and suspect FDE in cases with recurrent eyelid skin erythema and edema at same site following ingestion of paracetamol or other drugs. Patient should be advised to avoid the particular drug to prevent further adverse reactions.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Lee AY Fixed drug eruptions.Incidence, recognition, and avoidance Am J Clin Dermatol 2000 1 277 85 11702319 \n2 Nino M Francia MG Costa C Scalvenzi M Bullous fixed drug eruption induced by paracetamol: Report of a pediatric case Case Rep Dermatol 2009 16 56 9 \n3 Hire RC Sontakke S Dakhale GN Kamble A Kale AS Paracetamol induced fixed drug eruption: A case report Int J Basic Clin Pharmacol 2014 3 399 400 \n4 Fathallah N Ben Salem C Slim R Boussofara L Ghariani N Bouraoui K Acetaminophen-induced cellulitis-like fixed drug eruption Indian J Dermatol 2011 56 206 8 21716550 \n5 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 \n6 WHO-UMC. The use of the WHO-UMC system for standardised case causality assessment 2010 last accessed on 2018 Mar 09 Available from: http://who-umc.org/Graphics/24734.pdf \n7 Prabhu MM Prabhu S Mishra P Palaian S Cellulities like fixed drug eruption attributed to paracetamol (Acetoaminophen) Dermatology Online J 2005 11 24 \n8 Raipurkar SV Patel P Mucchal V Khurana R Wadagbalkar P Paracetamol induced fixed drug eruptions: Case report Int J Contemp Pediatr 2015 2 257 9 \n9 Ozkaya-Bayazit E Specific site involvement in fixed drug eruption J Am Acad Dermatol 2003 49 1003 7 14639376 \n10 Rubegni P Tognetti L Tosi GM Flori ML Fimiani M Ocular involvement in generalized fixed drug eruption from nimesulide Clin Exp Ophthalmol 2013 41 896 8 23448657 \n11 Maitra A Bhattacharyya S Paik S Pathak P Tripathi SK A Rare Case of Fixed Drug Eruption due to Ondansetron Iran J Med Sci 2017 42 497 500 29234184\n\n",
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"keywords": "Eyelid; fixed drug eruption (FDE); necrosis; paracetamol",
"medline_ta": "Indian J Ophthalmol",
"mesh_terms": "D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D002648:Child; D003875:Drug Eruptions; D005141:Eyelid Diseases; D005143:Eyelids; D006801:Humans; D008297:Male; D012867:Skin",
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"title": "Paracetamol-induced fixed drug eruption presenting as eyelid skin necrosis.",
"title_normalized": "paracetamol induced fixed drug eruption presenting as eyelid skin necrosis"
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
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"abstract": "BACKGROUND\nCrusted scabies (CS) is a rare, severe and highly contagious form of scabies, which has been reported in immunosuppressed patients. A high index of suspicion and awareness of CS is essential to treat this infestation.\n\n\nMETHODS\nA 13-year-old boy presented with pruritic hyperkeratotic squamous plaques located on both inner wrists, the web spaces of both his hands and his feet, and the genital area of 12 months duration. He was diagnosed with focal segmental glomerulosclerosis at the age of 5 and received a kidney transplant at the age of 9. He has been on a maintenance dose of prednisone (5 mg/d) and mycophenolate mofetil (250 mg/d) for the past 2 years. He had a contact history with a school friend with similar lesions. A skin punch biopsy demonstrated the presence of multiple mites in the stratum corneum confirming the diagnosis of CS. Ivermectin, the recommended drug of choice for crusted scabies, is not available in South Africa. The patient was commenced on topical benzoyl benzoate lotion but discontinued its use because of intolerable irritation. We subsequently prescribed the daily application of topical 5% sulfur in petrolatum to which his pruritus subsided significantly after 2 weeks with resolution of all skin lesions at the end of 8 weeks.\n\n\nCONCLUSIONS\nThis case is the first documented report of CS in a pediatric renal transplant patient. Our management highlights that classic formularies of magistral drugs are still effective treatment options and can be used especially when standard therapies cannot be tolerated or when optimum treatments are not available.",
"affiliations": "Division of Dermatology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.;Division of Dermatology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.;Division of Dermatology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.",
"authors": "Ede|Chioma|C|;Gunduz|Ozge|O|https://orcid.org/0000-0001-8541-9246;Modi|Deepak|D|",
"chemical_list": "D001565:Benzoates; D013455:Sulfur; D011241:Prednisone",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13193",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "22(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Norwegian scabies; children; crusted scabies; immunosuppression; renal transplant",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000293:Adolescent; D001565:Benzoates; D001706:Biopsy; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008297:Male; D011241:Prednisone; D011537:Pruritus; D012532:Scabies; D012867:Skin; D013455:Sulfur; D066027:Transplant Recipients",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13193",
"pmc": null,
"pmid": "31605666",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Crusted scabies in a pediatric renal transplant recipient on immunosuppressants.",
"title_normalized": "crusted scabies in a pediatric renal transplant recipient on immunosuppressants"
} | [
{
"companynumb": "ZA-GLENMARK PHARMACEUTICALS-2019GMK043979",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
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{
"abstract": "To investigate the efficacy and tolerance of systemic treatments for the prevention of HLA-B27-associated acute uveitis (AU) recurrence.\n\n\n\nRetrospective review of patients with HLA-B27-associated uveitis followed in our tertiary center over a 15-year period. Systemic treatments were prescribed to patients with frequent (more than 2 flares per year) or severe uveitis, according to a step-up strategy.\n\n\n\n101 patients (51.5% of men, 88.1% of white Europeans) with a median age of 37 years. AU was mostly recurrent (68.3%) and associated with spondyloarthritis (60.4%). After a median follow-up duration of 22 months (3-73), 37.6% of the patients have received systemic treatment. 88.5% of the patients have been treated with sulfasalazine (SSZ) for ophthalmologic purposes (23/26). Methotrexate (MTX) and anti-TNFα agents have been initiated for a rheumatologic indication in 81.8% (9/11) and 100% of the patients (13/13), respectively. The annual uveitis relapse rate significantly decreased on SSZ (0.37 recurrences/year versus baseline 2.46 recurrences/year; p<0.001) and MTX (1.54 recurrences/year versus 4.17/year; p = 0.008). Patients under ADA for ophthalmologic purposes (n = 2) did not experience any recurrence.\n\n\n\nWe report an open-label strategy to prevent the recurrences of HLA-B27-associated AU. First-line sulfasalazine reduced uveitis relapses. The use of anti-TNFα agents for ophthalmologic purposes was unnecessary with rare exceptions.",
"affiliations": "Service de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Université Claude Bernard-Lyon 1, Lyon, France.;Service de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Université Claude Bernard-Lyon 1, Lyon, France.;Service de Rhumatologie, Hôpital Édouard Herriot, Hospices Civils de Lyon, INSERM UMR 1033, Université de Lyon, Lyon, France.;Centre de Recherche Clinique, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Université Claude Bernard-Lyon 1, Lyon, France.;Service de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Université Claude Bernard-Lyon 1, Lyon, France.;Service d'Ophtalmologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Université Claude Bernard-Lyon 1, Lyon, France.;Service de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Université Claude Bernard-Lyon 1, Lyon, France.",
"authors": "Bouzid|Nabil|N|0000-0001-8407-3749;Jamilloux|Yvan|Y|0000-0001-5249-3650;Chapurlat|Roland|R|;Pradat|Pierre|P|;De Parisot|Audrey|A|;Kodjikian|Laurent|L|;Sève|Pascal|P|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D018501:Antirheumatic Agents; D015796:HLA-B27 Antigen; D014409:Tumor Necrosis Factor-alpha; D012460:Sulfasalazine; D000069285:Infliximab; D000068879:Adalimumab; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0230560",
"fulltext": "\n==== Front\nPLoS One\nPLoS ONE\nplos\nplosone\nPLoS ONE\n1932-6203 Public Library of Science San Francisco, CA USA \n\n10.1371/journal.pone.0230560\nPONE-D-19-27021\nResearch Article\nMedicine and Health Sciences\nOphthalmology\nUveitis\nResearch and Analysis Methods\nResearch Design\nClinical Research Design\nAdverse Events\nMedicine and Health Sciences\nDiagnostic Medicine\nSigns and Symptoms\nEdema\nMedicine and Health Sciences\nPathology and Laboratory Medicine\nSigns and Symptoms\nEdema\nMedicine and Health Sciences\nPharmaceutics\nDrug Therapy\nMedicine and Health Sciences\nSurgical and Invasive Medical Procedures\nOphthalmic Procedures\nCataract Surgery\nMedicine and Health Sciences\nOphthalmology\nMedicine and Health Sciences\nDiagnostic Medicine\nPrognosis\nMedicine and Health Sciences\nRheumatology\nImpact of systemic treatments on the course of HLA-B27-associated uveitis: A retrospective study of 101 patients\nHLA-B27-associated uveitis: Impact of systemic treatmentshttp://orcid.org/0000-0001-8407-3749Bouzid Nabil Formal analysisFunding acquisitionInvestigationMethodologyWriting – original draftWriting – review & editing1 http://orcid.org/0000-0001-5249-3650Jamilloux Yvan Writing – original draftWriting – review & editing1 Chapurlat Roland ConceptualizationData curationInvestigationResourcesWriting – review & editing2 Pradat Pierre Formal analysisWriting – review & editing3 De Parisot Audrey Writing – original draftWriting – review & editing1 Kodjikian Laurent ConceptualizationInvestigationProject administrationSupervision4 Sève Pascal ConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationResourcesSoftwareSupervisionValidationVisualizationWriting – review & editing1* 1 \nService de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Université Claude Bernard-Lyon 1, Lyon, France\n2 \nService de Rhumatologie, Hôpital Édouard Herriot, Hospices Civils de Lyon, INSERM UMR 1033, Université de Lyon, Lyon, France\n3 \nCentre de Recherche Clinique, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Université Claude Bernard-Lyon 1, Lyon, France\n4 \nService d’Ophtalmologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Université Claude Bernard-Lyon 1, Lyon, France\nRosenbaum James T. Editor Oregon Health and Science University, UNITED STATES\nCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: pascal.seve@chu-lyon.fr\n31 3 2020 \n2020 \n15 3 e02305602 11 2019 4 3 2020 © 2020 Bouzid et al2020Bouzid et alThis 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.Purpose\nTo investigate the efficacy and tolerance of systemic treatments for the prevention of HLA-B27-associated acute uveitis (AU) recurrence.\n\nMethods\nRetrospective review of patients with HLA-B27-associated uveitis followed in our tertiary center over a 15-year period. Systemic treatments were prescribed to patients with frequent (more than 2 flares per year) or severe uveitis, according to a step-up strategy\n\nResults\n101 patients (51.5% of men, 88.1% of white Europeans) with a median age of 37 years. AU was mostly recurrent (68.3%) and associated with spondyloarthritis (60.4%). After a median follow-up duration of 22 months (3–73), 37.6% of the patients have received systemic treatment. 88.5% of the patients have been treated with sulfasalazine (SSZ) for ophthalmologic purposes (23/26). Methotrexate (MTX) and anti-TNFα agents have been initiated for a rheumatologic indication in 81.8% (9/11) and 100% of the patients (13/13), respectively. The annual uveitis relapse rate significantly decreased on SSZ (0.37 recurrences/year versus baseline 2.46 recurrences/year; p<0.001) and MTX (1.54 recurrences/year versus 4.17/year; p = 0.008). Patients under ADA for ophthalmologic purposes (n = 2) did not experience any recurrence.\n\nConclusion\nWe report an open-label strategy to prevent the recurrences of HLA-B27-associated AU. First-line sulfasalazine reduced uveitis relapses. The use of anti-TNFα agents for ophthalmologic purposes was unnecessary with rare exceptions.\n\nThe authors received no specific funding for this work. Data AvailabilityAll relevant data are within the paper and supporting information files.Data Availability\nAll relevant data are within the paper and supporting information files.\n==== Body\nIntroduction\nAcute uveitis (AU) associated with the Human Leukocyte Antigen B27 (HLA-B27) is the most frequent cause of uveitis [1,2]. HLA-B27-associated uveitis may occur as an isolated eye disease, but is commonly associated with spondyloarthritis. The combination of uveitis and HLA-B27 has been described since 1973 and concomitantly with ankylosing spondylitis [3,4]. In white European population, the prevalence of HLA-B27 is 7% and reaches 80% in patients with spondyloarthritis [5]. Ocular involvement in spondyloarthritis is the most common extra-articular manifestation of the disease, affecting approximately 30% of the patients [6,7]. Among these ophthalmologic manifestations, acute anterior uveitis is the most common, especially in HLA-B27 positive patients with ankylosing spondylitis [6,8].\n\nThe prognosis of HLA-B27-associated uveitis is usually good in the long term but complications and recurrences may occur. The most common complications are posterior synechiae (13–90%) [9] and cataract in young adults (7–28%) [8]. Ocular hypertension (8–20%), papillitis (2–18%) and cystoid macular edema (6–13%) are less frequent [6]. The frequency of relapses varies from 0.6 to 3.3 flares / year according to studies and decreases over time [8].\n\nIn the majority of AU, topical corticosteroids, or in more severe cases periocular corticosteroids, associated with cycloplegic eye drops are sufficient to resolve inflammation [10–12]. However, recurrences may lead to start a disease-modifying anti-rheumatic drug (DMARD), such as sulfasalazine (SSZ) and methotrexate (MTX), as well as anti-TNFα agents [13]. These agents are used in case of sight-threatening complications (macular edema), in case of ocular side-effects (e.g., steroid-induced glaucoma), or in relapsing diseases. The rheumatic disease is also considered when introducing a systemic treatment for uveitis.\n\nA reduction in the recurrence rate of AU has been reported with SSZ, MTX and anti-TNFα agents, especially infliximab (IFX) and adalimumab (ADA) [14–23]. However, studies investigating the effects of systemic treatments on the course of HLA-B27-associated uveitis are rare. The main aim of this study was to evaluate an open-label step-up strategy for the prevention of recurrences of HLA-B27-associated AU. The secondary aim was to describe the efficacy and tolerance of systemic treatments for the prevention of recurrences and the visual prognosis.\n\nPatients and methods\nStudy design and population\nThis is a retrospective analysis of the medical records of patients with HLA-B27-associated uveitis, with at least one episode of AU, referred to the Department of Internal Medicine (Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France) between January 2003 and April 2018. Patients were referred either by the Department of Ophthalmology (Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France) or by ophthalmologists working in urban health service. Exclusion criteria were uveitis associated with another etiology than HLA-B27.\n\nTo avoid missing data, a standardized survey was sent to the ophthalmologist or to the general practitioner and a telephone interview with the patient was scheduled, and the data were cross-checked from the patient's medical record. The study design complies with French law. The institutional ethics committee of the Hospices Civils de Lyon approved the study. All participants were orally informed of the study and the participation to the study was notified in the patient’s medical record.\n\nThe systemic treatment was initiated by the internist or the rheumatologist, according to ophthalmologic data, rheumatologic data and clinical characteristics of patients, including the number and severity of relapses. All patients were questioned about back pain, psoriasis, enthesopathy, and bowel symptoms. The severity of uveitis includes prognostic factors, for visual loss such as: posterior uveitis, macular edema, uveitic complications of glaucoma, advanced cataract, synechiae, severe band keratopathy or ocular hypotony [36]. All patients were treated with the same step-up therapeutic strategy and by the same practitioner (PS) according to the algorithm shown in Fig 1. As described in previous studies, no systemic treatment was initiated for non-recurrent and/or non-severe uveitis [13–23]. Patients with active spondyloarthritis were treated by the rheumatologist or by the internist according to the ASAS-EULAR management recommendations for spondyloarthritis [24]. Patients with recurrent uveitis (more than 2 /year) or severe uveitis were referred for systemic therapy [15].\n\n10.1371/journal.pone.0230560.g001Fig 1 Algorithm to treatment of HLA-B27 associated uveitis.\n*decrease in number of recurrences.\n\nSSZ was administered orally every day, with an initial dosage of 500 mg/day and up to 2000 mg/day. MTX was administered, once a week, orally or subcutaneously (10–25 mg / week), with folic acid (5 mg) 24 to 48 hours later. Among anti-TNFα agents, ADA was administered every two weeks, subcutaneously (40mg/2 weeks), IFX was administered intravenously (5mg/kg at baseline, week 2, week 6 and every 8 weeks thereafter), etanercept (ETA) was administered once a week, subcutaneously (50 mg/week).\n\nA dose adjustment was performed by the practitioner who initiated the treatment (internist or rheumatologist), based on efficacy and tolerance. When patients were stable for several consecutive visits, the dose was gradually reduced over time. The treatment was usually stopped in case of toxicity.\n\nClinical examinations and investigations\nEach patient report was retrospectively reviewed for demographic data (age at first visit, sex, ethnic group), ophthalmologic characteristics (laterality, recurrences, associated ophthalmic complications including posterior synechiae, secondary cataract, ocular hypertension, papillitis, and macular edema), and for the presence of an associated spondyloarthritis using the European Spondylarthropathy Study Group Criteria [25] and the ASAS criteria for spondyloarthritis [26, 27].\n\nDiagnoses of recurrence were established by ophthalmologists during follow-up, using the SUN international criteria [28] for the anatomical classification of uveitis. At each recurrence, all patients had a complete ophthalmologic examination, including a slit-lamp examination and an indirect ophthalmoscopy.\n\nThe treatment efficacy was determined by the uveitis relapse rate as defined by the number of AU flares/patient/year, and the presence of sight-threatening complications.\n\nStatistical analysis\nData are described as frequencies and percentages for categorical variables, and medians (25th–75th percentiles) for quantitative variables. Categorical variables were compared using the Chi2 test or Fisher’s exact test, as appropriate. Relapse rates were compared using a Poisson regression model. All tests were two-sided and statistical significance was set at p<0.05. All statistical analyses were performed using R v.3.5.2 (R Foundation for Statistical Computing, Vienna, Austria).\n\nResults\nPopulation\nDuring the study, 101 patients with HLA-B27-associated uveitis were referred to our Department of Internal Medicine. Patients’ clinical characteristics are presented in Table 1.\n\n10.1371/journal.pone.0230560.t001Table 1 Epidemiologic and ophthalmologic characteristics of patients with HLA-B27-associated uveitis.\nCharacteristic\tPatients (N = 101)\t\nGender\tFemale\t49 (48.5)\t\nMale\t52 (51.5)\t\nMedian age (IQR)\t\t37 (26–47)\t\nEthnicity\tWhite European\t89 (88.1)\t\nNorth-African\t5 (4.9)\t\nCentral-African\t5 (4.9)\t\nCaribbean\t1 (1)\t\nSouth-American\t1 (1)\t\nRheumatologic history\tAnkylosing spondylitis\t55 (54.4)\t\nReactive arthritis\t3 (3)\t\nPsoriatic arthritis\t2 (2)\t\nInflammatory bowel disease\t1 (1)\t\nNo inflammatory rheumatism\t40 (39.6)\t\nOphthalmologic manifestations\tAnterior\t95 (94.1)\t\nVitreous haze\t9 (8.9)\t\nCystoid Macular Edema\t7 (6.9)\t\nPapillitis\t6 (5.9)\t\nVasculitis\t2 (2)\t\nChronic form\t10 (9.9)\t\nBilateral involvement\t10 (9.9)\t\nGranulomatous uveitis\t3 (3)\t\nElevated IOP\t6 (5.9)\t\nAll data shown are n (%), unless otherwise specified.\n\nIOP, intraocular pressure; IQR, interquartile range\n\nThe median age at uveitis onset was 37 years (interquartile range 26–47) with a sex ratio close to 1 (men = 52, women = 49). The patients were mostly white Europeans (88.1%). Sixty-one patients (60.4%) presented with spondyloarthritis, including ankylosing spondylitis (n = 55, 90.2%), psoriatic arthritis (n = 2), reactive arthritis (n = 3), and spondyloarthritis associated with inflammatory bowel disease (n = 1). Among these patients, the rheumatic involvement preceded uveitis in 46% of the cases (n = 28). In contrast, patients had initially isolated ophthalmologic manifestations in 54% of the cases (n = 33). Patients reported chronic low back pain (n = 42, 68.8%), unilateral or bilateral buttock pain (n = 13, 21.3%), alternating buttock pain (n = 11, 18%), asymmetric oligoarthritis (n = 8, 13.1%), enthesitis (n = 5, 8.2%), and dactylitis (n = 1, 1.6%).\n\nThe uveitis was anterior (n = 95, 94.1%), or complicated by macular edema (n = 7, 6.9%), papillitis (n = 6, 5.9%) and vasculitis (n = 2, 2%). Overall, uveitis was more frequently acute (n = 91, 90.1%), unilateral (n = 91, 90.1%), non-granulomatous (n = 98, 97%), and non-hypertensive (n = 85, 84.1%). Patients with granulomatous uveitis had psoriatic arthritis (n = 2, 66.7%) or reactive arthritis (n = 1, 33.3%). The main complication of AU was the presence of synechiae (n = 33, 32.6%). Six patients (6%) had a hypopyon. Anterior uveitis was recurrent in 69 patients (68.3%).\n\nAll patients received topical corticosteroids and cycloplegic eye drops and, in selected cases, periocular corticosteroids, for AU recurrences.\n\nThirty-eight patients (37.6%) received a systemic treatment (Table 2). Patients were treated with SSZ (n = 26, 68.4%), MTX (n = 11, 28.9%) and anti-TNFα agents (n = 13, 34.2%); because of recurrent and/or severe uveitis (n = 22, 57.9%), inflammatory rheumatism (n = 11, 28.9%) or for both (n = 5, 13.2%). Among anti-TNFα agents, ADA was introduced in 6 patients (46.1%), ETA in 5 patients (38.5%) and IFX in 2 patients (15.4%).\n\n10.1371/journal.pone.0230560.t002Table 2 Systemic treatments of patients with HLA-B27-associated uveitis.\nSystemic therapy\tPatients (n = 38)\tFor ophthalmologic conditions\tFor rheumatologic conditions\tFor both conditions\t\nSulfasalazine\t26 (68.4)\t21\t3\t2\t\nMethotrexate\t11 (28.9)\t2\t5\t4\t\nAdalimumab\t6 (15.8)\t0\t4\t2\t\nEtanercept\t5 (13.2)\t0\t5\t0\t\nInfliximab\t2 (5.2)\t0\t2\t0\t\nPatients could have been treated with more than one treatment.\n\nAll data shown are n (%).\n\nSSZ was prescribed for ophthalmic manifestations in 88.5% of the cases (n = 23). Three (11.5%) patients had SSZ for rheumatologic purposes only. MTX was started for rheumatologic purposes in 81.8% of the cases (n = 9) and for ophthalmic manifestations in 54.5% (n = 6). Two (18.2%) patients had MTX for ophthalmologic purposes only. Regarding anti-TNFα agents, ADA was started for rheumatologic purposes in 100% of the cases but also for ophthalmic manifestations in 2 of the 6 patients. ETA (n = 5, 13.2%) and IFX (n = 2, 5.2%) were always started for rheumatologic purposes. No anti-TNFα agent was started for an ophthalmologic involvement only. The flowchart shows the distribution and the modifications of the different treatments (Fig 2). The median follow-up duration in our study was 22 months (3–73). Sixty-three (62.4%) patients were followed for more than one year.\n\n10.1371/journal.pone.0230560.g002Fig 2 Flowchart to treatment of HLA-B27 associated uveitis.\nTreatment efficacy in patients with less than two recurrences per year\nPatients without systemic therapy\nSixty patients (59.4%) had at least one episode of AU but did not require any systemic therapy. These patients had significantly lower relapse rates (0.87 flares/ year) than patients treated for uveitis recurrences (2.57 flares/ year, p<0.001). No AU relapse occurred during follow-up in 39.7% of the patients (n = 25). Four patients (6.7%) without systemic therapy developed uveitis complications (papillitis (n = 1) and macular edema (n = 3)) which did not require the introduction of a systemic treatment.\n\nPatients with DMARDs and anti-TNFα agents for rheumatologic purposes\nEleven patients (10.9%) had at least one episode of uveitis but the treatment was introduced for rheumatologic purposes. Initially, patients with spondyloarthritis were treated with SSZ (n = 3, 27.3%), MTX (n = 3, 27.3%), ADA (n = 2, 18.2%), ETA (n = 3, 27.3%). All patients treated with SSZ had to switch their treatment to MTX (n = 2, 66.7%) and ETA (n = 1, 33.3%) because of gastric toxicity (n = 1) and insufficient rheumatologic response (n = 1). One patient treated with MTX had to switch to ETA because of hematologic toxicity. Due to inefficacy, two patients treated with ETA had to switch to ADA and two patients treated with MTX had to switch to IFX. The average number of uveitis recurrences was 1.29 flares/year before treatment and 0.20 flares/year after (p<0.001). No patient treated with SSZ (n = 3, 27.3%) and IFX (n = 2, 18.2%) for rheumatologic conditions had uveitis recurrences. The average recurrence rate under MTX, ADA and ETA were respectively 0.20, 0.23 and 0.13 flares/year.\n\nTreatment efficacy in patients with uveitis recurrences\nThirty patients (29.7%) with recurrent or severe AU required a systemic treatment. Among these patients, 5 (16.7%) also had active inflammatory rheumatism. In patients with ophthalmologic manifestations only, 3 (12%) declined SSZ (Fig 2).\n\nThe number of uveitis flares before treatment was 2.46 flares/year in patients who received SSZ; 4.17 flares/year in patients who received MTX and 2.17 flares/year in patients who received ADA.\n\nDuring follow-up, the AU relapse rates were significantly reduced in patients receiving either systemic SSZ, MTX or anti-TNFα agents. Patients treated with SSZ developed 0.37 AU flares/year (p<0.001 compared to pre-treatment values). Patients treated with MTX showed a significant reduction in the AU relapse rate from 4.17 before treatment to 1.54 flares/year (p = 0.008) (Fig 3). The patients treated with ADA (n = 2) did not develop AU during follow-up.\n\n10.1371/journal.pone.0230560.g003Fig 3 Uveitis relapse rate per year in patients with uveitis recurrences treated with sulfasalazine or methotrexate.\nIn patients treated for ophthalmologic purposes, 3 patients on SSZ switched for MTX (1 treatment failure, 2 toxicities) and 1 patient under MTX switched for adalimumab (ADA) due to lack of efficacy.\n\nNo AU relapse occurred during follow-up in 9 patients (39.1%) treated with SSZ, in 3 (50%) patients treated with MTX and in 2 (100%) patients treated with ADA.\n\nDuring follow-up, papillitis occurred in 2 (8.7%) patients and was treated with SSZ. No ocular complications were reported under MTX and ADA.\n\nTolerance\nEight of 26 patients (30.8%) treated with SSZ, 5/11 (45.4%) patients treated with MTX, 1/5 (20%) patient treated with ETA and 1/2 (50%) patient treated with IFX experienced adverse events (Table 3). The proportion of patients with adverse events did not differ significantly according to systemic treatments (p = 0.330). Four serious adverse events led to treatment discontinuation in patients treated with SSZ (50%), 3 with MTX (60%), 1 with ETA (100%) and 1 with IFX (100%) respectively.\n\n10.1371/journal.pone.0230560.t003Table 3 Adverse events in patients with HLA-B27-associated uveitis receiving systemic treatments.\nAdverse events\tSSZ (n = 26)\tMTX (n = 11)\tADA (n = 6)\tETA (n = 5)\tIFX (n = 2)\t\nAny adverse event**\t8 (30.8)\t5 (45.4)\t0 (0)\t1 (20)\t1 (50)\t\nAdverse event leading to discontinuation\t4 (15.4)\t3 (27.3)\t0 (0)\t1 (20)\t1 (50)\t\nCardiac rhythm disorder\t1* (3.8)\t0\t0\t0\t0\t\nInfectious pneumonia\t1* (3.8)\t0\t0\t0\t0\t\nHypersensitivity pneumonitis\t0\t1* (9.1)\t0\t0\t0\t\nDrug eruption\t2* (7.7)\t0\t0\t0\t0\t\nRepeated episcleritis\t0\t0\t0\t1* (20)\t0\t\nAllergic reaction\t0\t1* (9.1)\t0\t0\t0\t\nAnaphylactic shock\t0\t0\t0\t0\t1* (50)\t\nCytopenia\t0\t1* (9.1)\t0\t0\t0\t\nAdverse event leading to death\t0\t0\t0\t0\t0\t\nAll data shown are n (%).\n\n*Adverse event leading to discontinuation of the treatment\n\n**Others adverse events include gastrointestinal disorders, dyspepsia, epigastric pain\n\nStatus at final follow-up\nAt final follow-up, 30.7% of the patients had a systemic treatment. 16 patients were treated with SSZ; for ophthalmologic purposes in 100% (16/16). 4 patients were treated with MTX for ophthalmologic purposes in 50% (2/4). 11 patients were treated with anti-TNFα agents for a rheumatologic involvement (ADA (n = 6), IFX (n = 2) and ETA (n = 3)).\n\nThe long-term prognosis of patients was globally favourable. Seven patients only (6.9%) had uveitis sequelae with synechiae and one had active uveitis (1%). All patients had a normal intraocular pressure (IOP) at the end of follow-up. Ten patients underwent surgery during follow-up including surgical synechialysis (n = 1), cataract surgery (n = 10), epiretinal membrane surgery (n = 1) and retinal detachment surgery (n = 1). No patient needed filtration surgery.\n\nDiscussion\nStudies investigating the effects of systemic treatments on the course of HLA-B27-associated uveitis are rare [14–23]. We describe the efficacy and safety of systemic treatments following an step-up open-label strategy in patients with HLA-B27-associated uveitis. Our study suggests that SSZ positively influences the course of HLA-B27-associated uveitis and that our strategy may reduce relapses with mild side-effects. No patient received anti-TNFα agents for ophthalmologic purposes only.\n\nTherefore, we applied the same therapeutic strategy to patients who received treatments according to their rheumatologic and ophthalmologic characteristics. For comparison, we divided patients into 3 groups: patients who did not require a systemic treatment, those who needed DMARDs or anti-TNFα agents for rheumatologic purposes, and those who needed a systemic treatment for ophthalmologic purposes with or without a rheumatologic indication.\n\nPatients treated with SSZ showed a significant reduction in the AU relapse rate from 2.46 before treatment to 0.37 flares/year, with a relative risk reduction of 85%. Dougados et al., then Munoz-Fernandez et al. in a small prospective longitudinal open-label study (n = 10), reported a similar decrease in recurrence rate on SSZ [29,15]. Similarly, the criterion for a systemic treatment was 3 or more episodes of AU the year before inclusion or 2 or more episodes of uveitis 3 months before the study. Benitez et al. also showed SSZ efficacy in a prospective randomized study (versus placebo) including 22 patients with HLA-B27 [14]. A recent study investigating the effects of SSZ and MTX on the course of HLA-B27-positive remitting acute uveitis reported a significant reduction in uveitis rates in both groups [30]. SSZ with its mild side-effects (rash and digestive disorders), and its low cost, should be a first-line treatment in patients with recurrent and severe episodes of uveitis. However, clinicians should keep in mind that rare severe cytopenias and skin reactions have been described [31]. As in the literature, one third of our patients experienced adverse effects that led to SSZ discontinuation in one sixth of the patients. Three patients requiring the introduction of systemic therapy refused SSZ. Indeed, a daily oral administration may be restrictive for some patients. As rheumatologic effectiveness is restricted to peripheral symptoms, only 3 of our patients received SSZ for rheumatologic purposes [31].\n\nPatients treated with MTX showed a significant reduction in the AU relapse rate from 4.17 before treatment to 1.54 flares/year, with a relative risk reduction of 63%. As MTX is teratogenic and might be associated with exceptional severe adverse events, such as bone marrow failure, lung damage and hepatotoxicity [32], this drug should be a second-line therapy in patients with failure or intolerance to SSZ. In 2008, an open clinical trial of 9 patients also suggested the efficacy of MTX in decreasing the recurrence rate of AU, in patients with more than 3 recurrences of AU the year before, at an initial dosage of 7.5 to 20 mg/week [16]. Meyer Zu Hoerste et al. recently reported that MTX reduced the uveitis relapse rate in 20 HLA-B27-positive AU patients and showed a beneficial effect on uveitis-related macular edema [30]. This treatment, which is efficient for moderate and severe peripheral involvement, was mostly prescribed in our study for rheumatologic purposes [33].\n\nOur patients treated with ADA or ETA for rheumatologic purposes showed a lower AU relapse rate under treatment. Similarly, 2 patients treated with IFX for rheumatologic purposes did not experience any recurrence. Two patients treated for both ophthalmologic and rheumatologic manifestations with ADA did not develop any AU relapse during follow-up. Results should be interpreted cautiously because of the low number of patients. Anti-TNFα agents are effective in reducing uveitis recurrences by 50% to 80% according to studies. In 2008, a multicenter uncontrolled open-label study by Rudwaleit et al., demonstrated a more than 50% reduction in uveitis flares in patients with ADA [19]. Several observational studies and one meta-analysis showed that the soluble TNF receptor fusion protein (ETA) is less effective in preventing anterior uveitis, compared to the anti-TNFα monoclonal antibodies (IFX and ADA) [17,18,34]. However, the American and European rheumatology organizations do not recommend a treatment with these drugs over a treatment with ETA in patients with a single uveitis episode [35].\n\nADA and IFX are the biological agents of choice in the management of uveitis associated with spondyloarthritis according to recent studies [36]. In patients with recurrent or severe uveitis, anti-TNFα monoclonal antibodies should be preferred over ETA [35,37]. In the absence of a rheumatologic indication, SSZ and MTX could be considered as a priority in patients with severe and recurrent uveitis. In patients with axial rheumatic diseases, anti-TNFα agents should be preferred [24].\n\nAs in the literature, our study showed the efficacy of different treatments to prevent AU recurrences. In addition, our study parallels different treatments within a same step-up therapeutic strategy, with a large number of patients and a long follow-up time. Our study is one of the few studies evaluating the safety of systemic treatments for the prevention of HLA-B27-associated uveitis recurrences. Even if adverse events were not frequent in our patients, these treatments have short or long term adverse effects, especially anti-TNFα agents [38]. With regards to the visual prognosis, it was favourable in most patients with only 7% of long term complications (6.9% of synechiae and one case of chronic uveitis at final follow-up).\n\nThis study has limitations, because it is retrospective and therefore prone to patient memory bias and missing data, which is why data were cross-checked from the patient's medical record, and a standardized survey was sent to the ophthalmologist or to the general practitioner and a telephone interview was scheduled with the patient. Despite overlapping data, some records such as Tyndall values or visual acuity were often missing. Consequently, we focussed on recurrences and overall visual prognosis rather than visual acuity to evaluate treatment efficacy. Another limitation of the study is the regression to the mean. These results encourage the completion of a prospective study with a high-level of evidence. This study was not designed to address the superiority of a systemic treatment over the others but to suggest an effective therapeutic strategy with different treatment lines. In our opinion, a systemic therapy should be introduced for the prevention of HLA-B27-associated uveitis in patients with more than 2 relapses per year, or in case of severe uveitis. The introduction of a systemic treatment should be a multidisciplinary decision taking into account the underlying rheumatic disease and its characteristics (axial or peripheral).\n\nIn conclusion, most patients referred to our tertiary uveitis center for the management of HLA-B27-associated uveitis did not receive a systemic treatment. Due to its good therapeutic index, SSZ was used as a first-line therapy in patients with frequent recurrences of uveitis (more than 2 per year) without spondyloarthritis or with mild to moderate peripheral rheumatologic manifestations. In case of adverse events or contraindication to SSZ, MTX was used. The use of anti-TNFα agents for specific ophthalmologic purposes is unnecessary with rare exceptions. Their use seems restricted to patients with severe axial spondyloarthritis.\n\nSupporting information\nS1 Data (XLSX)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 McCannel CA , Holland GN , Helm CJ , et al (1996 ) Causes of uveitis in the general practice of ophthalmology. UCLA Community-Based Uveitis Study Group\n. Am J Ophthalmol . 121 :35 –46\n. 10.1016/s0002-9394(14)70532-x \n8554079 \n2 Jakob E , Reuland MS , Mackensen F , et al (2009 ) Uveitis Subtypes in a German Interdisciplinary Uveitis Center–Analysis of 1916\n\nPatients. J Rheumatol . 36 :127 –36\n. 10.3899/jrheum.080102 \n19132784 \n3 Brewerton DA , Caffrey M , Nicholls A , et al (1973 ) Acute anterior uveitis and HLA B27\n. Lancet \n2 (7836 ):994 –6\n.\n4 Brewerton DA , Hart FD , Nicholls A , et al (1973 ) Ankylosing spondylitis and HLA B27\n. Lancet . 1 :904 –7\n. 10.1016/s0140-6736(73)91360-3 \n4123836 \n5 Chang JH , McCluskey PJ , Wakefield D . (2005 ) Acute anterior uveitis and HLA-B27\n. Surv Ophthalmol . 50 :364 –88\n. 10.1016/j.survophthal.2005.04.003 \n15967191 \n6 Zeboulon N , Dougados M , Gossec . (2008 ) Prevalence and characteristics of uveitis in the spondyloarthropathies: a systematic literature review\n. Ann Rheum Dis 2008; 67 :955 –959\n\n10.1136/ard.2007.075754 \n17962239 \n7 Wach J , Maucort-Boulch D , Kodjikian L , Broussolle C , Sève P . (2015 ) Acute anterior uveitis and undiagnosed spondyloarthritis: usefulness of Berlin criteria\n. Graefes Arch Clin Exp Ophthalmol . 253 (1 ):115 –20\n. 10.1007/s00417-014-2772-6 \n25142374 \n8 Monnet D , Breban M , Hudry C , et al (2004 ) Ophthalmic findings and frequency of extraocular manifestations in patients with HLA-B27 uveitis: a study of 175 cases\n. Ophthalmology . 111 :802 –9\n. 10.1016/j.ophtha.2003.07.011 \n15051216 \n9 Suhler EB , Martin TM , Rosenbaum JT . (2003 ) HLA-B27-associated uveitis: overview and current perspectives\n. Curr Opin Ophthalmol . 14 :378 –83\n. 10.1097/00055735-200312000-00010 \n14615643 \n10 Dunn JP . Review of immunosuppressive drug therapy in uveitis\n. (2004 ) Curr Opin Ophthalmol .15 :293 –298\n\n10.1097/00055735-200408000-00003 \n15232467 \n11 Dunne JA , Jacobs N , Morrison A , Gilbert DJ . (1985 ) Efficacy in anterior uveitis of two known steroids and topical tolmetin\n. Br J Ophthalmol \n69 :120 –125\n\n10.1136/bjo.69.2.120 \n3881125 \n12 Gaudio PA . (2004 ) A review of evidence guiding the use of corticosteroids in the treatment of intraocular inflammation\n. Ocul Immunol Inflamm \n12 :169 –192\n\n10.1080/092739490500192 \n15385194 \n13 Jabs DA , Rosenbaum JT , Foster CS , Holland GN , Jaffe GJ , Louie JS , et al (2000 ) Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders\n. Am J Ophthalmol \n130 :492 –513\n\n10.1016/s0002-9394(00)00659-0 \n11024423 \n14 Benitez-Del-Castillo JM , Garcia-Sanchez J , Iradier T , Banares A . (2000 ) Sulfasalazine in the prevention of anterior uveitis associated with ankylosing spondylitis\n. Eye . 14 (Pt 3A ):340 –3\n.11026996 \n15 Muñoz-Fernández S , Hidalgo V , Fernández-Melón J , Schlincker A , Bonilla G , Ruiz-Sancho D , et al (2003 ) Sulfasalazine reduces the number of flares of acute anterior uveitis over a one-year period\n. J Rheumatol . 30 (6 ):1277 –9\n. 12784403 \n16 Muñoz-Fernández S , García-Aparicio AM , Hidalgo MV , Platero M , Schlincker A , Bascones ML , et al (2008 ) Methotrexate: an option for preventing the recurrence of acute anterior uveitis\n. Eye . 23 (5 ):1130 –3\n\n10.1038/eye.2008.198 \n18688259 \n17 Braun J , Baraliakos X , Listing J , Sieper J . (2005 ) Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti–tumor necrosis factor agents infliximab and etanercept\n. Arthritis & Rheumatism . 52 (8 ):2447 –51\n.16052578 \n18 Guignard S , Gossec L , Salliot C , Ruyssen-Witrand A , Luc M , Duclos M , et al (2006 ) Efficacy of tumour necrosis factor blockers in reducing uveitis flares in patients with spondylarthropathy: a retrospective study\n. Ann Rheum Dis . 65 (12 ):1631 –4\n. 10.1136/ard.2006.052092 \n16901960 \n19 Rudwaleit M , Rødevand E , Holck P , Vanhoof J , Kron M , Kary S , et al (2008 ) Adalimumab effectively reduces the rate of anterior uveitis flares in patients with active ankylosing spondylitis: results of a prospective open-label study\n. Ann Rheum Dis . 68 (5 ):696 –701\n. 10.1136/ard.2008.092585 \n18662932 \n20 Kim M , Won J-Y , Choi SY , Ju JH , Park Y-H . (2016 ) Anti-TNFα Treatment for HLA-B27-Positive Ankylosing Spondylitis–Related Uveitis\n. American Journal of Ophthalmology . 170 :32 –40\n. 10.1016/j.ajo.2016.07.016 \n27470062 \n21 Wendling D , Paccou J , Berthelot J-M , Flipo R-M , Guillaume-Czitrom S , Prati C , et al (2011 ) New onset of uveitis during anti-tumor necrosis factor treatment for rheumatic diseases\n. Semin Arthritis Rheum . 41 (3 ):503 –10\n. 10.1016/j.semarthrit.2011.05.005 \n21862108 \n22 Calvo-Río V , Blanco R , Santos-Gómez M , Rubio-Romero E , Cordero-Coma M , Gallego-Flores A , et al (2016 ) Golimumab in refractory uveitis related to spondyloarthritis. Multicenter study of 15 patients\n. Semin Arthritis Rheum . 46 (1 ):95 –101\n. 10.1016/j.semarthrit.2016.03.002 \n27060872 \n23 Yazgan S , Celik U , Işık M , Yeşil NK , AE Baki , Şahin H , et al (2017 ) Efficacy of golimumab on recurrent uveitis in HLA-B27- positive ankylosing spondylitis\n. Int Ophthalmol . 37 (1 ):139 –45\n. 10.1007/s10792-016-0239-y \n27154720 \n24 Van der Heijde D , Ramiro S , Landewé R , Baraliakos X , Van den Bosch F , Sepriano A , et al (2017 ) 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis\n. Ann Rheum Dis . 76 (6 ):978 –91\n. 10.1136/annrheumdis-2016-210770 \n28087505 \n25 Dougados M , van der Linden S , Juhlin R , Huitfeldt B , Amor B , Calin A , et al (1991 ) The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy\n. Arthritis Rheum .34 (10 ):1218 –27\n. 10.1002/art.1780341003 \n1930310 \n26 Rudwaleit M , van der Heijde D , Landewé R , Listing J , Akkoc N , Brandt J , et al (2009 ) The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection\n. Ann Rheum Dis . 68 (6 ):777 –83\n. 10.1136/ard.2009.108233 \n19297344 \n27 Rudwaleit M , van der Heijde D , Landewé R , Akkoc N , Brandt J , Chou CT , et al (2011 ) The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general\n. Ann Rheum Dis . 70 (1 ):25 –31\n. 10.1136/ard.2010.133645 \n21109520 \n28 Jabs DA , Nussenblatt RB , Rosenbaum JT . (2005 ) Standardization of uveitis nomenclature for reporting clinical data. Results of the first international workshop\n. Am J Ophthalmol \n140 :509 –516\n\n10.1016/j.ajo.2005.03.057 \n16196117 \n29 Dougados M , Berenbaum F , Maetzel A , Amor B . Prevention of acute anterior uveitis associated with spondylarthropathy induced by salazosulfapyridine\n. Rev Rhum Ed Fr . 1993 ;60 (1 ):81 –3\n\n7902159 \n30 Zu Hoerste MM , Walscheid K , Tappeiner C , Zurek-Imhoff B , Heinz C , Heiligenhaus A . (2018 ) The effect of methotrexate and sulfasalazine on the course of HLA-B27-positive anterior uveitis: results from a retrospective cohort study\n. Graefes Arch Clin Exp Ophthalmol . 256 (10 ):1985 –1992\n. 10.1007/s00417-018-4082-x \n30069748 \n31 Chen J , Liu C . (2006 ) Is sulfasalazine effective in ankylosing spondylitis? A systematic review of randomized controlled trials\n. J Rheumatol . 33 (4 ):722 –31\n. 16583475 \n32 Qiu Q , Huang J , Lin \net al (2017 ) Polymorphisms and pharmacogenomics for the toxicity of methotrexate monotherapy in patients with rheumatoid arthritis: A systematic review and meta-analysis\n. Medicine (Baltimore) . 96 (11 ):e6337 .28296761 \n33 Brown PM , Pratt AG , Isaacs JD . (2016 ) Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers\n. Nat Rev Rheumatol . 12 (12 ):731 –742\n. 10.1038/nrrheum.2016.175 \n27784891 \n34 Wendling D , Joshi A , Reilly P , et al (2014 ) Comparing the risk of developing uveitis in patients initiating anti-tumor necrosis factor therapy for ankylosing spondylitis: an analysis of a large US claims database\n. Curr Med Res Opin \n30 : 2515e2521 .25252590 \n35 Ward MM , Deodhar A , Akl EA , et al (2016 ) American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis\n. Arthritis Rheumatol . 68 : 282e298 .26401991 \n36 Dick AD , Rosenbaum JT , Al-Dhibi HA , et al (2018 ) Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative\n. Ophthalmology . 125 :758e774 .\n37 Jamilloux Y , Saadoun D , Sève P . (2018 ) Re Dick \net al: Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative\n. Ophthalmology . 125 :757 –773\n\n10.1016/j.ophtha.2017.11.017 \n29310963 \n38 Zochling J \net al (2015 ) TNF-alpha inhibitors for ankylosing spondylitis\n. Cochrane Database Syst Rev . 18 ;(4 ):CD005468 .\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "15(3)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000893:Anti-Inflammatory Agents; D018501:Antirheumatic Agents; D005260:Female; D015796:HLA-B27 Antigen; D006801:Humans; D000069285:Infliximab; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D012189:Retrospective Studies; D012460:Sulfasalazine; D014409:Tumor Necrosis Factor-alpha; D014605:Uveitis",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0230560",
"pmc": null,
"pmid": "32231384",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "16196117;25252590;28296761;11026996;14615643;19132784;4123836;15232467;3881125;21862108;15967191;7902159;8554079;18662932;27470062;25887212;26401991;11024423;27154720;16901960;12784403;1930310;19297344;30032797;15385194;30069748;21109520;4127279;27784891;16583475;17962239;18688259;15051216;16052578;28087505;27060872;25142374",
"title": "Impact of systemic treatments on the course of HLA-B27-associated uveitis: A retrospective study of 101 patients.",
"title_normalized": "impact of systemic treatments on the course of hla b27 associated uveitis a retrospective study of 101 patients"
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"abstract": "We describe a 67-year-old man admitted from a mental health unit with an incidental finding of hyponatraemia on routine blood tests. Laboratory investigations were in keeping with syndrome of inappropriate antidiuretic hormone secretion (SIADH). He had been recently commenced on mirtazapine. During his inpatient stay, he became increasingly confused. Review of a previous admission with hyponatraemia raised the possibility of voltage-gated potassium channel antibody-associated limbic encephalitis, although subsequent investigations deemed this unlikely as a cause of hyponatraemia. Although his sodium levels improved with fluid restriction, serial point-of-care testing proved misleading in monitoring the efficacy of treatment as inconsistencies were seen in comparison with laboratory testing. The cause of hyponatraemia may have been medication-induced SIADH and/or polydipsia. This case highlights the importance of collating detailed histories and laboratory blood testing to guide management in cases of hyponatraemia of unknown aetiology.",
"affiliations": "Acute Medicine, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK suyin.lim1@nhs.net.;Acute Medicine, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK.;Neurology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK.;Endocrinology & Diabetes, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK.",
"authors": "Lim|Su Yin|SY|;Bodagh|Neil|N|http://orcid.org/0000-0001-5475-5298;Scott|Gregory|G|;Hill|Neil E|NE|",
"chemical_list": "D011619:Psychotropic Drugs; D000078785:Mirtazapine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-229221",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "12(12)",
"journal": "BMJ case reports",
"keywords": "drugs: psychiatry; endocrinology; neuroendocrinology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D003221:Confusion; D006801:Humans; D007010:Hyponatremia; D007177:Inappropriate ADH Syndrome; D008297:Male; D008487:Medical History Taking; D000078785:Mirtazapine; D019095:Point-of-Care Systems; D059606:Polydipsia; D011619:Psychotropic Drugs; D013129:Spinal Puncture; D059020:Suicidal Ideation; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31822529",
"pubdate": "2019-12-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25097290;20157454;21726494;27211806;14558878;27435086;28670128;18675767;8804257;21143021;22862792;19435965;23392748;27485013;27303138;14960497;25396312;17507705;26069838",
"title": "Hyponatraemia: the importance of obtaining a detailed history and corroborating point-of-care analysis with laboratory testing.",
"title_normalized": "hyponatraemia the importance of obtaining a detailed history and corroborating point of care analysis with laboratory testing"
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"companynumb": "GB-MYLANLABS-2020M1010411",
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"activesubstancename": "MIRTAZAPINE"
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{
"abstract": "(1) Objective: Bacterial resistance to conventional antibiotic therapy is an increasingly significant worldwide challenge to human health. The objective is to evaluate whether bacteriophage therapy could complement or be a viable alternative to conventional antibiotic therapy in critical cases of bacterial infection related to cardiothoracic surgery. (2) Methods: Since September 2015, eight patients with multi-drug resistant or especially recalcitrant Staphylococcus aureus, Enterococcus faecium, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli infections were treated with bacteriophage preparations as a therapy of last resort according to Article 37 of the Declaration of Helsinki. Patients had infections associated with immunosuppression after organ transplantation or had infections of vascular grafts, implanted medical devices, and surgical wounds. Individualized phage preparations were administered locally, orally, or via inhalation for different durations depending on the case. All patients remained on conventional antibiotics during bacteriophage treatment. (3) Results: Patients ranged in age from 13 to 66 years old (average 48.5 ± 16.7) with seven males and one female. Eradication of target bacteria was reached in seven of eight patients. No severe adverse side effects were observed. (4) Conclusions: Phage therapy can effectively treat bacterial infections related to cardiothoracic surgery when conventional antibiotic therapy fails.",
"affiliations": "Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.;Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.;Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.;Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.;Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.;Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.;Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.;Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.;Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.;Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.;Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625 Hannover, Germany.;G.N. Gabrichevsky Research Institute for Epidemiology and Microbiology, Moscow 125212, Russia.;Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.;Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.",
"authors": "Rubalskii|Evgenii|E|;Ruemke|Stefan|S|;Salmoukas|Christina|C|0000-0003-2011-9108;Boyle|Erin C|EC|0000-0002-5963-3633;Warnecke|Gregor|G|;Tudorache|Igor|I|;Shrestha|Malakh|M|;Schmitto|Jan D|JD|;Martens|Andreas|A|;Rojas|Sebastian V|SV|;Ziesing|Stefan|S|;Bochkareva|Svetlana|S|;Kuehn|Christian|C|;Haverich|Axel|A|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.3390/antibiotics9050232",
"fulltext": "\n==== Front\nAntibiotics (Basel)\nAntibiotics (Basel)\nantibiotics\nAntibiotics\n2079-6382 MDPI \n\n10.3390/antibiotics9050232\nantibiotics-09-00232\nCase Report\nBacteriophage Therapy for Critical Infections Related to Cardiothoracic Surgery\nRubalskii Evgenii 12* Ruemke Stefan 12* https://orcid.org/0000-0003-2011-9108Salmoukas Christina 12 https://orcid.org/0000-0002-5963-3633Boyle Erin C. 1 Warnecke Gregor 1 Tudorache Igor 1 Shrestha Malakh 1 Schmitto Jan D. 1 Martens Andreas 1 Rojas Sebastian V. 1 Ziesing Stefan 3 Bochkareva Svetlana 4 Kuehn Christian 1256† Haverich Axel 1256† 1 Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany; Salmoukas.Christina@mh-hannover.de (C.S.); Boyle.Colleen@mh-hannover.de (E.C.B.); Warnecke.Gregor@mh-hannover.de (G.W.); Tudorache.Igor@mh-hannover.de (I.T.); Shrestha.Malakh.lal@mh-hannover.de (M.S.); Schmitto.Jan@mh-hannover.de (J.D.S.); Martens.Andreas@mh-hannover.de (A.M.); Rojas.Sebastian@mh-hanover.de (S.V.R.); Kuehn.Christian@mh-hannover.de (C.K.); Haverich.Axel@mh-hannover.de (A.H.)\n2 Lower Saxony Centre for Biomedical Engineering, Implant Research and Development, 30625 Hannover, Germany\n3 Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625 Hannover, Germany; Ziesing.Stefan@mh-hannover.de\n4 G.N. Gabrichevsky Research Institute for Epidemiology and Microbiology, Moscow 125212, Russia; cip1989@gmail.com\n5 German Center for Lung Research (DZL), 30625 Hannover, Germany\n6 Clinical Research Group (KFO 311), German Research Foundation, 30625 Hannover, Germany\n* Correspondence: Rubalskii.Evgenii@mh-hannover.de (E.R.); Ruemke.Stefan@mh-hannover.de (S.R.); Fax: +49-511-532-5404 (E.R. & S.R.)† These authors contributed equally to this work.\n\n\n05 5 2020 \n5 2020 \n9 5 23231 3 2020 28 4 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).(1) Objective: Bacterial resistance to conventional antibiotic therapy is an increasingly significant worldwide challenge to human health. The objective is to evaluate whether bacteriophage therapy could complement or be a viable alternative to conventional antibiotic therapy in critical cases of bacterial infection related to cardiothoracic surgery. (2) Methods: Since September 2015, eight patients with multi-drug resistant or especially recalcitrant Staphylococcus aureus, Enterococcus faecium, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli infections were treated with bacteriophage preparations as a therapy of last resort according to Article 37 of the Declaration of Helsinki. Patients had infections associated with immunosuppression after organ transplantation or had infections of vascular grafts, implanted medical devices, and surgical wounds. Individualized phage preparations were administered locally, orally, or via inhalation for different durations depending on the case. All patients remained on conventional antibiotics during bacteriophage treatment. (3) Results: Patients ranged in age from 13 to 66 years old (average 48.5 ± 16.7) with seven males and one female. Eradication of target bacteria was reached in seven of eight patients. No severe adverse side effects were observed. (4) Conclusions: Phage therapy can effectively treat bacterial infections related to cardiothoracic surgery when conventional antibiotic therapy fails.\n\nphage therapybacterial infectioncardiothoracic surgeryimplant-associated infectiontransplant-associated infectionsurgical site infection\n==== Body\n1. Introduction\nPatients that have undergone cardiothoracic surgery are at a particularly high risk of life-threatening infectious complications. Surgical site infections substantially contribute to postsurgical morbidity and mortality.\n\nImplant-associated infections often become chronic, as bacteria growing on artificial surfaces tend to form biofilms that are highly tolerant to antibiotics. In addition, drug-induced immunosuppression renders heart and lung transplant patients particularly vulnerable to life-threatening infections. Considering these challenges and the global rise in bacterial resistance to conventional antibiotics, there is a desperate need for new antibacterial agents and strategies.\n\nBacteriophages (or phages) are viruses that specifically infect bacteria. With the dawn of antibiotics, the notion of using bacteriophages to treat clinical infections was neglected for almost a century except in some Eastern European countries and the former USSR [1,2]. In recent years, revival of the use of lytic phages for hard-to-treat bacterial infections has gained significant interest, however, relatively few phages have shown clinical efficacy. Nevertheless, several recent case studies have reported success using local [3] and parenteral [4] phage therapy with natural bacteriophages, as well as with the genetically engineered bacteriophages [5].\n\nHere, we report a case series of implant- and transplant-associated multi-drug resistant or recalcitrant infections that were successfully treated with individualized bacteriophages. The current case series includes patients who were treated using our recently described strategy of phage application in combination with fibrin glue. Fibrin glue is a two-component hemostat, sealant, and tissue adhesive consisting of fibrinogen and thrombin. In this case, half of the thrombin solution is substituted with phage suspension [6] and the mixture applied intraoperatively to act as a phage-containing biocompatible scaffold or coating. This unique approach allows for the sustained release of phages to infected sites. These results demonstrate that modern phage therapy is a powerful alternative, or viable support, to standard antibiotic therapy for severe infections.\n\n2. Results\nDetails concerning phages and antibiotic administration, as well as microbiological results and survival data are presented in Table 1. The antibiotic regimens for each patient were the same before and during phage therapy. \n\nDetailed data of inflammation parameters are presented in the Supplementary Tables S1–S8 and Supplementary Figures S1–S8.\n\n2.1. Clinical Outcome\nPatient 1: After the second phage application, Staphylococcus aureus, Enterococcus faecium, and Pseudomonas aeruginosa were no longer detected and phage therapy was stopped. Bacteria were not detected for 16 days after the last phage application. Unfortunately, the patient developed a subsequent infection caused by P. aeruginosa and E. coli 17 days after phage therapy, which was treated only with conventional antibiotic therapy one month later in another hospital. It is not known whether the second P. aeruginosa isolate was the same as the first P. aeruginosa isolate, however, it did have a different antibiogram than the first isolate, which would suggest it was an independent infection.\n\nPatient 2: After phage therapy, Klebsiella pneumoniae was not detected in bronchial lavage samples but was found in stool samples. However, in contrast to the pan-resistant strain causing the lung infection, the K. pneumoniae strain isolated from the patient’s stool was susceptible to antibiotics. \n\nPatient 3: After the last phage application, blood culture samples were free of S. aureus. A positron emission tomography/computed tomography (PET-CT) scan obtained seven months after phage therapy showed no signs of graft infection (Figure 1B).\n\nPatient 4: After phage therapy, no bacteria were detected from wound swabs. The left ventricular assist device (LVAD) remained uninfected which was reflected on a PET-CT scan two months after phage therapy (Figure 1D). Patient 4 showed no further signs of bacterial infection, however, this patient died due to transplant failure 20 months after phage therapy ended. It is extremely unlikely that the transplant failure and subsequent death was related to the previously resolved infection or to phage therapy. \n\nPatient 5: The in vitro activity of phages was tested throughout phage therapy and there was no evidence of bacterial resistance to the bacteriophage strains used. After the first dose, viable phages were consistently detected in the drainage fluid (≥104 pfu/mL) prior to subsequent phage applications. Up to two weeks after phage application, there were no signs of bacteriophage-neutralizing antibodies in the patient’s serum. Nevertheless, moderate but steady levels of S. aureus were detected in the drainage fluid. To potentially improve delivery of the phages to the infection site, surgical intervention was offered but declined by the patient. \n\nIn Patients 6–8, intraoperative application of fibrin glue-bacteriophage preparations onto target devices or tissues resulted in the sustained release bacteriophages.\n\nPatient 6: S. aureus was not detected after phage therapy. Observation of the pump 1.5 months after phage application did not show signs of an infection or remnants of the fibrin glue.\n\nPatient 7: The wound completely healed and E.coli was no longer detected after phage therapy. \n\nPatient 8: The wound completely healed and P. aeruginosa was not detected after phage therapy.\n\n2.2. Safety and Adverse Events\nWe did not observe any major, minor, or unexpected side effects of phage therapy in our treated patients.\n\n3. Discussion\nDr. Victor-Henri Hutinel together with Félix d’Herelle applied bacteriophages for the first time in man in 1919 [7]. In the following decades, clinical use of phages gained popularity and application methods were refined. However, in the early 1940s with the discovery of antibiotics, phage therapy fell into obscurity [8]. Since the beginning of the 21st century, development and spread of multi- or pan-resistant bacteria has become a major health issue, leading to renewed interest in phage therapy. Here we report eight patients who had implant- or transplant-associated multi-drug resistant or recalcitrant infections and were successfully treated with individualized bacteriophages, with complete eradication of the target bacteria in seven of eight patients.\n\nBacteriophages are known as safe and effective antibacterial agents. They are nontoxic to plants and animals and highly specific in that they do not disrupt the composition of normal microflora [1,2,9]. Modern genetic engineering techniques allow the design of the new therapeutic phages with desired properties, for example, specific destruction of biofilms or lysis of previously incurable pathogens [5,10]. Another advantage of bacteriophages is that they are self-amplifying “auto dosing” drugs since they keep replicating in the presence of susceptible host bacteria.\n\nRecurrent or new bacterial infections after an initial round of phage therapy should not be a reason to avoid repeated courses of phage therapy if suitable phages are available. Patient 1 developed a second infection 17 days after ending phage therapy. At the time, we were not able to perform a rapid selection of phages against the isolated P. aeruginosa and E. coli due to the absence of a local phage collection. We have recently established a collection of strictly virulent, well-characterized bacteriophages at our clinics which now allows us to respond quickly in such cases. The collection consists of both imported and newly isolated phages. Moreover, nowadays, many research groups and organizations (e.g., DSMZ, Germany) have specialized collections of bacteriophages suitable for clinical application after a proper preparation.\n\nIn one case (Patient 2), we observed a relevant change in the antibiotic susceptibility of K. pneumoniae isolated later from stool (Supplementary Figure S9). The success of phage therapy in some cases can be explained by resensitizing bacteria to antibiotics under phage therapy-induced evolutionary pressure [11].\n\nOne major challenge of phage therapy is the delivery of phages to the desired site. The inefficiency of phage therapy of Patient 5 can be explained by complications of delivery of bacteriophages to all infected sites via a drainage and the presence of a preformed biofilm on the surface of the LVAD. The failure to completely eradicate the infection in this case made us consider alternative ways to deliver phages to patients at high risk of reinfection in the early postoperative period. We recently developed and tested medical fibrin sealant as a local and sustained phage delivery system in vitro [6]. We now report three successful first-in-man applications of fibrin glue-embedded bacteriophage preparations for sustained delivery of bacteriophages to infection sites and protection of the implant surfaces, as well as the surrounding tissue from reinfection.\n\nMammals elicit a humoral immune response to bacteriophages. Development of anti-bacteriophage antibodies can prevent the long-term efficacy phage therapy [12]. We performed the phage neutralization test [12] using serum from Patient 5 in order to assess this issue of phage therapy but did not find any neutralizing activity.\n\nPatients 1, 2, 3, 4, 6, and 7 had elevated CRP levels shortly after phage therapy which decreased within the next few days, similar to the previous experiences [13,14]. This can be explained either by normal postoperative conditions or by significant bacterial lysis due to phage therapy. On the one hand, an increase in inflammation can be considered as a possible downside of phage therapy. However, on the other hand, such a reaction can also be necessary to clear the infection and has also been observed with antibiotic therapy. Moreover, modern dialysis and blood filtration systems can often efficiently treat septic patients. Therefore, this effect should not be a reason to not apply phage therapy.\n\nOur clinical results support the growing data that individualized phage therapy is a promising therapeutic approach for patients suffering from bacterial infections that do not respond to conventional antibiotic therapy. However, measures such as surgical debridement, local drug delivery systems, and repeated courses of phage application are vital for clinical success in cases of surgical infections related to implanted medical devices or transplants.\n\n4. Materials and Methods \n4.1. Phage Preparation\nPotentially suitable bacteriophage strains were selected from the well-characterized collection housed in the Gabrichevsky Institute (Table 2). Lysis efficacy was evaluated by serial dilution spot testing and efficiency of plating was analyzed by the double layer plaque assay [15,16]. Phages with strong lytic capacity and ability to propagate on bacteria isolated from the patients were chosen for therapy. All therapeutic bacteriophage preparations were produced according to a previously established protocol with slight modifications [6,17]. Briefly, a fresh overnight broth culture of relevant host bacteria was inoculated on top of a solid nutrient media free of animal-derived material inside Roux flasks. LB Broth Vegitone (Sigma-Aldrich, USA) was utilized with w/v 2% of agar-agar (Carl Roth GmbH, Germany). After a 2.5–3.5 h incubation at 37 °C, excess liquid was discarded from the flasks, the phages were inoculated in separate Roux flasks on top of the preformed growing lawn, and the flasks were incubated for 12–15 h at 37 °C. Amplified bacteriophages were washed from the agar surface with 5–10 mL of equilibration buffer (Hyglos GmbH, Germany; BioVendor GmbH, Germany) and bacteria were removed by filtration through a 0.22 µm polyethersulfone syringe filter (Sarstedt AG, Germany). Cell-free phage lysates were concentrated and purified using Vivaspin 20 ultrafiltration units with a molecular weight cutoff of 100 kDa for Podoviridae and Siphoviridae or 1000 kDa for Myoviridae bacteriophages (Sartorius AG, Germany). After the final concentration step, purified bacteriophages were resuspended in sterile medical-grade 0.9% NaCl. Phage lysates of Gram-negative bacteria were additionally purified with the EndoTrap HD (Hyglos GmbH, Germany; BioVendor GmbH, Germany) affinity columns before ultrafiltration. The production procedures and characterization of phage strains were performed taking into account the modern principles of quality and safety for phage therapy products [18].\n\nThe preparation of a mixture of fibrin glue and phages was performed within the operation room directly before the application with the previously described protocol [6]. Briefly, a two-component fibrin sealant (Tisseel, Baxter, USA) was defrosted and half of the thrombin solution volume was substituted with a relevant phage suspension followed by gentle inverting to mix. The phage application was performed using the Tisseel Spray Set with an air pressure 1.5 bar.\n\n4.2. Pre-Study Evaluation\nPatients with various bacterial infections of different etiology underwent individualized phage therapy according to Article 37 of the Declaration of Helsinki using the following criteria:\npan-resistance of the bacterial agent to all available antibiotics;\n\ncomplication of the clinical picture despite continuous therapy with antibiotics deemed appropriate by an antibiogram; or\n\nrepetitive medical device infection despite appropriate antibiotic and surgical therapy.\n\n\n\n\nThe patients ranged from 13–66 years old (average 48.5 ± 16.7) with 7 males and 1 female. Informed consent was obtained from all treated patients. All relevant information concerning diagnoses, localization of infection, isolated bacterial species, and administration of phage therapy is presented in Table 1. Patients were numbered in chronological order. In the Methods section below, we have cases according to the infection type.\n\n4.3. Patients with Infected Vascular Grafts\nPatient 1 was in critical condition due to an infected aortic arch prosthesis 2 years after previous Stanford type-A aortic dissection. In the following 2 years, the patient was admitted to our clinic twice due to repetitive graft infection. As a consequence, the patient developed pleural empyema followed by a purulent infection of a bronchial tree via a fistula caused by S. aureus, E. faecium, and P. aeruginosa. The infection was unresponsive to conventional antibiotic therapy. The patient showed a normal body temperature, a leukocyte count of 7.0 × 109/L, a serum C-reactive protein (sCRP) value of 86.2 mg/L, and a serum procalcitonin (sPCT) value of 0.2 µg/L. A phage cocktail was administrated once via a pigtail drainage positioned close to the aortic arch and, on the same day, once orally. Two days later, the patient underwent a thoracotomy and decortication of the pleural empyema and a phage cocktail was locally applied intraoperatively.\n\nPatient 3 suffered from an infected aortic graft after Stanford type-A dissection confirmed by S. aureus-positive blood culture and PET-CT scan (Figure 1A). Infection was unresponsive to conventional antibiotic therapy. Body temperature measured 36.6 °C, leukocyte count was 4.7 × 109/L, sCRP was 31.6 mg/L, and sPCT was 0.2 µg/L. The patient received phages via a chest tube inserted under CT control close to the infected graft.\n\n4.4. Patients with Infected, Implanted, Metallic Medical Devices\nPatient 4 presented with a fulminant left-sided pleural empyema caused by S. aureus after implantation of a left-ventricular assist device (LVAD). Figure 1C illustrates the degree of inflammation in the infected area despite antibiotic therapy. Body temperature measured 36.5 °C, leukocyte count was 15.3 × 109/L, sCRP was 62.4 mg/L, and sPCT was 0.1 µg/L. Bacteriophages were applied twice per day for 1 week via a chest tube inserted during an operation for decortication of the empyema.\n\nPatient 5 experienced a chronic LVAD infection by S. aureus 4 months after device implantation. The patient had a case history of chronic S. aureus carriage in the nose and throat and suffered S. aureus septicemia several years beforehand. Before phage application, the patient had a normal body temperature, a leukocyte count of 8.3 × 109/L, sCRP of 29.8 mg/L, and sPCT of 1.2 µg/L. A phage cocktail was applied locally, intranasally, and orally for a prolonged period.\n\nPatient 6 had S. aureus infections of a treprostinil pump required for permanent therapy of pulmonary hypertension. The repetitive infection occurred despite reimplantation, surgical debridement, and conventional antibiotic therapy. Before phage therapy, body temperature was normal, leukocyte count was 6.1 × 109/L, sCRP was 6.0 mg/L, and sPCT was <0.1 µg/L. Fibrin glue-embedded bacteriophages were used to cover a new pump which was implanted after surgical debridement of the infected area. To do this, half of the thrombin solution was substituted by a high titer phage solution. The phage-thrombin mixture was combined with fibrinogen in a standard syringe attached to a spray applicator. In total, 4 mL of fibrin glue was used to cover the treprostinil pump surface.\n\n4.5. Patients Infected During Drug-Induced Immunosuppression After Organ Transplantation\nPatient 2 had a K. pneumoniae lung infection after heart transplantation. The patient’s immunosuppression regime consisted of mycophenolic acid, tacrolimus, and prednisolone. The antibiogram of the Klebsiella species isolated from the lungs and intestine were both pan-resistant against all relevant antibiotics. The patient had a normal body temperature, leukocyte count of 21.2 × 109/L, sCRP of 49.0 mg/L, and sPCT of 6.3 µg/L. Phages were applied once per day via inhalation and via a nasogastric tube for two days. Subsequently, the number of applications increased to two times per day for two more days.\n\nPatient 8 had a P. aeruginosa infected thoracotomy wound two months after a double lung transplantation for cystic fibrosis. For immunosuppression, the patient received mycophenolic acid, tacrolimus, and prednisolone. The patient had a normal body temperature, a leukocyte count of 4.8 × 109/L, sCRP of 113 mg/L, and sPCT < 0.1 µg/L. P. aeruginosa was isolated from the wound surface and was not eradicated despite surgical debridement, vacuum-assisted therapy, and continuous antibiotic therapy. The patient received 4 mL of phage-containing fibrin glue sprayed over the wound surface during debridement.\n\n4.6. Patient with a Deep Wound Infection\nPatient 7 had a deep sternal wound infection caused by Escherichia coli after coronary artery bypass surgery and mitral valve replacement. Surgical debridement, vacuum-assisted closure therapy, and over 2 weeks of antibiotic therapy were not successful in eradicating bacteria from the wound. The patient did not have a fever but had a leukocyte count of 6.9 × 109/L and a sCRP of 40.9 mg/L. Phage-embedded fibrin glue (4 mL) was sprayed over the wound once, intraoperatively.\n\nAcknowledgments\nWe are grateful to Karin Burgwitz, Gisela Rademacher, Sabine Waldmann, and Christiane Reineke for their support in performing of the experimental procedures.\n\nSupplementary Materials\nThe following are available online at https://www.mdpi.com/2079-6382/9/5/232/s1, Table S1: Patient 1, Figure S1: Patient 1, Table S2: Patient 2, Figure S2: Patient 2, Table S3: Patient 3, Figure S3: Patient 3, Table S4: Patient 4, Figure S4: Patient 4, Table S5: Patient 5, Figure S5: Patient 5, Table S6: Patient 6, Figure S6: Patient 6, Table S7: Patient 7, Figure S7: Patient 7, Table S8: Patient 8, Figure S8: Patient 8, Figure S9: Antibiogram from Patient 2.\n\nClick here for additional data file.\n\n Author Contributions\nConceptualization, E.R., S.R., S.B., C.K., and A.H.; methodology, E.R., S.R., S.Z., and S.B.; validation, C.K. and A.H.; formal analysis, E.C.B.; investigation, E.R., S.R., C.S., G.W., I.T., M.S., J.D.S., A.M., S.V.R., C.K., and A.H.; resources, E.R., S.B., C.K., and A.H.; data curation, E.R. and S.R.; writing—original draft preparation, E.R. and S.R.; writing—review and editing, E.C.B., C.K., and A.H.; visualization, E.R. and S.R.; supervision, C.K. and A.H.; project administration, C.K. and A.H.; funding acquisition, A.H. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 PET-CT scans of Patient 3 before (A) and seven months after (B) phage therapy in the area of the aortic graft and of Patient 4 before (C) and two months after (D) phage therapy in the area of the left ventricular assist device (LVAD) and pleural cavity empyema. Yellow emission shows level of accumulation of the tracer substance (2-[18F]fluoro-2-desoxy-D-glucose), which corresponds to inflammation.\n\nantibiotics-09-00232-t001_Table 1Table 1 Summary of phage therapy application and outcomes.\n\nPatient Data, Infection Site, and Date of Surgery 1\tSource and Date of Isolated Bacteria\tBasis for Phage Therapy\tTiter and Bacteriophage(s)\tDate, Dosage, and Route of Phage Administration\tAntibiotic Therapy Before & During Phage Application\tMicrobiological Control After Phage Therapy\tSurvival After Phage Therapy\t\nPatient 1,\n52 y.o., m.\nProsthetic infection after aortic arch replacement.\nReplacement: 03.12.2013.\tImplant drainage\nSince 20.08.2015:\nS. aureus, E. faecium.\nSince 09.09.2015:\nP. aeruginosa.\nBronchial lavage\nSince 27.08.2015:\nE. faecium, P. aeruginosa.\tContinuous isolation of S. aureus, E. faecium, P. aeruginosa despite conventional antibiotic therapy\t1 × 108 pfu/mL \nStaphylococcus phage CH1\nEnterococcus phage Enf1\nPseudomonas phage PA5\nPseudomonas phage PA10\t10.09.2015: One 25 mL local application with 6 mL gentamicin (240 mg) and 20 mL daptomycin (350 mg) via drainage\n\nOne 50 mL per os\n\n12.09.2015:\n\n25 mL locally, intraoperatively\n\n\t2000 mg cefepime,\n500 mg daptomycin,\n600 mg linezolid, tobramycin depending on drug concentration in blood (target concentration 2 mg/L).\nAll antibiotics intravenously once per day.\tS. aureus, E. faecium, and P. aeruginosa not detected\tDied 2 months after phage therapy due to a new bacterial infection caused by E. coli and P. aeruginosa\t\nPatient 2,\n40 y.o., m.\nLung infection during drug-induced immuno-suppression after heart transplantation.\nTransplantation: 23.07.2016.\tBronchial lavage\nSince 16.08.2016:\npan-resistant K. pneumoniae.\nRectal swab\nSince 27.06.2016:\npan-resistant K. pneumoniae.\tInfection with the pan-resistant bacteria\t1 × 108 pfu/mL\nKlebsiella phage KPV811\nKlebsiella phage KPV15\t29.08.2016–30.08.2016:2 mL inhalation once per day (mornings)\n\n18 mL via nasogastric tube once per day (mornings)\n\n31.08.2016–01.09.2016:\n\n2 mL inhalation two times per day (mornings and evenings)\n\n18 mL via nasogastric tube two times per day (mornings and evenings)\n\n\t2000 mg ceftazidime, 600 mg linezolid, 500 mg avibactam intravenously twice per day.\nInhalation of 1 MIU colistin three times per day. \n2000 mg meropenem intravenously three times per day.\n960 mg cotrimoxazole per os once per day.\nTobramycin depending on drug concentration in blood (target concentration 2 mg/L).\tK. pneumoniae not detected in bronchial lavage\tUntil present\t\nPatient 3,\n59 y.o., m.\nChronic vascular graft infection after aortic arch replacement.\nReplacement:\n22.10.2014.\tBlood culture\nSince 19.12.2016:\nS. aureus\tContinuous isolation of S. aureus and high inflammation parameters despite conventional antibiotic therapy\t1 × 109 pfu/mL\nStaphylococcus phage CH1\t06.01.2017–08.01.2017:20 mL local application via drainage every 12 hours (4 doses)\n\n\t600 mg rifampicin intravenously twice per day.\n2000 mg flucloxacillin intravenously four times per day.\tS. aureus not detected\tUntil present\t\nPatient 4,\n62 y.o., m.\nFulminant pleural empyema after LVAD implantation.\nImplantation:\n21.04.2017.\tWound swab\nSince 19.06.2017:\nS. aureus\tContinuous isolation of S. aureus and high inflammation parameters despite conventional antibiotic therapy\t1 × 109 pfu/mL\nStaphylococcus phage CH1\t30.06.2017–06.07.2017:20 mL local application via drainage every 12 hours (14 doses)\n\n\t500 mg daptomycin intravenously once per day.\tS. aureus not detected\tDied 20 months after heart transplantation due transplant failure\t\nPatient 5,\n51 y.o., m.\nChronic LVAD infection. \nImplantation:\n28.03.2017.\tImplant drainage\nSince 25.07.2017:\nS. aureus\nNasal swab\nSince 28.05.2014:\nS. aureus\nThroat swab\nSince 27.01.2015:\nS. aureus\tContinuous isolation of S. aureus and high inflammation parameters despite conventional antibiotic therapy\t1 × 109 pfu/mL\nStaphylococcus phage Sa30\nStaphylococcus phage CH1\nStaphylococcus phage SCH1\nStaphylococcus phage SCH111\t09.08.2017–17.08.2017:10 mL local application via drainage once per day after flushing with antiseptics and antibiotics\n\n2 mL intranasal once per day and 10–20 mL per os once per day\n\n18.08.2017–23.08.2017:\n\n10 mL local application via drainage every 12 hours after flushing with antiseptics and antibiotics\n\n10–20 mL per os once per day\n\n\t500 mg daptomycin intravenously once per day.\t100× reduction of S. aureus in the drainage fluid. Complete eradication of S. aureus from nose and throat\tDied 1.5 months after beginning phage therapy due to S. aureus sepsis\t\nPatient 6,\n45 y.o., m. Repetitive treprostinil pump infection.\nFirst implantation:\n08.08.2017.\nSecond implantation:\n12.09.2017.\tCatheter\nSince 16.11.2017:\nS. aureus\nBlood culture\nSince 16.11.2017:\nS. aureus\tContinuous isolation of S. aureus and pump reinfection despite conventional antibiotic and surgical therapy\t4 × 1010 pfu/mL\nStaphylococcus phage Sa30\t29.11.2017:4 mL locally, intraoperatively mixed with fibrin glue (Tisseel, Baxter, USA)\n\n\t375 mg sultamicillin two times per day per os.\tNot tested\tUntil present\t\nPatient 7,\n66 y.o., f.\nSternal wall healing disorder after mitral valve replacement and aortocoronary bypass surgery.\nSurgery:\n23.03.2018.\tWound swab\nSince 20.04.2018:\nE. coli\tContinuous isolation of E. coli and high inflammation parameters despite conventional antibiotic therapy\t4 × 1010 pfu/mL\nEscherichia phage ECD7\nEscherichia phage V18\t09.05.2018:4 mL locally, intraoperatively mixed with fibrin glue (Tisseel, Baxter, USA)\n\n\t600 mg clindamycin three times per day per os.\tE. coli not detected\tUntil present\t\nPatient 8,\n13 y.o., m.\nSternal wound abscesses after double lung transplantation.\nTransplantation: 10.03.2018.\tWound swab\nSince 27.05.2018:\nP. aeruginosa\tContinuous isolation of P. aeruginosa and high inflammation parameters despite conventional antibiotic therapy\t4 × 1010 pfu/mL\nPseudomonas phage PA5\nPseudomonas phage PA10\t13.06.2018:4 mL locally, intraoperatively mixed with fibrin glue (Tisseel, Baxter, USA)\n\n\t2 MIU colistin intravenously twice per day.\n750 mg ceftazidime, 187.5 mg avibactam intravenously three times per day.\tP. aeruginosa not detected\tUntil present\t\n1 f., female; m., male; and y.o., years old\n\nantibiotics-09-00232-t002_Table 2Table 2 List of bacteriophage strains.\n\nBacteriophage Name\tTaxonomy\tGenBank Accession Number\tIsolation Source\tSource\t\nEnterococcus phage Enf1\tOrder Caudovirales;\nfamily Siphoviridae;\ngenus Sap6virus\tMK800154.1\tWastewater, Moscow, Russia\tThis study\t\nEscherichia phage ECD7\tOrder Caudovirales;\nfamily Myoviridae;\nsubfamily Tevenvirinae;\ngenus Rb49virus\tKY683735.1\tChicken feces, Moscow Region, Russia\t[17,19]\t\nEscherichia phage V18\tOrder Caudovirales;\nfamily Myoviridae;\nsubfamily Vequintavirinae;\ngenus V5virus\tKY683736.1\tCowshed sewage, Moscow Region, Russia\t[17,19]\t\nPseudomonas phage PA5\tOrder Caudovirales;\nfamily Myoviridae;\ngenus Pbunavirus\tKY000082.1\tWastewater, Moscow region, Russia\t[6,20]\t\nPseudomonas phage PA10\tOrder Caudovirales;\nfamily Myoviridae;\ngenus Pakpunavirus\tKY000083.1\tWastewater, Moscow region, Russia\t[20]\t\nStaphylococcus phage Sa30\tOrder Caudovirales;\nfamily Myoviridae;\nsubfamily Spounavirinae;\ngenus Kayvirus\tMK331931.1\tClinical material, Astrakhan, Russia\tThis study\t\nStaphylococcus phage CH1\tOrder Caudovirales;\nfamily Myoviridae;\nsubfamily Spounavirinae;\ngenus Kayvirus\tMK331930.1\tPatient’s wound, Chelyabinsk, Russia\t[17,19]\t\nStaphylococcus phage SCH1\tOrder Caudovirales;\nfamily Podoviridae;\nsubfamily Picovirinae;\ngenus P68virus\tKY000084.1\tClinical material, Chelyabinsk, Russia\t[20]\t\nStaphylococcus phage SCH111\tOrder Caudovirales;\nfamily Podoviridae;\nsubfamily Picovirinae;\ngenus P68virus\tKY000085.1\tClinical material, Moscow, Russia\t[20]\t\nKlebsiella phage KPV811\tOrder Caudovirales;\nfamily Podoviridae;\nsubfamily Autographivirinae;\ngenus Drulisvirus\tKY000081.1\tWastewater, Moscow region, Russia\t[20]\t\nKlebsiella phage KPV15\tOrder Caudovirales;\nfamily Myoviridae;\nsubfamily Tevenvirinae;\ngenus Jiaodavirus\tKY000080.1\tWastewater, Moscow region, Russia\t[20]\n==== Refs\nReferences\n1. Sulakvelidze A. Alavidze Z. Morris J.G. Jr. Bacteriophage therapy Antimicrob. Agents Chemother. 2001 45 649 659 10.1128/AAC.45.3.649-659.2001 11181338 \n2. Summers W.C. Bacteriophage therapy Annu. Rev. Microbiol. 2001 55 437 451 10.1146/annurev.micro.55.1.437 11544363 \n3. Fish R. Kutter E. Wheat G. Blasdel B. Kutateladze M. Kuhl S. Bacteriophage treatment of intransigent diabetic toe ulcers: A case series J. Wound Care 2016 25 S27 S33 10.12968/jowc.2016.25.Sup7.S27 26949862 \n4. Schooley R.T. Biswas B. Gill J.J. Hernandez-Morales A. Lancaster J. Lessor L. Barr J.J. Reed S.L. Rohwer F. Benler S. Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection Antimicrob Agents Chemother. 2017 61 e00954-17 10.1128/AAC.00954-17 28807909 \n5. Dedrick R.M. Guerrero-Bustamante C.A. Garlena R.A. Russell D.A. Ford K. Harris K. Gilmour K.C. Soothill J. Jacobs-Sera D. Schooley R.T. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus Nat. Med. 2019 25 730 733 10.1038/s41591-019-0437-z 31068712 \n6. Rubalskii E. Ruemke S. Salmoukas C. Aleshkin A. Bochkareva S. Modin E. Mashaqi B. Boyle E.C. Boethig D. Rubalsky M. Fibrin glue as a local drug-delivery system for bacteriophage PA5 Sci. Rep. 2019 9 2091 10.1038/s41598-018-38318-4 30765740 \n7. Summers W.C. Félix d’Herelle and the Origins of Molecular Biology Yale University Press New Haven, CT, USA 1999 \n8. Merril C.R. Scholl D. Adhya S.L. The prospect for bacteriophage therapy in Western medicine Nat. Rev. Drug Discov. 2003 2 489 497 10.1038/nrd1111 12776223 \n9. Kutter E. De Vos D. Gvasalia G. Alavidze Z. Gogokhia L. Kuhl S. Abedon S.T. Phage therapy in clinical practice: Treatment of human infections Curr. Pharm. Biotechnol. 2010 11 69 86 10.2174/138920110790725401 20214609 \n10. Lu T.K. Collins J.J. Dispersing biofilms with engineered enzymatic bacteriophage Proc. Natl. Acad. Sci. USA 2007 104 11197 11202 10.1073/pnas.0704624104 17592147 \n11. Chan B.K. Sistrom M. Wertz J.E. Kortright K.E. Narayan D. Turner P.E. Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa Sci. Rep. 2016 6 26717 10.1038/srep26717 27225966 \n12. Łusiak-Szelachowska M. Zaczek M. Weber-Dąbrowska B. Międzybrodzki R. Kłak M. Fortuna W. Letkiewicz S. Rogóż P. Szufnarowski K. Jończyk-Matysiak E. Phage neutralization by sera of patients receiving phage therapy Viral Immunol. 2014 27 295 304 10.1089/vim.2013.0128 24893003 \n13. Jończyk-Matysiak E. Łusiak-Szelachowska M. Kłak M. Bubak B. Międzybrodzki R. Weber-Dąbrowska B. Żaczek M. Fortuna W. Rogóż P. Letkiewicz S. The effect of bacteriophage preparations on intracellular killing of bacteria by phagocytes J. Immunol. Res. 2015 2015 482863 10.1155/2015/482863 26783541 \n14. Samokhin A.G. Fedorov E.A. Kozlova Y.N. Tikunova N.V. Pavlov V.V. Morozova V.V. Kretien S.O. Application of the lytic bacteriophages during surgical treatment of the periprosthetic infection of the hip joint endoprosthesis (pilot study) Sovrem. Probl. Nauk. Obraz. 2016 6 10.17513/spno.25851 (in Russian) \n15. Hyman P. Abedon S.T. Bacteriophage host range and bacterial resistance Adv. Appl. Microbiol. 2010 70 217 248 20359459 \n16. Kutter E. Phage host range and efficiency of plating Methods Mol. Biol. 2009 501 141 149 19066818 \n17. Aleshkin A.V. Volozhantsev N.V. Svetoch E.A. Kiseleva I.A. Rubal’sky E.O. Afanas’ev S.S. Borzilov A.I. Zatevalov A.M. Vasil’ev D.A. Zolotukhin S.N. Bacteriophages as probiotics: Phage-based probiotic dietary supplement in prophylaxis against foodborne infections Infect. Dis. Infekt. Bolezn. 2016 14 31 40 10.20953/1729-9225-2016-2-31-40 \n18. Pirnay J.P. Blasdel B.G. Bretaudeau L. Buckling A. Chanishvili N. Clark J.R. Corte-Real S. Debarbieux L. Dublanchet A. De Vos D. Quality and safety requirements for sustainable phage therapy products Pharm. Res. 2015 32 2173 2179 10.1007/s11095-014-1617-7 25585954 \n19. Aleshkin A.V. Rubalskii E.O. Volozhantsev N.V. Verevkin V.V. Svetoch E.A. Kiseleva I.A. Bochkareva S.S. Borisova O.Y. Popova A.V. Bogun A.G. A small-scale experiment of using phage-based probiotic dietary supplement for prevention of E. coli traveler’s diarrhea Bacteriophage 2015 5 e1074329 10.1080/21597081.2015.1074329 26458758 \n20. Aleshkin A.V. Ershova O.N. Volozhantsev N.V. Svetoch E.A. Popova A.V. Rubalskii E.O. Borzilov A.I. Aleshkin V.A. Afanas’ev S.S. Karaulov A.V. Phagebiotics in treatment and prophylaxis of healthcare-associated infections Bacteriophage 2016 6 e1251379 10.1080/21597081.2016.1251379 28090384\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2079-6382",
"issue": "9(5)",
"journal": "Antibiotics (Basel, Switzerland)",
"keywords": "bacterial infection; cardiothoracic surgery; implant-associated infection; phage therapy; surgical site infection; transplant-associated infection",
"medline_ta": "Antibiotics (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101637404",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32380707",
"pubdate": "2020-05-05",
"publication_types": "D002363:Case Reports",
"references": "19066818;28090384;24893003;27225966;26783541;30765740;25585954;28807909;17592147;31068712;26458758;20359459;11544363;20214609;12776223;11181338",
"title": "Bacteriophage Therapy for Critical Infections Related to Cardiothoracic Surgery.",
"title_normalized": "bacteriophage therapy for critical infections related to cardiothoracic surgery"
} | [
{
"companynumb": "DE-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-250242",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "COLISTIN"
},
"drugad... |
{
"abstract": "Magnetic resonance (MRI) scanning of the heart is an established part of the investigation of cardiovascular conditions in children. In young children, sedation is likely to be needed, and multiple controlled periods of apnea are often required to allow image acquisition. Suppression of spontaneous ventilation is possible with remifentanil; however, the dose required is uncertain.\n\n\n\nTo establish the dose of remifentanil, by infusion, required to suppress ventilation sufficiently to allow a 30-s apnea during MRI imaging of the heart.\n\n\n\nPatients aged 1-6 years were exposed to different doses of remifentanil, and the success in achieving a 30-s apnea was recorded. A dose recommendation was made for each patient, informed by responses of previous patients using an adaptive Bayesian dose-escalation design. Other aspects of anesthesia were standardized. A final estimate of the dose needed to achieve a successful outcome in 80% of patients (ED80) was made using logistic regression.\n\n\n\n38 patients were recruited, and apnea achieved in 31 patients. The estimate of the ED80 was 0.184 µg/kg/min (95% CI 0.178-0.190). Post hoc analysis revealed that higher doses were required in younger patients.\n\n\n\nThe ED80 for this indication was 0.184 µg/kg/min (95% CI 0.178-0.190). This is different from optimal dosing identified for other indications and dosing of remifentanil should be specific to the clinical context in which it is used.",
"affiliations": "Jackson Rees Department of Paediatric Anaesthesia, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.;Jackson Rees Department of Paediatric Anaesthesia, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.;Department of Mathematics and Statistics, Lancaster University, Lancaster, UK.;Jackson Rees Department of Paediatric Anaesthesia, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.;Jackson Rees Department of Paediatric Anaesthesia, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.;Jackson Rees Department of Paediatric Anaesthesia, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.;Department of Radiology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.;Department of Radiology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.;Department of Mathematics and Statistics, Lancaster University, Lancaster, UK.;Department of Mathematics and Statistics, Lancaster University, Lancaster, UK.",
"authors": "Arnold|Philip|P|0000-0002-6606-351X;Sanaulla|Syed|S|;Hampson|Lisa V|LV|;Davis|Annette|A|;Tan|Jacinth|J|;Cowen|Ruth|R|;Kaleem|Musa|M|;Williams|Alexandra|A|;Wadsworth|Ian|I|;Jaki|Thomas|T|",
"chemical_list": "D018686:Anesthetics, Intravenous; D010880:Piperidines; D000077208:Remifentanil; D015742:Propofol",
"country": "France",
"delete": false,
"doi": "10.1111/pan.14164",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1155-5645",
"issue": "31(5)",
"journal": "Paediatric anaesthesia",
"keywords": "congenital heart disease; general anesthesia; magnetic resonance imaging; remifentanil",
"medline_ta": "Paediatr Anaesth",
"mesh_terms": "D000768:Anesthesia, General; D018686:Anesthetics, Intravenous; D001049:Apnea; D001499:Bayes Theorem; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D010880:Piperidines; D015742:Propofol; D000077208:Remifentanil",
"nlm_unique_id": "9206575",
"other_id": null,
"pages": "548-556",
"pmc": null,
"pmid": "33629430",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Study to evaluate the optimal dose of remifentanil required to ensure apnea during magnetic resonance imaging of the heart under general anesthesia.",
"title_normalized": "study to evaluate the optimal dose of remifentanil required to ensure apnea during magnetic resonance imaging of the heart under general anesthesia"
} | [
{
"companynumb": "GB-FRESENIUS KABI-FK202109840",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "REMIFENTANIL"
},
"drugadditional": null,
... |
{
"abstract": "Cases of intoxication in combination with extreme agitation, physical exertion and restraint are mainly associated with restraint-related deaths (RRD) in the context of police use of force. In these cases, the mechanism of death usually mentioned is RRD associated with drug-induced excited delirium. To the best of our knowledge, there are no cases published on RRD that occurred during a physical encounter among civilians. We present a case of a 39-year old man, who died during a struggle with another person while being chokehold in a prone position with a knee on his back. Detailed witness testimonies as well as reliable blood parameters, which were taken immediately after his death, helped to define a most probable diagnosis. The deceased suffered from schizophrenia, consumed amphetamine and bupropion. He showed typical symptoms of an agitated delirious state, most likely induced by bupropion intoxication. The cause of death was restraint asphyxia by a second party on the basis of an excited delirium. The manner of death was concluded to be manslaughter.",
"affiliations": "Department of Forensic Pathology, Landspítali University Hospital Reykjavik, Iceland; University of Iceland, Reykjavik, Iceland. Electronic address: sebastian@landspitali.is.;Department of Pharmacology and Toxicology, University of Iceland, Reykjavik, Iceland.;Department of Pathology, Landspítali University Hospital Reykjavik, Iceland.",
"authors": "Kunz|S N|SN|;Þórðardóttir|S|S|;Rúnarsdóttir|R|R|",
"chemical_list": null,
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2018.04.051",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "288()",
"journal": "Forensic science international",
"keywords": "Bupropion; Drug intoxication; Excited delirium; Forensic medicine; Restraint asphyxia",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D001237:Asphyxia; D003693:Delirium; D006801:Humans; D008297:Male; D016684:Prone Position; D012149:Restraint, Physical; D012559:Schizophrenia; D019966:Substance-Related Disorders",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "e5-e9",
"pmc": null,
"pmid": "29801701",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Restraint-related asphyxia on the basis of a drug-induced excited delirium.",
"title_normalized": "restraint related asphyxia on the basis of a drug induced excited delirium"
} | [
{
"companynumb": "IS-IMPAX LABORATORIES, INC-2018-IPXL-02182",
"fulfillexpeditecriteria": "1",
"occurcountry": "IS",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMPHETAMINE"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nImmune checkpoint inhibitors have improved overall survival rates for many cancers, yet the majority of patients do not respond to treatment and succumb to disease progression. One tumor-related mechanism limiting the efficacy of immunotherapies in melanoma is the recruitment and expansion of myeloid-derived suppressor cells (MDSCs). Therefore, targeting MDSCs in combination with immunotherapies is an attractive strategy to improve response rates and effectiveness.\n\n\nMETHODS\nWe tested this strategy by designing a randomized phase II clinical trial treating advanced melanoma patients with either Ipilimumab monotherapy or Ipilimumab plus all-trans retinoic acid (ATRA). Clinicaltrails.gov identifier (NCT02403778). The frequency of circulating MDSCs and the activation of CD8(+) T cells was measured by flow cytometry. Expression of immunosuppressive genes was measured with quantitative real time-PCR. T cell suppressive functions were measured by mixed lymphocyte reaction.\n\n\nRESULTS\nHere we show that in vitro treatment with ATRA decreases immunosuppressive function of MDSCs in mixed lymphocyte reactions. Additionally, ATRA reduces the expression of immunosuppressive genes including PD-L1, IL-10, and indoleamine 2,3‑dioxygenase by MDSCs. Furthermore, the addition of ATRA to standard of care Ipilimumab therapy appears safe, as ATRA did not increase the frequency of grade 3 or 4 adverse events. Finally, ATRA significantly decreased the frequency of circulating MDSCs compared to Ipilimumab treatment alone in advanced-stage melanoma patients.\n\n\nCONCLUSIONS\nThese results illustrate the importance of MDSCs in immunotherapy resistance and provide evidence that targeting MDSCs in cancer patients may augment immunotherapeutic approaches.",
"affiliations": "University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Division of Surgical Oncology, Department of Surgery, USA. Electronic address: richard.tobin@ucdenver.edu.;University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Department of Immunology and Microbiology, USA. Electronic address: kimberly.jordan@ucdenver.edu.;University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Division of Medical Oncology, Department of Medicine, USA; University of Colorado Cancer Center, Aurora, CO, USA. Electronic address: william.robinson@ucdenver.edu.;University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Division of Surgical Oncology, Department of Surgery, USA. Electronic address: dana.davis@ucdenver.edu.;University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Division of Medical Oncology, Department of Medicine, USA; Young Women's Breast Cancer Translational Program, USA; University of Colorado Cancer Center, Aurora, CO, USA. Electronic address: virginia.borges@ucdenver.edu.;University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Division of Medical Oncology, Department of Medicine, USA; University of Colorado Cancer Center, Aurora, CO, USA. Electronic address: rene.gonzalez@ucdenver.edu.;University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Division of Medical Oncology, Department of Medicine, USA; University of Colorado Cancer Center, Aurora, CO, USA. Electronic address: karl.lewis@ucdenver.edu.;University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; Division of Surgical Oncology, Department of Surgery, USA; University of Colorado Cancer Center, Aurora, CO, USA. Electronic address: martin.mccarter@ucdenver.edu.",
"authors": "Tobin|Richard P|RP|;Jordan|Kimberly R|KR|;Robinson|William A|WA|;Davis|Dana|D|;Borges|Virginia F|VF|;Gonzalez|Rene|R|;Lewis|Karl D|KD|;McCarter|Martin D|MD|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000074324:Ipilimumab; D014212:Tretinoin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.intimp.2018.08.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1567-5769",
"issue": "63()",
"journal": "International immunopharmacology",
"keywords": "ATRA; Immunotherapy; Ipilimumab; MDSC; Melanoma; Randomized Clinical Trial",
"medline_ta": "Int Immunopharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D000072737:Myeloid-Derived Suppressor Cells; D014212:Tretinoin",
"nlm_unique_id": "100965259",
"other_id": null,
"pages": "282-291",
"pmc": null,
"pmid": "30121453",
"pubdate": "2018-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "11842302;19789309;20525992;18432844;23589106;27903500;28052991;24777678;20547984;7749984;9225952;27381735;8537970;24072401;27178742;28167454;19088044;23439861;19118070;27828943;9363862;25840693;27916138;26208901;11704842;23160385;9039770;3165295;24060865;17433076;16982775;18006848;27827871;21933959;26858199;25891173;28108766;24357148;27667683;27433843;16900483;22437938",
"title": "Targeting myeloid-derived suppressor cells using all-trans retinoic acid in melanoma patients treated with Ipilimumab.",
"title_normalized": "targeting myeloid derived suppressor cells using all trans retinoic acid in melanoma patients treated with ipilimumab"
} | [
{
"companynumb": "US-ZO SKIN HEALTH-2018ZOS00011",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nWe describe a patient diagnosed with acute myeloid leukemia (AML) and low activity of thiopurine methyltransferase (TPMT) who developed secondary myelodysplastic syndrome after treatment.\n\n\nMETHODS\nA 10-year-old boy presented with AML-M2 with t(8;21)(q22;q22) and genotyping revealing 3*B TPMT heterozygosity. The patient was treated according to the NOPHO-AML 2004 protocol. Two years after the treatment, the patient presented with neutropenia and thrombocytopenia. Bone marrow, including fluorescent in situ hybridization and retrospective aCGH analysis, verified therapy-related myelodysplastic syndrome with ring chromosome 6.\n\n\nCONCLUSIONS\nThe clinical course of this patient raises the possibility that low-activity TPMT genotypes may influence 6TG toxicity in patients with AML and lead to an increased risk of developing secondary malignant neoplasms.",
"affiliations": "*Department of Pediatrics, Aarhus University Hospital Skejby †Cancer Cytogenetics Laboratory, Department of Hematology, Aarhus University Hospital, Aarhus ‡Department of Pediatrics and Adolescent Medicine, University Hospital, Rigshospitalet §Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.",
"authors": "Stensman|Lars M|LM|;Kjeldsen|Eigil|E|;Nersting|Jacob|J|;Schmiegelow|Kjeld|K|;Hasle|Henrik|H|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000211",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "37(4)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D002648:Child; D006579:Heterozygote; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D015122:Mercaptopurine; D008780:Methyltransferases; D009190:Myelodysplastic Syndromes",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e242-4",
"pmc": null,
"pmid": "25000470",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment-related myelodysplastic syndrome in a child with acute myeloid leukemia and TPMT heterozygosity.",
"title_normalized": "treatment related myelodysplastic syndrome in a child with acute myeloid leukemia and tpmt heterozygosity"
} | [
{
"companynumb": "DK-COR_00407_2015",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IDARUBICIN"
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"drugadditional": null,
"dr... |
{
"abstract": "Mucormycosis of the gastrointestinal tract is a rare infection that usually occurs in patients who are immunocompromised and carries a high mortality. We report four cases of gastrointestinal mucormycosis seen over a one year period with different presentations, risk factors and different anatomical sites of involvement. A preoperative diagnosis was made only in one patient. All underwent surgery, three survived and one died postoperatively from multiorgan failure.",
"affiliations": "Department of Surgical Gastroenterology and Liver Transplantation, Sir Ganga Ram Hospital, New Delhi 110 060, India. slalwani2008@yahoo.com",
"authors": "Lalwani|Shailendra|S|;Govindasamy|Mahendran|M|;Gupta|Manoj|M|;Siraj|Fouzia|F|;Varma|Vibha|V|;Mehta|Naimaish|N|;Kumaran|Vinay|V|;Mohan|Neelam|N|;Chopra|Prem|P|;Arora|Anil|A|;Agarwal|Shyam|S|;Soin|Arvinder|A|;Nundy|Samiran|S|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B",
"country": "India",
"delete": false,
"doi": "10.1007/s12664-012-0215-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0254-8860",
"issue": "31(3)",
"journal": "Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology",
"keywords": null,
"medline_ta": "Indian J Gastroenterol",
"mesh_terms": "D000328:Adult; D000666:Amphotericin B; D000935:Antifungal Agents; D003131:Combined Modality Therapy; D017809:Fatal Outcome; D005767:Gastrointestinal Diseases; D006801:Humans; D007223:Infant; D008297:Male; D009091:Mucormycosis; D009102:Multiple Organ Failure; D009894:Opportunistic Infections; D012307:Risk Factors; D014057:Tomography, X-Ray Computed; D055815:Young Adult",
"nlm_unique_id": "8409436",
"other_id": null,
"pages": "139-43",
"pmc": null,
"pmid": "22744237",
"pubdate": "2012-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11331930;8852973;1913115;7756485;517498;10895981;11025599;11792995;10659718;16020690;15940058;20180248;10460879;7807359;17174730;12546179;16080086;16925570;16511748;12447307",
"title": "Gastrointestinal mucormycosis--four cases with different risk factors, involving different anatomical sites.",
"title_normalized": "gastrointestinal mucormycosis four cases with different risk factors involving different anatomical sites"
} | [
{
"companynumb": "IN-MYLANLABS-2017M1076262",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
... |
{
"abstract": "Human epidermal growth factor receptor2 (HER2) overexpression/amplification is associated with high malignancy, rapid disease progression and poor overall survival in breast cancer. The application of anti-HER2 drugs has greatly improved the survival of patients with HER2-positive breast cancer, but drug resistance issues affect the long-term efficacy. The HER2 mutation is considered to be one of the reasons for resistance to anti-HER2 therapy, and there is currently no standard treatment. We report for the first time the detection of HER2 amplification with R157W mutation by second-generation sequencing (NGS) in a 57-year-old hormone receptor-negative, HER2-positive woman with advanced breast cancer who was resistant to multi-line anti-HER2 therapies. She subsequently received pyrotinib combined with capecitabine treatment and achieved partial response. The small-molecule pan-HER family irreversible inhibitor pyrotinib combined with capecitabine has shown a promising effect in the treatment of HER2 mutation-induced resistance, but the molecular mechanism and efficacy need to be further verified.",
"affiliations": "Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China.;The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China.;The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China.;Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China.;Nanjing Geneseeq Technology Inc, Nanjing, People's Republic of China.;Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China.",
"authors": "Qu|Yanchun|Y|;Liu|Yufeng|Y|0000-0003-4260-2168;Ding|Kailin|K|;Li|Yong|Y|;Hong|Xiaoyu|X|;Zhang|Haibo|H|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OTT.S289876",
"fulltext": "\n==== Front\nOnco Targets Ther\nOnco Targets Ther\nott\nott\nOncoTargets and therapy\n1178-6930\nDove\n\n289876\n10.2147/OTT.S289876\nCase Report\nPartial Response to Pyrotinib Plus Capecitabine in an Advanced Breast Cancer Patient with HER2 Amplification and R157W Mutation After Anti-HER2 Treatment: A Case Report and Literature Review\nQu et al\nQu et al\nQu Yanchun 123*\nhttp://orcid.org/0000-0003-4260-2168\nLiu Yufeng 3*\nDing Kailin 3\nLi Yong 12\nHong Xiaoyu 4\nZhang Haibo 12\n1 Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China\n2 Department of Oncology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, People’s Republic of China\n3 The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China\n4 Nanjing Geneseeq Technology Inc, Nanjing, People’s Republic of China\nCorrespondence: Haibo Zhang Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, No. 111 Dade Road, Yuexiu District, Guangzhou, 510120, People’s Republic of ChinaTel +86-020-81887233 Email haibozh@gzucm.edu.cn\n* These authors contributed equally to this work\n\n02 3 2021\n2021\n14 15811588\n01 11 2020\n07 1 2021\n© 2021 Qu et al.\n2021\nQu et al.\nThis work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nAbstract\n\nHuman epidermal growth factor receptor2 (HER2) overexpression/amplification is associated with high malignancy, rapid disease progression and poor overall survival in breast cancer. The application of anti-HER2 drugs has greatly improved the survival of patients with HER2-positive breast cancer, but drug resistance issues affect the long-term efficacy. The HER2 mutation is considered to be one of the reasons for resistance to anti-HER2 therapy, and there is currently no standard treatment. We report for the first time the detection of HER2 amplification with R157W mutation by second-generation sequencing (NGS) in a 57-year-old hormone receptor-negative, HER2-positive woman with advanced breast cancer who was resistant to multi-line anti-HER2 therapies. She subsequently received pyrotinib combined with capecitabine treatment and achieved partial response. The small-molecule pan-HER family irreversible inhibitor pyrotinib combined with capecitabine has shown a promising effect in the treatment of HER2 mutation-induced resistance, but the molecular mechanism and efficacy need to be further verified.\n\nKeywords\n\nbreast cancer\nHER2 amplification\nHER2 R157W mutation\npyrotinib plus capecitabine\nanti-HER2 treatment\n==== Body\nIntroduction\n\nBreast cancer is a malignant tumor with the highest morbidity and second highest mortality rate in women.1 HER2-positive (HER2 amplification) breast cancer accounts for about 15–20% of all breast cancers.2 Anti-HER2 drugs have greatly improved the survival of such patients. These drugs include humanized monoclonal antibodies like trastuzumab and pertuzumab, antibody-drug conjugates (ADC) like T-DM1, and novel oral small-molecule tyrosine kinase inhibitors like pyrotinib, neratinib, lapatinib and so on.\n\nAcquired drug resistance is inevitable in patients with advanced HER2-positive breast cancer after first-line and second-line anti-HER2 treatments, and the mechanism is still under investigation. HER2 mutations are rare in breast cancer patients. A systematic review showed that the frequency of HER2 mutation in breast cancer patients was about 3%,3 while previous gene sequencing results suggested that patients with primary HER2-positive breast cancer had a lower frequency of HER2 mutation.4,5 Therefore, HER2 amplification and mutation are considered mutually exclusive in breast cancer patients. In recent years, studies have found that the HER2 gene mutation rate is higher in breast cancer patients treated with multi-line anti-HER2 therapies,6,7 and HER2 mutation is one of the causes of resistance to anti-HER2 treatment. There is no standard treatment for HER2 mutation patients yet. Of these, HER2 R157W mutation is a rare mutation and there are currently only two reports in the literature. One was somatic mutation found in micropapillary urothelial carcinoma (MPUC),8 which was not accompanied by HER2 overexpression and HER2 amplification. FATHMM prediction determined that it was a pathogenic mutation according to the COSMIC database. The other one was germline mutation found in breast cancer,9 of which the clinical significance is unknown. This is the first report of a patient with HER2-positive advanced breast cancer who developed HER2-amplification with R157W missense mutation after treatment of lapatinib plus trastuzumab and achieved partial response (PR) after using pyrotinib plus capecitabine.\n\nCase Description\n\nA 57-year-old Chinese female was initially presented to an outside hospital and underwent radical resection of left breast cancer diagnosed with stage IIIC (pTxN3M0) in Jan 2013. Pathology indicated invasive ductal carcinoma of breast estrogen receptor (ER) (-), progesterone receptor (PR) (-), and HER2(3+) by immunohistochemistry. Then, she received one cycle of adjuvant chemotherapy with docetaxel and three cycles of oncolytic virus therapy in other hospital, but the patient could not provide detailed information. In March 2013, PET/CT showed bilateral lung metastases. However, the patient refused chemotherapy and received traditional Chinese medicine (TCM) decoction treatment. In March 2014, follow-up PET/CT revealed multiple metastases in liver, both lungs and bones. A liver biopsy conducted in our department suggested hepatic metastasis of the breast cancer (ER(-), PR(-), HER2(3+)). The patient received eight cycles of first-line-targeted treatment with trastuzumab (8mg/kg IV day 1 followed by 6mg/kg IV day 1 every 21 days) plus paclitaxel (135mg/m2 IV day 1 every 21 days), followed by maintenance treatment with trastuzumab (6mg/kg IV day 1 every 21 days), achieving partial response and progression-free survival (PFS) for approximately 1 year. Subsequently, she was treated with docetaxel (75mg/m2 IV day 1 every 21 days), xeloda (1000mg/m2 PO bid days 1–14 every 21 days), and trastuzumab (6mg/kg IV day 1 every 21 days) as the second-line treatment for six cycles, with the best efficacy of partial response and PFS for 10 months. Upon disease progression, the third-line treatment was gemcitabine (1000mg/m2 IV day 1 every 21 days) plus S-1 (40mg PO bid days 1–14 every 21 days) based chemotherapy for 4 cycles, with the best efficacy of stable disease (SD) and PFS for nearly 4 months. In the fourth-line treatment, she received epirubicin (80mg/m2 IV day 1 every 21 days) plus lapatinib (0.25g PO qd). However, after one cycle, due to impaired liver function (with her alanine aminotransferase [ALT] level reaching 1122U/L), use of epirubicin was discontinued. Liver function improved following liver protection therapy, and the patient then continued lapatinib monotherapy (0.5g PO qd), maintaining an SD with PFS of 2 months.\n\nIn October 2017, enlarged lesions revealed in the chest and abdomen CT indicated progressive disease (PD). Next-generation sequencing (NGS) of plasma detected HER2 and CDK12 amplification, NSD1 gene fusion, and TP53 L257R mutation. The patient began to receive trastuzumab (6mg/kg IV day 1 every 21 days) combined with lapatinib (1g PO qd) as the fifth-line treatment from November 2017. The best efficacy was SD, and PFS was about 9 months. In August 2018, plasma NGS showed R157W missense mutation in HER2 exon 4, along with HER2 amplification and TP53 L257R mutation. That September, a chest and abdomen CT confirmed PD. The patient began to receive pyrotinib(400mg PO qd) plus xeloda (1000mg/m2 PO bid days 1–14 every 21 days) as the sixth-line treatment, with the best efficacy of PR and PFS for 13 months. Plasma NGS monitoring during the period (December 2018) suggested a decrease in HER2 copy number and abundance of R157W mutation. In November 2019, when her disease progressed again, the re-examination of the plasma NGS showed CDK12 and HER2 amplification, DNMT3A inactivation mutation and TP53 L257R mutation. There was no HER2 mutation.\n\nFrom November 2019 to January 2020, the patient received the seventh-line treatment with Abraxane (200mg IV day 1 every 14 days), with the optimal efficacy of SD. In February 2020, she began to accept the eighth-line treatment with pertuzumab (840mg IV day 1 followed by 420mg IV day 1 every 21 days) combined with trastuzumab (8mg/kg IV da y1 followed by 6mg/kg IV day 1 every 21 days) and xeloda (1000mg/m2 PO bid days 1–14 every 21 days). The efficacy has not been evaluated at the time of writing this paper.\n\nDiscussion\n\nHER2-amplified breast cancer accounts for about 15–20% of all breast cancers2 and is often characterized by rapid progression and poor prognosis.10,11 The precise treatment of HER2 has completely changed the survival rate for breast cancer with HER2-amplification. However, as time goes by, anti-HER2 treatment will inevitably produce acquired drug resistance, which will affect the survival of patients. Therefore, it is imperative to clarify the mechanism of drug resistance and make targeted treatments. The resistance mechanism of anti-HER2 drugs is complex, and the resistance caused by HER2 mutation has attracted more and more attention and may become a new potential therapeutic target.12 We report a 57-year-old woman with advanced HER2-positive breast cancer who received multiple lines of anti-HER2 therapy and was confirmed to have the HER2 R157W missense mutation in exon 4 by plasma NGS, and obtained PR after treatment with pyrotinib and capecitabine. This case provides a new potential treatment option for HER2 mutations following resistance to HER2 therapy.\n\nProto-oncogene HER2, also known as ErbB2, belongs to the ERB family with ErbB1(EGFR), ErbB3(HER3), and ErbB4(HER4). No high-affinity ligand has been found in HER2 so far, so it must form homologously or as a heterodimer with other members of the family, binding with ATP to activate intracellular tyrosine kinases, thereby initiating the downstream signaling pathway and regulating the proliferation and differentiation of cells.13–15 HER2 is the most important driver gene of breast cancer, and the most common positive form is gene amplification. Amplification of HER2 would lead to increased protein synthesis (ie, overexpression of HER2 protein) or increased protein function, which would lead to overactivation of downstream signaling pathways and overgrowth of cells, playing an important role in the proliferation, invasion, metastasis, and evolution of breast cancer cells.16–18\n\nH0648g,19 M77001,20 EGF100151,21 EGF10490022 et al studies have shown that patients with HER2-positive breast cancer can benefit from anti-HER2 humanized trastuzumab and double HER2-EGFR tyrosine kinase inhibitor (TKI) lapatinib. However, approximately 50% of HER2-positive patients developed resistance to trastuzumab 1 year after treatment.23 Lapatinib has achieved certain clinical efficacy in metastatic HER2-positive breast cancer treated with trastuzumab, but a significant proportion of patients develop disease progression due to innate or acquired resistance to lapatinib.24,25 Studies on the molecular mechanisms of trastuzumab and lapatinib resistance26 found that overexpression of other HER family receptors and their ligands, loss of PTEN leading to activation of the PI3K/Akt/mTOR pathway, PI3KCA mutation, and Akt mutation or amplification were common causes of drug resistance. Drug resistance has become an urgent problem.\n\nThe patient developed resistance to lapatinib combined with trastuzumab. The HER2 gene mutation was not detected before the patient received lapatinib plus trastuzumab treatment, while the R157W mutation was found in the disease progression after treatment. Moreover, by comparing the two gene test results (Table 1), only the HER2 mutation was acquired, so it was believed that the HER2 mutation was the main mechanism of drug resistance in this case. In recent years, with the gradual deepening of the understanding of HER2, it is believed that HER2 mutation plays an important role in the incidence, development and resistance of breast cancer.27,28 The primary HER2 mutation mostly occurred in HER2 negative conditions, while in HER2 positive breast cancer the HER2 mutation mostly occurred after anti-HER2 treatment. Fang et al6 performed HER2 full-length gene sequencing on the tissues of 198 patients with metastatic breast cancer (MBC) after multiple cycles of treatment and found that the rate of HER2 mutations in patients treated with trastuzumab was as high as 17.7%. Park et al7 also carried out NGS tests on the tissues of 36 refractory MBC patients after multi-cycle and multi-drug treatment, and found that 5 out of 6 patients with HER2 mutation were HER2 positive and developed drug resistance after receiving anti-HER2 drugs (trastuzumab, lapatinib).Table 1 NGS Results Detected Before and After Treatment with Trastuzumab and Lapatinib\n\nGenes\t20171018\nBefore Trastuzumab with Lapatinib\t20180820\nAfter Resistance to Trastuzumab with Lapatinib\tMethodology\t\nVariations\tAbundance\tCN\tVariations\tAbundance\tCN\t\nHER2\tCNG\t\t2.1\tCNG\t\t7.7\tNGS\t\np.R157W\t2.0%\t\tNGS\t\nTP53\tp.L257R\t6.4%\t\tp.L257R\t49.9%\t\tNGS\t\nCDK12\tCNG\t\t1.8\tNegative\t\t\tNGS\t\nNSD1\tGF\t0.2%\t\tNegative\t\t\tNGS\t\nESR1\tNegative\t\t\tNegative\t\t\tNGS\t\nBRCA1\tNegative\t\t\tNegative\t\t\tNGS\t\nBRCA2\tNegative\t\t\tNegative\t\t\tNGS\t\nAbbreviations: HER2, human epidermal growth factor receptor-2; TP53, tumor protein p53; CDK12, cyclin-dependent kinase 12; NSD1, nuclear receptor binding SET domain protein 1; ESR1, estrogen receptor 1; BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; CNG, copy number gain; CN, copy number; GF, gene fusion; NGS, next-generation sequencing.\n\nIn the literature, the most common HER2 mutation sites in breast cancer were L755S, V777L, D769H, D769Y, G778_P780dup, Y772_A775dup in the kinase domain, and S310F and S310Y in the extracellular domain.3,29 There are no studies to prove the difference between HER2-negative combined mutation and HER2 positive-combined mutation, and most of the mutations can occur in both. The causes of resistance to HER2 therapy due to HER2 mutations are not fully understood. A cell-induced drug resistance test suggested that drug resistance of lapatinib might be related to the change of kinase structure caused by L755S and P780L mutations, which would activate the kinase activity and interfere with the inactive structure required for lapatinib binding.30,31 It may also be related to the production of larger amino acids after L726F, L785F, and other mutations, which interfered with the binding of lapatinib spatially.30 In addition, T789 mutation can stabilize the active conformation and directly compete with lapatinib for ATP binding sites, which may also be one of the causes of lapatinib resistance.30,31 Other studies have found that increased levels of EGFR-HER3 dimerization and expression of HER4 can also lead to lapatinib resistance. The extracellular resistance test of trastuzumab suggested that mutations in the HER2 kinase domain might alter the PI3K/AKT cascade signaling, thereby weakening the inhibition of trastuzumab to the PI3K/AKT pathway.32 It has also been observed in cell experiments that L755S mutation can lead to overactivation of PI3K/AKT/mTOR and MAPK pathways, leading to resistance to lapatinib and neratinib.33 Hanker B et al34 reported that a breast cancer patient with HER2 L869R mutation got new T798I mutation when neratinib resistance happened. Cell models confirmed that the presence of isoleucine at the 798 site leads to steric hindrance, reducing the binding affinity of neratinib. Smyth et al29 believed that HER2 mutation accompanied with other changes in HER family signaling pathways, such as HER3 mutation, might lead to drug resistance to neratinib.\n\nThis case reported that R157W missense mutation happened in the extracellular domain belonging to exon4 of HER2 which could be found in the cBioPortal database35,36 within the TCGA data set (Figure 1). Prior to this, only two cases of HER2 R157W mutation have been reported in the literature, and that which was found in breast cancer harbored germline mutations. As this residue is presented in the extracellular domain, we think the drug-resistant mechanism may be related to the change of the extracellular domain receptor structure, which interfered with the binding of trastuzumab. It may also strengthen dimerization with other family receptors, such as HER2/HER3, and HER2/HER4 polymerization, thereby weakening the inhibition of lapatinib, which activated downstream pathways and caused a cascade reaction, eventually leading to tumor progression.Figure 1 Mutation site map of R157W gene in TCGA dataset from cBioPortal database.35,36\n\nThere is no standard treatment for HER2 mutation, but many studies have begun to explore treatment strategies. A number of studies have demonstrated that the pan-HER2 irreversible inhibitor neratinib has a good inhibitory effect on certain mutations. Zuo et al28 found that neratinib had a strong inhibitory effect on drug-resistant mutant cell lines bearing K753E or L755S mutations. Cocco et al37 demonstrated that neratinib could not only effectively overcome the acquired resistance to HER2 therapy in breast cancer cells carrying both HER2 amplification and L755S somatic mutation but also significantly inhibit tumor growth in mice which are resistant to trastuzumab and lapatinib as well as carrying both D769Y mutation and HER2 amplification. At the same time, it was observed that neratinib had clinical activity in breast cancer patients with both HER2 gene amplification and mutation. SUMMIT is a Phase II basket clinical trial involving patients with cancers featuring HER2 mutations, and the result shows that neratinib has a good clinical effect on patients with breast cancer accompanied by HER2 mutations but without amplification, with an ORR of 32% at 8 weeks,4 but resistance to T798-related mutations.33 Overall, neratinib has a certain clinical efficacy against common HER2 mutations, but has not yet been marketed in China.\n\nPyrotinib is a new generation of small-molecule irreversible pan-ErbB receptor TKI, covalently binding with the ATP binding site in the intracellular kinase regions of HER1, HER2, and HER4, which prevents the formation of homodimers/heterodimers in the HER family, inhibits phosphorylation itself, blocks the activation of downstream signaling pathways, and inhibits tumor cell growth.38 Its structure and mechanism of action are similar to neratinib, but it has stronger inhibitory activity in vitro. In 2019, Jiang et al, reported a phenix study orally at the ASCO conference, confirming that to HER2 positive MBC females who previously received paclitaxel and trastuzumab, pyrotinib plus capecitabine, compared to placebo plus capecitabine, can effectively improve the median PFS. In this case, the patient developed disease progression in September 2018 after receiving trastuzumab combined with lapatinib, and received pyrotinib plus capecitabine. Three months later, she got partial response, (Figure 2) and symptoms were relieved. Plasma NGS indicated that both the copy number of HER2 amplification and the abundance of R157W mutations were decreased compared with previous results (Table 2). The relationship between gene dynamics and efficacy is shown in Figure 3.Table 2 NGS Results Detected Before and After Treatment with Pyrotinib and Capecitabine\n\nGenes\t20180820\nBefore Pyrotinib with Capecitabine\t20181212\nAfter Pyrotinib with Capecitabine\tMethodology\t\nVariations\tAbundance\tCN\tVariations\tAbundance\tCN\t\nHER2\tp.R157W\t2.0%\t\tp.R157W\t1.3%\t\tNGS\t\n\tCNG\t\t7.7\tCNG\t\t2.1\tNGS\t\nTP53\tp.L257R\t49.9%\t\tp.L257R\t5.7%\t\tNGS\t\nESR1\tNegative\t\t\tNegative\t\t\tNGS\t\nBRCA1\tNegative\t\t\tNegative\t\t\tNGS\t\nBRCA2\tNegative\t\t\tNegative\t\t\tNGS\t\nAbbreviations: HER2, human epidermal growth factor receptor-2; TP53, tumor protein p53; ESR1, estrogen receptor 1; BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; CNG, copy number gain; CN, copy number; NGS, next-generation sequencing.\n\nFigure 2 Changes of images before and after treatment. The red arrows indicate the metastatic tumor.\n\nFigure 3 The relationship between gene dynamics and efficacy. The red arrows indicate the metastatic tumor.\n\nConclusion\n\nDrug resistance has affected the efficacy of anti-HER2 therapy in breast cancer, and HER2 mutation is one of the causes. However, there is no standard treatment yet. We report for the first time the occurrence of HER2 amplification accompanied by R157W mutation after anti-HER2 treatment. This case is the first clinical report of pyrotinib plus capecitabine effective for HER2 mutation, which shows a good clinical efficacy against HER2 resistance accompanied with mutation in MBC patients, and provides a possible new management strategy of anti-HER2 treatment for patients with HER2-positive breast cancer.\n\nAcknowledgments\n\nThe authors thank the patient and her family. This study did not receive any funding support from external sources. Yanchun Qu and Yufeng Liu are co-first authors for this study.\n\nEthical Approval\n\nInstitutional approval was not required to publish the case details.\n\nPatient Informed Consent\n\nWritten informed consent was obtained from the patient for the publication of her case details and images.\n\nDisclosure\n\nXiaoyu Hong is the employee of Nanjing Geneseeq Technology Inc. The other authors have no conflicts of interest that are directly relevant to the content of this article.\n==== Refs\nReferences\n\n1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70 :7–30. doi:10.3322/caac.21590 31912902\n2. Waks AG, Winer EP. Breast cancer treatment: a review. JAMA. 2019;321 :288–300.30667505\n3. Petrelli F, Tomasello G, Barni S, Lonati V, Passalacqua R, Ghidini M. Clinical and pathological characterization of HER2 mutations in human breast cancer: a systematic review of the literature. Breast Cancer Res Treat. 2017;166 :339–349.28762010\n4. 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PLoS One. 2013;8 :e61757. doi:10.1371/journal.pone.0061757 23637902\n16. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235 :177–182. doi:10.1126/science.3798106 3798106\n17. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2 :127–137. doi:10.1038/35052073 11252954\n18. Hsu JL, Hung MC. The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer. Cancer Metastasis Rev. 2016;35 :575–588.27913999\n19. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344 :783–792.11248153\n20. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005;23 :4265–4274.15911866\n21. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355 :2733–2743.17192538\n22. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012;30 :2585–2592.22689807\n23. Mohd SM, Crown J, Hennessy BT. Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer. Ann Oncol. 2012;23 :3007–3016.22865781\n24. Takeda T, Yamamoto H, Kanzaki H, et al. Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer. PLoS One. 2017;12 :e171356.\n25. Eustace AJ, Conlon NT, McDermott M, et al. Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL. BMC Cancer. 2018;18 :965.30305055\n26. Esteva FJ, Yu D, Hung MC, Hortobagyi GN. Molecular predictors of response to trastuzumab and lapatinib in breast cancer. Nat Rev Clin Oncol. 2010;7 :98–107.20027191\n27. Bose R, Kavuri SM, Searleman AC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013;3 :224–237.23220880\n28. Zuo WJ, Jiang YZ, Wang YJ, et al. Dual characteristics of novel HER2 kinase domain mutations in response to HER2-targeted therapies in human breast cancer. Clin Cancer Res. 2016;22 :4859–4869.27697991\n29. Smyth LM, Piha-Paul SA, Won HH, et al. Efficacy and determinants of response to HER kinase inhibition in HER2-mutant metastatic breast cancer. Cancer Discov. 2020;10 :198–213.31806627\n30. Trowe T, Boukouvala S, Calkins K, et al. EXEL-7647 inhibits mutant forms of ErbB2 associated with lapatinib resistance and neoplastic transformation. Clin Cancer Res. 2008;14 :2465–2475.18413839\n31. Kancha RK, von Bubnoff N, Bartosch N, Peschel C, Engh RA, Duyster J. Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib. PLoS One. 2011;6 :e26760.22046346\n32. Kong X, Zhang K, Wang X, et al. Mechanism of trastuzumab resistance caused by HER-2 mutation in breast carcinomas. Cancer Manag Res. 2019;11 :5971–5982.31308740\n33. Li J, Xiao Q, Bao Y, et al. HER2-L755S mutation induces hyperactive MAPK and PI3K-mTOR signaling, leading to resistance to HER2 tyrosine kinase inhibitor treatment. Cell Cycle. 2019;18 :1513–1522.31135266\n34. Hanker AB, Brewer MR, Sheehan JH, et al. An acquired HER2(T798I) gatekeeper mutation induces resistance to neratinib in a patient with HER2 mutant-driven breast cancer. Cancer Discov. 2017;7 :575–585.28274957\n35. Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2 :401–404.22588877\n36. Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6 :l1.\n37. Cocco E, Javier CF, Razavi P, et al. Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2). Sci Signal. 2018;11 .\n38. Zhu Y, Li L, Zhang G, et al. Metabolic characterization of pyrotinib in humans by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2016;1033–1034 :117–127.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6930",
"issue": "14()",
"journal": "OncoTargets and therapy",
"keywords": "HER2 R157W mutation; HER2 amplification; anti-HER2 treatment; breast cancer; pyrotinib plus capecitabine",
"medline_ta": "Onco Targets Ther",
"mesh_terms": null,
"nlm_unique_id": "101514322",
"other_id": null,
"pages": "1581-1588",
"pmc": null,
"pmid": "33688205",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "27541626;27913999;26397225;31912902;23637902;19536107;25326805;31806627;22588877;15911866;30301790;31135266;29420467;27865536;24192927;22046346;28274957;11049052;27697991;28762010;22689807;3798106;20027191;29209536;23220880;11252954;12648469;18413839;28164408;30667505;30305055;17192538;28158234;23550210;31308740;11248153;22522925;22865781",
"title": "Partial Response to Pyrotinib Plus Capecitabine in an Advanced Breast Cancer Patient with HER2 Amplification and R157W Mutation After Anti-HER2 Treatment: A Case Report and Literature Review.",
"title_normalized": "partial response to pyrotinib plus capecitabine in an advanced breast cancer patient with her2 amplification and r157w mutation after anti her2 treatment a case report and literature review"
} | [
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"companynumb": "CN-PFIZER INC-2021334983",
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{
"abstract": "Previous studies have reported several cases of juvenile myelomonocytic leukemia (JMML) developing blastic transformation during an indolent clinical course, but the underlying mechanism of transformation is still not well understood. In this report, we describe a case of JMML with blastic transformation possibly caused by additional copy number gains of the KRAS mutant allele. We have discovered that the copy number gain of the mutant allele is an additional possible cause of blastic transformation in JMML.",
"affiliations": "Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.;Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.;Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.;Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Pediatrics, the University of Tokyo, Tokyo, Japan.;Department of Pediatrics, the University of Tokyo, Tokyo, Japan.;Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Human Genetics, National Research Institute for Child Health and Development, Tokyo, Japan.;Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.;Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.",
"authors": "Osumi|Tomoo|T|;Kato|Motohiro|M|;Ouchi-Uchiyama|Meri|M|;Tomizawa|Daisuke|D|;Kataoka|Keisuke|K|;Fujii|Yoichi|Y|;Seki|Masafumi|M|;Takita|Junko|J|;Ogawa|Seishi|S|;Uchiyama|Toru|T|;Ohki|Kentaro|K|;Kiyokawa|Nobutaka|N|",
"chemical_list": "C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26496",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "64(9)",
"journal": "Pediatric blood & cancer",
"keywords": "CNG; JMML; KRAS; blast crisis; duplication",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D016026:Bone Marrow Transplantation; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007223:Infant; D054429:Leukemia, Myelomonocytic, Juvenile; D008213:Lymphocyte Activation; D016283:Proto-Oncogene Proteins p21(ras)",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28244637",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Blastic transformation of juvenile myelomonocytic leukemia caused by the copy number gain of oncogenic KRAS.",
"title_normalized": "blastic transformation of juvenile myelomonocytic leukemia caused by the copy number gain of oncogenic kras"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1059217",
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"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MERCAPTOPURINE"
},
"drugadditional": "3",
... |
{
"abstract": "A 61-year old woman was admitted with increasing dyspnea and deranged liver function tests. A chest X-ray revealed small volume lungs with reticulo-nodular shadowing. High resolution computed tomography of the chest revealed interlobular septal thickening. The patient subsequently underwent an open lung biopsy and ultrasound-guided liver biopsy, which were consistent with a hypersensitivity pneumonitis and drug-induced liver injury respectively. The patient had previously been commenced on lansoprazole 10 days before the onset of symptoms; this had been stopped at diagnosis. High dose prednisolone was commenced, and the patient went on to make a full recovery. Hypersensitivity pneumonitis is a form of interstitial lung disease that is rarely associated with lansoprazole; this is the first report of it causing an idiosyncratic reaction affecting the lung and liver simultaneously. This case demonstrates the importance of obtaining a full drug history, as early identification of the offending agent will improve outcomes.",
"affiliations": null,
"authors": "Atkins|Christopher|C|;Maheswaran|Tina|T|;Rushbrook|Simon|S|;Kamath|Ajay|A|",
"chemical_list": "D064747:Lansoprazole",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP202110",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "52(12)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D055371:Acute Lung Injury; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D064747:Lansoprazole; D008875:Middle Aged",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "1102-4",
"pmc": null,
"pmid": "25373140",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lansoprazole-induced acute lung and liver injury: a case report.",
"title_normalized": "lansoprazole induced acute lung and liver injury a case report"
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{
"companynumb": "GB-TAKEDA-2015TEU001530",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
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{
"abstract": "Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases.\nIn this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609.\nBetween April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66-6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46-0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55-3·19, p=0·53).\nRituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases.\nNone.",
"affiliations": "Université de Paris, Service de Rhumatologie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Centre Université de Paris, Paris, France.;ULR 2694-METRICS: Évaluation des Technologies de Santé et des Pratiques Médicales, Université de Lille, CHU Lille, Lille, France.;Université de Lille, INSERM, CHU Lille, Service de Médecine Interne et Immunologie Clinique, Centre de Référence des Maladies Autoimmunes Systémiques Rares Du Nord et Nord-Ouest de France, U1286-INFINITE: Institute for Translational Research in Inflammation, Le Kremlin-Bicêtre, France.;Université Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Service de Rhumatologie, Centre de Référence des Maladies Autoimmunes Systémiques Rares, Hôpital Bicêtre, INSERM UMR 1184, Le Kremlin-Bicêtre, France.;Sorbonne Université, Service de Médecine Interne, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.;Service de Rhumatologie, Centre Hospitalier de Tourcoing, Tourcoing, France.;Service de Rhumatologie, Centre Hospitalier René Dubos, Pontoise, France.;Service de Rhumatologie, Aix-Marseille Université, Assistance Publique-Hôpitaux de Marseille, Marseille, France.;INSERM 1059, Université de Lyon, Saint-Etienne, France.;Service de Médecine Interne, Maladies Infectieuses et Immunologie Clinique, CHU Reims, Hôpital Robert Debré, Reims, France.;Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Service de Médecine Interne et Immunologie Clinique, Paris, France.;Service de Rhumatologie et Médecine Interne, Groupe Hospitalier Diaconesses-croix St-Simon, Paris, France.;Service de Médecine Interne, CHI Poissy Saint Germain, Poissy, France.;EpiDermE, Université Paris Est Créteil, Service de Rhumatologie, Hôpital Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France.;Service de Maladies Infectieuses et Médecine Interne, Groupe Hospitalier du Havre, Le Havre, France.;Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Service de Médecine Interne et Inflammation- (DMU i3), Paris, France.;Service de Médecine Interne: Maladies Multi-Organiques, CHU Montpellier, Montpellier, France.;Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Service de Rhumatologie, Hôpital de la Pitié-Salpêtrière, Paris, France.;Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Service de Rhumatologie, Hôpital de la Pitié-Salpêtrière, Paris, France.;Hôpital Européen Georges-Pompidou, Médecine Interne, Assistance Publique-Hôpitaux de Paris, Paris, France.;Service de Rhumatologie, Hôpital Nord, CHU de Saint-Etienne, INSERM U1059, Université de Lyon-Université Jean Monnet, Saint Etienne, France.;Service de Rhumatologie, Université Lille, CHU Lille, Lille.;Service de Rhumatologie, Centre de Référence des Maladies Autoimmunes Systémiques Rares de l'Est et du Sud-Ouest de France, CHU de Bordeaux and UMR-CNRS 5164, Université de Bordeaux, Bordeaux, France.",
"authors": "Avouac|Jérôme|J|;Drumez|Elodie|E|;Hachulla|Eric|E|;Seror|Raphaèle|R|;Georgin-Lavialle|Sophie|S|;El Mahou|Soumaya|S|;Pertuiset|Edouard|E|;Pham|Thao|T|;Marotte|Hubert|H|;Servettaz|Amélie|A|;Domont|Fanny|F|;Chazerain|Pascal|P|;Devaux|Mathilde|M|;Claudepierre|Pascal|P|;Langlois|Vincent|V|;Mekinian|Arsène|A|;Maria|Alexandre Thibault Jacques|ATJ|;Banneville|Béatrice|B|;Fautrel|Bruno|B|;Pouchot|Jacques|J|;Thomas|Thierry|T|;Flipo|René-Marc|RM|;Richez|Christophe|C|;|||;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/S2665-9913(21)00059-X",
"fulltext": null,
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"issn_linking": "2665-9913",
"issue": "3(6)",
"journal": "The Lancet. Rheumatology",
"keywords": null,
"medline_ta": "Lancet Rheumatol",
"mesh_terms": null,
"nlm_unique_id": "101765308",
"other_id": null,
"pages": "e419-e426",
"pmc": null,
"pmid": "33786454",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "33268442;33277981;19757444;32503849;32557623;32933879;32235945;32591357;32669297;22029846;32312768;26238958;33521659;20925139;32984017;32458534;32503854;32457048;32753417;33504483;32241793;32213337;32348641;32769153;32335513;32661059;32916559",
"title": "COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study.",
"title_normalized": "covid 19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab a cohort study"
} | [
{
"companynumb": "FR-CELLTRION INC.-2021FR004755",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nABL1 kinase mutations represent a major mechanism of imatinib resistance in Philadelphia-positive (Ph+) patients. There is a paucity of data on ABL1 kinase mutations in Ph+ patients in Korea.\n\n\nMETHODS\nWe used restriction fragment mass polymorphism (RFMP) analysis to detect ABL1 kinase mutations in blood or bone marrow specimens from 80 Ph+ patients.\n\n\nRESULTS\nFifty-seven patients met the criteria for inadequate molecular response (IMR). ABL1 kinase mutations were found in 2.6% of patients with chronic-phase chronic myelogenous leukemia (CML), 25.0% of accelerated-phase CML, 66.7% of blast-phase CML, and in 58.3% with Ph+ acute lymphoblastic leukemia. Twelve mutations were identified: 7 T315I, 2 E255V, 1 E255K, 1 F359V, and 1 Y253H. The majority of mutation-positive patients showed an unfavorable clinical course and often had an extra Ph or additional chromosomal abnormalities. Mutations were detected in two patients who had very low or absent BCR-ABL1 normalized ratios.\n\n\nCONCLUSIONS\nMutation analysis should be performed in Ph+ patients exhibiting an IMR to imatinib. RFMP analysis is helpful for revising therapeutic strategies because it can sensitively detect clinically relevant ABL1 kinase mutations with high frequencies.",
"affiliations": "Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, South Korea.",
"authors": "Cho|Y-U|YU|;Kim|S-O|SO|;Chi|H-S|HS|;Park|S-J|SJ|;Jang|S|S|;Park|C-J|CJ|;Seo|E-J|EJ|;Lee|J-H|JH|;Lee|J-H|JH|;Lee|K-H|KH|;Im|H-J|HJ|;Seo|J-J|JJ|;Hong|S P|SP|",
"chemical_list": "D003062:Codon; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl",
"country": "England",
"delete": false,
"doi": "10.1111/ijlh.12091",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1751-5521",
"issue": "35(6)",
"journal": "International journal of laboratory hematology",
"keywords": "ABL1 kinase mutation; inadequate molecular response; restriction fragment mass polymorphism",
"medline_ta": "Int J Lab Hematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002869:Chromosome Aberrations; D003062:Codon; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D059785:Karyotype; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012150:Polymorphism, Restriction Fragment Length; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101300213",
"other_id": null,
"pages": "589-600",
"pmc": null,
"pmid": "23575252",
"pubdate": "2013-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Detection of ABL1 kinase mutations in Philadelphia-positive patients exhibiting an inadequate molecular response using restriction fragment mass polymorphism and its clinical significance: a single-center experience in Korea.",
"title_normalized": "detection of abl1 kinase mutations in philadelphia positive patients exhibiting an inadequate molecular response using restriction fragment mass polymorphism and its clinical significance a single center experience in korea"
} | [
{
"companynumb": "PHHY2014KR101174",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugadditional": null,
"drugad... |
{
"abstract": "BACKGROUND\nSpinal cord infarction is rare but can be extremely disabling. Prompt diagnosis and treatment of these infarcts is important for patient outcomes. While intravenous thrombolytic therapy is a well-established form of treatment in circumstances of cerebral stroke, it has only recently been successfully used in a few incidents of spinal cord ischemia. We present a case of anterior spinal artery (ASA) territory ischemia treated with ASA intra-arterial thrombolytic therapy.\n\n\nMETHODS\nA 52-year-old male presented with acute onset of severe lumbar pain, rapidly progressing paraplegia and loss of pain and temperature sensation, with preservation of proprioception and vibratory sensation at the L1 level and below on the right and at the L3 level and below on the left. MRI showed restricted diffusion involving the cord at and below L1 level, with normal cord T2 signal. Digital subtraction spinal angiography showed ASA cutoff in the descending limb at the level of L1. Intra-arterial tissue plasminogen activator (t-PA) combined with verapamil and eptifibatide was administered within the ASA and the patient had significant neurological improvement immediately postoperatively and at 8-month clinical follow-up.\n\n\nCONCLUSIONS\nDirect ASA intra-arterial thrombolysis is feasible, and this drug combination might be an effective therapy for spinal stroke.",
"affiliations": "School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA.;Department of Radiology, Section of Neurointerventional Radiology, NYU Langone Health, New York, NY, USA; Department of Neurology, NYU Langone Health, New York, NY, USA.;Department of Radiology, Section of Neurointerventional Radiology, NYU Langone Health, New York, NY, USA.;Department of Neurology, NYU Langone Health, New York, NY, USA.;Department of Neurosurgery, NYU Langone Health, New York, NY, USA. Electronic address: Erez.nossek@nyulangone.org.",
"authors": "Haynes|Joseph|J|;Shapiro|Maksim|M|;Raz|Eytan|E|;Czeisler|Barry|B|;Nossek|Erez|E|",
"chemical_list": "D005343:Fibrinolytic Agents; D014700:Verapamil; C067262:PLAT protein, human; D010959:Tissue Plasminogen Activator; D000077542:Eptifibatide",
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2020.11.035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "84()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Anterior spinal artery; Anterior spinal artery occlusion; Intra-arterial thrombolytic therapy; Spinal stroke",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000077542:Eptifibatide; D005343:Fibrinolytic Agents; D006801:Humans; D007269:Injections, Intra-Arterial; D008297:Male; D008875:Middle Aged; D020760:Spinal Cord Ischemia; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome; D014700:Verapamil",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "102-105",
"pmc": null,
"pmid": "33358345",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intra-arterial thrombolytic therapy for acute anterior spinal artery stroke.",
"title_normalized": "intra arterial thrombolytic therapy for acute anterior spinal artery stroke"
} | [
{
"companynumb": "US-MICRO LABS LIMITED-ML2021-00558",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
},
"drugadd... |
{
"abstract": "Observational studies have demonstrated a decreased incidence of cancers among users of HMG CoA reductase inhibitors (statins) and a reduced risk of recurrence among statin users diagnosed with early stage breast cancer. We initiated a prospective study to identify potential biomarkers of simvastatin chemopreventive activity that can be validated in future trials. The contralateral breast of women with a previous history of breast cancer was used as a high-risk model. Eligible women who had completed all planned treatment of a prior stage 0-III breast cancer received simvastatin 40 mg orally daily for 24-28 weeks. At baseline and end-of-study, we measured circulating concentrations of high-sensitivity C-reactive protein (hsCRP), estrogens, and fasting lipids; breast density on contralateral breast mammogram; and quality of life by Rand Short Form 36-Item health survey. Fifty women were enrolled with a median age of 53 years. Total cholesterol, LDL cholesterol, triglyceride, and hsCRP fell significantly during the study (P values < 0.001, <0.001, 0.003, and 0.05, respectively). Estrone sulfate concentrations decreased with simvastatin treatment (P = 0.01 overall), particularly among post-menopausal participants (P = 0.006). We did not observe a significant change in circulating estradiol or estrone concentrations, contralateral mammographic breast density, or reported physical functioning or pain scores. This study demonstrates the feasibility of short-term biomarker modulation studies using the contralateral breast of high-risk women. Simvastatin appears to modulate estrone sulfate concentrations and its potential chemopreventive activity in breast cancer warrants further investigation.",
"affiliations": "The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRBI, Room 144, Baltimore, MD 21231, USA.",
"authors": "Higgins|Michaela J|MJ|;Prowell|Tatiana M|TM|;Blackford|Amanda L|AL|;Byrne|Celia|C|;Khouri|Nagi F|NF|;Slater|Shannon A|SA|;Jeter|Stacie C|SC|;Armstrong|Deborah K|DK|;Davidson|Nancy E|NE|;Emens|Leisha A|LA|;Fetting|John H|JH|;Powers|Pendleton P|PP|;Wolff|Antonio C|AC|;Green|Hannah|H|;Thibert|Jacklyn N|JN|;Rae|James M|JM|;Folkerd|Elizabeth|E|;Dowsett|Mitchell|M|;Blumenthal|Roger S|RS|;Garber|Judy E|JE|;Stearns|Vered|V|",
"chemical_list": "D014408:Biomarkers, Tumor; D004967:Estrogens; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D002097:C-Reactive Protein; D019821:Simvastatin; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10549-011-1858-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6806",
"issue": "131(3)",
"journal": "Breast cancer research and treatment",
"keywords": null,
"medline_ta": "Breast Cancer Res Treat",
"mesh_terms": "D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms; D002097:C-Reactive Protein; D004967:Estrogens; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D008875:Middle Aged; D011788:Quality of Life; D019821:Simvastatin",
"nlm_unique_id": "8111104",
"other_id": null,
"pages": "915-24",
"pmc": null,
"pmid": "22076478",
"pubdate": "2012-02",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "16260694;17652278;8990222;19597031;16391219;9166121;20403997;3815384;15284534;14588125;20368571;18598375;19470939;16754727;19360310;15623610;16705124;12869401;19394448;11821457;9429742;19901118;15070788;9747868;20404000;11959894;18375896;17221152;21813413;16192605;11535549;15767642;20805447;21639806;1593914;12101108;10927735;20304978;15199113;17131313;14671195;15100340;179369;18707867;21142270;15551535;9449206;15197200;14623518;16882749;20162380",
"title": "A short-term biomarker modulation study of simvastatin in women at increased risk of a new breast cancer.",
"title_normalized": "a short term biomarker modulation study of simvastatin in women at increased risk of a new breast cancer"
} | [
{
"companynumb": "US-MYLANLABS-2017M1030984",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SIMVASTATIN"
},
"drugadditional": "1",
... |
{
"abstract": "A 15-year-old girl with combined immune deficiency syndrome, diagnosed with metastatic squamous cell cancer of the anus, had significant pain secondary to vulvar-perianal condyloma. Conventional treatment with oral and intravenous analgesics was limited by significant side effects of mental status changes and urinary retention leading to clinical deterioration that precluded attempts at chemotherapy. An intrathecal pump was implanted in the challenging setting of neutropenia. There was a drastic improvement in her quality of life and the ability to tolerate further chemotherapy. The option of an intrathecal pump for pain control extended our patient's ability to enjoy important quality time with family by several months.",
"affiliations": "*Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital †Department of Pediatric Hematology & Oncology, Massachusetts General Hospital for Children, Boston, MA.",
"authors": "Bengali|Raheel|R|;Huang|Mary S|MS|;Gulur|Padma|P|",
"chemical_list": "D000700:Analgesics",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0b013e31828e5dca",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "36(3)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000700:Analgesics; D001005:Anus Neoplasms; D002294:Carcinoma, Squamous Cell; D003218:Condylomata Acuminata; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes; D015918:Infusion Pumps, Implantable; D007278:Injections, Spinal; D009503:Neutropenia; D010147:Pain Measurement; D010148:Pain, Intractable; D011379:Prognosis; D014845:Vulvar Diseases",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e162-4",
"pmc": null,
"pmid": "23652866",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The use of an intrathecal pump to manage intractable cancer pain in a pediatric patient: a case report.",
"title_normalized": "the use of an intrathecal pump to manage intractable cancer pain in a pediatric patient a case report"
} | [
{
"companynumb": "US-APOTEX-2015AP007644",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "4",
... |
{
"abstract": "Childhood Lymphoblastic leukemia's (ALL) early mortality (EM) is an undesirable treatment outcome for a disease for which >90% long term success is achievable. In the Western world EM constitutes no >3%; yet, in Chiapas, Mexico, remains around 15%. With the objective of improving on EM, we determined associated elements in 28 ALL who died within 60 days of arriving at Hospital de Especialidades Pediátricas in Chiapas (HEP), by comparing them to those in 84 controls who lived beyond the first 90 days. χ, t test, and binary logistic regression (BLR) were used to determine significant individual and multiple variables associated to outcome. On arrival, fever, liver and spleen enlargement, active bleeding, lower albumin, less platelets, higher creatinine, and uric acid, more diploid and less hyperdiploid cases were associated with EM cases. Time to diagnosis, nutritional status, risk group and leukocyte count were not related. Antileukemic treatment approach was similar in both groups. The BLR model including fever, active bleeding, liver enlargement, <10,000 platelets/µL, and >2X upper normal lactic dehydrogenase, determined outcome in 66.7% EM and 90.2% controls. To improve on EM in ALL, patients with characteristics defined here ought to be treated differently at HEP.",
"affiliations": "Hospital de Especialidades Pediátricas, Chiapas, México.",
"authors": "Lepe-Zuniga|Jose L|JL|;Ramirez-Nova|Virginia|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001337",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "41(1)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D008800:Mexico; D009026:Mortality; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; D012307:Risk Factors; D013997:Time Factors",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "30339656",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Elements Associated With Early Mortality in Children With B Cell Acute Lymphoblastic Leukemia in Chiapas, Mexico: A Case-control Study.",
"title_normalized": "elements associated with early mortality in children with b cell acute lymphoblastic leukemia in chiapas mexico a case control study"
} | [
{
"companynumb": "MX-PFIZER INC-2019042479",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
... |
{
"abstract": "High-dose methotrexate therapy (HDMTX) is a common form of chemotherapy used in children with high-grade malignancy such as osteosarcoma. Treatment with HDMTX requires careful monitoring of drug levels with folinic acid (leucovorin) rescue therapy. Toxicity from methotrexate is not uncommon and sometimes causes significant morbidity and mortality.\n\n\n\nWe report an 11-year-old child whose 24-h post-HDMTX serum level was 651.8 μmol/L (recommended level <20 μmol/L), which was complicated by septic shock and progressive renal and liver failure. As carboxypeptidase (glucarpidase) was not available locally, she was treated with the sequential use of charcoal hemoperfusion (CHP) and single-pass albumin dialysis (SPAD). The patient recovered without complications. Both liver and renal function recovered with no significant late sequelae.\n\n\n\nCHP and SPAD are effective extracorporeal methods of removing methotrexate. They provide alternative treatment options for critical care nephrologists in the management of methotrexate toxicity.",
"affiliations": "Department of Paediatrics, Queen Elizabeth Hospital, Hong Kong, SAR, China. chankyw@ha.org.hk.;Department of Paediatrics, Queen Elizabeth Hospital, Hong Kong, SAR, China.",
"authors": "Chan|Winnie Kwai Yu|WK|;Hui|Wun Fung|WF|",
"chemical_list": "D000418:Albumins; D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D002606:Charcoal; D002955:Leucovorin; D008727:Methotrexate",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-016-3389-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-041X",
"issue": "31(10)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": "Hemoperfusion; Methotrexate; Pediatrics; Single-pass albumin dialysis; Toxicity",
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D058186:Acute Kidney Injury; D000418:Albumins; D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D002606:Charcoal; D002648:Child; D005260:Female; D006464:Hemoperfusion; D006801:Humans; D002955:Leucovorin; D008727:Methotrexate; D006435:Renal Dialysis",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "1699-703",
"pmc": null,
"pmid": "27335061",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19889609;20030480;20337746;14754959;17567927;15122770;24823936;12376811;18723569;16794248;20938691;20628243",
"title": "Sequential use of hemoperfusion and single-pass albumin dialysis can safely reverse methotrexate nephrotoxicity.",
"title_normalized": "sequential use of hemoperfusion and single pass albumin dialysis can safely reverse methotrexate nephrotoxicity"
} | [
{
"companynumb": "HK-ACCORD-042173",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM BICARBONATE"
},
"drugadditional": null,
... |
{
"abstract": "Reversible cerebral vasoconstriction syndrome (RCVS) combined with posterior reversible encephalopathy syndrome (PRES) is a rare complication in patients treated with immunosuppressants. A 52-year-old male patient presented with seizures after heart transplantation. The patient was suspected of having PRES on brain images. Despite the strict blood pressure control, the patient presented with altered mentality and the brain images showed a newly developed large acute infarction. Digital subtraction angiography (DSA) revealed the classic \"sausage on a string\" appearance of the cerebral arteries - potential feature of RCVS. To our knowledge, this is the first case report to describe RCVS combined with PRES after heart transplantation.",
"affiliations": "Department of Neurosurgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.;Department of Neurosurgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.;Department of Neurosurgery, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea.;Department of Neurosurgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea. Electronic address: meurokwonoki@gmail.com.",
"authors": "Ban|Seung Pil|SP|;Hwang|Gyojun|G|;Kim|Chang Hyeun|CH|;Kwon|O-Ki|OK|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2017.03.042",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "42()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Cerebral infarction; Immunosuppressant; Posterior reversible encephalopathy syndrome; Reversible cerebral vasoconstriction syndrome; Vasoconstriction",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D015901:Angiography, Digital Subtraction; D002561:Cerebrovascular Disorders; D016027:Heart Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D054038:Posterior Leukoencephalopathy Syndrome; D011183:Postoperative Complications",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "118-121",
"pmc": null,
"pmid": "28416081",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reversible cerebral vasoconstriction syndrome combined with posterior reversible encephalopathy syndrome after heart transplantation.",
"title_normalized": "reversible cerebral vasoconstriction syndrome combined with posterior reversible encephalopathy syndrome after heart transplantation"
} | [
{
"companynumb": "KR-MYLANLABS-2017M1069611",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nWe compared the effectiveness of venlafaxine and propranolol for the prophylaxis of vestibular migraine (VM).\n\n\nMETHODS\nProspective, randomized, controlled clinical trial.\n\n\nMETHODS\nSixty-four subjects with definite VM were enrolled. The subjects were randomly assigned to receive propranolol (group P, n = 33) or venlafaxine (group V, n = 31) for VM prophylaxis. Dizziness Handicap Inventory (DHI) scores, the Vertigo Severity Score (VSS), and the number of vertiginous attacks were recorded before and 4 months after treatment. The Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) scores were also recorded to monitor the resolution of psychiatric symptoms.\n\n\nRESULTS\nAt 4 months after treatment, the DHI total score decreased from 55.8 ± 2.7 to 31.3 ± 3.7 and from 50.9 ± 2.5 to 19.9 ± 2.9 (P < .001), the mean number of total vertiginous attacks decreased from 12.6 ± 1.8 to 1.9 ± 0.7 and from 12.2 ± 1.8 to 2.6 ± 1.1 (P < .001), and VSS decreased from 7.3 ± 0.3 to 2.1 ± 0.4 and from 7.9 ± 0.3 to 1.8 ± 0.5 (P < .001) in groups P and V, respectively. However, the treatment effects were similar in both groups (P > .05). BAI scores significantly decreased in both groups, whereas BDI scores decreased only in group V.\n\n\nCONCLUSIONS\nThis study provided evidence that venlafaxine and propranolol show equal effectiveness as prophylactic drugs for ameliorating vertiginous symptoms in VM patients. However, venlafaxine may be superior to propranolol in ameliorating depressive symptoms.",
"affiliations": "Department of Otorhinolaryngology, Istanbul, Turkey.;Department of Otorhinolaryngology, Istanbul, Turkey.;Department of Neurology, Haseki Research and Training Hospital, Istanbul, Turkey.;Department of Otorhinolaryngology, Istanbul, Turkey.;Department of Otorhinolaryngology, Istanbul, Turkey.",
"authors": "Salviz|Mehti|M|;Yuce|Turgut|T|;Acar|Hurtan|H|;Karatas|Abdullah|A|;Acikalin|R Murat|RM|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D014665:Vasodilator Agents; D000069470:Venlafaxine Hydrochloride; D011433:Propranolol",
"country": "United States",
"delete": false,
"doi": "10.1002/lary.25445",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0023-852X",
"issue": "126(1)",
"journal": "The Laryngoscope",
"keywords": "Anxiety; depression; dizziness handicap inventory; migraine; prophylaxis; vertigo",
"medline_ta": "Laryngoscope",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D018687:Antidepressive Agents, Second-Generation; D003863:Depression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders; D011433:Propranolol; D011446:Prospective Studies; D014665:Vasodilator Agents; D000069470:Venlafaxine Hydrochloride; D015837:Vestibular Diseases",
"nlm_unique_id": "8607378",
"other_id": null,
"pages": "169-74",
"pmc": null,
"pmid": "26228645",
"pubdate": "2016-01",
"publication_types": "D018848:Controlled Clinical Trial; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Propranolol and venlafaxine for vestibular migraine prophylaxis: A randomized controlled trial.",
"title_normalized": "propranolol and venlafaxine for vestibular migraine prophylaxis a randomized controlled trial"
} | [
{
"companynumb": "TR-PFIZER INC-2020281588",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Leptomeningeal carcinomatosis, leptomeningeal meningitis, or, as referred here, leptomeningeal metastasis (LM), is a rare but frequently fatal complication seen in advanced stage of cancer either locally advanced or after a metastasis of a known primary cancer. We present a rare and uncommon case of leptomeningeal metastases from carcinoma of unknown primary. A 32-year-old female was diagnosed with LM; however, no known primary carcinoma was identified after 2 separate biopsies. The first biopsy of the right pre-tracheal lymph node showed poorly differentiated pan-keratin (AE1 and AE3) and placental alkaline phosphatase with the possibility of germ cell origin. Second cytology of cervical lymphadenopathy was remarkable for cytokeratin 7 and 20, placental alkaline phosphatase, and CDX2 suggestive of germ line tumor with both mucinous ovarian and gastrointestinal carcinomas. Unfortunately, the LM progressed rapidly despite multiple cycles of germ cell origin directed systemic and intrathecal chemotherapy, and the patient opted for hospice care without getting a chance to identify the primary source.",
"affiliations": "1 Kern Medical Center-UCLA, Bakersfield, CA, USA.;1 Kern Medical Center-UCLA, Bakersfield, CA, USA.;2 Ross University, Miramar, FL, USA.;1 Kern Medical Center-UCLA, Bakersfield, CA, USA.;1 Kern Medical Center-UCLA, Bakersfield, CA, USA.",
"authors": "Moosavi|Leila|L|0000-0001-8790-910X;D'Assumpcao|Carlos|C|0000-0001-9967-9612;Bowen|Jonathan|J|;Heidari|Arash|A|;Cobos|Everardo|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961986938010.1177_2324709619869380Case ReportLeptomeningeal Carcinomatosis From Carcinoma of Unknown Primary in a\nYoung Patient: A Case Report and a Literature Review https://orcid.org/0000-0001-8790-910XMoosavi Leila MD1https://orcid.org/0000-0001-9967-9612D’Assumpcao Carlos MD1Bowen Jonathan BSc2Heidari Arash MD1Cobos Everardo MD11 Kern Medical Center—UCLA, Bakersfield,\nCA, USA2 Ross University, Miramar, FL, USALeila Moosavi, MD, Kern Medical Center—UCLA,\n1700 Mount Vernon Avenue, Bakersfield, CA 93305-4144, USA. Email:\nlilimoosavi@gmail.com17 8 2019 Jan-Dec 2019 7 23247096198693808 6 2019 14 7 2019 18 7 2019 © 2019 American Federation for Medical\nResearch2019American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which\npermits any use, reproduction and distribution of the work without further\npermission provided the original work is attributed as specified on the SAGE\nand Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Leptomeningeal carcinomatosis, leptomeningeal meningitis, or, as referred here,\nleptomeningeal metastasis (LM), is a rare but frequently fatal complication seen\nin advanced stage of cancer either locally advanced or after a metastasis of a\nknown primary cancer. We present a rare and uncommon case of leptomeningeal\nmetastases from carcinoma of unknown primary. A 32-year-old female was diagnosed\nwith LM; however, no known primary carcinoma was identified after 2 separate\nbiopsies. The first biopsy of the right pre-tracheal lymph node showed poorly\ndifferentiated pan-keratin (AE1 and AE3) and placental alkaline phosphatase with\nthe possibility of germ cell origin. Second cytology of cervical lymphadenopathy\nwas remarkable for cytokeratin 7 and 20, placental alkaline phosphatase, and\nCDX2 suggestive of germ line tumor with both mucinous ovarian and\ngastrointestinal carcinomas. Unfortunately, the LM progressed rapidly despite\nmultiple cycles of germ cell origin directed systemic and intrathecal\nchemotherapy, and the patient opted for hospice care without getting a chance to\nidentify the primary source.\n\ncarcinoma of unknown primaryleptomeningeal metastasisleptomeningeal carcinomatosisovarian mucinous carcinomaplacental alkaline phosphatasecaudal type homeobox 2cytokeratincover-dateJanuary-December 2019\n==== Body\nIntroduction\nLeptomeningeal metastasis (LM) is defined as infiltration of the leptomeninges by\nmalignant cells. The most common solid tumors giving rise to leptomeningeal\nmetastases are reported to be breast, lung, melanoma,1 and cancers of unknown primary, which represents only 1% to 7% of all cases.2 Patients can present with a wide range of nonspecific signs and symptoms\nresulting from involvement of various sites in the craniospinal axis. Diagnosis can\nbe challenging and often requires a high index of suspicion by clinicians.\n\nCase Report\nA 32-year-old Hispanic female with no comorbidities initially presented to an outside\nhospital with persistent productive cough, dyspnea, decreased appetite, and\nunintentional weight loss of 4.5 kg. The patient underwent a computed tomography\n(CT) angiography to rule out pulmonary embolism, but the imaging found instead\nmoderately prominent intrathoracic lymphadenopathy of uncertain etiology (Figure 1). An infectious\nworkup including for coccidioidomycosis, of which she lives in an endemic area, was\nnegative. CT scan of the abdomen and pelvis demonstrated prominent lymph nodes in\nthe upper retroperitoneal region including a 3.3-cm ovarian cystic structure (Figure 2). However, no\ndiscrete lesion or adnexal masses was identified on ultrasound of pelvis (Figure 3). CA 125 was 100\nU/mL. And CA 19-9 was 75 U/mL. Lactate acid dehydrogenase was 937 U/L. HE4, AFP,\nCEA, and βHCG were within normal limits. Given the nonspecific findings on imaging,\nthe patient underwent a diagnostic mediastinoscopy of the right pre-tracheal lymph\nnode. Pathology was suggestive of a poorly differentiated pan-keratin (AE1 and AE3)\nand placental alkaline phosphatase (PLAP) positive malignant neoplasm. Germ cell\ntumor was suspected. During the same hospitalization, serum coccidioides\nimmunodiffusion returned immunoglobulin M very weakly reactive; however,\nimmunofixation of complement was less than 1:2. Nonetheless, the patient was started\non fluconazole 800 mg daily.\n\nFigure 1. Computed tomography chest angiography to rule out pulmonary embolism instead\nfound carinal, hilar (left), and paratracheal lymphadenopathy (right).\n\nFigure 2. Computed tomography scan of abdomen and pelvis revealed a cystic structure in\nthe right adnexa.\n\nFigure 3. Ultrasound of pelvis did not show any obvious lesions or cystic\nstructures.\n\nThe patient had another hospitalization for neck swelling. Imaging found a thrombus\nextending from the midportion of the right internal jugular vein down to the\nsuperior mediastinum (Figure\n4). She was diagnosed with superior vena cava syndrome. She was\nanticoagulated with rivaroxaban and successfully discharged in stable condition.\n\nFigure 4. Computed tomography scan of the neck with intravenous contrast revealed\nthrombus in the right internal jugular vein extending from the\nmediastinum.\n\nAs an outpatient, the patient was started on a germ cell origin carcinoma directed\nchemotherapy regimen of carboplatin and paclitaxel. She, unfortunately, developed an\nallergic reaction to paclitaxel and it was replaced with docetaxel anhydrous. She\nsubsequently tolerated 3 cycles of carboplatin and docetaxel anhydrous.\n\nFour months after the initial presentation, the patient presented with 1-week history\nof headache described as the worst headache of her life. Magnetic resonance\nvenography/magnetic resonance imaging (MRI) were remarkable for slight narrowing of\nthe distal portion of the straight sinus and leptomeningeal enhancement but negative\nfor hydrocephalus (Figure\n5).\n\nFigure 5. Magnetic resonance imaging of brain T1 axial showed no hydrocephalus (A),\nleptomeningeal enhancement most prominent in the falx cerebri (seen in axial\n[B], coronal [C], and sagittal [D] T1 images with gadolinium). Magnetic\nresonance venography showed a narrowing of the distal cerebral venous sinus\n(E).\n\nPatient’s headaches were initially relieved by lumbar punctures (LPs), which had\nelevated opening pressures. She received serial of LPs for symptomatic relief and\ndiagnostic workups. Broad infectious cerebral spinal fluid investigations were\ninconclusive. However, cytology found atypical malignant cells, suggestive of\nleptomeningeal carcinomatosis. It was decided to attempt intrathecal methotrexate\n(ITMX). Unfortunately, she developed worsening of headaches, photophobia, and neck\nstiffness with high opening pressures ranging from 30 to 600 cm H2O on\nLPs. The patient was subsequently switched to IT cytarabine twice a week.\n\nSearch for a primary malignancy began anew. CT scan of chest and neck showed new\nfindings of cervical lymphadenopathy that was not present on previous CT 6 weeks\nprior (Figure 6). Positron\nemission tomography scan revealed bulky adenopathy above and below the diaphragm and\nhypermetabolic pleural-based foci within the bilateral lung fields consistent with\nmalignancy/metastasis. Cervical lymph node biopsy was performed. Immunohistochemical\nstaining and cytopathology focusing on search for occult primary were positive for\ncytokeratin 7 and 20, PLAP, and CDX2 (Figure 7). Additionally, evidence of PLAP was\nidentified persistently on cerebrospinal fluid (CSF) cytology, which confirms\nleptomeningeal carcinomatosis (Figure 6).\n\nFigure 6. (A) Computed tomography scan of neck found several new lymphadenopathies of\nincreasing sizes. Cerebrospinal fluid (CSF) malignant cells are seen on CSF\ngram stain (B) and wet mount (C). Placental alkaline phosphatase staining\nnot shown.\n\nFigure 7. Immunohistochemistry stains of cervical lymph node biopsy. (A) Hematoxylin\nand eosin, 4×: Showing malignant cells infiltrating subcapsular sinus and\nspread throughout the sinusoids. (B) CK 7 positive, 10×: seen in lung,\nbreast, and upper gastrointestinal adenocarcinoma type malignancies. (C)\nCDX2 positive, 10×: Seen in gastrointestinal primary malignancies and\novarian mucinous carcinoma. (D) Placental alkaline phosphatase positive,\n10×: Nonspecific, typically associated with germ cell tumor. (E) TTF-1\nnegative, 10×: Seen in thyroid and lung malignancies.\n\nDespite aggressive intrathecal chemotherapy, she continued to deteriorate with\nprogressively worsening headaches, developed photophobia, and had loss of peripheral\nvision. Ventricular peritoneal shunt was considered for the elevated intracranial\npressures. The patient appeared to be severely deconditioned and continued to have\ndeclining performance (Eastern Cooperative Oncology Group performance score of 3 and\nKarnofsky Performance Status score of 50). After receiving 3 cycles of carboplatin\nand docetaxel, 1 dose of ITMX, and 4 doses of intrathecal cytarabine, oncology\ndetermined that she was a poor candidate to receive additional chemotherapy. In\naddition, she developed a hematoma at the site of LPs. Altogether, such severe\nleptomeningeal disease confers a poor prognosis.\n\nAfter 5 months of fighting her cancer, she refused the palliative intraventricular\nshunt, additional procedures, and treatment. The patient and her family bravely\nproceeded with comfort care measures and hospice, 5 weeks after the headache\nstarted.\n\nDiscussion\nLeptomeningeal metastasis is a devastating complication of almost every known cancer.\nIt has been reported in 5% to 10% of patients with metastatic cancers.1 We report an unusual case of LM of unknown primary with features of germ cell\ncarcinoma and gastrointestinal origin from 2 different biopsy sites.\n\nInitially, germ cell tumor primary was suspected (Table 1). The presence of an ovarian cyst,\nCA-125, LDH, and PLAP highly suggested a form of germ cell tumor; however, negative\nAFP, βHCG, HE4, and CEA did not allow for further differentiation. Presence of\nmediastinal lymphadenopathy staged the patient as T × N × M1 or Stage IV.\nPlatinum-based and microtubule-based chemotherapy were chosen to limit the spread of\nthe malignancy. The infusion was tolerable. Unfortunately, development of headache,\nphotophobia with matching CSF, and MRI findings meant leptomeningeal carcinomatosis\nhad developed. Repeat cervical lymph node biopsy was furthermore nonspecific, except\nfor PLAP, which was shared with the initial biopsy. Additionally, cells in the CSF\nalso tested positive for PLAP, further suggesting germ cell tumor metastasis to the\nmeninges. The presence of cytokeratin 7, 20, and CDX2 in the second biopsy of the\ncervical lymph node, markers used in occult primary malignancy search, suggest\nremaining tumor cells may have originated from a possible ovarian mucinous carcinoma\n(Table 1), with CA\n125 supporting this finding; however, serum CEA was negative. The strength of PLAP\non multiple biopsies and CSF cell staining lend more credence to germ line tumor\nwith some epithelial differentiation into ovarian mucinous carcinoma. Unfortunately,\nmetastasis had already spread to the meninges.\n\nTable 1. Summary of Immunohistochemistry Tumor Markers Studied in This Case of\nMetastasis of Unknown Origina\n\nTumor Marker\tResult\tInterpretation\t\nBroad-spectrum cytokeratin (pan-keratin) identified with AE1/AE3\nantibody\tPositive on second biopsy and cerebrospinal fluid (CSF)\ncells\tUsed in cell lineage determination (epithelial vs mesenchymal vs\nmelanocytic). Pan-keratin suggests epithelial\ndifferentiation.\t\nPlacental alkaline phosphatase (PLAP)\tPositive on first and second biopsy and CSF cells\tMembrane-bound isoenzyme produced by placental\nsyncytiotrophoblasts and many neoplasms. Sensitive for germ cell\ntumors such as seminomas and embryonal carcinomas, yolk sac\ntumors, and choriocarcinomas. Some non–germ cell carcinomas such\nas serous carcinomas.\t\nCytokeratin 7\tPositive on second biopsy\tBecause of overlap expression, CK7/20 profiles\nusually are combined with more specific markers. Cytokeratin 7\nand 20 positive tumors include:\nUrothelial carcinoma\n(uroplakin, thrombomodulin, p63, CK5/6)\nPancreatic ductal\nadenocarcinoma (CDA, CA19-9, CDX-2)\nOvarian mucinous\ncarcinoma (CDK-2)\nAdenocarcinoma of bladder\n(thrombomodulin, CDK-2)\nGastric adenocarcinoma\n(subset)\nCholangiocarcinoma (subset)\t\nCytokeratin 20\tFocal cells positive on second biopsy\t\nCaudal type homeobox 2 (CDX-2)\tPositive on second biopsy\tNuclear transcription factor expressed in >95% of colorectal\nand duodenal adenocarcinomas with nuclear staining. Also seen in\nurachal adenocarcinomas from urinary bladder and ovarian\nmucinous carcinomas and some neuroendocrine tumors.\t\nGlial fibrillary acidic protein (GFAP)\tNegative on CSF cells\tIntermediary filament protein important in astrocytes\ndevelopment. Used in glial cell differentiation.27\t\nAlpha fetoprotein (AFP)\tNegative\tOncofetal glycoprotein in yolk sac tumors and hepatocellular\ncarcinoma.\t\nBeta human chorionic gonadotropin (βHCG)\tNegative\tGlycoprotein with α and β subunits. β subunit is made in\nsyncytiotrophoblasts. Found in choriocarcinoma, multinucleated\nsyncytiotrophoblastic cells in seminomas, embryonal carcinomas,\nand yolk sac tumors.\t\nCD30 (tumor necrosis factor receptor family)\tNegative\tEmbryonal carcinomas\t\nc-Kit (CD117)\tNegative\tMast/stem cell growth factor receptor (tyrosine protein kinase\nkit) activated in gastrointestinal stromal tumors.28\t\nMelan A\tNegative\tMelanoma and steroid producing cells in adrenal cortex in\nadrenal cortical carcinomas.\t\nGross cystic disease fluid protein (GCDFP-15; BRST-2)\tNegative\tProlactin-inducing glycoprotein expressed by apocrine cells of\nbreast, axillary and anogenital skin apocrine glands, salivary\nglands, and Paget disease of skin; 50% to 74% sensitive and 95%\nspecific for breast primary.\t\nEstrogen receptor (ER)\tNegative\tNot specific to breast. Cannot be used as evidence of breast\nprimary. May be used in conjunction with GCDFP-15.\t\nGATA3\tNegative\tOne of 6 GATA transcription factors. Involved in luminal\ndifferentiation of breast epithelium, development of collecting\nsystem/urothelium and trophoblastic differentiation. Regulator\nof type 2 helper T-cells.29\t\nPaired box 8 (PAX8)\tNegative\tTranscription factor critical to development of eye, thyroid,\nurinary, and reproductive organs. Associated with tumors of\nthyroid, kidney/upper urinary tract, and Müllerian system.30\t\nThyroid transcription factor 1 (TTF-1)\tNegative\tThyroid adenocarcinoma. Lung adenocarcinoma or small cell lung\ncarcinoma, if thyroid adenocarcinoma is excluded. Also, small\ncell carcinomas from prostate, urinary bladder, and uterine\ncervix.\t\na Pathology results are from an initial mediastinal lymph node, a second\nbiopsy of cervical lymph node as part of search for occult primary, and\ncerebral spinal fluid cytology. Interpretations are adapted from Krishna31 unless otherwise cited. AE1/AE3, PLAP, CK7/20, and CDX-2\npositivity suggested a tumor of ovarian/germ cell linage, possibly\novarian mucinous carcinoma. Although CDX-2 is expressed in greater than\n95% of colorectal and duodenal adenocarcinomas, these gastrointestinal\ntumors are classically CK7/20 negative.\n\nThere is no guidance for LC with undifferentiated germ cell primary. When primary is\nunknown, a regimen should be selected to cover breast, lung, and epithelial ovarian\ncancer for broad coverage. Therefore, ITMX was chosen. Intrathecal cytarabine was\nalso tried after chemical meningitis developed. Unfortunately, chemical meningitis\nis suspected to have caused extreme pain and headache and increased intracranial\npressures without hydrocephalus. Despite multiple cycles of systemic and intrathecal\nchemotherapy, her disease progressed rapidly and the patient proceeded with hospice\ncare.\n\nThe prognosis of LM from known solid tumors is poor, ranging from 4 to 6 weeks\nwithout treatment3 to 3 to 6 months with treatment.4 The primary treatment goal is palliation to improve the neurological deficits\nas well as the quality of life. Once the diagnosis is made and risk status\nidentified, 3 therapeutic possibilities in LM for those with good risk status and\nwish to have further therapy. The National Comprehensive Cancer Network (NCCN)\nprovides the following recommendations at a category 2A level of evidence and consensus.5 Systemic chemotherapy is specific to primary cancer type, emphasizing drugs\nwith good central nervous system penetration. Intra-CSF chemotherapy can also be considered.6 Ommaya or intraventricular catheter placement is recommended. If there are\nsigns and symptoms of CSF flow blockage, it needs to be evaluated with CSF flow scan\nand treated with fractionated external beam radiotherapy to relieve flow\nabnormalities, if possible. Whole brain radiation therapy and/or involved-field\nradiation therapy to bulky disease and neurologically symptomatic (such as cranial\nneuropathies) or painful sites. Volumes and dose of radiotherapy will depend on\nprimary source and sites requiring palliation.\n\nChemotherapy options are based on primary malignancy. To date, NCCN recommendations\nare available for lymphoma, leukemia, breast, non–small cell lung cancers, and\noccult malignancy. If lymphoma/leukemia primary, additional options are IT\ncytarabine7-10 or ITMX.9,11 Lymphomas have additional\noptions in IT rituximab12 and systemic methotrexate13 as well. If breast cancer is the primary malignancy, ITMX14,15 and IT trastuzumab16 in addition to systemic methotrexate17 can be used. If systemic methotrexate is used in general, consider\nglucarpidase (carboxypeptidase G2) for prolonged methotrexate clearance due to\nmethotrexate-induced renal toxicity.18 If primary cancer is non–small cell lung cancer, options depend on mutation\nidentified. Systemic osimertinib can be used for EGFR mutation-positive tumors.19 Systemic weekly pulse erlotinib for EGFR exon 19 deletion or exon 21 L858R\nmutation can also be used (NCCN category 2B).5,20 When a primary malignancy is\nnot identified despite widespread search, occult malignancy is suspected. In these\ncases, IT N,NI,NII-triethylene phosphoramide (Thio-tepa),21 IT topotecan,22 IT etoposide,23 or IT interferon-α (NCCN category 2B)5,8 are recommended.\n\nEvaluation of treatment response depends on clinical status, CSF cytology results,\nand radiographic status. The goal of therapy is clinical stability or improvement,\nnegative CSF cytology, and no radiologic progression of LM disease. Reevaluation of\nCSF cytology every 4 to 8 weeks is warranted to assess treatment effectiveness. If\ntreatment is ineffective, switch chemotherapies, radiotherapy to symptom sites,\ncontinue systemic chemotherapy, or palliate with best supportive care.\n\nChemical meningitis is not uncommon with ITMX. Jacob et al24 prospectively observed patients undergoing prophylaxis ITMX for acute\nlymphoblastic leukemia or lymphoblastic lymphoma for signs of post-ITMX syndrome\ndefined as vomiting, headache, and fever. Of 297 doses, 6.7% post-ITMX syndrome were\nobserved.\n\nChemical meningitis has been also reported with intrathecal liposomal cytarabine.25 In this case, prompt identification of chemical meningitis after the first\ndose in patient with BRAF-V600E-mutated melanoma leptomeningeal metastases allowed\nfor dose delay and reduction and subsequent tolerability of 15 additional injections\nwith appropriate clinical and MRI enhancement response. This particular patient\nsurvived to 36 months at least.\n\nConclusion\nDespite newer targeted immunotherapeutic agents that are currently under\ninvestigation, an improved understanding of the etiology of LM, treatment as well as\nadditional randomized trials are needed to be conducted to determine optimal\ntreatment of such a devastating disease.26 Nonetheless, LM is still very difficult to treat. Our patient had a very\nrapid decline.\n\nThe authors wish to acknowledge the contribution of Dr William Stull for pathology\nand Dr Augustine Munoz for cerebrospinal fluid images.\n\nAuthors’ Note: The case described in this article was presented as an oral presentation at the\nWestern American Federation of Medical Research Conference in January 2019 and\nas a poster presentation at Kern Medical Research Forum in May 2019.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nEthics Approval: Kern Medical Institutional Review Board granted ethical approval to report this\ncase (Study #18083).\n\nInformed Consent: Written informed consent was obtained from the patient for the presentation of\nthe case along with associated imaging.\n\nORCID iDs: Leila Moosavi \nhttps://orcid.org/0000-0001-8790-910X\n\nCarlos D’Assumpcao \nhttps://orcid.org/0000-0001-9967-9612\n==== Refs\nReferences\n1 \nLe Rhun E Weller M Brandsma D et al\nEANO-ESMO clinical practice\nguidelines for diagnosis, treatment and follow-up of patients with\nleptomeningeal metastasis from solid tumors . 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"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "7()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "carcinoma of unknown primary; caudal type homeobox 2; cytokeratin; leptomeningeal carcinomatosis; leptomeningeal metastasis; ovarian mucinous carcinoma; placental alkaline phosphatase",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D055756:Meningeal Carcinomatosis; D009382:Neoplasms, Unknown Primary; D059906:Neuroimaging; D014057:Tomography, X-Ray Computed; D014463:Ultrasonography",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709619869380",
"pmc": null,
"pmid": "31423841",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "19668151;10506606;26425578;29057672;21865399;11161370;12002763;20737034;9720500;16344918;825215;16583432;10589750;18316473;20121608;8445432;18820836;5109411;23588955;29165794;19738466;12173336;3309199;29069871;28881917;26019420;29079637",
"title": "Leptomeningeal Carcinomatosis From Carcinoma of Unknown Primary in a Young Patient: A Case Report and a Literature Review.",
"title_normalized": "leptomeningeal carcinomatosis from carcinoma of unknown primary in a young patient a case report and a literature review"
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"abstract": "OBJECTIVE\nTo report a case of atypical infectious crystalline keratopathy-like stromal infection secondary to microsporidia wherein diagnosis of the causative organism was aided by use of the Center for Disease Control (CDC) DPDx program.\n\n\nMETHODS\nWe report the case of a 73-year-old woman who presented with atypical infectious crystalline keratopathy-like corneal infection without previous surgical history.\n\n\nRESULTS\nThe patient had previously been treated for recalcitrant corneal infection with topical antibiotics and steroids at an outside provider before referral. Further treatment with topical fortified antibiotics failed to improve the infection. Corneal biopsy was performed and sent to the CDC DPDx for diagnostic confirmation for presumptive microsporidia. The patient underwent therapeutic penetrating keratoplasty without recurrence of ocular infection.\n\n\nCONCLUSIONS\nUtilization of the DPDx resource may help guide appropriate and timely diagnosis and management strategies in atypical presentations of infectious keratitis.",
"affiliations": "Dean McGee Eye Institute/University of Oklahoma, Oklahoma City, OK.",
"authors": "Huck|Andrew|A|;Moore|Lee E|LE|;Firestone|Brian K|BK|;Siatkowski|Rhea L|RL|;Riaz|Kamran M|KM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000002715",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "41(1)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": null,
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "109-112",
"pmc": null,
"pmid": "34870625",
"pubdate": "2022-01-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Diagnostic Utility of CDC DPDx for an Atypical Presentation of Infectious Crystalline Keratopathy-Like Infiltrate Secondary to Microsporidia.",
"title_normalized": "diagnostic utility of cdc dpdx for an atypical presentation of infectious crystalline keratopathy like infiltrate secondary to microsporidia"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-332260",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
... |
{
"abstract": "BACKGROUND\nBeta-lactams are the most frequently used antibiotics in pediatric age. Anaphylactic reactions may occur and need to be properly studied, but studies in children are scarce.\n\n\nOBJECTIVE\nCharacterization of case reports of anaphylaxis in children referred to an allergy department with suspected beta-lactams hypersensitivity.\n\n\nMETHODS\nRetrospective analysis of all children referred to our Drug Allergy Center with suspected beta-lactams hypersensitivity between January 2011 and December 2016. Description of the drug allergy work-up performed studied according to standardized diagnostic procedures of ENDA/EAACI, including specific-IgE assay, skin prick and intradermal tests and diagnostic/alternative drug challenge tests.\n\n\nRESULTS\n146 children with suspected beta-lactams hypersensitivity were studied, and in 21 (14.4%) the diagnosis was confirmed. In all of them, except for three children, an alternative beta-lactam was found. In seven children (33.3% of those with confirmed beta-lactams hypersensitivity) anaphylaxis was confirmed, and all of them described reactions with cutaneous and respiratory or gastrointestinal involvement. The culprit drug was amoxicillin in six and flucloxacillin in one. In this sample, we also performed oral challenge with cefuroxime, being negative in all cases. Almost all cases of confirmed anaphylaxis (six from seven cases) were IgE mediated, with positive skin tests despite negative serum specific-IgE.\n\n\nCONCLUSIONS\nAllergic reactions to beta-lactams, although rare in children, require a detailed clinical history and a specialized drug allergy work-up to allow a correct diagnosis as well as to avoid the possibility of a potential life-threatening reaction and provide alternative drugs.",
"affiliations": "Immunoallergy Department, Coimbra Hospital Universitary Centre, Coimbra, Portugal.;Immunoallergy Department, CUF Descobertas Hospital, Lisbon, Portugal. Electronic address: angela.gaspar@sapo.pt.;Immunoallergy Department, CUF Descobertas Hospital, Lisbon, Portugal.;Immunoallergy Department, CUF Descobertas Hospital, Lisbon, Portugal.;Immunoallergy Department, CUF Descobertas Hospital, Lisbon, Portugal.;Immunoallergy Department, CUF Descobertas Hospital, Lisbon, Portugal.;Immunoallergy Department, CUF Descobertas Hospital, Lisbon, Portugal.",
"authors": "Azevedo|J|J|;Gaspar|Â|Â|;Mota|I|I|;Benito-Garcia|F|F|;Alves-Correia|M|M|;Chambel|M|M|;Morais-Almeida|M|M|",
"chemical_list": "D000485:Allergens; D047090:beta-Lactams; D007073:Immunoglobulin E",
"country": "Singapore",
"delete": false,
"doi": "10.1016/j.aller.2018.07.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0546",
"issue": "47(2)",
"journal": "Allergologia et immunopathologia",
"keywords": "Anaphylaxis; Beta-lactams; Children; Drug allergy",
"medline_ta": "Allergol Immunopathol (Madr)",
"mesh_terms": "D000293:Adolescent; D000485:Allergens; D000707:Anaphylaxis; D002648:Child; D002675:Child, Preschool; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D007073:Immunoglobulin E; D007223:Infant; D008297:Male; D012189:Retrospective Studies; D012867:Skin; D012882:Skin Tests; D011795:Surveys and Questionnaires; D047090:beta-Lactams",
"nlm_unique_id": "0370073",
"other_id": null,
"pages": "128-132",
"pmc": null,
"pmid": "30249451",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Anaphylaxis to beta-lactam antibiotics at pediatric age: Six-year survey.",
"title_normalized": "anaphylaxis to beta lactam antibiotics at pediatric age six year survey"
} | [
{
"companynumb": "PHHY2018PT137812",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN\\CLAVULANATE POTASSIUM"
},
"drugadditional... |
{
"abstract": "The case histories of three young women with ankylosing spondylitis, rheumatoid arthritis and a seronegative inflammatory polyarthritis undergoing investigations for infertility are presented. In each, non-steroidal anti-inflammatory drug (NSAID) therapy was associated with the recurrent development of luteinized unruptured ovarian follicles and normal ovulation following drug withdrawal. It is suggested that NSAID therapy may be an important and frequently overlooked cause of anovulation and infertility.",
"affiliations": "Rheumatic Diseases Unit, Western General Hospital, Edinburgh.",
"authors": "Smith|G|G|;Roberts|R|R|;Hall|C|C|;Nuki|G|G|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007986:Luteinizing Hormone",
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/35.5.458",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0263-7103",
"issue": "35(5)",
"journal": "British journal of rheumatology",
"keywords": null,
"medline_ta": "Br J Rheumatol",
"mesh_terms": "D000328:Adult; D000858:Anovulation; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001168:Arthritis; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D007247:Infertility, Female; D007986:Luteinizing Hormone; D006080:Ovarian Follicle; D010060:Ovulation; D013167:Spondylitis, Ankylosing",
"nlm_unique_id": "8302415",
"other_id": null,
"pages": "458-62",
"pmc": null,
"pmid": "8646437",
"pubdate": "1996-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Reversible ovulatory failure associated with the development of luteinized unruptured follicles in women with inflammatory arthritis taking non-steroidal anti-inflammatory drugs.",
"title_normalized": "reversible ovulatory failure associated with the development of luteinized unruptured follicles in women with inflammatory arthritis taking non steroidal anti inflammatory drugs"
} | [
{
"companynumb": "GB-MYLANLABS-2020M1105346",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugadditional": nul... |
{
"abstract": "Objectives: If clinicians can know that there are many life-threatening drugs left in the stomach through a non-invasive method over 60 min after drugs ingestion, it may be preferable to minimize absorption of remnant drugs through various methods according to the characteristic of the drug. Computed tomography (CT) has gained wide acceptance in the detection of drug mules. Therefore, we evaluated the prevalence of drugs in the gastric lumen using abdominal non-contrast CT, performed over 60 min after acute drug poisoning. Materials and methods: This was a prospective cohort study of patients with acute drug poisoning who were admitted to the emergency department (ED) between March 2017 and February 2018. If the patient visited the ED over 60 min after ingestion of life-threatening or unknown drugs, non-contrast CT scan was performed. \"Presence of drugs\" was defined in the non-contrast CT as a round-shaped lesion with higher density than the gastric mucosa. In addition, \"positive radiodense image\" was defined as that with higher density than the gastric mucosa regardless of drug appearance in the non-contrast CT scan. Results: Among a total of 482 patients with drug poisoning, 140 were finally included in the study. Residual drugs were detected in 36 patients (25.7%). Further, regardless of the presence of drugs, 58 patients (41.4%) showed positive radiodense image in the stomach. The median Hounsfield unit of drugs was 131.5 and that of food materials in the stomach was 34.5. Total duration of hospital stay was significantly longer in the \"absence of drug\" group and sustained-release drugs were detected more frequently in the \"presence of drugs\" group. Conclusions: Detection rate of drugs and presence of positive radiodense image, regardless of drug appearance, were as high as 25.7% and 41.4%, respectively. Sustained-release drugs were detected more frequently in the \"presence of drugs\" group.",
"affiliations": "a Department of Emergency Medicine , Yonsei University Wonju College of Medicine , Wonju , Republic of Korea.;b Department of Radiology , Yonsei University Wonju College of Medicine , Wonju , Republic of Korea.;a Department of Emergency Medicine , Yonsei University Wonju College of Medicine , Wonju , Republic of Korea.;a Department of Emergency Medicine , Yonsei University Wonju College of Medicine , Wonju , Republic of Korea.;a Department of Emergency Medicine , Yonsei University Wonju College of Medicine , Wonju , Republic of Korea.;a Department of Emergency Medicine , Yonsei University Wonju College of Medicine , Wonju , Republic of Korea.",
"authors": "Cha|Yong Sung|YS|0000-0001-9897-4273;Cha|Seung-Whan|SW|;Kim|Sun Ju|SJ|;Kim|Yoon Seop|YS|;Lee|Yoonsuk|Y|;Kim|Hyun|H|0000-0002-1696-9401",
"chemical_list": "D003692:Delayed-Action Preparations; D004364:Pharmaceutical Preparations",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2018.1542702",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "57(7)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Imaging; drug; study",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000005:Abdomen; D000328:Adult; D015331:Cohort Studies; D003692:Delayed-Action Preparations; D062787:Drug Overdose; D004636:Emergency Service, Hospital; D005260:Female; D005753:Gastric Mucosa; D006801:Humans; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D004364:Pharmaceutical Preparations; D011446:Prospective Studies; D013270:Stomach; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "632-637",
"pmc": null,
"pmid": "30757921",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The usefulness of non-contrast abdominal computed tomography for detection of residual drugs in the stomach of patients with acute drug overdose.",
"title_normalized": "the usefulness of non contrast abdominal computed tomography for detection of residual drugs in the stomach of patients with acute drug overdose"
} | [
{
"companynumb": "KR-JNJFOC-20190622208",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase.\n\n\n\nIn a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis).\n\n\n\nThe trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15).\n\n\n\nIn patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. (Funded by the European Union Seventh Framework Program; WAKE-UP ClinicalTrials.gov number, NCT01525290; and EudraCT number, 2011-005906-32 .).",
"affiliations": "From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).;From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).",
"authors": "Thomalla|Götz|G|0000-0002-4785-1449;Simonsen|Claus Z|CZ|;Boutitie|Florent|F|;Andersen|Grethe|G|;Berthezene|Yves|Y|;Cheng|Bastian|B|;Cheripelli|Bharath|B|;Cho|Tae-Hee|TH|;Fazekas|Franz|F|;Fiehler|Jens|J|;Ford|Ian|I|;Galinovic|Ivana|I|;Gellissen|Susanne|S|;Golsari|Amir|A|;Gregori|Johannes|J|;Günther|Matthias|M|;Guibernau|Jorge|J|;Häusler|Karl Georg|KG|;Hennerici|Michael|M|;Kemmling|André|A|;Marstrand|Jacob|J|;Modrau|Boris|B|;Neeb|Lars|L|;Perez de la Ossa|Natalia|N|;Puig|Josep|J|;Ringleb|Peter|P|;Roy|Pascal|P|;Scheel|Enno|E|;Schonewille|Wouter|W|;Serena|Joaquin|J|;Sunaert|Stefan|S|;Villringer|Kersten|K|;Wouters|Anke|A|;Thijs|Vincent|V|;Ebinger|Martin|M|;Endres|Matthias|M|;Fiebach|Jochen B|JB|;Lemmens|Robin|R|;Muir|Keith W|KW|;Nighoghossian|Norbert|N|;Pedraza|Salvador|S|;Gerloff|Christian|C|;|||",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa1804355",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "379(7)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000208:Acute Disease; D061605:Administration, Intravenous; D000368:Aged; D002545:Brain Ischemia; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D020300:Intracranial Hemorrhages; D053783:Magnetic Resonance Imaging, Interventional; D008297:Male; D008875:Middle Aged; D020521:Stroke; D017131:Thrombectomy; D015912:Thrombolytic Therapy; D061665:Time-to-Treatment; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "611-622",
"pmc": null,
"pmid": "29766770",
"pubdate": "2018-08-16",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset.",
"title_normalized": "mri guided thrombolysis for stroke with unknown time of onset"
} | [
{
"companynumb": "DE-BoehringerIngelheim-2018-BI-026775",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "... |
{
"abstract": "OBJECTIVE\nTo describe risk factors for geographic atrophy (GA) in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).\n\n\nMETHODS\nCohort within a randomized clinical trial.\n\n\nMETHODS\nWe analyzed 1024 CATT patients with no GA visible on color fundus photographs (CFPs) and/or fluorescein angiograms (FAs) at enrollment.\n\n\nMETHODS\nEyes were assigned to ranibizumab (0.5 mg) or bevacizumab (1.25 mg) treatment and to a 2-year monthly or pro re nata (PRN) injection regimen, or monthly injections for 1 year and PRN for 1 year. Demographic, genetic, and baseline ocular characteristics and lesion features of CFP/FA and optical coherence tomography (OCT) were evaluated as risk factors for GA through 2 years of follow-up. Time-dependent Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs).\n\n\nMETHODS\nDevelopment of GA.\n\n\nRESULTS\nBy 2 years, GA developed in 187 of 1024 patients (18.3%). Baseline risk factors for GA development included baseline visual acuity (VA) ≤20/200 (aHR, 2.65; 95% confidence interval [CI], 1.43-4.93), retinal angiomatous proliferation (RAP; aHR, 1.69; 95% CI, 1.16-2.47), GA in the fellow eye (aHR, 2.07; 95% CI, 1.40-3.08), and intraretinal fluid at the foveal center (aHR, 2.10; 95% CI, 1.34-3.31). Baseline factors associated with lower risk for GA development included blocked fluorescence (aHR, 0.49; 95% CI, 0.29-0.82), OCT measurements of subretinal fluid thickness of >25 μ (aHR, 0.52; 95% CI, 0.35-0.78), subretinal tissue complex thickness of >275 compared with ≤75 μ (aHR, 0.31; 95% CI, 0.19-0.50), and vitreomacular attachment (aHR, 0.55; 95% CI, 0.31-0.97). Ranibizumab compared with bevacizumab had a higher risk (aHR, 1.43; 95% CI, 1.06-1.93), and monthly dosing had a higher risk (aHR, 1.59; 95% CI, 1.17-2.16) than PRN dosing. There were no strong associations between development of GA and the presence of risk alleles for CFH, ARMS 2, HTRA1, C3, or TLR3.\n\n\nCONCLUSIONS\nApproximately one fifth of CATT patients developed GA within 2 years of treatment. Independent baseline risk factors included poor VA, RAP, foveal intraretinal fluid, monthly dosing, and treatment with ranibizumab. Anti-vascular endothelial growth factor therapy may have a role in the development of GA.",
"affiliations": "Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: juangrun@mail.med.upenn.edu.;Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Ophthalmology, Duke University, Durham, North Carolina; Department of Biomedical Engineering, Duke University, Durham, North Carolina.;Department of Ophthalmology, Duke University, Durham, North Carolina; Duke Reading Center, Duke University Eye Center, Durham, North Carolina.;Department of Ophthalmology, University of Colorado-Denver, Aurora, Colorado.;Department of Ophthalmology, University of Wisconsin, Madison, Wisconsin.;Casey Eye Institute, Oregon Health Sciences University, Portland, Oregon.;Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.;Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.;Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.",
"authors": "Grunwald|Juan E|JE|;Daniel|Ebenezer|E|;Huang|Jiayan|J|;Ying|Gui-Shuang|GS|;Maguire|Maureen G|MG|;Toth|Cynthia A|CA|;Jaffe|Glenn J|GJ|;Fine|Stuart L|SL|;Blodi|Barbara|B|;Klein|Michael L|ML|;Martin|Alison A|AA|;Hagstrom|Stephanie A|SA|;Martin|Daniel F|DF|;|||",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000069579:Ranibizumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ophtha.2013.08.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0161-6420",
"issue": "121(1)",
"journal": "Ophthalmology",
"keywords": null,
"medline_ta": "Ophthalmology",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D015331:Cohort Studies; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D060005:Genotyping Techniques; D057092:Geographic Atrophy; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D000069579:Ranibizumab; D012307:Risk Factors; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity; D057135:Wet Macular Degeneration",
"nlm_unique_id": "7802443",
"other_id": null,
"pages": "150-161",
"pmc": null,
"pmid": "24084496",
"pubdate": "2014-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "17021318;22705344;23481534;17628683;16458968;22939114;15078675;17021319;19752426;22247473;21526923;19841260;22661483;10562649;20920825;22039251;22555112;18753640;21317834;22512984;22547167;23870813;23337555;16156152;20381870;10562651;16547324;23642377;19823576",
"title": "Risk of geographic atrophy in the comparison of age-related macular degeneration treatments trials.",
"title_normalized": "risk of geographic atrophy in the comparison of age related macular degeneration treatments trials"
} | [
{
"companynumb": "US-ROCHE-775066",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Insulin autoimmune syndrome (IAS) is a disease characterized by hyperinsulinemic hypoglycemia associated with autoantibodies against endogenous insulin. A 56-year-old man was admitted to Ningbo First Hospital for the treatment of spontaneous hypoglycemia. He was found to have elevated fasting insulin level (>1,000 mIU/l) and presence of insulin autoantibodies, and after appropriate workup, was diagnosed with IAS. After treating with prednisone for 2 months, his insulin level started decreasing. In patients with repeated hypoglycemia, IAS should be considered in the differential diagnosis. Prednisone may be effective for the treatment of hypoglycemia in patients with IAS.",
"affiliations": "Department of Endocrinology, Ningbo First Hospital, Ningbo University, Ningbo, Zhejiang 315000, P.R. China.;School of Medicine, Ningbo University, Ningbo, Zhejiang 315000, P.R. China.;Department of Endocrinology, Ningbo First Hospital, Ningbo University, Ningbo, Zhejiang 315000, P.R. China.;School of Medicine, Ningbo University, Ningbo, Zhejiang 315000, P.R. China.;Department of Endocrinology, Ningbo First Hospital, Ningbo University, Ningbo, Zhejiang 315000, P.R. China.;Department of Endocrinology, Ningbo First Hospital, Ningbo University, Ningbo, Zhejiang 315000, P.R. China.;Department of Endocrinology, Ningbo First Hospital, Ningbo University, Ningbo, Zhejiang 315000, P.R. China.",
"authors": "Chu|Jian-Ping|JP|;Zheng|Xiao-Wei|XW|;Lu|Jie|J|;Zhong|Jin-Yan|JY|;Li|Jia-Lin|JL|;Xu|Miao|M|;Lin|Fang|F|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/etm.2016.3767",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-0981",
"issue": "12(5)",
"journal": "Experimental and therapeutic medicine",
"keywords": "continuous glucose monitoring system; insulin autoantibodies; insulin autoimmune syndrome",
"medline_ta": "Exp Ther Med",
"mesh_terms": null,
"nlm_unique_id": "101531947",
"other_id": null,
"pages": "3359-3362",
"pmc": null,
"pmid": "27882163",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": "19440117;24265369;3554614;26982011;25077287;27071154;23979685;27492703;26951054;26315093;26361032;25060673;9261935",
"title": "Insulin-induced autoimmune syndrome: A case report.",
"title_normalized": "insulin induced autoimmune syndrome a case report"
} | [
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"companynumb": "CN-NOVOPROD-517343",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
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"actiondrug": "1",
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"activesubstancename": "INSULIN ASPART"
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"drugadditional": "1",
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"abstract": "Dipeptidyl peptidase (DPP)-4 inhibitors are approved for use in monotherapy or in combination therapy for patients with type 2 diabetes mellitus for <1 decade. However, numerous reports of DPP-4 inhibitors induced acute pancreatitis were made through the US Food and Drug Administration Adverse Event Reporting System, and this led to a revision in the prescribing information for these drugs. Therefore, this study is designed to evaluate DPP-4 inhibitors induced acute pancreatitis via the spontaneous adverse drug reactions (ADRs) reporting system in a medical center. In four of 2305 ADR cases, it is suspected that DPP-4 inhibitors induced moderate to serious acute pancreatitis. Beyond drugs, other factors also contribute to acute pancreatitis and affect the possibility of ADRs assessed using the Naranjo algorithm. Finally, our results indicate that the incidence of DPP-4 inhibitors induced acute pancreatitis is low.",
"affiliations": "Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.;Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.;Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.;Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Pharmacy, Master Program in Clinical Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.;Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Pharmacy, Master Program in Clinical Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: jk2975525@hotmail.com.",
"authors": "Yang|Tzu-Lin|TL|;Shen|Mei-Chiou|MC|;Yu|Ming-Lung|ML|;Huang|Yaw-Bin|YB|;Chen|Chung-Yu|CY|",
"chemical_list": "D054873:Dipeptidyl-Peptidase IV Inhibitors; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases",
"country": "China (Republic : 1949- )",
"delete": false,
"doi": "10.1016/j.jfda.2016.01.009",
"fulltext": "\n==== Front\nJ Food Drug Anal\nJ Food Drug Anal\nJournal of Food and Drug Analysis\n1021-9498\n2224-6614\nTaiwan Food and Drug Administration\n\n28911601\n10.1016/j.jfda.2016.01.009\njfda-24-02-450\nCase Report\nAcute pancreatitis in patients with type 2 diabetes mellitus treated with dipeptidyl peptidase-4 inhibitors\nYang Tzu-Lin a\nShen Mei-Chiou a\nYu Ming-Lung bc\nHuang Yaw-Bin ad\nChen Chung-Yu ad*\na Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan\nb Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan\nc Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan\nd School of Pharmacy, Master Program in Clinical Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan\n* Corresponding author. Number 100, Shihcyuan 1st Road, Sanmin District, Kaohsiung City 80708, Taiwan, ROC. E-mail address: jk2975525@hotmail.com (C.-Y. Chen).\n2016\n21 2 2016\n24 2 450454\n18 10 2015\n08 12 2015\n05 1 2016\n© 2016 Taiwan Food and Drug Administration\n2016\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/).\nDipeptidyl peptidase (DPP)-4 inhibitors are approved for use in monotherapy or in combination therapy for patients with type 2 diabetes mellitus for <1 decade. However, numerous reports of DPP-4 inhibitors induced acute pancreatitis were made through the US Food and Drug Administration Adverse Event Reporting System, and this led to a revision in the prescribing information for these drugs. Therefore, this study is designed to evaluate DPP-4 inhibitors induced acute pancreatitis via the spontaneous adverse drug reactions (ADRs) reporting system in a medical center. In four of 2305 ADR cases, it is suspected that DPP-4 inhibitors induced moderate to serious acute pancreatitis. Beyond drugs, other factors also contribute to acute pancreatitis and affect the possibility of ADRs assessed using the Naranjo algorithm. Finally, our results indicate that the incidence of DPP-4 inhibitors induced acute pancreatitis is low.\n\nacute pancreatitis\ndipeptidyl peptidase-4 inhibitors\ntype 2 diabetes mellitus\n==== Body\npmc1. Introduction\n\nType 2 diabetes mellitus (T2DM) is a chronic, progressive illness that requires continuing medical care to prevent acute complications and to reduce the risk of long-term complications, particularly cardiovascular events [1]. According to the recommendations of the American Diabetes Association and the European Association for the Study of Diabetes, the main therapeutic goal in T2DM is the achievement and maintenance of glycemic levels as close to the nondiabetic range as possible [glycosylated hemoglobin (HbA1C) < 7.0%] [2].Traditional antihyperglycemic drugs include insulin and insulin analogues, insulin sensitizers (metformin and thiazolidinediones), insulin secretagogues (sulfonylureas and glinides), and agents that inhibit dietary carbohydrate breakdown (α-glucosidase inhibitors) [3]. Novel antidiabetic drugs, developed on the basis of an improved understanding of the mechanisms that govern glucose homeostasis, include the incretin-based agents, namely, glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors (also named “gliptins”). These drugs enhance glucose-dependent insulin secretion from pancreatic β cells and glucose-dependent suppression of glucagon release from pancreatic α cells, respectively, by mimicking the glucoregulatory effects of endogenous GLP-1 (GLP-1 receptor agonists or incretin mimetics) or enhancing endogenous GLP-1 concentrations (DPP-4 inhibitors or incretin enhancers) [4].\n\nDPP-4 inhibitors, such as sitagliptin and vildagliptin with metformin, have been approved for use in monotherapy or in combination therapy for patients with type 2 diabetes since 2006 [5]. A large body of evidence indicates that DPP-4 inhibitors as a class have a good safety and tolerability profile, with a low incidence of mostly mild to moderate adverse events. However, numerous reports of DPP-4 inhibitors induced acute pancreatitis were made through the US Food and Drug Administration Adverse Event Reporting System, and it led to a revision in the prescribing information for these drugs [6]. Therefore, this study is designed to evaluate DPP-4 inhibitors induced acute pancreatitis via the spontaneous adverse drug reaction (ADR) reporting system in a medical center.\n\n2. Case Report\n\nADR cases of DPP-4 inhibitors induced acute pancreatitis in our hospital, which had been reported to the National Reporting Center of Adverse Drug Reaction during January 2009 to December 2014, were collected, and the severity was analyzed using descriptive statistics. Moreover, the prescription amounts of suspected gliptins, sitagliptin, and vildagliptin with metformin, are analyzed to understand the incidence of DPP-4 inhibitors induced acute pancreatitis in the same period. A total of 2305 ADR cases were reported to the National Reporting Center of Adverse Drug Reaction between January 2009 and December 2014, including reports that four of regular follow-up type 2 diabetic patients had come to our emergency department for help with a discharge diagnosis of acute pancreatitis induced suspiciously by gliptins during the same period (Table 1). Because the average length of hospital stay for a patient with acute pancreatitis is approximately 5–6 days [7], one case (Patient 3) was defined as serious ADR because hospitalization lasted more than 7 days until recovery. The other three cases (Patients 1, 2, and 4) were defined as moderate because hospitalization lasted only 2–5 days. After withholding gliptins, medical intervention, nothing by mouth combined with adequate intravenous fluid supply, and medication for symptom relief, all patients achieved clinical recovery (Tables 1 and 2).\n\nMoreover, the initial data of the four cases, including underlying diseases as defined by International Classification of Disease, Ninth edition, Clinical Modification (ICD-9-CM) codes, suspected gliptins, concurrent hypoglycemic agents, HbA1C, duration of gliptins treatment, clinical manifestations, gastrointestinal outcomes, other risk factors, and the Naranjo scale [8], were presented (Table 2). The underlying diseases included T2DM with or without renal or neurological manifestations (ICD-9-CM codes: 250.00, 250.40, 250.60), malignant neoplasm of the thyroid gland (ICD-9-CM codes: 193), hyperlipidemia (ICD-9-CM codes: 272.4), hypercholesterolemia (ICD-9-CM codes: 272.0), hypertension (ICD-9-CM codes: 401.1, 401.9), constipation (ICD-9-CM codes: 564.0), transient disorder of initiating or maintaining sleep (ICD-9-CM codes: 307.41), and hepatitis (ICD-9-CM codes: 573.3). Suspected gliptins were sitagliptin and vildagliptin with metformin. Concurrent hypoglycemic agents were glimepiride, gliclazide, pioglitazone, and insulin. The four patients had been treated by sitagliptin (for 699–1455 days), and three had been further treated by vildagliptin with metformin (for 27–276 days). Before the first dose of gliptins was taken, the level of HbA1C was more than 7% in three cases and one patient’s level was equal to 7%. When Patient 3 stopped taking all gliptins, the level of HbA1C was < 7%. Clinical manifestations included abdominal pain (100%), abnormal serum amylase level (100%), abnormal serum lipase level (75%), and computed tomography-proven pancreas lesions (75%). Other risk factors were smoking (50%), alcohol consumption (25%), and obesity (50%). Applying the Naranjo scale, three reports were classified as possible (75%) and one as probable (25%).\n\nBy contrast, sitagliptin was prescribed 139,706 times, and the combination product, vildagliptin with metformin, was prescribed 20,631 times in our diabetic outpatient setting at the same time. The incidence of DPP-4 inhibitors induced acute pancreatitis is rare in our hospital during the past 5 years, accounting for approximately < 0.1%.\n\n3. Discussion\n\nAcute pancreatitis is an inflammatory condition of the pancreas characterized clinically by abdominal pain and elevated levels of pancreatic enzymes in the blood [9]. The pathogenesis of acute pancreatitis is not fully understood. Pancreatitis due to medications is rare (0.3–1.4%), although limited data suggest that the incidence may be increasing. Several medications have been associated with drug-induced pancreatitis, and a number of different mechanisms of drug-induced pancreatitis have been proposed [7]. These mechanisms include immunologic reactions, direct toxic effect, accumulation of a toxic metabolite, ischemia, intravascular thrombosis, and an increased viscosity of pancreatic juice. Acute pancreatitis has been reported in association with DPP-4 inhibitors treatment. However, there are insufficient data to determine if there is a causal relationship at present. In addition, a population-based study on a Taiwanese population had revealed that the risk of acute pancreatitis was not significantly higher among DPP-4 inhibitor users compared with nonusers [10]. Although our study is a simple descriptive one that did not involve a comparison group, it is noteworthy that the incidence, accounting for 0.17% of 5-year ADR reporting data, of DPP-4 inhibitors induced acute pancreatitis is rare in our study.\n\nSecond, other factors may also include the etiology of acute pancreatitis beyond drugs [7]. The approach to determine the etiology of acute pancreatitis are the following: previous symptoms or documentation of gallstones, alcohol use, history of hypertriglyceridemia or hypercalcemia, family history of pancreatic disease, prescription and nonprescription drug history, history of trauma, and the presence of concomitant autoimmune diseases. Aside from T2DM, some of our cases had dyslipidemia, some had liver problems, and some were smokers or alcohol users, which may also contribute to acute pancreatitis. These factors are known to affect the possibility of ADRs as assessed by the Naranjo algorithm.\n\nThird, there is no study concluding how long it takes for acute pancreatitis to occur after patients had started taking DPP-4 inhibitors. Intriguingly, even though the underlying conditions and other risk factors varied among patients, all our patients had been taking gliptins for more than 1 year (long term), and all had initial manifestations of accidental abdominal pain with abnormal serum amylase level. Therefore, pancreatitis should be considered in patients with persistent severe abdominal pain (with or without nausea), and DPP-4 inhibitors should be discontinued in such patients, even if they had been in use for a long time. If pancreatitis is confirmed, a DPP-4 inhibitor should not be restarted. In addition, DPP-4 inhibitors should not be initiated in patients with a history of pancreatitis. Furthermore, although further well-conducted studies are needed to prove it, female and elderly DPP-4 inhibitor users had significantly elevated risks of acute pancreatitis development [10]. Our study cannot reflect that sex and age are risk factors for DPP-4 inhibitors users to develop acute pancreatitis, but physicians may pay more attention to these groups.\n\n4. Conclusion\n\nFrom our results, the incidence of DPP-4 inhibitors induced acute pancreatitis in patients with T2DM is rare. Although physicians should remain attentive for this rare but potential complication, DPP-4 inhibitors are still reasonable options for type 2 diabetic patients who are being monitored for adverse symptoms. Otherwise, because pancreatitis could happen any time during care, patients and their caregivers should be on alert for signs of pancreatitis including severe stomach pain, back pain, very upset stomach, or throwing up. DPP-4 inhibitors should also be discontinued in such patients to prevent irreversible pancreatic harm.\n\nTable 1 Characteristics of reporting cases during 2009 to 2014.\n\nItem\tNo.\t(%)\t\nCase number (total)\t2305\t100\t\n ADR of DPP-4 inhibitors induced acute pancreatitis\t4\t0.17\t\n Severity of DPP-4 inhibitors induced acute pancreatitis\t\t\t\n Mild\t0\t0.00\t\n Moderate\t3\t0.23\t\n Serious\t1\t1.35\t\nADR = adverse drug reaction; DPP-4 inhibitors = dipeptidyl peptidase-4 inhibitors.\n\nTable 2 Demographic data, clinical characteristics, and outcome of four suspicious gliptins induced acute pancreatitis patients.\n\nSeverity\tAge (y)/sex\tUnderlying disorders (by ICD-9 codes)\tSuspected gliptins\tDuration of gliptins treatment (d)\tConcurrent hypoglycemic agents\tHbA1C (4–6%)\tClinical manifestations\tGastrointestinal outcome after gliptins were discontinued\tOther risk factors\tNaranjo Scale\t\n\t\t\nBefore the first dose of gliptins used\tWhen all gliptins were suspended\tSmoking\tAlcohol consumption\tObesity (BMI)\t\nModerate\t60/F\t193: malignant neoplasm of thyroid gland\tSitagliptin\tSitagliptin: 699\tGlimepiride\t7.4\t7.8\tAbdominal pain\t\tNonavailable\tNonavailable\tBWa: 70 kg\t3\t\n272.4: hyperlipidemia\t\t\t\t\t\t\t\t\t\t\t\n250.00: type\t\t\t\t\t\t\t\t\t\t\t\n2 diabetes mellitus\t\t\t\t\t\t\t\t\t\t\t\n401.1: hypertension\t\t\t\t\t\t\t\t\t\t\t\n\t\tMetformin\t\t\tAmylase: 163 U/L (basal: nonavailable)\tAmylase: 63 U/L\t\t\t\t\t\n\t\t\t\t\tLipase: 253 U/L (basal: nonavailable)\tLipase: 29 U/L\t\t\t\t\t\n\t\t\t\t\tCT-proven Grade\t\t\t\t\t\t\n\t\t\t\t\tA, B pancreatitis\t\t\t\t\t\t\nModerate\t53/F\t250.40: type 2 diabetes mellitus with renal manifestations\tVildagliptin with metformin (status post sitagliptin used)\tSitagliptin: 1445\tGliclazide\t13.1\t9.8\tAbdominal pain\t\tNo\tNo\tYes (26.9)\t4\t\n250.60: type 2 diabetes mellitus with neurological manifestations\tVildagliptin: 27\tInsulin\t\t\tAmylase: 294 U/L (basal: 16 U/L)\tAmylase: 66 U/L\t\t\t\t\t\n401.9: hypertension\t\t\t\t\t\t\t\t\t\t\t\n272.4: hyperlipidemia\t\t\t\t\tLipase: 18 U/L (basal: 13 U/L)\tLipase: 36 U/L\t\t\t\t\t\n307.41: transient disorder of initiating or maintaining sleep\t\t\t\t\t\t\t\t\t\t\t\nSerious\t68/M\t250.00: type 2 diabetes mellitus\tVildagliptin with metformin (status post sitagliptin used)\tSitagliptin: 980\tGliclazide\t7.0\t6.9\tAbdominal pain\t\tYes\tYes\tNo (21.2)\t5\t\n272.0: hyperlipidemia\tVildagliptin: 57\tPioglitazone\t\t\tAmylase: 379 U/L (basal: nonavailable)\tAmylase: 232 U/L\t\t\t\t\t\n\t\t\t\t\tLipase: 684 U/L (basal: nonavailable)\tLipase: 312 U/L\t\t\t\t\t\n\t\t\t\t\tCT-proven Grade B pancreatitis\tAutoimmune pancreatitis was suspected during further clinic visit\t\t\t\t\t\nModerate\t63/M\t250.00: type 2 diabetes mellitus\tVildagliptin with metformin (status post sitagliptin used)\tSitagliptin: 1355\tInsulin\t8.3\t10.3\tAbdominal pain\t\tYes\tNo\tYes (28.4)\t4\t\n250.60: type 2 diabetes mellitus with neurological manifestations\t\t\t\t\t\t\t\t\t\t\t\n573.3: hepatitis\t\t\t\t\t\t\t\t\t\t\t\n272.0 hyperlipidemia\t\t\t\t\t\t\t\t\t\t\t\n564.0: constipation\t\t\t\t\t\t\t\t\t\t\t\n\tVildagliptin: 276\t\t\t\tAmylase: 1550 U/L (basal: nonavailable)\tAmylase: 62 U/L\t\t\t\t\t\n\t\t\t\t\tLipase: 1698 U/L (basal: nonavailable)\tLipase: 50 U/L\t\t\t\t\t\n\t\t\t\t\tCT-proven groove pancreatitis\t\t\t\t\t\t\nBMI = body mass index; BW = body weight; CT = computed tomography; HbA1C = glycosylated hemoglobin; ICD-9 = International Classification of Disease, Ninth edition, Clinical Modification.\n\na Only body weight available.\n\nConflicts of interest\n\nAll contributing authors declare no conflicts of interest.\n==== Refs\nREFERENCES\n\n1 American Diabetes Association Standards of medical care in diabetes—2010 Diabetes Care 2010 33 S11 61 20042772\n2 Nathan DM Buse JB Davidson MB Ferrannini E Holman RR Sherwin R Zinman B Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes Diabetes Care 2009 32 193 203 18945920\n3 Kulasa KM Henry RR Pharmacotherapy of hyperglycemia Expert Opin Pharmacother 2009 10 2415 32 19743938\n4 Tahrani AA Piya MK Kennedy A Barnett AH Glycaemic control in type 2 diabetes: targets and new therapies Pharmacol Ther 2010 125 328 61 19931305\n5 Egan AG Blind E Dunder K de Graeff PA Hummer BT Bourcier T Rosebraugh C Pancreatic safety of incretin-based drugs—FDA and EMA assessment N Engl J Med 2014 370 794 7 24571751\n6 FDA Drug Safety Communication FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes Available from URL: http://www.fda.gov/drugs/drugsafety/ucm343187.htm accessed 25, 03, 14\n7 Van Woerkom RC Adler DG Acute pancreatitis: review and clinical update Hosp Physician 2009 Jan 9 19\n8 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA Janecek E Domecq C Greenblatt DJ A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508\n9 Working Group IAP/APA Acute Pancreatitis Guidelines IAP/APA evidence-based guidelines for the management of acute pancreatitis Pancreatology 2013 13 e1 15 24054878\n10 Lai YJ Hu HY Chen HH Chou P Dipeptidyl peptidase-4 inhibitors and the risk of acute pancreatitis in patients with type 2 dabetes in Taiwan: a population-based cohort study Medicine 2015 94 e1906 26512613\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "24(2)",
"journal": "Journal of food and drug analysis",
"keywords": "acute pancreatitis; dipeptidyl peptidase-4 inhibitors; type 2 diabetes mellitus",
"medline_ta": "J Food Drug Anal",
"mesh_terms": "D000208:Acute Disease; D003924:Diabetes Mellitus, Type 2; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D006801:Humans; D015994:Incidence; D010195:Pancreatitis; D014481:United States",
"nlm_unique_id": "101630927",
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"pages": "450-454",
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"pubdate": "2016-04",
"publication_types": "D016428:Journal Article",
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"title": "Acute pancreatitis in patients with type 2 diabetes mellitus treated with dipeptidyl peptidase-4 inhibitors.",
"title_normalized": "acute pancreatitis in patients with type 2 diabetes mellitus treated with dipeptidyl peptidase 4 inhibitors"
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"abstract": "Multifocal retinal arterial occlusions and choroidal infarctions due to embolic triamcinolone acetonide (TA) administered during a septoplasty were imaged using swept source OCT angiography (SS-OCTA) to demonstrate the utility of this imaging modality for the diagnosis and longitudinal follow-up of retinal and choroidal vascular diseases.\nA 37-year-old man presented with vision loss in his left eye upon awakening from a left-sided septoplasty during which TA was injected. Examination of the left eye demonstrated retinal whitening in the macula, white material in the distal lumen of retinal arterioles, and multifocal hypopigmented choroidal lesions. SS-OCTA imaging showed the absence of detectable flow in areas of retinal and choroidal whitening. Corresponding B-scans demonstrated hyperreflective material, thought to be embolic TA, within the retinal vessels and inner choroid.\nWide field SS-OCTA was sufficient for the diagnosis and longitudinal evaluation of retinal and choroidal occlusions without the need for dye-based angiography.",
"affiliations": "Bascom Palmer Eye Institute, Miami, FL, USA.;Bascom Palmer Eye Institute, Miami, FL, USA.;Bascom Palmer Eye Institute, Miami, FL, USA.;Bascom Palmer Eye Institute, Miami, FL, USA.;Bascom Palmer Eye Institute, Miami, FL, USA.;Bascom Palmer Eye Institute, Miami, FL, USA.;Bascom Palmer Eye Institute, Miami, FL, USA.",
"authors": "Al-Khersan|Hasenin|H|;Russell|Jonathan F|JF|;Shi|Yingying|Y|;Sridhar|Jayanth|J|;Gregori|Giovanni|G|;Flynn|Harry W|HW|;Rosenfeld|Philip J|PJ|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.ajoc.2020.100704",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(20)30063-3\n10.1016/j.ajoc.2020.100704\n100704\nCase Report\nWide field swept source OCT angiography of multifocal retinal and choroidal occlusions from embolic triamcinolone acetonide\nAl-khersan Hasenin Russell Jonathan F. Shi Yingying Sridhar Jayanth Gregori Giovanni Flynn Harry W. Rosenfeld Philip J. prosenfeld@med.miami.edu∗∗ Bascom Palmer Eye Institute, Miami, FL, USA\n∗ Corresponding author. Bascom Palmer Eye Institute, 900 NW 17th St, Miami, FL, 33136, USA. prosenfeld@med.miami.edu\n14 4 2020 \n6 2020 \n14 4 2020 \n18 10070429 11 2019 4 4 2020 7 4 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nMultifocal retinal arterial occlusions and choroidal infarctions due to embolic triamcinolone acetonide (TA) administered during a septoplasty were imaged using swept source OCT angiography (SS-OCTA) to demonstrate the utility of this imaging modality for the diagnosis and longitudinal follow-up of retinal and choroidal vascular diseases.\n\nObservations\nA 37-year-old man presented with vision loss in his left eye upon awakening from a left-sided septoplasty during which TA was injected. Examination of the left eye demonstrated retinal whitening in the macula, white material in the distal lumen of retinal arterioles, and multifocal hypopigmented choroidal lesions. SS-OCTA imaging showed the absence of detectable flow in areas of retinal and choroidal whitening. Corresponding B-scans demonstrated hyperreflective material, thought to be embolic TA, within the retinal vessels and inner choroid.\n\nConclusions\nWide field SS-OCTA was sufficient for the diagnosis and longitudinal evaluation of retinal and choroidal occlusions without the need for dye-based angiography.\n\nKeywords\nRetinaChoroidRetinal artery occlusionChoroidal infarctionSwept source optical coherence tomography angiography\n==== Body\n1 Introduction\nThe arterial vascular network of the face is interconnected. The nasal septum is supplied from both the internal and external carotid arteries.1,2 Kiesselbach's plexus, in the anterior nasal septum, is a common site of epistaxis and an anastomosis between the internal and external carotid arteries.3\n\nInjection into the face and inadvertent intraoperative cannulation of an artery within the nasal septum can lead to retrograde flow into the ophthalmic artery. This can lead to embolic retinal arterial and choroidal occlusions. Previous reports in the literature have described retinal artery4, 5, 6, 7, 8, 9, 10, 11 and choroidal occlusions5,12,13 after hyaluronic acid filler, periocular steroid, and autologous fat injections around the face. Within the field of otolaryngology, intraoperative injections during septoplasties and other rhinological surgeries can also lead to retinal arterial14, 15, 16, 17, 18 and choroidal occlusions.16,19\n\nTraditionally, fluorescein angiography (FA) has been used to diagnose and longitudinally follow patients with retinal arterial and choroidal occlusions.20 However, swept source optical coherence tomography angiography (SS-OCTA) offers a fast, non-invasive, safe, and easily repeatable alternative to FA for the diagnosis and monitoring of retinal and choroidal occlusions.21,22 Furthermore, boundary-specific segmentation strategies with OCTA can be used to isolate and evaluate different layers of retinal and choroidal vasculature.\n\nThe present report describes SS-OCTA imaging of a case of retinal and choroidal arterial occlusion after intraoperative triamcinolone acetonide injection during a septoplasty.\n\n2 Case report\nA 37-year-old man presented to the Bascom Palmer Eye Institute with decreased vision in his left eye. Earlier that day, the patient underwent a left-sided septoplasty. Upon awakening, he immediately noted a fixed central scotoma in his left eye. He denied any ocular history, trauma, or pain.\n\nOn initial examination, vision acuity was 20/20 in the right eye and 20/40 in the left. Pupillary response, intraocular pressure, and anterior segment examination were normal in both eyes. Posterior examination of the right eye was normal. Fundus examination of the left eye showed multifocal whitening of the macula along with white material at the distal ends of retinal arterioles (Fig. 1A and B). In addition, multifocal, hypopigmented foci were present deep to the retina throughout the posterior pole (Fig. 1A and B).Fig. 1 Fundus photographs of multifocal retinal and choroidal triamcinolone acetonide emboli at presentation(A) Ultrawide-field fundus photograph of the left eye at presentation demonstrated multifocal whitening of the macula along with diffuse deposition at the distal ends of retinal arterioles with white material (white arrows). Multifocal, hypopigmented areas deep to the retina were also present (black arrowheads). Fundus photographs at presentation (B) and one month (C) demonstrated resolution of the retinal whitening, multifocal retinal emboli, and foci of choroidal hypopigmentation. There was subtle retinal atrophy at one month that was most prominent temporally (C).\n\nFig. 1\n\nHaving undergone his septoplasty earlier that morning and distressed by his complication, the patient refused further invasive testing including fluorescein angiography. Instead, wide field SS-OCTA imaging was performed using the PLEX® Elite 9000 instrument (Carl Zeiss Meditec, Inc., Dublin, CA). At presentation, SS-OCTA imaging showed evidence of multifocal retinal flow deficits (Fig. 2A). At the areas of the white material within the retinal arterioles (Fig. 1B), OCT en face structural images showed hyporeflectivity (Fig. 2C), the angiographic images showed a decrease in surrounding retinal perfusion, and B-scans showed superficial hyperreflective material associated with the white material (Fig. 3B) (see Fig. 3 Legend for an explanation for this discordance). SS-OCTA of the choriocapillaris demonstrated multifocal flow deficits (Fig. 2B) that corresponded to the deep hypopigmented foci seen on color imaging and the stellate areas of hyperreflectivity seen on the en face structural SS-OCT images (Fig. 2D).Fig. 2 Wide field swept source OCT angiography (WF SS-OCTA) of multifocal retinal and choroidal triamcinolone emboli at presentation(A) WF SS-OCTA 12 × 12mm en face OCTA slabs show detectable flow within the total retina and demonstrate multifocal retinal flow deficits (A) that correspond to material in distal retinal arterioles on the corresponding OCT en face structural image (C) (see Fig. 3 Legend for explanation of why these lesions appeared hyporeflective). Paracentral acute middle maculopathy was seen on the B-scan (E) and manifested as geographic areas of increased signal reflectivity on the OCT en face structural image (C) corresponding to areas of retinal whitening seen on fundus photographs (Fig. 1B). SS-OCTA of the choriocapillaris demonstrated multifocal flow deficits (B) that corresponded to stellate areas of hyperreflectivity seen on the en face structural image (D). There was relative decreased signal on choriocapillaris OCTA slab and decreased reflectivity on the choriocapillaris structural slab in the areas of PAMM. Yellow dashed lines depict the locations of corresponding B-scans. Blue dotted lines in E and F depict segmentation for the total retinal (A, C) and choriocapillaris (B, D) slabs, respectively. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 2Fig. 3 Evolution of paracentral acute middle maculopathy and reperfusion of retinal vessels over time on wide field swept source OCT angiography (WF SS-OCTA) (A) WF SS-OCTA 12 × 12mm en face OCT structural slabs of the total retinal vasculature at baseline demonstrated geographic areas of hyperreflectivity corresponding to areas of paracentral acute middle maculopathy (PAMM; white arrow in B). Corresponding B-scans through areas of triamcinolone acetonide emboli in the distal retinal arterioles showed hyperreflective material (yellow arrow in B) within the superficial retina, and an absence of detectable flow. These hyperreflective lesions caused such intense shadowing of the PAMM that the lesions appeared hyporeflective on structural slabs (A). At one week (C, D), the PAMM persisted (white arrow in D) but the hyperreflective embolic material had disappeared and the retinal vessel had recanalized (yellow arrow in D). At one month (E, F), the PAMM had evolved into inner retinal atrophy (white arrow in E), and the vessel that had been occluded at baseline continued to have flow (yellow arrow in F). Yellow dashed lines depict the locations of corresponding B-scans. Blue dotted lines depict segmentation for the total retinal slabs. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 3\n\nOn SS-OCT B-scans, hyperreflectivity in the inner nuclear layer (INL) representing paracentral acute middle maculopathy (PAMM) was seen corresponding to the areas of retinal whitening on clinical exam (Fig. 3B and D). Hyperreflective material within superficial retinal vessels was seen with associated shadowing (Fig. 3B). At baseline, these vessels were associated with flow deficits (Fig. 3B). Moreover, the hyperreflective material associated with shadowing seen within the inner choroid (Fig. 4C) corresponded with areas of choriocapillaris flow deficits (Fig. 4A).Fig. 4 Resolution of choriocapillaris triamcinolone acetonide emboli and corresponding flow deficits over time on wide field swept source OCT angiography (WF SS-OCTA)(A) Flow deficits seen on the WF SS-OCTA 12 × 12mm choriocapillaris slab at presentation corresponded to hyperreflective lesions on the en face structural images (B) and B-scans (C). The B-scan (C) illustrates shadowing from the hyperreflective lesions that represent embolic triamcinolone acetonide. At the one-week visit, the choriocapillaris flow deficits had resolved (D) and the hyperreflective lesions had resolved on the structural image (E) and B-scan (F). Paracentral acute middle maculopathy in the temporal macula caused shadowing with consequent geographic areas of hyporeflectivity on structural slabs and artefactual hypoperfusion on OCTA slabs. Yellow dashed lines depict the locations of corresponding B-scans. Blue dotted lines depict segmentation for the choriocapillaris slabs. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 4\n\nThe patient's surgeon was contacted and disclosed that an intraoperative injection of TA into the septal mucosa had been performed. Since the patient lost vision upon awakening after TA injection and lacked systemic risk factors, the etiology of his multifocal retinal and choroidal arterial occlusions was concluded to have been due to embolic TA.\n\nThe patient underwent neuroimaging to ensure that larger vessels were not involved, and no cerebral emboli were identified. Computed tomography (CT) of the head and CT angiography of the head and neck did not reveal any abnormalities. An electrocardiogram and echocardiogram with bubble study did not demonstrate any abnormalities to suggest an alternative embolic source.\n\nFundus examination at one week and one month demonstrated total resolution of the white material occluding the retinal arteries (Fig. 1C). Repeat SS-OCTA also demonstrated resolution of the hyperreflective material previously seen filling the retinal arterioles (Fig. 3F) and in the choriocapillaris (Fig. 4F). Over the course of one month, the areas of PAMM evolved into inner retinal atrophy (Figs. 1C and 3F). Repeat SS-OCTA at 1 week and 1 month demonstrated restoration of flow within the retinal capillaries and choriocapillaris (Fig. 5). The patient's vision in the affected eye remained 20/40 with a fixed scotoma.Fig. 5 Wide field swept source OCT angiography (WF SS-OCTA) of multifocal retinal and choroidal flow deficits over one month(A) WF SS-OCTA 12 × 12mm total retinal vessel slabs at presentation, 1 week (B), and 1 month (C) demonstrated resolution of retinal flow deficits. Choriocapillaris slabs at presentation (G), 1 week (H), and 1 month (I) demonstrated resolution of choriocapillaris flow deficits. Paracentral acute middle maculopathy (PAMM) in the temporal macula (J) caused shadowing with consequent geographic areas of hyporeflectivity on structural slabs and artefactual hypoperfusion on OCTA slabs at baseline (G) and 1 week (H). At 1 week a new area of PAMM appeared inferotemporal to the optic disc that caused shadowing and artefactual choriocapillaris hypoperfusion (H) that had nearly resolved by 1 month (I). Yellow dashed lines depict the locations of corresponding B-scans. Blue dotted lines depict segmentation for the total retinal (D-F) and choriocapillaris (J-L) slabs. . (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.sss\n\nFig. 5\n\n3 Discussion\nTraditionally, dye-based angiography (FA and indocyanine green angiography) has been used to characterize retinal and choroidal vascular occlusions. Dye-based angiography is time consuming and requires intravenous access, necessitates selection of a transit eye that limits interpretation of arterial perfusion of the non-transit eye, cannot be performed in patients with certain allergies, and has side effects.23 In this report, we have shown that an alternative form of angiography, SS-OCTA, can be used to diagnose and longitudinally evaluate retinal and choroidal arterial occlusions in a fast, safe, non-invasive, and repeatable manner.\n\nOur case demonstrates the importance of utilizing both en face OCTA and OCT structural slabs for proper interpretation of SS-OCTA images. Structural slabs depict reflectivity, whereas OCTA slabs depict changes in blood flow due to changes in reflectivity of repeated scans at the same position. In areas where there are no changes in reflectivity detected on repeated scans, OCTA flow slabs are dark, indicating the absence of detectable flow. However, if the corresponding structural slab also shows dark areas, then the absence of detectable flow seen on the OCTA slab may be artefactual because of poor signal strength from media opacity or from the attenuation of the reflected signal due to overlying hyperreflective material (retinal vessels, retinal vascular emboli, drusen, etc.), which causes a shadowing artifact in the deeper slabs.\n\nFor example, the choriocapillaris OCTA slab in Fig. 2B shows two types of flow deficits: stellate areas most concentrated temporally and linear lesions superotemporal to the fovea. The stellate areas on the OCTA slab correlate with hyperreflective lesions on the corresponding structural slab (Fig. 2D). These lesions represent TA emboli within the inner choroid, likely lodged within individual lobules of the choriocapillaris, and therefore these flow deficits seen on the OCTA slab can be interpreted as genuine. In contrast, the linear flow deficits on the choriocapillaris OCTA slab (Fig. 2B) are associated with loss of reflectivity on the corresponding choriocapillaris structural slab (Fig. 2D). These lesions are an artifact of shadowing from TA emboli within superficial retinal vessels and do not reflect actual loss of choriocapillaris perfusion.\n\nEn face SS-OCT structural slabs were also helpful in delineating borders of paracentral acute middle maculopathy (PAMM). PAMM, which is defined by hyperreflectivity of the INL,24,25 caused an overall increase in reflectivity of the total retinal slab. Areas of PAMM on the total retinal structural slab (Fig. 2C) matched the distribution of retinal whitening on fundus photography (Fig. 1B). These areas of PAMM were detectable even on OCTA slabs segmented for the choriocapillaris (Fig. 4A and D) because the hyperreflective inner retina caused shadowing, but these areas of relatively low signal were distinguishable from genuine choriocapillaris flow deficits because of hyporeflectivity on the corresponding choriocapillaris structural slabs (Fig. 4B and E).\n\nThe repeatability of SS-OCTA enabled us to perform angiography at the 1 week and 1 month visits, which would not have been practical for dye-based angiography. We were thus able to characterize interval disappearance of retinal and choroidal emboli, resolution of PAMM, and restoration of retinal and choriocapillaris flow. Unlike edema of the inner retinal layers that is often seen in retinal arterial occlusion and results from superficial capillary ischemia, PAMM is thought to be associated with ischemia in the intermediate and deep retinal capillary plexuses and may be the only sign of retinal ischemia and evolving retinal artery occlusion.26,27 In our case, the initial area of PAMM progressed to inner retinal atrophy over the course of 1 month. However, there was also a new area of PAMM (Fig. 5H) that developed by the 1 week follow up visit and eventually resolved by the 1 month follow up visit (Fig. 5I). This new PAMM lesion may have occurred secondary to breakdown and/or migration of triamcinolone particles into downstream retinal vessels. The ease of repeating the OCTA allowed us to capture these dynamic changes over time.\n\nRestoration of retinal flow is known to occur after retinal arterial occlusion, but restoration of choriocapillaris flow has been harder to study prior to the advent of OCTA. It is generally accepted that if retinal circulation is not restored within about 90 minutes, the damage from retinal ischemia becomes irreversible.28 Whether the same is true for the function of the outer retina and retinal pigment epithelium (RPE) supplied by choriocapillaris perfusion is less well characterized. We observed subtle loss of RPE on OCT at the 1 month visit that corresponded to areas of choriocapillaris ischemia on presentation (Fig. 5G, L), suggesting that anatomic and possibly functional deficits can persist despite reconstitution of choriocapillaris flow.\n\nAn additional strength of WF SS-OCTA in this case was the ability to image the entire macula and beyond by using widefield scans. WF SS-OCTA montages are able to image the entire posterior pole in just a few minutes,29 though montages were not performed in this case. Current limitations of SS-OCTA include the cost of current instruments and inability to obtain commercial reimbursement that is commensurate with the amount of physician interpretation time that can be required, as demonstrated by this case.\n\nIn summary, SS-OCTA imaging was sufficient, in the absence of dye-based angiography, for the diagnosis and longitudinal evaluation of multifocal retinal and choroidal embolic occlusions. The repeatability of SS-OCTA allowed us to observe the dynamic course of the disease as demonstrated in this patient over time. The imaging and interpretation strategies demonstrated here can be applied more generally to occlusive retinal and choroidal vascular disease of various etiologies.\n\n3.1 Patient consent\nWritten consent to publish this case has not been obtained. This report does not contain any personal identifying information.\n\nFunding\nResearch supported by grants from Carl Zeiss Meditec, Inc. (Dublin, CA), the Salah Foundation, an unrestricted grant from the Research to Prevent Blindness, Inc. (New York, NY), and the National Eye Institute Center Core Grant (P30EY014801) to the Department of Ophthalmology, University of Miami\nMiller School of Medicine. Dr. Russell was supported in part by a Heed Fellowship. The funding organizations had no role in the design or conduct of the present research.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for authorship.\n\nDeclaration of competing interest\nPhilip Rosenfeld and Giovanni Gregori received research support from Carl Zeiss Meditec, Inc. and the University of Miami co-owns a patent that is licensed to Carl Zeiss Meditec, Inc.\n\nPhilip Rosenfeld is a consultant for Apellis, Boehringer-Ingelheim, Carl Zeiss Meditec, Chengdu Kanghong Biotech, Ocunexus Therapeutics, Hemera Biosciences, F. Hoffmann-La Roche Ltd., Isarna Pharmaceuticals, Ocunexus, Ocudyne, and Unity Biotechnology.\n\nPhilip Rosenfeld has equity interest in Apellis, Verana Health, and Ocudyne.\n\nJayanth Sridhar reports personal fees from Alcon, Alimera, and Oxurion.\n\nThe following authors have nothing to disclose: HA, JFR, YS, and HWF.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 Krulewitz N.A. Fix M.L. Epistaxis. Emerg Med Clin N Am. 37 2019 29 39 \n2 MacArthur F.J.D. McGarry G.W. The arterial supply of the nasal cavity Eur Arch Oto-Rhino-Laryngol 274 2017 809 815 \n3 Venettacci O. Nettlefold C. Chan L. Daniel M. Curotta J. Sub-labial packing: a novel method of stopping epistaxis from Little's area Int J Pediatr Otorhinolaryngol 77 2013 1370 1371 23806741 \n4 Peter S. Mennel S. Retinal branch artery occlusion following injection of hyaluronic acid (Restylane) Clin Exp Ophthalmol 34 2006 363 364 16764658 \n5 Li G. Xu D. Hu Z. Li H. Embolic retinal and choroidal vascular occlusion after 307 peribulbar triamcinolone injection: a case report Medicine (Baltim) 97 2018 e0467 308 e0467 \n6 Gaur N. Singh P. Chawla R. Takkar B. Triamcinolone emboli leading to central retinal artery occlusion: a multimodal imaging study BMJ Case Rep 2017 10.1136/bcr2016-218908 2017 \n7 Szantyr A. Orski M. Marchewka I. Szuta M. Orska M. Zapala J. Ocular complications following autologous fat injections into facial area: case report of a recovery from visual loss after ophthalmic artery occlusion and a review of the literature Aesthetic Plast Surg 41 2017 580 584 28233134 \n8 Kim Y.K. Jung C. Woo S.J. Park K.H. Cerebral angiographic findings of cosmetic facial filler-related ophthalmic and retinal artery occlusion J Kor Med Sci 30 2015 1847 1855 \n9 Park S.W. Woo S.J. Park K.H. Huh J.W. Jung C. Kown O.K. Iatrogenic retinal artery occlusion caused by cosmetic facial filler injections Am J Ophthalmol 154 2012 653 662 22835509 \n10 Lee C.M. Hong I.H. Park S.P. Ophthalmic artery obstruction and cerebral infarction following periocular injection of autologous fat Kor J Ophthalmol 25 2011 358 361 \n11 Danesh-Meyer H.V. Savino P.J. Sergott R.C. Ocular and cerebral ischemia following facial injection of autologous fat JAMA Ophthalmology 119 2001 777 778 \n12 Thomas E.L. Laborde R.P. Retinal and choroidal vascular occlusion following intralesional corticosteroid injection of a chalazion Ophthalmology 93 1986 405 407 3703510 \n13 Lu L. Xu X. Wang Z. Ye F. Fan X. Retinal and choroidal vascular occlusion after fat injection into the temple area Circulation 128 2013 1797 1798 24126325 \n14 Awad J. Awad A. Wong Y. Thomas S. Unilateral visual loss after a nasal airway surgery Clin Med Insights Case Rep 6 2013 119 123 23843719 \n15 Dąbrowska-Bień J. Skarżyński P.H. Gwizdalska I. Łazęcka K. Skarżyński H. Complications in septoplasty based on a large group of 5639 patients Eur Arch Oto-Rhino-Laryngol 275 2018 1789 1794 \n16 Whiteman D.W. Rosen D.A. Pinkerton R.M.H. Retinal and choroidal microvascular embolism after intranasal corticosteroid injection Am J Ophthalmol 89 1980 851 853 7386564 \n17 Kim K.E. Ahn S.J. Woo S.J. Kim N. Hwang J.M. Central retinal artery occlusion caused by fat embolism following endoscopic sinus surgery J Neuro Ophthalmol 33 2013 149 150 \n18 Leng T. Moshfeghi D.M. Branch retinal artery occlusion after septoplasty Ophthalmic Surg Laser Imag 41 2010 e1 2 \n19 Wilkinson W.S. Morgan C.M. Baruh E. Gitter K.A. Retinal and choroidal vascular occlusion secondary to corticosteroid embolisation Br J Ophthalmol 73 1989 32 34 2920152 \n20 David N.J. Norton E.W.D. Gass J.D. Beauchamp J. Fluorescein angiography in central retinal artery occlusion JAMA Ophthalmology 77 1967 619 629 \n21 Huang Y. Swept-source OCT angiography of the retinal vasculature using intensity differentiation-based optical microangiography algorithms Ophthalmic Surg Laser Imag 45 2014 382 389 \n22 Schaal K.L. Widefield en face optical coherence tomography imaging of subretinal drusenoid deposits Ophthalmic Surg Laser Imag 46 2015 550 559 \n23 Marcus D.F. Bovino J.A. Williams D. Adverse reactions during intravenous fluorescein angiography JAMA Ophthalmology 102 1984 825-825 \n24 Pecen P.E. Smith A.G. Ehlers J.P. Optical coherence tomography angiography of acute macular neuroretinopathy and paracentral acute middle maculopathy JAMA Ophthalmology 133 2015 1478 1480 26513596 \n25 Chu S. Nesper P.L. Soetikno B.T. Bakri S.J. Fawzi A.A. Projection-resolved OCT angiography of microvascular changes in paracentral acute middle maculopathy and acute macular neuroretinopathy Invest Ophthalmol Vis Sci 59 2018 2913 2922 30025133 \n26 Yu S. The spectrum of superficial and deep capillary ischemia in retinal artery occlusion Am J Ophthalmol 159 2015 53 63 25244976 \n27 Sarraf D. Paracentral acute middle maculopathy: a new variant of acute macular neuroretinopathy associated with retinal capillary ischemia JAMA Ophthalmology 131 2013 1275 1287 23929382 \n28 Hayreh S.S. Zimmerman M.B. Kimura A. Sanon A. Central retinal artery occlusion: retinal survival time Exp Eye Res 78 2004 723 736 15106952 \n29 Russell J.F. Longitudinal wide-field swept-source OCT angiography of neovascularization in proliferative diabetic retinopathy after panretinal photocoagulation Ophthalmol Retina 3 2019 350 361 31014688\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "18()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Choroid; Choroidal infarction; Retina; Retinal artery occlusion; Swept source optical coherence tomography angiography",
"medline_ta": "Am J Ophthalmol Case Rep",
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"pmid": "32322753",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": "11346413;28228436;30454778;29703002;25244976;30025133;6022731;2920152;28233134;3703510;23929382;22835509;31014688;26513596;26057758;26713062;16764658;27568352;21976947;6732561;21117572;25230403;7386564;23806741;29770875;23571187;15106952;24126325;23843719",
"title": "Wide field swept source OCT angiography of multifocal retinal and choroidal occlusions from embolic triamcinolone acetonide.",
"title_normalized": "wide field swept source oct angiography of multifocal retinal and choroidal occlusions from embolic triamcinolone acetonide"
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"abstract": "Dexmedetomidine is an alpha-2 agonist sedative and analgesic used in anesthesia practice, and it has become more prevalent in the critically ill patients requiring short-term mechanical ventilation. While dexmedetomidine is known to have minimal effects on respiratory drive, it has been well-documented to cause bradycardia and hypotension, especially in patients with existing comorbidities. We present a patient without cardiovascular comorbidities who was in the surgical ICU under dexmedetomidine sedation. The patient went into asystole cardiac arrest after vagal stimulation. Return of spontaneous circulation was achieved using ACLS protocol. We offer a review of reported cases and make recommendations on the management of similar situations that may arise given the increasing use of dexmedetomidine.",
"affiliations": "University of North Carolina Hospital at Chapel Hill, Chapel Hill, NC 27599, United States of America.;University of North Carolina Hospital at Chapel Hill, Chapel Hill, NC 27599, United States of America.;University of North Carolina Hospital at Chapel Hill, Chapel Hill, NC 27599, United States of America.",
"authors": "Bahraini|Anoosh|A|;Banerjee|Oyshik|O|;Ra|Jin|J|",
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"doi": "10.1016/j.tcr.2021.100548",
"fulltext": "\n==== Front\nTrauma Case Rep\nTrauma Case Rep\nTrauma Case Reports\n2352-6440\nElsevier\n\nS2352-6440(21)00153-9\n10.1016/j.tcr.2021.100548\n100548\nCase Report\nBradycardia resulting in cardiac arrest in a critically ill patient receiving dexmedetomidine\nBahraini Anoosh Anoosh.bahraini@unchealth.unc.edu\n⁎\nBanerjee Oyshik\nRa Jin\nUniversity of North Carolina Hospital at Chapel Hill, Chapel Hill, NC 27599, United States of America\n⁎ Corresponding author at: 201 S Elliott Rd, Apt 338, Chapel Hill, NC 27514, United States of America. Anoosh.bahraini@unchealth.unc.edu\n25 10 2021\n12 2021\n25 10 2021\n36 10054823 10 2021\n© 2021 Published by Elsevier Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nDexmedetomidine is an alpha-2 agonist sedative and analgesic used in anesthesia practice, and it has become more prevalent in the critically ill patients requiring short-term mechanical ventilation. While dexmedetomidine is known to have minimal effects on respiratory drive, it has been well-documented to cause bradycardia and hypotension, especially in patients with existing comorbidities. We present a patient without cardiovascular comorbidities who was in the surgical ICU under dexmedetomidine sedation. The patient went into asystole cardiac arrest after vagal stimulation. Return of spontaneous circulation was achieved using ACLS protocol. We offer a review of reported cases and make recommendations on the management of similar situations that may arise given the increasing use of dexmedetomidine.\n\nKeywords\n\nDexmedetomidine\nCardiac arrest\nCritically ill\n==== Body\npmcIntroduction\n\nDexmedetomidine is a selective alpha-2-adrenergic agonist. It is used for sedation, anxiolysis and analgesia. It does not depress the respiratory drive which is a desirable affect in critically ill patients [1]. Moreover, it can be administered in non-intubated patients making it useful in patients who will require short-term mechanical ventilation. While it is known to cause bradycardia and hypotension, little is known regarding the extent of these affects and its interactions with other drugs.\n\nCase report\n\nA 50-year-old female with a past medical history including only alcohol abuse was involved in a motor vehicle collision. She was intubated at the scene for low GCS. On presentation, she was hemodynamically stable. Hydromorphone continuous infusion was initiated on arrival. Imaging revealed bilateral rib fractures, left acetabulum fracture, and intra-abdominal free fluid.\n\nShe was taken to the operating room and found to have a full-thickness tear greater than 50% of the bowel lumen in the mid transverse colon with gross spillage. She underwent a colonic resection and left in discontinuity. Dexmedetomidine continuous infusion was initiated on hospital day 0 at a dose of 0.2 μg/kg/h (4.5 mL/h) and titrated to a maximum of 0.6 μg/kg/h (13.5 mL/h on hospital day 2) for ventilator dyssynchrony. She was taken back the following day for abdominal closure and the dexmedetomidine was weaned off. It was restarted at 0300 on hospital day 4 at 0.2 μg/kg/h for ventilator dyssynchrony.\n\nThroughout her hospital stay, she required vasopressor support with norepinephrine (reaching 14 μg/min) and vasopressin thought to be secondary to hypovolemic and distributive shock. Both agents were weaned hospital day 3. Furthermore, given her history of alcohol use, she was placed on a phenobarbital taper in addition to thiamine and folate. On hospital day 4, the patient's heart rate dropped about 30 beats per minute (from 97 to 69) after starting the dexmedetomidine at 0.2 μg/kg/h, but her mean arterial pressure remained stable between 65 and 76. Up to this point, daily EKG showed normal sinus rhythm. While having her endotracheal tube suctioned, she went into asystole. ACLS was initiated. She required one round of chest compressions and 1 mg of epinephrine before return of spontaneous circulation (ROSC) was achieved. She remained bradycardic with her heart rate ranging from 30 to 50 despite being on an epinephrine infusion. Cardiology was consulted and performed an echocardiogram demonstrating global hypokinesia with an ejection fraction (EF) of 45% which was a significant change from her echocardiogram three days prior showing an EF 65%. Laboratory values including troponin were unremarkable, and she was later extubated after meeting standard criteria.\n\nUnfortunately, she remained bradycardic and shortly after extubation on dexmedetomidine at 0.2 μg/kg/h, she went into asystole a second time. Atropine was immediately given and ROSC was achieved without chest compressions. Dexmedetomidine was discontinued. Her heart rate improved to 82 beats per minute. She remained asymptomatic and an echocardiogram two weeks later showed an EF back to her baseline of 65%. She recovered without further complications.\n\nDiscussion\n\nThe popularity of dexmedetomidine has been on the rise following the MIDEX-PRODEX trials which compared midazolam and propofol (respectively) to dexmedetomidine in primarily medical as well as surgical intensive care units. Dexmedetomidine was shown to provide sedation to patients without the effects of respiratory depression, allowing for quicker extubation when compared to midazolam and propofol [2]. This desirable effect propelled its use in surgical intensive care units, especially in patients expected to be extubated within a short amount of time [1], [3]. Unfortunately, one of the undesirable side effects of the drug includes its actions on the cardiac system. When compared to midazolam (5.2%), the rate of bradycardia was significantly higher in the group receiving dexmedetomidine (14.2%) [2]. There was also a considerable risk of first-degree atrioventricular block when comparing propofol (0.8%) to dexmedetomidine (3.7%) [2]. Even though these statistics show an increased risk of adverse cardiac affects in patients receiving dexmedetomidine, the rate may be higher if studied in the surgical ICU [2], [3].\n\nThere have been cases of cardiac arrest reported in patients undergoing neurosurgery with a cardiac history. Bharati et al. concluded that dexmedetomidine should be used with caution in patients who are over the age of 50 or have a cardiac history [4]. The six reported cases occurred within 30 min of drug administration, and five out of the six cases were associated with the administration of a loading dose [4]. A separate series reported three cases of bradycardia with dexmedetomidine and fentanyl, suggesting a synergistic effect [5].\n\nThere is conflicting data regarding the extent to which dexmedetomidine effects the cardiovascular system. A pharmacological study showed plasma concentrations up to 0.8 ng/mL were associated with a decrease in catecholamine release and a reduction in mean arterial pressure. Moreover, above 0.8 ng/mL, patients began to exhibit bradycardia and decreased cardiac output [3]. However, other studies have failed to replicate the same dose-dependent bradycardia in the ICU [6].\n\nWhether there is a dose-dependent effect or not, it seems clear that dexmedetomidine is associated with bradycardia in the clinical setting [2]. In addition, it is well established that a vagal response can occur after stimulations such as coughing and gagging and endotracheal intubation to name a few. This triggers a parasympathetic release of acetylcholine to slow the rate at the sinoatrial and atrioventricular node. During such events, bradycardia can be worsened [7], [8].\n\nTo our knowledge, this is the first case of a patient on dexmedetomidine with bradycardia who went into asystole following vagal stimulation. Though there are many variables that can accentuate the side effects of dexmedetomidine, a trigger like suctioning leading to cough seems to act as a synergistic modifier to worsen bradycardia. We recommend clinicians be cautious with maneuvers that vagally stimulate patients who are bradycardic on dexmedetomidine and have a low threshold for the administration of atropine. Further studies are required to investigate and clarify the effects of dexmedetomidine based on dosage.\n\nConclusion\n\nDexmedetomidine has been shown to be a useful drug for sedation in intubated patients. It has minimal effects on the respiratory drive, but it is associated with bradycardia and hypotension. Much is unknown regarding the dose related effects but practitioners should be wary of exacerbating dexmedetomidine-associated bradycardia, especially in the context of vagal maneuvers.\n==== Refs\nReferences\n\n1 Keating G.M. Dexmedetomidine: a review of its use for sedation in the intensive care setting Drugs 75 10 2015 Jul 1119 1130 10.1007/s40265-015-0419-5 26063213\n2 Jakob S.M. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials JAMA 307 11 2012 1151 1160 22436955\n3 Ebert T.J. Hall J.E. Barney J.A. Uhrich T.D. Colinco M.D. The effects of increasing plasma concentrations of dexmedetomidine in humans Anesthesiology 93 2 2000 Aug 382 394 10.1097/00000542-200008000-00016 10910487\n4 Bharati S. Pal A. Biswas C. Biswas R. Incidence of cardiac arrest increases with the indiscriminate use of dexmedetomidine: a case series and review of published case reports Acta Anaesthesiol. Taiwanica 49 4 2011 Dec 165 167 10.1016/j.aat.2011.11.010 Epub 2011 Dec 19\n5 Hui C. Cardinale M. Yegneswaran B. Significant bradycardia in critically ill patients receiving dexmedetomidine and fentanyl Case Rep. Crit. Care 2017 2017 4504207 10.1155/2017/4504207 29038737\n6 Jones G.M. Murphy C.V. Gerlach A.T. Goodman E.M. Pell L.J. High-dose dexmedetomidine for sedation in the intensive care unit: an evaluation of clinical efficacy and safety Ann. Pharmacother. 45 6 2011 Jun 740 747 10.1345/aph.1P726 Epub 2011 Jun 10 21666095\n7 Yamakawa K. So E.L. Rajendran P.S. Electrophysiological effects of right and left vagal nerve stimulation on the ventricular myocardium Am. J. Physiol. Heart Circ. Physiol. 307 5 2014 H722 H731 10.1152/ajpheart.00279.2014 25015962\n8 Takata K. Adachi Y.U. Suzuki K. Dexmedetomidine-induced atrioventricular block followed by cardiac arrest during atrial pacing: a case report and review of the literature J. Anesth. 28 2014 116 120 10.1007/s00540-013-1676-7 23948748\n\n",
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"keywords": "Cardiac arrest; Critically ill; Dexmedetomidine",
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"title": "Bradycardia resulting in cardiac arrest in a critically ill patient receiving dexmedetomidine.",
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"abstract": "Primary peritoneal clear cell carcinoma (PP-CCC), which is a rare tumor with poor prognosis, is typically managed with surgery and/or chemotherapy. We present a unique treatment approach for a patient with a pelvic PP-CCC, consisting of postchemotherapy intensity-modulated radiation therapy (IMRT) followed by interstitial high-dose-rate (HDR) brachytherapy. A 54-year-old female with an inoperable pelvic-supravaginal 5.6 cm T3N0M0 PP-CCC tumor underwent treatment with 6 cycles of carboplatin and taxol chemotherapy. Postchemotherapy PET/CT scan revealed a residual 3.3 cm tumor. The patient underwent CT and MR planning simulation, and was treated with 50 Gy to the primary tumor and 45 Gy to the pelvis including the pelvic lymph nodes, using IMRT to spare bowel. Subsequently, the patient was treated with an interstitial HDR brachytherapy implant, planned using both CT and MR scans. A total dose of 15 Gy in 5 Gy fractions over two days was delivered with Ir-192 HDR brachytherapy. The total prescribed equivalent 2 Gy dose (EQD2) to the HDR planning target volume (PTV) from both the EBRT and HDR treatments ranged between 63 and 68.8 Gy2 due to differential dosing of the primary and pelvic targets. The patient tolerated radiotherapy well, except for mild diarrhea not requiring medication. There was no patient-reported acute toxicity one month following the radiotherapy course. At four months following adjuvant radiation therapy, the patient had near complete resolution of local tumor on PET/CT without any radiation-associated toxicity. However, the patient was noted to have metastatic disease outside of the radiation field, specifically lesions in the liver and bone. This case report illustrates the feasibility of the treatment of a pelvic PP-CCC with IMRT followed by interstitial HDR brachytherapy boost, which resulted in near complete local tumor response without significant morbidity.",
"affiliations": "University of Michigan. skylerj@med.umich.edu.",
"authors": "Johnson|Skyler B|SB|;Prisciandaro|Joann I|JI|;Zhou|Jessica|J|;Hadley|Scott W|SW|;Reynolds|R Kevin|RK|;Jolly|Shruti|S|",
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"doi": "10.1120/jacmp.v15i1.4520",
"fulltext": "\n==== Front\nJ Appl Clin Med PhysJ Appl Clin Med Phys10.1002/(ISSN)1526-9914ACM2Journal of Applied Clinical Medical Physics1526-9914John Wiley and Sons Inc. Hoboken 10.1120/jacmp.v15i1.4520ACM20202Radiation Oncology PhysicsRadiation Oncology PhysicsPrimary peritoneal clear cell carcinoma treated with IMRT and interstitial HDR brachytherapy: a case report Johnson Skyler B. \n1\nPrisciandaro Joann I. \n1\nZhou Jessica \n1\nHadley Scott W. \n1\nReynolds R. Kevin \n2\nJolly Shruti shrutij@med.umich.edu \n1\n\n1 \nDepartment of Radiation Oncology\nUniversity of Michigan\nAnn Arbor\nMI\n\n2 \nDepartment of Gynecologic Oncology\nUniversity of Michigan\nAnn Arbor\nMI\nUSA\n* a Corresponding author: Shruti Jolly, University of Michigan Medical Center, 1500 East Medical Center Dr., Ann Arbor, MI 48109, USA; phone: (734) 936 7810; fax: (734) 763 7370; email: shrutij@med.umich.edu\n06 1 2014 1 2014 15 1 10.1002/acm2.2014.15.issue-1202 212 02 5 2013 01 8 2013 © 2014 The Authors.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.Primary peritoneal clear cell carcinoma (PP‐CCC), which is a rare tumor with poor prognosis, is typically managed with surgery and/or chemotherapy. We present a unique treatment approach for a patient with a pelvic PP‐CCC, consisting of postchemotherapy intensity‐modulated radiation therapy (IMRT) followed by interstitial high‐dose–rate (HDR) brachytherapy. A 54‐year‐old female with an inoperable pelvic‐supravaginal 5.6 cm T3N0M0 PP‐CCC tumor underwent treatment with 6 cycles of carboplatin and taxol chemotherapy. Postchemotherapy PET/CT scan revealed a residual 3.3 cm tumor. The patient underwent CT and MR planning simulation, and was treated with 50 Gy to the primary tumor and 45 Gy to the pelvis including the pelvic lymph nodes, using IMRT to spare bowel. Subsequently, the patient was treated with an interstitial HDR brachytherapy implant, planned using both CT and MR scans. A total dose of 15 Gy in 5 Gy fractions over two days was delivered with Ir‐192 HDR brachytherapy. The total prescribed equivalent 2 Gy dose (EQD2) to the HDR planning target volume (PTV) from both the EBRT and HDR treatments ranged between 63 and 68.8Gy2 due to differential dosing of the primary and pelvic targets. The patient tolerated radiotherapy well, except for mild diarrhea not requiring medication. There was no patient‐reported acute toxicity one month following the radiotherapy course. At four months following adjuvant radiation therapy, the patient had near complete resolution of local tumor on PET/CT without any radiation‐associated toxicity. However, the patient was noted to have metastatic disease outside of the radiation field, specifically lesions in the liver and bone. This case report illustrates the feasibility of the treatment of a pelvic PP‐CCC with IMRT followed by interstitial HDR brachytherapy boost, which resulted in near complete local tumor response without significant morbidity.\n\nPACS number: 87.55.‐x\n\nprimary peritoneal clear cell carcinomabrachytherapyIMRTradiation source-schema-version-number2.0component-idacm20202cover-dateJanuary 2014details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.5 mode:remove_FC converted:17.11.2017Conflict of Interest statement: The authors declare there are no conflicts of interest.\n==== Body\nI. INTRODUCTION\nPrimary peritoneal clear cell carcinoma (PP‐CCC) is extremely rare, accounting for approximately 3% of primary peritoneal carcinomas (PPC) with an incidence of 0.46 per 100,000.\n1\n, \n2\n, \n3\n Other PPCs include serous adenocarcinoma, peritoneal serous borderline tumor, serous papillary adenocarcinoma, and mesotheliomas.\n(4)\n These tumors are histologically similar to ovarian tumors and are believed to behave similarly.\n4\n, \n5\n Therefore, treatment for PPC has historically reflected this belief, utilizing debulking surgery followed by chemotherapy or chemotherapy and second‐look surgery.\n(3)\n However, mortality remains high, with a median survival of approximately 24 months\n6\n, \n7\n, \n8\n, \n9\n and five‐year survival rate of 18%.\n(10)\n Unfortunately, most studies on outcomes of PPC do not include PP‐CCC.\n6\n, \n7\n, \n8\n, \n11\n To date, there are only nine reported cases of PP‐CCC in the English medical literature, none of which were treated with radiation.\n12\n, \n13\n, \n14\n, \n15\n, \n16\n, \n17\n, \n18\n, \n19\n In those cases reporting outcomes, prognosis was much poorer than has been seen in retrospective studies of PPC, with 33% (two of six cases) mortality within six months, and 100% mortality within six months in those with residual disease following initial therapy.\n(3)\n New treatment strategies may be necessary to improve local control and decrease mortality for patients with PP‐CCC.\n\nThis case report describes treatment of an inoperable PP‐CCC with adjuvant radiation that did not achieve complete resolution following chemotherapy. The tumor was treated with intensity‐modulated radiation therapy (IMRT) to the pelvis followed by intraoperative interstitial catheter placement and high‐dose‐rate (HDR) brachytherapy. Both CT and MR simulations were performed for clear delineation of the tumor and organs at risk (OARs) for planning purposes prior to both external‐beam radiation therapy (EBRT) and HDR treatment. Specifically, the gross tumor volume (GTV) and the OARs (e.g., rectum, bladder, and bowel) were delineated.\n\nII. CASE REPORT\nA 54‐year‐old Japanese Gl P0 female was referred to the University of Michigan Comprehensive Cancer Center (UMCCC) for examination and review of a 3.7×3.9cm high‐grade PP‐CCC by CT scan and vaginal biopsy confirmation by her gynecologist. Her gynecologic history was significant for three myomectomies, and a total abdominal hysterectomy and bilateral salpingo‐oopherectomy for uterine leiomyomas and menorrhagia, 15 years prior to presentation. At initial presentation, the patient complained of a three‐month history of pelvic discomfort, which she described as pressure and constipation, along with early satiety, fatigue, and a ten‐pound weight loss. A vaginal biopsy was performed, which showed high‐grade clear cell adenocarcinoma. PAP smear at the time was reported as atypical glandular cells of undetermined significance (AGUS). The patient then underwent completion staging workup, including CT scan of the abdomen and pelvis, which showed a 3.7cm×3.9cm soft tissue mass in the deep pelvis (Fig. 1(a)).\n\nOn initial consultation with Radiation Oncology prior to the initiation of chemotherapy, the patient reported slight vaginal bleeding since biopsy, as well as persistent fatigue. Pelvic exam revealed an irregular, firm, polypoid, friable lesion involving the entire horizontal extent of the vaginal apex, which extended inferiorly to the upper one‐third of the vagina. Rectal exam showed an approximately 4 cm length of abutment of the anterior aspect of the rectum. The rectovaginal septum was intact and there was no palpable lymphadenopathy. One month following initial presentation and CT, an MRI of the pelvis confirmed the presence of a 5.6×3.7×3.5cm mass on the proximal vagina and vaginal cuff, which appeared to be inseparable from the anterior wall of the proximal rectum and rectosigmoid junction, likely representing local invasion (Figs. 1(b) and 1(c)).\n\nOne month following initial presentation, the patient completed six cycles of carboplatin and taxol chemotherapy over the next four months. Following chemotherapy, a 18F‐FDG PET/CT scan revealed a 3.3 cm prerectal soft tissue mass with FDG activity in the posterior vagina consistent with active neoplasm (Fig. 2).\n\nThe patient then underwent MR simulation and on the following day, a CT simulation, in the Department of Radiation Oncology. For both the MR and CT simulations, the patient was positioned supine on a foam pad with legs straight and feet banded together. To improve the visualization of the vaginal apex and vault, a 2 cm diameter radiopaque vaginal marker was inserted at time of each simulation (ShadowForm, Izi Medical Products, Owings Mills, MD). The MR simulation was then performed using a Siemens Skyra 3T scanner (Siemens Healthcare Diagnostics, Inc., Erlangen, Germany). The following MR scans were acquired: T2‐weighted TSE axial, coronal, and sagittal images at 3 mm slice thickness, T1‐weighted TSE coronal images with large field of view at 4 mm slice thickness, T1‐weighted TSE axial images at 3 mm slice thickness, and postgadolinium T1‐weighted axial, sagittal, and coronal images at 3 mm slice thickness. The T1W images were acquired to assist with nodal volume delineation, and the T2W images were used to define the gross and microscopic disease. The CT scan was performed using a 16 slice Philips Brilliance CT scanner (Royal Philips Electronics, Eindhoven, Netherlands). Images were acquired from the top of the T10 vertebral body to 5 cm inferior of the ischial tuberosities with 3 mm slice thickness.\n\nFigure 1 Diagnostic imaging: (a) axial CT image of the pelvis obtained at presentation shows a supravaginal 3.7×3.9cm primary peritoneal clear cell carcinoma (PP‐CCC) and an (b) axial and (c) sagittal T2‐weighted MR image of the pelvis obtained one month following presentation which shows a supravaginal 5.6×3.7×3.5cm primary peritoneal clear cell carcinoma. The lesion appears inseparable from the anterior wall of the proximal rectum.\n\nFigure 2 Postchemotherapy (a) axial CT and (b) PET image of the pelvis shows a residual 3.3 cm prerectal/primary peritoneal clear cell carcinoma with FDG activity in the posterior vagina.\n\nA treatment plan was generated for external beam radiotherapy based on the CT images. The CT and MR images were not registered for the EBRT plan. The structures were contoured by the physician on the CT images, using anatomic guidance from the MR, as well as the PET/CT for the delineation of gross disease. One month following completion of chemotherapy, the patient began a course of EBRT with a nine‐field coplanar 16 MV IMRT plan with gantry angles spanning from 20∘–340∘ (IEC coordinate system) at 40° intervals. The treatment plan was designed to deliver a total dose of 50 Gy in 2 Gy daily fractions to the primary tumor (PTVIMRT=CTV+1cm uniform margin) and 45 Gy in 1.8 Gy fractions to the pelvis including the pelvic lymph nodes (PTVLNs=CTVLNs+1cm uniform margin). The dose distribution for the approved plan is shown in parasagittal and paracoronal view in Figs. 3(a) and 3(b), respectively. The objectives of the IMRT plan was to deliver at least 95% of the prescription dose to the PTV with a uniformity of ±5% while minimizing dose to the organs at risk (OARs). The dose constraints to the OARs were: bowel max dose ≤50Gy (in 2 Gy fractions), V45≤25%; femoral head V30≤20%; rectum V50≤50%; bladder ALARA. IMRT treatment planning was performed with an in‐house treatment planning system, UMPlan. The cumulative dose‐volume histograms (DVHs) for PTVIMRT,PTVLNs, bladder, and rectum are presented in Fig. 4(a).\n\nOne week following EBRT, the patient received an HDR brachytherapy boost. For the interstitial HDR brachytherapy boost, the patient was taken to the operating room and underwent a minilaparotomy and placement of the interstitial applicator by the gynecologic oncologist, as recommended per the American Brachytherapy Society guidelines for interstitial brachytherapy.\n(20)\n The patient was examined, prepped, and draped in the low anterior lithotomy position with a Foley catheter inserted and radiocontrast injected into the balloon. A custom 30 mm HDR interstitial cylindrical applicator was then placed into the vagina and a custom perineal template was sutured into place (Fig. 5). Although not used, the perineal template allows for the insertion of interstitial needles either perpendicular to the template or at a 15° angle from normal incidence, which may be desirable in the case of pubic arch interference. A minilaparotomy and omental J‐flap were performed. The omental J‐flap allowed for increased distance between the interstitial needles and surrounding bowel. Nine interstitial needles were manually inserted into the cylinder, including eight along the periphery and one in the center of the vaginal cylinder. Following the implant procedure, the patient underwent CT and MR simulation in the department of Radiation Oncology with the same imaging units detailed above. Prior to both simulation scans, the Foley catheter was tugged to ensure the balloon was positioned at the bladder neck. The CT scan was performed from the L4/L5 interspace to 5 cm inferior of the ischial tuberosities with 1 mm slice thickness. To minimize applicator displacement, the patient was transferred to a detachable MR couch using a slide board. The following MR scans were acquired based on GEC‐ESTRO recommendations:\n(21)\n T2 TSE axial, coronal, and sagittal images at 3 mm slice thickness, 3D T2 (SPC) sagittal images at 0.9 mm slice thickness, 3D T1 (MPRAGE) sagittal images at 0.9 mm slice thickness, and postgadolinium T1 TSE axial, coronal, and sagittal images at 3 mm slice thickness.\n\nFigure 3 Isodose distributions on the (a) parasagittal and (b) paracoronal CT view for the approved external beam radiotherapy, and (c) parasagittal and (d) paracoronal T2‐weighted MR view for the approved HDR brachytherapy treatment plan. The external beam PTVIMRT and PTVLNs volumes are shown in the shadowed red and green contours, and the HDR PTV volume is shown in the shadowed red contour.\n\nFigure 4 Cumulative dose‐volume histograms for (a) external beam and (b) high‐dose‐rate brachytherapy plans.\n\nFollowing the MR simulation, the patient was transferred to an HDR suite on the MR detachable couch as the HDR treatment plan was developed. The CT and MR images were imported into a commercial brachytherapy planning system, BrachyVision 8.9 (Varian Medical Systems, Palo Alto, CA). The CT and MR images were then manually aligned based on the position of the cylindrical vaginal applicator in BrachyVision. The alignment was visually evaluated by comparing the position of the cylindrical applicator and the neighboring anatomy between the CT and MR images. The clinical target volume (CTVHDR) was drawn on the CT scan using the superimposed T2‐weighted axial MR images, and the interstitial needles were digitized employing the CT dataset, based on evidence of gross residual disease and areas of close proximity intraoperatively. The PTVHDR volume was equivalent to the CTVHDR volume. Figure 6 shows representative CT, MR (T2‐weighted 3D), and registered CT/MR images (using the T2‐weighted 3D image) at the level of midcylinder. Figure 7 illustrates the difference between soft tissue on the CT and MR scans, as well as the visualization of the applicator channels, in both paracoronal and parasagittal images. An HDR treatment plan was designed to deliver 5 Gy per fraction to a minimum of 95% of the PTVHDR(V100(PTVHDR)≥95%), while minimizing dose to the rectum and bladder. The final dose was determined by the cumulative tolerable doses to the normal critical structures, including small bowel, bladder, and rectum. The dose distribution for the approved plan is shown on parasagittal and paracoronal MR T2W images in Figs. 3(c) and 3(d), respectively. Additionally, the cumulative dose‐volume histograms (DVHs) for PTV(HDR), bladder, and rectum are presented in Fig. 4(b). Following planning, Ir‐192 HDR brachytherapy was used to deliver 15 Gy in 5 Gy fractions over two days. Each fraction was at least six hours apart to allow for normal tissue repair, and was delivered with a GammaMedPlus iX afterloader (Varian Medical Systems, Palo Alto, CA).\n\nFigure 5 A custom 30 millimeter diameter interstitial vaginal cylinder with perineal template.\n\nAt one‐month follow‐up there were no signs of acute toxicity. The patient did report mild vaginal discomfort and pelvic pain, however denied fatigue, nausea, abdominal pain, incontinence, vaginal discharge, and blood per rectum or vagina. Her pretreatment constipation had resolved and she was passing one to two stools per day. At four months follow‐up, the patient underwent PET/CT imaging which revealed near complete resolution of tumor within the radiation fields (Fig. 8). Unfortunately, the imaging also revealed multiple new lesions not seen on the initial PET/CT, including metastases to the bone and liver.\n\nFigure 6 CT (a), T2‐weighted MR (b), and registered CT/MR (c) axial images of the custom interstitial brachytherapy cylinder at time of planning simulation. The yellow, red, and blue outlines represent the bladder, PTV, and rectum contours, respectively.\n\nFigure 7 Paracoronal ((a) and (c)) and parasagittal ((b) and (d)) T2‐weighted MR and CT, respectively, through the custom interstitial applicator.\n\nFigure 8 Postradiotherapy CT (a) and PET image (b) of the pelvis obtained four months following radiotherapy shows near complete resolution of tumor.\n\nIII. DISCUSSION\nThis is the first reported case regarding the benefit of radiation in the treatment of an inoperable PP‐CCC. Following six cycles of carboplatin and taxol chemotherapy and incomplete tumor resolution, IMRT was delivered to the primary tumor and pelvic lymph nodes followed by an interstitial HDR brachytherapy boost. Although the posttreatment PET/CT imaging revealed metastatic disease, the radiation therapy resulted in local tumor control, defined as no evidence of disease recurrence within the treatment field, and limited treatment morbidity.\n\nPP‐CCC is a rare disease with poor patient outcomes. Currently, there are no retrospective studies or consensus agreements on the appropriate therapy. Case reports provide limited data, as there are only nine reports in the English medical literature.\n12\n, \n13\n, \n14\n, \n15\n, \n16\n, \n17\n, \n18\n, \n19\n Although debulking surgery,\n12\n, \n15\n, \n17\n, \n18\n as well as debulking surgery with chemotherapy,\n14\n, \n16\n, \n17\n, \n19\n were used in these reports, outcomes remained suboptimal with two of six patients dying within six months\n17\n, \n19\n and one recurrence at 32 months.\n(14)\n The other cases remained disease free at 6 months, 12 months, and 20 months following completion of treatment.\n16\n, \n17\n, \n18\n Both cases of death occurred within six months when the patients had residual tumors of >2cm, whereas the other cases had no evidence of residual tumor following treatment.\n(3)\n In our case, the patient presented with inoperable disease that was inseparable from the anterior wall of the proximal rectum and rectosigmoid on MR. She also had residual disease on PET/CT scan following chemotherapy. Inoperable or residual gross disease requires higher doses of radiation to the pelvis, which can also result in increased GI or GU toxicity including pain, bleeding, bladder irritation, and diarrhea. Interstitial HDR brachytherapy is an ideal treatment option because it optimizes radiation dose to the gross tumor while limiting dose to the adjacent normal tissue. Furthermore, the intraoperative approach of HDR catheter placement with minilaparotomy allows for ideal catheter placement within the residual tumor and displacement of bowel, which may increase local control and decrease morbidity.\n22\n, \n23\n Intraoperative catheter placement has less surgical morbidity compared with debulking surgery. Nearly one‐quarter of patients may experience major complications following surgery, such as invasive radiologic intervention, reoperation, unplanned ICU admission, chronic disability, or death,\n(24)\n and more than one‐third of women older than 75 have morbidity following debulking surgery.\n(25)\n Additionally, CT and MR simulations were performed on the patient prior to both EBRT and HDR, and were used to help delineate the GTV/CTV (for EBRT), the CTV (for HDR), and the organs at risk. We achieved a V95 of 96.5% and 98.7% to the PTVIMRT(CTV+1cm uniform margin) and PTVHDR, respectively, and the total prescribed equivalent 2 Gy dose (EQD2[EQD2=Bioeffective dose/(1+(2/(α/β))]) to PTVHDR ranged from 63 to 68.8Gy2 due to differential dosing of the primary and pelvic targets, assuming an α/β of ten. The D2cc (most exposed 2 cm3) of the bladder and the rectum was 50.5 Gy and 49.3 Gy, respectively, for EBRT and 11.8 Gy and 11.9 Gy, respectively, for the HDR treatment plan. This resulted in an EQD2 of 50.7Gy2 and 16.5Gy2 for the bladder and 49.0Gy2 and 16.7Gy2 for the rectum with the EBRT and HDR, respectively, assuming an α/β of three (Table 1). Perioperative interstitial catheter placement and CT and MR‐based planning allowed for dose optimization and resulted in decreased morbidity and improved local control.\n\nAlthough there are no retrospective studies of PP‐CCC, there is evidence to suggest that EBRT may improve local control for women with clear cell histology associated with uterine and ovarian carcinoma. Adjuvant EBRT has been shown to improve overall survival in patients with uterine clear cell carcinoma (UCCC) in a recent retrospective review.\n(26)\n Thomas et al.\n(27)\n conducted a multi‐institutional review of 99 patients with UCCC and concluded that adjuvant EBRT improved progression‐free survival (67% vs. 36%), and reduced pelvic sidewall (18% vs. 53%) and vaginal recurrences (7% vs. 35%) for those at risk of local failure. There is also evidence that HDR brachytherapy improves local control and improves outcomes in endometrial\n28\n, \n29\n and uterine\n30\n, \n31\n clear cell cancer types. Radiation remains an effective treatment that produces tumor resolution, as identified in case reports of clear cell histology with recurrent\n(32)\n and chemotherapy‐resistant\n(33)\n ovarian clear cell carcinoma. In this report, postradiation therapy PET/CT revealed near complete tumor response, showing that this treatment approach was effective. Concurrent systemic therapy may have limited metastatic progression, although there is evidence that PP‐CCC tumors are resistance to conventional platinum‐based chemotherapies,\n(17)\n suggesting the need for novel therapies.\n\nWe attempted to control local micrometastatic progression through treatment of the pelvic lymph nodes using an initial course of IMRT. The patient did have distant metastatic progression four months following adjuvant radiation. However, she did experience resolution of gross tumor, with no evidence of local progression. For this patient, brachytherapy was the ideal treatment solution because of the location of the tumor, which was near the proximal vagina, and because residual tumor disease requires high doses of radiation. Interstitial HDR brachytherapy catheter placement and CT/MR planning allowed for dose optimization to the primary tumor. The patient tolerated the procedure well, reporting no postoperative morbidity and minimal acute radiation related side effects.\n\nTable 1 Summary of the dose quality parameters for the EBRT (PTVIMRT) and HDR treatment plans\n\n\t\t\t\nEQD2(Gy2)\n\na\n\n\t\n\nDose Quality Parameter\n\t\nEBRT\n\t\nHDR\n\t\nEBRT\n\t\nHDR\n\t\nPTV V100 (%)\t61.60\t97.36\t—\t—\t\nPTV V95 (%)\t96.54\t98.68\t—\t—\t\nPTV V90 (%)\t99.98\t99.42\t—\t—\t\nPTV D100 (Gy)\t44.22\t9.45\t43.4\t10.4\t\nPTV D95 (Gy)\t47.74\t15.81\t47.4\t20.1\t\nPTV D90 (Gy)\t48.40\t17.1\t48.1\t22.4\t\nBladder D2cc (Gy)\t50.49\t11.85\t50.7\t16.5\t\nBladder point\nb\n (Gy)\tN/A\t13.02\t—‐\t19.1\t\nRectum D2cc (Gy)\t49.28\t11.94\t49.0\t16.7\t\na \na The equivalent 2 Gy dose, EQD2, has been calculated assuming an α/β of ten for the PTV and three for the bladder and rectum.\n\nb \nb The bladder point was positioned based on the recommendations of ICRU 38.(34)\n\nV. CONCLUSIONS\nWhile surgery and chemotherapy remain the mainstay for treatment of PP‐CCC, radiotherapy for local control appears to be effective in local control of PP‐CCC. Advancements in imaging and radiation techniques may make it possible to deliver radiation to residual areas of disease without causing excessive morbidity.\n\nACKNOWLEDGMENTS\nThe authors would like to thank Dr. Yue Cao, Dr. James Balter, and Jeremy French for their guidance and assistance with developing the appropriate MRI protocols used for both the EBRT and brachytherapy components of this study.\n\nSupporting information\nSupplementary Material\n\nClick here for additional data file.\n==== Refs\nREFERENCES\n1 \n\nMoll \nUM \n, \nValea \nF \n, \nChumas \nJ \n. Role of p53 alteration in primary peritoneal carcinoma . Int J Gynecol Pathol. \n1997 ;16 (2 ):156 –62 .9100070 \n2 \n\nGoodman \nMT \n and \nShvetsov \nYB \n. Rapidly increasing incidence of papillary serous carcinoma of the peritoneum in the United States: fact or artifact? \nInt J Cancer. \n2009 ;124 (9 ):2231 –35 .19127596 \n3 \n\nWuntakal \nR \n and \nLawrence \nA \n. Are oestrogens and genetic predisposition etiologic factors in the development of clear cell carcinoma of the peritoneum? \nMed Hypotheses. \n2013 ;80 (2 ):167 –71 .23265355 \n4 \n\nFox \nH \n. Primary neoplasia of the female peritoneum . Histopathology. \n1993 ;23 (2 ):103 –10 .8406381 \n5 \n\nJaaback \nKS \n, \nLudeman \nL \n, \nClayton \nNL \n, \nHirschowitz \nL \n. Primary peritoneal carcinoma in a UK cancer center: comparison with advanced ovarian carcinoma over a 5‐year period . Int J Gynecol Cancer. \n2006 ;16 \nSuppl 1 :123 –28 .16515579 \n6 \n\nBarda \nG \n, \nMenczer \nJ \n, \nChetrit \nA \n, et al. Comparison between primary peritoneal and epithelial ovarian carcinoma: a population‐based study . Am J Obstet Gynecol. \n2004 ;190 (4 ):1039 –45 .15118638 \n7 \n\nFromm \nGL \n, \nGershenson \nDM \n, \nSilva \nEG \n. Papillary serous carcinoma of the peritoneum . Obstet Gynecol. \n1990 ;75 (1 ):89 –95 .2296429 \n8 \n\nKillackey \nMA \n and \nDavis \nAR \n. Papillary serous carcinoma of the peritoneal surface: matched‐case comparison with papillary serous ovarian carcinoma . Gynecol Oncol. \n1993 ;51 (2 ):171 –74 .8276289 \n9 \n\nRoh \nSY \n, \nHong \nSH \n, \nKo \nYH \n, et al. Clinical characteristics of primary peritoneal carcinoma . Cancer Res Treat. \n2007 ;39 (2 ):65 –68 .19746214 \n10 \n\nNam \nJH \n, \nKim \nYM \n, \nJung \nMH \n, et al. Primary peritoneal carcinoma: experience with cytoreductive surgery and combination chemotherapy . Int J Gynecol Cancer. \n2006 ;16 (1 ):23 –28 .16445605 \n11 \n\nBloss \nJD \n, \nBrady \nMF \n, \nLiao \nSY \n, \nRocereto \nT \n, \nPartridge \nEE \n, \nClarke‐Pearson \nDL \n. Extraovarian peritoneal serous papillary carcinoma: a phase II trial of cisplatin and cyclophosphamide with comparison to a cohort with papillary serous ovarian carcinoma – a Gynecologic Oncology Group Study . Gynecol Oncol. \n2003 ;89 (1 ):148 –54 .12694669 \n12 \n\nEvans \nH \n, \nYates \nWA \n, \nPalmer \nWE \n, \nCartwright \nRL \n, \nAntemann \nRW \n. Clear cell carcinoma of the sigmoid mesocolon: a tumor of the secondary mullerian system . Am J Obstet Gynecol. \n1990 ;162 (1 ):161 –63 .2301485 \n13 \n\nHama \nY \n, \nIwasaki \nY \n, \nSakata \nI \n, \nKusano \nS \n. Primary peritoneal clear cell carcinoma . J Comput Assist Tomogr. \n2004 ;28 (5 ):617 –19 .15480034 \n14 \n\nIchimura \nT \n, \nIshiko \nO \n, \nNishimura \nS \n, \nKojima \nT \n, \nShimura \nK \n. Primary peritoneal clear cell carcinoma: excellent results from paclitaxel and carboplatin combination chemotherapy . Oncol Rep. \n2001 ;8 (6 ):1243 –45 .11605041 \n15 \n\nLee \nKR \n, \nVerma \nU \n, \nBelinson \nJ \n. Primary clear cell carcinoma of the peritoneum . Gynecol Oncol. \n1991 ;41 (3 ):259 –62 .1714418 \n16 \n\nMuezzinoglu \nB \n, \nCorak \nS \n, \nYucesoy \nI \n. Primary peritoneal clear cell adenocarcinoma associated with endometriosis . Appl Immunohistochem Mol Morphol. \n2011 ;19 (4 ):384 –85 .\n17 \n\nTakano \nM \n, \nYoshikawa \nT \n, \nKato \nM \n, et al. Primary clear cell carcinoma of the peritoneum: report of two cases and a review of the literature . Eur J Gynaecol Oncol. \n2009 ;30 (5 ):575 –78 .19899421 \n18 \n\nTerada \nT \n and \nKawaguchi \nM \n. Primary clear cell adenocarcinoma of the peritoneum . Tohoku J Exp Med. \n2005 ;206 (3 ):271 –75 .15942157 \n19 \n\nTziortzioti \nV \n, \nApessou \nD \n, \nAntoniou \nS \n, \nGiantzoglou \nA \n, \nPaissios \nP \n. Clear cell adenocarcinoma of the peritoneum associated with clear cell adenocarcinoma arising in an endometrial polyp . J Obstet Gynaecol. \n1999 ;19 (5 ):557 –58 .15512397 \n20 \n\nBeriwal \nS \n, \nDemanes \nDJ \n, \nErickson \nB \n, et al. American Brachytherapy Society consensus guidelines for interstitial brachytherapy for vaginal cancer . Brachytherapy. \n2012 ;11 (1 ):68 –75 .22265440 \n21 \n\nDimopoulos \nJC \n, \nPetrow \nP \n, \nTanderup \nK \n, et al. Recommendations from Gynaecological (GYN) GEC‐ESTRO Working Group (IV): Basic principles and parameters for MR imaging within the frame of image based adaptive cervix cancer brachytherapy . Radiother Oncol. \n2012 ;103 (1 ):113 –22 .22296748 \n22 \n\nHu \nKS \n, \nEnker \nWE \n, \nHarrison \nLB \n. High‐dose‐rate intraoperative irradiation: current status and future directions . Semin Radiat Oncol. \n2002 ;12 (1 ):62 –80 .\n23 \n\nNag \nS \n and \nHu \nKS \n. Intraoperative high‐dose‐rate brachytherapy . Surg Oncol Clin N Am. \n2003 ;12 (4 ):1079 –97 .14989134 \n24 \n\nChi \nDS \n, \nZivanovic \nO \n, \nLevinson \nKL \n, et al. The incidence of major complications after the performance of extensive upper abdominal surgical procedures during primary cytoreduction of advanced ovarian, tubal, and peritoneal carcinomas . Gynecol Oncol. \n2010 ;119 (1 ):38 –42 .20609464 \n25 \n\nLangstraat \nC \n, \nAletti \nGD \n, \nCliby \nWA \n. Morbidity, mortality and overall survival in elderly women undergoing primary surgical debulking for ovarian cancer: a delicate balance requiring individualization . Gynecol Oncol. \n2011 ;123 (2 ):187 –91 .21794902 \n26 \n\nKim \nA \n, \nSchreiber \nD \n, \nRineer \nJ \n, \nChoi \nK \n, \nRotman \nM \n. Impact of adjuvant external‐beam radiation therapy in early‐stage uterine papillary serous and clear cell carcinoma . Int J Radiat Oncol Biol Phys. \n2011 ;81 (4 ): e639 –44 .21507584 \n27 \n\nThomas \nM \n, \nMariani \nA \n, \nWright \nJD \n, et al. Surgical management and adjuvant therapy for patients with uterine clear cell carcinoma: a multi‐institutional review . Gynecol Oncol. \n2008 ;108 (2 ):293 –97 .18096208 \n28 \n\nTownamchai \nK \n, \nBerkowitz \nR \n, \nBhagwat \nM \n, et al. Vaginal brachytherapy for early stage uterine papillary serous and clear cell endometrial cancer . Gynecol Oncol. \n2013 ;129 (1 ):18 –21 .23262378 \n29 \n\nBatchelor \nEC \n, \nWatkins \nJM \n, \nJenrette \nJM \n\n3rd. Definitive radiotherapy for medically inoperable early‐stage serous and clear cell uterine carcinoma . Radiat Med. \n2007 ; 25 (10 ):536 –40 .18085405 \n30 \n\nVarughese \nJ \n, \nHui \nP \n, \nLu \nL \n, \nYu \nH \n, \nSchwartz \nPE \n. Clear cell cancer of the uterine corpus: the association of clinico‐pathologic parameters and treatment on disease progression . J Oncol. \n2011 ;2011 :628084 .22187554 \n31 \n\nBatchelor \nEC \n, \nWatkins \nJM \n, \nCreasman \nWT \n, \nKohler \nMF \n, \nSinha \nD \n, \nJenrette \nJM \n. The role of radiotherapy in the management of resected uterine papillary serous and clear cell carcinoma . Eur J Obstet Gynecol Reprod Biol. \n2008 ;141 (2 ):163 –68 .18774213 \n32 \n\nSuzuki \nM \n, \nSaga \nY \n, \nTsukagoshi \nS \n, \nTamura \nN \n, \nSato \nI \n. Recurrent ovarian clear cell carcinoma: complete remission after radiation in combination with hyperthermia; a case study and in vitro study . Cancer Biother Radiopharm. \n2000 ;15 (6 ):625 –28 .11190494 \n33 \n\nTakai \nN \n, \nUtsunomiya \nH \n, \nKawano \nY \n, \nNasu \nK \n, \nNarahara \nH \n, \nMiyakawa \nI \n. Complete response to radiation therapy in a patient with chemotherapy‐resistant ovarian clear cell adenocarcinoma . Arch Gynecol Obstet. \n2002 ;267 (2 ):98 –100 .12439556 \n34 \nInternational Commission on Radiation Units and Measurements (ICRU). \nDose and volume specification for reporting intracavitary therapy in gynecology . ICRU Report No. 38. Bethesda (MD) : ICRU ; 1985 .\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1526-9914",
"issue": "15(1)",
"journal": "Journal of applied clinical medical physics",
"keywords": null,
"medline_ta": "J Appl Clin Med Phys",
"mesh_terms": "D018262:Adenocarcinoma, Clear Cell; D001918:Brachytherapy; D019583:Dose Fractionation, Radiation; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008198:Lymph Nodes; D008875:Middle Aged; D058958:Organs at Risk; D010388:Pelvis; D010534:Peritoneal Neoplasms; D049268:Positron-Emission Tomography; D011379:Prognosis; D011880:Radiotherapy Planning, Computer-Assisted; D020266:Radiotherapy, Conformal; D050397:Radiotherapy, Intensity-Modulated; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101089176",
"other_id": null,
"pages": "4520",
"pmc": null,
"pmid": "24423851",
"pubdate": "2014-01-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21794902;8406381;2296429;19899421;8276289;22296748;12439556;20609464;1714418;12694669;19127596;2301485;23265355;23262378;16445605;16515579;11190494;11605041;18774213;22265440;18096208;19746214;14989134;15942157;22187554;9100070;21507584;15512397;11813152;18085405;15480034;15118638;21293258",
"title": "Primary peritoneal clear cell carcinoma treated with IMRT and interstitial HDR brachytherapy: a case report.",
"title_normalized": "primary peritoneal clear cell carcinoma treated with imrt and interstitial hdr brachytherapy a case report"
} | [
{
"companynumb": "US-CIPLA LTD.-2014US01577",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nPrevalence of bisphosphonate-associated osteonecrosis of the jaws within the catchment area of a university hospital maxillofacial unit and to review the outcome of treatment.\n\n\nMETHODS\nIn a retrospective study, all patients with osteonecrosis, osteomyelitis and osteoradionecrosis treated in the period from January 2000 to March 2005 in the department for Maxillo Facial Surgery at the University of Mainz, Germany were analysed.\n\n\nRESULTS\nForty percent of the patients are grouped to odontogenic or surgically induced osteomyelitis. The second largest group (28%) were patients with osteoradionecrosis (ORN). Ten percent of all patients developed an osteonecrosis after treatment with bisphosphonates (BOJ). Eight percent showed osteomyelitis or sequester due to a trauma while 14% of all patients had osteomyelitis of unknown origin. All BOJ patients took bisphosphonates because of metastatic diseases of the bone (plasmocytoma, mamma carcinoma and prostate cancer) for up to 5 years. All had been administered a nitrogen-containing bisphosphonate (either pamidronat or zoledronat). Thirteen out of the 17 patients with BOJ and 14 of the 45 with ORN reported a possible trigger like previous tooth extraction, pressure denture sore or periodontal diseases.\n\n\nCONCLUSIONS\nThese findings support the association of bisphosphonate therapy and osteonecrosis of the jaw. The importance of this new disease is characterised by the growing number of patients. The role of dental trigger factors and the poor surgical outcome both seem to justify a prophylactic dental care concept in high-risk patients.",
"affiliations": "Klinik für Mund-, Kiefer- und Gesichtschirurgie, Johannes Gutenberg-Universität Mainz, Augustusplatz 2, 55131, Mainz, Germany. walter@mkg.klinik.uni-mainz.de",
"authors": "Walter|Christian|C|;Grötz|Knut A|KA|;Kunkel|Martin|M|;Al-Nawas|Bilal|B|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-006-0120-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "15(2)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": null,
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D005858:Germany; D006801:Humans; D007571:Jaw Diseases; D008297:Male; D008334:Mandible; D008437:Maxilla; D008875:Middle Aged; D010020:Osteonecrosis; D015995:Prevalence; D012189:Retrospective Studies",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "197-202",
"pmc": null,
"pmid": "16941133",
"pubdate": "2007-02",
"publication_types": "D016428:Journal Article",
"references": "15389307;11373877;9191633;16454811;12570716;12006522;15667977;9307266;20758614;9125274;8833200;1464749;14615459;2963910;15161327;8698861;11879557;12767877;14753746;14586868;12438248;15607935;12183663;8686503;1573666;15122554;12927572;15181903;14738134;3461965;14965623;15590626;10898340;12966493",
"title": "Prevalence of bisphosphonate associated osteonecrosis of the jaw within the field of osteonecrosis.",
"title_normalized": "prevalence of bisphosphonate associated osteonecrosis of the jaw within the field of osteonecrosis"
} | [
{
"companynumb": "DE-ROCHE-498477",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "IBANDRONIC ACID"
},
"drugadditional": null,
"... |
{
"abstract": "In the 26th week of gestation, a 29-year-old pregnant office employee was referred to the pulmonary department of Linz General Hospital (AKH) under the suspicion of tuberculosis. She complained of a cough with intermittent hemoptysis and pain in the thoracic spine from which she had been suffering the past 9 weeks. A plain chest X-ray showed a dense infiltrate on the right side and multiple smaller shadows in both lungs. Laboratory testing revealed anemia, leukocytosis, and an increase of C-reactive protein. All tests for tuberculosis were negative.A bronchoscopy was performed and biopsies were taken from the right upper and middle lobe. The histopathological examination found cells of an adenocarcinoma. A magnetic resonance imaging (MRI) revealed a large tumor and surrounding atelectasis were seen in the right upper and middle lobe, as well as multiple intrapulmonary metastases in both lungs. In addition, not only metastases in the thoracic spine (level Th2/3) but also at other osseous locations and multiple cerebral metastases were detected. The patient received one cycle of chemotherapy consisting of docetaxel and carboplatin (AUC5) in the 27th week of gestation. Additional radiotherapy was applied to the involved thoracic spine. Due to positive epidermal growth factor receptor mutation, therapy with gefitinib 250 mg/day was started 2 days after a Caesarean section (preceded by treatment for fetal lung maturation). A healthy girl was delivered in the 30th week of pregnancy. Staging with computed tomography (CT) after delivery revealed an unstable fracture of Th2 with compression of the spinal cord. Neurosurgery was performed, consisting of a ventral corporectomy of Th1-2 followed by an anterior and posterior osteosynthesis for stabilization. The patient was discharged without neurological deficits within 1 week. Subsequent treatment with gefitinib improved the performance status of the patient, and CT scans of the chest and an MRI of the brain showed the size of the tumor to be shrinking. Meanwhile, the infant developed appropriately for her age.After 14 months of the first diagnosis, the patient experienced neurological symptoms (aphasia, confusion) due to neoplastic meningeosis and cerebral venous sinus thrombosis together with local tumor progression in the lung. One course of chemotherapy, combining carboplatin/pemetrexed/bevacizumab, was given without clinical response. Despite best supportive care, the patient died 17 months after diagnosis in October 2013.",
"affiliations": "Department of Pulmonary Medicine, General Hospital Linz (AKH), Linz, Austria, korneliaholzmann@hotmail.com.",
"authors": "Holzmann|Kornelia|K|;Kropfmüller|Roland|R|;Schinko|Herwig|H|;Bogner|Stephan|S|;Fellner|Franz|F|;Arzt|Wolfgang|W|;Lamprecht|Bernd|B|",
"chemical_list": null,
"country": "Austria",
"delete": false,
"doi": "10.1007/s00508-015-0726-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0043-5325",
"issue": "127(15-16)",
"journal": "Wiener klinische Wochenschrift",
"keywords": null,
"medline_ta": "Wien Klin Wochenschr",
"mesh_terms": "D000328:Adult; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D013125:Spinal Neoplasms; D013904:Thoracic Vertebrae; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "21620870R",
"other_id": null,
"pages": "639-44",
"pmc": null,
"pmid": "25732916",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11574771;17688967;12185292;18985677;18701186;18063195;18558586;19767090;22534670;23328112;19112460;18242765;23856754;18291591;19896236;19064969",
"title": "Lung cancer in pregnancy.",
"title_normalized": "lung cancer in pregnancy"
} | [
{
"companynumb": "AT-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-112930",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drug... |
{
"abstract": "According to registry studies of capecitabine, grade 3-4 hypertriglyceridemia can occur in 0.1-1% of patients, unexplained by the drug's mechanism of action. This retrospective study aimed at estimating the incidence of capecitabine-induced hypertriglyceridemia (CIH) and attempted to identify the risk factors for its occurrence. In a retrospective survey, the files of 289 patients treated with capecitabine as a single agent or combined with other drugs were reviewed. A total of 102 patients without grade 2 or more hypertriglyceridemia at baseline and with at least one test of triglyceride blood level (TGBL) at least 2 months from the start of capecitabine were eligible for the study. The mean TGBL was 149±80 mg/dl at the onset of treatment and the mean maximal level after two or more cycles of capecitabine was 236±137 mg/dl (P<0.001; average increase 93 mg/dl). Nineteen (19%) patients developed grade≥2 CIH, four (4%) of whom had grade 3-4. The median time to developing grade≥2 CIH was 79 days (range, 16-243 days). A high rate of grade≥2 CIH, without statistical significance, was observed on the basis of several risk factors: pre-existing hypertriglyceridemia grade 1 (11/45; 24%), diabetes (7/25; 37%), hypertension (10/60; 17%), and ischemic heart disease (IHD) (5/14; 36%). The only identified risk factor for grade≥3 CIH was IHD (2/14; P=0.02). Increased capecitabine-induced TGBL is common and grade≥2 was detected in 19% of patients in this series. Close monitoring of lipid profile is recommended in patients on capecitabine treatment. IHD may be a risk factor for development of severe hypertriglyceridemia.",
"affiliations": "Division of Oncology, Rambam Health Care Campus, Technion-Israel Institute of Technology, Faculty of Medicine, Haifa, Israel.",
"authors": "Bar-Sela|Gil|G|;Cohensius-Kent|Dorit|D|;Vornikova|Olga|O|;Haim|Nissim|N|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D014280:Triglycerides; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000000097",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": "25(6)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D003841:Deoxycytidine; D005260:Female; D005472:Fluorouracil; D006801:Humans; D015228:Hypertriglyceridemia; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014280:Triglycerides",
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "729-34",
"pmc": null,
"pmid": "24595094",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Increase in triglyceride blood level in patients treated with capecitabine: a retrospective survey.",
"title_normalized": "increase in triglyceride blood level in patients treated with capecitabine a retrospective survey"
} | [
{
"companynumb": "IL-MYLANLABS-2015M1004113",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
... |
{
"abstract": "Cinacalcet is an effective and safe alternative to parathyroidectomy in end stage renal disease (ESRD) patients with secondary hyperparathyroidism. Hypocalcemia is a known complication of treatment that is usually readily reversible upon discontinuation of the drug. It rarely manifests severely and symptomatically requiring hospital admission. We present the case of a 55 year old man with severe, symptomatic and prolonged hypocalcemia that occurred 2 weeks after starting cinacalcet. Cinacalcet induced a state of pharmacological parathyroidectomy with subsequent hungry bone syndrome. Serum calcium returned to normal range after 4 weeks of stopping the drug while receiving high doses of elemental calcium and vitamin D receptor activation therapy (VDRA).",
"affiliations": "Division of Nephrology, Department of Internal Medicine, American University of Beirut, Riad El Solh, P.O. Box 11-0236, Beirut, 1107 2020, Lebanon. sk62@aub.edu.lb.;Division of Nephrology, Department of Internal Medicine, Maine Medical Center, Maine, USA.;Division of Nephrology, Department of Internal Medicine, American University of Beirut, Riad El Solh, P.O. Box 11-0236, Beirut, 1107 2020, Lebanon.;Division of Nephrology, Department of Internal Medicine, American University of Beirut, Riad El Solh, P.O. Box 11-0236, Beirut, 1107 2020, Lebanon.",
"authors": "Koubar|Sahar H|SH|;Qannus|Abd Assalam|AA|;Medawar|Walid|W|;Abu-Alfa|Ali K|AK|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-017-0284-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "7(1)",
"journal": "CEN case reports",
"keywords": "Cinacalcet; Hungry bone syndrome; Hypocalcemia; Secondary hyperparathyroidism",
"medline_ta": "CEN Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "21-23",
"pmc": null,
"pmid": "29124559",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": "17244128;16360386;23121374;9159312;11912261;26621501;23594726;25949410",
"title": "Hungry bone syndrome two weeks after starting cinacalcet: a call for caution.",
"title_normalized": "hungry bone syndrome two weeks after starting cinacalcet a call for caution"
} | [
{
"companynumb": "LB-AMGEN-LBNSP2018063212",
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"activesubstancename": "CINACALCET HYDROCHLORIDE"
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{
"abstract": "OBJECTIVE\nTo report a patient with a significant amlodipine self-poisoning who failed to clinically respond to conventional treatment and was managed with metaraminol (Aramine).\n\n\nMETHODS\nA 43-year old male presenting after ingestion of 560 mg amlodipine, who failed to respond clinically to treatment with fluid resuscitation, calcium salts, glucagon and norepinephrine/epinephrine inotropic support.\n\n\nRESULTS\nFollowing a loading bolus of 2 mg and intravenous infusion (83 microg/min) of metaraminol (Aramine) there was improvement in his blood pressure, cardiac output and urine output.\n\n\nCONCLUSIONS\nThis is the first case report of the beneficial use of metaraminol (aramine) in the management of significant amlodipine poisoning unresponsive to conventional therapy.",
"affiliations": "Pharmacology and Clinical Pharmacology, Department of Basic Medical Sciences, St George's Hospital Medical School, Jenner Wing, Cranmer Terrace, London SW17 ORE, UK. dwood@sghms.ac.uk",
"authors": "Wood|D M|DM|;Wright|K D|KD|;Jones|A L|AL|;Dargan|P I|PI|",
"chemical_list": "D000316:Adrenergic alpha-Agonists; D002121:Calcium Channel Blockers; D017311:Amlodipine; D008680:Metaraminol",
"country": "England",
"delete": false,
"doi": "10.1191/0960327105ht538oa",
"fulltext": null,
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"issn_linking": "0960-3271",
"issue": "24(7)",
"journal": "Human & experimental toxicology",
"keywords": null,
"medline_ta": "Hum Exp Toxicol",
"mesh_terms": "D000316:Adrenergic alpha-Agonists; D000328:Adult; D017311:Amlodipine; D002121:Calcium Channel Blockers; D062787:Drug Overdose; D006439:Hemodynamics; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008680:Metaraminol; D013406:Suicide, Attempted",
"nlm_unique_id": "9004560",
"other_id": null,
"pages": "377-81",
"pmc": null,
"pmid": "16119252",
"pubdate": "2005-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metaraminol (Aramine) in the management of a significant amlodipine overdose.",
"title_normalized": "metaraminol aramine in the management of a significant amlodipine overdose"
} | [
{
"companynumb": "GB-LUPIN PHARMACEUTICALS INC.-2015-03666",
"fulfillexpeditecriteria": "1",
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"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
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"abstract": "Although metformin has become a drug of choice for the treatment of type 2 diabetes mellitus, some patients may not receive it owing to the risk of lactic acidosis. Metformin, along with other drugs in the biguanide class, increases plasma lactate levels in a plasma concentration-dependent manner by inhibiting mitochondrial respiration predominantly in the liver. Elevated plasma metformin concentrations (as occur in individuals with renal impairment) and a secondary event or condition that further disrupts lactate production or clearance (e.g., cirrhosis, sepsis, or hypoperfusion), are typically necessary to cause metformin-associated lactic acidosis (MALA). As these secondary events may be unpredictable and the mortality rate for MALA approaches 50%, metformin has been contraindicated in moderate and severe renal impairment since its FDA approval in patients with normal renal function or mild renal insufficiency to minimize the potential for toxic metformin levels and MALA. However, the reported incidence of lactic acidosis in clinical practice has proved to be very low (<10 cases per 100,000 patient-years). Several groups have suggested that current renal function cutoffs for metformin are too conservative, thus depriving a substantial number of type 2 diabetes patients from the potential benefit of metformin therapy. On the other hand, the success of metformin as the first-line diabetes therapy may be a direct consequence of conservative labeling, the absence of which could have led to excess patient risk and eventual withdrawal from the market, as happened with earlier biguanide therapies. An investigational delayed-release metformin currently under development could potentially provide a treatment option for patients with renal impairment pending the results of future studies. This literature-based review provides an update on the impact of renal function and other conditions on metformin plasma levels and the risk of MALA in patients with type 2 diabetes.",
"affiliations": "University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.;Kinexum LLC, Harpers Ferry, WV, USA.;Elcelyx Therapeutics, Inc., San Diego, CA, USA.;Elcelyx Therapeutics, Inc., San Diego, CA, USA. Electronic address: thomas.bicsak@elcelyx.com.",
"authors": "DeFronzo|Ralph|R|;Fleming|G Alexander|GA|;Chen|Kim|K|;Bicsak|Thomas A|TA|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0026-0495",
"issue": "65(2)",
"journal": "Metabolism: clinical and experimental",
"keywords": "Drug mechanism; Lactic acidosis; MALA; Metformin; Renal impairment",
"medline_ta": "Metabolism",
"mesh_terms": "D000140:Acidosis, Lactic; D003924:Diabetes Mellitus, Type 2; D006801:Humans; D007004:Hypoglycemic Agents; D008687:Metformin; D012307:Risk Factors",
"nlm_unique_id": "0375267",
"other_id": null,
"pages": "20-9",
"pmc": null,
"pmid": "26773926",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Metformin-associated lactic acidosis: Current perspectives on causes and risk.",
"title_normalized": "metformin associated lactic acidosis current perspectives on causes and risk"
} | [
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"companynumb": "PT-IMPAX LABORATORIES, INC-2018-IPXL-00797",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
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... |
{
"abstract": "When prescribing lithium, the risk of toxicity remains a concern. In this study, we examined a cohort of patients exposed to lithium between 1997 and 2013. The aims of this study were to determine the frequency of lithium intoxication and to evaluate the clinical course and changes in renal function. Of 1340 patients, 96 had experienced at least one episode of lithium levels ⩾1.5 mmol/L, yielding an incidence of 0.01 per patient-year. Seventy-seven patients available for review had experienced 91 episodes, of whom 34% required intensive care and 13% were treated with haemodialysis. There were no fatalities. Acute kidney injury occurred, but renal function at baseline was not different to renal function after the episode. Renal impairment was often associated with co-morbidities and other factors. Both intermittent and continuous-venovenous haemodialysis were used, but the clearance of continuous-venovenous haemodialysis can be too low in cases where large amounts of lithium have been ingested. Saline and forced diuresis have been used and are safe. Lithium intoxication seems rare and can be safely managed in most cases. Physicians should not withhold lithium for fear of intoxication in patients who benefit from it. Yet, physicians should have a low threshold to screen for toxicity.",
"affiliations": "Department of Public Health and Clinical Medicine - Medicine, University Hospital, Umeå, Sweden author@ottm.eu.;Department of Public Health and Clinical Medicine - Medicine, University Hospital, Umeå, Sweden.;Department of Clinical Sciences - Psychiatry, University Hospital, Umeå, Sweden.;Sunderby Research Unit - Psychiatry, Department of Clinical Sciences, Umeå University, Umeå, Sweden.",
"authors": "Ott|Michael|M|;Stegmayr|Bernd|B|;Salander Renberg|Ellinor|E|;Werneke|Ursula|U|",
"chemical_list": "D008094:Lithium",
"country": "United States",
"delete": false,
"doi": "10.1177/0269881116652577",
"fulltext": "\n==== Front\nJ PsychopharmacolJ. Psychopharmacol. (Oxford)JOPspjopJournal of Psychopharmacology (Oxford, England)0269-88111461-7285SAGE Publications Sage UK: London, England 10.1177/026988111665257710.1177_0269881116652577Original PapersLithium intoxication: Incidence, clinical course and renal function – a population-based retrospective cohort study Ott Michael 1Stegmayr Bernd 1Salander Renberg Ellinor 2Werneke Ursula 31 Department of Public Health and Clinical Medicine – Medicine, University Hospital, Umeå, Sweden2 Department of Clinical Sciences – Psychiatry, University Hospital, Umeå, Sweden3 Sunderby Research Unit – Psychiatry, Department of Clinical Sciences, Umeå University, Umeå, SwedenMichael Ott, Department of Public Health and Clinical Medicine – Medicine, University Hospital, 901 85 Umeå, Sweden. Email: author@ottm.eu14 6 2016 10 2016 30 10 1008 1019 © The Author(s) 20162016British Association for PsychopharmacologyThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).When prescribing lithium, the risk of toxicity remains a concern. In this study, we examined a cohort of patients exposed to lithium between 1997 and 2013. The aims of this study were to determine the frequency of lithium intoxication and to evaluate the clinical course and changes in renal function. Of 1340 patients, 96 had experienced at least one episode of lithium levels ⩾1.5 mmol/L, yielding an incidence of 0.01 per patient-year. Seventy-seven patients available for review had experienced 91 episodes, of whom 34% required intensive care and 13% were treated with haemodialysis. There were no fatalities. Acute kidney injury occurred, but renal function at baseline was not different to renal function after the episode. Renal impairment was often associated with co-morbidities and other factors. Both intermittent and continuous-venovenous haemodialysis were used, but the clearance of continuous-venovenous haemodialysis can be too low in cases where large amounts of lithium have been ingested. Saline and forced diuresis have been used and are safe. Lithium intoxication seems rare and can be safely managed in most cases. Physicians should not withhold lithium for fear of intoxication in patients who benefit from it. Yet, physicians should have a low threshold to screen for toxicity.\n\nLithiumbipolar affective disorderintoxicationrenal impairmenthaemodialysis\n==== Body\nIntroduction\nLithium has recently been endorsed as the first-line maintenance treatment of bipolar affective disorder (BPAD; NICE, 2014) and treatment refractory depression (Cleare et al., 2015; Edwards et al., 2013). Yet, its use is in decline in many countries (Shorter, 2009; Young and Hammond, 2007) due to the introduction of other mood stabilisers such as some anticonvulsants and second-generation antipsychotics (SGAs). Long-term lithium use is associated with an increased risk of loss of renal function (Bocchetta et al., 2015; Close et al., 2014). To limit those risks, lithium levels are carefully monitored and kept as low as possible. Unfortunately, the risk of chronic kidney disease (CKD) cannot be eliminated by adherence to modern treatment principles (Aiff et al., 2015). When using lithium, we trade off a small morbidity and mortality risk of CKD against the morbidity and mortality risk of mental ill-health associated with lack of effective prophylaxis (Werneke and Ott, 2014; Werneke et al., 2012).\n\nLittle is known about the incidence, clinical course and associated factors of acute lithium toxicity. Oruch et al. (2014) suggest that lithium poisoning occurs frequently, ‘since it is used by individuals at high risk of taking an overdose’. A correlation between CKD and sudden lithium intoxication has been postulated (Azab et al., 2015), but the relationship between both remains unclear. CKD may give rise to lithium intoxication, and lithium intoxication may increase the risk of CKD (Close et al., 2014; Lepkifker et al., 2004).\n\nThe aims of this study were to determine the frequency of lithium intoxication, to evaluate associated factors, clinical course and treatment, and to clarify how great the risk is that toxic lithium levels cause acute or chronic renal failure. Such information can help to improve pharmacological treatment of patients suffering from severe affective disorders.\n\nMethods and materials\nWe collected the data as part of a retrospective cohort study (LISIE) into side effects and effects of lithium treatment compared to other mood stabilisers for the maintenance treatment of BPAD. The Regional Ethics Review Board at Umeå University, Sweden, approved this study (DNR 2010-227-31M, DNR 2011-228-32M, DNR 2014-10-32M).\n\nParticipants\nWe identified all patients with BPAD in the Swedish county of Norrbotten who were at least 18 years of age and had been exposed to lithium. The study covered a 17-year period from 1997 to 2013. Lithium exposure was determined by at least one blood lithium concentration >0.2 mmol/L in the central laboratory database where all measurements were stored. We defined a lithium level of ⩾1.2 mmol/L as our cut-off point for all intoxication, since this is the upper limit of recommended therapeutic levels. A lithium level of ⩾1.5 mmol/L was set as the cut-off point for a risk of clinically significant intoxication (Chen et al., 2004). We then determined how many patients had experienced such episodes.\n\nTo estimate the incidence of intoxication, we first calculated the episodes per patient treated over the entire 17-year observation period. Then, we estimated the incidence of lithium intoxication per treatment year based on lithium prescribing data from the Swedish National Board of Health and Welfare (Socialstyrelsen) from 2006 to 2013, to ensure that all patients having received lithium prescriptions were covered.\n\nFor all patients who had consented to participate in this study or whose records we were approved to access because the patients had deceased, we reviewed in detail the episodes with lithium levels of ⩾1.5 mmol/L as documented in the electronic medical records. Both primary-care and secondary-care records were accessed. To control for selection bias, we compared key parameters that were available in anonymous form, including sex, age, maximum serum creatinine and maximum serum lithium concentration for consenting and non-consenting patients in accordance with the ethical approval granted.\n\nChart review and analysis\nRegarding each episode of lithium intoxication eligible for review, we determined the mode of detection, presenting symptoms, somatic co-morbidities and co-medications, aetiology, treatment including need for dialysis, clinical outcome and renal function before and at least one month after lithium intoxication. Episodes with acute intoxication, defined as cases of supra-therapeutic lithium doses leading to toxic blood levels within 24 hours after ingestion, were classified as ‘acute’ in lithium naive patients and ‘acute on therapeutic’ in patients on lithium maintenance treatment. Cases in whom recent supra-therapeutic doses had been ruled out were defined as ‘chronic’. We used estimated glomerular filtration rate (eGFR) as a more reliable parameter of renal function than creatinine for baseline and one month after intoxication. eGFR was estimated with the CKD-EPI formula (Levey et al., 2009). For acute kidney injury (AKI), we used creatinine, since eGFR would render false results. AKI was defined as a rise in creatinine ⩾26.5 µmol/L/48 hours, according to the KDIGO Clinical Practice Guideline for Acute Kidney Injury (2012). Baseline creatinine was defined as last creatinine measured before intoxication or occurrence of the relevant co-morbidity (e.g. infection). Co-morbidities and associated factors were classified according to the likelihood of causing AKI. Such were considered ‘probable’ if the clinical data showed patterns that would induce AKI in a lithium-naive patient. Episodes with co-morbidities essentially able to cause AKI but without enough clinical information were considered ‘possible’. All information was then entered into a database and anonymised before analysis.\n\nWe conducted a descriptive analysis, establishing the frequency of all variables in our database. Then, we compared moderate with severe intoxication, using a cut-off point of 2.5 mmol/L (Price and Heninger, 1994). Group comparisons were made with a two-tailed t-test. When data of the same individual were compared over time, a paired t-test was used. Differences were considered statistically significant with a p-value of <0.05. We did not correct for multiple testing because our data were ‘observational’ but not ‘random’ in nature (Rothman, 1990). Statistical analysis was performed using IBM SPSS Statistics for Windows v23 (IBM Corp., Armonk, NY). We analysed categorical data using the chi-square test and Fisher’s exact test (GraphPad Prism; GraphPad Software, Inc., La Jolla, CA; Preacher, 2001).\n\nFigure 1. Identification of cases with lithium intoxication.\n\nResults\nEpidemiology\nWe identified 1340 patients who had been exposed to lithium over the 17-year period of observation. Of these, 228 had experi-enced at least one episode of lithium levels ⩾1.2 mmol/L, and 96 (7.16%) had experienced at least one episode of lithium levels ⩾1.5 mmol/L. The mean number of patients treated with lithium between 2006 and 2013 in the catchment area was 667 per year, corresponding to 2.67 patients/1000 inhabitants, according to national prescription data. These numbers were stable over the observation period. Our study covered an estimate of 11,339 patient-years on lithium. Under the assumption that the patients not consenting to have their charts reviewed had a similar distribution of episodes, the incidence of moderate to severe lithium intoxication amounted to 0.01 patients per year.\n\nCase analysis\nOf the eligible patients, 75% consented to the study. Including patients who had passed away, 1101 patients (82%) were analysed. Patients not consenting did not differ significantly in age, sex, maximal measured creatinine or maximum lithium level from the patients who were included.\n\nOf the 1101 patients who were analysed, 77 had experienced 91 episodes of lithium intoxication with lithium levels ⩾1.5 mmol/L. Of these, 10 patients had two episodes and two patients had three episodes of intoxication, but there was no obvious pattern in these repeated episodes. Fourteen per cent had a diagnosis of paranoid schizophrenia, 7% schizoaffective disorder, 71% BPAD and 8% depression.\n\nTwenty-nine episodes occurred during the first two years of lithium treatment. The proportion of cases of acute intoxication was significantly higher in this subgroup (p<0.01).\n\nSeventy-two (79%) episodes concerned moderate plasma elevations in the range 1.50–2.5 mmol/L, and 19 (21%) episodes concerned severe plasma elevations >2.5 mmol/L. The highest lithium level detected was 9.26 mmol/L in the context of an intentional overdose. In all groups, women accounted for about two-thirds of intoxication episodes (p<0.01). The mean age for all these episodes was 54.3 years (SD=17.9 years, range 22–86 years). Patients with severe intoxication were significantly younger (p< 0.05; Table 1).\n\nTable 1. Lithium intoxication episodes – basic characteristics.\n\n\tAll\tEpisodes with lithium serum levels between 1.5 and 2.5 mmol/L\tEpisodes with lithium serum levels >2.5 mmol/L\t\n\nN\n\t91\t72\t19\t\n\nAge\n\t\t\t\t\n Mean age (SD; range)\t54.3 (17.9; 22–86)\t56.4 (17.5; 22–86)\t46.3 (17.5; 22–78)*\t\n ⩾65 years, n (%)\t31 (34.1)\t28 (38.9)\t3 (15.8)*\t\n\nSex\n\t\t\t\t\n Male, n (%)\t29 (31.9)\t23 (31.9)\t6 (31.6)\t\n Female, n (%)\t62 (68.1)***\t49 (68.1)***\t13 (68.4)\t\n\nMode\n\t\t\t\t\n Acute, n (%)\t24 (26.4)\t14 (19.4)\t10 (52.6)*\t\n Chronic, n (%)\t54 (59.3)\t46 (63.9)\t8 (42.1)*\t\n Unknown, n (%)\t13 (14.3)\t12 (16.7)\t1 (5.3)\t\n\nTreatment\n\t\t\t\t\n ICU, n (%)\t31 (34.1)\t16 (22.2)\t15 (78.9)**\t\n Haemodialysis, n (%)\t12 (13.2)\t4 (5.6)\t8 (42.1)**\t\n* p<0.05 between groups; **p<0.01 between groups; ***p<0.01 within groups.\n\nICU: intensive care unit.\n\nEpisodes of intoxication were significantly more frequent in summer and autumn, with a p-value of ⩽0.01 for the whole sample and a p-value of 0.025 for episodes not concerning intentional overdoses. There was no seasonal variation for episodes of unknown cause.\n\nSymptoms of lithium intoxication\nSymptoms of lithium intoxication were only recorded for a minority of patients. Most commonly, patients presented with altered level of consciousness (confusion, disorientation or somnolence). This was significantly more likely to occur in patients with severe intoxication (p<0.05). Less likely to occur in an acute overdose setting were tremor (p<0.05), vomiting and diarrhoea (p<0.05) and ataxia or falls (p<0.001) (see Table 2).\n\nTable 2. Symptoms of lithium intoxication.\n\n\tAll\tLithium concentration (mmol/L)\tAcute intoxication\tChronic intoxication\t\n\t1.50–2.50\t>2.50\t\nN episodes\t91\t72\t19\t24\t54\t\nSymptoms (%)\t\nGastrointestinal symptoms:\t\nVomiting and/or diarrhoea\t9.9\t11.1\t5.3\t0*\t18.6*\t\nMental status changes:\t\nConfusion/disorientation/somnolence\t27.5\t22.2*\t47.4*\t33.3\t27.8\t\nAgitation\t6.6\t5.6\t10.5\t12.5\t1.9\t\nTiredness\t13.2\t12.5\t15.8\t16.7\t14.8\t\nNeurological symptoms:\t\nAtaxia/fall\t18.7\t12.5\t20.0\t4.2**\t24.1**\t\nTremor\t22\t25.0\t21.0\t4.2*\t33.3*\t\nHyperreflexia\t2.2\t2.8\t0\t0\t3.7\t\nMuscle rigidity\t5.5\t4.2\t10.5\t4.2\t5.6\t\nMuscle weakness\t5.5\t6.9\t0\t4.2\t7.4\t\nEye symptoms: blurred vision/nystagmus\t2.2\t2.8\t0\t0\t3.7\t\nSlurred speech\t7.7\t8.3\t5.3\t8.3\t9.1\t\n* p<0.05; **p<0.01.\n\nMode of identification\nSeventy-seven per cent of cases of intoxication were detected after unscheduled blood tests, and 22% were identified during routine monitoring conducted every four months. Twenty-four (26%) episodes were related to acute intoxication. Of these, 23 episodes occurred in patients with maintenance treatment (‘acute on therapeutic’) and one episode in a patient not previously treated with lithium. Fifty-four (59%) episodes related to chronic intoxication. For the remaining 13 episodes, there was insufficient data to attempt classification. Patients <65 years of age were significantly more likely to have taken an overdose than patients ⩾65 years (odds ratio [OR]=6.7, confidence interval [CI] 1.8–24.4; p<0.01; Table 1).\n\nAssociated factors\nInfections were associated with nine (9.9%) episodes of the cases of intoxication. Eleven (12.1%) cases of intoxication were associated with initiation of interacting drugs. Four (4.4%) of these episodes were linked to initiation of therapy with non-steroidal anti-inflammatory drugs (NSAID). Thiazide and loop-diuretics were associated with another three (3.3%) episodes. Blockade of the renin-angiotensin-aldosterone-system (RAAS) with ACE inhibitors, angiotensin receptor blockers or spironolactone accounted for a further seven (7.7%) episodes. Of the 1101 patients analysed, 760 had at least one prescription of NSAID, 247 patients RAAS-blocking drugs and 112 patients thiazides over the 17-year study period. Patients ⩾65 years of age accounted for all of the RAAS-associated, none of the NSAID associated episodes and only one of the episodes related to infections.\n\nRenal function\nMean eGFR at baseline was 80 mL/min/1.73 m2, corresponding to a mild decrease (category G2 according to the KDIGO Clinical Practice Guideline, 2013). In 32 (34%) episodes, AKI was present. In another five patients, the rise of creatinine was borderline between 22 and 26 µmol/L. In 27/37 episodes, the decline of renal function was probably and in eight episodes possibly caused by co-morbidities or factors other than lithium. In two episodes, AKI occurred after the first week of lithium treatment (Table 3).\n\nTable 3. Patients with acute kidney impairment: co-morbidities and associated factors.\n\nCase\tCreatinine baseline\tDays to intoxication from creatinine baseline\tMax. lithium level\tMax. creatinine\tCreatinine after event\tCo-morbidities/associated factors\tCause for AKI\t\n1\t131\t45\t2.12\t1085\t155\tStroke, post-renal obstruction\tProbable\t\n2\t90\t122\t1.58\t720\t64\tGastroenteritis+NSAID\tProbable\t\n3\t149\t19\t1.81\t670\t146\tSepsis, prerenal AKI\tProbable\t\n4\t120\t35\t2.60\t621\tCensoreda\tHanta virus infection (Puumala)/nephropathia epidemica\tProbable\t\n5\t96\t54\t4.20\t357\t83\tInfection/pyelonephritis\tProbable\t\n6\t62\t52\t2.36\t249\t74\tGastroenteritis and pyelonephritis\tProbable\t\n7\t54\t17\t2.68\t218\t64\tColonoscopy 4 days before, metastatic cancer\tPossible\t\n8\t81\t5\t2.27\t226\t77\t\tNot explainedb\t\n9\t70\t34\t2.50\t179\t68\tInfection (abdominal abscess), start on diuretics\tProbable\t\n10\t162\t15\t1.99\t269\t184\tFebrile UTI\tPossible\t\n11\t92\t58\t1.96\t198\t91\tUTI, fall and humerus fracture 6 days before, dehydration, fever\tProbable\t\n12\t54\t10\t2.20\t152\t49\tPostoperative NSAID after gastric bypass\tProbable\t\n13\t104\t33\t1.61\t180\t109\t4 weeks after start with candesartan and spironolactone\tProbable\t\n14\t100\t7\t1.69\t169\t90\tTreatment with amiloride/hydrochlorothiazide 6 weeks before\tProbable\t\n15\t80\t69\t1.54\t145\t96\tPre-renal (stopped drinking, orthostatism)\tProbable\t\n16\t115\t19\t2.02\t179\t117\tTreatment with amiloride/hydrochlorothiazide 2 weeks before\tProbable\t\n17\t78\t324\t2.47\t139\t90\tVomiting and fever\tProbable\t\n18\t92\t80\t2.04\t161\t119\tBreast cancer, chronic UTI\tPossiblec\t\n19\t103\t15\t1.68\t150\t93\tHip fracture and dehydration\tProbable\t\n20\t84\t14\t2.11\t140\t80\tSpironolactone\tProbable\t\n21\t142\t58\t1.61\t193\t144\tStroke\tProbable\t\n22\t74\t108\t1.79\t124\t82\tUTI, chronic diarrhoea, loperamide treatment\tPossible\t\n23\t66\t279\t2.56\t115\t86\tPneumonia and dehydration (influenza?)\tProbable\t\n24\t86\t15\t2.34\t133\t87\tMyocardial infarction 10 days before, anaemia, gastroscopy 2 days before\tPossible\t\n25\t115\t77\t1.93\t161\t124\tIntermittent diarrhoea, leukocytosis\tPossible\t\n26\t79\t2\t2.49\t119\tCensoredd\tTerminal lung cancer, palliative furosemide treatment\tProbable\t\n27\t91\t64\t1.71\t130\t103\tSpironolactone and ACEI started 8 weeks before and dose doubled 5 weeks before\tProbable\t\n28\t84\t7\t1.57\t120\t94\tDehydration, colitis\tProbable\t\n29\t81\t112\t2.59\t116\t79\tACEI and thiazide 11 weeks before\tProbable\t\n30\t94\t98\t1.68\t125\t76\tPsychotic episode, did not eat or drink\tPossible\t\n31\t104\t93\t1.73\t133\t106\tACEI treatment, post-renal obstruction\tProbable\t\n32\t79\t72\t2.78\t106\t80\tFever, UTI\tPossible\t\n33\t91\t42\t1.64\t117\t98\tScrotal infection\tPossible\t\n34\t83\t4\t1.67\t108\t77\tContrast induced nephropathy\tProbable\t\n35\t88\t87\t2.62\t112\t90\tDehydration, colitis\tProbable\t\n36\t100\t490\t1.72\t123\t108\tMetformin-induced diarrhoea, NSAID\tProbable\t\n37\t64\t43\t2.30\t86\t61\tEnalapril one month before\tProbable\t\na Patient never recovered from renal impairment due to infection.\n\nb Started on lithium 6 days before.\n\nc Started on lithium 7 days before.\n\nd Patient died before follow-up.\n\nAKI: acute kidney injury; NSAID: non-steroidal anti-inflammatory drugs; UTI: urinary tract infection; ACEI: angiotensin converting enzyme inhibitor.\n\nPatients ⩾65 years of age were more likely to have had renal impairment prior to intoxication (p<0.01). No patient with acute intoxication had AKI.\n\nFor 88 episodes, serum creatinine levels were analysed comparing baseline and maximum creatinine and creatinine at least one month after intoxication. For one episode, creatinine was not measured during intoxication. The other two episodes concerned a patient who died of lung cancer within one month of intoxication, and another patient who had nephropathia epidemica (Hanta virus infection) and did not recover from renal impairment.\n\nCreatinine was significantly higher during intoxication (p<0.01). Kidney function did not differ before and after intoxication (Table 4). GFR at least one month after intoxication was 81.33 mL/min/1.73 m2. Eighteen (20%) patients had a lost >5 mL/min/1.73 m2 and six patients (7%) >10 mL/min/1.73 m2. The highest loss of GFR was 25 mL/min/1.73 m2. The median change in GFR was 0 mL/min for all episodes. A decline in GFR did not correlate with GFR at baseline, age ⩾65 years, sex or maximum creatinine. However, it correlated inversely with maximal lithium level (R=−0.21, p<0.05).\n\nTable 4. Creatinine levels (µmol/L) before, during and after intoxication.\n\n\tBefore intoxication (baseline)\tMaximum during intoxication\tAt least one month after intoxication\t\n\tAll episodes, n=88a\t\nMean (SD)\t82.6 (20.4)\t133.3 (145.2)**\t84.5 (23.1)\t\nMedian\t80.5\t92\t79\t\nMinimum\t46\t44\t47\t\nMaximum\t162\t1085\t184\t\n\tEpisodes with lithium serum levels between 1.5 and 2.5 mmol/L, n=70\t\nMean (SD)\t84.5 (21.3)\t139.7 (158.4)*\t86.5 (24.8)\t\nMedian\t83\t95\t79.5\t\nMinimum\t51\t44\t49\t\nMaximum\t162\t1085\t184\t\n\tEpisodes with lithium serum levels >2.5 mmol/L, n=18\t\nMean (SD)\t75.2 (14.5)\t108.3 (72.1)\t76.8 (12.6)\t\nMedian\t77.5\t82.5\t79\t\nMinimum\t46\t53\t47\t\nMaximum\t98\t357\t99\t\n\tEpisodes caused by acute intoxication, n=24\t\nMean (SD)\t72.5 (11)\t73.7 (13.9)\t72.7 (12.1)\t\nMedian\t74\t75.5\t74\t\nMinimum\t50\t44\t47\t\nMaximum\t98\t96\t99\t\n\tEpisodes caused by chronic overdoses, n=54/52a\t\nMean (SD)\t87.7 (21.3)\t178.2 (187.9)**\t89.9 (24.6)\t\nMedian\t85\t117\t87\t\nMinimum\t52\t57\t49\t\nMaximum\t162\t1085\t184\t\na Creatinine at least one month after intoxication censored for two patients.\n\n* p<0.05 compared with baseline before intoxication.\n\n** p<0.01 compared with baseline before intoxication.\n\nSix patients had potassium levels >5.0 mmol/L, and two patients had levels >5.5 mmol/L.\n\nTreatment and outcome\nNo fatalities occurred in connection with lithium intoxication. Detailed information on treatment was available for 77 episodes (Figure 2). Of these, 34.1% received intensive care. Patients with severe intoxication were significantly more likely to receive intensive care (p<0.01; Table 1). Most episodes were managed conservatively. Twelve episodes were treated with haemodialysis (HD; 15.6%). Nine patients received intermitted HD (IHD). Seven of these patients were dialysed between 2 and 5.5 hours; two received two treatment sessions. Two patients were treated with continuous venovenous HD (CVVHD) for 21 and 48 hours, respectively. One patient was started on IHD after an overdose (5.5 hours) and then continued on CVVHD. Despite CVVHD, the patient suffered from a rebound of lithium plasma levels and was switched back to IHD. HD did not induce adverse events.\n\nFigure 2. Treatment modality.\n\nTwelve patients were treated with forced diuresis (e.g. concomitant infusion with sodium chloride 0.9% [saline] and furosemide). Three of these had moderate to severe renal impairment at presentation (creatinine 155–670 µmol/L). Three had nephrogenic diabetes insipidus (NDI), and for three, the NDI status was not known. Sodium at presentation was normal in 10 patients; one patient had low (130 mmol/L) and one patient high sodium (175 mmol/L). The patient with hyponatremia normalised under the treatment. The patient with hypernatremia decreased to 157 mmol/L during the first 48 hours under controlled infusion of dextrose 5%. Sodium follow-up was available in 9/10 of the patients with normal sodium. In these, sodium stayed normal during treatment, even in the presence of NDI. Twenty-three patients were treated with saline alone.\n\nIn the majority of cases (79.1%), long-term maintenance treatment with lithium was continued despite the intoxication episode.\n\nDiscussion\nConcerns about the risk of acute and chronic intoxication and the need of regular monitoring with lithium treatment have led to the perception that other mood stabilisers such as some anticonvulsants and SGAs are safer than lithium and hence preferable. In this work, we examined the toxicity profile in 91 episodes observed over a 17-year period in our county.\n\nThe epidemiology of lithium intoxication\nThe incidence of lithium intoxication was 1/100 patient-years. Based on this incidence, only 1/100 patients per year treated with lithium can be expected to experience moderate to severe lithium intoxication ⩾1.5 mmol/L. We reported an incidence of 7.2% patients with lithium intoxication over 17 years. This is in line with findings from a large population-based study from Canada in elderly patients treated with lithium (Juurlink et al., 2004). As in other studies, we saw that women were nearly twice as likely to experience an episode of lithium intoxication (Table 4). However, our study was not sufficiently powered to examine potential sex differences arising from differences in body mass, kidney function and overdose propensity.\n\nSymptoms of lithium toxicity\nIn many cases, symptoms of lithium intoxication were relatively bland or non-existent. Most symptoms related to mental status changes, which were more frequent in cases of severe intoxication. The statement from a recent expert consensus panel that ‘gastrointestinal symptoms tend to distinguish acute poisoning, where they are expected and prominent, from chronic toxicity, where they are almost invariably absent’ (Decker et al., 2015) could not be endorsed in our study. In our study, no patient having taken an overdose had gastrointestinal symptoms, and all cases with diarrhoea belonged to the group of chronic toxicity. As many patients present with unspecific or mild symptoms, it is important to have a low threshold to check lithium levels. It is important not to ascribe mental status changes to psychiatric symptoms automatically, since mental state changes are prominent in lithium intoxication. Equally, it is important not to discard falls in the elderly treated with lithium as age related and hence ‘normal’ and omit to check lithium levels. Ultimately, clinical symptoms may be poor indicators of actual lithium levels (Kehoe and Mander, 1992; Vermeire et al., 2010). Conversely, it has even been suggested that intoxication can occur even despite normal lithium levels (Peng, 2014; Thompson and Johnson, 2011). This could occur in the context of lithium-mediated serotonergic toxicity or in the context of acute overdoses, when levels are taken before lithium tablets have entered the bloodstream.\n\nAetiology of lithium intoxication\nDrug interactions are an important cause of increased lithium levels. The risk of drug interactions does not seem limited to the elderly population. However, the type of drug interaction may depend on age. In our sample, all drug interactions with NSAID related to patients <65 years of age, and all drug interactions with RAAS-blockade to patients aged ⩾65 years of age. Considering the number of prescriptions of potentially interacting drugs, lithium intoxication caused by these drugs is relatively uncommon. But this does not make co-prescription safe. Circumstances regarding the initiation of these interacting drugs, specifically the need for adaptation of lithium dosage, requires further exploration.\n\nRenal function\nLithium is exclusively eliminated by the kidneys. Therefore, impaired renal function increases the risk for lithium retention and hence for lithium toxicity. This was confirmed by our study, since in the majority of cases, decline of renal function preceded lithium intoxication. Acute lithium exposure can lead to overt diabetes insipidus (Erden et al., 2013) and consequently to dehydration. This may partly explain a transient increase of serum creatinine during the acute intoxication period. Possibly, lithium-induced water loss and reduced fluid ingestion add up to pre-renal AKI. Patients suffering from NDI due to chronic lithium treatment must drink large volumes or receive large parenteral quantities of hypo-osmolar fluids to compensate for NDI associated water loss. As any other AKI, lithium-associated AKI can lead to CKD in individual patients. In a few patients in our study, kidney function was decreased after the episode; in others, it increased. It cannot be ruled out that creatinine-based estimated GFR might have been inaccurately high due to decreased muscle mass caused by inactivity and malnutrition in some patients. For the whole group, kidney function at least one month after intoxication did not differ from baseline. Baseline kidney function or maximum creatinine did not predict changes in GFR after one month. Our study was not designed to look at long-term changes of GFR. Hence, the question remains whether lithium intoxication can contribute to a long-term decline in renal function, even if the kidneys have recovered in the short term. Some studies have suggested that this may be so (Clos 2015; Lepkifker, 2004). This would then suggest an increased renal vulnerability after lithium intoxication. In our study, higher lithium levels correlated with better kidney function. Lithium levels in acute overdoses were higher than those in chronic intoxication. Possibly, longer exposure to lower but still supra-therapeutic lithium levels is more toxic than short exposure to high levels (Chen et al., 2004; Waring et al., 2007). Yet, the very nature of chronicity implies that such cases of intoxication may go undetected for a long time.\n\nTreatment\nOur study depicted real-life treatment. The type of treatment occurred in a hierarchy of invasiveness, from reducing or temporarily discontinuing lithium to saline rehydration to forced diuresis to HD. HD was performed in 13.2% of episodes with both intermittent HD and CVVHF. In the published cohorts, HD treatment was used in 1–11% of cases (Table 4). It remains unclear which patients to dialyze, and clinical practice remains variable (Roberts and Gosselin, 2014). Recent recommendations indicate a need for HD in patients with a lithium level >5 mmol/L or a level of 4 mmol/L in the presence of renal impairment as long as life-threatening symptoms are absent (Decker et al., 2015). This is a much higher threshold than that used by the clinicians in our study. The lowest lithium level leading to treatment with HD in our study was 1.93 mmol/L; the highest level treated without HD treatment was 4.91 mmol/L. Both related to patients who had taken overdoses and presented with mild symptoms. Clearly, the decision of whether to instigate HD depends not only on the highest mean lithium level, but also on the associated symptoms, pharmacokinetic factors and even logistic considerations.\n\nInterestingly, forced diuresis was used as frequently as HD, despite not being recommended in the guidelines. Yet, other studies in the field report a similar treatment approach. In a study by Montagnon et al. (2002), ‘most’ patients received forced diuresis. In another cohort (Eyer et al., 2006), 12/22 patients received furosemide. The rationale for treating lithium toxicity with forced diuresis is based on furosemide increasing the lithium clearance by decreasing the reabsorption in the thick ascending limb of the Henle loop. If a patient were euvolemic and had preserved GFR, furosemide could theoretically increase endogenous clearance up to 20% (Hannedouche et al., 1990). The statement that forced diuresis is not effective and is potentially harmful (Scharman, 1997; Zimmerman, 2003) seems based on two cases from 1978 (Hansen and Amdisen), where volume losses have been replaced by isotonic glucose. This leads to increased reabsorption in the proximal tubule. Another study investigating lithium clearances in an intoxication setting compared 12 patients under forced diuresis with a single reference patient not receiving diuretics and did not find any benefit (Eyer et al., 2006). As GFR varies greatly between patients, it is difficult to evaluate benefit of forced diuresis. In our study, no harm was associated with forced diuresis.\n\nIt is now widely accepted to address volume depletion and consecutive reabsorption of sodium and lithium by saline infusion (Decker et al., 2015). Because of the risk of dehydration due to NDI in lithium-exposed patients, tight measurements of serum sodium and eventually treatment with dextrose are mandatory. This should allow patients to be hydrated generously with saline, even in the absence of overt hypovolemia.\n\nOutcome in lithium intoxication\nLithium intoxication is potentially life-threatening. Large case series from poison-control centres (PCC) report neurological or cardiac causes (de Haro et al., 2003; Offerman et al., 2010) or renal failure and aspiration pneumonia (Bailey and McGuigan, 2000) for fatal outcomes. It is difficult to deduct mortality rates from PCC data due to selection bias and high variability in severity. Published case series investigating mortality on the base of hospital admission data or laboratory data (Chen et al., 2004; Dennison et al., 2011; Webb et al., 2001) did not report any deaths in 236 cases. Juurlink et al. (2004) had a much higher mortality in a cohort of elderly patients identified from prescription data, but it remains unclear how many fatalities were caused by lithium. Despite the life-threatening potential of lithium intoxication, only a minority will require treatment with HD, and surprisingly few result in death (Table 5).\n\nTable 5. Lithium intoxication – case series with a sample size >50 reporting outcome in the literature after the year 2000.\n\nAuthor, publication year, country\tType of study, length\tSample/incidence\tMale: female ratio, age\tSymptoms\tRisk factors\tOverdoses (OD) %, mean lithium, mmol/L, (range)\tHD, ICU\tFatalities\t\nBretaudeau Deguigne et al., 2013, France\tRetrospective, 4.7 years\tPoison control centre, 59 patients with lithium intoxication undergoing early digestive tract decontamination.\t1:3\tGI symptoms 69%\nsomnolence/coma 51%\ntremor 24%\nhypertonia 8%\nECG signs 31%\nCV symptoms 8%\nconfusion/agitation 29%\nmyoclonus 17%\nconvulsions 8%\nacute renal failure 22%\ndiabetes insipidus 5%\naspiration pneumonia 3%\t\t100%\tICU 49%\nHD 19%\tNone\t\nLopez et al., 2012, Spain\tRetrospective, 4.25 years\tHospital admission data, 65 patients with lithium intoxication, 14 patients with HD analysed\t1:1\tneurological signs 78.5%\nleukocytosis 85.7%\nArt. hypotension 57.1% GI symptoms 35.7%\nrenal failure 64.3%\t\tOD 71.4% (10/14)\t23% ICU (15/65) 22% HD (14/65)\tNone\t\nDennison et al., 2011, Ireland\tRetrospective, 5 years\tLaboratory data.\n130 cases of lithium toxicity with lithium levels >1.5 mmol/L referred to hospital. 47 cases reviewed.\nIncidence 5.4/100,000 population/year.\t1: 1.7, 55 years (19–86)\tConfusion 44.7%;\ndrowsiness 36.2%;\naltered arousal 21.3%;\nfatigue 26%;\nlethargy: 23%\nslurred speech 19.1%;\ntremor 51%;\nataxia 38%;\nseizure 4.3%;\nanorexia 30%;\nnausea/diarrhoea 28%\tDiuretics 21.3%;\nNSAID 4.2%\tOD 25.5%\n2.16 mmol/L (1.5–6.7)\tHD 11%,\nICU 2.1%\tNone\t\nOfferman et al., 2010, USA\tRetrospective, 5 years\tPoison control system.\n629 cases of lithium toxicity resulting in hospital admission reported. 502 cases included.\t1:1.9, 48 years (20–84)\tAltered level of consciousness 69.3%, more common in chronic exposures;\ntremor 37.1%;\nGI symptoms 18.6%;\nCV complications 5.7%\nseizures 3.0%\t\tOD 33.5% mean 2.92 mmol/L (0.5–7.0)\tHD 11.0%\t4 (0.8%), 3 not related to lithium, one bradycardic arrest\t\nJuurlink et al., 2004, Canada\tRetrospective, 10 years\tPrescription data.\n413/10,615 (3.9%) patients ⩾66 years treated with lithium admitted to hospital at least once for lithium toxicity. Lithium intoxication diagnosed as lithium exposure+ICD-9 code 985.9 or 969.8.\t1:1.9, 72 years (66–)\tNot given in detail\tACEH 3.4%;\nloop diuretics 2.9%,\nthiazides 1.2%;\nNSAID 1.0%\t\tHD 3%,\nICU 15%\t19 (5%)\nunclear reasons\t\nChen et al., 2004, Taiwan\tRetrospective, 3.5 years\tLaboratory data.\n78 patients with excessive lithium levels ⩾1.2 mmol/L identified by a psychiatric centre. 38 patients ⩾1.5 mmol/L\t1:1.7, 44 years (15–76)\tNot given in detail\t\tOD 55.1%. Lithium level range 1.2–3.1 mmol/L\tHD 1%\tNone\t\nde Haro et al., 2003, France\tRetrospective, 10 years\tPoison centre.\n304 cases reported.\t1:2.1, 1–85, 13 children\tFor intentional OD (n=190):\nSomnolence 76%;\ndisorientation 11%;\ncoma 5%\ntremor 16%\nhypertension 21%;\nCV complications 8%;\nvomiting 8%\tLoop diuretics 2.6%;\nrenal impairment 4.9%;\ndehydration 11.5%\tOD 62.5%. Lithium level range 0.2–12 mmol/L\tHD 5%\t6 (2%) seizures, ventricular fibrillation, hypotension\t\nMontagnon et al., 2002, France\tRetrospective, 8 years\tHospital admission data, 81 cases treated in toxicological intensive care\tMen<women\tUnclear: ‘most patients were admitted with grade 1 coma’\tRenal insufficiency 9.8%;\nAcute pyelonephritis 2.5%;\nInteraction between alactazine and captopril 2.5%,\npoor medication compliance 2.5%;\ndrunkenness 2.5%\nnephrogenic diabetes insipidus 1.2%\t77.8% OD\tICU 100%\nHD 3–6%\t3 (3.7%)\t\nWebb et al., 2001, USA\tProspective, 7 years\tDrug use evaluation programme. 151 (6.8%) of 2210 patients on lithium admitted to hospital with Li ⩾1.5.\t1:1.7, 45 years\tSymptoms 28%\nataxia 15.8%\nlethargia 9.9%\ndelirium 4.0%\npolydipsia 4.0%\nvomiting 3.3%\ntremor 2.0%\tDiuretics 6%\nACEI 2.6%\nrenal impairment 6.6%\t\t\tNone\t\nBailey and McGuigan, 2000, Canada\tProspective, 1 year\tPoison information centre. 205 cases reported. 110 cases >1.5 mmol/L\t1:2.0, 11–94 years\tDrowsiness 32%;\nconfusion 4%;\nstupor/obtunded 3%\ncoma 4%;\nslurred speech 13%;\ntremor 12%\nhyperreflexia 4%\nrigidity: <1%\nseizures: <1%;\nCV complications 12%;\nGI symptoms 8%\tRenal impairment 12.1%\tLithium level range 0–8.9 mmol/L\t4%\t2: one in renal failure, one after pulmonary aspiration under HD\t\nHD: haemodialysis; GI: gastrointestinal; CV: cardiovascular.\n\nLithium may be potentially neurotoxic, but neurologic sequelae of lithium intoxication seem rare. A review of the literature between 1964 and 2004 revealed 90 patients with irreversible neurologic sequelae, also called syndrome of irreversible lithium-effectuated neurotoxicity (SILENT), presenting with persistent cerebellar dysfunction, extrapyramidal symptoms, brainstem dysfunction or ‘dementia with varying degrees of mental syndromes’. The authors suggested that this risk of neurotoxicity supports longer dialysis sessions as a potential preventive measure (Adityanjee et al., 2005). With regard to the risk of SILENT, it seems justified to have a low threshold for HD treatment. Current recommendations on when to start extra-corporal removal of lithium depend on expert consensus rather than on systematic evidence. Non-adherence to current recommendations has not led to adverse events (Bailey and McGuigan, 2000).\n\nStrengths\nAll patients treated with lithium were registered in one single central laboratory database in our county. Together with national prescription data, this allowed the incidence of lithium intoxication to be estimated. The vast majority of patients consenting to access to their medical chart resulted in us being able to include 82% of patients. The electronic medical records for both primary and secondary care have been electronically available since 1997. Thus, we had a long period of observation, including all laboratory parameters and prescription data across services. To our knowledge, this is the first study reporting systematically on renal function before, during and after lithium intoxication.\n\nLimitations\nThis study had some limitations. We limited our review to episodes with lithium levels of at least 1.5 mmol/L to avoid a bias towards mild and borderline intoxication. Also, we wished to avoid false positive results. Lithium levels to screen for toxicity tend to be taken at any time after the last lithium ingestion, in contrast to therapeutic plasma levels, which are taken as trough levels. Lithium intoxication may have been more frequent than shown but clinically not recognised. In such cases, the lithium levels may not have been taken.\n\nThe study depended on the quality of the information recorded in the medical records. Hence, we may have underestimated the prevalence of symptoms, since these were not always comprehensively recorded. This, coupled with a relatively small sample size, yielded insufficient power to explore further potential contributing factors to the renal outcome. Our relatively small sample size also made the detection of rare events such as deaths and SILENT unlikely.\n\nIn this study, we did not follow up on renal function longer than the next measurement of creatinine after at least one month; whether lithium intoxication leads to increased vulnerability and higher risk of risk of long-term decline of renal function was not addressed.\n\nConclusions\nSevere to moderate cases of lithium intoxication are rare. If they occur, they can be managed safely in most cases. AKI occurs, but sustained loss of renal function is rare. In our study, in the majority of cases, renal impairment was most likely a cause rather than a consequence of lithium intoxication. Intensive care may be needed. Both intermittent HD and CVVHD can be used, but the clearance of CVVHD can be too low in cases where large amounts of lithium have been ingested. Both volume expansion with saline and forced diuresis have been used and are safe. As lithium can cause irreversible neurotoxic effects, it makes sense intuitively to remove lithium assertively, since HD has a low complication rate.\n\nUltimately, as lithium intoxication is rare and can be safely managed in most cases, physicians should not withhold lithium for fear of intoxication in patients who benefit from it. Yet, physicians should have a low threshold to screen for toxicity if changes in mental and somatic status occur. It is important to discuss such risks in the context of benefits with patients, who may have become concerned about the safety of lithium through reports on the Internet. In order to manage lithium treatment safely, it is important to educate patients about the risks of lithium toxicity and enable them to understand under which circumstances lithium levels can rise.\n\nDeclaration of Conflicting Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Ursula Werneke received funding for educational activities (Masterclass Psychiatry Programme/EAPM 2016, Luleå, Sweden): Astra Zeneca, Janssen, Lilly, Lundbeck, Novartis, Servier, Otsuka and Shire. Michael Ott, Bernd Stegmayr and Ellinor Salander Renberg declare that there is no conflict of interest.\n\nFunding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a grant of the Norrbotten County Research & Development Fund, Sweden and the Swedish Kidney Association (Njurförbundet Norrbotten).\n==== Refs\nReferences\n\nAdityanjee Munshi KR Thampy A (2005 ) The syndrome of irreversible lithium-effectuated neurotoxicity . Clin Neuropharmacol \n28 : 38 –49 .15714160 \n\nAiff H Attman PO Aurell M (2015 ) Effects of 10 to 30 years of lithium treatment on kidney function . J Psychopharmacol \n29 : 608 –614 .25735990 \n\nAzab AN Shnaider A Osher Y (2015 ) Lithium nephrotoxicity . Int J Bipolar Disord \n3 : 28 .26043842 \n\nBailey B McGuigan M (2000 ) Lithium poisoning from a poison control center perspective . 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PLoS One \n9 : e90169 .24670976 \n\nClos S Rauchhaus P Severn A (2015 ) Long-term effect of lithium maintenance therapy on estimated glomerular filtration rate in patients with affective disorders: a population-based cohort study . Lancet Psychiatry \n2 : 1075 –1083 .26453408 \n\nde Haro L Roelandt J Pommier P (2003 ) [Aetiologies of lithium overdose: 10-year experience of Marseille poison centre ]. Ann Fr Anesth Reanim \n22 : 514 –519 .12893375 \n\nDecker BS Goldfarb DS Dargan PI (2015 ) Extracorporeal treatment for lithium poisoning: systematic review and recommendations from the EXTRIP workgroup . Clin J Am Soc Nephrol \n10 : 875 –887 .25583292 \n\nDennison U Clarkson M O’Mullane J (2011 ) The incidence and clinical correlates of lithium toxicity: a retrospective review . Ir J Med Sci \n180 : 661 –665 .21516355 \n\nEdwards SJ Hamilton V Nherera L (2013 ) Lithium or an atypical antipsychotic drug in the management of treatment-resistant depression: a systematic review and economic evaluation . Health Technol Assess \n17 : 1 –190 .\n\nErden A Karagoz H Basak M (2013 ) Lithium intoxication and nephrogenic diabetes insipidus: a case report and review of literature . Int J Gen Med \n6 : 535 –539 .23861592 \n\nEyer F Pfab R Felgenhauer N (2006 ) Lithium poisoning: pharmacokinetics and clearance during different therapeutic measures . J Clin Psychopharmacol \n26 : 325 –330 .16702900 \n\nHannedouche T Natov S Ikeni A (1990 ) Does lithium affect renal sodium handling and renal haemodynamics in normal man? \nNephrol Dial Transplant \n5 : 1007 –1012 .2128949 \n\nHansen HE Amdisen A (1978 ) Lithium intoxication. (Report of 23 cases and review of 100 cases from the literature) . Q J Med \n47 : 123 –144 .356084 \n\nJuurlink DN Mamdani MM Kopp A (2004 ) Drug-induced lithium toxicity in the elderly: a population-based study . J Am Geriatr Soc \n52 : 794 –798 .15086664 \n\nKehoe RF Mander AJ (1992 ) Lithium treatment: prescribing and monitoring habits in hospital and general practice . BMJ \n304 : 552 –554 .1559064 \n\nKidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group (2012 ) KDIGO Clinical Practice Guideline for Acute Kidney Injury 2011 . Kidney Int Suppl \n6 : p. 8 .\n\nKidney Disease: Improving Global Outcomes (KDIGO) (2013 ) Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease 2012 . Kidney Int Suppl \n3 : p. X .\n\nLepkifker E Sverdlik A Iancu I (2004 ) Renal insufficiency in long-term lithium treatment . J Clin Psychiatry \n65 : 850 –856 .15291664 \n\nLevey AS Stevens LA Schmid CH (2009 ) A new equation to estimate glomerular filtration rate . Ann Intern Med \n150 : 604 –612 .19414839 \n\nLopez JC Perez X Labad J (2012 ) Higher requirements of dialysis in severe lithium intoxication . Hemodial Int \n16 : 407 –413 .22962699 \n\nMontagnon F Said S Lepine JP (2002 ) Lithium: poisonings and suicide prevention . Eur Psychiatry \n17 : 92 –95 .11973117 \n\nOfferman SR Alsop JA Lee J (2010 ) Hospitalized lithium overdose cases reported to the California Poison Control System . Clin Toxicol (Phila) \n48 : 443 –448 .20515402 \n\nOruch R Elderbi MA Khattab HA (2014 ) Lithium: a review of pharmacology, clinical uses, and toxicity . Eur J Pharmacol \n740 : 464 –473 .24991789 \n\nPeng J (2014 ) Case report on lithium intoxication with normal lithium levels . Shanghai Arch Psychiatry \n26 : 103 –104 .25092957 \n\nPreacher KJ (2001 ) Calculation for the chi-square test: an interactive calculation tool for chi-square tests of goodness of fit and independence [Computer software] , http://quantpsy.org (accessed 12 October 2015 ).\n\nPrice LH Heninger GR (1994 ) Lithium in the treatment of mood disorders . N Engl J Med \n331 : 591 –598 .8047085 \n\nRoberts DM Gosselin S (2014 ) Variability in the management of lithium poisoning . Semin Dial \n27 : 390 –394 .24655138 \n\nRothman KJ (1990 ) No adjustments are needed for multiple comparisons . Epidemiology \n1 : 43 –46 .2081237 \n\nScharman EJ (1997 ) Methods used to decrease lithium absorption or enhance elimination . J Toxicol Clin Toxicol \n35 : 601 –608 .9365427 \n\nShorter E (2009 ) The history of lithium therapy . Bipolar Disord \n11 Suppl 2 : 4 –9 .19538681 \n\nThe National Institute for Health an Care Excellence (NICE) (2014 ) Bipolar Disorder: the assessment and management of bipolar disorder in adults, children and young people in primary care . NICE clinical guideline 185 , www.nice.org.uk/guidance/cg185 (accessed 12 October 2015 ).\n\nThompson JW Johnson AC (2011 ) Acute lithium intoxication: properly directing an index of suspicion . South Med J \n104 : 371 –372 .21606724 \n\nVermeire S Vanbrabant P Van Boxstael P (2010 ) Severity (and treatment) of chronic lithium poisoning: clinical signs or lab results as a criterion? \nActa Clin Belg \n65 : 127 –128 .20491363 \n\nWaring WS Laing WJ Good AM (2007 ) Pattern of lithium exposure predicts poisoning severity: evaluation of referrals to a regional poisons unit . QJM \n100 : 271 –276 .17412747 \n\nWebb AL Solomon DA Ryan CE (2001 ) Lithium levels and toxicity among hospitalized patients . Psychiatr Serv \n52 : 229 –231 .11157124 \n\nWerneke U Ott M (2014 ) Response to ‘The impact of modern treatment principles may have eliminated lithium-induced renal failure’ Aiff et al. 2014 . J Psychopharmacol \n28 : 1189 –1190 .25392462 \n\nWerneke U Ott M Renberg ES (2012 ) A decision analysis of long-term lithium treatment and the risk of renal failure . Acta Psychiatr Scand \n126 : 186 –197 .22404233 \n\nYoung AH Hammond JM (2007 ) Lithium in mood disorders: increasing evidence base, declining use? \nBr J Psychiatry \n191 : 474 –476 .18055949 \n\nZimmerman JL (2003 ) Poisonings and overdoses in the intensive care unit: general and specific management issues . Crit Care Med \n31 : 2794 –2801 .14668617\n\n",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D015994:Incidence; D007668:Kidney; D007677:Kidney Function Tests; D008094:Lithium; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D055815:Young Adult",
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"title": "Lithium intoxication: Incidence, clinical course and renal function - a population-based retrospective cohort study.",
"title_normalized": "lithium intoxication incidence clinical course and renal function a population based retrospective cohort study"
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"abstract": "A 81-year-old female was diagnosed with symptomatic multiple myeloma (MM; IgG κ type, D&S: IIB, ISS: 2) in August 2017. Although treatment with lenalidomide and dexamethasone was started, she developed deep venous thrombosis in the lower extremities as a complication; therefore, the treatment was changed to DBd. In February 2018, she required hospitalization due to general weakness and altered consciousness. Her IgG level and κ/λ ratio were elevated at 4,156 mg/dl and 605.56, respectively, revealing that MM was treatment-resistant. A protein-cell dissociation (cell blood count, 0/µl; protein, 100.6 mg/dl) was detected in the cerebrospinal fluid, whereas the ammonia level in serum was high (172 µg/dl). T2-weighted magnetic resonance imaging showed a broad range of high-density area in deep cerebral white matter suggesting leukoencephalopathy, whereas the cerebrospinal fluid was negative for JC virus. No pathological conditions causing secondary hyperammonemia were found. Although the involvement of drug-induced leukoencephalopathy in altered consciousness could not be ruled out since the chromosome with the normal karyotype at the first visit had a complex chromosomal abnormality, an originally minor clone of MM cells with a chromosomal abnormality might have contributed to the ammonia production resulting in altered consciousness.",
"affiliations": "Department of Internal Medicine, Kohsei Chuo General Hospital.;Department of Internal Medicine, Kohsei Chuo General Hospital.;Department of Internal Medicine, Kohsei Chuo General Hospital.;Department of Internal Medicine, Kohsei Chuo General Hospital.;Department of Internal Medicine, Kohsei Chuo General Hospital.;Department of Internal Medicine, Kohsei Chuo General Hospital.;Department of Internal Medicine, Kohsei Chuo General Hospital.;Department of Internal Medicine, Kohsei Chuo General Hospital.;Department of Internal Medicine, Kohsei Chuo General Hospital.;Department of Internal Medicine, Kohsei Chuo General Hospital.",
"authors": "Konuma|Hikari|H|;Aota|Yasuo|Y|;Udagawa|Shohei|S|;Honda|Tadahiro|T|;Okuda|Yuko|Y|;Iwai|Tetsu|T|;Sujino|Hiroki|H|;Takahashi|Maya|M|;Kitagawa|Naoyuki|N|;Gotoh|Akihiko|A|",
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"keywords": "Chromosomal abnormalities; Hyperammonemia; Leukoencephalopathy; Multiple myeloma",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000369:Aged, 80 and over; D003243:Consciousness; D005260:Female; D006801:Humans; D022124:Hyperammonemia; D007577:JC Virus; D056784:Leukoencephalopathies; D009101:Multiple Myeloma",
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"title": "Refractory multiple myeloma with impaired consciousness accompanied by hyperammonemia and leukoencephalopathy-like findings.",
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"abstract": "The dose-dense epirubicin and cyclophosphamide (EC) therapy for breast cancer decreases the risk of cancer recurrence and death. However, epirubicin and cyclophosphamide also cause cardiotoxicity, and cardiomyopathy is the most well-known related adverse effect. A 58-year-old woman presented to our hospital with palpitations 2 weeks after her final dose-dense EC therapy for breast cancer. Holter electrocardiogram (ECG) showed transitory complete atrioventricular block (CAVB) and torsade de pointes. A 12-lead ECG showed QT prolongation in addition to CAVB. Patients receiving dose-dense EC therapy should be monitored more carefully with ECG due to their risk of fatal arrhythmias.",
"affiliations": "Division of Cardiology, National Hospital Organization Hamada Medical Center, 777-12 Asaichō, Hamada, Shimane 697-8511 Japan.;Department of Digestive and General Surgery, Shimane University Faculty of Medicine, Hamada, Shimane Japan.;Division of Cardiology, Shimane University Faculty of Medicine, Hamada, Shimane Japan.;Division of Cardiology, Shimane University Faculty of Medicine, Hamada, Shimane Japan.;Division of Cardiology, Shimane University Faculty of Medicine, Hamada, Shimane Japan.;Clinical Laboratory Department, Shimane University Faculty of Medicine, Hamada, Shimane Japan.;Division of Cardiology, Shimane University Faculty of Medicine, Hamada, Shimane Japan.",
"authors": "Okada|Taiji|T|0000-0002-8878-3446;Hyakudomi|Miki|M|;Yamaguchi|Kazuto|K|;Watanabe|Nobuhide|N|;Endo|Akihiro|A|;Yoshitomi|Hiroyuki|H|;Tanabe|Kazuaki|K|",
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"keywords": "Breast cancer; Complete atrioventricular block; Dose-dense epirubicin and cyclophosphamide therapy; QT prolongation; Torsade de pointes",
"medline_ta": "Int Cancer Conf J",
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"title": "Complete atrioventricular block and torsade de pointes due to dose-dense epirubicin and cyclophosphamide therapy.",
"title_normalized": "complete atrioventricular block and torsade de pointes due to dose dense epirubicin and cyclophosphamide therapy"
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"abstract": "Background: Intracavernosal injection of phenylephrine is a commonly used therapy for ischemic priapism and is typically well tolerated with few severe adverse side effects. We report a case of intracranial hemorrhage related to hypertensive emergency due to intracavernosal phenylephrine. Case Report: A 43-year-old Caucasian man with history of hypertension, diabetes mellitus type I, end-stage renal disease status post a combination kidney-pancreas transplant, and recurrent idiopathic priapism presented to emergency department with an episode of priapism. His home medications were lisinopril, metoprolol tartrate, mycophenolate mofetil, prednisone, sulfamethoxazole-trimethoprim, and tacrolimus. After local injection of 2 rounds (1 hour apart) of 100 µg phenylephrine into each corpus cavernosa, priapism resolved. Within 5 minutes, the patient had headaches, dyspnea, and excruciating chest pain. His blood pressure (BP) was noted to be 240/130 mm Hg but normalized spontaneously within few minutes. During this period, he developed new-onset right arm and leg weakness and found to have intracranial hemorrhage in the midbrain. Conclusion: A careful review for pharmacologic interactions should be performed prior to intracavernosal phenylephrine administration, and close monitoring should occur after its administration.",
"affiliations": "University of Arkansas for Medical Sciences, Little Rock, USA.;University of Arkansas for Medical Sciences, Little Rock, USA.;University of Arkansas for Medical Sciences, Little Rock, USA.;Rush University, Chicago, IL, USA.",
"authors": "Palagiri|Raga Deepak Reddy|RDR|;Chatterjee|Kshitij|K|;Jillella|Anusha|A|;Hammond|Drayton A|DA|",
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"issue": "54(3)",
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"keywords": "hypertension /chemically induced; phenylephrine /adverse effects; priapism",
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"title": "A Case Report of Hypertensive Emergency and Intracranial Hemorrhage Due to Intracavernosal Phenylephrine.",
"title_normalized": "a case report of hypertensive emergency and intracranial hemorrhage due to intracavernosal phenylephrine"
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"abstract": "Several amphetamine-like appetite suppressants are known to have cardiovascular adverse effects, in particular pulmonary arterial hypertension and cardiac valve disease. Is this also the case with methylphenidate, an amphetamine-like psychostimulant used in attention-deficit hyperactivity disorder (especially in children) and also in narcolepsy? Cases of pulmonary hypertension and heart valve disease have been reported with methylphenidate, including in children. The risk appears to be low, but epidemiological studies are needed to estimate the incidence. This risk should be minimised by only using methylphenidate to treat serious disorders, at the lowest effective dose. Attention should be paid to warning signs such as dyspnoea.",
"affiliations": null,
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"chemical_list": "D000697:Central Nervous System Stimulants; D008774:Methylphenidate",
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"issue": "24(161)",
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"mesh_terms": "D000367:Age Factors; D001289:Attention Deficit Disorder with Hyperactivity; D000697:Central Nervous System Stimulants; D006349:Heart Valve Diseases; D006801:Humans; D006976:Hypertension, Pulmonary; D008774:Methylphenidate; D018570:Risk Assessment; D012307:Risk Factors",
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"publication_types": "D016428:Journal Article",
"references": null,
"title": "Methylphenidate: pulmonary hypertension and heart valve disease.",
"title_normalized": "methylphenidate pulmonary hypertension and heart valve disease"
} | [
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"companynumb": "FR-ENDO PHARMACEUTICALS INC-2015-004466",
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"abstract": "The renin-angiotensin system plays a very critical role in hypertension, diabetes, and kidney and heart diseases. The blockade of the renin-angiotensin system results in the prevention of progression of renal and cardiac damage. There have been controversial hypotheses raised regarding the safety of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in COVID-19 (coronavirus disease 2019). We present the case series of four patients (2 men and 2 women; 1 Caucasian and 3 African Americans; two survived and two died) with confirmed COVID-19, presenting with respiratory symptoms and acute kidney injury, who have been on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Membrane-bound angiotensin-converting enzyme 2 (ACE2) has been implicated as the gateway for viral entry into the human cell in causing the infection. The factors contributing to acute kidney injury are diuretics, iodinated contrast administration, hemodynamic instability apart from ACE inhibitors, and angiotensin receptor blockers. The ACE inhibitors and ARBs were stopped in these patients due to acute kidney injury. We also discussed the role of ACE2 and the renin-angiotensin system (RAS) blockade in patients with COVID-19 infection along with pathogenesis.",
"affiliations": "Department of Internal Medicine, Division of Nephrology, Phobe Putney Memorial Hospital, Medical College of Georgia, 417 W 3 Avenue, Albany 31701, GA, USA.;Department of Internal Medicine, Division of Medical Oncology, Ashland Bellefonte Cancer Center, 122 St Christopher Dr, Ashland 41169, KY, USA.;Lynchburg Nephrology Physicians, Lynchburg, VA, USA.;Lynchburg Nephrology Physicians, Lynchburg, VA, USA.;Fellow in Hematology and Oncology, Sunny Upstate Medical University, Syracuse, NY, USA.;Department of Medicine, Interfaith Medical Center, Brooklyn, NY, USA.;Department of Internal Medicine, Division of Rheumatology, Adventist Medical Center, Hanford 93230, CA, USA.;Department of Internal Medicine, Division of Nephrology, Adventist Medical Center, Hanford 93230, CA, USA.",
"authors": "Chenna|Avantika|A|;Konala|Venu Madhav|VM|;Bose|Subhasish|S|;Roy|Sasmit|S|https://orcid.org/0000-0002-2509-3915;Madhira|Bhaskar Reddy|BR|;Gayam|Vijay|V|;Naramala|Srikanth|S|https://orcid.org/0000-0003-1238-856X;Adapa|Sreedhar|S|https://orcid.org/0000-0001-5608-5654",
"chemical_list": null,
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"doi": "10.1155/2020/8811931",
"fulltext": "\n==== Front\nCase Rep Nephrol\nCase Rep Nephrol\nCRIN\nCase Reports in Nephrology\n2090-6641 2090-665X Hindawi \n\n10.1155/2020/8811931\nCase Series\nAcute Kidney Injury in a Case Series of Patients with Confirmed COVID-19 (Coronavirus Disease 2019): Role of Angiotensin-Converting Enzyme 2 and Renin-Angiotensin System Blockade\nChenna Avantika \n1\n Konala Venu Madhav \n2\n Bose Subhasish \n3\n https://orcid.org/0000-0002-2509-3915Roy Sasmit \n3\n Madhira Bhaskar Reddy \n4\n Gayam Vijay \n5\n https://orcid.org/0000-0003-1238-856XNaramala Srikanth \n6\n https://orcid.org/0000-0001-5608-5654Adapa Sreedhar sreedharadapa@gmail.com\n7\n \n1Department of Internal Medicine, Division of Nephrology, Phobe Putney Memorial Hospital, Medical College of Georgia, 417 W 3rd Avenue, Albany 31701, GA, USA\n\n2Department of Internal Medicine, Division of Medical Oncology, Ashland Bellefonte Cancer Center, 122 St Christopher Dr, Ashland 41169, KY, USA\n\n3Lynchburg Nephrology Physicians, Lynchburg, VA, USA\n\n4Fellow in Hematology and Oncology, Sunny Upstate Medical University, Syracuse, NY, USA\n\n5Department of Medicine, Interfaith Medical Center, Brooklyn, NY, USA\n\n6Department of Internal Medicine, Division of Rheumatology, Adventist Medical Center, Hanford 93230, CA, USA\n\n7Department of Internal Medicine, Division of Nephrology, Adventist Medical Center, Hanford 93230, CA, USA\nAcademic Editor: Rumeyza Kazancioglu\n\n\n2020 \n29 6 2020 \n2020 88119313 4 2020 4 6 2020 11 6 2020 Copyright © 2020 Avantika Chenna et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The renin-angiotensin system plays a very critical role in hypertension, diabetes, and kidney and heart diseases. The blockade of the renin-angiotensin system results in the prevention of progression of renal and cardiac damage. There have been controversial hypotheses raised regarding the safety of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in COVID-19 (coronavirus disease 2019). We present the case series of four patients (2 men and 2 women; 1 Caucasian and 3 African Americans; two survived and two died) with confirmed COVID-19, presenting with respiratory symptoms and acute kidney injury, who have been on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Membrane-bound angiotensin-converting enzyme 2 (ACE2) has been implicated as the gateway for viral entry into the human cell in causing the infection. The factors contributing to acute kidney injury are diuretics, iodinated contrast administration, hemodynamic instability apart from ACE inhibitors, and angiotensin receptor blockers. The ACE inhibitors and ARBs were stopped in these patients due to acute kidney injury. We also discussed the role of ACE2 and the renin-angiotensin system (RAS) blockade in patients with COVID-19 infection along with pathogenesis.\n==== Body\n1. Introduction\nThe severe acute respiratory syndrome by coronavirus 2 (SARS-CoV-2) has resulted in mortality worldwide and has been declared a global pandemic. The United States has the highest number of positively tested cases in the world, and the virus has been spreading relentlessly. The lung is the main organ affected by COVID-19 resulting in respiratory failure, but there is also the involvement of other organs like the heart, kidney, and gastrointestinal tract. The patients who tend to have severe disease or need intensive care unit (ICU) admission have multiorgan involvement. Membrane-bound angiotensin-converting enzyme 2 (ACE 2) has been implicated as the gateway for viral entry into the human cell in causing the infection [1, 2].\n\nThe renin-angiotensin system (RAS) plays a very critical role in hypertension, diabetes, and kidney and heart diseases. The blockade of RAS results in the prevention of progression of renal and cardiac damage. The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) needs to be elucidated in COVID-19. There have been controversial hypotheses raised regarding the safety of ACEIs/ARBs in COVID-19 [1]. Here, we describe the case series of four patients with confirmed COVID-19 who developed AKI. We also discuss the role of ACE2 in pathogenesis and in AKI and the perspectives of ACEIs/ARBs in COVID-19.\n\n1.1. First Case\nA 49-year-old male presented to the emergency room with complaints of cough and shortness of breath started getting worse for one week. Associated symptoms included fever, chills, and generalized body aches. The patient was found to be hypoxic in the emergency room, requiring oxygen via a nasal cannula. Past medical history was significant for type 2 diabetes mellitus, hypertension, dyslipidemia, depression, and gastroesophageal reflux disease. The patient had a 28-pack-year smoking history and quit smoking four years ago. The patient denied any chest pain, orthopnea, paroxysmal nocturnal dyspnea, or swelling of his extremities. The patient denied any recent travel history. His home medications included metformin 1000 mg by mouth twice a day, hydrochlorothiazide 25 mg by mouth daily, amlodipine 10 mg by mouth daily, duloxetine 60 mg by mouth daily, atorvastatin 40 mg by mouth daily, lisinopril 40 mg by mouth daily, and aspirin 81 mg by mouth daily. The patient had no significant family history.\n\nInitial vital signs showed a blood pressure of 132/89 mmHg, heart rate of 88 beats per minute (bpm), oxygen saturation of 80% on room air, which improved to 89% on a 5 L nasal cannula, respiratory rate of 30 breaths/min, and temperature of 99.1°F. Physical examination revealed an unkempt obese male with mild tachypnea and coarse breath sounds bilaterally. The rest of the physical examination was within normal limits.\n\nLaboratory data revealed normal hemoglobin at 13.9 g/dL and platelet count of 220K/mm3. Liver function tests were within normal limits. Lactic acid was slightly elevated at 1.7 mmol/L. The rest of the laboratory data are summarized in Table 1. His influenza A and B testing was negative. Chest X-ray PA and lateral view revealed bibasilar infiltrate consistent with bilateral pneumonia. The patient had a CT of the chest with IV contrast showing bilateral ground-glass opacities. The patient's nasopharyngeal swab was sent for COVID-19 testing, and he was placed in isolation.\n\nThe patient's clinical course was complicated by transferring to the intensive care unit due to worsening hypoxic respiratory failure requiring high flow oxygen. He was subsequently intubated. The patient was started on treatment for possible community-acquired pneumonia with ceftriaxone 1 g intravenously daily and azithromycin 500 mg once followed by 250 mg by mouth daily. The patient was also started on lopinavir and ritonavir as per protocol at that time.\n\nHis clinical course was also complicated by worsening renal function with the increased blood urea nitrogen to 21 mg/dL and serum creatinine to 2.2 mg/dL. The patient's lisinopril and hydrochlorothiazide were held, and he was started on 0.9% normal saline intravenously. His urine analysis was significant for 2+ protein and no RBC casts. The patient complement levels were within normal limits. Testing for hepatitis B, hepatitis C, and HIV screen was all negative. Serum protein electrophoresis did not reveal any monoclonal protein. His COVID-19 testing returned positive. The patient's urine output subsequently continued to drop, and hence he was started on dialysis due to volume overload and hyperkalemia in the setting of acute respiratory distress syndrome type. The patient is currently receiving dialysis three times a week, and his antibiotic coverage was expanded to pulse-dose vancomycin and cefepime. The patient remains intubated and ventilated in the intensive care unit.\n\n1.2. Second Case\nA 48-year-old female was admitted with worsening shortness of breath for two days after attending a funeral where some people have tested positive for COVID-19. The patient complained of dry cough but denied any chest pain, orthopnea, or paroxysmal nocturnal dyspnea. The patient denied any nausea, vomiting, or diarrhea. Her past medical history was significant for hypertension, dyslipidemia, and hypothyroidism. Her surgical history was positive for thyroidectomy in 2001. The patient denied any history of smoking or illicit drug use. Her home medications included rosuvastatin 20 mg by mouth daily, hydrochlorothiazide/losartan 25–100 mg by mouth daily, amlodipine 10 mg by mouth daily, levothyroxine 150 mcg by mouth daily, and aspirin 81 mg by mouth daily.\n\nInitial vital signs were a blood pressure of 132/56 mmHg, heart rate of 109 bpm, respiratory rate of 22 breaths/min, oxygen saturation of 80% on room air, which improved to 90% on 5 L of oxygen via a nasal cannula, and temperature of 101°F. Her physical examination was significant for morbidly obese female in mild acute distress with decreased breath sounds and positive rales bilaterally. The rest of the physical examination was unremarkable.\n\nLaboratory testing: CBC was significant for hemoglobin of 12 g/dL and platelet count of 160K/mm3. Liver function testing was within normal limits. The rest of the laboratory data are summarized in Table 1. Initial arterial blood gas showed a pH of 7.3, PO2 of 58 mmHg, PCO2 of 63 mmHg, and oxygen saturation of 83% on a high flow nasal cannula at 40 liters. Influenza A and B testing was negative. Chest X-ray PA and lateral showed cardiomegaly and pulmonary edema. The patient's nasopharyngeal swab was sent for COVID-19 testing, and she was placed in appropriate isolation.\n\nThe patient was initially admitted to the medical floor, and subsequently, her oxygen requirements escalated to high flow oxygen and venti mask and she was subsequently transferred to the intensive care unit for worsening hypercapnic hypoxic respiratory failure requiring intubation and ventilation. The patient was started on intravenous Lasix 80 mg every 8 hours and was also started on hydroxychloroquine 200 mg twice a day and azithromycin 500 mg once followed by 250 mg daily for five days as per protocol. The patient's creatinine continued to increase to 3.65 mg/dL, and blood urea nitrogen increased to 92 mg/dL over three days. Lisinopril and hydrochlorothiazide were held since admission, and later Lasix was also held. Her urine analysis was negative for any protein or RBC casts. The patient is currently being monitored without any requirement for dialysis at present.\n\n1.3. Third Case\nA 64-year-old female was admitted with complaints of cough and shortness of breath getting worse over one week. She also had fever, nausea, vomiting, and diarrhea. The patient also complained of decreased appetite. Her cough was productive with greenish sputum. The patient denied any chest pain, orthopnea, paroxysmal nocturnal dyspnea, or pedal edema. The patient denied any history of recent travel. The patient's past medical history was significant for type 2 diabetes mellitus, hypertension, dyslipidemia, and seasonal allergies. The patient denied any history of smoking or illicit drug use. The patient's home medications included metformin 750 mg by mouth twice a day, spironolactone 25 mg by mouth daily, amlodipine 10 mg by mouth daily, and azilsartan 80 mg by mouth daily.\n\nInitial vital signs showed a blood pressure of 132/89 mmHg, heart rate of 88 bpm, respiratory rate of 30 breaths/min, temperature of 100.1°F, and oxygen saturation of 82% on room air, which improved to 89% on 5 L of oxygen via a nasal cannula. Her physical examination revealed an obese female with mild respiratory distress. Her respiratory examination revealed coarse breath sounds bilaterally. The rest of her physical examination was unremarkable.\n\nLaboratory testing: the patient's initial CBC revealed anemia with hemoglobin 9.5 g/dL and platelet count 121K/mm3. Liver function tests were within normal limits. The rest of the laboratory data are summarized in Table 1. Patient's influenza A and B testing was negative. Chest X-ray PA and lateral view suggested multifocal pneumonia. The patient had a CT angiogram of the chest with PE protocol showing bilateral ground-glass opacities concerning COVID-19. The patient's nasopharyngeal swab was sent for COVID-19 testing, and she was placed in appropriate isolation.\n\nThe patient was admitted to the medical floor initially but later transferred to the intensive care unit due to hypoxic respiratory failure requiring high flow oxygen. The patient was also started on lopinavir and ritonavir per protocol at that time. The patient's clinical course continued to get worse with continued worsening of renal function with an increase in creatinine from 1.1 mg/dL to 1.7 mg/dL and then to 6.9 mg/dL for the next 3-4 days. The patient was treated with IV fluids and intravenous bicarbonate. Her medications, azilsartan and spironolactone, were discontinued because of hypotension and worsening renal function. Urine analysis was negative for protein or RBC casts. Testing for hepatitis B and C and HIV screening were negative. Testing for antinuclear antibody, anti-neutrophilic cytoplasmic antibody, and anti-glomerular basement membrane antibodies was either negative or within normal limits. Complement levels, including C3 and C4, were 65 mg/dL and 8 mg/dL, respectively, which were low. Serum protein electrophoresis revealed no M spike.\n\nThe patient's COVID-19 testing came back as positive. Her urine output dropped to 5–10 milliliters/hour. The patient developed acute respiratory distress syndrome with fluid overload and was started on Lasix 80 mg IV every 8 hours and was also placed in a prone position. The patient failed medical management and was started on dialysis due to oliguric renal failure. Despite the above efforts, the patient's clinical condition continued to deteriorate with hypoxia and hypotension, which persisted despite being maximized on four vasopressors. The family decided to opt for comfort measures only, and the patient, unfortunately, died 11 days after the presentation.\n\n1.4. Fourth Case\nA 77-year-old African American male presented with a chief complaint of dry cough, shortness of breath, and fever for one week. The patient was encephalopathic on presentation and went into cardiac arrest, received 1 round of cardiopulmonary resuscitation, and was able to achieve the return of spontaneous circulation. He was then placed on the hypothermic protocol. The patient was also hypotensive, requiring norepinephrine. The patient's past medical history was significant for type 2 diabetes mellitus, hypertension, dyslipidemia, and hypothyroidism. The patient has no travel history, but the wife reported a concern that he might have encountered a person who was sick. The patient has no history of smoking or illicit drug use. His home medications were pioglitazone 30 mg by mouth daily, olmesartan 40 mg by mouth daily, levothyroxine 100 mcg by mouth daily, glimepiride 4 mg by mouth daily, fenofibrate 160 mg by mouth daily, aspirin 81 mg by mouth daily, and sitagliptin 100 mg by mouth daily. His vital signs were a blood pressure of 102/66 mmHg, heart rate of 92 bpm, respiratory rate of 26 breaths per minute, oxygen saturation of 89% on 100% FiO2, and temperature of 95.8°F. Physical examination revealed an obese patient who was intubated and sedated. Respiratory examination revealed coarse breath sounds bilaterally.\n\nHis laboratory examination was significant for hemoglobin 14.1 g/dL and platelet count 306K/mm3. The rest of the laboratory data are summarized in Table 1. Liver function tests were significant for AST elevated at 125 U/L. Lactic acid was elevated at 14 mmol/L. The patient's influenza A and B testing was negative. The patient's nasopharyngeal swab was sent for COVID-19 testing, and he was placed in isolation, with the result being positive couple of days later. A portable chest X-ray revealed bilateral pulmonary infiltrates concerning COVID-19.\n\nAll antihypertensives and hypoglycemics were held, including olmesartan. The patient was treated with aggressive IV fluid resuscitation along with IV bicarbonate. The patient was administered insulin therapy for hyperglycemia.\n\nThe patient's vasopressor requirement continued to increase due to hypotension. His renal failure continued to get worse. Dialysis was considered but was not done due to hemodynamic instability, and the patient was able to urinate. Due to persistent hypotension despite the use of vasopressors and continued hypoxia despite intubation and ventilation, after discussion with the family, the family chose to opt for do not resuscitate (DNR) and comfort care only. The patient died immediately after extubation.\n\n2. Discussion\nWe presented the case series of four patients who were on angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin receptor blockers (ARBs) with COVID-19 infection and acute renal failure. We summarize the findings, including patient characteristics, comorbidities, presenting symptoms, types of ACE inhibitors, or ARB use, including diuretic use at home as well as in the hospital, whether the patient had a computed tomography with IV contrast, dialysis initiation in hospital, and outcome of the patients in Table 2. In our case series, there were two men and two women: 1 Caucasian and 3 African Americans. All of them developed acute kidney injury and mortality was 50%. We summarized creatinine trends during hospital stay in Table 3.\n\nSARS-CoV-2 utilizes ACE2 and type 2 transmembrane serine proteases (TMPRSS 2) to enter the human cell [2]. The spike (S) protein of the virus binds to the catalytic domain of the ACE2 with high affinity [3], which can cause conformational changes in the S protein [4]. These cellular proteases (TMPRSS 2) are needed for the S protein priming, cleavage, and allow the fusion of viral and cellular membranes [2]. A prior study by Kuba and colleagues showed the first genetic proof that SARS-CoV needs ACE2 as a receptor in vivo [5]. Wrapp et al. have shown that on the cryoelectron microscopy, the S protein of the nCoV has 10- to 20-fold higher affinities to ACE2 compared to SARS-CoV [4].\n\nAngiotensin-converting enzyme 2 (ACE2) is a zinc metalloprotease discovered in 2000 and has substantial homology with human angiotensin-converting enzymes (ACEs) [6]. The mRNA (messenger ribonucleic acid) of ACE2 is widely distributed in all human tissues, and the protein is widely expressed in the oral and nasal mucosa, nasopharynx, lung, gastrointestinal tract, kidney, and lymphoid tissue [7]. There is a high expression of ACE2 receptors on the epithelial cells of oral mucosa that plays a vital role in the transmission of COVID-19 [8]. Type II alveolar cells and the capillary endothelium express ACE2 receptors [7].\n\nACE2 is expressed in the proximal tubular cells significantly compared to other components in the kidney [9]. In kidney tubules, there is significant ACE2 expression on brush border and less expression in the cytoplasm [9]. The gene expression for ACE2 is 100-fold higher in kidney tissue compared to the lung [10]. There are significant proteinuria and hematuria in the patients infected with COVID-19 [10]. Of the patients who developed severe disease, a significant proportion of patients developed acute kidney injury and was associated with mortality [11].\n\nHypertension, diabetes, and cardiovascular disease are the common comorbidities associated with COVID-19 [11]. ACEI and ARB are the commonly used medications for the treatment of hypertension and kidney and heart diseases. Angiotensinogen is converted to angiotensin I by renin, which in turn is converted to angiotensin II (Ang II) by ACE. Angiotensin II activates angiotensin receptor type 1 (AT1R) and aldosterone and exerts vasoconstriction and sodium retention, resulting in hypertension. ACE2 converts angiotensin II to angiotensin (Ang)-(1–7), which exerts vasodilatory effects through the MAS receptor and thus negatively regulates the RAS system [12].\n\nAngiotensin II causes inflammation, fibrosis, and edema through AT1R, and the absence of ACE2 causes the unrestricted activity of Ang II, which results in acute severe respiratory distress syndrome (ARDS). ACE2/Ang-(1–7)/Mas axis has an inhibitory effect on the signaling pathways of inflammation, fibrinogenesis, and cellular proliferation [12]. The net effect of ACE2 is anti-inflammatory, antifibrogenic, and antiproliferative [12]. A mice study showed that higher Ang II levels cause ACE2 to be internalized in the cell and undergo lysosomal degradation [13]. The internalization was prevented by losartan [13]. There is also speculation that the ACE2 and AT1R physically interact and form complexes on the cell membrane in the absence of Ang II, thus reducing the potential virus interaction with ACE2 [14].\n\nIncreased cardiac ACE2 gene expression and cardiac ACE2 activity were seen in Lewis rats after selective use of lisinopril or losartan, whereas the combination resulted in elevated cardiac ACE2 but not cardiac ACE2 mRNA [15]. In adult Sprague-Dawley rats, enalapril abated/mitigated the downregulation of ACE2 in the late phase of ventricular dysfunction of experimental myocardial infarction [16]. There was no increased cardiac ACE2 expression with ramipril or valsartan or in combination in the rat myocardial infarction model [17].\n\nIn a study of 79 patients that evaluated plasma ACE2 activity and long-term cardiovascular outcomes in patients with obstructive coronary artery disease (CAD), the ACE2 levels did not vary with age and the use of ACE1/ARBs did not alter the levels [18]. This study revealed that there were 83% of male patients in the high ACE2 level group [18]. In a study of 617 hypertensive patients that evaluated the urinary ACE2 level, only patients treated with olmesartan had increased levels [19]. The urinary ACE2 measured is soluble and is not membrane-bound [19].\n\nKuba et al., in a mouse model, showed that the RAS blockade attenuated the lung injury in SARS-CoV [5]. In a retrospective study of 1055 adult patients admitted with pneumonia, continued use of ACEI and statins resulted in lower rates of deaths and intubations [20]. Severe acute lung injury induced by influenza (H7N9) virus was observed in an experimental ACE2 knockout (KO) mouse model [21]. This study shows that ACE2 plays a critical role in pathogenesis; the blockade of AT1R resulted in the mitigation of acute lung injury [21].\n\nFang et al. hypothesized that the use of ACE2 modulation medications in hypertensive and diabetic patients increased the risk of developing severe COVID-19 infection [1]. This hypothesis has created widespread confusion in healthcare providers and was perpetuated by media channels and social media [22]. Many international societies have released statements on the continued use of the ACEIs/ARBs [14].\n\nThe understanding of COVID-19 and its pathogenesis sheds light on the potential targets for the treatment: development of spike subunit 1 protein-based vaccine, inhibiting viral spike protein priming proteases, through the serine protease inhibitor camostat mesylate, blocking ACE2 receptors to inhibit the viral interaction with ACE2 [23]; soluble ACE2 utilization to overwhelm the body membrane-bound ACE2 that can prevent the virus entry into the cell [24]; and baricitinib, which inhibits the endocytosis via G-associated kinase and AP2-associated protein kinase (AAK1), which is critical for virus entry [25].\n\nThere are currently few clinical trials underway to analyze ACE2 and RAAS blockade, a potential target for COVID-19: recombinant human angiotensin-converting enzyme 2 (rhACE2) as a treatment for patients with COVID-19 (NCT04287686) [26], losartan for patients with COVID-19 not requiring hospitalization (NCT04311177) [27], and losartan for patients with COVID-19 requiring hospitalization (NCT04312009) [27].\n\n2.1. COVID-19 Infection and AKI\nThe incidence of AKI in patients infected with COVID-19 is around 3–15% as per recently published studies from China [11, 28]. The rates of AKI increased significantly to 14.5–50% in patients with severe COVID-19 infection requiring ICU admission [11, 29]. AKI in COVID-19 infection could be due to combination of cytokine-induced systemic inflammatory response and virus-induced direct cytotropic effect and acute tubular necrosis (ATN) due to multiorgan failure and shock. Other factors like volume depletion, drug toxicity, contrast exposure, and hypotension can result in AKI.\n\n2.2. Acute Kidney Injury and Mortality with COVID-19 Infection\nAKI is associated with increased mortality in patients infected with COVID-19. The incidence of AKI was 23% in 101 patients reported by Shi et al., who died from COVID-19 infection [30]. Elevated BUN, elevated baseline serum creatinine, peak serum creatinine >1.5, AKI stages 2 and 3, proteinuria, and hematuria are all associated with mortality as per Cheng et al., after adjusting for confounding factors [28]. Since AKI was associated with increased in-hospital mortality, the patients should be managed by providing hemodynamic support, avoiding nonsteroidal anti-inflammatory drugs (NSAIDs), nephrotoxins, and contrast along with early institution of continuous renal replacement therapy (CRRT).\n\n3. Conclusion\nIn the above case series, all the patients developed acute kidney injury, but other factors were contributing to acute kidney injury like diuretics, iodinated contrast administration, hemodynamic instability apart from ACE inhibitors, and angiotensin receptor blockers. The ACE inhibitors and ARBs were stopped in these patients due to acute kidney injury.\n\nThere is no established evidence that suggests that the use of ACEIs/ARBs is associated with the COVID-19 or can potentiate the severe infection. Preclinical and clinical studies have shown beneficial evidence in viral pneumonia. The patients must follow the healthcare provider's advice before changing the medications. The medical professionals should follow the guidance of the national and international societies.\n\nData Availability\nThe data used to support the findings of this study are available from the corresponding author on request.\n\nConsent\nConsent was obtained from all the cases and from power of attorney where needed.\n\nConflicts of Interest\nThe authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nTable 1 Laboratory data for all the patients on admission.\n\nPatient\tSodium (mmol/l)\tPotassium (mmol/l)\tBicarbonate (mmol/dl)\tBlood urea nitrogen (mg/dl)\tSerum creatinine (mg/dl)\tCPK (units/L)\tWhite cell count (K/mm3)\tLymphocyte count (K/mm3)\tUrine analysis\tUrine protein creatinine ratio (mg/g)\t\n1\t130\t4.4\t22\t14\t0.96\t233\t5.3\t0.8\t2+ protein and no RBC casts\tNot available\t\n2\t130\t4.0\t34\t22\t0.87\t458\t6.9\t0.6\tNo protein and no RBC casts\tNot available\t\n3\t143\t3.5\t17\t26\t1.1\t287\t8.8\t0.7\tNo protein and no RBC casts\t524\t\n4\t154\t3.2\t23\t25\t1.8\t278\t10.6\t0.3\t3+ protein and no RBC casts (RBC—30/HPF)\t270\t\nTable 2 Clinical characteristics and outcome of the patients.\n\nPatient\tAge\tSex\tSymptoms\tSmoking\tComorbidities\tACEI or ARB\tDiuretic use at home\tDiuretic use in the hospital\tDialysis\tComputed tomography with IV contrast\tOutcome\t\n1\t49\tCaucasian male\tFever, cough, SOB, chills, and body aches\tEx-smoker, 28-pack-year smoking history\tHypertension, diabetes, and dyslipidemia\tLisinopril 40 mg\tHCTZ 25 mg\tNo\tYes\tYes\tDied (DNR, comfort measures)\t\n2\t48\tAfrican American female\tDry cough and fever\tNonsmoker\tHypertension and dyslipidemia\tLosartan 100 mg\tHCTZ 25 mg\tYes\tNo\tNo\tDNR, still remains critically ill and intubated\t\n3\t64\tAfrican American female\tCough, SOB, and fever\tNonsmoker\tHypertension, diabetes, and dyslipidemia\tAzilsartan 80 mg\tSpironolactone 25 mg\tYes\tYes\tYes\tDied (patient made DNR)\t\n4\t77\tAfrican American male\tCough, SOB, and fever\tNonsmoker\tHypertension, dyslipidemia, and diabetes\tOlmesartan 40 mg\tNo\tNo\tNo\tNo\tDied (patient made DNR)\t\nTable 3 Summary of serum creatinine trend during hospital stay.\n\nPatient\tSerum creatinine on presentation (mg/dl)\tSerum creatinine values during hospital stay (mg/dl)\tSerum creatinine level at outcome (mg/dl)\t\n1\t0.96\t0.96 ⟶ 2.2 ⟶ 3.8 ⟶ 4.9\t5.4\t\n2\t0.87\t0.87 ⟶ 1.2 ⟶ 1.9 ⟶ 2.7\t3.65\t\n3\t1.1\t1.7 ⟶ 2.5 ⟶ 3.3 ⟶ 5.3\t6.9\t\n4\t1.8\t1.8 ⟶ 2.4 ⟶ 3.9 ⟶ 5.6\t7.4\n==== Refs\n1 Fang L. 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"pages": "8811931",
"pmc": null,
"pmid": "32685221",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "32167153;32311650;25391767;32247631;15141377;23488800;22715807;29897923;15897343;16908757;15538735;32075877;30948970;32171076;32222168;14647384;25225202;32032529;24842388;32125455;16007097;10924499;32171062;32142651;32094336",
"title": "Acute Kidney Injury in a Case Series of Patients with Confirmed COVID-19 (Coronavirus Disease 2019): Role of Angiotensin-Converting Enzyme 2 and Renin-Angiotensin System Blockade.",
"title_normalized": "acute kidney injury in a case series of patients with confirmed covid 19 coronavirus disease 2019 role of angiotensin converting enzyme 2 and renin angiotensin system blockade"
} | [
{
"companynumb": "US-PFIZER INC-2021442481",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LOPINAVIR"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nRespiratory syncytial virus (RSV) infection causes significant morbidity and mortality in allogeneic stem cell transplant (allo-SCT) recipients. Although ribavirin and immunoglobulins are common components of therapy, the role of adjunct corticosteroids is not established.\n\n\nOBJECTIVE\nWe sought to evaluate corticosteroid utilization in the setting of post-allo-SCT RSV infection in our center and assess post-transplant outcomes including pulmonary function decline.\n\n\nMETHODS\nPatients with a history of RSV infection from 2008 to 2014 seen at our institution were identified. Treatment and outcome data were retrospectively collected. Forced expiratory volume at 1 s (FEV1) and carbon monoxide diffusion capacity (DLCO) were collected pre- and post-RSV infection.\n\n\nRESULTS\nDuring the observation period, RSV was isolated in 53 of 552 patients undergoing allo-SCT (10%) and 45 had evaluable therapy data. RSV-related mortality in this cohort was 4/45 (9%). Twenty-one (47%) were on corticosteroids prior to RSV diagnosis, of whom 11 (24%) had a dose increase post symptom onset. Eight (18%) patients were started on corticosteroids at the time of RSV infection. Corticosteroid therapy at symptom onset was associated with a higher rate of upper respiratory infection (URTI) to lower respiratory infection (LRTI) progression risk ratio (RR) 2.49 (1.21-5.13; P = 0.016), hospital admission RR 2.05 (1.24-3.37; P = 0.005), or intensive care unit admission RR 2.91 (1.89-5.01; P = 0.002). No significant difference was seen with FEV1 and DLCO decline (P = 0.3 and 0.24, respectively) or mortality (P = 0.26).\n\n\nCONCLUSIONS\nAdjunct corticosteroid use in the setting of RSV infection did not improve RSV-related outcomes including long-term pulmonary function. Our results do not support the routine use of corticosteroids; however, this finding does need to be verified in a larger cohort of patients.",
"affiliations": "Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Department of Pharmacy Services, Mayo Clinic, Rochester, Minnesota, USA.;Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Department of Pharmacy Services, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Damlaj|M|M|;Bartoo|G|G|;Cartin-Ceba|R|R|;Gijima|D|D|;Alkhateeb|H B|HB|;Merten|J|J|;Hashmi|S|S|;Litzow|M|M|;Gastineau|D|D|;Hogan|W|W|;Patnaik|M M|MM|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000998:Antiviral Agents; D016756:Immunoglobulins, Intravenous; D012254:Ribavirin",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12513",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "18(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "allogeneic stem cell transplant; bronchiolitis obliterans; corticosteroids; respiratory syncytial virus",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D008875:Middle Aged; D018357:Respiratory Syncytial Virus Infections; D012189:Retrospective Studies; D012254:Ribavirin; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "216-26",
"pmc": null,
"pmid": "26909896",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Corticosteroid use as adjunct therapy for respiratory syncytial virus infection in adult allogeneic stem cell transplant recipients.",
"title_normalized": "corticosteroid use as adjunct therapy for respiratory syncytial virus infection in adult allogeneic stem cell transplant recipients"
} | [
{
"companynumb": "US-ROCHE-1755349",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "A 49-year-old man presented with verapamil toxicity complicated by hypotension and a junctional rhythm, in the context of deliberate self-poisoning with multiple drugs. The patient's hypotension normalised following the early use of high-dose insulin euglycaemic therapy (HIET), without the need for additional vasopressors; it recurred when HIET was prematurely stopped, and again stabilised when HIET was recommenced. Consideration should be given to the early use of HIET in treating severe calcium channel blocker toxicity, rather than as a last resort after other therapies have failed.",
"affiliations": "Intensive Care Unit, Sir Charles Gairdner Hospital, Perth, WA, Australia.",
"authors": "Nickson|Christopher P|CP|;Little|Mark|M|",
"chemical_list": "D002121:Calcium Channel Blockers; D007328:Insulin; D014700:Verapamil",
"country": "Australia",
"delete": false,
"doi": "10.5694/j.1326-5377.2009.tb02822.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-729X",
"issue": "191(6)",
"journal": "The Medical journal of Australia",
"keywords": null,
"medline_ta": "Med J Aust",
"mesh_terms": "D002121:Calcium Channel Blockers; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007022:Hypotension; D007262:Infusions, Intravenous; D007328:Insulin; D008297:Male; D008875:Middle Aged; D014700:Verapamil",
"nlm_unique_id": "0400714",
"other_id": null,
"pages": "350-2",
"pmc": null,
"pmid": "19769561",
"pubdate": "2009-09-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Early use of high-dose insulin euglycaemic therapy for verapamil toxicity.",
"title_normalized": "early use of high dose insulin euglycaemic therapy for verapamil toxicity"
} | [
{
"companynumb": "AU-RECRO GAINESVILLE LLC-REPH-2021-000009",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nThe use of valproic acid during pregnancy has been associated with adverse fetal outcomes, including major and minor congenital malformations, intrauterine growth retardation (IUGR), hyperbilirubinemia, hepatotoxicity, transient hyperglycemia, and fetal and neonatal distress. In addition, intrauterine exposure to valproic acid has been associated with an increased risk of central nervous system abnormalities, primarily neural tube defects. Optic nerve hypoplasia has been reported in association with other prenatal anticonvulsant exposures, but the occurrence of septo-optic dysplasia as a manifestation of valproic acid embryopathy has not been reported previously.\n\n\nRESULTS\nWe report on a woman who received Depakote (valproic acid) throughout her pregnancy for the treatment of a seizure disorder. The patient presented with features typical of valproic acid embryopathy, including bitemporal narrowing, hypertelorism, short palpebral fissures, epicanthal folds, microphthalmia, a flat broad nasal bridge, small mouth, hypoplastic nails, mild clinodactyly, and camptodactyly. MRI showed hypoplasia of the optic chiasm and absence of the septum pellucidum.\n\n\nCONCLUSIONS\nWe report the first case of septo-optic dysplasia associated with maternal exposure to valproic acid throughout pregnancy. This case expands the clinical phenotype of valproate embryopathy.",
"affiliations": "Section of Reproductive Genetics, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA.",
"authors": "McMahon|C L|CL|;Braddock|S R|SR|",
"chemical_list": "D018692:Antimanic Agents; D014635:Valproic Acid",
"country": "United States",
"delete": false,
"doi": "10.1002/tera.1049",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-3709",
"issue": "64(2)",
"journal": "Teratology",
"keywords": null,
"medline_ta": "Teratology",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000015:Abnormalities, Multiple; D000293:Adolescent; D018692:Antimanic Agents; D002675:Child, Preschool; D005124:Eye Abnormalities; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008431:Maternal-Fetal Exchange; D009897:Optic Chiasm; D011247:Pregnancy; D011248:Pregnancy Complications; D012688:Septum Pellucidum; D014635:Valproic Acid",
"nlm_unique_id": "0153257",
"other_id": null,
"pages": "83-6",
"pmc": null,
"pmid": "11460259",
"pubdate": "2001-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Septo-optic dysplasia as a manifestation of valproic acid embryopathy.",
"title_normalized": "septo optic dysplasia as a manifestation of valproic acid embryopathy"
} | [
{
"companynumb": "US-ABBVIE-01P-163-0111193-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIVALPROEX SODIUM"
},
"drugadditional": nu... |
{
"abstract": "A 24-year-old woman with a history of idiopathic dilated cardiomyopathy status post heart transplant gave birth to a healthy term female infant. At 5 months of age, the infant was diagnosed with severe left ventricular dysfunction with an ejection fraction of 18% and moderate non-compaction of the left ventricle. She received a heart transplant at 7 months of age. Familial dilated cardiomyopathy was diagnosed. Genetic testing revealed a likely pathogenic variant in the TPM1 gene. Fetal cardiac screening is critical for offspring of heart transplant recipients, especially when the reason for transplant was cardiomyopathy. Early genetic consultation and counselling is necessary for all heart transplant recipients, preferably prenatally. Postnatal screening of offspring is essential at birth, at 3-month intervals until 1 year of age, and then annually until the risk for familial cardiomyopathy is assessed.",
"affiliations": "1Department of Pediatrics,Division of Child Neurology,Loma Linda University Children's Hospital,Loma Linda,CA,USA.;2Department of Pediatrics,Division of Cardiology,Loma Linda University Children's Hospital,Loma Linda,CA,USA.;3Department of Pediatrics,Division of Pediatric Genetics,Loma Linda University Children's Hospital,Loma Linda,CA,USA.",
"authors": "Liu|Yin|Y|;Bock|Matthew J|MJ|;Gold|June-Anne|JA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1017/S1047951118001191",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1047-9511",
"issue": "28(11)",
"journal": "Cardiology in the young",
"keywords": "Fetal echocardiogram dilated cardiomyopathy; genetic screening; heart transplant; missed opportunity",
"medline_ta": "Cardiol Young",
"mesh_terms": "D002311:Cardiomyopathy, Dilated; D004562:Electrocardiography; D005260:Female; D005500:Follow-Up Studies; D005820:Genetic Testing; D016027:Heart Transplantation; D006353:Heart-Assist Devices; D006801:Humans; D007223:Infant; D010375:Pedigree; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D012086:Reoperation; D013997:Time Factors; D055815:Young Adult",
"nlm_unique_id": "9200019",
"other_id": null,
"pages": "1356-1358",
"pmc": null,
"pmid": "30021666",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The importance of preconception and prenatal genetic evaluation in heart transplant individuals and fetal and postnatal cardiac monitoring in their offspring.",
"title_normalized": "the importance of preconception and prenatal genetic evaluation in heart transplant individuals and fetal and postnatal cardiac monitoring in their offspring"
} | [
{
"companynumb": "US-009507513-1811USA006115",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALLOPURINOL"
},
"drugadditional": "3",
... |
{
"abstract": "A large majority of patients diagnosed with pancreatic cancer have advanced metastatic disease with unresectable malignancies. Despite treatment advances, the survival benefit from chemotherapeutic regimens and targeted drugs is limited. Moreover, their application is limited in China because of high toxicity and cost. Recently, inhibitors of epidermal growth factor receptor activity have shown promise for the treatment of solid cancers when used in combination with standard therapy. However, these drugs have not been evaluated extensively for the treatment of pancreatic cancer. Here, we report the treatment of a 64-year-old male with metastatic pancreatic cancer using a novel regimen of icotinib with gemcitabine. Marked shrinkage of the mass was observed after two treatment cycles, and partial remission was achieved. The abdominal pain was relieved. The adverse effects were tolerable and treatment cost was acceptable. This is the first reported case for the treatment of advanced pancreatic cancer with icotinib plus gemcitabine and demonstrates a promising therapeutic alternative.",
"affiliations": "Jing Zhao, Hong Shen, Han-Guang Hu, Jian-Jin Huang, Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China.;Jing Zhao, Hong Shen, Han-Guang Hu, Jian-Jin Huang, Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China.;Jing Zhao, Hong Shen, Han-Guang Hu, Jian-Jin Huang, Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China.;Jing Zhao, Hong Shen, Han-Guang Hu, Jian-Jin Huang, Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China.",
"authors": "Zhao|Jing|J|;Shen|Hong|H|;Hu|Han-Guang|HG|;Huang|Jian-Jin|JJ|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D043844:Crown Ethers; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D003841:Deoxycytidine; C531470:icotinib; C056507:gemcitabine",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v21.i11.3441",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "21(11)",
"journal": "World journal of gastroenterology",
"keywords": "Epidermal growth factor receptor tyrosine kinase inhibitor; Gemcitabine; Icotinib; Metastatic pancreatic cancer; Regimen",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000230:Adenocarcinoma; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D043844:Crown Ethers; D003841:Deoxycytidine; D006801:Humans; D008113:Liver Neoplasms; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D047368:Tumor Burden",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "3441-6",
"pmc": null,
"pmid": "25805958",
"pubdate": "2015-03-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "14749620;25120710;20606093;21561347;12579331;24131140;15051286;10850439;24142531;19097774;22458527;18337605;24588695;23948351;17452677;21144613;9196156;12492110",
"title": "Icotinib plus gemcitabine for metastatic pancreatic cancer: a case report.",
"title_normalized": "icotinib plus gemcitabine for metastatic pancreatic cancer a case report"
} | [
{
"companynumb": "CN-ACCORD-029933",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ICOTINIB"
},
"drugadditional": null,
"drugad... |
{
"abstract": "BACKGROUND\nAbout 1%-5% of acquired haemophilia A cases affect mothers in the postpartum setting.\n\n\nOBJECTIVE\nThis study delineates the characteristics of this disease, specific to the postpartum setting, notably relapse in subsequent pregnancies.\n\n\nMETHODS\nReport of two cases and literature study (1946-2019), yielding 73 articles describing 174 cases (total 176 cases).\n\n\nRESULTS\nPatients were aged 29.9 years (17-41) and 69% primigravidae. Diagnosis was made at a median of 60 days after delivery (range 0-308). Bleeding types were obstetrical (43.4%), cutaneous (41.3%), and muscular (36.7%). In >90% of the cases, FVIII at diagnosis was <1% (range 0%-8%). FVIII inhibitor was documented in 75.4% cases (median titre of 20 BU/ml, range 1-621). Haemostatic treatment was necessary in 57.1% using fresh frozen plasma (16%), factor concentrate (27.6%) and/or bypassing agents (37.4%). Immunosuppressive treatment was administered in 90.8%, mostly steroids (85.3%), alone or combined with immunosuppressants (27%). Rituximab was used mostly as a second line treatment. Only 24 patients (13.6%) had documented subsequent pregnancies and 6 (22.2%) suffered haemophilia recurrence during pregnancy.\n\n\nCONCLUSIONS\nThis study allows better definition of: (1) clinical and laboratory characteristics of postpartum acquired haemophilia, (2) response to therapy, and (3) the risk of relapse for subsequent pregnancies.",
"affiliations": "Service and Central Laboratory of Haematology, Department of Oncology and Department of Laboratories and Pathology, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland.;Service and Central Laboratory of Haematology, Department of Oncology and Department of Laboratories and Pathology, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland.;Department of Haematology and Central Haematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.;Service and Central Laboratory of Haematology, Department of Oncology and Department of Laboratories and Pathology, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland.;Service and Central Laboratory of Haematology, Department of Oncology and Department of Laboratories and Pathology, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland.;Division of Haematology, University Hospital, Basel, Switzerland.;Service and Central Laboratory of Haematology, Department of Oncology and Department of Laboratories and Pathology, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland.;Service and Central Laboratory of Haematology, Department of Oncology and Department of Laboratories and Pathology, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland.",
"authors": "Dewarrat|Natacha|N|https://orcid.org/0000-0002-0237-1505;Gavillet|Mathilde|M|https://orcid.org/0000-0002-2485-8197;Angelillo-Scherrer|Anne|A|;Naveiras|Olaia|O|;Grandoni|Francesco|F|https://orcid.org/0000-0003-2208-2070;Tsakiris|Dimitrios A|DA|;Alberio|Lorenzo|L|https://orcid.org/0000-0001-9686-9920;Blum|Sabine|S|https://orcid.org/0000-0003-2275-3081",
"chemical_list": "D006490:Hemostatics; D005169:Factor VIII",
"country": "England",
"delete": false,
"doi": "10.1111/hae.14233",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1351-8216",
"issue": "27(2)",
"journal": "Haemophilia : the official journal of the World Federation of Hemophilia",
"keywords": "Factor VIII deficiency; Haemophilia A; acquired; postpartum haemorrhage; postpartum period; recurrence",
"medline_ta": "Haemophilia",
"mesh_terms": "D005169:Factor VIII; D005260:Female; D006467:Hemophilia A; D006490:Hemostatics; D006801:Humans; D049590:Postpartum Period; D011247:Pregnancy; D012008:Recurrence",
"nlm_unique_id": "9442916",
"other_id": null,
"pages": "199-210",
"pmc": null,
"pmid": "33550699",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Acquired haemophilia A in the postpartum and risk of relapse in subsequent pregnancies: A systematic literature review.",
"title_normalized": "acquired haemophilia a in the postpartum and risk of relapse in subsequent pregnancies a systematic literature review"
} | [
{
"companynumb": "CH-NOVOPROD-789640",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "COAGULATION FACTOR VIIA RECOMBINANT HUMAN"
},
"druga... |
{
"abstract": "Digestive graft-versus-host disease (GVHD) is a frequent complication after bone marrow transplantation, but small bowel obstruction is an extremely rare event. We present herein the first pediatric series of 4 cases of small bowel obstruction after bone marrow transplantation with detailed gross, histological data and their genetic status of the NOD2 gene. All patients had a history of severe acute GVHD treated by immunosuppressive agents and/or infliximab (in 3 cases). Acute or progressively worsening abdominal pain accompanied by small bowel occlusion occurred 5-16 months after graft, and computed tomographic scan revealed multiple small intestinal stenoses. Failure of intensive medical treatment led to surgical resection of affected loops. Stigmata of acute (apoptosis of crypts and satellitosis) and chronic GVHD features (submucosal fibrosis and serosae sclerolipomatosis), as well as extensive ulcerations, were observed in all ileal specimens. NOD2 mutation was found in only 1 patient. The follow-up showed successful outcome after surgery.",
"affiliations": "Pathology Department, Robert Debré Hospital, APHP, 75019, Paris, France. Electronic address: mickael_tordjman@hotmail.com.;Hematology Department, Robert Debré Hospital, APHP, 75019, Paris, France.;General Surgery Department, Robert Debré Hospital, APHP, 75019, Paris, France; Diderot Paris 7 University-SPC, Paris, France.;Imaging Department, Robert Debré Hospital, APHP, 75019, Paris, France.;Hematology Department, Robert Debré Hospital, APHP, 75019, Paris, France.;Diderot Paris 7 University-SPC, Paris, France; Gastroenterology Department, Robert Debré Hospital, APHP, 75019, Paris, France.;Pathology Department, Robert Debré Hospital, APHP, 75019, Paris, France; Diderot Paris 7 University-SPC, Paris, France.;Pathology Department, Robert Debré Hospital, APHP, 75019, Paris, France; Diderot Paris 7 University-SPC, Paris, France.",
"authors": "Tordjman|Mickael|M|;Ouachee|Marie|M|;Bonnard|Arnaud|A|;Tilea|Bogdana|B|;Yakouben|Karima|K|;Viala|Jerome|J|;Peuchmaur|Michel|M|;Berrebi|Dominique|D|",
"chemical_list": "D007166:Immunosuppressive Agents; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein",
"country": "United States",
"delete": false,
"doi": "10.1016/j.humpath.2017.08.034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0046-8177",
"issue": "72()",
"journal": "Human pathology",
"keywords": "Children; Graft-versus-host disease; NOD2; Small bowel stenosis; Surgery",
"medline_ta": "Hum Pathol",
"mesh_terms": "D000293:Adolescent; D016026:Bone Marrow Transplantation; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease; D006801:Humans; D007166:Immunosuppressive Agents; D007415:Intestinal Obstruction; D007421:Intestine, Small; D008297:Male; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D016896:Treatment Outcome",
"nlm_unique_id": "9421547",
"other_id": null,
"pages": "174-179",
"pmc": null,
"pmid": "28899741",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Small bowel stenosis: a manifestation of chronic graft-versus-host disease in children?",
"title_normalized": "small bowel stenosis a manifestation of chronic graft versus host disease in children"
} | [
{
"companynumb": "FR-ASTELLAS-2018US005483",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Pituitary carcinoma is a rare and aggressive malignancy with a poor prognosis and few effective treatment options.\n\n\n\nA 35-year-old woman presented with an aggressive ACTH-secreting pituitary adenoma that initially responded to concurrent temozolomide and capecitabine prior to metastasizing to the liver. Following treatment with ipilimumab and nivolumab, the tumor volume of the dominant liver metastasis reduced by 92%, and the recurrent intracranial disease regressed by 59%. Simultaneously, her plasma ACTH level decreased from 45,550 pg/mL to 66 pg/mL.\n\n\n\nBoth prospective clinical sequencing with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and retrospective whole-exome sequencing were performed to characterize the molecular alterations in the chemotherapy-naive pituitary adenoma and the temozolomide-resistant liver metastasis. The liver metastasis harbored a somatic mutational burden consistent with alkylator-induced hypermutation that was absent from the treatment-naive tumor. Resistance to temozolomide treatment, acquisition of new oncogenic drivers, and subsequent sensitivity to immunotherapy may be attributed to hypermutation.\n\n\n\nCombination treatment with ipilimumab and nivolumab may be an effective treatment in pituitary carcinoma. Clinical sequencing of pituitary tumors that have relapsed following treatment with conventional chemotherapy may identify the development of therapy-induced somatic hypermutation, which may be associated with treatment response to immunotherapy.",
"affiliations": "Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.;Marie-Josée and Henry R. Kravis Center for Molecular Oncology Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.;Weill Cornell Medical College, New York, New York.;Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.;Multidisciplinary Pituitary and Skull Base Tumor Center, Memorial Sloan Kettering Cancer Center, New York, New York.;Weill Cornell Medical College, New York, New York.;Weill Cornell Medical College, New York, New York.;Weill Cornell Medical College, New York, New York.;Weill Cornell Medical College, New York, New York.;Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.;Marie-Josée and Henry R. Kravis Center for Molecular Oncology Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.;Weill Cornell Medical College, New York, New York.;Multidisciplinary Pituitary and Skull Base Tumor Center, Memorial Sloan Kettering Cancer Center, New York, New York.",
"authors": "Lin|Andrew L|AL|;Jonsson|Philip|P|;Tabar|Viviane|V|;Yang|T Jonathan|TJ|;Cuaron|John|J|;Beal|Katherine|K|;Cohen|Marc|M|;Postow|Michael|M|;Rosenblum|Marc|M|;Shia|Jinru|J|;DeAngelis|Lisa M|LM|;Taylor|Barry S|BS|;Young|Robert J|RJ|;Geer|Eliza B|EB|",
"chemical_list": "D000074324:Ipilimumab; D000077594:Nivolumab; D000324:Adrenocorticotropic Hormone",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2018-01347",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-972X",
"issue": "103(10)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D049913:ACTH-Secreting Pituitary Adenoma; D000236:Adenoma; D000324:Adrenocorticotropic Hormone; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D008113:Liver Neoplasms; D008279:Magnetic Resonance Imaging; D009154:Mutation; D000077594:Nivolumab",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "3925-3930",
"pmc": null,
"pmid": "30085142",
"pubdate": "2018-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "21713528;26901067;28889792;20660056;9024719;19451168;25409260;26582653;25416723;23396013;15191336;20868211;25538262;28481359;20497937;25485838;27670697;25078147;21478889;1620587;18957500;25675982;24695685;19561018;25646794;17404084;24226425;24336570;25801821",
"title": "Marked Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and Nivolumab.",
"title_normalized": "marked response of a hypermutated acth secreting pituitary carcinoma to ipilimumab and nivolumab"
} | [
{
"companynumb": "US-ACCORD-090933",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Intravitreal fluocinolone acetonide implant (Retisert) has a high potency, a low solubility, and a very short duration of action in the systemic circulation, enabling the steroid pellet to be small and reducing the risk of systemic side effects. Scleral melt has not been reported as a possible complication of Retisert implant. The authors describe the occurrence of scleral melt 18 months after the implantation of fluocinolone acetonide implant in a 42-year-old Caucasian woman. To the authors' knowledge, this is the first report of this possible complication.",
"affiliations": "Ophthalmology Department, University of Athens, Athens, Greece.;Ophthalmology Department, University of Athens, Athens, Greece.;Ophthalmology Department, University of Athens, Athens, Greece.;Ophthalmology Department, University of Athens, Athens, Greece.;Ophthalmology Department, University of Athens, Athens, Greece ; Moorfields Eye Hospital, London, UK.",
"authors": "Georgalas|Ilias|I|;Koutsandrea|Chrysanthi|C|;Papaconstantinou|Dimitrios|D|;Mpouritis|Dimitrios|D|;Petrou|Petros|P|",
"chemical_list": "D005446:Fluocinolone Acetonide",
"country": "New Zealand",
"delete": false,
"doi": "10.2147/DDDT.S66634",
"fulltext": "\n==== Front\nDrug Des Devel TherDrug Des Devel TherDrug Design, Development and TherapyDrug Design, Development and Therapy1177-8881Dove Medical Press 10.2147/DDDT.S66634dddt-8-2373Case ReportScleral melt following Retisert intravitreal fluocinolone implant Georgalas Ilias 1Koutsandrea Chrysanthi 1Papaconstantinou Dimitrios 1Mpouritis Dimitrios 1Petrou Petros 121 Ophthalmology Department, University of Athens, Athens, Greece2 Moorfields Eye Hospital, London, UKCorrespondence: Petros Petrou, 43 Delaware Mansions, Delaware Road, Maida Vale, W9 2LH London, UK, Tel +44 776 549 6468, Email petrospetrou2@yahoo.com/petros. petrou@moorfields.nhs.uk2014 28 11 2014 8 2373 2375 © 2014 Georgalas et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2014The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Intravitreal fluocinolone acetonide implant (Retisert) has a high potency, a low solubility, and a very short duration of action in the systemic circulation, enabling the steroid pellet to be small and reducing the risk of systemic side effects. Scleral melt has not been reported as a possible complication of Retisert implant. The authors describe the occurrence of scleral melt 18 months after the implantation of fluocinolone acetonide implant in a 42-year-old Caucasian woman. To the authors’ knowledge, this is the first report of this possible complication.\n\nKeywords\nRetisertscleral meltcomplicationsurgical management\n==== Body\nIntroduction\nInflammatory macular edema represents one of the main causes of significant vision loss in patients with uveitis, as a result of the breakdown of the blood–retinal barrier by inflammatory mediators such as tumor necrosis factor-alpha and interleukin-1beta.1 In an effort to intercept the circulation of these mediators, corticosteroids have been used in variable delivery forms (oral, intravitreal, sub-Tenon’s administration) as a treatment modality for macular edema on the background of various types of chronic posterior uveitis.\n\nThe repeated administration nature of periocular and intravitreal steroid injections as well as the increased incidence of side effects associated both with topically and systemically administered corticosteroids2–4 led to the development of slow-release therapeutic modalities. Based on a Phase III study showing that the 34-week risk of uveitic recurrence fell significantly from 51.4% to 6.1% and visual acuity improved significantly,5,6 the Food and Drug Administration approved an intravitreal fluocinolone acetonide (FA) implant that could deliver a sustained dose of corticosteroid (Retisert; Bausch & Lomb Incorporated, Bridgewater, NJ, USA) for the treatment of the posterior uveitis.\n\nSince 2005, the use of FA implant gained popularity among ophthalmologists. Nonetheless, the identification and management of possible intraoperative or postoperative complications associated with its use remains an ongoing process. The purpose of the present work is to report the unusual but serious postoperative complication associated with the implantation of Retisert, which to the best of our knowledge has never been reported before, and describe the surgical management of scleral melt at the site of the Retisert implantation in a patient with posterior uveitis on the background of psoriatic arthritis.\n\nCase report\nA 42-year-old Caucasian woman was referred to our department complaining of sudden vision loss, watery discharge from her right eye (RE), and pain. She had a complex past ocular history that included the implantation of Retisert in her RE to treat persistent uveitis-associated cystoid macular edema on the background of psoriatic arthritis 18 months earlier. In addition, according to her notes, she had undergone combined phacoemulsification and vitrectomy with epiretinal membrane peeling 2 years before the FA implant. One year after the Retisert implantation, she underwent right trabeculectomy to treat persistently high intraocular pressure.\n\nOn examination, the intraocular pressure (IOP) was 2 mmHg, the anterior chamber was flat, and the visual acuity was counting fingers in the RE. An anterior segment examination revealed scleral melt with active leaking (positive Seidel test) at the site of the FA implant. The patient underwent urgent surgical repair under general anesthesia. Intraoperatively, an anterior chamber maintainer was used and surgical exploration confirmed significant scleral melt at the site of implantation with leaking aqueous humor (Figure 1). A scleral patch graft was sutured over the leaking sclerotomy.\n\nOn the following day, the IOP was 9 mmHg and the fundus examination revealed that the FA implant had detached from the scleral sutures and was free floating in the vitreous cavity.\n\nThree weeks later, the IOP was 18 mmHg, the visual acuity recovered to 20/30, and the patch graft was in good position (Figure 2). Benefits and risks of vitrectomy to remove the Retisert implant were discussed with the patient; however, she decided against surgery.\n\nTwo years later, visual acuity remained 20/30 with no recurrence of the cystoid macular edema, and IOP within normal limits, without additional medication.\n\nDiscussion\nFA has a high potency, a low solubility, and a very short duration of action in the systemic circulation, enabling the steroid pellet to be small and reducing the risk of systemic side effects.\n\nThe implant consists of a tablet encased in a silicone elastomer cup containing a release orifice and a polyvinyl alcohol membrane positioned between the tablet and the orifice. The silicone elastomer cup assembly is attached to a polyvinyl alcohol suture tab with silicone adhesive, which is supported to the sclera with sutures. The most common side effects of Retisert are cataract formation (all patients require cataract surgery within 3 years) and significantly raised ocular pressure (40% of patients require trabeculectomy surgery). More rare side effects are vitreous hemorrhage, retinal detachment, vitreous bands, scleral thinning over the implant, and hypotony (IOP <6 mmHg in 9.4% of implanted eyes).2,6–9\n\nScleral melt has not been reported as a possible complication of FA implant. In a study aiming to evaluate whether intravitreal FA implantation (Retisert) leads to scleral thinning, Taban et al10 reported that FA implant appears to lead to overall statistically nonsignificant scleral thinning with few exceptions.\n\nIn our case, significant scleral melt developed 18 months after the implantation of FA implant, which to the best of our knowledge has never been reported before. Of course, the patient had previously undergone vitrectomy with epiretinal membrane peel before FA implant as well as a trabeculectomy post-Retisert implantation. It is possible that these procedures could represent an additional factor for the significant scleral melt observed in our patient, although no significant inflammation or infection had been recorded post-vitrectomy or post-trabeculectomy. Scleral patch graft appeared to be adequate for the surgical management in our case. No adverse events were observed to be associated with the presence of the free-floating implant in the vitreous cavity.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Intraoperative photo of the right eye.\n\nNotes: Photo demonstrates an anterior chamber maintainer inferonasally (green arrow) and the leaking site of scleral melt inferotemporally (yellow arrow).\n\nFigure 2 Anterior segment image of the right eye 3 weeks postoperatively.\n\nNote: Image demonstrates good position of the scleral patch graft inferotemporally.\n==== Refs\nReferences\n1 Gallagher MJ Yilmaz T Cervantes-Castañeda RA Foster CS The characteristic features of optical coherence tomography in posterior uveitis Br J Ophthalmol 2007 91 1680 1685 17591668 \n2 Brumm MV Nguyen QD Fluocinolone acetonide intravitreal sustained release device – a new addition to the armamentarium of uveitic management Int J Nanomedicine 2007 2 55 64 17722513 \n3 Jabs DA Rosenbaum JT Foster CS Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel Am J Ophthalmol 2000 130 492 513 11024423 \n4 Vavvas D Foster CS Immunomodulatory medications in uveitis Int Ophthalmol Clin 2004 44 187 203 15211185 \n5 Jaffe GJ Martin D Callanan D Fluocinolone Acetonide Uveitis Study Group Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four-week results of a multicenter randomized clinical study Ophthalmology 2006 113 1020 1027 16690128 \n6 Fluocinolone acetonide ophthalmic – Bausch & Lomb: fluocinolone acetonide Envision TD implant Drugs R D 2005 6 116 119 15777105 \n7 Taban M Lowder CY Kaiser PK Outcome of fluocinolone acetonide implant (Retisert) reimplantation for chronic noninfectious posterior uveitis Retina 2008 28 9 1280 1288 18628725 \n8 Lim LL Smith JR Rosenbaum JT Retisert Curr Opin Investig Drugs 2005 6 11 1159 1167 \n9 Berger BB Mendoza W Sclerotomy closure for Retisert implant Retina 2013 33 2 436 438 23298955 \n10 Taban M Lowder CY Ventura AA Scleral thickness following fluocinilone acetonide implant (retisert) Ocul Immunol Inflamm 2010 18 4 305 313 20482407\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-8881",
"issue": "8()",
"journal": "Drug design, development and therapy",
"keywords": "Retisert; complication; scleral melt; surgical management",
"medline_ta": "Drug Des Devel Ther",
"mesh_terms": "D000328:Adult; D005260:Female; D005446:Fluocinolone Acetonide; D006801:Humans; D058449:Intravitreal Injections; D015423:Scleritis",
"nlm_unique_id": "101475745",
"other_id": null,
"pages": "2373-5",
"pmc": null,
"pmid": "25489235",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20482407;16690128;11024423;15211185;15777105;16312138;23298955;17722513;17591668;18628725",
"title": "Scleral melt following Retisert intravitreal fluocinolone implant.",
"title_normalized": "scleral melt following retisert intravitreal fluocinolone implant"
} | [
{
"companynumb": "GB-BAUSCH-BL-2014-011377",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOCINOLONE ACETONIDE"
},
"drugadditional": ... |
{
"abstract": "A heparin induced thrombocytopenia Type II (HIT) is a dangerous complication of heparin therapy. Bleeding, but above all serious thromboembolic complications, which may result in crippling disabilities or even death, can develop. Twelve heart surgery patients who were diagnosed with a HIT Type II are reported. Seven of the patients were diagnosed post operatively, the other five pre-operatively. Two of these patients underwent heart surgery with r-Hirudin (Behringwerke AG, Marburg, Germany) on cardiopulmonary bypass and two on Orgaran (AKZO Organon, the Netherlands). Of the seven post operative HIT patients, four had had a bypass operation and each had received a mitral or aortic valve replacement. Another patient had received an artificial biventricular support system (Berlin Heart) and was diagnosed with HIT Type II post operatively. Because of his special condition, this patient underwent anticoagulation with Orgaran and heart transplantation with Orgaran on a heart lung machine. Upon suspicion of HIT Type II, heparin therapy was immediately halted and an alternative treatment of Orgaran or r-Hirudin was begun. One patient encountered bleeding of a gastric ulcer on Orgaran therapy. Heart surgery patients, especially patients with an artificial support system, are potentially lethally threatened by serious thromboembolic complications accompanying HIT Type II. Therefore, these patients must be diagnosed as early as possible. Orgaran along with r-Hirudin are effective heparin substitutes in patients with HIT Type II. These medications can be widely administered to heart surgery patients pre-, intra-, and post operatively without complication.",
"affiliations": "Department of Cardiovascular and Thoracic Surgery, Deutsches Herzzentrum Berlin, Germany.",
"authors": "Sodian|R|R|;Loebe|M|M|;Gorman|K F|KF|;Riess|H|H|;Hetzer|R|R|",
"chemical_list": "D000925:Anticoagulants; D003871:Dermatan Sulfate; D006493:Heparin; D002809:Chondroitin Sulfates; D006497:Heparitin Sulfate; C035838:danaparoid",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-2916",
"issue": "43(5)",
"journal": "ASAIO journal (American Society for Artificial Internal Organs : 1992)",
"keywords": null,
"medline_ta": "ASAIO J",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D002315:Cardiopulmonary Bypass; D002809:Chondroitin Sulfates; D001026:Coronary Artery Bypass; D003871:Dermatan Sulfate; D005260:Female; D016027:Heart Transplantation; D019918:Heart Valve Prosthesis Implantation; D006353:Heart-Assist Devices; D006493:Heparin; D006497:Heparitin Sulfate; D024764:Hirudin Therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D013921:Thrombocytopenia; D013923:Thromboembolism",
"nlm_unique_id": "9204109",
"other_id": null,
"pages": "M430-3",
"pmc": null,
"pmid": "9360077",
"pubdate": "1997",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Heparin induced thrombocytopenia. Experiences in 12 heart surgery patients.",
"title_normalized": "heparin induced thrombocytopenia experiences in 12 heart surgery patients"
} | [
{
"companynumb": "DE-PFIZER INC-2021178569",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nFour major clinical trials have established that trastuzumab added to adjuvant systemic chemotherapy for women with HER2+ breast cancer significantly improves disease-free and overall survival compared with chemotherapy alone. We evaluated pathologic complete response (pCR) rate and cardiac safety of preoperative doxorubicin and cyclophosphamide followed by a taxane with or without trastuzumab.\n\n\nMETHODS\nWe reviewed pCR rate and change in left ventricular ejection fraction in women with operable HER2+ breast cancer (defined as immunohistochemical 3+ or fluorescence in situ hybridization ratio > or = 2.2) who were treated between 2002 and 2008 with doxorubicin and cyclophosphamide followed by a taxane with or without trastuzumab before definitive breast surgery.\n\n\nRESULTS\nWe identified 33 patients, of whom 42.4% received preoperative chemotherapy without trastuzumab and 57.6% of whom received trastuzumab with chemotherapy. The pCR rates were 28.6% and 52.6% in the group that received chemotherapy alone or with trastuzumab, respectively (odds ratio, 2.78; 95% CI, 0.64-12.1; P = .173). Severe cardiac events or treatment delays as a result of cardiac toxicity were not observed. With a median follow-up time of 14 months, 21.4% of patients in the non-trastuzumab group and 10.5% in the trastuzumab group had disease recurrence.\n\n\nCONCLUSIONS\nSequential administration of preoperative doxorubicin and cyclophosphamide followed by a taxane and trastuzumab combination is safe in women with primary operable HER2+ breast cancer and is associated with a high pCR rate. Large randomized phase III clinical trials are evaluating the role of preoperative trastuzumab when added to anthracycline- and/or taxane-based regimens.",
"affiliations": "University of Maryland Greenebaum Cancer Center, Baltimore, MD 21231, USA.",
"authors": "Chumsri|Saranya|S|;Jeter|Stacie|S|;Jacobs|Lisa K|LK|;Nassar|Hind|H|;Armstrong|Deborah K|DK|;Emens|Leisha A|LA|;Fetting|John H|JH|;Lange|Julie R|JR|;Riley|Carol|C|;Tsangaris|Theodore N|TN|;Wolff|Antonio C|AC|;Zellars|Richard|R|;Zhang|Zhe|Z|;Stearns|Vered|V|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001952:Bridged-Ring Compounds; D043823:Taxoids; C080625:taxane; D004317:Doxorubicin; D003520:Cyclophosphamide; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"country": "United States",
"delete": false,
"doi": "10.3816/CBC.2010.n.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-8209",
"issue": "10(1)",
"journal": "Clinical breast cancer",
"keywords": null,
"medline_ta": "Clin Breast Cancer",
"mesh_terms": "D000328:Adult; D000465:Algorithms; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D001952:Bridged-Ring Compounds; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D018719:Receptor, ErbB-2; D012189:Retrospective Studies; D013318:Stroke Volume; D043823:Taxoids; D000068878:Trastuzumab; D016896:Treatment Outcome",
"nlm_unique_id": "100898731",
"other_id": null,
"pages": "40-5",
"pmc": null,
"pmid": "20133257",
"pubdate": "2010-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pathologic complete response to preoperative sequential doxorubicin/cyclophosphamide and single-agent taxane with or without trastuzumab in stage II/III HER2-positive breast cancer.",
"title_normalized": "pathologic complete response to preoperative sequential doxorubicin cyclophosphamide and single agent taxane with or without trastuzumab in stage ii iii her2 positive breast cancer"
} | [
{
"companynumb": "US-JNJFOC-20130610555",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "BACKGROUND\nOver-the-counter medication overdose is a difficult diagnostic challenge for many physicians as common drug screening assays cannot detect these substances. We present a case of acute psychosis, serotonin syndrome, and anticholinergic overdose-like properties in the setting of Coricidin HBP Cough & Cold tablets, known by their street name Triple-C. This is the first case report we are aware of involving a patient presenting with these symptoms and requiring critical-care-level support.\n\n\nMETHODS\nA 31-year-old African American female with a past medical history of anxiety, childhood asthma, previous methamphetamine abuse, and coronavirus disease 2019 infection in August 2020 was brought to the emergency department by the local police department with altered mental status. Initial blood work, including extended drug screens, were unremarkable for a definitive diagnosis. This patient required critical-care-level support and high sedation because of her symptoms. Collateral history revealed the patient regularly consumed Triple-C daily for the 6 weeks prior to admission. A trial off sedation was attempted after 24 hours with no complications. The patient admitted to regular Triple-C consumption and auditory hallucinations since adolescence. She was discharged safely after 48 hours back into the community. She was lost to follow-up with psychiatry and internal medicine; however, she was evaluated in the emergency room 1 month later with a similar psychiatric presentation.\n\n\nCONCLUSIONS\nOverdose of Triple-C should be kept in the differential diagnosis of patients presenting with a triad of psychosis, serotonin syndrome, and anticholinergic overdose, in the setting of unknown substance ingestion.",
"affiliations": "Indiana University School of Medicine, 520 S. St, Vincennes, Indiana, 47591, USA. robachar@iu.edu.;Indiana University School of Medicine, 520 S. St, Vincennes, Indiana, 47591, USA.;Indiana University School of Medicine, 520 S. St, Vincennes, Indiana, 47591, USA.;Indiana University School of Medicine, 520 S. St, Vincennes, Indiana, 47591, USA.",
"authors": "Bachar|Roudi|R|http://orcid.org/0000-0001-8113-7110;Majewski|John Robert|JR|;Shrack|Christopher|C|;El-Khoury|Anthony|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13256-021-03163-z",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n3163\n10.1186/s13256-021-03163-z\nCase Report\nAcute psychosis and serotonin syndrome in the setting of “Triple-C” overdose: a case report\nhttp://orcid.org/0000-0001-8113-7110\nBachar Roudi robachar@iu.edu\n\nMajewski John Robert\nShrack Christopher\nEl-Khoury Anthony\ngrid.257413.6 0000 0001 2287 3919 Indiana University School of Medicine, 520 S. St, Vincennes, Indiana 47591 USA\n4 11 2021\n4 11 2021\n2021\n15 54815 9 2021\n20 10 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\nOver-the-counter medication overdose is a difficult diagnostic challenge for many physicians as common drug screening assays cannot detect these substances. We present a case of acute psychosis, serotonin syndrome, and anticholinergic overdose-like properties in the setting of Coricidin HBP Cough & Cold tablets, known by their street name Triple-C. This is the first case report we are aware of involving a patient presenting with these symptoms and requiring critical-care-level support.\n\nCase presentation\n\nA 31-year-old African American female with a past medical history of anxiety, childhood asthma, previous methamphetamine abuse, and coronavirus disease 2019 infection in August 2020 was brought to the emergency department by the local police department with altered mental status. Initial blood work, including extended drug screens, were unremarkable for a definitive diagnosis. This patient required critical-care-level support and high sedation because of her symptoms. Collateral history revealed the patient regularly consumed Triple-C daily for the 6 weeks prior to admission. A trial off sedation was attempted after 24 hours with no complications. The patient admitted to regular Triple-C consumption and auditory hallucinations since adolescence. She was discharged safely after 48 hours back into the community. She was lost to follow-up with psychiatry and internal medicine; however, she was evaluated in the emergency room 1 month later with a similar psychiatric presentation.\n\nConclusion\n\nOverdose of Triple-C should be kept in the differential diagnosis of patients presenting with a triad of psychosis, serotonin syndrome, and anticholinergic overdose, in the setting of unknown substance ingestion.\n\nKeywords\n\nOverdose\nDextromethorphan hydrobromide\nSerotonin syndrome\nPsychosis\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcIntroduction\n\nDextromethorphan hydrobromide (DXM) is a popular antitussive medication in the USA. It is commonly combined with other medications, including chlorpheniramine maleate (CPM). Coricidin HBP Cough & Cold tablets, otherwise known by their street name Triple-C, is a common drug that is abused for its euphoric properties [1, 2]. Over-the-counter medication overdose can present as a diagnostic challenge in the acute setting. One of the most serious adverse effects of Triple-C is due to the anticholinergic properties of CPM [3] and serotonergic effects of DXM [4]. Acute overdose of Triple-C can present as an anticholinergic overdose, serotonin syndrome, or respiratory depression [4–6]. We report a patient who presented with acute psychosis, anticholinergic overdose, and serotonin syndrome in the setting of habitual Triple-C abuse who may have had an underlying undiagnosed psychiatric disorder.\n\nCase presentation\n\nA 31-year-old African American female with a past medical history of anxiety, childhood asthma, previous methamphetamine abuse, and coronavirus disease 2019 (COVID-19) infection in August 2020 was brought to the emergency department (ED) by the local police department with altered mental status. The patient is a halfway-house resident who was reportedly sober for 90 days.\n\nED vital signs showed a heart rate of 166 beats per minute, blood pressure 125/94 mmHg, respiratory rate 24 breaths per minute, 90% oxygen saturation on room air, and temperature 103.5 °F. Physical examination and full history were unable to be performed due to her agitation. She required intramuscular ketamine twice in order to be sedated and the assistance of multiple police officers to restrain the patient for safety.\n\nBlood work revealed white blood cell count (WBC) of 7.4/μL (normal range 4.0–10.8/μL), hemoglobin 13.50 g/dL (normal range 11.8–14.8 g/dL), and platelet count 440/μL (normal range 140–350/μL). Comprehensive metabolic panel (CMP) revealed potassium of 3.4 mmol/L (normal range 3.5–5.5 mmol/L), bicarbonate 16 mmol/L (normal range 20–31 mmol/L), creatinine 1.33 mg/dL (normal range 0.55–1.02 mg/dL), and glucose 213 mg/dL (normal range 74–106 mg/dL). Other lab values included ammonia of 204 μmol/L (normal range 19–54 μmol/L), lactic acid > 12.20 mmol/L (normal range 0.5–1.9 mmol/L), lipase 61 U/L (normal range 12–53 U/L), and creatinine kinase 206 U/L (normal range 34–145 U/L). Beta-human chorionic gonadotropin (β-hCG), troponins, procalcitonin, urine drug screen including phencyclidine (PCP), extended serum drug screen, cerebrospinal fluid, alcohol, and Tylenol levels were negative/within normal limits. Urinalysis showed moderate blood, glucose 70 mg/dL (normal range 0 mg/dL), and protein 300 mg/dL (normal range 0 mg/dL). Arterial blood gas (ABG) revealed pH 7.365 (normal range 7.35–7.45), pCO2 39.6 mmHg (normal range 35–45 mmHg), pO2 154 mmHg (normal range 80–100 mmHg), bicarbonate 22.1 mmHg (normal range 22–26 mmHg), and lactate 0.8 mmol/L (normal range 0.5–1.9 mmol/L). Computed tomography (CT) of the head without contrast and CT chest abdomen and pelvis were negative for acute abnormalities.\n\nThe patient required large amounts of sedatives because of her agitation. Multiple attempts were made to titrate sedating medication to normal mentation or decreased agitation. Unfortunately, the patient did not respond to increasing doses of sedative medication to the point of normal mentation and continued to be aggressive and violent towards staff. It was agreed upon by the emergency medicine physicians and critical care team that she would need to be sedated, intubated, and ventilated due to her extreme agitation and aggression. Rapid sequence intubation was uneventful, and the patient was moved from the emergency department to the intensive care unit. She was started on propofol and fentanyl infusions with intravenous maintenance fluids. The patient continued to be agitated while sedated and required a third agent in the form of midazolam for adequate sedation. Management was primarily supportive, including temperature regulation (hyperthermia), intubation and mechanical ventilation (agitation and tachypnea), intravenous fluids (hypotension), and sedation (agitation). Serial ABGs were unremarkable with no lactic acidosis.\n\nCollateral history obtained from co-residents from the patient’s halfway house revealed that the patient was in possession of large amounts of the common over-the-counter cough medication Coricidin HBP Cough & Cold tablets. The recovery home did not report her having any cough or upper respiratory symptoms in the 4 weeks prior to admission. She was diagnosed with Triple-C intoxication and overdose, complicated by serotonin syndrome and acute psychosis.\n\nAfter 24 hours of critical care support, a trial off sedation was attempted. A spontaneous awaken trial was performed. The patient awoke with normal mentation and appropriate behavior. After a successful spontaneous awakening trial, a spontaneous breath trial was performed. The patient was able to protect her airway, had appropriate inspiratory and expiratory effort, and was able to maintain SpO2 > 92%. She was successfully liberated from mechanical ventilation with no complications.\n\nWhen asked about the Triple-C, she stated that she had been using approximately six tablets twice daily for the past few weeks. Upon further discussion, she reported that her acute psychosis episode started after hearing voices in her head. She stated these voices had been present since adolescence, although never aggressive in nature. Her agitation and harmful ideation were the first instance of its kind.\n\nShe was evaluated by psychiatry, who deemed her fit for discharge. She did not present to her scheduled clinic appointments and was lost to follow-up in the outpatient setting to both psychiatry and internal medicine.\n\nDiscussion and conclusions\n\nWe found this to be an interesting case of intoxication with an over-the-counter substance. There are previous reports of DXM-CPM-induced psychotic episodes in patients with established psychiatric disorders [5]. It is unclear in the literature if Triple-C-induced psychosis occurs only in patients with underlying psychiatric disorders or if it can produce psychosis de novo. Further research is required to determine this relationship. When she was interviewed by the inpatient psychiatry team, she denied hearing voices at that time. It was determined that she may have an underlying psychiatric pathology but would need further evaluation upon discharge. Unfortunately, she was lost to follow-up in the clinic. She presented to the emergency department with an acute psychotic episode less than 1 month later.\n\nThe patient denied an acute increase in her Triple-C use. However, as the patient’s urine drug screen, including an extended drug screen that was sent to an outside facility for testing, was negative, we attribute her acute psychosis to the ingestion of large amounts of Triple-C. There is evidence in the literature that DXM-CMP metabolization can vary widely within individuals [7], which also may have contributed to her sudden symptomatology. At high doses, DXM has a similar pharmacological effect as PCP and produces similar behavioral manifestations [5]. It can even cause a false-positive on certain drug assays for PCP [8]. Serotonin syndrome is a disease of neuro-hyperexcitability of the 5-Ht subgroup receptors. Patients classically present with tachycardia and hypertension as well as hyperthermia, agitation, ocular clonus, dilated pupils, tremor, hyperreflexia, spontaneous muscle clonus, and dry mucus membranes [9]. Anticholinergic overdose is due to competitive antagonism of muscarinic receptors. These are primarily located in the central nervous system and are responsible for cognitive function and delirium. Peripheral muscarinic receptors are responsible for multiple functions in the autonomic nervous system [10]. This combination of central and peripheral receptor antagonism is the mechanism for the manifestations of agitation, delirium, hyperthermia, and visual perception abnormalities. The hyperthermia, tachycardia, tachypnea, hypertension, and altered mental status are most likely due to the synergistic anticholinergic and serotonergic properties of DXM-CMP.\n\nThis case is important as it provides another differential for clinicians to keep in mind in the acutely psychotic patient with both anticholinergic and serotonergic signs and symptoms in the setting of a negative drug screen. Patients may even require critical-care-level support. However, these drugs are metabolized relatively quickly, and trial off sedation can be attempted in less than 24 hours. The other learning point is the importance of a collateral history. This prevents the treatment team from administering costly and even harmful antidotes that will provide no therapeutic effect. The family of the patient, recovery home mentor, and recovery home administrators were all crucial in ruling in and out different etiologies. Multidisciplinary teams are not just limited to medical staff within a hospital system. Social staff outside of the immediate clinical setting can provide valuable information and often know the patient better than medical staff.\n\nAbbreviations\n\nABG Arterial blood gas\n\nCPM Chlorpheniramine maleate\n\nCBC Complete blood count\n\nCMP Comprehensive metabolic panel\n\nTriple-C Coricidin HBP Cough & Cold tablets\n\nDXM Dextromethorphan hydrobromide\n\nPCP Phencyclidine\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nRB, JM, and CS participated in direct care of the patient. RB, JM, CS, and AEK participated in manuscript drafting and editing. All authors read and approved the final manuscript.\n\nFunding\n\nThere was no funding provided for this research.\n\nAvailability of data and materials\n\nAny supporting data can be obtained by direct correspondence with the corresponding author (RB).\n\nDeclarations\n\nEthics approval and consent to participate\n\nOur institute did not require ethical approval owing to the nature of this study.\n\nConsent for publication\n\nWritten informed consent for publication was obtained from the patient for publication of this case report and any accompanying images. A copy of written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nAll authors have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Schifano F Chiappini S Miuli A Mosca A Santovito MC Corkery JM Guirguis A Pettorruso M Di Giannantonio M Martinotti G Focus on over-the-counter drugs' misuse: a systematic review on antihistamines, cough medicines, and decongestants Front Psychiatry. 2021 7 12 657397 10.3389/fpsyt.2021.657397\n2. Schwartz RH Adolescent abuse of dextromethorphan Clin Pediatr (Phila) 2005 44 7 565 568 10.1177/000992280504400702 16151560\n3. Fang SY Druce HM Baraniuk JN Anticholinergic properties of brompheniramine, chlorpheniramine, and atropine in human nasal mucosa in vitro Am J Rhinol. 1998 12 2 131 133 10.2500/105065898781390271 9578932\n4. Schwartz AR Pizon AF Brooks DE Dextromethorphan-induced serotonin syndrome Clin Toxicol (Phila) 2008 46 8 771 773 10.1080/15563650701668625 19238739\n5. Okland T A case of aggressive psychosis in the setting of regular dextromethorphan abuse Psychosomatics 2016 10.1016/j.psym.2016.06.002 27814836\n6. Romanelli F Smith KM Dextromethorphan abuse: clinical effects and management J Am Pharm Assoc 2009 49 2 e20 e25 10.1331/JAPhA.2009.08091\n7. Wiegand TJ Wax PM Schwartz T Finkelstein Y Gorodetsky R Brent J Toxicology Investigators Consortium Case Registry Investigators. The Toxicology Investigators Consortium Case Registry—the 2011 experience J Med Toxicol. 2012 8 4 360 377 10.1007/s13181-012-0264-9 23055123\n8. Drug Enforcement Administration, Dextromethorphan (Street Names: DXM, CCC, Triple C, Skittles, Robo, Poor Man's PCP), https://www.deadiversion.usdoj.gov/drug_chem_info/dextro_m.pdf. Accessed 10 Sept 2021.\n9. Scotton WJ Hill LJ Williams AC Barnes NM Serotonin syndrome: pathophysiology, clinical features, management, and potential future directions Int J Tryptophan Res. 2019 10.1177/1178646919873925 31523132\n10. Dawson AH Buckley NA Pharmacological management of anticholinergic delirium—theory, evidence and practice Br J Clin Pharmacol 2016 81 3 516 524 10.1111/bcp.12839 26589572\n\n",
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"keywords": "Dextromethorphan hydrobromide; Overdose; Psychosis; Serotonin syndrome",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000086382:COVID-19; D002648:Child; D062787:Drug Overdose; D005260:Female; D006801:Humans; D011618:Psychotic Disorders; D000086402:SARS-CoV-2; D020230:Serotonin Syndrome",
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"title": "Acute psychosis and serotonin syndrome in the setting of \"Triple-C\" overdose: a case report.",
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"abstract": "BACKGROUND\nWe describe here 2 patients who developed late-onset neutropenia after Rituximab treatment. While this phenomenon is well described among patients suffering from hematological malignancies, such adverse effects are rare among patients with rheumatic diseases.\n\n\nMETHODS\nTwo patients, the first with rheumatoid arthritis and the second with granulomatosis with polyangiitis, were treated by Rituximab after all previous treatments failed. The patients developed late-onset neutropenia after several courses of treatment. The first patient, with symptomatic neutropenia, recovered after a single dose of granulocyte macrophage stimulating factor, and the second patient's neutrophils increased spontaneously. Both patients were retreated by rituximab in their scheduled time without further complications.\n\n\nCONCLUSIONS\nOur case series is unique because the same phenomenon appeared in patients with different rheumatic diseases. This case series confirms the possibility of continuing the treatment without further adverse effects.",
"affiliations": "Department of Rheumatology, Barsilai Medical Center, Ashkelon, Israel.;Department of Nephrology, Barsilai Medical Center, Ashkelon, Israel.;Department of Rheumatology, Barsilai Medical Center, Ashkelon, Israel.",
"authors": "Reitblat|Tatiana|T|;Wechsler|Alexander|A|;Reitblat|Olga|O|",
"chemical_list": "D018501:Antirheumatic Agents; D000069283:Rituximab; D016178:Granulocyte-Macrophage Colony-Stimulating Factor",
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"mesh_terms": "D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005500:Follow-Up Studies; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D000069283:Rituximab; D013997:Time Factors",
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"pubdate": "2015-04-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16840190;17079695;17916218;19399690;19933905;20350665;20827108;21560117;22301823;24599679;12007508;12649096;12826650",
"title": "Rituximab-related late-onset neutropenia in patients with rheumatic diseases: successful re-challenge of the treatment.",
"title_normalized": "rituximab related late onset neutropenia in patients with rheumatic diseases successful re challenge of the treatment"
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"abstract": "BACKGROUND\nA patient with chronic lithium toxicity developed a life-threatening ventricular arrhythmia that resolved during removal of lithium by hemodialysis. Chronic lithium toxicity commonly results from diminished elimination and can produce neurotoxicity. Cardiovascular complications have been reported and generally affect the sinoatrial node and produce bradyarrhythmias. The majority of these arrhythmias require no emergent intervention. Ventricular arrhythmias associated with lithium toxicity are occasionally mentioned in the literature, but actual cases are rarely reported.\n\n\nMETHODS\nA 74-year-old man was brought into the emergency department with a 3-day history of progressive encephalopathy, tremor, and weakness. The lithium level was elevated at 2.2 mmol/L, with a normal serum potassium. Electrocardiography revealed nonsustained monomorphic ventricular tachycardia (120-130 beats/min) lasting up to 1 min, alternating with sinus bradycardia and wandering atrial pacemaker. Episodes of monomorphic ventricular tachycardia recurred >100 times. The patient required a norepinephrine infusion for hypotension. Emergent hemodialysis was initiated to remove lithium and to treat the monomorphic ventricular tachycardia, which was felt to be secondary to lithium toxicity. Episodes of monomorphic ventricular tachycardia abated as hemodialysis progressed. The episodes resolved completely within 4 h of initiating hemodialysis. The patient was discharged home in sinus rhythm on day 5. Lithium was not reinstated.\n\n\nCONCLUSIONS\nMonomorphic ventricular tachycardia associated with chronic lithium toxicity is exceptionally rare. Hemodialysis is a treatment option.",
"affiliations": "Department of Medical Toxicology, Banner Good Samaritan Medical Center, 925 East McDowell Road, Phoenix, AZ, 85006, USA, adam.bosak@bannerhealth.com.",
"authors": "Bosak|Adam R|AR|;Graeme|Kimberlie A|KA|;Evans|Matt D|MD|",
"chemical_list": "D016651:Lithium Carbonate",
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"delete": false,
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"mesh_terms": "D000368:Aged; D004562:Electrocardiography; D006801:Humans; D016651:Lithium Carbonate; D008297:Male; D006435:Renal Dialysis; D017180:Tachycardia, Ventricular",
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"title": "Hemodialysis treatment of monomorphic ventricular tachycardia associated with chronic lithium toxicity.",
"title_normalized": "hemodialysis treatment of monomorphic ventricular tachycardia associated with chronic lithium toxicity"
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"abstract": "BACKGROUND We present a case of Group B Streptococcus (Streptococcus agalactiae or GBS) meningitis in a non-pregnant woman that likely originated from acute otitis media. Although invasive Group B Streptococcal infections are increasing in the United States, GBS meningitis is still rare in non-pregnant adults. At the end, we discuss risk factors for this disease and data that suggest that invasive GBS infection is increasing in the adult and elderly populations of the United States. CASE REPORT Our patient was a 55-year-old woman with a history of juvenile rheumatoid arthritis who presented with altered mental status after failure of outpatient treatment of otitis media with oral doxycycline and steroids. Upon admission, she was initially afebrile and hemodynamically stable, but she had a rapid decline and required emergent intubation. Blood cultures grew GBS. CSF PCR analysis performed by BioFire® FilmArray® Meningitis/Encephalitis Panel revealed GBS. Middle-ear fluid and CSF cultures drawn after 1 day of antibiotic therapy did not grow any organisms. Treatment was achieved with high-dose intravenous ceftriaxone for 14 days, and tympanoplasty. At the end of 14 days of antibiotic therapy, the patient had full neurological recovery, without any residual neurological deficits. CONCLUSIONS GBS meningitis is classically associated with neonatal disease, but invasive GBS infection is fairly common in adults and appears to be increasing in incidence secondary to increasing populations living with diabetes, immunosuppressed conditions, and advanced age. Central nervous system infection with this organism is still rare. In this case report we describe a non-pregnant woman who presented with GBS meningitis.",
"affiliations": "Department of Internal Medicine, HCA Midwest Overland Park Regional Medical Center, Overland Park, KS, USA.;Department of Internal Medicine, HCA Midwest Overland Park Regional Medical Center, Overland Park, KS, USA.;Department of Infectious Disease, Metro Infectious Disease Consultants, Kansas City, KS, USA.",
"authors": "Villareal|Kenneth|K|;Goslin|Amelia|A|;Bajracharya|Himal|H|",
"chemical_list": "D002443:Ceftriaxone",
"country": "United States",
"delete": false,
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"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n34601486\n10.12659/AJCR.933093\n933093\nArticles\nGroup B Streptococcus Meningitis Associated with Acute Otitis Media in an Adult Patient\nVillareal Kenneth A B C D E F 1\nGoslin Amelia A E 1\nBajracharya Himal A D E F 2\n1 Department of Internal Medicine, HCA Midwest Overland Park Regional Medical Center, Overland Park, KS, USA\n2 Department of Infectious Disease, Metro Infectious Disease Consultants, Kansas City, KS, USA\nCorresponding Author: Kenneth Villareal, e-mail: kenneth.villareal@hcamidwest.com\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nFinancial support: None declared\n\nConflict of interest: None declared\n\n2021\n03 10 2021\n22 e933093-1e933093-3\n10 5 2021\n23 7 2021\n26 8 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Female, 55-year-old\n\nFinal Diagnosis: Streptococcus agalactiae meningitis\n\nSymptoms: Altered mental status • seizures\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Infectious Diseases\n\nObjective:\n\nUnusual clinical course\n\nBackground:\n\nWe present a case of Group B Streptococcus (Streptococcus agalactiae or GBS) meningitis in a non-pregnant woman that likely originated from acute otitis media. Although invasive Group B Streptococcal infections are increasing in the United States, GBS meningitis is still rare in non-pregnant adults. At the end, we discuss risk factors for this disease and data that suggest that invasive GBS infection is increasing in the adult and elderly populations of the United States.\n\nCase Report:\n\nOur patient was a 55-year-old woman with a history of juvenile rheumatoid arthritis who presented with altered mental status after failure of outpatient treatment of otitis media with oral doxycycline and steroids. Upon admission, she was initially afebrile and hemodynamically stable, but she had a rapid decline and required emergent intubation. Blood cultures grew GBS. CSF PCR analysis performed by BioFire® FilmArray® Meningitis/Encephalitis Panel revealed GBS. Middle-ear fluid and CSF cultures drawn after 1 day of antibiotic therapy did not grow any organisms. Treatment was achieved with high-dose intravenous ceftriaxone for 14 days, and tympanoplasty. At the end of 14 days of antibiotic therapy, the patient had full neurological recovery, without any residual neurological deficits.\n\nConclusions:\n\nGBS meningitis is classically associated with neonatal disease, but invasive GBS infection is fairly common in adults and appears to be increasing in incidence secondary to increasing populations living with diabetes, immunosuppressed conditions, and advanced age. Central nervous system infection with this organism is still rare. In this case report we describe a non-pregnant woman who presented with GBS meningitis.\n\nKeywords:\n\nCritical Care\nInfectious Disease Medicine\nMeningitis, Bacterial\nStreptococcal Infections\n==== Body\npmcBackground\n\nGroup B Streptococcus is one of the most common causes of sepsis and meningitis in neonates and is a major cause of concern during the postpartum period. However, the incidence of invasive GBS infection in non-pregnant adults is also increasing in the United States. The incidence of GBS meningitis in adults is still rare. Invasive GBS infection in adults is commonly associated with other comorbidities or concurrent infections elsewhere in the body [1]. Here, we present the case of a non-pregnant woman who developed a GBS meningitis preceded by several days of ear infection, leading to bacteremia.\n\nCase Report\n\nOur patient was a 55-year-old obese woman with a history of juvenile rheumatoid arthritis who presented to the hospital with acute metabolic encephalopathy. Before admission, she had been undergoing treatment for right-sided acute otitis media and right middle-ear effusion through her primary care provider and ENT specialist for the past 3 weeks. Her treatment included a trial of doxycycline and steroids. There was a tentative plan for a tympanoplasty if her tympanic ef-fusion remained. Despite treatment, her effusion remained. About 2 days before presentation, the patient started developing severe right-sided headaches with associated nausea and emesis. While these symptoms persisted, her mentation worsened and she became increasingly confused, prompting her husband to bring her to the hospital.\n\nAt presentation to the hospital Emergency Department (ED), the patient appeared acutely ill, with altered mental status. She was unable to coherently provide a history. On examination, she had a significant amount of right-ear tympanic bulging and effusion but she did not have any meningismus. She was otherwise afebrile, without leukocytosis on laboratory testing and with an unremarkable CT head scan. She rapidly deteriorated, with acute respiratory failure and required emergent intubation.\n\nThe patient was started on empiric antibiotics (vancomycin 1.5 g Q8h and ceftriaxone 1g q12h.) She became febrile with marked leukocytosis. A maxillofacial MRI revealed significant fluid in the right mastoid and right middle ear, which was suggestive of acute otitis media and mastoiditis. An ear, nose, and throat (ENT) specialist performed emergent tympanoplasty with tube placement and the patient was then started on systemic steroids. A lumbar puncture was done and revealed profound leukocytosis with a WBC count of 12 815/cmm. CSF glucose was low at 39 mg/dl and CSF protein was elevated at 564 mg/dl. Blood cultures grew GBS but no other pathogens. Cultures from the CSF and the middle-ear fluid drawn during the tympanoplasty did not have any growth, as the patient had been on 1 day of antibiotics by then. However, CSF PCR performed with a BioFire® FilmArray® Meningitis/Encephalitis Panel kit confirmed the presence of GBS.\n\nIn response, her antibiotics were adjusted to a high dose (ceftriaxone 2 g i.v. q12). On day 4 of her ICU stay, she was noted to have myoclonic activity in her right arm. A follow-up MRI brain revealed a 1.5-cm foci of diffusion restriction with increased FLAIR signal in the parasagittal left frontal lobe on axial DWI (Figure 1) along with multiple additional small foci of diffusion restriction (<5 mm) scattered throughout the cortex, raising concerns for cerebritis. She completed 2 weeks of high-dose intravenous ceftriaxone, with full neurological recovery. The infectious disease physician signed off at that point. However, without the knowledge of the infectious disease consultant, ENT started the patient again on doxycycline before discharge. This highlights the importance of educating other specialities in appropriate antibiotic selection.\n\nDiscussion\n\nGroup B Streptococcus (Streptococcus agalactiae) is an encapsulated gram-positive, beta hemolytic, catalase negative, facultative anaerobe that is commensal with humans. This bacterium has a tendency to colonize tissues such as the gastrointestinal, respiratory, and vaginal tracts and it is believed that about 15–40% of all women have vaginal colonization [2]. Despite its widespread presence, it most commonly presents as a less serious non-invasive disease such as asymptomatic bacteriuria. However, GBS is a major pathogen causing neonatal sepsis meningitis and peripartum infection [3].\n\nStudies suggest the incidence of invasive GBS infection in non-pregnant adults is rising in the USA. From 2008 to 2016, Watkins et al performed an epidemiologic study evaluating invasive GBS infection in the USA, finding an increasing incidence, from 8.1% in 2008 to 10.9% in 2016 (P=0.002 for trend). What was particularly striking is that many positive cases in 2016 also were associated with either obesity or diabetes [4]. An epidemiological study by Schwartz et al also found a nearly 10-fold higher risk of invasive GBS in diabetics [1]. It appears that more investigation in defining individuals at risk of invasive GBS may be important in the future as the obesity and diabetes epidemics continue to progress in the United States. There is already a suggestion that African American communities may be at higher risk [1,5].\n\nIn regards to CNS infection, the incidence of Group B Streptococcus meningitis in adults appears to be exceptionally low and incidence data are very limited in the USA. Van Kessel et al calculated an incidence rate of about 0.16 per 1 million adults based on 33 cohort studies done in the Netherlands [6]. Previous epidemiological studies in the USA have suggested that CNS involvement occurs in around 1.6% of all cases of invasive GBS infection for both children (non-neonatal) and adults [7]. In their population study, Farley et al reported that out of 137 non-pregnant adult patients with invasive GBS infection detected in Atlanta GA, only 5 presented with meningitis (3.7%) [5]. Jackson et al reported 8 cases of GBS meningitis out of a total of 219 observed invasive GBS infections (8%) [8]. These studies suggest that patients who are immunocompromised, elderly, diabetic, or with endocarditis are at particular risk of GBS meningitis [6,9,10]. A large outbreak of GBS meningitis in Asia was reported after consumption of raw fish [11].\n\nPresentation of GBS meningitis is clinically very similar to other forms of bacterial meningitides. Empiric antibiotics for the coverage of more common bacterial pathogens such as Neisseria meningitidis and Streptococcus pneumoniae include third-generation cephalosporins, which typically are used to treat GBS infection. Mortality rates based on previous literature reviews suggest the fatality rate may be as high as 30% [9,10]. Risk of mortality has been correlated with advanced age and immunocompromised state [7].\n\nConclusions\n\nIncidence of Invasive Group B Streptococcus (Streptococcus agalactiae) infection in non-pregnant adults may be increasing in the United States with the growing elderly and diabetic populations. Fortunately, GBS meningitis in non-pregnant adults is still rare.\n\nFigure 1. 1.5-cm ovoid foci of diffusion restriction with increased FLAIR, raising suspicion of cerebritis.\n\nStatement\n\nThis manuscript for submission is original research, conducted by the authors above. All authors above participated in creating the manuscript and had the opportunity to edit and revise as they saw fit. There are no conflicts of interest, affiliations, or involvement with any other third-party entities that may benefit from the discussion of the material in this manuscript to declare. This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities. Informed consent was obtained from the patient and is available upon request. There are no other funding or supporting sources to declare.\n\nDeclaration of Figures Authenticity\n\nAll figures submitted have been created by the authors who confirm that the images are original with no duplication and have not been previously published in whole or in part.\n==== Refs\nReferences:\n\n1. Schwartz B Schuchat A Oxtoby MJ Invasive group B streptococcal disease in adults. A population-based study in metropolitan Atlanta JAMA 1991 266 8 1112 14 1865545\n2. Regan JA Klebanoff MA Nugent RP The epidemiology of group B streptococcal colonization in pregnancy. Vaginal Infections and Prematurity Study Group Obstet Gynecol 1991 77 4 604 10 2002986\n3. Yeo KT Lahra M Bajuk B Long-term outcomes after group B streptococcus infection: A cohort study Arch Dis Child 2019 104 2 172 78 30018069\n4. Francois Watkins LK McGee L Schrag SJ Epidemiology of invasive group B streptococcal infections among nonpregnant adults in the United States, 2008–2016 JAMA Intern Med 2019 179 4 479 88 30776079\n5. Farley MM Harvey RC Stull T A population-based assessment of invasive disease due to group B Streptococcus in nonpregnant adults N Engl J Med 1993 328 25 1807 11 8502269\n6. van Kassel MN Bijlsma MW Brouwer MC Community-acquired group B streptococcal meningitis in adults: 33 cases from prospective cohort studies J Infect 2019 78 1 54 57 30063913\n7. Phares CR Lynfield R Farley MM Active Bacterial Core surveil-lance/Emerging Infections Program Network. Epidemiology of invasive group B streptococcal disease in the United States, 1999–2005 JAMA 2008 299 17 2056 65 18460666\n8. Jackson LA Hilsdon R Farley MM Risk factors for group B streptococcal disease in adults Ann Intern Med 1995 123 6 415 20 7639440\n9. Domingo P Barquet N Alvarez M Group B streptococcal meningitis in adults: Report of twelve cases and review Clin Infect Dis 1997 25 5 1180 87 9402379\n10. van Kassel MN van Haeringen KJ Brouwer MC Community-acquired group B streptococcal meningitis in adults J Infect 2020 80 3 255 60 31830496\n11. Tan S Lin Y Foo K Group B streptococcus serotype III sequence type 283 bacteremia associated with consumption of raw fish, Singapore Emerg Infect Dis 2016 22 11 1970 73 27767904\n12. Edwards MS Baker CJ Streptococcus agalactiae (Group B Streptococci) Bennet J Dolin R Douglas Blaser M Mandell Bennett’s Principles and Practice of Infectious Diseases 9th ed. Philadelphia, PA Elsevier 2020 2205 251\n\n",
"fulltext_license": "CC BY-NC-ND",
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"mesh_terms": "D000328:Adult; D000368:Aged; D002443:Ceftriaxone; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D016920:Meningitis, Bacterial; D008875:Middle Aged; D010033:Otitis Media; D013290:Streptococcal Infections; D013292:Streptococcus agalactiae",
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"title": "Group B Streptococcus Meningitis Associated with Acute Otitis Media in an Adult Patient.",
"title_normalized": "group b streptococcus meningitis associated with acute otitis media in an adult patient"
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"abstract": "Pulmonary hypertension (PH) is often a difficult condition to diagnose, since it occurs insidiously and is a diagnosis of exclusion. Patients with neurofibromatosis type 1 (NFT1) have been associated with severe exacerbations of PH. To our knowledge, less than 20 cases of PH in NFT1 patients have been reported. However, the severity of presenting symptoms requires physicians to be aware of this association and pursue the appropriate diagnostic workup. In our report, we present a 54-year-old NFT1 patient who presented with worsening dyspnea secondary to PH, which was being treated with trepostanil and macitetan. She required a right heart catheterization to assess her pulmonary artery pressures (which remained elevated). She was placed on tadalafil in addition to trepostanil and macitetan and noted significant resolution of her symptoms. Further studies are required to explore the association between PH and NFT1 and examine the efficacy of triple therapy with endothelin receptor antagonists, phosphodiesterase 5 inhibitors, and parenteral prostanoids in the initial treatment of PH in the aforementioned patient population.",
"affiliations": "SUNY Upstate Medical University, Syracuse, NY, USA.;SUNY Upstate Medical University, Syracuse, NY, USA.;SUNY Upstate Medical University, Syracuse, NY, USA.;SUNY Upstate Medical University, Syracuse, NY, USA.;SUNY Upstate Medical University, Syracuse, NY, USA.",
"authors": "Rao|Suman|S|0000-0003-1746-1025;Khan|Alisha|A|;Sampat|Parth|P|0000-0002-7849-3955;Sandhu|Michael|M|;Weinberg|Andrew M|AM|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096\nSAGE Publications Sage CA: Los Angeles, CA\n\n34269074\n10.1177/23247096211032821\n10.1177_23247096211032821\nCase Report\nAn Uncommon Incidence of Pulmonary Hypertension Associated With Neurofibromatosis Type 1: A Case Report\nhttps://orcid.org/0000-0003-1746-1025\nRao Suman MD 1\nKhan Alisha MD 1\nhttps://orcid.org/0000-0002-7849-3955\nSampat Parth MBBS 1\nSandhu Michael MD 1\nWeinberg Andrew M. DO 1\n1 SUNY Upstate Medical University, Syracuse, NY, USA\nSuman Rao, MD, Department of Medicine, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA. Email: raosu@upstate.edu\n16 7 2021\nJan-Dec 2021\n9 2324709621103282126 3 2021\n19 6 2021\n26 6 2021\n© 2021 American Federation for Medical Research\n2021\nAmerican Federation for Medical Research\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nPulmonary hypertension (PH) is often a difficult condition to diagnose, since it occurs insidiously and is a diagnosis of exclusion. Patients with neurofibromatosis type 1 (NFT1) have been associated with severe exacerbations of PH. To our knowledge, less than 20 cases of PH in NFT1 patients have been reported. However, the severity of presenting symptoms requires physicians to be aware of this association and pursue the appropriate diagnostic workup. In our report, we present a 54-year-old NFT1 patient who presented with worsening dyspnea secondary to PH, which was being treated with trepostanil and macitetan. She required a right heart catheterization to assess her pulmonary artery pressures (which remained elevated). She was placed on tadalafil in addition to trepostanil and macitetan and noted significant resolution of her symptoms. Further studies are required to explore the association between PH and NFT1 and examine the efficacy of triple therapy with endothelin receptor antagonists, phosphodiesterase 5 inhibitors, and parenteral prostanoids in the initial treatment of PH in the aforementioned patient population.\n\npulmonary hypertension\nneurofibromatosis type 1\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nTo our knowledge, there are less than 20 documented cases of pulmonary hypertension (PH) occurring in patients with neurofibromatosis type 1 (NFT1). Although the association is still very much being explored, it appears that NFT1 patients initially present with rapidly worsening symptoms of PH, such as dyspnea with minimal physical activity. Prompt recognition is required in order to pursue appropriate diagnostic workup, such as echocardiography and right heart catheterization, as well as initiation of appropriate medical therapy.\n\nCase Presentation\n\nWe present a 54-year-old female with past medical history most significant for NFT1, PH, breast cancer treated previously with chemotherapy and radiation therapy, who presented from home with worsening dyspnea and chest pain.\n\nOur patient was diagnosed with PH 3 months prior to the current admission. She had a transthoracic echocardiogram (TTE) performed at that time which showed a severely dilated right-sided chambers along with severe tricuspid regurgitation. The estimated right ventricular systolic pressure was 101 mm Hg. A right heart catheterization revealed a pulmonary artery pressure of 87/37 mm Hg and a mean pressure of 55 mm Hg. She was treated with trepostanil infusion at 45 ng/kg/min and was discharged to home on macitetan 10 mg daily, furosemide 20 mg twice daily, and spironolactone 25 mg daily.\n\nPast surgical history was significant for bilateral mastectomy and hysterectomy. She denied cigarette smoking, alcohol use, or recreational drug use.\n\nDuring her admission, our patient stated that her symptoms started 3 days prior to presentation. Her symptoms of dyspnea were progressive to a point where she was unable to walk around her house. She attested to chest pain that accompanied the dyspnea, which was left sided, constant, and nonradiating. She denied weight loss, and did not have a history of HIV, venous thromboembolism, or pulmonary embolism.\n\nIn the emergency department, she was noted to have a blood pressure of 92/72 mm Hg (concurrent with her baseline), heart rate of 114 beats per minute, respiratory rate of 25 breaths per minute, and an oxygen saturation of 84% on room air. Physical examination showed a woman in acute respiratory distress, with tachycardia, tachypnea, and 1+ bilateral lower extremity pitting edema. Her initial troponin was noted to be <0.01 ng/dL. Chest radiography (Figure 1) showed prominent pulmonary arteries, consistent with PH. Computed tomography angiography (CTA) of the thorax (Figure 2) showed a small pleural effusion and a prominent pulmonary trunk, likely secondary to increased pressure in the pulmonary system. A TTE (Figure 3) was performed, which showed an ejection fraction of 65% to 70% along with an enlarged right ventricle with decreased right ventricular systolic function and moderate tricuspid regurgitation (Figure 4). She was continued on her home dose of furosemide and spironolactone.\n\nFigure 1. Chest radiography showed prominent pulmonary arteries, concurrent with pulmonary hypertension.\n\nFigure 2. Computed tomography angiography of the thorax and a prominent pulmonary trunk (arrow).\n\nFigure 3. Computed tomography scan showing lung windows with left-sided pleural effusion (blue arrow).\n\nFigure 4. A transthoracic echocardiogram was performed, which showed an ejection fraction of 65% to 70%, enlarged right ventricle (arrow) with decrease right ventricular systolic function, and moderate tricuspid regurgitation.\n\nA right heart catheterization was performed during this admission showed a right atrial pressure of 6 mm Hg, right ventricular pressures of 74/10 mm Hg, pulmonary artery pressure of 73/25 mm Hg with a mean pulmonary artery pressure of 47 mm Hg, and pulmonary capillary wedge pressure of 10 mm Hg.\n\nOur patient was restarted on all her home medications in addition to tadalafil 20 mg daily. Her symptoms improved drastically, and she was discharged from the hospital.\n\nDiscussion\n\nPH can be divided into 5 subclasses according to the World Health Organization (WHO) classification. Of these, group V is considered to be PH in the setting of unclear multifactorial mechanisms, such as in the setting of neurofibromatosis type 1. 1\n\nThe clinical features of PH are insidious in onset and may initially consist of fatigue and generalized weakness. As the disease progresses, patients may complain of signs and symptoms of right-sided heart failure, including bilateral pedal edema, abdominal swelling, and syncope. Chest radiography and chest computed tomography could show enlargement of the pulmonary trunk and arteries, as well as bilateral pleural effusions.\n\nThe initial step in diagnosis would be pursuing a TTE, which would reveal a pulmonary artery systolic pressure >35 mm Hg in young adults or >40 mm Hg in older adults. A right heart catheterization is required for the confirmation of the diagnosis of PH.\n\nThe management of PH is very extensive. Patients who are asymptomatic can be placed on vasodilator monotherapy, usually phosphodiesterase 5 inhibitors (PDE5I). Patients who are unable to climb a flight of stairs, walk 2 blocks, or experience limitations of daily activities would require an endothelin receptor antagonist (ERA) and a PDE5I. 2 Patients who are unable to carry out any physical activity require parenteral prostenoids, such as intravenous epoprostanol or trepostanil in addition to an ERA or a PDE5I.\n\nLess than 20 cases of PH have been reported in patients with NFT1. In addition to being aware of this association, health care providers must be aware of the sudden decline in function due to PH in this population. Our patient initially presented with shortness of breath and was tried on macitetan (ERA) and trepostanil (parenteral prostanoid). However, within the course of just 2 months, she began experiencing worsening dyspnea and fatigue with minimal physical activity prompting hospitalization and initiation of tadalafil, a PDE5I. Given a PCWP (pulmonary capillary wedge pressure) of 10 mm Hg on right heart catheterization, the likelihood of this presentation belonging to WHO group II (PH secondary to heart failure) was low. It was important to rule out PH secondary to WHO group II, since the initiation of vasodilators would be contraindicated. A computed tomography scan of thorax did not show any inherent lung disease, nor pulmonary emboli, making WHO groups III and IV less likely. Several other cases document similar PH exacerbations in patients with NFT1 who showed improvement after the initiation of PDE5I’s, which drove the decision to initiate tadalafil in our patient.3-7 Currently, there is minimal data to support the use of vasodilators in the management of WHO group V PH. 7 Since pulmonary venous involvement is implicated in group V PH, the use of pulmonary vasodilators is not standard of care. However, our patient did show improvement with pulmonary vasodilators. Further studies are necessary to assess the efficacy of starting triple therapy with PDE5I, ERA, and parenteral prostanoids in order to decrease hospitalization and improve quality of life.\n\nThere are several other cases that have tried different modalities to manage PH in NFT1. Atrial septostomy was found to be successful in managing PH in one study. 8 Additionally, another study was able to demonstrate a decrease in pulmonary artery systolic pressure on repeat right heart catheterization after the initiation of sorafenib, a tyrosine kinase inhibitor. 9\n\nConclusion\n\nThe diagnosis of PH can be difficult to make, until symptoms and signs of right-sided heart failure develop. In patients with NFT1, symptoms of dyspnea and fatigue should prompt health care providers to pursue a diagnostic work up for PH, including a right heart catheterization. Further studies are required to assess the efficacy of initially starting a triple therapy regimen consisting of parenteral prostanoids, PDE5Is, and ERAs in NFT1 patients diagnosed with PH (regardless of WHO subclass presentation), in order to avoid rapid exacerbation of the disease.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.\n\nORCID iDs: Suman Rao https://orcid.org/0000-0003-1746-1025\n\nParth Sampat https://orcid.org/0000-0002-7849-3955\n==== Refs\nReferences\n\n1 Frost A Badesch D Gibbs JSR , et al . Diagnosis of pulmonary hypertension. Eur Respir J. 2019;53 :1801904.30545972\n2 Galiè N Barberà JA Frost AE , et al ; AMBITION Investigators. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373 :834-844.26308684\n3 Gumbiene L Petrulioniene Z Rucinskas K , et al . Pulmonary hypertension: a fatal complication of neurofibromatosis type 1. Respir Care. 2011;56 :1844-1848.21605478\n4 Carrascosa MF Larroque IC Rivero JLG , et al . Pulmonary arterial hypertension associated with neurofibromatosis type 1. BMJ Case Rep. 2010;2010 :bcr0520102961.\n5 Chaddha U Puscas I Prosper A , et al . 63-year-old woman with neurofibromatosis type 1 and pulmonary hypertension with worsening hypoxemia. Chest. 2017;152 :e89-e93.\n6 Rojas M Mubarik A Henderson EA , et al . Pulmonary arterial hypertension: a rare yet fatal complication of neurofibromatosis type 1. Respir Med Case Reports. 2019;27 :100832.\n7 Jutant EM Girerd B Jaïs X , et al . Pulmonary hypertension associated with neurofibromatosis type 1. Eur Respir Rev. 2018;27 :180053.30158278\n8 Giannakoulas G Savvoulidis P Grosomanidis V Mouratoglou SA Karvounis H Hadjimiltiades S. Atrial septostomy and disease targeting therapy in pulmonary hypertension secondary to neurofibromatosis. BMC Pulm Med. 2016;16 :175.27927206\n9 Tamura Y Ono T Sano M Fukuda K Kataoka M Satoh T. Favorable effect of sorafenib in a patient with neurofibromatosis-associated pulmonary hypertension. Am J Respir Crit Care Med. 2012;186 :291-292.22855545\n\n",
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"issue": "9()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "neurofibromatosis type 1; pulmonary hypertension",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D015994:Incidence; D008875:Middle Aged; D009456:Neurofibromatosis 1",
"nlm_unique_id": "101624758",
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"title": "An Uncommon Incidence of Pulmonary Hypertension Associated With Neurofibromatosis Type 1: A Case Report.",
"title_normalized": "an uncommon incidence of pulmonary hypertension associated with neurofibromatosis type 1 a case report"
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"abstract": "OBJECTIVE\nThere is a high comorbidity of schizophrenia and obsessive-compulsory disorder (OCD) associated with more severe symptoms. Standard pharmacotherapy achieve symptom improvement in approximately 60% only.\n\n\nRESULTS\nWe report about a 48-old women treated for depression which developed successively psychotic symptoms (ideas of reference, psychotic worries), negative symptoms (blunted affect, impoverished thinking, difficulties in planning), and obsessive-compulsive symptoms (mainly repeating rituals, avoidance behaviour, collecting and hoarding). She did not respond to combined treatment with neuroleptics and high dose selective serotonin re-uptake inhibitors. She acutely improved during a course of electroconvulsive therapy (ECT) and was maintained on outpatient ECTs fortnightly together with 12 mg sertindol and 45 mg mirtazapine for 42 weeks.\n\n\nCONCLUSIONS\nMaintenance ECT is not an approved therapy in OCD but might be an option in pharmacotherapy refractory cases of comorbid OCD and schizophrenic/schizoaffective disorder.",
"affiliations": "Klinik und Poliklinik für Neurologie, Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube Str. 40, 06097 Halle/Saale, Germany. frank.hanisch@medizin.uni-halle.de",
"authors": "Hanisch|F|F|;Friedemann|J|J|;Piro|J|J|;Gutmann|P|P|",
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"mesh_terms": "D015897:Comorbidity; D004351:Drug Resistance; D004565:Electroconvulsive Therapy; D005260:Female; D006801:Humans; D008875:Middle Aged; D009771:Obsessive-Compulsive Disorder; D012559:Schizophrenia; D012565:Schizophrenic Psychology; D016896:Treatment Outcome",
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"references": "15846598;8238655;17474809;9220110;16518135;8055290;12426414;15816802;8942468;11940981;10813075",
"title": "Maintenance electroconvulsive therapy for comorbid pharmacotherapy-refractory obsessive-compulsive and schizoaffective disorder.",
"title_normalized": "maintenance electroconvulsive therapy for comorbid pharmacotherapy refractory obsessive compulsive and schizoaffective disorder"
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"abstract": "Venous thromboembolism in tuberculosis is not a well recognised entity. It is a less frequently reported complication of severe pulmonary tuberculosis. It is exceedingly rare when it complicates extrapulmonary tuberculosis. Here, we present a case of 22-year-old young female with abdominal tuberculosis complicated with reverse ileocecal intussusception, deep vein thrombosis and pulmonary embolism. An emergency vena cava filter was inserted prior to a limited right hemicolectomy. In this article, we discuss the rare association of venous thromboembolism with ileocecal tuberculosis.",
"affiliations": "Medical Officer, Department of General Surgery, Hospital Sultanah Aminah, Johor Bahru, Johor, Malaysia.;Medical Officer, Department of General Surgery, Hospital Sultanah Aminah, Johor Bahru, Johor, Malaysia.;General Surgeon, Department of General Surgery, Hospital Sultanah Aminah, Johor Bahru, Johor, Malaysia.;General and Trauma Surgeon, Department of General Surgery, Hospital Sultanah Aminah, Johor Bahru, Johor, Malaysia.",
"authors": "Huei|Tan Jih|TJ|;Henry|Tan Chor Lip|TCL|;Ho|Choon Aik|CA|;Mohamad|Yuzaidi|Y|",
"chemical_list": null,
"country": "India",
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"issue": "11(7)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Gastrointestinal tuberculosis; Ileocecal intussusception; Venous thromboembolism",
"medline_ta": "J Clin Diagn Res",
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"nlm_unique_id": "101488993",
"other_id": null,
"pages": "PD03-PD04",
"pmc": null,
"pmid": "28892968",
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"references": "2569610;12782695;8703831;24759354;27274846;22348256;28003904;10448473;24062943",
"title": "A Rare Case of Ileocecal Tuberculosis with Pulmonary Embolism and Deep Vein Thrombosis.",
"title_normalized": "a rare case of ileocecal tuberculosis with pulmonary embolism and deep vein thrombosis"
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"abstract": "The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.",
"affiliations": "The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel. erezbaruch@mail.tau.ac.il gal.markel@sheba.health.gov.il.;Pediatric Division and the Microbiome Research Center, Shamir (Assaf Harofeh) Medical Center, Be'er Ya'akov, Israel.;The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel.;The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel.;Department of Gastroenterology, Sheba Medical Center, Tel HaShomer, Israel.;Department of Gastroenterology, Hadassah Medical Center, Jerusalem, Israel.;Department of Mathematics, Bar Ilan University, Ramat Gan, Israel.;Institute of Pathology, Sheba Medical Center, Tel-HaShomer, Israel.;School of Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel.;Institute of Pathology, Sheba Medical Center, Tel-HaShomer, Israel.;Institute of Pathology, Sheba Medical Center, Tel-HaShomer, Israel.;Institute of Pathology, Sheba Medical Center, Tel-HaShomer, Israel.;The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel.;The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel.;Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, USA.;The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel.;The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel.;The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel.;Infectious Diseases Unit, Assuta Ashdod University Hospital, Ashdod, Israel.;School of Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel.;Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel.;Program for Innovative Microbiome and Translational Research, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Program for Innovative Microbiome and Translational Research, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;School of Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel.;Program for Innovative Microbiome and Translational Research, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel.;The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel. erezbaruch@mail.tau.ac.il gal.markel@sheba.health.gov.il.;School of Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"authors": "Baruch|Erez N|EN|https://orcid.org/0000-0001-6001-6598;Youngster|Ilan|I|https://orcid.org/0000-0001-5233-1213;Ben-Betzalel|Guy|G|;Ortenberg|Rona|R|https://orcid.org/0000-0002-3472-431X;Lahat|Adi|A|;Katz|Lior|L|;Adler|Katerina|K|https://orcid.org/0000-0001-5769-8284;Dick-Necula|Daniela|D|;Raskin|Stephen|S|https://orcid.org/0000-0002-3549-0594;Bloch|Naamah|N|;Rotin|Daniil|D|https://orcid.org/0000-0003-3386-0077;Anafi|Liat|L|;Avivi|Camila|C|;Melnichenko|Jenny|J|https://orcid.org/0000-0002-2332-0088;Steinberg-Silman|Yael|Y|https://orcid.org/0000-0002-2003-5062;Mamtani|Ronac|R|;Harati|Hagit|H|https://orcid.org/0000-0002-4840-9994;Asher|Nethanel|N|https://orcid.org/0000-0002-4094-8045;Shapira-Frommer|Ronnie|R|https://orcid.org/0000-0001-6170-080X;Brosh-Nissimov|Tal|T|;Eshet|Yael|Y|https://orcid.org/0000-0002-8339-5823;Ben-Simon|Shira|S|;Ziv|Oren|O|;Khan|Md Abdul Wadud|MAW|https://orcid.org/0000-0001-5258-240X;Amit|Moran|M|;Ajami|Nadim J|NJ|https://orcid.org/0000-0002-3808-8576;Barshack|Iris|I|;Schachter|Jacob|J|;Wargo|Jennifer A|JA|https://orcid.org/0000-0003-3438-7576;Koren|Omry|O|https://orcid.org/0000-0002-7738-1337;Markel|Gal|G|https://orcid.org/0000-0003-4835-891X;Boursi|Ben|B|https://orcid.org/0000-0002-1304-8340",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab",
"country": "United States",
"delete": false,
"doi": "10.1126/science.abb5920",
"fulltext": null,
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"issn_linking": "0036-8075",
"issue": "371(6529)",
"journal": "Science (New York, N.Y.)",
"keywords": null,
"medline_ta": "Science",
"mesh_terms": "D000328:Adult; D000074322:Antineoplastic Agents, Immunological; D018414:CD8-Positive T-Lymphocytes; D000069467:Fecal Microbiota Transplantation; D005260:Female; D000069196:Gastrointestinal Microbiome; D006801:Humans; D007167:Immunotherapy; D007413:Intestinal Mucosa; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor; D012878:Skin Neoplasms; D059467:Transcriptome; D059016:Tumor Microenvironment",
"nlm_unique_id": "0404511",
"other_id": null,
"pages": "602-609",
"pmc": null,
"pmid": "33303685",
"pubdate": "2021-02-05",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients.",
"title_normalized": "fecal microbiota transplant promotes response in immunotherapy refractory melanoma patients"
} | [
{
"companynumb": "IL-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-003102",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
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{
"abstract": "Fluconazole (FLCZ) is an azole antifungal agent and it has shown excellent clinical activities in suppressing fungemia with Candida albicans after hematopoietic stem cell transplantation. Increased administration of prophylactic FLCZ seems to have given rise to the relatively higher incidence of more resistant Candida non-albicans infection. We present a case with a rare breakthrough fungemia with C. guilliermondii after cord blood transplantation for Extranodal NK cell Lymphoma, nasal type (ENKL), during antifungal prophylaxis with FLCZ. High level of caution is needed for the breakthrough, especially after long-term azole administration.",
"affiliations": "Department of Internal Medicine, Division of Hematology, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Internal Medicine, Division of Hematology, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Internal Medicine, Division of Hematology, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Internal Medicine, Division of Hematology, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Internal Medicine, Division of Hematology, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Infectious Diseases, Tokyo Women's Medical University, Tokyo, Japan.;Department of Internal Medicine, Division of Hematology, Shinshu University School of Medicine, Matsumoto, Japan.",
"authors": "Nakazawa|Hideyuki|H|http://orcid.org/0000-0002-6457-5052;Nishina|Sayaka|S|;Senoo|Yasushi|Y|;Sakai|Hitoshi|H|;Ito|Toshiro|T|;Kikuchi|Ken|K|;Ishida|Fumihiro|F|",
"chemical_list": "D000935:Antifungal Agents; D015725:Fluconazole",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12922",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "20(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nCandida guilliermondii\n; breakthrough; cord blood transplantation; extranodal NK cell lymphoma; fluconazole",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D019072:Antibiotic Prophylaxis; D000935:Antifungal Agents; D002175:Candida; D058387:Candidemia; D058365:Candidiasis, Invasive; D036101:Cord Blood Stem Cell Transplantation; D026141:Drug Resistance, Multiple, Fungal; D005260:Female; D015725:Fluconazole; D006801:Humans; D054391:Lymphoma, Extranodal NK-T-Cell; D008826:Microbial Sensitivity Tests; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D050497:Stillbirth; D055815:Young Adult",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e12922",
"pmc": null,
"pmid": "29797683",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Breakthrough Candida guilliermondii (Meyerozyma guilliermondii) fungemia after cord blood transplantation for extranodal NK-cell lymphoma with azole prophylaxis.",
"title_normalized": "breakthrough candida guilliermondii meyerozyma guilliermondii fungemia after cord blood transplantation for extranodal nk cell lymphoma with azole prophylaxis"
} | [
{
"companynumb": "JP-JNJFOC-20181007695",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "We report the cases of 2 breast cancer patients who received capecitabine(CAP)and concomitant anticonvulsant therapy with either phenytoin(PHT)or valproate(VPA)for brain metastasis. The effect of CAP on the blood levels of the 2 anticonvulsants was different and it depended on the variation in metabolism of each drug. Case 1 involved a 59-year-old woman with recurrent breast cancer. After radiation therapy for brain metastases, the patient received PHT(400mg/day)to prevent convulsions. After 5 days of PHT administration, CAP therapy was initiated, and her blood PHT levels increased to 33.8 mg/mL. Although the PHT dose was reduced to 300mg/day, the blood PHT levels markedly increased to 45.5 mg/mL 7 days after the withdrawal of CAP. Case 2 involved a 60-year-old woman with breast cancer who underwent surgery for brain metastases and subsequently received controlled-release VPA tablets(400mg/day). No remarkable change was observed in her blood VPA levels during CAP treatment or after CAP withdrawal(the blood VAP level after 7 days of treatment was, 78.4 mg/mL; after 14 days of treatment, 73.2 mg/mL; and 7 days after withdrawal, 79.7 mg/mL). CAP has been reported to inhibit nucleic acid synthesis and/or folic acid activity rather than cytochrome P450(CYP)directly. CAP had a significant effect on the blood levels of PHT, which is metabolized via the CYP pathway. However, VPA levels remained unchanged because VPA metabolism involves other pathways, such as the beta-oxidation and conjugation pathways.",
"affiliations": "Dept. of Pharmacy, National Hospital Organization.",
"authors": "Tanaka|Hiroyuki|H|;Jotoku|Hiromi|H|;Takasaki|Masahiko|M|;Ibayashi|Yukihiro|Y|;Watanabe|Kenichi|K|;Takahashi|Masato|M|",
"chemical_list": "D000927:Anticonvulsants; D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D014635:Valproic Acid; D010672:Phenytoin; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "41(4)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000927:Anticonvulsants; D000964:Antimetabolites, Antineoplastic; D001932:Brain Neoplasms; D001943:Breast Neoplasms; D000069287:Capecitabine; D003841:Deoxycytidine; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008875:Middle Aged; D010672:Phenytoin; D012640:Seizures; D014635:Valproic Acid",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "527-30",
"pmc": null,
"pmid": "24743375",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Effect of capecitabine therapy on the blood levels of antiepileptic drugs - report of two cases.",
"title_normalized": "effect of capecitabine therapy on the blood levels of antiepileptic drugs report of two cases"
} | [
{
"companynumb": "JP-ACTAVIS-2014-14215",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
... |
{
"abstract": "Lenvatinib is an oral tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, as well as platelet-derived growth factor receptor α, RET, and KIT. At present, lenvatinib is used in the treatment of thyroid cancer and renal cell carcinoma. We herein report a case of a 67-year-old patient with squamous cell carcinoma of unknown primary who was effectively treated with lenvatinib. The patient was initially diagnosed as having undifferentiated thyroid cancer, and after total thyroidectomy and bilateral lymph node dissection, lenvatinib was administered for the treatment of residual lymph node metastasis. A computed tomography scan after 1 month of lenvatinib administration showed marked regression of the lymph nodes, but interstitial pneumonia was also detected. Because the drug lymphocyte stimulation test for lenvatinib was strongly positive, we concluded that the interstitial pneumonia was induced by lenvatinib. The interstitial pneumonia only improved by the withdrawal of lenvatinib. Finally, his thyroid tumor was diagnosed as a metastasis of squamous cell carcinoma; however, we were unable to identify the primary lesion. This is the first reported case of interstitial pneumonia induced by lenvatinib.",
"affiliations": "aDepartment of Medical Oncology, Fukushima Medical University, Fukushima, Japan.;aDepartment of Medical Oncology, Fukushima Medical University, Fukushima, Japan.;bDepartment of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan.;bDepartment of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan.;cDepartment of Diagnostic Pathology, Fukushima Medical University, Fukushima, Japan.;bDepartment of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan.;bDepartment of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan.;cDepartment of Diagnostic Pathology, Fukushima Medical University, Fukushima, Japan.;bDepartment of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, Japan.;aDepartment of Medical Oncology, Fukushima Medical University, Fukushima, Japan.",
"authors": "Kimura-Tsuchiya|Reiko|R|;Sasaki|Eisaku|E|;Nakamura|Izumi|I|;Suzuki|Satoshi|S|;Kawana|Satoshi|S|;Okouchi|Chiyo|C|;Fukushima|Toshihiko|T|;Hashimoto|Yuko|Y|;Suzuki|Shinichi|S|;Saji|Shigehira|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000486569",
"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 10.1159/000486569cro-0011-0075Case ReportA Case of Squamous Cell Carcinoma of Unknown Primary that Responded to the Multi-Tyrosine Kinase Inhibitor Lenvatinib Kimura-Tsuchiya Reiko aSasaki Eisaku aNakamura Izumi bSuzuki Satoshi bKawana Satoshi cOkouchi Chiyo bFukushima Toshihiko bHashimoto Yuko cSuzuki Shinichi bSaji Shigehira a*aDepartment of Medical Oncology, Fukushima Medical University, Fukushima, JapanbDepartment of Thyroid and Endocrinology, Fukushima Medical University, Fukushima, JapancDepartment of Diagnostic Pathology, Fukushima Medical University, Fukushima, Japan*Shigehira Saji, MD, PhD, Department of Medical Oncology, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295 (Japan), E-Mail ssaji@fmu.ac.jpJan-Apr 2018 9 2 2018 9 2 2018 11 1 75 80 3 1 2018 3 1 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Lenvatinib is an oral tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, as well as platelet-derived growth factor receptor α, RET, and KIT. At present, lenvatinib is used in the treatment of thyroid cancer and renal cell carcinoma. We herein report a case of a 67-year-old patient with squamous cell carcinoma of unknown primary who was effectively treated with lenvatinib. The patient was initially diagnosed as having undifferentiated thyroid cancer, and after total thyroidectomy and bilateral lymph node dissection, lenvatinib was administered for the treatment of residual lymph node metastasis. A computed tomography scan after 1 month of lenvatinib administration showed marked regression of the lymph nodes, but interstitial pneumonia was also detected. Because the drug lymphocyte stimulation test for lenvatinib was strongly positive, we concluded that the interstitial pneumonia was induced by lenvatinib. The interstitial pneumonia only improved by the withdrawal of lenvatinib. Finally, his thyroid tumor was diagnosed as a metastasis of squamous cell carcinoma; however, we were unable to identify the primary lesion. This is the first reported case of interstitial pneumonia induced by lenvatinib.\n\nKeywords\nCarcinoma of unknown primaryLenvatinibSquamous cell carcinoma\n==== Body\nIntroduction\nLenvatinib is an oral, multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1, 2, 3, and 4, platelet-derived growth factor receptor α, and RET and KIT signaling networks, which are involved in tumor growth [1, 2, 3]. Lenvatinib has been approved in 50 countries, including the US and the European Union, for the treatment of radioiodine-refractory differentiated thyroid cancer, and in Japan for the treatment of unresectable thyroid cancer [4, 5].\n\nWe herein report a case of squamous cell carcinoma of unknown primary that was effectively treated with lenvatinib.\n\nCase Presentation\nA 67-year-old man presented to a regional hospital with a tumor over the right clavicle. A computed tomography (CT) scan with contrast enhancement showed enlarged lymph nodes in the neck, mediastinum, and left axilla (Fig. 1a–c). A right supra-clavicular lymph node biopsy revealed poorly differentiated carcinoma. 18F-fluorodeoxyglucose positron emission tomography/CT showed hot spots in the right lobe of the thyroid and lymph nodes (Fig. 1d). Although the tumor was unclear on CT and ultrasonography images, fine needle aspiration cytology of the right lobe of the thyroid showed poorly differentiated carcinoma cells similar to those in the observed lymph node. The serum level of the tumor marker carcinoembryonic antigen (CEA) was 1,390.0 ng/mL and the levels of the carbohydrate antigens 19-9 and 125 were 44.2 and 294 U/mL, respectively. Based on a provisional diagnosis of undifferentiated thyroid cancer with lymph node metastasis, the patient underwent total thyroidectomy and bilateral lymph node dissection. Microscopically, undifferentiated carcinoma was suspected (Fig. 2). Lenvatinib (24 mg/day) was administered for the treatment of residual lymph node metastasis. A CT scan after 1 month of lenvatinib administration showed marked regression of the lymph nodes in the mediastinum and left axilla; however, interstitial pneumonia was also detected in the bilateral lung (Fig. 3). The patient complained of mild cough and dyspnea on exertion, but had no fever. His oxygen saturation on room air was 98%. Chest auscultation of both lung fields revealed no crackles, wheezes, or rhonchi, and chest X-ray showed bilateral infiltrative shadows (Fig. 3). His KL-6 (Krebs von den Lungen-6) levels (< 500 U/mL) were 582 U/mL, and his serum CEA levels decreased from 687 to 338 ng/mL after the administration of lenvatinib. The drug lymphocyte stimulation test for lenvatinib was strongly positive (1,276 cpm, stimulation index 383; normal range: lower than 180). Broncho-alveolar lavage fluid revealed inflammatory changes with a cell differential count of 36.0% macrophages, 61.1% lymphocytes, 0% neutrophils, 2.9% eosinophils, and decreased CD 4/8 ratio (0.1). From these results, we diagnosed the patient as having lenvatinib-induced interstitial pneumonia. Lenvatinib was discontinued on the day of the CT scan (day 30). Due to the withdrawal, interstitial pneumonia improved remarkably. A pathologist who specializes in thyroid cancer diagnosed the patient's thyroid tumor as a possible metastasis of poorly differentiated epithelial tumor. Further evaluation revealed that the tumor cells were positive for p40, demonstrating metastatic squamous cell carcinoma. Although the lung, head and neck were suspected as possible locations for the primary lesion, we were unable to identify the origin. During the 2-month period in which lenvatinib was not being administrated, the patient's CEA level increased, and a CT scan showed enlarged lymph nodes in the mediastinum and left axilla. He was treated for carcinoma of unknown primary with carboplatin and paclitaxel as second-line treatment. Following three cycles of chemotherapy with carboplatin and paclitaxel, stable disease was achieved in accordance with RECIST criteria (Fig. 4).\n\nDiscussion\nThere are two points of importance to be taken from this case: (1) lenvatinib was effective for squamous cell carcinoma and (2) to the best of our knowledge, this is the first report of interstitial pneumonia induced by administration of lenvatinib, which was confirmed by the drug lymphocyte stimulation test.\n\nLenvatinib is generally used to treat advanced and rapidly progressing thyroid cancer that can no longer be treated with radioactive iodine. Lenvatinib is also used with mammalian target of rapamycin inhibitor everolimus to treat advanced renal cell carcinoma as a second-line treatment. Lenvatinib for the treatment of hepatocellular carcinoma is in the process of approval in Japan, the US, Europe, and China.\n\nIn Europe and the US, lenvatinib is indicated for the treatment of locally recurrent or metastatic progressive, radioiodine-refractory differentiated thyroid cancer. In Japan, lenvatinib is not only used for differentiated but also for undifferentiated thyroid cancer. Therefore, in the current case, we administered lenvatinib for undifferentiated thyroid cancer that was finally diagnosed as squamous cell carcinoma of unknown primary. Currently, phase Ib/II studies are being undertaken to investigate the efficacy and safety of lenvatinib in combination with pembrolizumab in some solid tumors (non-small cell lung cancer, endometrial cancer, urothelial cancer, head and neck cancer, and melanoma). The current report suggests that lenvatinib is also effective for some types of squamous cell carcinoma, probably because of tyrosine kinases targeted by this drug like vascular endothelial growth factor receptors, fibroblast growth factor receptors, platelet-derived growth factor receptor α, KIT, and RET.\n\nTo date, new anticancer drugs, including molecular targeted drugs, have been developed and approved based on tumor origin. However, in May 2017, the US Food and Drug Administration approved treatment for patients whose cancers have specific biomarkers. In particular, pembrolizumab is indicated for the treatment of patients with unresectable or metastatic solid tumors that have been identified as having one of the following biomarkers: MSI-H (microsatellite instability-high) or dMMR (deficient mismatch repair). Going forward, drugs should be developed and approved based on the tumor's biomarker, rather than its original location.\n\nAmong the clinical trials, no cases with interstitial pneumonia induced by lenvatinib have been reported. In an interim report of all cases of post-marketing surveillance (June 2017), this was the only case of interstitial pneumonia induced by lenvatinib.\n\nOther tyrosine kinase inhibitors, such as gefitinib and erlotinib, are known to induce interstitial pneumonia, and as risk factors, performance status 2–4, smoking history, and complications of interstitial lung disease were reported [6, 7]. Our patient had performance status 0, with a 15 pack-year smoking history and no complications of interstitial lung disease. Interstitial pneumonia was found on CT during follow-up observation, and was only improved by withdrawal of lenvatinib.\n\nA limitation of this study was that comprehensive gene analysis of the tumor was not performed; therefore, it is not known whether an activated tyrosine kinase targeted by lenvatinib was present in squamous cell carcinoma in our patient.\n\nConclusions\nThe current report confirms the clinical effect of lenvatinib in a case with squamous cell carcinoma. In addition, to the best of our knowledge, this is the first case of interstitial pneumonia induced by lenvatinib.\n\nStatement of Ethics\nThe authors have no ethical conflicts to declare.\n\nDisclosure Statement\nS. Saji has received honoraria and a research grant from Eisai Inc. The remaining authors declare that there are no conflicts of interest.\n\nFig. 1. Computed tomography (CT) scans with contrast enhancement (a–c) showed lymph node swelling of the neck, mediastinum, and left axilla. 18F-fluorodeoxyglucose positron emission tomography/CT (d) showed a hot spot in the right lobe of the thyroid.\n\nFig. 2. Hematoxylin and eosin staining showed numerous foci of atypical cells between follicles in the thyroid tissue. The tumor cells in a and b showed sheet-like arrangement, but no keratinization, intercellular bridge, glandular structure or mucin production. Because of such undifferentiated features, the tumor was diagnosed as undifferentiated thyroid cancer at first. Further study revealed that all tumor cells were within the D2-40-positive lymph ducts, did not infiltrate thyroid parenchyma (c), and were positive for p40 (d). These results showed that the tumor is metastatic squamous cell carcinoma of unknown primary.\n\nFig. 3. A chest CT scan showed mosaic patterns with ground-glass opacities in both lungs (left). A chest X-ray taken on day 35. Diffuse infiltrative shadows were observed in both lung fields (right).\n\nFig. 4. Clinical course of the patient. Day 1 is the starting date of the first cycle of lenvatinib administration. CBDCA, carboplatin; PTX, paclitaxel.\n==== Refs\nReferences\n1 Okamoto K Kodama K Takase K Sugi NH Yamamoto Y Iwata M Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models Cancer Lett 2013 Oct 340 (1) 97 103 23856031 \n2 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 Sep 14 (17) 5459 65 18765537 \n3 Matsui J Yamamoto Y Funahashi Y Tsuruoka A Watanabe T Wakabayashi T 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 Feb 122 (3) 664 71 17943726 \n4 Schlumberger M Tahara M Wirth LJ Robinson B Brose MS Elisei R Lenvatinib versus placebo in radioiodine-refractory thyroid cancer N Engl J Med 2015 Feb 372 (7) 621 30 25671254 \n5 Kiyota N Schlumberger M Muro K Ando Y Takahashi S Kawai Y Subgroup analysis of Japanese patients in a phase 3 study of lenvatinib in radioiodine-refractory differentiated thyroid cancer Cancer Sci 2015 Dec 106 (12) 1714 21 26426092 \n6 Murashige N Tanimoto T Oshima Y Interstitial lung disease and gefitinib N Engl J Med 2010 Oct 363 (16) 1578 9 20942679 \n7 Inoue A Saijo Y Maemondo M Gomi K Tokue Y Kimura Y Severe acute interstitial pneumonia and gefitinib Lancet 2003 Jan 361 (9352) 137 9 12531582\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "11(1)",
"journal": "Case reports in oncology",
"keywords": "Carcinoma of unknown primary; Lenvatinib; Squamous cell carcinoma",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "75-80",
"pmc": null,
"pmid": "29515414",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "25671254;17943726;26426092;20942679;12531582;23856031;18765537",
"title": "A Case of Squamous Cell Carcinoma of Unknown Primary that Responded to the Multi-Tyrosine Kinase Inhibitor Lenvatinib.",
"title_normalized": "a case of squamous cell carcinoma of unknown primary that responded to the multi tyrosine kinase inhibitor lenvatinib"
} | [
{
"companynumb": "JP-EISAI MEDICAL RESEARCH-EC-2018-036603",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LENVATINIB"
},
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{
"abstract": "BACKGROUND\nThe prevalence of parvovirus B19 infection in renal transplantation ranges from 2% to 30%. The age and immune status of the patient influence the severity of the clinical picture. A diagnosis is made by taking as evidence the giant proerythroblasts on a bone marrow sample and the parvovirus B19 viral replication with a polymerase chain reaction (PCR) technique at the blood level. Clinically, parvovirus B19 may appear with fever and severe anemia, which can be followed by pancytopenia and thrombotic microangiopathy in some cases. The literature reports a graft dysfunction rate ranging from 10% to 36%. An infection relapse may happen in 30% of cases.\n\n\nMETHODS\nWe report the case of a 33-year-old patient who underwent a kidney transplant in January of 2018. After transplantation, he reached a creatinine value of 1.1 mg/dL and a hemoglobin (Hb) level of 14 g/dL. In April 2019, he developed mycoplasma pneumonia, with signs of hemolytic anemia on bone marrow aspiration. Eventually, he was admitted because of fever, arthralgia, and anemia, with serologic and bone marrow biopsy evidence of red cell aplasia secondary to parvovirus B19 infection. He was treated with 400 mg/kg intravenous immunoglobulin (IVIg) for 10 days; 18 days after the end of treatment, he reached a creatinine value of 1.15 mg/dL, an Hb of 12.5 g/dL, and a reduction of the viral load from 25,000,000 copies/mL to 1,600,000 copies/mL.\n\n\nCONCLUSIONS\nAnemia with both an aplasic and hemolytic component was successfully treated using immunoglobulin therapy, with a significant fall in the parvovirus B19 viral load.",
"affiliations": "Renal Transplant Unit, AO Brotzu, Cagliari, Italy. Electronic address: giac.mascia@hotmail.it.;Renal Transplant Unit, AO Brotzu, Cagliari, Italy.;Renal Transplant Unit, AO Brotzu, Cagliari, Italy.;Renal Transplant Unit, AO Brotzu, Cagliari, Italy.;Renal Transplant Unit, AO Brotzu, Cagliari, Italy.",
"authors": "Mascia|Giacomo|G|;Argiolas|Davide|D|;Carta|Elisabetta|E|;Ibba|Sabrina|S|;Piredda|Gian Benedetto|GB|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D003404:Creatinine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.02.077",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "52(5)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000740:Anemia; D003404:Creatinine; D016731:Erythema Infectiosum; D005334:Fever; D006801:Humans; D016756:Immunoglobulins, Intravenous; D016030:Kidney Transplantation; D008297:Male; D016133:Polymerase Chain Reaction; D012008:Recurrence; D012010:Red-Cell Aplasia, Pure; D014652:Vascular Diseases; D019562:Viral Load",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1619-1622",
"pmc": null,
"pmid": "32389489",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment of Anemia With Anaplastic and Microangiopathic Characteristics in a Kidney Transplant Recipient With Parvovirus B19 Infection: A Case Report.",
"title_normalized": "successful treatment of anemia with anaplastic and microangiopathic characteristics in a kidney transplant recipient with parvovirus b19 infection a case report"
} | [
{
"companynumb": "IT-PFIZER INC-2020368128",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Invasive pulmonary aspergillosis (IPA) is an opportunistic infection that usually threatens immunocompromised patients. However, there are some reports of IPA in immunocompetent patients without the obvious classic risk factors. We present the case of an 82-year-old woman with a prior medical history of chronic obstructive pulmonary disease (COPD) and a recent short-term corticosteroid regimen for an acute exacerbation. She was admitted with dyspnoea, cough, and pleuritic pain and was diagnosed with pneumonia. Clinical deterioration occurred, and a diagnosis of IPA was made. She received treatment with voriconazole but died 14 days after admission. This case highlights the importance of considering IPA among the possible causes of infection in this population. Prompt institution of appropriate antifungal therapy is paramount for the management of this condition.",
"affiliations": "Internal Medicine, Unidade Local de Saúde do Alto Minho, Viana do Castelo, PRT.;Internal Medicine, Unidade Local de Saúde do Alto Minho, Viana do Castelo, PRT.;Internal Medicine, Unidade Local de Saúde do Alto Minho, Viana do Castelo, PRT.;Internal Medicine, Unidade Local de Saúde do Alto Minho, Viana do Castelo, PRT.;Internal Medicine, Unidade Local de Saúde do Alto Minho, Viana do Castelo, PRT.",
"authors": "Teixeira da Silva|Francisco|F|;Romano|Miguel|M|;Esteves|Alexandra|A|;Carvalho|José|J|;Ferreira|Manuel|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.10238",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.10238\nInternal Medicine\nInfectious Disease\nPulmonology\nInvasive Pulmonary Aspergillosis in an (Apparently) Immunocompetent Patient\nMuacevic Alexander Adler John R Teixeira da Silva Francisco 1 Romano Miguel 1 Esteves Alexandra 1 Carvalho José 1 Ferreira Manuel 1 \n1 \nInternal Medicine, Unidade Local de Saúde do Alto Minho, Viana do Castelo, PRT \n\nFrancisco Teixeira da Silva f.teixeirasilva@gmail.com\n4 9 2020 \n9 2020 \n12 9 e1023820 8 2020 4 9 2020 Copyright © 2020, Teixeira da Silva et al.2020Teixeira da Silva 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/39963-invasive-pulmonary-aspergillosis-in-an-apparently-immunocompetent-patientInvasive pulmonary aspergillosis (IPA) is an opportunistic infection that usually threatens immunocompromised patients. However, there are some reports of IPA in immunocompetent patients without the obvious classic risk factors. We present the case of an 82-year-old woman with a prior medical history of chronic obstructive pulmonary disease (COPD) and a recent short-term corticosteroid regimen for an acute exacerbation. She was admitted with dyspnoea, cough, and pleuritic pain and was diagnosed with pneumonia. Clinical deterioration occurred, and a diagnosis of IPA was made. She received treatment with voriconazole but died 14 days after admission. This case highlights the importance of considering IPA among the possible causes of infection in this population. Prompt institution of appropriate antifungal therapy is paramount for the management of this condition.\n\ninvasive aspergillosiscopdimmune responseThe 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\nAspergillus spp. are ubiquitous fungi found in the soil, rubble, and indoor environment. They may cause infectious or allergic diseases depending on the host’s immune situation and pulmonary structure [1]. Invasive pulmonary aspergillosis (IPA) occurs most frequently in patients receiving long-term corticosteroids and in transplant and oncologic patients, predominantly those with haematological disease. Aspergillosis may, in rare situations, occur in immunocompetent individuals [2].\n\nCase presentation\nWe present the case of an 82-year-old female nursing-home resident with a previous medical history of valvular heart failure and chronic obstructive pulmonary disease (COPD). One month before her admission, she was diagnosed with infected bronchiectasis. She received in-hospital treatment with levofloxacin and systemic corticosteroids (methylprednisolone) during 14 days and recovered completely. She presented to our emergency department with a two-day history of worsening dyspnoea, productive cough, and pleuritic pain. On clinical examination, she was tachypneic and hypotensive, with decreased breathing sounds and bibasal crackles on pulmonary auscultation. Laboratory workup showed leucocytosis with neutrophilia, hypoxia (pO2 51 mmHg - fiO2 0.21), and elevation of C-reactive protein (CRP) and brain natriuretic peptide (BNP) (Table 1).\n\nTable 1 Laboratory workup\nHtc, haematocrit; CRP, C-reactive protein; BNP, brain natriuretic peptide; HBV, hepatitis B virus; HCV, hepatitis C virus \n\nTests\tReference values\tResults\t\nHaemoglobin (g/dL)\t11.8-15.8\t12\t\nHtc (%)\t36-46\t35.7\t\nLeuocytes (µL)\t4.0-10.0\t21.670\t\nNeutrophils\t1,800–7,700\t19.280 (89%)\t\nLymphocytes\t800-4,000\t910 (4.2%)\t\nPlatelets (109/µL)\t150-400\t220\t\nGlucose (mg/dL)\t70-110\t175\t\nUrea (mg/dL)\t17-43\t90\t\nCreatinine (mg/dL)\t0.6-1.0\t0.81\t\nSodium (mmol/L)\t136-145\t131\t\nPotassium (mmol/L)\t3.5-5.1\t5.4\t\nCRP (mg/dL)\t0.01-0.82\t3.34\t\nBNP (pg/mL)\t<100\t334.5\t\nHBV, HCV, HIV1-2 serologies\t \tNegative\t\nA chest X-ray revealed an image of condensation in the right upper lobe (Figure 1). A diagnosis of nosocomial pneumonia was made and she started empirical antibacterial therapy with piperacillin-tazobactam. She continued with persistent fever, shortness of breath, and hypoxaemia and did not respond to initial therapy with inhaled bronchodilators plus systemic corticosteroids. \n\nFigure 1 Chest X-ray\nCondensation image in the right upper lobe (arrow).\n\nA chest CT scan revealed areas of consolidation in the right upper lobe with gas-fluid levels inside, indicating necrotizing pneumonia and several scattered micronodules suggesting endobronchial dissemination of an acute infective aetiology (Figure 2). Sputum samples for acid-fast bacilli (AFB) were negative, and the patient was evaluated for eosinophilia but peripheral blood smear did not show any relevant abnormalities. Antibiotics were escalated and the patient was started on imipenem and clindamycin. A bronchoscopy was performed and the bronchoalveolar lavage (BAL) fluid was negative for AFB and bacterial pathogens. BAL cytology showed hyphae, and numerous colonies of Aspergillus fumigatus were found on culture examination. The patient was managed with voriconazole but developed multiorgan failure and died on hospital day 14. \n\nFigure 2 CT scan\nAreas of consolidation in the right upper lobe with gas-fluid levels inside, suggesting necrotizing pneumonia (arrow).\n\nDiscussion\nIn most cases, infectious Aspergillus spores are introduced to the lower respiratory tract by inhalation. They can germinate into hyphae and can then invade the mucosa leading to IPA [3]. The diagnosis remains difficult; symptoms, which include fever unresponsive to antibiotics, productive cough, and dyspnoea, are non-specific and usually mimic pneumonia [4].\n\nTissue biopsy with histopathologic demonstration of tissue invasion by fungal hyphae is the ‘gold standard’ but is not always possible. Regarding imaging exams, a chest CT scan is recommended for the evaluation of lung parenchyma. Pulmonary nodules are the most commonly identified abnormalities, and the historic ‘halo sign’ is fairly specific for pulmonary aspergillosis. Laboratory tests to identify antigens in body fluids (e.g. serum or BAL) are also helpful. Galactomannan (GM) testing or Aspergillus polymerase chain reaction (PCR) assay in BAL has decent specificity and sensitivity for IPA [4].\n\nThe revised EORTC/MSG criteria define invasive fungal disease and were designed to advance clinical and epidemiological research as well as to help and guide clinicians in daily practice [5]. The isolation of Aspergillus spp. from a sterile BAL fluid from immunosuppressed patients is highly indicative of invasive aspergillosis.\n\nClassic risk factors for API include prolonged neutropenia, transplantation (the highest risk with lung transplant and haematopoietic stem-cell transplantation), chemotherapy, immunosuppression, and neoplasia (namely haematological). Several recent studies reinforce that the host's immune status and response play a fundamental role in the onset and evolution of the disease. Critical and COPD patients should therefore also be considered at risk [1,2].\n\nIt is not completely established why COPD patients may develop IPA. Potential risk factors predisposing COPD patients include corticosteroid therapy, the severity of underlying lung disease and COPD staging, critical illness, previous colonization of airways by Aspergillus spp., impaired mucociliary clearance, frequent use of broad-spectrum antibiotics, and possibly genetic factors (such as surfactant proteins or mannose-binding protein defects) [6].\n\nDespite the introduction of several new antifungal agents, the treatment of IPA remains difficult and mortality rates are still high. Voriconazole is the first-line treatment of IPA, and alternative agents include caspofungin, itraconazole, and amphotericin B. Treatment duration should be individualized to clinical and radiological response. The treatment is often lengthy, lasting from several months to up to one year. Surgical resection has a very limited role in the management of such patients but should be considered in cases with extrapulmonary involvement, such as bone invasion, burn victims, epidural abscesses, and ocular disease [1,2].\n\nConclusions\nThis case illustrates that COPD, short-term corticosteroid, and older age should be considered as risk factors for IPA. The diagnosis is often delayed due to lack of suspicion. When presented with worsening or refractory symptoms and increasing pulmonary abnormalities on imaging studies, investigation to rapidly confirm the diagnosis is warranted.\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 Pulmonary aspergillosis: a clinical review Eur Respir Rev Kousha M Tadi R Soubani AO 156 174 20 2011 21881144 \n2 Invasive pulmonary aspergillosis: case report and review of literature J Community Hosp Intern Med Perspect Naaraayan A Kavian R Lederman J Basak P Jesmajian S 26322 5 2015 25656673 \n3 An unusual case of invasive aspergillosis in an immunocompetent individual BMJ Case Rep Mohammed AP Dhunputh P Chiluka R Umakanth S 0 2015 2015 \n4 Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America Clin Infect Dis Patterson TF Thompson GR III Denning DW 1 60 63 2016 27048748 \n5 Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group Clin Infect Dis De Pauw B Walsh TJ Donnelly JP 1813 1821 46 2008 18462102 \n6 Invasive pulmonary aspergillosis in patients with COPD: a report of five cases and systematic review of the literature Chron Respir Dis Samarakoon P Soubani AO 19 27 5 2008 18303098\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(9)",
"journal": "Cureus",
"keywords": "copd; immune response; invasive aspergillosis",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e10238",
"pmc": null,
"pmid": "33042679",
"pubdate": "2020-09-04",
"publication_types": "D002363:Case Reports",
"references": "18303098;25656673;27365388;21881144;26123468;18462102",
"title": "Invasive Pulmonary Aspergillosis in an (Apparently) Immunocompetent Patient.",
"title_normalized": "invasive pulmonary aspergillosis in an apparently immunocompetent patient"
} | [
{
"companynumb": "PT-ALVOGEN-2020-ALVOGEN-115029",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND\nCauses of acute limb ischemia are classically mainly emboli and thrombosis. Nicolau syndrome is a very rare complication of intramuscular injection presumed to be related to the inadvertent intravascular injection. It was first reported after intramuscular injection of bismuth salt, but it can occur as a complication of various other drugs. Acute limb ischemia is one of its severe outcomes but is rarely encountered and reported.\n\n\nMETHODS\nPatients admitted with the final diagnosis of Nicolau syndrome in our institution in 3 years (2016 2017 and 2018) are reviewed in terms of etiology, clinical presentation, management, and outcome.\n\n\nRESULTS\nWe present here 4 cases of Nicolau syndrome that lead to acute limb ischemia and with the same outcome: limb or fingers loss; there were 2 upper extremities for 2 women secondary to diclofenac and dexamethasone intramuscular administration and 2 lower extremities for 2 men in relation with Benzathine Penicillin intramuscular administration. The medical and surgical management that we attempted did not prevent this severe outcome.\n\n\nCONCLUSIONS\nNicolau syndrome should be considered when looking for rare etiologies of acute limb ischemias.",
"affiliations": "Department of Surgery, Yaounde General Hospital, Yaounde, Cameroon. Electronic address: mfokou@yahoo.com.;Department of Surgery, Yaounde General Hospital, Yaounde, Cameroon.;Department of Medicine, Yaounde General Hospital, Yaounde, Cameroon.;Department of Surgery, Yaounde General Hospital, Yaounde, Cameroon.",
"authors": "Marcus|Fokou|F|;Claude|Eyenga Victor|EV|;Josephine|Meli|M|;Teyang|Abel|A|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.avsg.2018.11.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-5096",
"issue": "58()",
"journal": "Annals of vascular surgery",
"keywords": null,
"medline_ta": "Ann Vasc Surg",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000671:Amputation; D003646:Debridement; D000071938:Fasciotomy; D005260:Female; D005734:Gangrene; D006801:Humans; D007273:Injections, Intramuscular; D007511:Ischemia; D035002:Lower Extremity; D008297:Male; D008875:Middle Aged; D013577:Syndrome; D016896:Treatment Outcome; D034941:Upper Extremity; D014945:Wound Healing; D055815:Young Adult",
"nlm_unique_id": "8703941",
"other_id": null,
"pages": "383.e7-383.e11",
"pmc": null,
"pmid": "30769069",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An Exceptional Cause of Acute Limb Ischemia: Nicolau Syndrome-Single-Center Experience with 4 Cases.",
"title_normalized": "an exceptional cause of acute limb ischemia nicolau syndrome single center experience with 4 cases"
} | [
{
"companynumb": "CM-ASSERTIO THERAPEUTICS, INC.-CM-2019DEP000636",
"fulfillexpeditecriteria": "1",
"occurcountry": "CM",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC POTASSIUM"
},
... |
{
"abstract": "A case history is presented of a 34-year-old woman who was treated postoperatively for breast cancer with combination chemotherapy including epirubicin. The catheter of the port penetrated the wall of the superior vena cava, and extravasation in the mediastinum occurred. Severe pain, fever, and bilateral pleural effusion developed that necessitated two drainage procedures. She recovered well without sequelae. A comprehensive search of the medical literature was conducted using MEDLINE including bibliographies of all selected articles. Six additional cases of intrathoracic cytostatic agent extravasation were identified and the etiologic factors, clinical course, treatment strategy, and outcome were reviewed for each case.",
"affiliations": "Department of Thoracic and Cardiovascular Surgery, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey.",
"authors": "Bozkurt|A Kürşat|AK|;Uzel|Burak|B|;Akman|Canan|C|;Ozgüroğlu|Mustafa|M|;Molinas Mandel|Nil|N|",
"chemical_list": "D003287:Contrast Media; D015251:Epirubicin",
"country": "United States",
"delete": false,
"doi": "10.1097/00000421-200304000-00003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3732",
"issue": "26(2)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D002408:Catheters, Indwelling; D003131:Combined Modality Therapy; D003287:Contrast Media; D004322:Drainage; D015251:Epirubicin; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005260:Female; D006801:Humans; D006876:Hydrothorax; D008482:Mediastinum; D010996:Pleural Effusion; D013350:Subclavian Vein; D014057:Tomography, X-Ray Computed; D014683:Vena Cava, Superior",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "121-3",
"pmc": null,
"pmid": "12714879",
"pubdate": "2003-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Intrathoracic extravasation of antineoplastic agents: case report and systematic review.",
"title_normalized": "intrathoracic extravasation of antineoplastic agents case report and systematic review"
} | [
{
"companynumb": "TR-PFIZER INC-2020501925",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nType B insulin resistance is a very rare disease caused by autoantibodies against the insulin receptor. The mortality of type B insulin resistance is high (>50%), and management of this disease is not yet standardized. We report the successful treatment of a patient with type B insulin resistance with rituximab, cyclophosphamide, and prednisone.\n\n\nMETHODS\nA 45-year-old woman presented with unintended weight loss of 20 kg, unusually widespread acanthosis nigricans, and glucose levels > 500 mg/dL, which could not be controlled with up to 600 IU/d of insulin. Because of the severity of the insulin resistance combined with features of insulin deficiency, type B insulin resistance was suspected. Detection of high levels of insulin receptor autoantibodies confirmed the diagnosis. Neither immunosuppressive therapy with Ig iv nor plasmapheresis had an effect on glucose levels or insulin dose. Because the patient's condition was deteriorating, we started rituximab (750 mg/m(2) in two doses 2 wk apart) together with cyclophosphamide (100 mg/d orally) and dexamethasone 40 mg/d for 4 days. Two months after initiation of rituximab therapy, fasting glucose levels ranged from 80 to 110 mg/dL and could be controlled with very low insulin doses. Glycated hemoglobin decreased from 11.8 to 6.5%. Two months later, insulin therapy was stopped, and the patient showed normal blood glucose readings.\n\n\nCONCLUSIONS\nIn this patient with type B insulin resistance, Ig treatment and plasmapheresis failed to improve the condition. Finally, treatment with rituximab, cyclophosphamide, and steroids was successful in inducing a complete remission.",
"affiliations": "University Duisburg-Essen (E.-D.M., D.F., L.C.M.), Department of Endocrinology and Metabolism and Division of Laboratory Research, 45147 Essen, Germany; Wellcome Trust-Medical Research Council Institute of Metabolic Science (I.I., R.K.S.), Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and University of Maryland School of Medicine (R.M.), Division of Endocrinology, Diabetes, and Nutrition, Baltimore, Maryland 21201.",
"authors": "Manikas|Emmanouil-Dimitrios|ED|;Isaac|Iona|I|;Semple|Robert K|RK|;Malek|Rana|R|;Führer|Dagmar|D|;Moeller|Lars C|LC|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D001323:Autoantibodies; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D000069283:Rituximab; D011972:Receptor, Insulin",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2014-3552",
"fulltext": "\n==== Front\nJ Clin Endocrinol MetabJ. Clin. Endocrinol. MetabjcemjcemejcemThe Journal of Clinical Endocrinology and Metabolism0021-972X1945-7197Endocrine Society Chevy Chase, MD 14-355210.1210/jc.2014-35524Special FeaturesClinical Case SeminarSuccessful Treatment of Type B Insulin Resistance With Rituximab Manikas Emmanouil-Dimitrios Isaac Iona Semple Robert K. Malek Rana Führer Dagmar Moeller Lars C. University Duisburg-Essen (E.-D.M., D.F., L.C.M.), Department of Endocrinology and Metabolism and Division of Laboratory Research, 45147 Essen, Germany; Wellcome Trust-Medical Research Council Institute of Metabolic Science (I.I., R.K.S.), Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and University of Maryland School of Medicine (R.M.), Division of Endocrinology, Diabetes, and Nutrition, Baltimore, Maryland 21201Address all correspondence and requests for reprints to: Lars Moeller, MD, Department of Endocrinology and Metabolism and Division of Laboratory Research, University Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany. E-mail: lars.moeller@uni-due.de.5 2015 12 2 2015 12 2 2015 100 5 1719 1722 16 9 2014 6 2 2015 This article has been published under the terms of the Creative Commons Attribution License (CC-BY; https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s).Context:\nType B insulin resistance is a very rare disease caused by autoantibodies against the insulin receptor. The mortality of type B insulin resistance is high (>50%), and management of this disease is not yet standardized. We report the successful treatment of a patient with type B insulin resistance with rituximab, cyclophosphamide, and prednisone.\n\nCase Description:\nA 45-year-old woman presented with unintended weight loss of 20 kg, unusually widespread acanthosis nigricans, and glucose levels > 500 mg/dL, which could not be controlled with up to 600 IU/d of insulin. Because of the severity of the insulin resistance combined with features of insulin deficiency, type B insulin resistance was suspected. Detection of high levels of insulin receptor autoantibodies confirmed the diagnosis. Neither immunosuppressive therapy with Ig iv nor plasmapheresis had an effect on glucose levels or insulin dose. Because the patient's condition was deteriorating, we started rituximab (750 mg/m2 in two doses 2 wk apart) together with cyclophosphamide (100 mg/d orally) and dexamethasone 40 mg/d for 4 days. Two months after initiation of rituximab therapy, fasting glucose levels ranged from 80 to 110 mg/dL and could be controlled with very low insulin doses. Glycated hemoglobin decreased from 11.8 to 6.5%. Two months later, insulin therapy was stopped, and the patient showed normal blood glucose readings.\n\nConclusion:\nIn this patient with type B insulin resistance, Ig treatment and plasmapheresis failed to improve the condition. Finally, treatment with rituximab, cyclophosphamide, and steroids was successful in inducing a complete remission.\n==== Body\nThe syndrome of type B insulin resistance is caused by circulating autoantibodies against the insulin receptor. The manifestation occurs mainly in the fourth to sixth decade of life with female preponderance and is commonly associated with other autoimmune conditions, eg, systemic lupus erythematosus. Clinically, the condition presents with widespread acanthosis nigricans, often with severe insulin resistance, and less often with hyperandrogenism and hirsutism (1). Acanthosis nigricans tends to improve with the disappearance of circulating antibodies (2). The syndrome is caused by polyclonal antibodies (typically IgG) against the insulin receptor that lead to either insulin resistance or fasting hypoglycemia, depending on the blocking or stimulating activity of the antibodies and their titers. Mortality of type B insulin resistance is high (>50% within 10 y) (2). Therapeutic approaches such as insulin sensitization with metformin and thiazolidinediones, immunomodulating agents (corticosteroids, cyclophosphamide, cyclosporine A, azathioprine), plasmapheresis, or combinations of the above have shown mixed results (2–8), and treatment is not yet standardized. In 2010, a group at the National Institutes of Health (NIH) published the largest case series in which a new treatment protocol with rituximab, a B-cell-depleting monoclonal anti-CD20 antibody, was tested in their patient population (6). To date, this has not been validated in other patients outside of the NIH.\n\nCase Report\nA 45-year-old Caucasian woman presented with weight loss of 20 kg over 9 months and acanthosis nigricans of her face and lumbar and groin areas (Figure 1A). One year earlier, diabetes mellitus had been diagnosed. The initial treatment with metformin and sitagliptin was unsuccessful. Plasma glucose levels (500 mg/dl) and glycated hemoglobin (HbA1c, 11.3%) were high. Intensive conventional insulin therapy and administration of 600 IU/d via insulin pump failed to achieve acceptable blood glucose levels.\n\nFigure 1. A 45-year-old female patient with acanthosis nigricans due to type B insulin resistance at diagnosis (A) and 4 months after rituximab treatment (B).\n\nAt admission, her body mass index was only 18 kg/m2. We initiated continuous iv insulin. To achieve blood glucose levels of approximately 300 mg/dL, approximately 6 IU/h were required. After administering insulin iv for 72 hours, we started an intensive conventional insulin therapy plan (isophan insulin [NPH; Protaphane, Novo Nordisk Pharma GmbH] 50–50–50 IU, Insulin human rDNS [NovoRapid, Novo Nordisk Pharma GmbH] 26–34–34 IU, plus correction with a factor of 1:15, with a blood glucose target of 90–120 mg/dL).\n\nExtensive examination failed to reveal any (para)neoplastic cause for the weight loss and insulin resistance. We considered the possibility of type B insulin resistance syndrome because of acanthosis nigricans combined with weight loss and elevated serum markers of autoimmunity, especially anti-Sjögren's-syndrome-related antigen A and antiribosomal P protein (Supplemental Table 1). However, an initial insulin receptor antibody assay was negative. Finally, an immunoprecipitation assay was strongly positive for anti-insulin-receptor antibodies (Figure 2A), confirming the diagnosis of type B insulin resistance.\n\nFigure 2. A, Anti-INSR autoantibody assay for our patient (P1070) before and after treatment (25-min exposure). Lane 1, Negative control serum (2 μL), negative for anti-INSR autoantibody; lane 2, positive control serum (2 μL), positive for anti-INSR autoantibody; lane 3, positive control serum (0.2 μL), positive for anti-INSR autoantibody; lane 4, P1070 serum before therapy (2 μL); lane 5, P1070 before therapy (0.2 μL); lane 6, P1070 after therapy (2 μL); lane 7, P1070 after therapy (0.2 μL); lane 8, cell lysate containing insulin receptor 1:3 dilution; and lane 9, cell lysate containing insulin receptor. INSR, insulin-receptor. B, Time line (weeks) for fasting glucose (mg/dL; solid line), daily insulin dose (IU/d; dashed line), and HbA1c (%; dotted line) as well as white blood cell (WBC) and B cell count. The arrows indicate application of rituximab/cyclophosphamide/prednisone, the short lines indicate the Ig treatment and plasmapheresis, and the dots indicate timing of insulin receptor antibody tests. ab, antibodies; Ig, immunoglobulins; IR, insulin-receptor; Tx, treatment.\n\nNeither Ig iv (Intratect 20 g/d; Biotest Pharma GmbH) over 6 days nor plasmapheresis (five times in 14 d) improved her blood glucose or allowed reduction of the daily insulin dose. We therefore started the patient on a combination protocol of rituximab (750 mg/m2 in two doses 2 wk apart), cyclophosphamide (100 mg/d orally, continuously), and dexamethasone (40 mg/d for 4 days every month), in accordance with the NIH protocol (Figure 2B) (6), which was well tolerated. B cells were depleted already 2 weeks after the first rituximab application but returned to almost normal levels 4 months later without relapse (Figure 2B). Cyclophosphamide was temporarily withdrawn due to low white blood cells. No other major side effects were reported. Over the next 2 months, her daily insulin doses could be reduced to 30 IU/d, already indicating a response to therapy. The patient's well-being greatly improved. Fasting glucose levels ranged from 80 to 110 mg/dL, and the HbA1c decreased from 11.8 to 9.9%. Four months after her initial rituximab dose, insulin treatment could be withdrawn completely, and blood glucose levels remained within the normal range from 66 to 107 mg/dL. HbA1c continued to decrease to 6.5% (Figure 2B). The acanthosis nigricans improved (Figure 1B). Congruent with the complete clinical remission, insulin receptor autoantibodies were now negative (Figure 2A). We therefore discontinued cyclophosphamide and dexamethasone and started her on a maintenance regime with azathioprine 100 mg daily for 1 year. Azathioprine was chosen because of the experience with this immunosuppressive drug in systemic lupus erythematosus and because many type B insulin resistance patients are positive for lupus-associated antibodies, including our patient. She has been in remission since then (Figure 2B).\n\nDiscussion\nWe report a patient with extreme insulin resistance with features of insulin deficiency due to insulin receptor autoantibodies. Treatment of type B insulin resistance is challenging. Its prevalence is unknown but is very low, precluding prospective and controlled trials. We initially tried plasmapheresis and Ig iv, expecting that this would eliminate the anti-insulin receptor autoantibodies rapidly. Yet, blood glucose levels and insulin requirements did not respond. We therefore tried a previously published protocol including rituximab, cyclophosphamide, and pulse corticosteroids aiming to control antibody-producing B lymphocytes and to suppress the activity of pre-existing antibody-producing plasma cells. An initial case report of a patient with type B insulin resistance treated with rituximab was published in 2004 (9). In 2010, Malek et al (6) published the largest case series using a standardized protocol for type B insulin resistance in seven patients. Our 45-year-old female Caucasian patient resembles these patients (five females, two males; average age, 41.7 y; range, 17–64 y), but she has a different ethnic background (six African American, one First Nation Canadian). All initially reported patients were positive for antinuclear antibodies; three had systemic lupus erythematosus, and one had mixed connective tissue disease. Our patient also was antinuclear antibody-positive, especially for lupus-associated antibodies (see Supplementa1 Table 1), but without cutaneous signs of lupus erythematosus. Her metabolic parameters, fasting glucose and HbA1c, were similar to the hyperglycemic NIH patients, but her insulin dose shortly before rituximab treatment was relatively low at 360 IU/d, compared to 750 to 18 000 (average 5000) IU/d in the NIH patients. Relatively less severe insulin resistance may explain why our patient reached complete remission within 4 months after one treatment cycle, whereas the NIH patients required on average 1.6 cycles (range, 1–2.5) and reached remission within 8 months (range, 2.5–27).\n\nUse of rituximab in our patient was off label, but this was well justified by the data from the NIH patients, the severity of the disease with a mortality rate > 50%, and the lack of alternative treatments for a patient who was clinically deteriorating. This view was shared by the patient's health insurance provider, and the costs of this off-label treatment were covered by insurance.\n\nRecently, we learned of the success of this treatment regime in a patient from Ecuador (10). Therefore, in addition to the mostly African American patients of the NIH series, success of this treatment regime could be confirmed in patients from Europe and from Latin America.\n\nConclusion\nType B insulin resistance is a rare disease with high mortality. Its therapy is not yet standardized. A treatment regime with rituximab, cyclophosphamide, and steroids led to complete remission in all nine patients known to be treated with this regime so far, which suggests that this protocol should be used as first-line treatment.\n\nAbbreviation:\nHbA1cglycated hemoglobin.\n\n\n\nAcknowledgments\nR.K.S. is supported by the Wellcome Trust (Grant WT098498). R.K.S. and I.I. are supported by the Medical Research Council Centre for Obesity and Related Disorders, and the United Kingdom National Institute for Health Research Cambridge Biomedical Research Centre.\n\nDisclosure Summary: The authors have nothing to disclose.\n==== Refs\nReferences\n1. \nFlier JS Kahn CR Roth J Bar RS \nAntibodies that impair insulin receptor binding in an unusual diabetic syndrome with severe insulin resistance . Science . 1975 ;190 :63 –65 .170678 \n2. \nArioglu E Andewelt A Diabo C Bell M Taylor SI Gorden P \nClinical course of the syndrome of autoantibodies to the insulin receptor (type B insulin resistance): a 28-year perspective . Medicine . 2002 ;81 :87 –100 .11889410 \n3. \nFareau GG Maldonado M Oral E Balasubramanyam A \nRegression of acanthosis nigricans correlates with disappearance of anti-insulin receptor autoantibodies and achievement of euglycemia in type B insulin resistance syndrome . Metabolism . 2007 ;56 :670 –675 .17445543 \n4. \nPage KA Dejardin S Kahn CR Kulkarni RN Herold KC Inzucchi SE \nA patient with type B insulin resistance syndrome, responsive to immune therapy . Nat Clin Pract Endocrinol Metab . 2007 ;3 :835 –840 .18026162 \n5. \nKawanishi K Kawamura K Nishina Y Goto A Okada S \nSuccessful immunosuppressive therapy in insulin resistant diabetes caused by anti-insulin receptor autoantibodies . J Clin Endocrinol Metab . 1977 ;44 :15 –21 .833253 \n6. \nMalek R Chong AY Lupsa BC \nTreatment of type B insulin resistance: a novel approach to reduce insulin receptor autoantibodies . J Clin Endocrinol Metab . 2010 ;95 :3641 –3647 .20484479 \n7. \nZhang S Wang G Wang J \nType B insulin resistance syndrome induced by systemic lupus erythematosus and successfully treated with intravenous immunoglobulin: case report and systematic review . Clin Rheumatol . 2013 ;32 :181 –188 .23053690 \n8. \nEriksson JW Bremell T Eliasson B Fowelin J Fredriksson L Yu ZW \nSuccessful treatment with plasmapheresis, cyclophosphamide, and cyclosporin A in type B syndrome of insulin resistance. Case report . Diabetes Care . 1998 ;21 :1217 –1220 .9702422 \n9. \nColl AP Thomas S Mufti GJ \nRituximab therapy for the type B syndrome of severe insulin resistance . N Engl J Med . 2004 ;350 :310 –311 .14724317 \n10. \nPasquel M Alvaro O Jara N Duran P Narvaez L Pasquel FJ \nSevere acanthosis nigricans and diabetes resolution after immunosuppresion in Latin-American female with multiple autoimmune disorders . In: Proceedings from The Endocrine Society's 96th Annual Meeting ; June 21–24, 2014 ; Chicago, IL ; Abstract SAT-1034 .\n\n",
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"abstract": "Durvalumab, a programmed cell death ligand 1 inhibitor, induces various immune-related adverse events (irAEs), including lung injury. However, diffuse alveolar hemorrhage (DAH) is a rare type of lung injury due to immune checkpoint inhibitors. A 76-year-old man with c-stage IIIA squamous cell carcinoma of the lung received maintenance durvalumab therapy after chemoradiotherapy. He developed dyspnea and malaise after 11 cycles of durvalumab. Chest computed tomography showed rapidly spreading bilateral ground-glass opacity in the lungs. We diagnosed DAH by hemosiderin-laden macrophages in bloody bronchoalveolar lavage fluid. Despite mechanical ventilation, steroids, and cyclophosphamide, he died of respiratory failure. The autopsy revealed that fresh and old bleeding areas coexisted, and neither pulmonary vasculitis nor diffuse alveolar damage was detected microscopically. Furthermore, CD3+ and CD8+ lymphocytes were observed in the lung interstitium, whereas CD20+ and CD4+ lymphocytes were scarcely detected. We report the first case of durvalumab-induced DAH. We should be alert to irAEs with DAH as a potential differential diagnosis of lung injury during durvalumab treatment.",
"affiliations": "Department of Respiratory Medicine, Osaka Police Hospital, Osaka, Japan.;Department of Respiratory Medicine, Osaka Police Hospital, Osaka, Japan.;Department of Respiratory Medicine, Osaka Police Hospital, Osaka, Japan.;Department of Pathology, Osaka Police Hospital, Osaka, Japan.;Department of Pathology, Osaka Police Hospital, Osaka, Japan.;Department of Respiratory Medicine, Osaka Police Hospital, Osaka, Japan.",
"authors": "Kanaoka|Kensuke|K|;Ikebe|Saori|S|;Ihara|Shouichi|S|;Tsuji|Hiromi|H|;Yasuoka|Hironao|H|;Minami|Seigo|S|",
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"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\n10.1159/000507848\ncro-0013-0696\nCase Report\nDurvalumab-Induced Diffuse Alveolar Hemorrhage: An Autopsy Case Report\nKanaoka Kensuke a Ikebe Saori a Ihara Shouichi a Tsuji Hiromi b Yasuoka Hironao b Minami Seigo a* aDepartment of Respiratory Medicine, Osaka Police Hospital, Osaka, Japan\nbDepartment of Pathology, Osaka Police Hospital, Osaka, Japan\n*Seigo Minami, Department of Respiratory Medicine, Osaka Police Hospital, 10-31, Kitayama-cho, Tennoji-ku, Osaka-City 543-0035 (Japan), seigominami@oph.co.jp\nMay-Aug 2020 \n22 6 2020 \n22 6 2020 \n13 2 696 701\n9 4 2020 10 4 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.Durvalumab, a programmed cell death ligand 1 inhibitor, induces various immune-related adverse events (irAEs), including lung injury. However, diffuse alveolar hemorrhage (DAH) is a rare type of lung injury due to immune checkpoint inhibitors. A 76-year-old man with c-stage IIIA squamous cell carcinoma of the lung received maintenance durvalumab therapy after chemoradiotherapy. He developed dyspnea and malaise after 11 cycles of durvalumab. Chest computed tomography showed rapidly spreading bilateral ground-glass opacity in the lungs. We diagnosed DAH by hemosiderin-laden macrophages in bloody bronchoalveolar lavage fluid. Despite mechanical ventilation, steroids, and cyclophosphamide, he died of respiratory failure. The autopsy revealed that fresh and old bleeding areas coexisted, and neither pulmonary vasculitis nor diffuse alveolar damage was detected microscopically. Furthermore, CD3+ and CD8+ lymphocytes were observed in the lung interstitium, whereas CD20+ and CD4+ lymphocytes were scarcely detected. We report the first case of durvalumab-induced DAH. We should be alert to irAEs with DAH as a potential differential diagnosis of lung injury during durvalumab treatment.\n\nKeywords\nImmune checkpoint inhibitorsDurvalumabDiffuse alveolar hemorrhageBronchoalveolar lavage fluidImmune-related adverse events\n==== Body\nIntroduction\nDurvalumab maintenance therapy after chemoradiotherapy improves progression-free and overall survival for patients with inoperable stage III non-small cell lung cancer [1, 2]. Among various immune-related adverse events (irAEs) induced by programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors, lung injury is one of the most serious adverse events [3]. In the PACIFIC trial, lung injury occurred in 33.9% of patients treated with durvalumab, and was the most frequent grade 5 irAE [2]. According to a study on lung injury in patients treated with PD-1/PD-L1 inhibitors, the most common pathological feature was cellular interstitial pneumonitis, and the second most common was organizing pneumonia [4]. However, to the best of our knowledge, diffuse alveolar hemorrhage (DAH) has never been reported as a lung injury induced by durvalumab. It is difficult to distinguish DAH from other types of lung injury based on clinical presentation and radiographic examination [5]. Hemoptysis is a specific symptom of DAH, but it is initially absent in 33% of patients with DAH [6]. Radiologic findings of bilateral and central ground-glass opacities (GGOs) are nonspecific and can change throughout the course of the disease [5, 7]. In clinical practice, DAH is often diagnosed by bronchoalveolar lavage (BAL). Bloody BAL fluid (BALF), intra-alveolar red blood cells, and hemosiderin-laden macrophages indicate a diagnosis of DAH [6, 7]. Herein, we report an autopsy case of durvalumab-induced DAH.\n\nCase Report\nA 76-year-old man was diagnosed with squamous cell carcinoma of the lung (cT2aN2M0, c-stage IIIA). He regularly took edoxaban for atrial fibrillation, and he received chemoradiotherapy (2 Gy × 33 fractions with weekly carboplatin and weekly paclitaxel). Nine days after the end of thoracic radiation, he developed a fever of 38.6°C. Chest computed tomography (CT) showed a new GGO in the irradiation area. We suspected radiation pneumonitis and then initiated oral prednisolone therapy (initial dose: 1 mg/kg/day). We gradually reduced the dose and then discontinued prednisolone for 6 months. When the dose of prednisolone had decreased to 10 mg/day, 41 days after the thoracic radiotherapy, we initiated durvalumab maintenance treatment (10 mg/kg, bi-weekly).\n\nAfter 11 cycles of durvalumab therapy, 3 weeks after the discontinuation of prednisolone, he developed dyspnea and malaise. His body temperature was 37.3°C, heart rate was 75 beats per minute, blood pressure was 111/81 mm Hg, and oxygen saturation on room air was 96%. Chest CT showed new GGOs in the bilateral lower lobes, extending beyond the irradiated areas (Fig. 1A). Laboratory blood tests exhibited an increase in C-reactive protein (8.24 mg/dL) and KL-6 (515 U/mL). He was hospitalized and underwent fiberoptic bronchoscopy on hospital day 2. The BALF from the right B8 gradually became bloody (Fig. 2A), and revealed a cell count of 13.4 × 105 cells/mL with 70% neutrophils, 10.5% lymphocytes, 11% eosinophils, and 8.5% macrophages. Despite immediate discontinuation of edoxaban and administration of ciprofloxacin, his symptoms and respiratory conditions rapidly deteriorated. Thereafter, although there was a negative bacterial culture in the BALF, we detected hemosiderin-laden macrophages (Fig. 2B). Myeloperoxidase ANCA (antineutrophil cytoplasmic antibody), proteinase-3 ANCA, and anti-glomerular basement membrane antibody were all negative. Thus, we suspected durvalumab-induced DAH. On hospital day 7, we initiated oral prednisolone (1 mg/kg/day). Chest CT on hospital day 10 showed an expansion of GGOs to the left lung (Fig. 1B). A methylprednisolone pulse (1,000 mg/day) was administered for 3 consecutive days, followed by oral prednisolone (1 mg/kg/day). On hospital day 14, due to his deteriorated respiratory condition, we introduced invasive mechanical ventilation with endotracheal intubation. On hospital day 15, we administered cyclophosphamide (750 mg/m2). The second BALF from the left B5 and B9 on hospital day 24 were both bloody and contained hemosiderin-laden macrophages. Due to exacerbated respiratory failure, the patient died on day 50.\n\nWe performed an autopsy 14 h after his death. In the macroscopically bloody lung areas with decreased aeration (Fig. 3A, B), the alveolar spaces were microscopically filled with red blood cells, which suggested fresh bleeding (Fig. 3C). In the macroscopically white lung areas, hemosiderin-laden macrophages were still present, which suggested old bleeding (Fig. 3D). Almost all parts of the lungs exhibited one of these two histological findings. Neither pulmonary vasculitis nor diffuse alveolar damage was detected in the autopsy. Immunohistochemical analyses showed that CD3-positive (CD3+) and CD8+ lymphocytes were present in the lung interstitium, but not around capillaries. On the other hand, CD20+ and CD4+ lymphocytes were scarcely observed (Fig. 3E–H).\n\nDiscussion\nTo our knowledge, this was the first case of durvalumab-induced DAH, and the second case of an autopsy after an irAE of DAH. The clinically important finding is that DAH is a possible irAE due to durvalumab. There have been only 3 case reports of DAH induced by PD-1 inhibitors (Table 1) [8, 9, 10]. Except for an autopsy case of DAH due to nivolumab-induced Goodpasture's disease, the etiology of the other 2 DAH cases is unknown. In these 2 cases, unlike in our case, the responses to steroids were good. A higher proportion of lymphocytes in BALF might be associated with better outcomes. In our case, we did not suspect DAH until BALF, because the patient did not complain of hemoptysis and the radiologic findings were not typical of DAH. We are afraid of underdiagnosed immune checkpoint inhibitor (ICI)-induced DAH when BAL is not performed; thus, we should not hesitate to perform BAL when we suspect lung injury as an irAE.\n\nThe pathologically important finding was that bland pulmonary hemorrhage was the histopathological feature of our DAH. There are three pathological patterns that can induce DAH: pulmonary capillaritis, diffuse alveolar damage, and bland pulmonary hemorrhage [6]. Except for the autopsy case of Goodpasture's disease, neither an autopsy nor a lung biopsy was performed in the other 2 DAH cases [8, 9, 10]. Thus, the pathological mechanism underlying DAH as an irAE has remained unknown. Our autopsy showed a bland pulmonary hemorrhage pattern. Although anticoagulant drugs, including edoxaban, can induce bland pulmonary hemorrhage, in previous case reports the hemorrhage disappeared immediately after the drugs were stopped [11]. In our case, there was still fresh bleeding at death, which means that the bleeding continued 7 weeks after the discontinuation of edoxaban. Therefore, edoxaban did not cause DAH in our case. There were 2 cases in which lung injury as an irAE had occurred 6 and 8 months after stopping ICIs [12]. These 2 cases do not contradict our finding that DAH continued for more than 10 weeks after discontinuation of durvalumab. Thus, we should be particularly alert to lung injury as an irAE for several months after ICI therapy.\n\nInterestingly, immunostaining revealed that the predominant infiltrating lymphocytes in the lung interstitium were exclusively CD3+ and CD8+ cells, and there were few CD20+ and CD4+ cells. Our immunostaining patterns in the lungs were similar to those of an irAE of liver injury, which are characterized by the infiltration of predominantly CD3+ and CD8+ lymphocytes, with fewer CD20+ or CD4+ lymphocytes detected [13]. Furthermore, the CD20+/CD3+ and CD4+/CD8+ ratios were significantly lower than those in autoimmune or drug-induced liver injuries. However, it is still unclear whether CD3+ and CD8+ lymphocytes increase or not in an irAE of lung injury. Immunostaining for CD4 and CD8 might be useful for distinguishing lung injury as an irAE from other types of lung injuries.\n\nIn conclusion, we report the first case of durvalumab-induced DAH. We should be alert to an irAE of DAH as a potential differential diagnosis of lung injury during durvalumab treatment.\n\nStatement of Ethics\nThe patient's son has given informed consent to publish this case including publication of images.\n\nDisclosure Statement\nAll authors declare no potential conflicts of interest related to the publication of this case report.\n\nFunding Sources\nWe declare that the authors received no funds for this research.\n\nAuthor Contributions\nK. Kanaoka, S. Ikebe, S. Ihara, and S. Minami were involved in treatment of this patient. H. Tsuji and H. Yasuoka performed the pathological diagnosis of the tumor and DAH. K. Kanaoka drafted the report. All authors read and critically reviewed the report. All authors approved the final submitted version.\n\nAcknowledgements\nWe thank Dr. Kazunori Moriizumi, Dr. Kanako Nishimatsu, and Dr. Hideyasu Okada (the Department of Respiratory Medicine, Osaka Police Hospital) for their contributions to the care and management of this patient.\n\nFig. 1 Chest CT images on the first hospital day showed ground-glass opacity in the bilateral lower lobes, extending beyond the irradiated areas (A), and on the tenth hospital day showed ground-grass opacity spread to the entire left lung (B).\n\nFig. 2 Macroscopic (A) and microscopic (B) findings of bronchoalveolar lavage fluid from the right B8 on the second hospital day. B Berlin blue staining. ×100. Arrows indicate hemosiderin-laden macrophages.\n\nFig. 3 Autopsy findings. Microscopic view of autopsied right lung before formalin fixation (A) and after formalin fixation (B). Microscopic finding of alveolar spaces filled with red blood cells in a fresh bleeding area of the lung (C) (hematoxylin and eosin stain; ×40) and hemosiderin-laden macrophages in an old bleeding area of the lung (D) (hematoxylin and eosin stain; ×200). Immunostaining (×100) for CD3 (E), CD4 (F), CD8 (G), and CD20 (H); predominantly CD3+ and CD8+ lymphocytes infiltrated the lung interstitium (E, G), while there were few CD20+ and CD4+ lymphocytes (F, H).\n\nTable 1 Review of diffuse alveolar hemorrhage caused by immune checkpoint inhibitors in the English literature\n\n\tTakahashi et al. [8], 2018\tSugano et al. [9], 2018\tIkeda et al. [10], 2018\tOur report\t\nCancer (histology)\tLung (Ad)\tLung (Ad)\tMelanoma\tLung (sq)\t\n\t\nICIs\tNivolumab\tPembrolizumab\tNivolumab\tDurvalumab\t\n\t\nTPS\tNot described\t50–74%\tNot described\t10–20%\t\n\t\nPatient's age, years (sex)\t74 (M)\t67 (F)\t41 (F)\t76 (M)\t\n\t\nSymptoms\tHematuria, hemoptysis\tNo symptoms\tBloody sputum, respiratory distress\tDyspnea, malaise\t\n\t\nDAH onset timing\t16 weeks (8 cycles)\t4 cycles\t3 months\t5 months (11 cycles)\t\n\t\nCT images\tGGO (unilateral and not central) effusion\tGGO and consolidation (unilateral and not central)\tGGO (bilateral and not central)\tGGO (bilateral and not central)\t\n\t\nCRP, mg/dL\tNot described\t4.7\t11.85\t8.24\t\n\t\nDiagnosis of DAH\tAutopsy\tBALF\tBALF\tBALF\t\n\t\nLymphocytes in BALF\tNot described\t45.0%\t32.2%\t10.5%\t\n\t\nTreatment\tmPSL pulse Plasma exchange\tOral PSL (1 mg/kg/day)\tmPSL pulse\tmPSL pulse Cyclophosphamide\t\n\t\nOutcome\tDied (35 days)\tImproved\tImproved\tDied (50 days)\t\n\t\nNote\tGoodpasture's disease\t\tPseudoprogression\t\t\nAd, adenocarcinoma; BALF, bronchoalveolar lavage fluid; CRP, C-reactive protein; DAH, diffuse alveolar hemorrhage; F, female; GGO, ground-glass opacity; ICI, immune checkpoint inhibitor; M, Male; mPSL, methylprednisolone; PSL, prednisolone; Sq, squamous cell carcinoma; TPS, tumor proportion score.\n==== Refs\nReferences\n1 Antonia SJ Villegas A Daniel D Vicente D Murakami S Hui R Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC N Engl J Med 2018 379 (24) 2342 50 30280658 \n2 Antonia SJ Villegas A Daniel D Vicente D Murakami S Hui R Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer N Engl J Med 2017 377 (20) 1919 29 28885881 \n3 Wang DY Salem JE Cohen JV Chandra S Menzer C Ye F Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis JAMA Oncol 2018 4 (12) 1721 8 30242316 \n4 Naidoo J Wang X Woo KM Iyriboz T Halpenny D Cunningham J Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy J Clin Oncol 2017 35 (7) 709 17 27646942 \n5 Lichtenberger JP Digumarthy SR Abbott GF Shepard JA Sharma A Diffuse pulmonary hemorrhage: clues to the diagnosis Curr Probl Diagn Radiol 2014 43 (3) 128 39 24791616 \n6 Lara AR Schwarz MI Diffuse alveolar hemorrhage Chest 2010 137 (5) 1164 71 20442117 \n7 Krause ML Cartin-Ceba R Specks U Peikert T Update on diffuse alveolar hemorrhage and pulmonary vasculitis Immunol Allergy Clin North Am 2012 32 (4) 587 600 23102067 \n8 Takahashi N Tsuji K Tamiya H Shinohara T Kuroda N Takeuchi E Goodpasture's disease in a patient with advanced lung cancer treated with nivolumab: an autopsy case report Lung Cancer 2018 122 22 4 30032835 \n9 Sugano T Seike M Noro R Kaburaki S Tozuka T Takahashi A A case of interstitial lung disease with alveolar hemorrhage induced by pembrolizumab Onco Targets Ther 2018 11 5879 83 30271171 \n10 Ikeda T Yamaguchi H Dotsu Y Taniguchi H Gyoutoku H Senju H Diffuse alveolar hemorrhage with pseudoprogression during nivolumab therapy in a patient with malignant melanoma Thorac Cancer 2018 9 (11) 1522 4 30253076 \n11 Nitta K Imamura H Yashio A Kashima S Mochizuki K Diffuse alveolar hemorrhage associated with edoxaban therapy Case Rep Crit Care 2016 2016 7938062 27872767 \n12 Couey MA Bell RB Patel AA Romba MC Crittenden MR Curti BD Delayed immune-related events (DIRE) after discontinuation of immunotherapy: diagnostic hazard of autoimmunity at a distance J Immunother Cancer 2019 7 (1) 165 11 31269983 \n13 Zen Y Yeh MM Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury Mod Pathol 2018 31 (6) 965 73 29403081\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "13(2)",
"journal": "Case reports in oncology",
"keywords": "Bronchoalveolar lavage fluid; Diffuse alveolar hemorrhage; Durvalumab; Immune checkpoint inhibitors; Immune-related adverse events",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
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"title": "Durvalumab-Induced Diffuse Alveolar Hemorrhage: An Autopsy Case Report.",
"title_normalized": "durvalumab induced diffuse alveolar hemorrhage an autopsy case report"
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"abstract": "We conducted a multicenter study to improve the treatment of B-cell non-Hodgkin's lymphoma and acute lymphoblastic leukemia (NHL/ALL) in Japanese children. The subjects were a total of 57 untreated patients with the B-cell type of either NHL (27 Burkitt's and 9 diffuse large) or ALL between 2 and 15 years old (median: 8 years) seen between 1988 and 1994. All patients received the same cytoreductive therapy (half doses of vincristine and prednisolone) and the same first and second induction courses (vincristine, prednisolone, high-dose methotrexate, repetitive high-dose cyclophosphamide, and adriamycin). Three cycles of consolidation blocks A and B (consisting of reduced doses of similar agents used in the second induction course) followed for patients with stage III or IV NHL or B-ALL, while only one cycle was given for stage I or II disease. Fifty-three patients (93.0%) achieved complete remission. Eight patients had relapse all occurring within 1 year. Another patient had secondary myelodysplastic syndrome. The median follow-up period was 48 months (range: 24-94 months). The overall survival and event-free survival (EFS) rates for all patients were, respectively, 75.9% (S.E.: 5.9) and 70.1 (S.E.: 6.1). The relapse-free interval rate of the 53 patients who achieved CR was 83.5% (S.E.: 5.3). EFS was 75.0% (S.E.: 21.7) in stage I, 84.6% (S.E.: 10.0) in stage II, 78.63% (S.E.: 11.0) in stage III, 80.0% (S.E.: 17.9) in stage IV, and 52.4% (S.E.: 10.9) in ALL. Among the stage IV NHL and ALL patients, EFS was significantly worse in patients with initial CNS involvement than in those without it (14.3% (S.E.: 13.2) vs. 73.7% (S.E.: 10.1); P = 0.0025). In conclusion, our regimen (AT-B88) produced a more than 70% cure-rate for children with any stage of B-cell NHL/ALL without initial CNS involvement. However, a new regimen is needed for patients with initial CNS involvement.",
"affiliations": "Department of Pediatrics, Nagoya University School of Medicine, Japan.",
"authors": "Horibe|K|K|;Akiyama|Y|Y|;Kobayashi|M|M|;Ishii|E|E|;Matsuyama|T|T|;Matsuzaki|A|A|;Minegishi|M|M|;Ueda|K|K|",
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"issue": "66(1)",
"journal": "International journal of hematology",
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"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D016896:Treatment Outcome",
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"references": null,
"title": "Treatment outcome of AT-B88 regimen for B-cell non-Hodgkin's lymphoma and surface immunoglobulin-positive acute lymphoblastic leukemia in children.",
"title_normalized": "treatment outcome of at b88 regimen for b cell non hodgkin s lymphoma and surface immunoglobulin positive acute lymphoblastic leukemia in children"
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"abstract": "A 70s woman with pancreatic metastases of HER2-negative breast cancer was being treated with bevacizumab plus paclitaxel. Tumor markers decreased after treatment initiation. After 8 months of treatment, the patient developed abdominal pain and distention, along with loss of appetite. Contrast-enhanced abdominal CT scan images showed the presence of a large 25 cm pseudopancreatic cyst and disappearance of the pancreatic metastatic lesions. Endoscopic ultrasound-guided cystogastrostomy was performed and an AXIOS stent was placed in the lower part of the gastric body. Subsequently, the cyst disappeared and her abdominal symptoms improved. The patient was able to resume treatment with other drugs and did not experience any recurrence of pancreatitis. Four months later, the AXIOS stent was removed. Bevacizumab plus paclitaxel is reportedly effective against HER2-negative metastatic breast cancer. Bevacizumab is a molecular targeted therapy against vascular endothelial growth factor, and the mechanism of its antitumor effect and complications are different from those of conventional drugs. Paclitaxel has also been reported to cause pancreatitis in rare cases. In this case, the mechanism of response to bevacizumab plus paclitaxel for metastatic pancreatic lesions or the development of drug-induced pancreatitis was considered to be the cause of pseudopancreatic cyst formation.",
"affiliations": "Dept. of Breast Surgery, Inoue Memorial Hospital.",
"authors": "Shiina|Nobumitsu|N|;Fujisaki|Kaoru|K|;Miyoshi|Tetsutaro|T|;Yokomizo|Jissei|J|;Sai|Gyokusen|G|;Wakabayashi|Yasuo|Y|;Ootsubo|Yoshihisa|Y|",
"chemical_list": "D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D017239:Paclitaxel",
"country": "Japan",
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"issue": "48(8)",
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"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001943:Breast Neoplasms; D003560:Cysts; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel; D010190:Pancreatic Neoplasms; D042461:Vascular Endothelial Growth Factor A",
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"title": "A Case of Pseudopancreatic Cyst Development during Bevacizumab plus Paclitaxel Therapy for Pancreatic Metastasis of Breast Cancer.",
"title_normalized": "a case of pseudopancreatic cyst development during bevacizumab plus paclitaxel therapy for pancreatic metastasis of breast cancer"
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"abstract": "Genital herpes is one of the sexually transmitted diseases that is reported with a greater incidence of primary and secondary recurrence. In this study, olive leaf extract was used for its antiviral properties to treat the infection. The randomized-clinical trials using such a therapeutic approach are required in this field.",
"affiliations": "Department of Obstetrics and Gynecology Faculty of Medicine Lorestan University of Medical Sciences Khorramabad Iran.;Faculty of Dentistry Medipol University Istanbul Turkey.;Faculty of Medicine Tehran University of Medical Sciences Tehran Iran.",
"authors": "Lorzadeh|Nahid|N|https://orcid.org/0000-0003-1492-8582;Kazemirad|Yasaman|Y|;Kazemirad|Nastran|N|",
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"doi": "10.1002/ccr3.3723",
"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/ccr3.3723\nCCR33723\nCase Report\nCase Reports\nTreatment of genital herpes using olive leaf extract\nLORZADEH et al.Lorzadeh Nahid https://orcid.org/0000-0003-1492-8582\n1\ndr.n.lorzadeh@gmail.com Kazemirad Yasaman \n2\n Kazemirad Nastran \n3\n \n1 \nDepartment of Obstetrics and Gynecology\nFaculty of Medicine\nLorestan University of Medical Sciences\nKhorramabad\nIran\n\n\n2 \nFaculty of Dentistry\nMedipol University\nIstanbul\nTurkey\n\n\n3 \nFaculty of Medicine\nTehran University of Medical Sciences\nTehran\nIran\n\n* Correspondence\n\nNahid Lorzadeh, Lorestan University of Medical Sciences, Khorramabad, Iran.\n\nEmail: dr.n.lorzadeh@gmail.com\n\n29 12 2020 \n2 2021 \n9 2 10.1002/ccr3.v9.2986 989\n15 12 2019 22 10 2020 16 12 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\nGenital herpes is one of the sexually transmitted diseases that is reported with a greater incidence of primary and secondary recurrence. In this study, olive leaf extract was used for its antiviral properties to treat the infection. The randomized‐clinical trials using such a therapeutic approach are required in this field.\n\nGenital herpes is one of the sexually transmitted diseases that is reported with a greater incidence of primary and secondary recurrence. In this study, olive leaf extract was used for its antiviral properties to treat the infection. The randomized‐clinical trials using such a therapeutic approach are required in this field.\n\n\nacyclovirantiviralgenital herpesinfectionolive leaf extract 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\nLorzadeh \nN \n, \nKazemirad \nY \n, \nKazemirad \nN \n. Treatment of genital herpes using olive leaf extract\n. Clin Case Rep .2021 ;9 :986 –989\n. 10.1002/ccr3.3723\n==== Body\n1 INTRODUCTION\nGenital herpes is one of the most commonly reported sexually transmitted infections (STI) that is associated with a greater incidence of recurrence and does not respond to conventional treatments. Type I and II viruses are involved in the pathogenesis of the disease where it affects lips, face, and genitals.\n1\n\n\n\nThe infection begins with irritation and itching followed by pain up to 24 hours, after which the virus widespread to sensory nerves.\n2\n Due to the weakening of the immune system, the virus in the sensory nerves returns to the surface of the skin to cause reinfection. Factors that can worsen the infection include stress, fatigue, cold wind, burn, loss of immunity, infection, fever, and cold, to name few.\n3\n The symptoms usually last 4‐7 days after the first contact with the virus carrying virus or virus‐containing secretions.\n4\n The most common symptom of the disease is the appearance of small blisters in the genital area that when puncture, produce painful ulcers. Some people may find only red or prominent lesions, and some are likely to be presented with painful urination.\n5\n In women, vaginal vesiculate secretions may also be observed. Urination, with clear watery secretions from the urethra, is often a known complication of the infection. Ulceration usually occurs 4‐7 days after the first infection, and the symptoms are similar to that of cold, such as fever, sore throat, and lumbago swelling.\n6\n\n\n\nConventional treatment for herpes includes antiviral drugs, which inhibit the replication of viral RNA.\n4\n These drugs include acyclovir, ganciclovir, valaciclovir, and penciclovir. The overuse of drugs has led to drug resistance.\n7\n On the other hand, they are not cost‐effective, owing to the long course of treatment.\n8\n Currently, two herbal remedies, Melissa and Myrtoplex, are used in Iran.\n9\n Herbal medicine is currently under investigation for its effectiveness in the treatment of the herpes virus. Studies have indicated that plants and derived compounds can be used to treat herpes viruses.\n10\n, \n11\n\n\n\nOlive extracts are reported to be effective against various pathological conditions. Polyphenolic compounds, including oleuropein (OLE) and hydroxytyrosol (HT), are active ingredients in olive leave extracts. In this report, we present a case of acyclovir‐resistant herpes that was reported to our center, due to the severity of the symptoms. Olive leaf extract ointment led to the patient recovery in 48 hours.\n\n2 OLIVE LEAF EXTRACTION METHOD\nOlive leaves were collected in Mid‐November and dried at ambient room temperature, and the powdered extract was stored in dark until further usage. The powder was dissolved in 100 mL of extraction solvent that was made of 80% ethanol at 60°C. The mixture was filtered using Whatman filter paper NO: 1. The extract was evaporated at room temperature under vacuum conditions. The leaves were obtained at the best possible time of the year, which had the highest amount of active ingredients; washed, dried, and hydroalcoholic extract was extracted. The extract analysis using the HPLC showed that the active ingredient, oleuropein, was 0.475 mg/g of the total extract. The ointment was prepared in 2% and was provided to the patient.\n\n3 CASE REPORT\nThe patient was a married 19‐year‐old woman with multiple mucocutaneous, round polycyclic lesions in the perineal region, dysuria and had severe burning sensations and pain, especially during defecation and her vulva was inflamed with swollen and tender inguinal lymph node. She reported that the appearance of the lesion started a week before her referral. Her husband (only sexual partner) did not have any such lesions, and she did not have any travel history for past 6 months. She visited her gynecologist for pap test 4 months ago. No other body part had lesions or rashes. The patient was healthy otherwise and did not have any medical or surgical history. The patient was referred to Asali Women's Hospital. During this period, the patient underwent multiple visits to general practitioners and general surgery specialists with a primary diagnosis of anal fissure. Her blood chemistry did not show any abnormality in exception to increased white blood cell counts: 15 000/mm3. During her referral to dermatologist, she was diagnosed with herpes infection from lesion biopsy, PCR test, and serologic tests for herpes glycoprotein (ELISA) and was treated with acyclovir ointment. At this time, her husband was not tested positive for the infection. Nonetheless, the patient did not respond to the treatment and was known to be a case of acyclovir‐resistant herpes infection. She was thereby, treated with the localized application of topical olive leaf extract, twice a day, owing to the lesion biopsy reports. The response to this treatment was evaluated on day 3 and 6, and 2 weeks after treatment. Following 3 days of the treatment, the pain and wounds completely disappeared whereas the lesions of the perineal and rectal areas were completely recovered on day 6, and after 2 weeks of follow‐up, no relapse was observed (Figure 1).\n\nFIGURE 1 A, Indicates a first‐day lesion before treatment. B, indicates a third‐day post‐treatment lesion. C, indicates a lesion on day 6 after treatment. D, indicates a lesion 2 wk after treatment\n\nWritten consent of the patient was obtained from the patient for this study.\n\n4 DISCUSSION\nHerpes infection is one of the most common STI, worldwide. Acyclovir ointment and creams are usually used for the treatment of the infection. However, cases of acyclovir resistance and related agents have been reported widely, as a result of thymidine kinase deficiency. Hence, alternative drugs are used for the treatment. Some researchers, in addition to direct antiviral effects, seek to boost the immune system against these viruses. Recently, Olea Europrae plant with antibacterial, antifungal, and antiviral effects has been reported for immune‐boosting effects to treat HSV infection.\n12\n, \n13\n Similarly, imiquimod, as an immune‐modifier, is also used for the purpose.\n14\n\n\n\nIn vivo studies have shown the efficacy of olive leaves extract against HSV‐1.\n15\n The application of olive leaf extract is also indicated for the treatment of HSV.\n16\n In a patent, it has been pointed out that the olive leaf extract in six patients with herpes genitalis eliminated lesions in three of them after 48 hours and in a patient after 72 hours. The remaining two patients showed 66% improvement.\n17\n Oleuropein is one of the active phenolic compounds in olive leaves that is known for the treatment of cancer, microbes, viruses, and hyperlipidemia. It is effective against rotavirus, hepatitis, parvovirus, influenza virus, herpes, and human immunodeficiency viruses. Furthermore, anti‐inflammatory and analgesic effects are also reported.\n18\n\n\n\nIn this case, we have reported the treatment of herpes simplex virus infection using olive leaf extract in an acyclovir‐resistant patient. It was seen that the ointment with the 2% of the extract can control itching, bleeding, and pain. It was also effective against the lesions, similar to acyclovir. These outcomes are likely to direct cost‐effective methods for treating herpes using herbal medicine with low‐to‐no adverse effects. Therefore, further clinical studies are recommended in the area.\n\n5 CONCLUSION\nOlive leaf extracts are the potential antiviral compounds that can be used to treat genital herpes.\n\nCONFLICT OF INTEREST\nThe authors deny any conflict of interest in any terms or by any means during the study.\n\nAUTHOR CONTRIBUTIONS\nDr NL: conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. Dr NK: designed the data collection instruments, collected data, carried out the initial analyses, and reviewed and revised the manuscript. Dr YK: coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content.\n\nETHICAL APPROVAL\nAll procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.\n\nCONSENT FOR PUBLICATION\nNot applicable.\n\nDATA AVAILABILITY STATEMENT\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nREFERENCES\n1 \n\nLorzadeh \nN \n, \nSepavand \nF \n, \nSoleimaninezhad \nM \n, \nKazemirad \nN \n. The effect of extract of oak gall for vaginal tightening and rejuvenation in women with vaginal relaxation\n. Open J Obstet Gynecol . 2016 ;6 (13 ):879 ‐887\n.\n2 \n\nAkbariasbagh \nF \n, \nLorzadeh \nN \n, \nAzmoodeh \nA \n, \nGhaseminejad \nA \n, \nMohamadpoor \nJ \n, \nKazemirad \nS \n. Association among diameter and volume of follicles, oocyte maturity, and competence in intracytoplasmic sperm injection cycles\n. Minerva Ginecol . 2015 ;67 (5 ):397 ‐403\n.26491821 \n3 \n\nWhitley \nRJ \n, \nRoizman \nB \n. Herpes simplex virus infections\n. Lancet . 2001 ;357 (9267 ):1513 ‐1518\n.11377626 \n4 \n\nLorzadeh \nN \n, \nGhasem Nejad \nA \n, \nMohmad Pour \nJ \n. The effect of metformin on outcome of intrauterine insemination (IUI) in insulin non‐resistant infertile women with polycystic ovarian syndrome\n. Iran J Obstet Gynecol Infertil . 2014 ;17 (128 ):1 ‐11\n.\n5 \n\nLorzadeh \nN \n, \nKazemirad \nS \n, \nLorzadeh \nM \n, \nNajafi \nS \n. Comparison of the effect of oral and intravenous fluid therapy on women with oligohydramnios\n. Res J Obstet Gynecol . 2008 ;1 (1 ):25 ‐29\n.\n6 \n\nLorzadeh \nN \n, \nSamimi \nS \n, \nBirjandi \nM \n. Association of fetal gender with maternal serum β‐hCG and testosterone in normotensive and preeclamptic pregnancies\n. Iran J Obstet Gynecol Infertil . 2010 ;13 (1 ):13 ‐19\n.\n7 \n\nWhitley \nRJ \n, \nKimberlin \nDW \n, \nRoizman \nB \n. Herpes simplex viruses\n. Clin Infect Dis . 1998 ;541 ‐553\n.9524821 \n8 \n\nKhan \nMTH \n, \nAther \nA \n, \nThompson \nKD \n, \nGambari \nR \n. Extracts and molecules from medicinal plants against herpes simplex viruses\n. Antiviral Res . 2005 ;67 (2 ):107 ‐119\n.16040137 \n9 \n\nLorzadeh \nN \n, \nSepavand \nF \n, \nSoleimaninezhad \nM \n, \nKazemi \nRN .\nThe effect of extract of internal layer of quercus (OAK GAL) in contraction of vaginal smooth muscles in women with vaginal relaxation\n. 2016 .\n10 \n\nChattopadhyay \nD \n, \nKhan \nMTH \n. Ethnomedicines and ethnomedicinal phytophores against herpesviruses\n. Biotechnol Annu Rev . 2008 ;14 :297 ‐348\n.18606369 \n11 \n\nChattopadhyay \nD \n, \nNaik \nTN \n. Antivirals of ethnomedicinal origin: structure‐activity relationship and scope\n. Mini Rev Med Chem . 2007 ;7 (3 ):275 ‐301\n.17346219 \n12 \n\nSudjana \nAN \n, \nD’Orazio \nC \n, \nRyan \nV \n, et al. Antimicrobial activity of commercial Olea europaea (olive) leaf extract\n. Int J Antimicrob Agents . 2009 ;33 (5 ):461 ‐463\n.19135874 \n13 \n\nLee \nO‐H \n, \nLee \nB‐Y \n. Antioxidant and antimicrobial activities of individual and combined phenolics in Olea europaea leaf extract\n. Biores Technol . 2010 ;101 (10 ):3751 ‐3754\n.\n14 \n\nPerkins \nN \n, \nNisbet \nM \n, \nThomas \nM \n. Topical imiquimod treatment of aciclovir‐resistant herpes simplex disease: case series and literature review\n. Sex Transm Infect . 2011 ;87 (4 ):292 ‐295\n.21406577 \n15 \n\nMotamedifar \nM \n, \nNekooeian \nA \n, \nMoatari \nA \n. The effect of hydroalcoholic extract of olive leaves against herpes simplex virus type 1\n. Iran J Med Sci . 2015 ;32 (4 ):222 ‐226\n.\n16 \n\nHsu \nPP \n. Natural medicines comprehensive database\n. J Med Libr Assoc . 2002 ;90 (1 ):114 .\n17 \n\nFredrickson \nWR \n. Method and composition for antiviral therapy\n. 2002 . Google Patents.\n18 \n\nOmar \nSH \n. Oleuropein in olive and its pharmacological effects\n. Sci Pharm . 2010 ;78 (2 ):133 ‐154\n.21179340\n\n",
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"keywords": "acyclovir; antiviral; genital herpes; infection; olive leaf extract",
"medline_ta": "Clin Case Rep",
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"title": "Treatment of genital herpes using olive leaf extract.",
"title_normalized": "treatment of genital herpes using olive leaf extract"
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"abstract": "Objective Systemic anticoagulation remains the standard for acute lower extremity (LE) deep venous thrombosis (DVT), but growing interest in catheter-directed thrombolysis (CDT) and its potential to reduce the incidence of post-thrombotic syndrome (PTS) has led to advent of ultrasound-accelerated CDT (US-CDT). Few studies to date have examined the outcomes of US-CDT against traditional CDT (T-CDT). Methods This is a retrospective, single-center review of all patients treated for acute LE DVT over a five-year period with either US- and T-CDT. Patients were stratified based on demographics, presentation, co-morbidities, risk factors, and peri-procedural data. Results Seventy-six limbs in 67 patients were treated; 51 limbs in 42 patients were treated with US-CDT, and 25 limbs in 25 patients were treated with T-CDT. Adjuncts include: pharmacomechanical thrombolysis ( n = 28 vs. 20, p = 0.04), angioplasty ( n = 22 vs. 18, p = 0.11), stenting ( n = 30 vs. 6, p ≤ 0.001), and IVC filter insertion ( n = 5 vs. 0, p = 0.07). Mean lysis times were 21 ± 1.7 and 24 ± 1.8 h for US- and T-CDT, respectively ( p = 0.26). Thirty (25 ultrasound, 5 traditional) limbs had complete lysis. Thirty-one (22 ultrasound, 9 traditional) limbs had incomplete lysis. Fifteen (4 ultrasound, 11 traditional) limbs had ineffective lysis ( p = 0.002 in favor of ultrasound). Four patients (3 US-CDT, 1 T-CDT) had recurrent ipsilateral thrombosis within 30 days ( p = 0.60). By Kaplan-Meier analysis, there were no significant difference between primary patency, primary-assisted patency, secondary patency, re-thrombosis, and recurrent symptoms at 6, 12, and 24 months. Conclusion US-CDT does not significantly improve mid-term patencies but results in greater acute clot burden reduction in patients with acute LE DVTs compared to T-CDT, which may be beneficial in reducing the long-term incidence of PTS.",
"affiliations": "1 Division of Vascular and Endovascular Surgery, Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, TX, USA.;1 Division of Vascular and Endovascular Surgery, Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, TX, USA.;2 Division of Vascular Diseases and Surgery, Department of Surgery, Wexner Medical Center, Ohio State University, Columbus, OH, USA.;3 Division of Vascular and Endovascular Surgery, Department of Surgery, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.",
"authors": "Lu|Tony|T|;Loh|Thomas M|TM|;El-Sayed|Hosam F|HF|;Davies|Mark G|MG|",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "England",
"delete": false,
"doi": "10.1177/1708538117702061",
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"issue": "25(5)",
"journal": "Vascular",
"keywords": "CDT; DVT; EKOS; outcomes; thrombolysis; ultrasound",
"medline_ta": "Vascular",
"mesh_terms": "D018572:Disease-Free Survival; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D053208:Kaplan-Meier Estimate; D035002:Lower Extremity; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D054070:Postthrombotic Syndrome; D012008:Recurrence; D019233:Retreatment; D012189:Retrospective Studies; D012307:Risk Factors; D013781:Texas; D015912:Thrombolytic Therapy; D013997:Time Factors; D016896:Treatment Outcome; D014464:Ultrasonic Therapy; D014654:Vascular Patency; D020246:Venous Thrombosis",
"nlm_unique_id": "101196722",
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"pmid": "28372484",
"pubdate": "2017-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Single-center retrospective review of ultrasound-accelerated versus traditional catheter-directed thrombolysis for acute lower extremity deep venous thrombosis.",
"title_normalized": "single center retrospective review of ultrasound accelerated versus traditional catheter directed thrombolysis for acute lower extremity deep venous thrombosis"
} | [
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"abstract": "We evaluated the efficacy and toxicity profiles of the combination of fludarabine, high-dose cytosine arabinoside (AraC), idarubicin, and granulocyte colony-stimulating factor (G-CSF) in refractory/relapsed acute myeloblastic leukemia (AML) patients. Between October 1998 and February 2002, 46 AML patients were treated with FLAG-IDA (fludarabine 30 mg/m(2), AraC 2 g/m(2) for 5 days, idarubicin 10 mg/m(2) for 3 days, and G-CSF 5 micro g/kg from day +6 until neutrophil recovery). Thirty patients were in relapse after conventional chemotherapy including cytarabine, etoposide, and daunorubicin or mitoxantrone according to the GIMEMA protocols. Four were in relapse after autologous peripheral stem cell transplantation and two after allogeneic bone marrow transplantation. Ten patients had refractory disease (after 10 days of standard doses of cytarabine, 3 days of mitoxantrone or daunorubicin, and 5 days of etoposide). Recovery of neutrophils and platelets required a median of 19 and 22 days from the start of therapy. Complete remission (CR) was obtained in 24 of 46 patients (52.1%) and 3 of 46 (6.6%) died during reinduction therapy: 2 due to cerebral hemorrhage and 1 due to fungemia ( Candida tropicalis). Fever >38.5 degrees C was observed in 40 of 46 patients (86.9%), 27 had fever of unknown origin (FUO) and 13 documented infections; 31 of 46 (67.3%) developed mucositis and 14 of 46 (30.4%) had grade 2 WHO transient liver toxicity. After achieving CR, 11 patients received allogeneic stem cell transplantation, 4 patients received autologous stem cell transplantation, 4 were judged unable to receive any further therapy, and 5 refused other therapy. Ten patients are at present in continuous CR after a median follow-up of 13 months (range: 4-24). In our experience, FLAG-IDA is a well-tolerated and effective regimen in relapsed/refractory AML. The toxicity is acceptable, enabling most patients to receive further treatment, including transplantation procedures.",
"affiliations": "Department DIMIMP, University of Bari, Piazza Giulio Cesare n 11, 70124 Bari, Italy.",
"authors": "Pastore|D|D|;Specchia|G|G|;Carluccio|P|P|;Liso|A|A|;Mestice|A|A|;Rizzi|R|R|;Greco|G|G|;Buquicchio|C|C|;Liso|V|V|",
"chemical_list": "D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D014740:Vidarabine; D015255:Idarubicin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-003-0624-2",
"fulltext": null,
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"issn_linking": "0939-5555",
"issue": "82(4)",
"journal": "Annals of hematology",
"keywords": null,
"medline_ta": "Ann Hematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D016026:Bone Marrow Transplantation; D003561:Cytarabine; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D015255:Idarubicin; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D016896:Treatment Outcome; D014740:Vidarabine",
"nlm_unique_id": "9107334",
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"pages": "231-5",
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"pmid": "12707726",
"pubdate": "2003-04",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D018848:Controlled Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience.",
"title_normalized": "flag ida in the treatment of refractory relapsed acute myeloid leukemia single center experience"
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"activesubstancename": "IDARUBICIN HYDROCHLORIDE"
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"abstract": "A patient with adenoid cystic carcinoma was treated with mitoxantrone at a dose of 12 mg/m2 every 3 weeks. After the fifth dose, she developed amenorrhea accompanied by vasomotor instability (hot flashes). Subsequent serum gonadotropin and estradiol levels confirmed the postmenopausal state. The mechanism of mitoxantrone-associated amenorrhea is most likely due to direct toxic effects on the ovary, as is seen with other forms of chemotherapy. Ovarian dysfunction with mitoxantrone has not been previously reported. The important consequences of chemotherapy-induced ovarian failure are described. This toxic effect may be more frequently described as the drug becomes more widely available.",
"affiliations": null,
"authors": "Shenkenberg|T D|TD|;Von Hoff|D D|DD|",
"chemical_list": "D000880:Anthraquinones; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D008942:Mitoxantrone",
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"issue": "70(5)",
"journal": "Cancer treatment reports",
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"mesh_terms": "D000328:Adult; D000568:Amenorrhea; D000880:Anthraquinones; D003528:Carcinoma, Adenoid Cystic; D004958:Estradiol; D005260:Female; D005640:Follicle Stimulating Hormone; D006801:Humans; D008175:Lung Neoplasms; D007986:Luteinizing Hormone; D008441:Maxillary Neoplasms; D008593:Menopause; D008942:Mitoxantrone; D010049:Ovarian Diseases",
"nlm_unique_id": "7607107",
"other_id": null,
"pages": "659-61",
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"pmid": "3011260",
"pubdate": "1986-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Possible mitoxantrone-induced amenorrhea.",
"title_normalized": "possible mitoxantrone induced amenorrhea"
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"abstract": "Acute-onset obsessive-compulsive disorder can be challenging, especially when triggered by an underlying disease process. Clinicians often turn to Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS), but it is important to consider a broad differential in these patients. We present a case of a 9-year-old girl with acute-onset obsessive-compulsive behavior likely triggered by a post-infectious phenomenon that ultimately resolved following treatment with plasmapheresis.",
"affiliations": "Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.;Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.;Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.",
"authors": "Freeman|Cecilia G|CG|https://orcid.org/0000-0002-0211-260X;Langeveldt|Antanoid J|AJ|https://orcid.org/0000-0002-5532-7890;Miller|Robyn R|RR|",
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"doi": "10.1155/2021/6672028",
"fulltext": "\n==== Front\nCase Rep Psychiatry\nCase Rep Psychiatry\nCRIPS\nCase Reports in Psychiatry\n2090-682X\n2090-6838\nHindawi\n\n10.1155/2021/6672028\nCase Report\nA Diagnostic Dilemma of Antiglutamic Acid Decarboxylase 65 (Anti-GAD 65) and Mycoplasma Pneumoniae Antibodies in a Girl Presenting with Acute-Onset Obsessive-Compulsive Disorder\nhttps://orcid.org/0000-0002-0211-260X\nFreeman Cecilia G. 1\nhttps://orcid.org/0000-0002-5532-7890\nLangeveldt Antanoid J. antanoid.langeveldt@nemours.org\n2\nMiller Robyn R. 2\n1Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA\n2Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA\nAcademic Editor: Lut Tamam\n\n2021\n19 3 2021\n2021 667202820 10 2020\n27 12 2020\n8 1 2021\nCopyright © 2021 Cecilia G. Freeman et al.\n2021\nThis 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.\nAcute-onset obsessive-compulsive disorder can be challenging, especially when triggered by an underlying disease process. Clinicians often turn to Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS), but it is important to consider a broad differential in these patients. We present a case of a 9-year-old girl with acute-onset obsessive-compulsive behavior likely triggered by a post-infectious phenomenon that ultimately resolved following treatment with plasmapheresis.\n==== Body\n1. Introduction\n\nObsessive-compulsive disorder (OCD) is a debilitating disease characterized by repetitive, ritualistic, and distressing thoughts and behavior which can be very difficult to control. It affects about 1-3% of school-aged children and adolescents [1, 2]. The cause of obsessive-compulsive disorder is unknown; however, a combination of genetic and environmental factors may be contributory [3]. In a subset of patients, underlying disease processes such as infectious, postinfectious, and autoimmune phenomena can trigger OCD [4]. We report a 9-year-old girl with no significant past medical history who presented to the emergency department (ED) with acute-onset obsessive-compulsive behavior in the setting of positive anti-glutamic acid decarboxylase 65 (anti-GAD 65) and Mycoplasma pneumoniae antibodies. Here, we discuss her symptoms, diagnostic evaluation, and the treatment she received.\n\n2. Case Presentation\n\nOur patient was a 9-year-old previously healthy girl who presented to the ED with a chief complaint of acute-onset obsessive-compulsive behavior. Eleven days prior to presentation, she became emotionally labile, manifested as sudden episodes of sadness, withdrawal, and unwillingness to participate in social events. Five days prior to admission, her parents observed her displaying ritualistic behaviors such as watching a YouTube commercial 75 times, walking in certain patterns, taking her pajamas on and off a certain amount of times before going to school, picking her lips, and banging her ankles and the side of her abdomen against the kitchen counter. These behaviors would occupy the patient for 4-6 hours, affecting her ability to function normally. She explained that if she did not engage in these behaviors, she would continue to think about them and was worried that something bad may happen to her or her parents. She was also described as having decreased concentration and difficulty performing simple mathematical equations. This was very unusual, as her parents described her as a highly spirited and functional child who is popular at school—participating in advanced math classes, piano, tennis, and gymnastics.\n\nConcerned with her behavior, she was taken to her primary doctor whose workup included Epstein-Barr virus (EBV) serology, anti-deoxyribonuclease (anti-DNase), antistreptolysin O (ASO), thyroid function tests (TFTs), complete blood count (CBC), comprehensive metabolic panel (CMP), thyroid-stimulating hormone/thyroxine (TSH/T4), and Lyme serology (all within normal limits). An impression of PANDAS was made, and she went home on amoxicillin and fluoxetine, which she took for two days prior to her presentation to our ED.\n\nThe family considered stress as a possible contributing factor and spent a weekend away from home for a change in environment. In their hotel room, she would ritualize walking back and forth several times. If she failed to complete these rituals, it would result in emotional outbursts and a strong urge to repeat them. Her ability to eat and drink was also impaired, causing her to become dehydrated and prompting her parents to bring her to the ED. This process took five hours due to her extreme reluctance to leave the hotel room before completing her rituals.\n\nReview of systems was significant for the following: constitutional—negative for malaise and weight loss; skin—negative for rash, positive for bruising on ankles and waist; gastrointestinal—negative for vomiting and abdominal pain; neurologic—negative for weakness, neck pain, neck stiffness, paresthesia, and seizures.\n\nFamily history was significant for anxiety in both parents. Socially, she was living with her parents with strong support from her grandparents who live nearby. No report of sexual abuse, physical abuse, or bullying at school. Her medications included fluoxetine and amoxicillin that were started two days prior to hospitalization by her pediatrician. Allergies included oseltamivir.\n\nOn examination, she appeared well looking, in no apparent distress. Her vitals were normal; central nervous system (CNS)—neck supple, pupils equal and round, reactive to light (PEARRL), cranial nerves II-XII intact, motor, sensation, and power normal; Her affect was normal, and her mood was congruent; Head, eyes, ears, nose, and throat (HEENT)—mucous membranes dry; skin—healing bruises on her ankles and waist; cardiovascular, respiratory, and abdominal exams were normal.\n\nIn the ED, she received maintenance intravenous fluids (IVF) and was admitted to the general pediatrics floor with a presumptive diagnosis of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS).\n\nShe continued to perform rituals in the hospital, requesting the participation of her parents to suppress them. When moving objects in the room, they would need to carry them over her in a certain way several times to complete the ritual without upsetting her. As her admission progressed, her urges became overwhelming, and she ultimately returned to performing the rituals herself. She paced several times across the hospital, resisting the urge to urinate until she had completed the task. This resulted in episodes of pain and distress attributed to acute urinary retention that resolved with voiding. She also regressed developmentally, showing more interest in cartoons targeted for younger children, and continued to refuse to drink, requiring IVF intermittently.\n\n2.1. Diagnostic Evaluation\n\nPsychiatry, psychology, and neurology services were consulted to help guide the patient's evaluation and treatment. She underwent a series of tests to identify a secondary cause of her presentation. This included a CBC [mild microcytic anemia], CMP [normal], Lyme serology [normal], brain magnetic resonance imaging (MRI) [mild prominence of sulci likely secondary to dehydration], repeat brain MRI about 3 weeks from the first [normal], lumbar puncture (LP) with opening pressure [normal], cerebrospinal fluid (CSF) microscopy and chemistry [normal], CSF autoimmune profile [normal], electroencephalogram (EEG) [normal], serum autoimmune encephalopathy panel [positive for anti-GAD 65 at 0.05, resulted day 16], serum N-methyl D-aspartate (NMDA) antibodies [negative], and M. pneumoniae serum antibodies [IgG and IgM positive, resulted day 3] with confirmatory M. pneumoniae IgM indirect immunofluorescence assay (IFA) [positive, resulted day 3].\n\n2.2. Therapeutic Interventions\n\nAmongst the consulting services, there were varying opinions regarding the diagnosis and treatment of the patient. Psychiatry cited case reports and experiences with patients with M. pneumoniae infections associated with OCD that responded to azithromycin. At their recommendation, azithromycin was initiated for a 30-day course. However, this was discontinued on day 13 because she developed diarrhea in the setting of underlying dehydration, in addition to a lack of clinical improvement. At this time, psychotropic medications were not started so as not to confound the possible response to azithromycin.\n\nPsychology attempted a reward system to encourage oral (PO) intake, but she continued to intermittently require IVF due to inadequate intake as a result of interference from her rituals.\n\nOn day 9 of hospitalization, psychiatry recommended starting intravenous methylprednisolone (1.5 mg/kg/dose), however, no clinical response was observed after a 5-day course. Lorazepam was initiated as needed for agitation and ritual control at this time.\n\nDue to the lack of response to the above treatments (azithromycin, reward system, steroids), intravenous immunoglobulin (IVIG) was considered, however not initiated due to a national shortage. The ultimate decision to attempt plasmapheresis was made on day 16 of hospitalization when the anti-GAD 65 was found to be positive. After her first session of plasmapheresis, she showed some improvement— she was able to participate in Halloween activities (trick-or-treat), and her rituals were less repetitive with an improvement in her PO intake. She received a total of five rounds of plasmapheresis before her compulsions decreased significantly. Sertraline 10 mg daily was initiated on day 23 of hospitalization. She was ultimately discharged after about one month of inpatient care, and continued to follow up with her outpatient psychologist, psychiatrist, and pediatrician. Her outpatient psychiatrist increased her sertraline dosage to 15 mg and added Vitamin D 1000-2000 units daily. She also completed an outpatient intensive behavioral health program after her discharge. Within a few weeks of her discharge, her compulsions and intrusive thoughts had dissipated completely.\n\n3. Discussion\n\nOur patient was positive for Mycoplasma pneumoniae IgM and IgG in the setting of a recent upper respiratory infection (URI), suggesting an antecedent M. pneumoniae infection. The medical literature describes case reports of the association of M. pneumoniae with acute-onset OCD and other neuropsychiatric disorders [5, 6]. She was also positive for anti-GAD 65 antibodies, which are reportedly associated with reduced gamma-aminobutyric acid (GABA) transmission and can lead to seizures, increased anxiety, behavioral changes, and encephalitis [7]. However, anti-GAD 65 levels > 20 have a higher positive predictive value for encephalitis, and her level of 0.05 is unlikely to be clinically significant [8].\n\nShe did not respond to azithromycin despite receiving a 13-day course. We hypothesize that she did not have an active M. pneumoniae infection on presentation, rendering the antibiotics ineffective, but may have experienced a post-infectious process in the form of M. pneumoniae-induced antineuronal antibodies.\n\nShe also received steroids with minimal effect. Steroids are estimated to reduce antibody production by 10-20 percent [9], which may not be an adequate nadir to produce a clinical response. However, the dramatic response to plasmapheresis suggests that the inciting antibodies were ultimately cleared and no longer exerting their antineuronal effect. Whether this improvement was secondary to clearance of M. pneumoniae-associated antibodies or anti-GAD 65 antibodies remains unclear.\n\nOur patient's initial diagnosis was PANDAS/PANS which is a controversial diagnosis with conflicting evidence in the medical literature. The diagnostic criteria for PANDAS were first proposed in 1998 [4], and further revised as PANS in 2012 to include patients without group A streptococcal (GAS) infection [10], but are beyond the scope of this discussion.\n\nSome authors have proposed steering away from PANDAS/PANS and coining childhood acute-onset neuropsychiatric syndrome (CANS) as an umbrella term with a strong emphasis on identifying the underlying etiology [11]. Using this approach, the differential diagnosis for any child presenting with neuropsychiatric symptoms includes infections, postinfectious sequelae, autoimmune disease, drug-induced, metabolic, traumatic, primary psychiatric disorder, and idiopathic, which we have listed as a guide to clinicians (Table 1).\n\nA list of investigations has been proposed to guide clinicians (Table 2) [11]; however, no consensus has been documented. Clinicians should therefore obtain a thorough history and physical examination in order to formulate a comprehensive differential diagnosis, appropriate investigations, and a management plan. In patients with severe symptoms such as ours, an extensive evaluation is warranted.\n\nLimitations of our evaluation included the lack of throat culture for GAS, which was arguably appropriate as the patient had no URI symptoms. More importantly, an ANA was not performed, which is commonly overlooked. This is an important test to consider as childhood-onset SLE can present with neuropsychiatric symptoms in two-thirds of patients [12].\n\nFor treatment, antibiotics should be used only when an active infection has been documented, for example, M. pneumoniae. Prolonged antibiotic use increases the risk of adverse drug reactions, as in this case, and antimicrobial resistance. The use of steroids, IVIG, and plasmapheresis should be determined on a case-by-case basis, strongly evaluating the risk-to-benefit ratio for each modality. Institutions are encouraged to develop clinical pathways and multidisciplinary team meetings to ensure appropriate use of the aforementioned modalities. Cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) are reasonable adjuncts as the risk of harm is low.\n\nOur patient underwent an extensive and invasive diagnostic workup, several unsuccessful treatments, and spent nearly an entire month admitted to the hospital before her symptoms improved. This is a severely debilitating condition that requires more high-quality research to fully understand its pathophysiology and evaluate the efficacy of various treatment options.\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nTable 1 Differential diagnosis for CANS.\n\nInfection\tMetabolic\tDrugs\tToxins\tAutoimmune\t\nBacterial or viral meningitis, encephalitis, acute disseminated encephalomyelitis (ADEM)\tHypoglycemia, diabetic ketoacidosis (DKA), hyperammonemia, hyperthyroidism, hypothyroidism, uremia\tSteroids, antihistamines, antipsychotics, phencyclidine (PCP), methamphetamine, benzodiazepines, anticholinergics, cannabis, cocaine\tOrganophosphates, heavy metals, alcohol\tNMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), GABA receptor antibodies, Hashimoto's, antiphospholipid, systemic lupus erythematosus (SLE)\t\n\t\nVascular\tPsychiatric\tIdiopathic\t\t\t\nStroke, hypertensive emergency, subdural hemorrhage, epidural hemorrhage\tPrimary psychiatric disorder\tNo underlying etiology identified\t\t\t\n\nTable 2 List of suggested investigations for CANS.\n\nBlood\tCSF\tBrain imaging\t\nCBC, CMP, ammonia, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ASO, anti-DNAse B, TSH, T4, anti-thyroglobulin, anti-thyroperoxidase, urine drug screen (UDS), ethanol level, acetaminophen and salicylate levels, antinuclear antibodies (ANA), autoimmune encephalitis panel\tCell count, differential, glucose, protein, gram stain, bacterial and viral polymerase chain reaction (PCR), autoimmune encephalitis panel, oligoclonal bands\tVideo EEG,\nComputed tomography (CT),\nMRI\n==== Refs\n1 Kessler R. C. Berglund P. Demler O. Jin R. Merikangas K. R. Walters E. E. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication Archives of General Psychiatry 2005 62 6 593 602 10.1001/archpsyc.62.6.593 2-s2.0-20344385026 15939837\n2 Weissman M. M. Bland R. C. Canino G. J. The cross national epidemiology of obsessive compulsive disorder. The Cross National Collaborative Group The Journal of Clinical Psychiatry 1994 1 p. 55\n3 Hanna G. L. Himle J. A. Curtis G. C. Gillespie B. W. A family study of obsessive-compulsive disorder with pediatric probands American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 2005 134B 1 13 19 10.1002/ajmg.b.30138 2-s2.0-15744375050\n4 Swedo S. E. Leonard H. L. Garvey M. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases The American Journal of Psychiatry 1998 155 2 264 271 10.1176/ajp.155.2.264 9464208\n5 Ercan T. E. Ercan G. Severge B. Arpaozu M. Karasu G. Mycoplasma pneumoniae infection and obsessive-compulsive disease: a case report Journal of Child Neurology 2008 23 3 338 340 10.1177/0883073807308714 2-s2.0-39049160222 18079308\n6 Frankovich J. Thienemann M. Rana S. Chang K. Five youth with pediatric acute-onset neuropsychiatric syndrome of differing etiologies Journal of Child and Adolescent Psychopharmacology 2015 25 1 31 37 10.1089/cap.2014.0056 2-s2.0-84923265890 25695942\n7 Tohid H. Anti-glutamic acid decarboxylase antibody positive neurological syndromes Neurosciences (Riyadh) 2016 21 3 215 222 10.17712/nsj.2016.3.20150596 2-s2.0-84976516976 27356651\n8 McKeon A. Tracy J. A. GAD65 neurological autoimmunity Muscle & Nerve 2017 56 1 15 27 10.1002/mus.25565 2-s2.0-85017628863 28063151\n9 Settipane G. A. Pudupakkam R. K. McGowan J. H. Corticosteroid effect on immunoglobulins The Journal of Allergy and Clinical Immunology 1978 62 3 162 166 10.1016/0091-6749(78)90101-x 2-s2.0-0018189368 681628\n10 Swedo S. E. Leckman J. F. Rose N. R. From research subgroup to clinical syndrome: modifying the PANDAS criteria to describe PANS (pediatric acute-onset neuropsychiatric syndrome) Pediatrics & Therapeutics 2012 2 p. 113\n11 Singer H. S. Gilbert D. L. Wolf D. S. Mink J. W. Kurlan R. Moving from PANDAS to CANS The Journal of Pediatrics 2012 160 5 725 731 10.1016/j.jpeds.2011.11.040 2-s2.0-84859888875 22197466\n12 Benseler S. M. Silverman E. D. Neuropsychiatric involvement in pediatric systemic lupus erythematosus Lupus 2016 16 8 564 571 10.1177/0961203307078971 2-s2.0-34548422414\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6838",
"issue": "2021()",
"journal": "Case reports in psychiatry",
"keywords": null,
"medline_ta": "Case Rep Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101583308",
"other_id": null,
"pages": "6672028",
"pmc": null,
"pmid": "33791138",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "681628;25695942;27356651;17711889;15635694;22197466;18079308;8077177;28063151;9464208;15939837",
"title": "A Diagnostic Dilemma of Antiglutamic Acid Decarboxylase 65 (Anti-GAD 65) and Mycoplasma Pneumoniae Antibodies in a Girl Presenting with Acute-Onset Obsessive-Compulsive Disorder.",
"title_normalized": "a diagnostic dilemma of antiglutamic acid decarboxylase 65 anti gad 65 and mycoplasma pneumoniae antibodies in a girl presenting with acute onset obsessive compulsive disorder"
} | [
{
"companynumb": "US-TEVA-2021-US-1910210",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
"drugadditional": nu... |
{
"abstract": "Takotsubo cardiomyopathy (TCM) is also known as stress-induced cardiomyopathy. The occurrence of TCM due to infusion reaction is extremely rare. A 65-year-old man began receiving trastuzumab monotherapy for gastric cancer. However, he developed an infusion reaction after administration. Electrocardiography revealed negative T waves, ST segment elevation, and apical akinesis and hypokinesis of the left ventricle with apical ballooning in the systole and diastole. Furthermore, troponin I and creatinine kinase (CK) levels and CK-myocardial band were elevated. Based on these findings, he was diagnosed with TCM. This is the first report of TCM due to an infusion reaction.",
"affiliations": "1Department of Internal Medicine, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan.;1Department of Internal Medicine, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan.;2Department of Cardiology, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan.;1Department of Internal Medicine, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan.;1Department of Internal Medicine, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan.;1Department of Internal Medicine, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan.;1Department of Internal Medicine, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan.;1Department of Internal Medicine, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan.;1Department of Internal Medicine, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan.",
"authors": "Matsumoto|Toshihiko|T|0000-0002-7397-1006;Oda|Takashi|T|;Yoshida|Yu|Y|;Kimura|Shogo|S|;Himei|Hitomi|H|;Tsuduki|Takao|T|;Takagi|Shinjiro|S|;Takatani|Masahiro|M|;Morishita|Hirofumi|H|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1007/s13691-019-00396-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-3183",
"issue": "9(1)",
"journal": "International cancer conference journal",
"keywords": "Chemotherapy; Infusion reaction; Takotsubo cardiomyopathy",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "28-31",
"pmc": null,
"pmid": "31950014",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports",
"references": "22147738;21275498;14507946;8300889;16258084;23349345;19300240;18241629;21771988;20529041;20728210;19305108;23434354;21423045;26332547;19353811;30806878;16908934",
"title": "Takotsubo cardiomyopathy caused by infusion reaction to trastuzumab.",
"title_normalized": "takotsubo cardiomyopathy caused by infusion reaction to trastuzumab"
} | [
{
"companynumb": "JP-CELLTRION INC.-2020JP018189",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "A 15-month-old boy presented with new onset symmetric erythema of the conchal bowls bilaterally in the setting of treatment with cytarabine. Findings were consistent with a diagnosis of toxic erythema of chemotherapy, an adverse effect of chemotherapy. In this report, we detail this uncommon manifestation in a young child along with a brief literature review of the background, pathophysiology, and treatment strategies of toxic erythema of chemotherapy to increase awareness of this presentation in pediatric populations.",
"affiliations": "Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.;Section of Pediatric Dermatology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Section of Pediatric Dermatology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.;Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.;Section of Pediatric Dermatology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Section of Pediatric Dermatology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.",
"authors": "Tamazian|Shant|S|https://orcid.org/0000-0002-7841-8883;Oboite|Michelle|M|;Larijani|Mary|M|;Oliver|Brittany|B|;Milbar|Heather|H|;Jen|Melinda|M|;Treat|James R|JR|https://orcid.org/0000-0001-9945-8713",
"chemical_list": "D003561:Cytarabine",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14522",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "38(2)",
"journal": "Pediatric dermatology",
"keywords": "Ara-c ears; toxic erythema of chemotherapy",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D002648:Child; D003561:Cytarabine; D004890:Erythema; D006801:Humans; D007223:Infant; D008297:Male",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "512-513",
"pmc": null,
"pmid": "33481261",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Toxic erythema of chemotherapy affecting the ears of an infant: A case report.",
"title_normalized": "toxic erythema of chemotherapy affecting the ears of an infant a case report"
} | [
{
"companynumb": "US-PFIZER INC-2021109306",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
... |
{
"abstract": "The case of a 54-year-old man with delirium secondary to phenytoin and disulfiram administration is presented. The pharmacology, interaction, and resulting toxicity of these two drugs are explored. The patient made an uneventful recovery when the medications were withheld.",
"affiliations": null,
"authors": "Brown|C G|CG|;Kaminsky|M J|MJ|;Feroli|E R|ER|;Gurley|H T|HT|",
"chemical_list": "D010672:Phenytoin; D004221:Disulfiram",
"country": "United States",
"delete": false,
"doi": "10.1016/s0196-0644(83)80516-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-0644",
"issue": "12(5)",
"journal": "Annals of emergency medicine",
"keywords": null,
"medline_ta": "Ann Emerg Med",
"mesh_terms": "D003693:Delirium; D004221:Disulfiram; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D010672:Phenytoin",
"nlm_unique_id": "8002646",
"other_id": null,
"pages": "310-3",
"pmc": null,
"pmid": "6625283",
"pubdate": "1983-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Delirium with phenytoin and disulfiram administration.",
"title_normalized": "delirium with phenytoin and disulfiram administration"
} | [
{
"companynumb": "US-PFIZER INC-2016237322",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"drugadditional": null,
... |
{
"abstract": "Calcium channel blockers (CCBs) are responsible for a substantial portion of the mortality associated with cardiovascular medication overdose cases. Amlodipine, a dihydropyridine CCB, can cause prolonged hypotension in overdose. This report describes a severe amlodipine overdose case that was refractory to multiple therapeutic approaches. A 53-year-old male presented after ingesting eighty 10 mg amlodipine tablets in a suicide attempt. The patient was initially managed with calcium boluses, glucagon, multiple vasoactive agents, lipid emulsion infusions and hyperinsulinemic euglycemic therapy. Methylene blue boluses were initiated when hypotension persisted despite conventional treatments. Refractory hypotension prompted the use of plasmapheresis in an attempt to lower serum amlodipine levels. Finally, the patient was placed on extracorporeal membrane oxygenation (ECMO) to maintain perfusion while the effects of the amlodipine ingestion dissipated. Following an episode of asystole and pulseless electrical activity prior to the start of ECMO, the patient suffered an anoxic brain injury and suspected herniation prompting the family to withdraw medical care. There is limited evidence in the literature describing the refractory treatment modalities utilized in this patient. This report is unique as it describes the clinical course of a patient when a multitude of unique treatments were combined.",
"affiliations": "Department of Pharmacotherapeutics and Clinical Research, University of South Florida College of Pharmacy, 12901 Bruce B. Downs Blvd, MDC 30, Tampa, FL, 33612, USA. mchudow@health.usf.edu.;Tampa General Hospital, 1 Tampa General Circle, Tampa, FL, 33606, USA.",
"authors": "Chudow|Melissa|M|0000-0002-7832-1416;Ferguson|Kevin|K|",
"chemical_list": "D002121:Calcium Channel Blockers; D014665:Vasodilator Agents; D017311:Amlodipine",
"country": "United States",
"delete": false,
"doi": "10.1007/s12012-017-9419-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-7905",
"issue": "18(2)",
"journal": "Cardiovascular toxicology",
"keywords": "Amlodipine; Extracorporeal membrane oxygenation; Hypotension; Methylene blue; Overdose; Plasma exchange",
"medline_ta": "Cardiovasc Toxicol",
"mesh_terms": "D017311:Amlodipine; D001794:Blood Pressure; D002121:Calcium Channel Blockers; D062787:Drug Overdose; D017809:Fatal Outcome; D006801:Humans; D007022:Hypotension; D008297:Male; D008875:Middle Aged; D013405:Suicide; D016896:Treatment Outcome; D014665:Vasodilator Agents",
"nlm_unique_id": "101135818",
"other_id": null,
"pages": "192-197",
"pmc": null,
"pmid": "28688059",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Severe, Refractory Hypotension After Amlodipine Overdose.",
"title_normalized": "a case of severe refractory hypotension after amlodipine overdose"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-16-02977",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
... |
{
"abstract": "61-year-old woman with Neuromyelitis optica (NMO) diagnosis treated with rituximab was referred to our hospital with severe hypovolemic shock and anasarca. The laboratory findings showed marked hemoconcentration and a decrease in total serum protein. She developed a multiple organ failure and died three hours later. We diagnosed the patient as having capillary leak syndrome (CLS). CLS is a very rare condition caused by unexplained episodic capillary hyperpermeability, which can be idiopathic or secondary to some conditions like infection, malignant disease and some drugs like monoclonal antibodies. We reported the first CLS case in NMO patient treated with rituximab.",
"affiliations": "Critical Care Department, Virgen de la Arrixaca Hospital, Murcia, Spain.;Multiple Sclerosis Unit, Neurology Department, Virgen de la Arrixaca Hospital, Murcia, Spain. Electronic address: rociohclares@hotmail.com.;Multiple Sclerosis Unit, Neurology Department, Virgen de la Arrixaca Hospital, Murcia, Spain.;Multiple Sclerosis Unit, Neurology Department, Virgen de la Arrixaca Hospital, Murcia, Spain.",
"authors": "Fuentes Fernandez|Ignacio|I|;Hernandez-Clares|Rocio|R|;Carreón Guarnizo|Ester|E|;Meca Lallana|Jose E|JE|",
"chemical_list": "D007155:Immunologic Factors; D000069283:Rituximab",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2017.06.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "16()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "Capillary leak syndrome; Neuromyelitis optica; Rituximab",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D019559:Capillary Leak Syndrome; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D008875:Middle Aged; D009471:Neuromyelitis Optica; D000069283:Rituximab",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "22-23",
"pmc": null,
"pmid": "28755680",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Capillary leak syndrome in neuromyelitis optica treated with rituximab.",
"title_normalized": "capillary leak syndrome in neuromyelitis optica treated with rituximab"
} | [
{
"companynumb": "ES-ROCHE-1955750",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "OBJECTIVE\nTo compare \"sandwich chemo-radiotherapy\" with six cycles of chemotherapy followed by adjuvant radiotherapy with respect to tolerability and acute toxicity.\n\n\nMETHODS\nTwenty-five women with surgically staged IIIC endometrial cancer were included. Treatment consisted of either three cycles of paclitaxel (175 mg/m²) and carboplatin (AUC 6) on a q21-day schedule followed by irradiation (45-50.4 Gy) or six cycles of the same chemotherapy followed by radiotherapy. Acute toxicity related to either chemotherapy or radiotherapy was evaluated.\n\n\nRESULTS\nMedian age was 61.5 years (range 36-83 years). Eleven patients had sandwich chemo-radiotherapy, and the other 14 patients had 6 cycles of chemotherapy followed by radiotherapy. Three out of the five patients who could not complete all the cycles in the sandwich chemo-radiotherapy group had pelvic and para-aortic radiotherapy. Acute radiotherapy related grade 1-2 gastrointestinal system (GIS) and genitourinary system (GUS) toxicities were observed in 72.8 and 63.6 % of patients, respectively, for sandwich group. Undesired treatment breaks in the course of radiotherapy were observed in six patients for sandwich chemo-radiotherapy and in one patient receiving six cycles of chemotherapy followed by radiotherapy. All the patients who had undesired treatment breaks in the sandwich chemo-radiotherapy group had pelvic and para-aortic radiotherapy.\n\n\nCONCLUSIONS\nSandwich chemo-radiotherapy seems to be more toxic particularly for patients who had pelvic and para-aortic irradiation. Therefore, it might be more convenient to delay radiotherapy after six cycles of chemotherapy for patients with the indication of pelvic para-aortic radiotherapy.",
"affiliations": "Department of Gynecologic Oncology, Faculty of Medicine, Selcuk University, Tip fakultesi Alaeddin Keykubat Kampusu, Kadin hastalikları ve dogum AD, Selcuklu, 42075, Konya, Turkey, nasuhutkudogan@yahoo.com.",
"authors": "Dogan|Nasuh Utku|NU|;Yavas|Guler|G|;Yavas|Cagdas|C|;Ata|Ozlem|O|;Yılmaz|Setenay Arzu|SA|;Celik|Cetin|C|",
"chemical_list": "D000970:Antineoplastic Agents; D016190:Carboplatin; D017239:Paclitaxel",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00404-013-2817-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0932-0067",
"issue": "288(4)",
"journal": "Archives of gynecology and obstetrics",
"keywords": null,
"medline_ta": "Arch Gynecol Obstet",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002277:Carcinoma; D017024:Chemotherapy, Adjuvant; D004334:Drug Administration Schedule; D016889:Endometrial Neoplasms; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007044:Hysterectomy; D008197:Lymph Node Excision; D008875:Middle Aged; D009367:Neoplasm Staging; D010052:Ovariectomy; D017239:Paclitaxel; D018714:Radiotherapy, Adjuvant; D020266:Radiotherapy, Conformal; D012189:Retrospective Studies; D058994:Salpingectomy; D016896:Treatment Outcome",
"nlm_unique_id": "8710213",
"other_id": null,
"pages": "845-50",
"pmc": null,
"pmid": "23553195",
"pubdate": "2013-10",
"publication_types": "D003160:Comparative Study; D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Comparison of \"sandwich chemo-radiotherapy\" and six cycles of chemotherapy followed by adjuvant radiotherapy in patients with stage IIIC endometrial cancer: a single center experience.",
"title_normalized": "comparison of sandwich chemo radiotherapy and six cycles of chemotherapy followed by adjuvant radiotherapy in patients with stage iiic endometrial cancer a single center experience"
} | [
{
"companynumb": "TR-MYLANLABS-2014M1014604",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Transplant recipients receiving a kidney from an extended-criteria donor (ECD) are exposed to calcineurin inhibitor (CNI) nephrotoxicity, as demonstrated by severe delayed graft function and/or a low GFR. Belatacept is a nonnephrotoxic drug that is indicated as an alternative to CNIs. We reported 25 cases of conversion from a CNI to belatacept due to CNI intolerance within the first 6 mo after transplantation. The mean age of the recipients was 59 years, and 24 of 25 patients received ECD kidneys. At the date of the medication switch, 12 of 25 patients displayed a calculated GFR (cGFR) <15 mL/min, six patients remained on dialysis, and the biopsies showed evidence of acute tubular damage associated with severe vascular or tubulointerstitial chronic lesions. Three patients did not recover renal function, and three patients died during the follow-up period. Among the remaining patients, renal function improved: The cGFR was 18.28 ± 12.3 mL/min before the medication switch compared with 34.9 ± 14.5 mL/min at 1 year after conversion to belatacept (p = 0.002). Tolerance of and compliance with belatacept were good, and only one patient experienced acute rejection. Belatacept is an effective therapy that preserves renal function in kidney transplant patients who are intolerant of CNIs.",
"affiliations": "Department of Nephrology and Transplantation, University Hospital La Cavale Blanche, European University of Brittany, Brest, France.;Department of Renal Transplantation, Necker-Enfants Malades University Hospital, AP-HP, Paris, France.;Department of Nephrology, University Hospital, Rouen, France.;Department of Nephrology, University Hospital, Clermont-Ferrand, France.;Department of Nephrology and Transplantation, University Hospital, Reims, France.;Department of Nephrology and Renal Transplantation, Hospices Civils, Strasbourg, France.;Department of Nephrology and Clinical Immunology-EA4245, Bretonneau Hospital, University Hospital, Tours, France.;Department of Renal Transplantation, Necker-Enfants Malades University Hospital, AP-HP, Paris, France.;Department of Anatomy and Pathology, University Hospital, Brest, France.;Department of Nephrology and Transplantation, University Hospital La Cavale Blanche, European University of Brittany, Brest, France.;Department of Renal Transplantation, Necker-Enfants Malades University Hospital, AP-HP, Paris, France.",
"authors": "Le Meur|Y|Y|;Aulagnon|F|F|;Bertrand|D|D|;Heng|A E|AE|;Lavaud|S|S|;Caillard|S|S|;Longuet|H|H|;Sberro-Soussan|R|R|;Doucet|L|L|;Grall|A|A|;Legendre|C|C|",
"chemical_list": "D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D000069594:Abatacept",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.13698",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "16(7)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; delayed graft function (DGF); donors and donation: extended criteria; drug toxicity; fusion proteins and monoclonal antibodies: adhesion molecule specific; immunosuppressant; immunosuppression/immune modulation; kidney (allograft) function/dysfunction; kidney transplantation/nephrology",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000069594:Abatacept; D000368:Aged; D065095:Calcineurin Inhibitors; D051799:Delayed Graft Function; D004351:Drug Resistance; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D066027:Transplant Recipients",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "2181-6",
"pmc": null,
"pmid": "26718625",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effect of an Early Switch to Belatacept Among Calcineurin Inhibitor-Intolerant Graft Recipients of Kidneys From Extended-Criteria Donors.",
"title_normalized": "effect of an early switch to belatacept among calcineurin inhibitor intolerant graft recipients of kidneys from extended criteria donors"
} | [
{
"companynumb": "FR-WATSON-2016-16952",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nMultiple myeloma remains incurable and retreatment with available therapies is of substantial interest.\n\n\nMETHODS\nThis retrospective observational study included data from 35 patients treated initially and at the first relapse with bortezomib-containing regimens.\n\n\nRESULTS\nBortezomib retreatment provided a similar depth and time to response as first-line therapy; however, as could be expected, the duration of response was shorter with retreatment. The tolerability profile was similar with bortezomib as the first- and second-line therapy, with no evidence of cumulative toxicity.\n\n\nCONCLUSIONS\nThese findings support bortezomib retreatment after a treatment-free interval of ≥6 months in patients who achieved at least a partial response to the first-line bortezomib-based therapy.",
"affiliations": null,
"authors": "Oriol|Albert|A|;Giraldo|Pilar|P|;Kotsianidis|Ioannis|I|;Couturier|Catherine|C|;Olie|Robert|R|;Angermund|Ralf|R|;Corso|Alessandro|A|",
"chemical_list": "D000069286:Bortezomib",
"country": "England",
"delete": false,
"doi": "10.1179/1607845414Y.0000000218",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1024-5332",
"issue": "20(7)",
"journal": "Hematology (Amsterdam, Netherlands)",
"keywords": "Bortezomib; Efficacy; Multiple myeloma; Retreatment; Safety",
"medline_ta": "Hematology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000069286:Bortezomib; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D012008:Recurrence; D012189:Retrospective Studies",
"nlm_unique_id": "9708388",
"other_id": null,
"pages": "405-9",
"pmc": null,
"pmid": "25494809",
"pubdate": "2015-08",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and safety of bortezomib-based retreatment at the first relapse in multiple myeloma patients: A retrospective study.",
"title_normalized": "efficacy and safety of bortezomib based retreatment at the first relapse in multiple myeloma patients a retrospective study"
} | [
{
"companynumb": "ES-TAKEDA-2015MPI005889",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
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