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{
"abstract": "To reduce the overall time spent in the ED, triage nurses are encouraged to treat patients with a topical anesthetic cream, eutectic mixture of local anesthetics (EMLA). We present a case in which a 28-day-old neonate who was treated with EMLA cream in triage developed severe methemoglobinemia 18 hours post admission to the pediatric ward. This case demonstrates that there may be some risks associated with this approach, and that protocols for the use of EMLA at triage should include not only the indications for its use, but also need to ensure that there is a process to have the EMLA removed before patient discharge or transfer.",
"affiliations": "Pediatric Department A, Meyer Children's Hospital, Rambam Medical Center, Haifa, Israel.",
"authors": "Shachor-Meyouhas|Yael|Y|;Galbraith|Roger|R|;Shavit|Itai|I|",
"chemical_list": "D000779:Anesthetics, Local; D004791:Enzyme Inhibitors; D000077442:Lidocaine, Prilocaine Drug Combination; D011318:Prilocaine; D008012:Lidocaine; D008751:Methylene Blue",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2007.07.071",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "35(1)",
"journal": "The Journal of emergency medicine",
"keywords": null,
"medline_ta": "J Emerg Med",
"mesh_terms": "D000287:Administration, Topical; D000779:Anesthetics, Local; D016529:Emergency Nursing; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008012:Lidocaine; D000077442:Lidocaine, Prilocaine Drug Combination; D008708:Methemoglobinemia; D008751:Methylene Blue; D011318:Prilocaine; D014218:Triage",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "39-41",
"pmc": null,
"pmid": "18281179",
"pubdate": "2008-07",
"publication_types": "D002363:Case Reports; D016429:Clinical Conference; D016428:Journal Article",
"references": null,
"title": "Application of topical analgesia in triage: a potential for harm.",
"title_normalized": "application of topical analgesia in triage a potential for harm"
} | [
{
"companynumb": "IL-WATSON-2014-18506",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LIDOCAINE\\PRILOCAINE"
},
"drugadditional": null,
... |
{
"abstract": "A liver, heart, iliac vessel and two kidneys were recovered from a 39-year-old man who died of traumatic head injury and were transplanted into five recipients. The liver recipient 18 days posttransplantation presented with headache, ataxia and fever, followed by rapid neurologic decline and death. Diagnosis of granulomatous amebic encephalitis was made on autopsy. Balamuthia mandrillaris infection was confirmed with immunohistochemical and polymerase chain reaction (PCR) assays. Donor and recipients' sera were tested for B. mandrillaris antibodies. Donor brain was negative for Balamuthia by immunohistochemistry and PCR; donor serum Balamuthia antibody titer was positive (1:64). Antibody titers in all recipients were positive (range, 1:64-1:512). Recipients received a four- to five-drug combination of miltefosine or pentamidine, azithromycin, albendazole, sulfadiazine and fluconazole. Nausea, vomiting, elevated liver transaminases and renal insufficiency were common. All other recipients survived and have remained asymptomatic 24 months posttransplant. This is the third donor-derived Balamuthia infection cluster described in solid organ transplant recipients in the United States. As Balamuthia serologic testing is only available through a national reference laboratory, it is not feasible for donor screening, but may be useful to determine exposure status in recipients and to help guide chemotherapy.",
"affiliations": "University of Florida College of Medicine, Gainesville, FL.",
"authors": "Gupte|A A|AA|;Hocevar|S N|SN|;Lea|A S|AS|;Kulkarni|R D|RD|;Schain|D C|DC|;Casey|M J|MJ|;Zendejas-Ruiz|I R|IR|;Chung|W K|WK|;Mbaeyi|C|C|;Roy|S L|SL|;Visvesvara|G S|GS|;da Silva|A J|AJ|;Tallaj|J|J|;Eckhoff|D|D|;Baddley|J W|JW|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.12726",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "14(6)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "Amebic encephalitis; Balamuthia mandrillaris; donor-derived infection; miltefosine",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000328:Adult; D000562:Amebiasis; D059611:Balamuthia mandrillaris; D006801:Humans; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D014019:Tissue Donors",
"nlm_unique_id": "100968638",
"other_id": "HHSPA732695",
"pages": "1417-24",
"pmc": null,
"pmid": "24840013",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article",
"references": "22729402;11906014;15072770;20847719;18625680;18165529;20550438;15043486;21435080;2280005;21192259;19685076;15503402;20847722;20123772;17021087;12843060;19236272;15347743;16579814;18681845;17428307;21073255;14583863",
"title": "Transmission of Balamuthia mandrillaris through solid organ transplantation: utility of organ recipient serology to guide clinical management.",
"title_normalized": "transmission of balamuthia mandrillaris through solid organ transplantation utility of organ recipient serology to guide clinical management"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/14/0044213",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "Germinomas are highly immunogenic tumors eliciting a strong peri-tumoral immune response that can spillover into the surrounding healthy tissues. This phenomenon can also occur in intracranial germinomas, manifesting as secondary hypophysitis. Herein, we report a case of 12-year-old-girl presenting with polyuria and polydispsia. She had central diabetes insipidus (CDI) and panhypopituitarism. Imaging revealed a sellar-suprasellar mass with infundibular stalk thickening. Transphenoidal biopsy revealed epithelioid granulomas with immunostaining negative for germinomatous cells. Other causes of hypophysitis were ruled out. Accordingly, she was diagnosed as primary granulomatous hypophysitis and treated with high-dose corticosteroids. Three years later she again presented with headache, vomiting and diminution of vision. Imaging showed a heterogeneous, solid-cystic peripheral rim-enhancing lesion at the same location with involvement of hypothalamus, ependyma and pineal gland. Cerebrospinal fluid beta-human chorionic gonadotropin was markedly elevated, confirming the diagnosis of an intracranial germ cell tumor. She was started on chemotherapy; however, she succumbed to febrile neutropenia. We performed a literature search and found 18 anecdotal cases of secondary hypophysitis associated with intracranial germinomas. There was a slight male preponderance (male:female 5:4). Two-thirds of the cases were below 18 years of age. Polyuria was the most common presenting manifestation (83%). CDI and panhypopituitarism were seen in 89 and 78% cases, respectively. Imaging evidence of pituitary stalk thickening was seen in 12 cases (67%), while pituitary enlargement and/or sellar mass were reported in 11 cases (61%). Pineal involvement was extremely rare, being reported in only 1 case, implying the predilection of suprasellar (rather than pineal) germinomas in causing secondary hypophysitis. Histologically, 82% had lymphocytic hypophysitis, while 18% had granulomatous hypophysitis. Initially, the diagnosis of germinoma was missed in 60% of the cases who were wrongly treated with corticosteroids. To conclude, physicians should make it a dictum that all children and adolescents presenting with CDI and pituitary stalk thickening should be rigorously screened for an underlying intracranial germinoma before labeling them as primary hypophysitis.",
"affiliations": "Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Neurosurgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Endocrinology, IQRAA Hospital, Calicut, India.;Department of Neurosurgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Neurosurgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India, pinaki_dutta@hotmail.com.",
"authors": "Pal|Rimesh|R|;Rai|Ashutosh|A|;Vaiphei|Kim|K|;Gangadhar|Prathosh|P|;Gupta|Prakamya|P|;Mukherjee|Kanchan Kumar|KK|;Singh|Paramjeet|P|;Ray|Nirmalya|N|;Bhansali|Anil|A|;Dutta|Pinaki|P|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000501886",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3835",
"issue": "110(5)",
"journal": "Neuroendocrinology",
"keywords": "Diabetes insipidus; Germinoma; Granulomatous hypophysitis; Hypopituitarism; Secondary hypophysitis",
"medline_ta": "Neuroendocrinology",
"mesh_terms": "D000293:Adolescent; D001932:Brain Neoplasms; D002648:Child; D005260:Female; D018237:Germinoma; D006099:Granuloma; D006801:Humans; D000072659:Hypophysitis; D007018:Hypopituitarism; D008297:Male",
"nlm_unique_id": "0035665",
"other_id": null,
"pages": "422-429",
"pmc": null,
"pmid": "31269501",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Intracranial Germinoma Masquerading as Secondary Granulomatous Hypophysitis: A Case Report and Review of Literature.",
"title_normalized": "intracranial germinoma masquerading as secondary granulomatous hypophysitis a case report and review of literature"
} | [
{
"companynumb": "IN-ACCORD-187064",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "We retrospectively reviewed a paediatric intensive care unit database that supports a tertiary oncology service to explore safety and outcome of tracheostomy in oncology patients over a 12-year period and reviewed literature. A total of 895 patients were admitted with a haematological or a solid tumour malignancy of which 222 were ventilated. Six of 222 (2.7%) ventilated children were tracheostomised. Four of six children tracheostomised for ventilatory support received intensive chemotherapy complicated by neutropenia and thrombocytopenia. There was no significant tracheostomy-related complication. Tracheostomy improved patient comfort, reduced sedative requirement, and may have helped recovery. Tracheostomy should be considered early in selected children with haemato-oncological diagnoses requiring prolonged ventilation.",
"affiliations": "Paediatric Intensive Care, Lanesborough Wing, St George's University Hospital NHS Foundation Trust, London, UK.;Paediatric Intensive Care, Lanesborough Wing, St George's University Hospital NHS Foundation Trust, London, UK.;Paediatric Intensive Care, Lanesborough Wing, St George's University Hospital NHS Foundation Trust, London, UK.;Paediatric Intensive Care, Lanesborough Wing, St George's University Hospital NHS Foundation Trust, London, UK.",
"authors": "Manna|Soumendu S|SS|0000-0002-1575-9461;Malik|Rubina|R|;Douthwaite|Amy|A|;Vaidya|Sucheta|S|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28105",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "67(4)",
"journal": "Pediatric blood & cancer",
"keywords": "children; intensive chemotherapy; malignancy; myelosuppression; tracheostomy",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D015278:Intensive Care Units, Pediatric; D008297:Male; D009369:Neoplasms; D011878:Radiotherapy; D012121:Respiration, Artificial; D012131:Respiratory Insufficiency; D012189:Retrospective Studies; D014139:Tracheostomy",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28105",
"pmc": null,
"pmid": "31876351",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Surgical tracheostomy in children with malignancy receiving intensive chemotherapy: A case series and review of literature.",
"title_normalized": "surgical tracheostomy in children with malignancy receiving intensive chemotherapy a case series and review of literature"
} | [
{
"companynumb": "GB-MYLANLABS-2020M1035782",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nDigoxin remains widely used today despite its narrow therapeutic index and toxicity. The objective of this study was to investigate the percentage of inappropriate use of digoxin and long-term outcomes of elderly patients hospitalized for digoxin toxicity.\n\n\nMETHODS\nThe study included 99 consecutive patients hospitalized for digoxin toxicity. The other study criteria for the inappropriate use of digoxin was regarded if participants having depressed left ventricular systolic function (ejection fraction < 45%) who were not on optimal medical therapy including beta-blocker and angiotensin-converting-enzyme inhibitor therapy or if participants having permanent AF who were not on optimal beta-blocker therapy.\n\n\nRESULTS\nAppropriate digoxin usage was confirmed in 33 of patients in spite of its narrow therapeutic index. A total of 16 of 99 patients died, with a mean follow-up time of 22.1 ± 10.3 months.\n\n\nCONCLUSIONS\nContrary to popular belief, the rate of inappropriate digoxin usage remains high. On account of its narrow therapeutic index and toxicity, digoxin should be used more carefully according to the current evidence and guidelines.",
"affiliations": "Department of Cardiology, Sivas Numune State Hospital, Rahmi Gunay Street, Sivas 58000, Turkey.;Department of Cardiology, Kocaeli Derince Education and Research Hospital, İbni Sina Street, Kocaeli 41900, Turkey.;Department of Cardiology, Dr.Siyami Ersek Cardiovascular Surgery Education and Research Hospital, Tıbbiye street, Istanbul, 34668, Turkey.;Department of Cardiology, Dr.Siyami Ersek Cardiovascular Surgery Education and Research Hospital, Tıbbiye street, Istanbul, 34668, Turkey.;Department of Cardiology, Dr.Siyami Ersek Cardiovascular Surgery Education and Research Hospital, Tıbbiye street, Istanbul, 34668, Turkey.;Department of Cardiology, Istanbul Medipol University, Kosuyolu, Istanbul, 34718, Turkey.",
"authors": "Tatlisu|Mustafa Adem|MA|;Ozcan|Kazim Serhan|KS|;Gungor|Baris|B|;Zengin|Ahmet|A|;Karatas|Mehmet Baran|MB|;Nurkalem|Zekeriya|Z|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.11909/j.issn.1671-5411.2015.02.007",
"fulltext": "\n==== Front\nJ Geriatr CardiolJ Geriatr CardiolJGCJournal of Geriatric Cardiology : JGC1671-5411Science Press jgc-12-02-14310.11909/j.issn.1671-5411.2015.02.007Research ArticleInappropriate use of digoxin in patients presenting with digoxin toxicity Tatlisu Mustafa Adem 1Ozcan Kazim Serhan 2Gungor Baris 3Zengin Ahmet 3Karatas Mehmet Baran 3Nurkalem Zekeriya 41 Department of Cardiology, Sivas Numune State Hospital, Rahmi Gunay Street, Sivas 58000, Turkey2 Department of Cardiology, Kocaeli Derince Education and Research Hospital, İbni Sina Street, Kocaeli 41900, Turkey3 Department of Cardiology, Dr.Siyami Ersek Cardiovascular Surgery Education and Research Hospital, Tıbbiye street, Istanbul, 34668, Turkey4 Department of Cardiology, Istanbul Medipol University, Kosuyolu, Istanbul, 34718, TurkeyCorrespondence to: Mustafa Adem Tatlisu, MD, Department of Cardiology, Sivas Numune State Hospital, Rahmi Gunay Street, Sivas 58000, Turkey. E-mail: ademtatlisu@gmail.com. Telephone:+90-536-4439906Fax:+90-346-44444583 2015 12 2 143 146 29 12 2014 31 12 2014 31 12 2014 Institute of Geriatric Cardiology2015This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License, which allows readers to alter, transform, or build upon the article and then distribute the resulting work under the same or similar license to this one. The work must be attributed back to the original author and commercial use is not permitted without specific permission.Background\nDigoxin remains widely used today despite its narrow therapeutic index and toxicity. The objective of this study was to investigate the percentage of inappropriate use of digoxin and long-term outcomes of elderly patients hospitalized for digoxin toxicity.\n\nMethods\nThe study included 99 consecutive patients hospitalized for digoxin toxicity. The other study criteria for the inappropriate use of digoxin was regarded if participants having depressed left ventricular systolic function (ejection fraction < 45%) who were not on optimal medical therapy including beta-blocker and angiotensin-converting-enzyme inhibitor therapy or if participants having permanent AF who were not on optimal beta-blocker therapy.\n\nResults\nAppropriate digoxin usage was confirmed in 33 of patients in spite of its narrow therapeutic index. A total of 16 of 99 patients died, with a mean follow-up time of 22.1 ± 10.3 months.\n\nConclusions\nContrary to popular belief, the rate of inappropriate digoxin usage remains high. On account of its narrow therapeutic index and toxicity, digoxin should be used more carefully according to the current evidence and guidelines.\n\nDigoxinEjection fractionIndicationsToxicity\n==== Body\n1 Introduction\nDigoxin remains widely used today despite its narrow therapeutic index and toxicity. According to the current guidelines, digoxin is recommended in patients with an ejection fraction (EF) ≤ 45% and persisting symptoms [New York Heart Association (NYHA) class II–IV] despite treatment with a beta-blocker, an angiotensin-converting-enzyme (ACE) inhibitor.[1] Digoxin is indicated in patients with permanent atrial fibrillation (AF), heart failure and left ventricular dysfunction, and inactive patients.[2] The objective of this study was to investigate the percentage of inappropriate use of digoxin and long-term outcomes of elderly patients hospitalized for digoxin toxicity.\n\n2 Methods\n2.1 Study design\nThe study included 99 consecutive patients hospitalized for digoxin toxicity from 1 January to 1 December, 2012 at the Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Hospital. A digital 12-lead standard electrocardiogram (ECG) was obtained immediately after admission. Demographic and clinical data including age, sex, blood pressure, diabetes mellitus, hyperlipidemia, hypertension, NYHA class, laboratory data, digoxin plasma concentration, and medication use were assessed at baseline. Left ventricular ejection fraction was evaluated by transthoracic echocardiography immediately after admission. Informed consent was obtained from each patient involved in this study. The study was approved by the Institutional Ethics Committee. Clinical follow-up was performed by telephone interviews with the patient and/or relatives and by review of hospital medical records.\n\n2.2 Study criteria for inappropriate use of digoxin and toxicity\nThe study criteria for the inappropriate use of digoxin was permitted whether participants had transient AF, or they had preserved left ventricular (LV) systolic function (EF > 45%). Also, the inappropriate use of digoxin was permitted whether participants with depressed systolic LV who are not on optimal medical therapy (beta-blocker and ACE inhibitor), or participants with permanent AF who are not on optimal beta-blocker therapy. A normal digoxin level was not considered as an excluding criteria for toxicity due to the fact that the normal plasma concentration cannot exclude the toxicity.[3] Clinical diagnoses, such as loss of appetite, nausea, vomiting, diarrhea, headaches, visual disturbance, confusion, fatigue and ECG finding was used for exclusion.\n\n2.3 Statistical analysis\nAll statistical analyses were carried out using SPSS, version 21.0 (SPSS for Mac; SPSS Inc., Chicago, Illinois, USA) and a P value less than 0.05 was considered statistically significant. Categorical variables are expressed as n (%) and continuous variables are expressed as mean ± SD. Continuous variables were checked for the normal distribution assumption using the Kolmogorov–Smirnov statistics. Differences between patients and control participants were evaluated using the two-sample t-test and the Mann–Whitney U-test as appropriate. Categorical variables were tested using Pearson's X2 test and Fisher's exact test.\n\n3 Results\nThe study included 99 consecutive patients hospitalized for digoxin toxicity. Their baseline demographic and clinical data are presented in Table 1. The mean age of the patients was 78.8 ± 9.7 years old and seventy-five patients (76%) were female. A total of 91 of 99 patients had permanent AF and left ventricular systolic dysfunction was seen in 44 (44%) of patients. A total of 91 (91%) of 99 patients had gastrointestinal complaints, such as loss of appetite, nausea, vomiting, and diarrhea. Appropriate digoxin usage was confirmed in 33 (33%) of patients in spite of its narrow therapeutic index.\n\nLaboratory parameters of the study population are presented in Table 2. The mean digoxin plasma concentration of the patients was 3.34 ± 1.23 ng/mL. Digoxin plasma concentration was 3.61 ± 1.27 ng/mL in patients taking 0.25 mg daily. On the other hand, digoxin plasma concentration was 2.93 ± 1.06 ng/mL in patients taking 0.125 mg daily. The correlation between the digoxin plasma concentration and the dose of digoxin was found to be r = 0.26 (P = 0.01). Besides, the correlation between the digoxin plasma concentration and the creatinine level was found to be r = 0.29 (P = 0.01). However, there was no correlation between the digoxin plasma concentration and age (r = 0.01, P = 0.95).\n\nIn-hospital and long-term adverse cardiac events are presented in Table 3. A total of 16 (16%) of 99 patients died, with a mean follow-up time of 22.1 ± 10.3 months. Five patients represented in-hospital mortality, who had documented ventricular tachycardia/ventricular fibrillation. During the follow-up, 11 patients died, six of whom had been hospitalized for acute ischemic stroke. In the remaining five patients, sudden cardiac death occurred. As shown in Table 3, eleven of patients required temporary pacing, and eight patients required permanent pacing.\n\nTable 1. Baseline characteristics of study population\nCharacteristics\tStudy group (n = 99)\t\nAge, yrs\t78.8 ± 9.7\t\nFemale gender\t75 (76%)\t\nAF\t91 (91%)\t\nHypertension\t86 (87%)\t\nDiabetes\t18 (18%)\t\nHyperlipidemia\t16 (16%)\t\nCoronary artery disease\t43 (43%)\t\nLV sistolic dysfunction\t44 (44%)\t\nChronic renal failure\t30 (30%)\t\nAdmission complaints\t\t\n Gastrointestinal complaints\t91 (92%)\t\n Syncope/Presyncope\t5 (5%)\t\nPalpitation\t1 (1%)\t\n Visual disturbance\t2 (2%)\t\nPrevious medications\t\t\nAcetylsalicylic acid\t68 (68%)\t\n Warfarin\t31 (31%)\t\n Beta blockers\t57 (58%)\t\n Calcium channel blockers\t35 (35%)\t\n ACE-I\t47 (47%)\t\n ARB\t8 (8%)\t\n Potassium-sparing diuretics\t24 (24%)\t\n Loop diuretics\t23 (23%)\t\n Statins\t19 (19%)\t\nNYHA class 1\t14 (14%)\t\nNYHA class 2\t21 (21%)\t\nNYHA class 3\t8 (8%)\t\nNYHA class 4\t1 (1%)\t\nPrevious digoxin dosage\t\t\n 0.25 mg/d\t61 (61%)\t\n 0.125 mg/d\t38 (38%)\t\nIndications for digoxin treatment\t\t\nLV systolic dysfunction with AF\t33 (33%)\t\n LV systolic dysfunctionwithout AF\t8 (8%)\t\n AF without LV systolic dysfunction\t58 (58%)\t\nAppropriate digoxin usage\t33 (33%)\t\nInappropriate digoxin usage\t66 (66%)\t\nLV ejection fraction (%)\t48.7 ± 12.4\t\nParametric variables are reported in mean ± SD or n (%). ACE-I: angiotensin converting enzyme inhibitor; AF: atrial fibrillation; ARB; angiotensin receptor blocker; LV: left ventricular; NYHA: New York Heart Association.\n\nTable 2. Laboratory parameters of the study population.\nCharacteristics\tStudy group, n = 99\t\nBUN, mg/dL\t37.3 ± 23.7\t\nCreatine, mg/dL\t1.43 ± 0.73\t\nAST, U/L\t24 (10)\t\nALT, U/L\t16 (8)\t\nNa, mmol/L\t137 ± 5.8\t\nK, mmol/L\t5.1 ± 4.1\t\nMg, mg/dL\t2.2 ± 0.9\t\nCa, mg/dL\t8.8 ± 1.9\t\nTSH, µIU/mL\t1.5 (1.4)\t\nDigoxin, ng/mL\t3.34 ± 1.23\t\nParametric variables are reported in mean ± SD or median (interquartile range). AST: aspartate aminotransferase; ALT: alanine aminotransferase; BUN: blood urea nitrogen; Ca: calcium; K: potassium; Mg: magnesium; Na: sodium; TSH: thyroid stimulating hormone.\n\nTable 3. In-hospital and long-term adverse cardiac events.\nCardiac events\tStudy population (n = 99)\t\nIn-hospital mortality\t5 (5%)\t\nLong-term mortality\t11 (11%)\t\nTotal mortality\t16 (16%)\t\nTemporary pacemaker implantation\t11 (11%)\t\nPermanent pacemaker implantation\t8 (8%)\t\nCardiopulmonary arrest\t6 (6%)\t\nData are presented as n (%).\n\nThe study population was divided into two groups: group 1 (n = 33) prescribed digoxin therapy with appropriate indication, and group 2 (n = 66) prescribed digoxin therapy with inappropriate indication, as shown in Table 4. In-hospital mortality in groups 1 and 2 was 6% (n = 2) and 5% (n = 3), respectively (P = 0.75). All-cause mortality at long-term follow-up in groups 1 and 2 was 6% (n = 2) and 14% (n = 9), respectively (P = 0.26). There was no significant difference between the two groups with regard to the need for temporary pacing (P = 0.82), and the need for permanent pacing (P = 0.61).\n\n4 Discussion\nThe objective of this study was to investigate the percentage of appropriate use of digoxin and long-term outcomes of elderly patients hospitalized for digoxin toxicity. Despite the recommended dosage of digoxin is 0.125 mg daily, especially in the elderly, and patients with impaired renal function;[4] the number of patients taking 0.125 mg daily was only 38, (Table 1). Serum digoxin level is also useful to allow adjustment of dosage.[5],[6] Lindenfeld, et al.[5] determined decreased mortality in men as long as the digoxin plasma concentration was maintained between 0.5 ng/mL and 1.0 ng/mL. They also showed higher risk (23%) of death among women. There is also evidence that digoxin may be harmful in women. In our study, the mean digoxin plasma concentration of the patients was 3.34 ± 1.23 ng/mL, where seventy-five patients (76%) were female.\n\nTable 4. In-hospital and long-term adverse cardiac events in appropriate and inappropriate digoxin usage.\nCardiac event\tGroup 1 (n = 33)\tGroup 2 (n = 66)\tP value\t\nIn-hospital mortality\t2 (6%)\t3 (5%)\t0.75\t\nLong-term mortality\t2 (6%)\t9(14%)\t0.26\t\nTotal mortality\t4(12%)\t12(18%)\t0.57\t\nTemporary pacemaker implantation\t4(12%)\t7(11%)\t0.82\t\nPermanent pacemaker implantation\t2 (6%)\t6 (9%)\t0.61\t\nCardiopulmonary arrest\t2 (6%)\t4 (6%)\t0.99\t\nData are presented as n (%).\n\nDigoxin is still widely used despite its limited indication. In light of the current evidence and guidelines, digoxin has not been recommended as first line therapy for patients with systolic heart failure (HF), or permanent AF.[1],[2] Digoxin can be used for patients with an EF ≤ 45% and persisting symptoms (NYHA class II–IV) despite treatment with a beta-blocker, an ACE inhibitor.[1] Withdrawal studies[7] and prospective studies, such as the Digoxin Investigator Group (DIG) trial, showed that digoxin reduced hospitalizations.[8] However, they found that digoxin did not affect mortality. Despite this recent evidence, digoxin is still used in patients with systolic HF who are not on optimal medical therapy (beta-blocker and ACE inhibitor). In this study, eight of 99 patients with systolic HF were not on beta-blocker therapy. Moreover, digoxin can be used for patients with permanent AF for control of heart rate at rest, but not during exercise.[2] Digoxin can be combined with a beta-blocker which may be effective either with or without HF, especially with inactive patients. However, digoxin should be used carefully in patients without HF. Nonetheless, a total of 58 of 99 patients without systolic HF were not on optimal beta-blocker therapy. Our study also shows that old habits die hard.\n\nMultiple studies have already reported inappropriate digoxin use in patients with systolic HF. For instance, Aronow studied 500 consecutive patients admitted to a nursing home.[9] A total of 96 of 500 patients were receiving digoxin and inappropriate digoxin usage was confirmed in 47%. Ahmed, et al.[10] studied 603 older patients hospitalized for HF in whom inappropriate digoxin usage was confirmed in 37% of patients. Biteker, et al.[11] investigated inappropriate digoxin usage in elderly patients presenting to an outpatient cardiology clinic and found that forty-eight of the 124 patients receiving digoxin had an inappropriate indication for digoxin use. See, et al.[12] showed that an estimated 5156 emergency departmentvisits for digoxin toxicity occurred annually in the United States.\n\nThe study was carried out in a tertiary referral hospital in Istanbul and the study population was aged 67–92 years. Therefore, the results should not be generalized to all patients receiving digoxin.\n\nIn conclusion, contrary to popular belief, the rate of inappropriate digoxin usage remains high. Due to its narrow therapeutic index and toxicity, digoxin should be used more carefully according to the current evidence and guidelines.\n\nThe authors declare that there is no conflict of interest\n==== Refs\nReferences\n1 McMurray JJ Adamopoulos S Anker SD ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC Eur J Heart Fail 2012 14 803 869 22828712 \n2 Camm AJ Kirchhof P Lip GY Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC) Europace 2010 12 1360 1420 20876603 \n3 Lip GY Metcalfe MJ Dunn FG Diagnosis and treatment of digoxin toxicity Postgrad Med J 1993 69 337 339 8346128 \n4 Mann DL Mann DL Zipes DP Libby P Management of patients with heart failure with reduced ejection fraction 10th Edition Elsevier Saunders 2015 534 \n5 Lindenfeld J Albert NM Boehmer JP HFSA 2010 Comprehensive heart failure practice guideline J Card Fail 2010 16 1 20123311 \n6 Rathore SS Curtis JP Wang Y Association of serum digoxin concentration and outcomes in patients with heart failure JAMA 2003 289 871 12588271 \n7 Gheorghiade M Adams KF Jr Colucci WS. Digoxin in the management of cardiovascular disorders Circulation 2004 109 2959 15210613 \n8 Bourge RC Fleg JL Fonarow GC Digoxin reduces 30-day all-cause hospital admission in older patients with chronic systolic heart failure Am J Med 2013 126 701 23490060 \n9 Aronow WS Prevalence of appropriate and inappropriate indications for use of digoxin in older patients at the time of admission to a nursing home J Am Geriatr Soc 1996 44 588 590 8617911 \n10 Ahmed A Allman RM DeLong JF Inappropriate use of digoxin in older hospitalized heart failure patients J Gerontol A Biol Sci Med Sci 2002 57 138 143 \n11 Biteker M Duman D Dayan A Inappropriate use of digoxin in elderly patients presenting to an outpatient cardiology clinic of a tertiary hospital in Turkey Turk Kardiyol Dern Ars 2011 39 365 370 21743259 \n12 See I Shehab N Kegler SR Emergency department visits and hospitalizations for digoxin toxicity: United States, 2005 to 2010 Circ Heart Fail 2014 7 28 34 24300242\n\n",
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"abstract": "We have performed ten pediatric kidney transplantations from living-related ABO-incompatible donors. All patients underwent preoperative plasmapheresis with or without immunoadsorption to reduce isoagglutinin. Primary immunosuppression consisted of methyl-prednisolone, cyclosporin or tacrolimus, azathioprine, anti-lymphocyte globulin, and/or deoxyspergualin. At transplantation splenectomy was simultaneously performed in all patients. Median follow-up is 65 months (range 4-95 months). The patient and graft survival rates are 100% to date. Post-transplantation isoagglutinin titers did not increase more than 1:32, except for 1 patient, without uncontrollable vascular rejection episodes. Despite the heavy immunosuppressive regimen, cytomegalovirus infection occurred in only three patients, who were successfully treated with ganciclovir and cytomegalovirus high-titer gamma globulin. Our small series clearly shows that the preoperative reduction of isoagglutinin, splenectomy, and strict immunosuppressive therapy lead to successful long-term results in children.",
"affiliations": "Department of Pediatric Nephrology, Tokyo Women's Medical College, Japan.",
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"abstract": "OBJECTIVE\nTo assess hemoglobin (Hb) outcomes and fatigue-related quality-of-life (QoL) (electronic assessment) in patients with solid tumors and symptomatic chemotherapy-induced anemia receiving cytotoxic chemotherapy and darbepoetin alfa (DA) or another erythropoiesis-stimulating agent according to European indication.\n\n\nMETHODS\neAQUA was a Phase IV prospective observational study. The primary outcome (assessed in the primary analysis set [PAS]: patients receiving one or more DA dose who had baseline and week 9 assessments for Hb and QoL) was the proportion of patients receiving DA having both Hb increases ≥1 g/dL and improved QoL between baseline and week 9. Functional Assessment of Cancer Therapy-Fatigue (FACT-F) subscale scores were anchored to fatigue visual analog scale scores to determine the minimally important difference for improved QoL. Overall data/data over time are reported for the full analysis set (patients receiving one or more erythropoiesis-stimulating agent dose, n=1,158); week 9 data (ie, data relating to the primary and secondary outcomes) are reported for the PAS (n=510). Baseline and safety data are included for both the full analysis set and PAS.\n\n\nRESULTS\nIn the PAS, 69% of patients had stage IV disease and 96% were fatigued. The minimally important difference in FACT-F change score for QoL improvement was 3.5. From baseline to week 9, 32% (95% confidence interval: 28%-36%) of patients had both improved QoL and an Hb increase ≥1 g/dL; proportions were similar across the most common tumor types. At week 9, 49% and 58% of patients had improved QoL or Hb increases ≥1 g/dL, respectively; 70% and 76% had QoL or Hb improvements between baseline and study end, respectively. In the PAS, 16% of patients required transfusions and 32% required iron supplementation. Few patients (<1%) reported adverse drug reactions.\n\n\nCONCLUSIONS\nIn this study, patients with solid tumors receiving DA per European indication for symptomatic chemotherapy-induced anemia had clinically meaningful improvements in Hb and QoL.",
"affiliations": "Department of Medical Oncology, Clinique Rambot Provencale, Aix en Provence, France.;Clinical Oncology, Wojewodzki Szpital Specjalistyczny, Wroclaw, Poland.;Department of Internal Medicine/Oncology, Albert Schweitzer Ziekenhuis locatie Dordwijk, Dordrecht, the Netherlands.;Radiotherapy Service, Medical Oncology, Polyclinique Francheville, Périgueux, France.;Central Pharmacy, AZ Sint-Jan Brugge-Oostende AV, Brugge, Belgium.;Private Oncology Practice. Goslar, Germany.;LB Biostatistics, London, UK.;Clinical Research, Amgen Inc., Thousand Oaks, CA, USA.;Medical Development - Oncology, Amgen (Europe) GmbH, Zug, Switzerland.;Department of Medical Oncology, Università Campus Bio-Medico, Roma, Italy.",
"authors": "Mouysset|Jean-Loup|JL|;Freier|Beata|B|;van den Bosch|Joan|J|;Levaché|Charles Briac|CB|;Bols|Alain|A|;Tessen|Hans Werner|HW|;Belton|Laura|L|;Bohac|G Chet|GC|;Terwey|Jan-Henrik|JH|;Tonini|Giuseppe|G|",
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"fulltext": "\n==== Front\nCancer Manag ResCancer Manag ResCancer Management and ResearchCancer Management and Research1179-1322Dove Medical Press 10.2147/CMAR.S88110cmar-8-001Original ResearchHemoglobin levels and quality of life in patients with symptomatic chemotherapy-induced anemia: the eAQUA study Mouysset Jean-Loup 1Freier Beata 2van den Bosch Joan 3Levaché Charles Briac 4Bols Alain 5Tessen Hans Werner 6Belton Laura 7Bohac G Chet 8Terwey Jan-Henrik 9Tonini Giuseppe 101 Department of Medical Oncology, Clinique Rambot Provencale, Aix en Provence, France2 Clinical Oncology, Wojewodzki Szpital Specjalistyczny, Wroclaw, Poland3 Department of Internal Medicine/Oncology, Albert Schweitzer Ziekenhuis locatie Dordwijk, Dordrecht, the Netherlands4 Radiotherapy Service, Medical Oncology, Polyclinique Francheville, Périgueux, France5 Central Pharmacy, AZ Sint-Jan Brugge-Oostende AV, Brugge, Belgium6 Private Oncology Practice. Goslar, Germany7 LB Biostatistics, London, UK8 Clinical Research, Amgen Inc., Thousand Oaks, CA, USA9 Medical Development – Oncology, Amgen (Europe) GmbH, Zug, Switzerland10 Department of Medical Oncology, Università Campus Bio-Medico, Roma, ItalyCorrespondence: Jean-Loup Mouysset, Department of Medical Oncology, Clinique Rambot Provencale – 67 cours Gambetta-Aix en Provence, Service de Chimiothérapie, Aix en Provence 13100, France, Tel +33 42 264 332; +33 60 384 9660, Fax +33 44 293 4679, Email jean-loup.mouysset@wanadoo.fr2016 21 1 2016 8 1 10 © 2016 Mouysset et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2016The 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.Purpose\nTo assess hemoglobin (Hb) outcomes and fatigue-related quality-of-life (QoL) (electronic assessment) in patients with solid tumors and symptomatic chemotherapy-induced anemia receiving cytotoxic chemotherapy and darbepoetin alfa (DA) or another erythropoiesis-stimulating agent according to European indication.\n\nMethods\neAQUA was a Phase IV prospective observational study. The primary outcome (assessed in the primary analysis set [PAS]: patients receiving one or more DA dose who had baseline and week 9 assessments for Hb and QoL) was the proportion of patients receiving DA having both Hb increases ≥1 g/dL and improved QoL between baseline and week 9. Functional Assessment of Cancer Therapy-Fatigue (FACT-F) subscale scores were anchored to fatigue visual analog scale scores to determine the minimally important difference for improved QoL. Overall data/data over time are reported for the full analysis set (patients receiving one or more erythropoiesis-stimulating agent dose, n=1,158); week 9 data (ie, data relating to the primary and secondary outcomes) are reported for the PAS (n=510). Baseline and safety data are included for both the full analysis set and PAS.\n\nResults\nIn the PAS, 69% of patients had stage IV disease and 96% were fatigued. The minimally important difference in FACT-F change score for QoL improvement was 3.5. From baseline to week 9, 32% (95% confidence interval: 28%–36%) of patients had both improved QoL and an Hb increase ≥1 g/dL; proportions were similar across the most common tumor types. At week 9, 49% and 58% of patients had improved QoL or Hb increases ≥1 g/dL, respectively; 70% and 76% had QoL or Hb improvements between baseline and study end, respectively. In the PAS, 16% of patients required transfusions and 32% required iron supplementation. Few patients (<1%) reported adverse drug reactions.\n\nConclusion\nIn this study, patients with solid tumors receiving DA per European indication for symptomatic chemotherapy-induced anemia had clinically meaningful improvements in Hb and QoL.\n\nKeyword\ndarbepoetin alfaerythropoiesis-stimulating agentfatigue visual analog scaleFunctional Assessment of Cancer Therapy-Fatigue subscaletransfusion\n==== Body\nIntroduction\nFatigue is a common symptom in patients with cancer1–3 that can adversely impact quality of life (QoL).4 Many studies report that for cancer patients receiving chemotherapy, fatigue incidence is ~60%;5 however, reported prevalence rates vary widely depending on how fatigue is defined and measured, as well as the patient population studied.\n\nAlthough it is difficult to manage fatigue directly caused by disease, effective therapies exist for chemotherapy-induced anemia (CIA), and correcting anemia in patients receiving chemotherapy is, therefore, recommended as a method for managing fatigue.6–10 The effectiveness of erythropoiesis-stimulating agents (ESAs) and/or red blood cell (RBC) transfusions in managing CIA by raising hemoglobin (Hb) levels is well documented.11,12 However, data on the impact of such treatments on fatigue are more limited.\n\nA major difficulty in studying fatigue in cancer is that its etiology is often multifactorial, with both disease- and treatment-related effects likely to contribute. Consequently, many tools aimed at assessing fatigue in patients with cancer have been developed. Multi-item measures, such as the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) subscale, are generally preferred in research settings as they aim to capture the complex nature of cancer-related fatigue. Single-item measures (eg, the fatigue visual analog scale [VAS]13) capture a patient’s perception of their fatigue and are often preferred in clinical practice as they are quick and simple to apply. However, as the level and impact of fatigue for a given patient is subjective, the clinical relevance of a change in score can sometimes be difficult to interpret.\n\nIn the eAQUA (electronic assessment of QoL in patients with symptomatic anemia) clinical practice study, we used an anchor-based approach14–17 to calculate the minimally important difference (MID) for a fatigue-related QoL improvement in patients with CIA receiving darbepoetin alfa (DA) or another ESA according to current European indication. The MID was defined as the smallest change in QoL score perceived to be beneficial by this population of patients. eAQUA also aimed to assess the effectiveness of ESAs at improving Hb levels, which was an important assessment because although DA has been available for several years, there are few data on its use in line with the recently updated European indication for symptomatic CIA.18 This mandates that DA should now only be used in patients with a baseline Hb level of ≤10 g/dL. eAQUA also adds to the limited data relating to improvements in Hb levels and QoL in clinical practice.\n\nMethods\nStudy design\neAQUA (NCT01444456) was a large, Phase IV, multicenter, international, prospective, observational study of patients who were receiving systemic chemotherapy for solid tumors and who were receiving DA or another ESA to treat symptomatic CIA. Although DA is the focus of this study, local regulations in some countries do not permit observational study participation by only patients receiving a specific agent in a drug class. Therefore, enrollment of patients who were receiving an ESA other than DA was permitted in these countries. Target recruitment was ~1,300 patients across approximately ten countries and the enrollment period was ~12 months. Data collection was from enrollment up to 4 weeks after the last recorded dose of ESA or current chemotherapy regimen, the date of withdrawal, or a maximum of 13 weeks after enrollment (whichever occurred first).\n\nThe study protocol was approved by the relevant Independent Ethics Committee and the study was conducted in compliance with International Conference on Harmonization Good Clinical Practice guidelines and with the ethical standards laid down in the 1964 Declaration of Helsinki. All patients provided informed consent before data collection commenced.\n\nStudy outcomes\nThe primary outcome was the proportion of patients receiving DA who had both an Hb increase ≥1 g/dL and a QoL improvement, between baseline and week 9. Secondary outcomes included: the proportion of patients with improved QoL and an Hb increase ≥1 g/dL at any time up to end of study (EOS); the proportion of patients with QoL improvement and an Hb increase ≥1 g/dL at week 9, by most common tumor type (tumor types occurring in ~40+ patients); the proportion of patients with Hb increase ≥1 g/dL by EOS; and time to first Hb increase ≥1 g/dL and characterization of the QoL improvement. As the primary endpoint of this study is a composite one including both Hb and QoL components, the Hb, QoL and MID determination data are reported ahead of the primary endpoint data, which were derived from the former.\n\nThe use of RBC transfusions and iron supplementation during the study were recorded, as were data on DA exposure. Treatment-emergent adverse drug reactions (ADRs) reported up to and including the last dose of study drug plus 28 days were also recorded.\n\nPatients\nKey inclusion criteria\nEligible patients were ≥18 years of age, had an Eastern Cooperative Oncology Group performance status of 0–2, and had been diagnosed with a solid tumor and symptomatic CIA. They were required to be undergoing chemotherapy and were expected to receive ≥8 additional weeks of chemotherapy after enrollment and to have started treatment with an ESA in line with the relevant European Summaries of Product Characteristics for symptomatic CIA. Symptomatic CIA was defined as an Hb level ≤10.0 g/dL (from most recent sample) and physician confirmation of one or more anemia symptom/sequelae. Patients also needed to have the ability and awareness to complete electronic fatigue assessments and to provide informed consent.\n\nPatients in receipt of ESA treatment or RBC transfusion within 28 days prior to enrollment and/or with a known primary benign/malignant hematologic disorder that can cause anemia were excluded.\n\nTreatments and assessments\nThe decision to prescribe treatment must have been freely undertaken by the clinician prior to considering enrolling a patient in the study. Treatment administration was, therefore, independent and dissociated from participation in the study. No study-specific clinical tests were required; all medical data collected on electronic case report forms (eCRFs) were expected to be part of standard patient records. Common chemotherapy regimens for each cancer type were prespecified in the eCRF. For simplicity, these were referred to as “standard” regimens. Regimens not listed in the eCRF could be added manually by the treating clinician and were referred to as “non-standard” regimens.\n\nFACT-F subscale scores and fatigue VAS scores were used to assess QoL. FACT-F scores range from 0 to 52, with higher scores indicating better QoL. VAS scores range from 0 to 100, with 0 being least fatigued. Patients completed electronic fatigue assessments during visits (no more frequently than every 7 days) for receipt of chemotherapy and/or ESA treatment.\n\nStatistical analyses\nThe main analysis set for the primary and secondary outcomes (the primary analysis set [PAS]) included patients who had received one or more DA dose and had baseline and week 9 assessments for Hb, FACT-F, and VAS. The PAS is a subset of the full analysis set (FAS) which consisted of all patients who received one or more dose of an ESA. Overall data and data over time are reported for the FAS; week 9 data are reported for the PAS (ie, data that relate to the primary and secondary outcomes). Baseline data and safety information are included for both the FAS and PAS for completeness.\n\nBaseline was defined as the day of (day 1), or the 14 days prior to, the initiation of an ESA. If more than one result was available, data for the day closest to day 1 was included. Due to the observational nature of the study and potential variation in ESA dosing schedules, Hb, FACT-F, and VAS data closest to day 57 and within days 43–70 (inclusive) were used to calculate the week 9 assessments. Note that for data presented over time (ie, by study week), week 9 constitutes study days 57–63 only (week 1: days 1–7, week 2: days 8–14, … week 13: days 85–91).\n\nThe MID was determined using a modified anchor-based approach16 based on FACT-F and VAS change scores between baseline and week 9. The MID was derived for PAS patients as the mean FACT-F change score for patients who had a prespecified small improvement in VAS score. A patient was deemed to have improved QoL if their FACT-F change score was greater than or equal to the calculated MID. In the literature, a seven-point improvement is considered a small but clinically relevant change in VAS score.19 However, to ensure that only those patients with a minimal improvement in VAS were used to determine the MID for our study, we prespecified that a VAS change score of 7±3, 5±3, 5±2, or 5±1 would be used depending on the number of patients in each of these categories compared with 20% of the number of patients who had a VAS improvement of ≥1 point. The first category to have fewer patients than 20% of the number of patients with a VAS improvement of ≥1 point was used to determine the MID.\n\nFor the time-to-event analyses, time was measured in days from day 1 (day of ESA initiation) based on Kaplan–Meier methodology. Data for patients who did not experience the event of interest were censored at their EOS visit.\n\nAs an exploratory analysis, univariate logistic regression was used to estimate the odds of having improved QoL at week 9 for patients who had an Hb increase ≥1 g/dL compared with an Hb increase <1 g/dL at week 9. Further covariates were investigated individually for inclusion in this model at a significance level of 10%. These were baseline covariates (age [years], sex, tumor type, disease stage, chemotherapy type [platinum, non-platinum], baseline Hb, line of chemotherapy) and post-baseline covariates (iron use [by week 9], concomitant medication use [by week 9]).\n\nResults\nPatients\nOverall, 1,262 patients were enrolled from nine European countries between 10 October, 2011 and 28 May, 2013; the last patient visit was on 27 August 2013. In total, 1,158 patients received one or more ESA dose and so comprised the FAS. Of these, 24 patients received an ESA other than DA (epoetin alfa n=20, epoetin beta n=1, epoetin zeta n=3) and, of these, nine patients (epoetin alfa n=6, epoetin beta n=1, epoetin zeta n=2) received another ESA and had baseline and week 9 Hb and QoL assessments. Overall, 1,134 patients received DA and 510 of these had both baseline and week 9 Hb and QoL data, and so comprised the PAS.\n\nBaseline demographics and disease characteristics were similar for the FAS and the PAS (Table 1). Mean age was 64 years and breast cancer was the most common tumor type. Most patients had an Eastern Cooperative Oncology Group performance status of 0/1 and had stage III/IV disease. Fatigue was the most common anemia symptom, being reported in nearly all of the patients. Overall, just over one-quarter of patients were receiving curative-intent treatment and approximately three-quarters were in their first chemotherapy cycle or had completed between one and three cycles. Most patients were receiving concomitant therapy, with antiemetics and corticosteroids being the most common.\n\nThe types of chemotherapy received differed by tumor type. No “standard” (as prespecified in the eCRF) regimen was received by ≥10% of breast cancer patients in the FAS or PAS (n=289 and n=152, respectively). In both the FAS and PAS (respectively), paclitaxel (26% and 25%), docetaxel (17% and 18%), trastuzumab (14% and 11%), vinorelbine (12% and 11%), and capecitabine (9% and 11%) were the most commonly used agents in “non-standard” regimens. Among patients with ovarian cancer, the most common “standard” regimens in the FAS and PAS (n=157 and n=79, respectively) were carboplatin plus paclitaxel (29% in both populations) and carboplatin plus gemcitabine (9% and 11%, respectively). Carboplatin (17% and 20%), paclitaxel (16% and 14%), topotecan (12% and 9%), gemcitabine (10% and 15%), and bevacizumab (10% and 11%) were the most commonly used agents in “non-standard” regimens (for FAS and PAS, respectively). In patients with colorectal cancer in the FAS and PAS (n=153 and n=71, respectively), 5-fluorouracil (5-FU) plus oxaliplatin (14% in both populations), 5-FU plus irinotecan (13% and 20%), capecitabine plus oxaliplatin (12% and 10%), and 5-FU plus irinotecan plus bevacizumab (9% and 11%) were the most common “standard” regimens. Of the “non-standard” regimens used, 5-FU (18% in both populations), irinotecan (12% and 13%), and oxaliplatin (11% and 10%) were the most commonly used agents (for FAS and PAS, respectively). Among patients with non-small cell lung cancer, the most common “standard” regimens in the FAS and PAS (n=221 and n=70, respectively) were carboplatin plus gemcitabine (16% in both populations), carboplatin plus pemetrexed (11% and 6%), and cisplatin plus vinorelbine (6% and 13%). All the patients with prostate cancer in the FAS and the PAS (n=82 and n=39, respectively) received “non-standard” regimens; in these, docetaxel (67% and 59%) and cabazitaxel (16% and 26%) were the most commonly used agents.\n\nChange in Hb levels\nMean Hb levels over time for the FAS are shown in Figure 1. For the PAS, the mean Hb change at week 9 was 1.2 (standard deviation [SD]: 1.4) g/dL; the median (quartile 1, quartile 3) Hb change was 1.2 (0.3, 2.0) g/dL. At week 9, 295 patients (58% [95% confidence intervals {CI}: 54–62]) had an Hb increase ≥1 g/dL. Up to EOS, 386 patients (76% [95% CI: 72–79]) had an Hb increase ≥1 g/dL (at any point). The median time to first Hb increase ≥1 g/dL was 36.5 (95% CI: 30–43) days (Figure 2); the Kaplan–Meier estimate for the proportion of patients with an Hb increase ≥1 g/dL by EOS was 79% (95% CI: 75–83).\n\nChange in QoL scores\nMean FACT-F and VAS scores for the FAS over time are shown in Figure 3. In the PAS, mean change in FACT-F and VAS scores between baseline and week 9 were 3.5 (SD: 10.5) and 4.3 (SD: 24.7), with 64% and 54% of patients showing an improvement (of ≥1 point) in score, respectively (Table 2).\n\nMID in QoL\nAs the number of patients in the PAS with an improvement in VAS of 7±3 points (n=69) was more than 20% of the number of patients with a VAS improvement ≥1 point (n=55), and the number of patients with a VAS improvement of 5±3 points (n=44) was less than 20% of the number of patients with a VAS improvement ≥1 point (n=55), a VAS improvement of 5±3 points was used to determine the MID for this study.\n\nThe mean FACT-F change score for patients in the PAS with a VAS improvement of 5±3 points was 3.5 (SD: 5.5) and so this was defined as the MID for a QoL improvement. Based on achieving/exceeding this score at week 9, 249 patients (49% [95% CI: 45–53]) had a QoL improvement. At any time up to EOS, 357 patients (70% [95% CI: 26–34]) had improved QoL. The median time to first QoL improvement was 40 (95% CI: 34–43) days (Figure 4); the Kaplan–Meier estimate for the proportion of patients with a QoL improvement by EOS was 72% (95% CI: 68–76).\n\nPrimary endpoint\nOverall, 162 patients in the PAS (32% [95% CI: 28–36]) achieved both improved QoL and an Hb increase ≥1 g/dL at week 9, and thereby achieved the study primary endpoint. In an analysis according to the most common tumor types in the PAS, the proportions of patients having both a QoL improvement and an Hb increase ≥1 g/dL at week 9 were 39% (95% CI: 31–47), 38% (95% CI: 27–49), 31% (95% CI: 20–42), 29% (95% CI: 18–39), and 28% (95% CI: 14–42) for patients with breast, ovarian, colorectal, non-small cell lung, and prostate cancers, respectively.\n\nFactors impacting on QoL improvement\nIn a univariate exploratory analysis, the odds ratio of having improved QoL at week 9 for patients in the PAS who had an Hb increase ≥1 g/dL compared with <1 g/dL at week 9 was 1.79 (95% CI: 1.26–2.56; P=0.001). No further covariates were found to be significant when added to this model.\n\nRBC transfusions and iron use\nIn the FAS, 261 patients (23%) required one or more RBC transfusion during the study and there were a total of 392 transfusion events. The mean units transfused per event were 1.8 (SD: 0.6); mean Hb levels within the 7 and 14 days prior to transfusion were 8.3 (SD: 1.0) g/dL and 8.4 (SD: 1.0) g/dL, respectively. The reasons for transfusion were symptomatic anemia (47%), rapid decline in Hb levels (35%), asymptomatic anemia (13%), presurgical transfusion (<1%), and significant hemorrhage (<1%), and were listed as “other” for 3% of patients. In the PAS, 82 patients (16%) required one or more RBC transfusions and there were a total of 117 transfusion events. The mean units transfused per event were 1.8 (SD: 0.6); mean Hb levels within both the 7 and 14 days prior to transfusion were 8.4 (SD: 1.0) g/dL. The reasons for transfusion were symptomatic anemia (51%), rapid decline in Hb levels (28%), and asymptomatic anemia (21%). In an analysis according to the most common tumor types in the FAS, the proportions of patients requiring an RBC transfusion were 19%, 29%, 26%, 11%, and 26% for patients with breast, non-small cell lung, ovarian, colorectal, and prostate cancers, respectively.\n\nOverall for the FAS, 370 patients (32%) received iron supplementation during the study, with intravenous (IV) iron being used in 235 patients (20%) and oral iron in 166 patients (14%). In the PAS, 163 patients (32%) received iron supplementation, with IV iron being used in 96 patients (19%) and oral iron in 86 patients (17%).\n\nDA exposure\nIn the FAS, 1,134 patients received DA and the median daily DA dose during the study was 33.3 (range: 9–500) μg; the median weekly dose was 208.3 (range: 62–1,000) μg. The median duration of DA exposure was 43.0 (range: 1–91) days and the median total dose was 1,350.0 (range: 150–5,500) μg. The median number of visits in which DA was administered was 3.0 (range: 1–13).\n\nFor the PAS, the median daily DA dose during the study was 29.9 (range: 12–71) μg and the median weekly dose was 200.0 (range: 80–500) μg. The median duration of DA exposure was 64.0 (range: 21–91) days and the median total dose was 1,800.0 (range: 600–5,000) μg. The median number of visits in which DA was administered was 4.0 (range: two to 13).\n\nSafety\nIn the FAS (n=1,158), ten patients (<1%) reported eleven ADRs (thrombocytosis, arrhythmia, cardiac arrest, cystoid macular edema, abdominal pain, injection-site pain, drug hypersensitivity, hyperglycemia, cerebrovascular accident, pruritus, rash). Two serious ADRs (cardiac arrest, cerebrovascular accident) and three ADRs leading to study discontinuation (cystoid macular edema, abdominal pain, drug hypersensitivity) were reported. There was one reported fatal ADR (cardiac arrest).\n\nFour patients (<1%) in the PAS (n=510) reported a total of five ADRs during the study (cystoid macular edema, injection-site pain, hyperglycemia, pruritus, rash). In this population, there were no serious or fatal ADRs reported and only one ADR was reported to lead to study discontinuation (cystoid macular edema).\n\nDiscussion\nThe primary outcome used in this study was a stringent measure necessitating both a QoL improvement and an Hb increase ≥1 g/dL at week 9 during DA treatment; 32% of patients achieved the primary outcome. The proportion of patients achieving both improved QoL and an Hb increase ≥1 g/dL was generally consistent across the most common tumor types. Week 9 was selected for the primary outcome as one would expect a patient to have responded by this time. The flexibility of timing around this time point was to allow for the observational nature of the study and the potential differences in ESA dosing regimens. The true proportion of patients achieving both a QoL improvement and an Hb increase ≥1 g/dL at any time between baseline and EOS was not assessed in this study, although this is likely to be higher than that observed for the primary outcome. In line with this, more patients were found to have a QoL improvement (70% vs 49%) or an Hb increase ≥1 g/dL (76% vs 58%) at any time during the study vs week 9 and so the concordance between these two measures is likely to be higher.\n\nTo determine which patients had improved QoL in the present study, we used an anchor-based approach; however, there are no gold standard anchor-based methodologies or accepted methods of analyzing the resultant data. In our study, patients were deemed to have improved QoL if they had an improvement in FACT-F score of ≥3.5 points – the calculated MID. This is similar to the FACT-F MID utilized in two previous ESA studies (MID: ≥3).20,21 We could have used alternative methodology, for example, looking at the difference between mean FACT-F change scores for patients with an improvement in VAS scores compared to no improvement in VAS. This would have been more in line with reported methodology for an anchor-based approach to calculating the MID; however, such methodology was deemed to be too conservative. By prespecifying that VAS change scores of 7±3, 5±3, 5±2, or 5±1 would be used depending on the number of patients in each of these categories compared with 20% of the number of patients who had a VAS improvement of ≥1 point, we attempted to limit data to only those patients who had a small but beneficial QoL improvement.\n\nAn Hb increase ≥1 g/dL was used as one of the other components of the primary outcome measure in the present study. Such an increase has been consistently used in studies assessing the efficacy of ESAs.22–25 According to current guidelines, an Hb increase of 1 g/dL and Hb maintenance in the target range of 10–12 g/dL offers a clinically meaningful benefit to patients. In eAQUA, DA was initiated at Hb levels of 9–10 g/dL in most patients and Hb was generally maintained within the target range of 10–12 g/dL; therefore, patients appeared to be treated in accordance with the labeled indication and went on to experience clinically meaningful improvements in Hb levels and fatigue-related QoL. Although we cannot conclude that an Hb increase leads to improved QoL from these data, an Hb increase ≥1 g/dL at week 9 was significantly predictive of improved QoL. This supports the observations of Vansteenkiste et al, who reported significant improvements in FACT-F scores (56% vs 44% any improvement [chi-square test; P=0.052] and 32% vs 19% with a ≥25% improvement [P=0.019], respectively) for DA vs placebo in a study including patients with lung cancer undergoing chemotherapy.26\n\nIn eAQUA, only an Hb increase ≥1 g/dL at week 9 significantly predicted a QoL improvement in the multivariate model. Other baseline (age, sex, tumor type, disease stage, chemotherapy type, Hb levels, line of chemotherapy) and post-baseline (iron use, concomitant medication use) covariates did not significantly impact on the occurrence of a QoL improvement, suggesting that DA had similar efficacy across the spectrum of patients likely to be seen in clinical practice. Few patients (n=24) received an ESA other than DA during this study and even fewer of these had both baseline and week 9 assessments for each of Hb, FACT-F, and VAS (n=9). Therefore, although results for the FAS and PAS appear similar, we cannot generalize the results for DA to all other ESAs.\n\nAs this was an observational study, attendance/data collection at specific study visits was not required and data were collected as per normal clinical practice or when the patient was visiting the clinic in relation to chemotherapy and/or ESA administration. Therefore, the number of visits/data points for each patient may have varied. It is expected that patients with more frequently dosed ESA and/or chemotherapy regimens will have more hospital visits and thus more data than those who are dosed less frequently.\n\nFrom a patient perspective, agents that may prevent/reduce the need for transfusions are important as they can help decrease feelings of helplessness and help patients feel involved with the treatment process. Relatively few patients (FAS: 23%; PAS: 16%) required RBC transfusions during eAQUA. This is consistent with previous studies in which DA was shown to reduce the risk of transfusion in patients with solid tumors.26–28 In these studies, 17%–27% of DA-treated patients required transfusions compared with 39%–52% of placebo-treated patients.26–28 Concomitant IV iron use can increase hematopoietic response and reduce the need for transfusions in patients receiving an ESA.29–31 In the present study, ~80%–81% of patients received no IV iron supplementation, suggesting that DA alone effectively managed Hb levels in most patients. Approximately 14%–17% of patients in this study received oral iron supplementation. However, oral iron has not been shown to significantly improve hematopoietic response or reduce the need for transfusions in patients undergoing ESA treatment31 and so is unlikely to impact on the apparent efficacy of DA in the present study.\n\nDA treatment appeared to be well tolerated, with few patients (<1%) reporting ADRs during this study and few serious or fatal ADRs or discontinuations due to ADRs reported. However, ADRs may be under-reported in observational studies and so the overall incidence of ADRs may not reflect the true tolerability profile of DA in this population.\n\nConclusion\nIn this clinical practice study, patients undergoing chemotherapy and treated with DA, in line with the current European indication for symptomatic CIA, had clinically meaningful improvements in both Hb levels and QoL. There was also a low incidence of transfusions. Clinicians appeared to be using DA appropriately to keep Hb levels within the licensed target Hb range of 10–12 g/dL. Consistent with previous studies, DA appeared effective at improving Hb levels, reducing fatigue and transfusion requirements, and thereby improving QoL in patients with CIA.\n\nAcknowledgments\nMedical writing support (funded by Amgen [Europe] GmbH) was provided by Dawn Batty PhD of Bioscript Medical Ltd.\n\nDisclosure\n\nJLM, BF, JvdB, CBL, AB, HWT, and GT received research funding from Amgen for participation in the eAQUA study; AB and GT have also acted in consultant/advisory roles for Amgen. LB is a contractor for Amgen. GCB and JHT are Amgen employees and stock owners. The authors report no other conflicts of interest in this work.\n\nFigure 1 Mean (95% confidence intervals) change in hemoglobin levels over time in the full analysis set.\n\nNotes: For patients with more than one hemoglobin value per study week, the mean hemoglobin value has been used. Hemoglobin measurements within 28 days after a transfusion are excluded from the analysis.\n\nFigure 2 Time to first hemoglobin increase ≥1 g/dL in the primary analysis set.\n\nNote: Values within 28 days of a transfusion were set to missing.\n\nFigure 3 FACT-F subscale and fatigue VAS scores over time in the full analysis set.\n\nNotes: Mean (95% confidence intervals) change in (A) FACT-F subscale scores and (B) fatigue VAS scores over time in the FAS. (A) For patients with more than one FACT-F subscale score per study week, the mean FACT-F subscale score has been used. FACT-F subscale data recorded within 28 days after an RBC transfusion were set to missing. FACT-F scores range from 0 to 52: the higher the score, the better the quality of life. (B) For patients with more than one VAS score per study week, the mean VAS score has been used. VAS data recorded within 28 days after an RBC transfusion were set to missing. VAS scores range from 0 (least fatigue) to 100 (worst fatigue).\n\nAbbreviations: FACT-F, functional assessment of cancer therapy-fatigue; FAS, full analysis set; RBC, red blood cell; VAS, visual analog scale.\n\nFigure 4 Time to first quality of life improvement (primary analysis set).\n\nNote: Values within 28 days of a transfusion were set to missing.\n\nTable 1 Baseline characteristics of the FAS and PAS\n\n\tFAS (n=1,158)\tPAS (n=510)\t\nMale sex, n (%)\t467 (40.3)\t177 (34.7)\t\nAge, years, mean (SD)\t63.9 (11.1)\t64.2 (11.4)\t\n ≥65 years, n (%)\t592 (51.1)\t266 (52.2)\t\nDisease stage,a n (%)\t\n I or II\t107 (9.2)\t58 (11.4)\t\n III or IV\t1,050 (90.7)\t452 (88.6)\t\nECOG score,b n (%)\t\t\t\n 0 or 1\t921 (79.5)\t425 (83.3)\t\n 2\t219 (18.9)\t79 (15.5)\t\nTumor type, n (%)\t\n Breast\t289 (25.0)\t152 (29.8)\t\n Non-small cell lung\t221 (19.1)\t70 (13.7)\t\n Ovarian\t157 (13.6)\t79 (15.5)\t\n Colorectal\t153 (13.2)\t71 (13.9)\t\n Prostate\t82 (7.1)\t39 (7.6)\t\n Other/missingc\t256 (22.1)\t99 (19.4)\t\nChemotherapy cycles completed, n (%)\t\n In the first cycle\t175 (15.1)\t77 (15.1)\t\n 1–3\t624 (53.9)\t285 (55.9)\t\n 4–6\t236 (20.4)\t93 (18.2)\t\n >6\t123 (10.6)\t55 (10.8)\t\nTreatment intention, n (%)\t\n Curative\t310 (26.8)\t149 (29.2)\t\n Palliative\t840 (72.5)\t358 (70.2)\t\n Other\t8 (0.7)\t3 (0.6)\t\nReceived prior radiotherapy, n (%)\t316 (27.3)\t140 (27.5)\t\nReceiving concomitant medication, n (%)\t990 (85.5)\t440 (86.3)\t\nTypes of concomitant medication, n (%)\t\n Antiemetics\t501 (43.3)\t211 (41.4)\t\n Corticosteroids\t313 (27.0)\t141 (27.6)\t\n Analgesics\t184 (15.9)\t80 (15.7)\t\n Narcotics\t145 (12.5)\t55 (10.8)\t\n Anxiolytics\t72 (6.2)\t39 (7.6)\t\n Antihistamines\t43 (3.7)\t23 (4.5)\t\n Antidepressants\t25 (2.2)\t13 (2.5)\t\n Antipsychotics\t5 (0.4)\t2 (0.4)\t\nAnemia symptom, n (%)\t\n Fatigue\t1,102 (95.2)\t491 (96.3)\t\n Dyspnea\t276 (23.8)\t112 (22.0)\t\n Cold skin\t154 (13.3)\t74 (14.5)\t\n Dizziness\t153 (13.2)\t72 (14.1)\t\n Palpitations\t126 (10.9)\t52 (10.2)\t\n Headaches\t114 (9.8)\t50 (9.8)\t\n Depression\t111 (9.6)\t52 (10.2)\t\n Loss of libido\t68 (5.9)\t27 (5.3)\t\n Impaired cognitive function\t57 (4.9)\t25 (4.9)\t\n Other\t118 (10.2)\t49 (9.6)\t\nHemoglobin, g/dL,d mean (SD)\t9.3 (0.6)\t9.4 (0.6)\t\nHemoglobin subgroup, n (%)\t\n Hb ≤8 g/dL\t44 (3.9)\t22 (4.3)\t\n Hb >8 to ≤9 g/dL\t254 (22.4)\t103 (20.2)\t\n Hb >9 to ≤10 g/dL\t799 (70.5)\t374 (73.3)\t\n Hb >10 g/dL\t36 (3.2)\t11 (2.2)\t\nFACT-F score, mean (SD)\t28.4 (10.5)\t29.2 (10.3)\t\nFatigue VAS score, mean (SD)\t51.2 (22.6)\t49.2 (22.6)\t\nNotes:\n\na Disease stage missing for one patient in the FAS (0.1%);\n\nb ECOG score was missing for 18 patients in the FAS (1.6%), and for six patients in the PAS (1.2%);\n\nc in the FAS, “other” includes bladder (5.5%), pancreatic (4.7%), gastric (3.4%), small-cell lung (3.3%), endometrial (2.0%), esophageal (1.6%), and renal (1.5%) cancers, and was missing for 0.2% of patients. In the PAS, “other” includes pancreatic (6.1%), bladder (3.1%), gastric (2.9%), endometrial (2.4%), small-cell lung (2.4%), renal (2.0%), and esophageal (0.6%) cancers;\n\nd Hemoglobin data available for 1,133 FAS patients and for all patients in the PAS.\n\nAbbreviations: ECOG, Eastern Cooperative Oncology Group; FACT-F, functional assessment of cancer therapy-fatigue; FAS, full analysis set; Hb, hemoglobin; PAS, primary analysis set; SD, standard deviation; VAS, visual analog scale.\n\nTable 2 Change in quality of life scores at week 9 (primary analysis set), as assessed by VAS and FACT-F\n\n\tFACT-F subscale (n=510)\tFatigue VAS (n=510)\t\nMean (SD)\t3.5 (10.5)\t4.3 (24.7)\t\nMedian (Q1, Q3)\t3.0 (−2.0, 10.0)\t2.0 (−10.0, 20.0)\t\nMinimum, maximum\t−35, 34\t−84, 84\t\nImprovement in score,a n (%)\t328 (64.3)\t277 (54.3)\t\n >20 points\t26 (5.1)\t115 (22.5)\t\n 10–20 points\t92 (18.0)\t65 (12.7)\t\n 5–10 points\t85 (16.7)\t58 (11.4)\t\n ≤5 points\t125 (24.5)\t39 (7.6)\t\nNo change in score, n (%)\t19 (3.7)\t36 (7.1)\t\nDeterioration in score,b n (%)\t163 (32.0)\t197 (38.6)\t\n >20 points\t8 (1.6)\t60 (11.8)\t\n 10–20 points\t33 (6.5)\t50 (9.8)\t\n 5–10 points\t49 (9.6)\t42 (8.2)\t\n ≤5 points\t73 (14.3)\t45 (8.8)\t\nNotes:\n\na Improvement = increase in score for FACT-F and a decrease in score for VAS;\n\nb deterioration = decrease in score for FACT-F and an increase in score for VAS.\n\nAbbreviations: FACT-F, functional assessment of cancer therapy-fatigue; Q1, quartile 1; Q3, quartile 3; SD, standard deviation; VAS, visual analog scale.\n==== Refs\nReferences\n1 Ahlberg K Ekman T Gaston-Johansson F Mock V Assessment and management of cancer-related fatigue in adults Lancet 2003 362 9384 640 650 12944066 \n2 Harper P Littlewood T Anaemia of cancer: impact on patient fatigue and long-term outcome Oncology 2005 69 Suppl 2 2 7 16244504 \n3 Weis J Cancer-related fatigue: prevalence, assessment and treatment strategies Expert Rev Pharmacoecon Outcomes Res 2011 11 4 441 446 21831025 \n4 Campos MP Hassan BJ Riechelmann R Del Giglio A Cancer-related fatigue: a review Rev Assoc Med Bras 2011 57 2 211 219 English, Portuguese 21537710 \n5 Iop A Manfredi AM Bonura S Fatigue in cancer patients receiving chemotherapy: an analysis of published studies Ann Oncol 2004 15 5 712 720 15111337 \n6 Minton O Richardson A Sharpe M Hotopf M Stone P A systematic review and meta-analysis of the pharmacological treatment of cancer-related fatigue J Natl Cancer Inst 2008 100 16 1155 1166 18695134 \n7 Minton O Richardson A Sharpe M Hotopf M Stone P Drug therapy for the management of cancer-related fatigue Cochrane Database Syst Rev 2010 7 CD006704 20614448 \n8 Tonelli M Hemmelgarn B Reiman T Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: a meta-analysis CMAJ 2009 180 11 E62 E71 19407261 \n9 Bokemeyer C Aapro MS Courdi A EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update Eur J Cancer 2007 43 2 258 270 17182241 \n10 Aapro MS Link H September 2007 update on EORTC guidelines and anemia management with erythropoiesis-stimulating agents Oncologist 2008 13 Suppl 3 33 36 18458123 \n11 Vansteenkiste J Wauters I Elliott S Glaspy J Hedenus M Chemotherapy-induced anemia: the story of darbepoetin alfa Curr Med Res Opin 2013 29 4 325 337 23323876 \n12 Schrijvers D Management of anemia in cancer patients: transfusions Oncologist 2011 16 Suppl 3 12 18 21930830 \n13 Hauser K Walsh D Visual analogue scales and assessment of quality of life in cancer J Support Oncol 2008 6 6 277 282 18724538 \n14 Stone P Richardson A Ream E Smith AG Kerr DJ Kearney N Cancer-related fatigue: inevitable, unimportant and untreatable? Results of a multi-centre patient survey. Cancer Fatigue Forum Ann Oncol 2000 11 8 971 975 11038033 \n15 Cella D Eton DT Lai JS Peterman AH Merkel DE Combining anchor and distribution-based methods to derive minimal clinically important differences on the Functional Assessment of Cancer Therapy (FACT) anemia and fatigue scales J Pain Symptom Manage 2002 24 6 547 561 12551804 \n16 Revicki DA Cella D Hays RD Sloan JA Lenderking WR Aaronson NK Responsiveness and minimal important differences for patient reported outcomes Health Qual Life Outcomes 2006 4 70 17005038 \n17 Cella D Quality of life and clinical decisions in chemotherapy-induced anemia Oncology (Williston Park) 2006 20 8 Suppl 6 25 28 16925108 \n18 Amgen Inc. Aranesp® (darbepoetin alfa) Summary of Product Characteristics Thousand Oaks Amgen Inc. 2012 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000332/WC500026149.pdf Accessed May 6, 2015 \n19 Pickard AS Neary MP Cella D Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer Health Qual Life Outcomes 2007 5 70 18154669 \n20 Revicki DA Stull D Vernon M Rader M Tomita D Viswanathan HN Assessing the effect of darbepoetin alfa on patient-reported fatigue in chemotherapy-induced anemia in four randomized, placebo-controlled clinical trials Qual Life Res 2012 21 2 311 321 21644007 \n21 Bohlius J Tonia T Nuesch E Effects of erythropoiesis-stimulating agents on fatigue- and anaemia-related symptoms in cancer patients: systematic review and meta-analyses of published and unpublished data Br J Cancer 2014 111 1 33 45 24743705 \n22 Martelli O Garassino M Sacchetta S Darbepoetin alfa administered every three weeks (Q3W) in anemic cancer patients receiving chemotherapy (CT) Anticancer Res 2008 28 3B 1767 1771 18630457 \n23 Ludwig H Crawford J Osterborg A Pooled analysis of individual patient-level data from all randomized, double-blind, placebo-controlled trials of darbepoetin alfa in the treatment of patients with chemotherapy-induced anemia J Clin Oncol 2009 27 17 2838 2847 19380447 \n24 Kerkhofs L Boschetti G Lugini A Stanculeanu DL Palomo AG Use of biosimilar epoetin to increase hemoglobin levels in patients with chemotherapy-induced anemia: real-life clinical experience Future Oncol 2012 8 6 751 756 22443466 \n25 Gómez A Salgado M Valladares-Ayerbes M Efficacy of epoetin-beta 30,000 IU/week in correcting anaemia in patients with gastrointestinal tumours subjected to concomitant chemoradiotherapy Clin Transl Oncol 2010 12 12 843 848 21156416 \n26 Vansteenkiste J Pirker R Massuti B Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy J Natl Cancer Inst 2002 94 16 1211 1220 12189224 \n27 Pirker R Ramlau RA Schuette W Safety and efficacy of darbepoetin alpha in previously untreated extensive-stage small-cell lung cancer treated with platinum plus etoposide J Clin Oncol 2008 26 14 2342 2349 18467726 \n28 Hernandez E Ganly P Charu V Randomized, double-blind, placebo-controlled trial of every-3-week darbepoetin alfa 300 micrograms for treatment of chemotherapy-induced anemia Curr Med Res Opin 2009 25 9 2109 2120 19601709 \n29 Karlsson T Effects of iron supplementation on erythropoietic response in patients with cancer-associated anemia treated by means of erythropoietic stimulating agents ISRN Hematol 2011 2011 108397 22111015 \n30 Gafter-Gvili A Rozen-Zvi B Vidal L Intravenous iron supplementation for the treatment of chemotherapy-induced anaemia – systematic review and meta-analysis of randomised controlled trials Acta Oncol 2013 52 1 18 29 22877242 \n31 Petrelli F Borgonovo K Cabiddu M Lonati V Barni S Addition of iron to erythropoiesis-stimulating agents in cancer patients: a meta-analysis of randomized trials J Cancer Res Clin Oncol 2012 138 2 179 187 21972052\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-1322",
"issue": "8()",
"journal": "Cancer management and research",
"keywords": "Functional Assessment of Cancer Therapy-Fatigue subscale; darbepoetin alfa; erythropoiesis-stimulating agent; fatigue visual analog scale; transfusion",
"medline_ta": "Cancer Manag Res",
"mesh_terms": null,
"nlm_unique_id": "101512700",
"other_id": null,
"pages": "1-10",
"pmc": null,
"pmid": "26855598",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "18458123;19601709;17182241;12189224;21156416;19407261;12551804;19380447;17005038;18630457;21972052;24743705;18724538;18154669;21537710;18695134;11038033;22443466;16244504;16925108;23323876;20614448;22877242;21831025;12944066;22111015;15111337;18467726;21644007;21930830",
"title": "Hemoglobin levels and quality of life in patients with symptomatic chemotherapy-induced anemia: the eAQUA study.",
"title_normalized": "hemoglobin levels and quality of life in patients with symptomatic chemotherapy induced anemia the eaqua study"
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{
"abstract": "BACKGROUND\nRecent clinical trials have demonstrated the benefit and feasibility of perioperative chemotherapy for treatment of gastroesophageal adenocarcinoma (GEA). Despite convincing results, patients entering such trials usually represent only a fraction of those who are candidates for treatment. Confirmation of trial-reported effects and tolerability in unselected cohorts is therefore required. The aims of this study were to confirm the safety and efficacy of perioperative chemotherapy for resectable GEA and to delineate risks of treatment failure.\n\n\nMETHODS\nWe conducted a national retrospective cohort analysis of patients admitted for perioperative chemotherapy for resectable GEA. Regimens were epirubicin and capecitabine combined with oxaliplatin or cisplatin.\n\n\nRESULTS\nThe intention-to-treat analysis included 271 patients. Eighty-seven percent of patients completed preoperative chemotherapy, and 63 % received radical resection. Age >70 years (odds ratio 2.58) and hypoalbuminemia (odds ratio 4.10) were independent predictors of not undergoing scheduled surgery (P = 0.033). Grade 3 or higher febrile neutropenia, fatigue, and diarrhea were common in the oxaliplatin group (n = 128), but hypomagnesaemia and tinnitus/hearing loss were more common in the cisplatin group (n = 135). The median overall survival was 26.4 months, and the 1- and 2-year survival rates were 76 and 53 %, respectively. Performance status >0 (hazard ratio 1.64) and elevated serum lactate dehydrogenase (hazard ratio 3.03) were independent predictors of poor prognosis (P ≤ 0.05).\n\n\nCONCLUSIONS\nPerioperative chemotherapy is feasible and well tolerated in patients with good performance status and low incidence of comorbidities.",
"affiliations": "Department of Gastrointestinal Surgery, Aalborg University Hospital, Aalborg, Denmark, anchl@rn.dk.",
"authors": "Larsen|Anders Christian|AC|;Holländer|Cecilie|C|;Duval|Lone|L|;Schønnemann|Katrine|K|;Achiam|Michael|M|;Pfeiffer|Per|P|;Yilmaz|Mette Karen|MK|;Thorlacius-Ussing|Ole|O|;Bæksgaard|Lene|L|;Ladekarl|Morten|M|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D015251:Epirubicin; D002945:Cisplatin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1245/s10434-014-4127-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1068-9265",
"issue": "22(5)",
"journal": "Annals of surgical oncology",
"keywords": null,
"medline_ta": "Ann Surg Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D003131:Combined Modality Therapy; D003841:Deoxycytidine; D015251:Epirubicin; D004938:Esophageal Neoplasms; D004943:Esophagogastric Junction; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D019990:Perioperative Care; D011379:Prognosis; D012189:Retrospective Studies; D013274:Stomach Neoplasms; D015996:Survival Rate",
"nlm_unique_id": "9420840",
"other_id": null,
"pages": "1540-7",
"pmc": null,
"pmid": "25348777",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A nationwide retrospective study of perioperative chemotherapy for gastroesophageal adenocarcinoma: tolerability, outcome, and prognostic factors.",
"title_normalized": "a nationwide retrospective study of perioperative chemotherapy for gastroesophageal adenocarcinoma tolerability outcome and prognostic factors"
} | [
{
"companynumb": "DK-SA-2014SA158436",
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"activesubstancename": "PREDNISONE"
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{
"abstract": "To determine whether tumour necrosis factor inhibitor (TNFi) use is associated with an increased rate of incident malignancy compared with no TNFi use in the treatment of juvenile idiopathic arthritis (JIA), paediatric inflammatory bowel disease (pIBD) and paediatric plaque psoriasis (pPsO).\n\n\n\nWe performed a retrospective cohort study of administrative claims data from the USA from 2000 to 2014. Exposure to TNFi was considered permanent from the first observed exposure onward. The malignancy outcome was defined by diagnosis codes with evidence of cancer treatment. We calculated standardised incidence ratios (SIRs) comparing the observed number of malignancies to the expected numbers according to cancer surveillance data. We used multivariable Cox proportional hazards models to estimate adjusted HRs (aHRs) for incident malignancy.\n\n\n\nWe identified 15 598 children with TNFi use and 73 839 children with no TNFi use (30 703 and 121 801 person-years of follow-up, respectively). We identified 15 malignancies among children with TNFi use (SIR 2.9 (1.6 to 4.9)) and 42 malignancies among children without TNFi use (SIR 2.1 (1.5 to 2.9)). The aHR was 1.58 (0.88 to 2.85) for TNFi use versus no TNFi use. In pIBD, TNFi use with thiopurine use was associated with a higher SIR (6.0 (1.2 to 17.5)) compared with TNFi use without thiopurine use (2.5 (0.7 to 6.4)).\n\n\n\nChildren diagnosed with JIA, pIBD and pPsO had an increased rate of malignancy compared with the general population, but treatment with TNFi did not appear to significantly further increase the risk compared with no TNFi use. More data are needed about the long-term risks of TNFi use.",
"affiliations": "Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.;Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.;Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.;Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.;Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.;Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.;Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.;Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.;Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.",
"authors": "Beukelman|Timothy|T|;Xie|Fenglong|F|;Chen|Lang|L|;Horton|Daniel B|DB|;Lewis|James D|JD|;Mamtani|Ronac|R|;Mannion|Melissa M|MM|;Saag|Kenneth G|KG|;Curtis|Jeffrey R|JR|",
"chemical_list": "D014409:Tumor Necrosis Factor-alpha",
"country": "England",
"delete": false,
"doi": "10.1136/annrheumdis-2017-212613",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4967",
"issue": "77(7)",
"journal": "Annals of the rheumatic diseases",
"keywords": "Anti-tnf; Epidemiology; Juvenile Idiopathic Arthritis; Treatment",
"medline_ta": "Ann Rheum Dis",
"mesh_terms": "D017677:Age Distribution; D001171:Arthritis, Juvenile; D002648:Child; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D015999:Multivariate Analysis; D009369:Neoplasms; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D017678:Sex Distribution; D014409:Tumor Necrosis Factor-alpha; D014481:United States",
"nlm_unique_id": "0372355",
"other_id": null,
"pages": "1012-1016",
"pmc": null,
"pmid": "29440001",
"pubdate": "2018-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "16508929;28424093;18716298;20712883;22562021;10717011;21315483;24938563;17324398;26265015;18199863;25853748;22511558;23055441;24361468;24879926;22328538;28162854;27749226;28193515;17447148;22155755;20827782;20506368;25174953;28416023;23541909;22948700;21885875;23514635;28931512;23845151",
"title": "Risk of malignancy associated with paediatric use of tumour necrosis factor inhibitors.",
"title_normalized": "risk of malignancy associated with paediatric use of tumour necrosis factor inhibitors"
} | [
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"companynumb": "US-AMGEN-USASP2019123414",
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"occurcountry": "US",
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"activesubstancename": "ETANERCEPT"
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... |
{
"abstract": "An 18-year-old man diagnosed with ileocolonic Crohn's disease with circumferential strictures of the ascending colon started treatment with mesalazine and subsequently underwent right hemicolectomy. After surgery, the patient was started on adalimumab, and the clinical course was favorable. Nine months postoperatively, colonoscopy revealed granular mucosa with circumferential and continuous involvement from the transverse colon down to the rectum, findings which resembled ulcerative colitis. Mesalazine allergy was suspected, and the inflammatory findings resolved after discontinuing mesalazine. In patients of inflammatory bowel disease receiving mesalazine with an atypical clinical course, the possibility of mesalazine allergy must be borne in mind.",
"affiliations": "Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, Japan.;Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, Japan.;Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, Japan.;Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, Japan.",
"authors": "Tsuboi|Rumiko|R|;Matsumoto|Satohiro|S|;Miyatani|Hiroyuki|H|;Mashima|Hirosato|H|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine; D000068879:Adalimumab",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.1607-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3033341310.2169/internalmedicine.1607-18Case ReportCrohn's Disease with Mesalazine Allergy that Was Difficult to Differentiate from Comorbid Ulcerative Colitis Tsuboi Rumiko 1Matsumoto Satohiro 1Miyatani Hiroyuki 1Mashima Hirosato 1\n1 Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, JapanCorrespondence to Dr. Satohiro Matsumoto, satomatsumoto@jichi.ac.jp\n\n17 10 2018 1 3 2019 58 5 649 654 29 5 2018 19 7 2018 Copyright © 2019 by The Japanese Society of Internal Medicine2019The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).An 18-year-old man diagnosed with ileocolonic Crohn's disease with circumferential strictures of the ascending colon started treatment with mesalazine and subsequently underwent right hemicolectomy. After surgery, the patient was started on adalimumab, and the clinical course was favorable. Nine months postoperatively, colonoscopy revealed granular mucosa with circumferential and continuous involvement from the transverse colon down to the rectum, findings which resembled ulcerative colitis. Mesalazine allergy was suspected, and the inflammatory findings resolved after discontinuing mesalazine. In patients of inflammatory bowel disease receiving mesalazine with an atypical clinical course, the possibility of mesalazine allergy must be borne in mind. \n\nmesalazine allergyCrohn's diseaseulcerative colitis\n==== Body\nIntroduction\nMesalazine is the mainstay of pharmacologic treatment for inflammatory bowel disease, including ulcerative colitis and Crohn's disease. However, this drug can sometimes exacerbate symptoms, such as a fever, diarrhea, and bloody stool. Some patients show intolerance to mesalazine, with manifestations that are often difficult to differentiate from those of exacerbation of the underlying inflammatory bowel disease (1,2). While mesalazine has been reported to cause diarrhea in 4.6% of patients and bloody stool and a fever in 1.4% of patients with ulcerative colitis (1), the prevalence of mesalazine intolerance in patients with Crohn's disease remains unknown.\n\nWe encountered a patient with Crohn's disease with mesalazine allergy in whom the condition was difficult to differentiate from comorbid ulcerative colitis because the colonoscopic findings resembled those of ulcerative colitis.\n\nCase Report\nAn 18-year-old man without any history of diseases or allergies visited a neighborhood clinic with a 3-month history of abdominal pain, diarrhea, and bloody stool. Intestinal regulators were prescribed, but the symptoms persisted. Colonoscopy revealed erosions, longitudinal ulcers, and a cobblestone appearance in the mucosa of the ileocecum and ascending colon, so Crohn's disease was suspected. The patient was admitted to our hospital for further management. On admission, the Crohn's disease activity index (CDAI) was determined to be 243, the serum C-reactive protein (CRP) level was 8.98 mg/dL, and the serum albumin level was 3.4 mg/dL.\n\nColonoscopy performed at our hospital revealed longitudinal ulcers and circumferential strictures blocking the advance of the scope into the ascending colon; however, the mucosa extending from the transverse colon downward towards the anus was normal (Fig. 1a-f). A fluoroscopic examination revealed stenosis in the ascending colon measuring over 10 cm in length (Fig. 1g). Non-necrotizing granulomas were not found on a tissue biopsy. Neither computed tomography nor magnetic resonance enterography revealed any evidence of inflammation at any other part of the bowel than the ileocecum and ascending colon. Upper endoscopy showed no abnormal findings. Given these findings as well as those reported from the previous clinic, we made a diagnosis of ileocolonic Crohn's disease.\n\nFigure 1. Colonoscopic findings on admission. a, b: Longitudinal ulcers and circumferential strictures blocking the advance of the scope were observed in the ascending colon. c: Transverse colon, d: Descending colon, e: Sigmoid colon, f: The rectal mucosa was normal. g: A fluoroscopic examination revealed stenosis in the ascending colon measuring over 10 cm in length.\n\nAs no relief of the circumferential strictures of the ascending colon could be expected from conservative medical treatment, we decided to introduce adalimumab as reset therapy after performing laparoscopic right hemicolectomy. While waiting for surgery, the patient was started on oral administration of time-dependent-release mesalazine at 3 g/d and an enteral elemental diet. A histopathological examination of the resected surgical specimen revealed longitudinal ulcers extending from the ascending colon to the ileocecum, inflammatory cell infiltration in all the bowel mucosal layers, and non-necrotizing granulomas in the mucosal and submucosal layers (Fig. 2), features that were consistent with the diagnosis of Crohn's disease. After surgery, the patient was started on subcutaneous adalimumab. By 2 months after the treatment initiation, the CDAI had improved to 5, and the serum CRP level had decreased to 0.05 mg/dL.\n\nFigure 2. Surgical specimen. a: Macroscopic image of the surgical specimen. Longitudinal ulcers were observed in the segment of the bowel extending from the ascending colon to the ileocecum. The ascending colon was hard in consistency and shortened because of inflammation. b: Hematoxylin and Eosin (H&E) staining, low magnification. Inflammatory cell infiltration was observed in all mucosal layers. c: H&E staining, high magnification. Non-necrotizing granulomas (arrow) were observed in the mucosal and submucosal layers.\n\nHowever, 9 months after the surgery, the serum CRP level increased to 1.05 mg/dL, and repeat colonoscopy was performed (Fig. 3). No abnormalities were observed in the terminal ileum or at the bowel anastomosis site, and the Rutgeerts score was i,0. However, granular mucosa was found, with circumferential and continuous involvement of the colon extending from the transverse colon to the rectum, resembling the endoscopic features of ulcerative colitis. While the Mayo Endoscopic subscore was 1, a biopsy revealed crypt abscesses. Ulcerative colitis of the total colitis type was therefore suspected. In accordance with the diagnosis of ulcerative colitis, the dose of mesalazine was increased to 4 g/d. Six months later, colonoscopy revealed slight aggravation of the inflammatory findings of the large bowel, with the patient complaining of persistent diarrhea. Therefore, the time-dependent-release mesalazine was switched to pH-dependent-release mesalazine at 3.6 g/d.\n\nFigure 3. Colonoscopic findings at nine months after surgery. No abnormalities were observed in the terminal ileum (a) or at the postoperative bowel anastomotic site (b). Granularity of the mucosa was observed with circumferential and continuous bowel involvement, resembling the endoscopic features of ulcerative colitis of total colitis type (c: Descending colon. d: Sigmoid colon. e: Rectum). f: Histopathological findings of the biopsy specimen. Hematoxylin and Eosin staining, high magnification. Crypt abscesses (arrow) are seen.\n\nSix months after this change in treatment, colonoscopy still showed no marked improvement in the findings of the large bowel, and the Mayo Endoscopic subscore was 1. In addition, erosions were observed at the terminal ileum and at the bowel anastomotic site, which were diagnosed as representing diffuse aphthous ileitis, and the Rutgeerts score was i,3. Although backwash colitis could not be completely denied, we considered exacerbation of Crohn's disease (Fig. 4). The dose of adalimumab was increased to 40 mg/wk. Mesalazine was switched again to the time-dependent-release type at 4 g/d doubling as treatment for UC, and the enteral elemental diet was resumed. Six months later, colonoscopy revealed slight improvement in the inflammatory findings, and the Rutgeerts score was i,2. In contrast, the CDAI was 109, and the serum CRP level was 1.96 mg/dL. Thus, the serum CRP level remained high, with persistent diarrhea.\n\nFigure 4. Colonoscopic findings at six months after time-dependent-release mesalazine was switched to the pH-dependent-release type at 3.6 g/d. Erosions were detected in the terminal ileum (a) and at the postoperative bowel anastomotic site (b). c: No improvement was observed in the findings of the large bowel (c: Transverse colon. d: Descending colon. e: Sigmoid colon. f: Rectum).\n\nNone of the treatments attempted-increasing the dose of mesalazine, changing the type of mesalazine preparation used, and increasing the dose of adalimumab under suspicion of ulcerative colitis or inflammatory bowel disease unclassified (IBDU) complicating Crohn's disease-yielded any improvement. Given the atypical clinical course, we considered the possibility of mesalazine allergy. The results of the drug-induced lymphocyte stimulation test (DLST) were 1,119 cpm with a stimulation index (SI) of 207% for time-dependent-release mesalazine and 1,048 cpm with a SI of 194% for pH-dependent-release mesalazine. Thus, the DLST revealed positive reactions (SI >180) for both types of mesalazine. Therefore, the administration of mesalazine was discontinued, and by 1 month after the discontinuation of mesalazine, the CDAI had improved to 55, and the serum CRP level had decreased to 0.12 mg/dL (Fig. 5). Colonoscopy also revealed signs of improvement (Fig. 6). We were subsequently able to reduce the dose of adalimumab to 40 mg every 2 weeks. Thus, based on the clinical course described above, the postoperative exacerbation of the inflammatory findings on colonoscopy was considered to be attributable to mesalazine allergy.\n\nFigure 5. Clinical course.\n\nFigure 6. Colonoscopic findings at one month after the discontinuation of mesalazine. Improvement was observed in the findings of the large bowel (a: Postoperative bowel anastomotic site. b, c: Transverse colon. d: Descending colon. e: Sigmoid colon. f: Rectum).\n\nDiscussion\nMesalazine, a commonly used drug for treating both ulcerative colitis and Crohn's disease, can cause allergic reactions. The incidence of allergic reactions to mesalazine in patients with ulcerative colitis has been reported to range from 2.1% to 24% (3,4); however, that in patients with Crohn's disease remains unknown. There are few reports of allergic reactions to mesalazine in Crohn's disease patients. Although a DLST may be performed to complement the diagnosis of mesalazine allergy, as in our case, the sensitivity and specificity of a DLST in patients with ulcerative colitis are reportedly only 24% and 80.5%, respectively (4). As such, the diagnosis should be mainly based on the clinical course.\n\nIn patients with mesalazine allergy, although the administration of mesalazine initially yields transient relief from clinical symptoms, patients often begin to suffer from diarrhea, exacerbation of bloody stool, or a fever relatively soon thereafter, typically within two weeks of starting treatment (4). However, if the symptomatic exacerbation is mistakenly diagnosed as being caused by exacerbation of the underlying inflammatory bowel disease and treated by the immediate addition of steroids, the symptoms will be masked. Then, when the symptoms relapse during tapering of the steroid dose, patients may be judged as having become steroid-dependent. Thus, they may be over-treated, or the diagnosis of mesalazine allergy may be delayed (5). In addition, the DLST detects type IV allergy, in which T-lymphocytes are involved, and adalimumab inhibits this type of allergic reaction. Thus, it is also plausible that in our case, adalimumab masked the mesalazine allergy and alleviated the symptoms. However, no association has been reported between adalimumab, an anti-tumor necrosis factor (TNF) α antibody, and mesalazine allergy, although there is a report of increased blood TNF-α levels in patients with multiple-drug hypersensitivity receiving adalimumab (6).\n\nThe two most likely reasons for the delay in the diagnosis of mesalazine allergy in our patient were as follows: First, the clinical symptoms and inflammatory findings may have transiently improved because right hemicolectomy was performed for circumferential strictures of the ascending colon on the 25th day of treatment with mesalazine, followed by the early initiation of treatment with adalimumab after surgery. Second, because the postoperative endoscopic findings resembled those of ulcerative colitis and a biopsy revealed the presence of crypt abscesses, we suspected comorbid ulcerative colitis or IBDU. Crypt abscess is a collection of neutrophils within the crypt lumen and is well-recognized as a histological feature of ulcerative colitis (7). Although crypt abscesses have not been described in cases of mesalazine allergy to date, they have been observed in other inflammatory diseases of the bowel, such as infectious enterocolitis (8) and diverticular colitis (9). Therefore, crypt abscesses are not unique to ulcerative colitis, so caution should be exercised when encountering them.\n\nIn our case, we were able to longitudinally observe the changes in the bowel mucosa. Although there was no evidence of inflammation of the mucosa extending from the transverse colon to the rectum before the initiation of treatment with mesalazine, granularity of the mucosa with circumferential and continuous involvement from the transverse colon to the rectum, resembling the features of ulcerative colitis, was observed after the patient was started on mesalazine treatment. A previous case report of a patient with ulcerative colitis who underwent a challenge test with a mesalazine suppository stated that the endoscopic findings before administration of the suppository were only the loss of a visible vascular pattern and mild edema; in contrast, after the start of mesalazine administration, endoscopy revealed granular mucosa and contact bleeding, and a biopsy revealed diffuse neutrophilic infiltration up to the basement membrane and crypt epithelium, as well as mucus depletion (10).\n\nRegarding Crohn's disease, there have been almost no reports of such subjects or of how the normal mucosal appearance in these patients changes with mesalazine allergy. Thus, the further accumulation of cases is necessary to determine whether or not there are any endoscopic findings specific to mesalazine allergy. Our experience with present case indicates that mesalazine allergy can manifest with endoscopic or histological findings resembling those of ulcerative colitis. In addition, our case showed diffuse aphthous ileitis in the terminal ileum and at the bowel anastomotic site after the time-dependent-release mesalazine was switched to pH-dependent-release mesalazine. Because the effects of mesalazine allergy on the small intestine have not yet been reported, whether or not mesalazine allergy can affect the small intestine remains unclear. However, because the small intestinal findings were exacerbated after the time-dependent-release mesalazine was switched to the pH-dependent-release type under suspicion of comorbid ulcerative colitis, we assume that pH-dependent-release mesalazine was ineffective, resulting in the exacerbation of the features of Crohn's disease in the terminal ileum and at the bowel anastomotic site.\n\nIf patients with positive DLST findings for mesalazine have only a mild allergic reaction, hyposensitization therapy may permit the continuous administration of mesalazine (11). Although we considered introducing hyposensitization therapy to this patient, we ultimately did not perform it because he achieved clinical and endoscopic remission with adalimumab treatment, and mesalazine as a maintenance treatment in Crohn's disease is no longer recommended under the European Crohn's and Colitis Organization (ECCO) guideline (12).\n\nIn conclusion, this case serves to highlight the need to consider the possibility of mesalazine allergy in patients with inflammatory bowel disease receiving the drug who show an atypical clinical course. We consider this case to be a valuable one, as we were able to longitudinally observe the development of the lesions caused by mesalazine allergy in previously normal mucosa. Because mesalazine allergy may manifest with endoscopic findings resembling those of ulcerative colitis, the further accumulation of cases in the future will be needed in order to determine the characteristic histological features of mesalazine allergy.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nHanauer S , Schwartz J , Robinson M , et al \nMesalamine capsules for treatment of active ulcerative colitis: results of a controlled trial. Pentasa Study Group . Am J Gastroenterol \n88 : 1188 -1197 , 1993 .8338086 \n2. \nGupta MK , Pollack S , Hutchings JJ \nMesalamine induced symptom exacerbation of ulcerative colitis: case report and brief discussion . World J Gastrointest Pharmacol Ther \n1 : 132 -134 , 2010 .21577308 \n3. \nMotoya S , Simodate Y , Tanaka H , Imamura A \nMesalamine intolerance of ulcerative colitis . IBD Research \n4 : 127 -131 , 2010 (in Japanese).\n4. \nSaito D , Hayashida M , Sato T , et al \nEvaluation of the drug-induced lymphocyte stimulation test for diagnosing mesalazine allergy . Intest Res \n16 : 273 -281 , 2018 .29743840 \n5. \nSturgeon JB , Bhatia P , Hermens D , Miner PB Jr \nExacerbation of chronic ulcerative colitis with mesalamine . Gastroenterology \n108 : 1889 -1893 , 1995 .7768395 \n6. \nAkhmaltdinova LL , Gazalieva MA , Akhmetova SB \nLevels of cytokines in drug hypersensitivity . Cent Eur J Immunol \n42 : 354 -357 , 2017 .29472812 \n7. \nGramlich T , Petras RE \nPathology of inflammatory bowel disease . Semin Pediatr Surg \n16 : 154 -163 , 2007 .17602970 \n8. \nGriffin PM , Olmstead LC , Petras RE \nEscherichia coli O157:H7-associated colitis. A clinical and histological study of 11 cases . Gastroenterology \n99 : 142 -149 , 1990 .2188868 \n9. \nTorii Y , Katano Y , Yoshino J , et al \nA case of diverticular colitis with lesions resembling ulcerative colitis and correlation of tumor necrosis factor-alpha staining with clinical manifestations . Clin J Gastroenterol \n8 : 377 -384 , 2015 .26464173 \n10. \nKapur KC , Williams GT , Allison MC \nMesalazine induced exacerbation of ulcerative colitis . Gut \n37 : 838 -839 , 1995 .8537058 \n11. \nMotoya S , Miyakawa M , Nasuno M , Tanaka H \nApproach for mesalamine intolerance . IBD Research \n9 : 17 -286 , 2015 (in Japanese).\n12. \nFernando G , Axel D , Vito A , et al \n3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: Part 1: diagnosis and medical management . J Crohn's Colitis \n11 : 3 -25 , 2017 .27660341\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(5)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Crohn's disease; mesalazine allergy; ulcerative colitis",
"medline_ta": "Intern Med",
"mesh_terms": "D000068879:Adalimumab; D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003093:Colitis, Ulcerative; D003113:Colonoscopy; D003424:Crohn Disease; D003937:Diagnosis, Differential; D004342:Drug Hypersensitivity; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D019804:Mesalamine",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "649-654",
"pmc": null,
"pmid": "30333413",
"pubdate": "2019-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17602970;21577308;2188868;26464173;27660341;29472812;29743840;7768395;8338086;8537058",
"title": "Crohn's Disease with Mesalazine Allergy that Was Difficult to Differentiate from Comorbid Ulcerative Colitis.",
"title_normalized": "crohn s disease with mesalazine allergy that was difficult to differentiate from comorbid ulcerative colitis"
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{
"companynumb": "JP-TEVA-2019-JP-1040713",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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"actiondrug": null,
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"activesubstancename": "ADALIMUMAB"
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{
"abstract": "This report documents a rare case of COVID-19-associated constrictive pericarditis (CP) in the setting of a recent COVID-19 infection. A 55-year-old man with a history of hypertension and gout presented with acute hypoxic respiratory failure and was diagnosed with COVID-19 pneumonia with progression to acute respiratory distress syndrome. His hospital course was complicated by a large pericardial effusion; an emergent bedside transthoracic echocardiography was concerning for cardiac tamponade, so pericardiocentesis was performed. A workup with cardiac magnetic resonance imaging showed changes consistent with a diagnosis of CP. Viral and idiopathic aetiologies are the most common cause of CP in the developed world, with COVID-19 now a proposed predisposing viral illness. The virus induces systemic inflammation and pericardial changes that can lead to CP physiology. Imaging modalities including echocardiogram and cardiac magnetic resonance play an integral role in confirming the diagnosis.",
"affiliations": "Department of Internal Medicine, George Washington University School of Medicine, Washington, DC, USA jkbeckerman@gmail.com.;Department of Internal Medicine, George Washington University School of Medicine, Washington, DC, USA.;Division of Cardiology, George Washington University School of Medicine, Washington, DC, USA.;Division of Cardiology, George Washington University School of Medicine, Washington, DC, USA.;Division of Cardiology and Department of Radiology, George Washington University School of Medicine, Washington, DC, USA.",
"authors": "Beckerman|Jennifer Kate|JK|http://orcid.org/0000-0003-1967-3662;Alarfaj|Mohammad|M|;Tracy|Cynthia M|CM|;Faiwiszewski|Ariel D|AD|;Choi|Andrew D|AD|",
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"journal": "BMJ case reports",
"keywords": "COVID-19; cardiovascular medicine; cardiovascular system; infectious diseases; pericardial disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000086382:COVID-19; D002305:Cardiac Tamponade; D006801:Humans; D008297:Male; D008875:Middle Aged; D010490:Pericardial Effusion; D020519:Pericardiocentesis; D010493:Pericarditis; D010494:Pericarditis, Constrictive; D000086402:SARS-CoV-2",
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"pmid": "33975843",
"pubdate": "2021-05-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32656050;32730619;32359887;32534109;32816925;33002620;32763118;32027573;32835093;32925751;32256706;26320112;32118615;32227076;32866659;33415315;32523921;32734502;29175978;32606285;32838332;33133870;32658005;32230900;32909890",
"title": "Coronavirus disease 2019 (COVID-19)-associated constrictive pericarditis.",
"title_normalized": "coronavirus disease 2019 covid 19 associated constrictive pericarditis"
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"abstract": "Congenital factor XI (FXI) deficiency is associated with a variable bleeding phenotype. Recent reports have documented the use of therapeutic plasma exchange to rapidly and isovolumetrically increase FXI levels before invasive procedures in patients with congenital FXI deficiency. We report a case of acquired FXI deficiency in a pregnant woman with lupus. We proved that the inhibitor was an IgG, therefore potentially capable of crossing the placenta. While immune suppression eliminated detectable circulating inhibitor, the woman's FXI remained quite low. A multi-disciplinary team was formed and therapeutic plasma exchange with 100% plasma replacement was performed when the patient went into labor, to acutely raise her FXI level and remove any potential non-neutralizing inhibitor. The mother had a controllable level of bleeding during post-TPE cesarean section; the baby had no bleeding and the baby's FXI levels were not overtly abnormal. Therapeutic plasma exchange in acquired FXI deficiency (or other acquired hemophilias) can both acutely isovolumetrically raise factor levels and remove any circulating inhibitor.",
"affiliations": "Department of Pathology, University of Chicago, Chicago, Illinois.;Department of Pathology, University of Chicago, Chicago, Illinois.;Department of Pathology, University of Chicago, Chicago, Illinois.",
"authors": "Wool|Geoffrey D|GD|http://orcid.org/0000-0002-3335-2905;Treml|Angela|A|;Miller|Jonathan L|JL|",
"chemical_list": "D007074:Immunoglobulin G",
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"keywords": "Factor XI; acquired inhibitor; therapeutic plasma exchange",
"medline_ta": "J Clin Apher",
"mesh_terms": "D002585:Cesarean Section; D005173:Factor XI Deficiency; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D008180:Lupus Erythematosus, Systemic; D010951:Plasma Exchange; D011247:Pregnancy; D016896:Treatment Outcome",
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"title": "Acquired factor XI deficiency and therapeutic plasma exchange.",
"title_normalized": "acquired factor xi deficiency and therapeutic plasma exchange"
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"abstract": "Presented here is a case of long-term lithium use, with multiple emerging lithium-associated side effects. An 82-year-old woman was brought into the emergency department because of loss of consciousness. According to the physical examination and laboratory analyses, patient was diagnosed with lithium-associated hypercalcemia, hyperparathyroidism, nephrogenic diabetes insipidus (NDI), symptomatic sinus bradycardia, and thyroid dysfunction. In the literature, there is a limited number of case reports with lithium induced multiple clinical conditions. Multiple clinical manifestations due to the side effects of chronic lithium use might be seen. Health care professionals should keep in mind that lithium-related side effects might trigger or exacerbate each other. To avoid toxicity, close follow-up and clinical supervision are important for the early diagnosis and treatment of these side effects, due to the narrow therapeutic index and obscure clinical signs and symptoms of toxicity.",
"affiliations": "Department of Internal Medicine, School of Medicine, Erzincan University, 24100 Erzincan, Turkey.;Department of Endocrinology, School of Medicine, Erzincan University, 24100 Erzincan, Turkey.;Department of Cardiology, School of Medicine, Erzincan University, 24100 Erzincan, Turkey.;Mengucek Gazi Training and Research Hospital, Department of Nephrology, 24100 Erzincan, Turkey.;Department of Internal Medicine, School of Medicine, Erzincan University, 24100 Erzincan, Turkey.",
"authors": "Demirtas|Levent|L|;Akbas|Emin Murat|EM|;Degirmenci|Husnu|H|;Gurel|Ali|A|;Duzgun|Eren|E|",
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"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2015/473931Case ReportMultisystemic Side Effects of an Indispensable Old Drug: A Case Report of Chronic Lithium Use (A Patient with Multiple Side Effects of Lithium) Demirtas Levent \n1\n\n*\nAkbas Emin Murat \n2\nDegirmenci Husnu \n3\nGurel Ali \n4\nDuzgun Eren \n1\n1Department of Internal Medicine, School of Medicine, Erzincan University, 24100 Erzincan, Turkey2Department of Endocrinology, School of Medicine, Erzincan University, 24100 Erzincan, Turkey3Department of Cardiology, School of Medicine, Erzincan University, 24100 Erzincan, Turkey4Mengucek Gazi Training and Research Hospital, Department of Nephrology, 24100 Erzincan, Turkey*Levent Demirtas: drleventdemirtas@hotmail.comAcademic Editor: Bernardo Carpiniello\n\n2015 28 10 2015 2015 47393114 8 2015 11 10 2015 18 10 2015 Copyright © 2015 Levent Demirtas et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Presented here is a case of long-term lithium use, with multiple emerging lithium-associated side effects. An 82-year-old woman was brought into the emergency department because of loss of consciousness. According to the physical examination and laboratory analyses, patient was diagnosed with lithium-associated hypercalcemia, hyperparathyroidism, nephrogenic diabetes insipidus (NDI), symptomatic sinus bradycardia, and thyroid dysfunction. In the literature, there is a limited number of case reports with lithium induced multiple clinical conditions. Multiple clinical manifestations due to the side effects of chronic lithium use might be seen. Health care professionals should keep in mind that lithium-related side effects might trigger or exacerbate each other. To avoid toxicity, close follow-up and clinical supervision are important for the early diagnosis and treatment of these side effects, due to the narrow therapeutic index and obscure clinical signs and symptoms of toxicity.\n==== Body\n1. Introduction\nLithium is one of the first treatment options for bipolar affective disorder and it has been used in modern psychiatric treatments since 1949 [1]. Although its efficacy has been proven as a prophylactic in the relapse and recurrence of unipolar depression, hypomania, mania, short-term mortality, and suicidal risk, it has many side effects [1, 2].\n\nThe clinical problems caused by lithium include narrow therapeutic index, cardiac toxicity, thyroid abnormalities, hyperparathyroidism, transient hyperglycemia, and nephrogenic diabetes insipidus (NDI) caused by renal tubular dysfunction [1, 3, 4]. Multiple side effects from lithium are rarely seen in the same patient. Therefore, we present a case study of long-term lithium use in a patient diagnosed with lithium-associated hypercalcemia, hyperparathyroidism, NDI, symptomatic bradycardia, and thyroid dysfunction. Our aim was to discuss the combination of multiple side effects because the symptoms of lithium intoxication are often overlooked by physicians. Moreover, we discuss the finding that the problems caused by lithium may be associated with each other and aggravate each other.\n\n2. Clinical Presentation and Intervention\nAn 82-year-old woman was brought to the emergency department with mental confusion, and it was determined that she had complaints of weakness, fatigue, excessive thirst with increasing severity, frequent urination, and palpitations over the previous year. Her medication history was as follows: lithium, 300 mg twice daily; quetiapine, 25 mg once daily for a bipolar mood disorder for 20 years; ramipril, 2.5 mg daily for hypertension for 10 years; levodopa/benserazide, 100/25 mg three times daily for Parkinson's disease for two years; ibandronic acid, 150 mg monthly; and calcium/cholecalciferol, 1000/880 mg daily for osteoporosis for one year. There was no history of nonsteroidal anti-inflammatory drugs (NSAIDs), thiazide, and loop diuretics use. The patient had not previously been under our follow-up care and her relatives did not declare a history of lithium intoxication. The patient's lithium levels and renal functions were within normal limits during regular monitoring within the previous one-year period. Two days before hospitalization, a psychiatrist discontinued the lithium treatment because the patient's blood lithium level was 1.3 mmol/L (0.6–1.2). The physical examination findings were as follows: 36 beats/min heart rate via electrocardiogram (ECG) with sinus bradycardia, without signs of ischemia on ECG (Figure 1), blood pressure 80/50 mmHg, and body temperature 36.8°C. Additionally, weak cooperation and orientation, decreased skin turgor tone, dry skin, and mucous membranes were detected. Upon admission, the patient's laboratory values were reported as follows: glucose 8.82 mmol, BUN 10.71 mmol/L (2.9–8.2), creatinine 114.92 μmol/L (53–106), albumin 39 g/L (35–50), sodium 134 mmol/L (135–145), potassium 4.7 mmol/L (3.5–5.2), calcium 2.9 mmol/L (2.05–2.55), thyrotropin 0.145 mIU/L (0.4–4.2), free thyroxine 10.55 pmol/L (12–30), triiodothyronine 3.45 pmol/L (5.08–7.39), cortisol 496.86 nmol/L (140–690), and PTH 128 ng/L (10–65). The values observed in the blood gas analysis were as follows: pH 7.31 (7.35–7.45), PCO2 4.68 kPa (4.7–5.9), and HCO3 17.2 mmol/L (21–28). Based on the urinalysis, the urine density was 1.000, while the calculated plasma osmolality was 297 mmol/kg (275–295).\n\nThe patient was hospitalized in the cardiology clinic with sinus bradycardia due to lithium toxicity, and a temporary pacemaker was inserted. Her central venous pressure (CVP) was measured as 6 cm H2O. Intravenous hydration treatment was begun, based on the CVP and urine output. On the 3rd day of hospitalization, the transient bradycardia was improved and the pacemaker was removed. Because of the increased sodium level (162 mmol/L), the patient was transferred to the internal medicine clinic with a diagnosis of lithium-induced NDI.\n\nAt the internal medicine clinic, the intravenous hydration therapy was revised based on the plasma sodium level and urine output because the CVP value had decreased to 2 cm H2O and the plasma osmolality had increased to 341 mmol/kg. On the 5th day of hospitalization, the patient's blood lithium level was 0.02 mmol/L. During the follow-up period, despite hydration, the sodium levels did not decrease significantly, and the daily urine output was still 6–8 L. The water deprivation test could not be performed in our patient due to severe dehydration; therefore, desmopressin acetate (trihydrate), at 120 mcg twice daily, was begun with a presumptive diagnosis of lithium-induced NDI. On the 2nd day, the desmopressin acetate (trihydrate) dose was increased to 120 mcg three times daily, because the urine output was still 6 L/day, despite the fact that the sodium level had decreased to 156 mmol/L, and the patient's consciousness had partially improved. On the 6th day of the desmopressin treatment, the urine output decreased to 2.5 L/day, the sodium value decreased to 140 mmol/L, and the plasma osmolality decreased to 297 mmol/kg. Additionally, the urine density was 1.008, and the calcium levels reverted to normal levels. Both the consciousness and oral intake were completely improved, and the patient was discharged. On the 7th day after discharge, her daily urine output was 2.5–3.5 L, and no electrolyte imbalance was detected.\n\n3. Discussion\nLithium salts are effective and inexpensive agents that have been used in the treatment of bipolar disorders for a long time [1]. Although the drug is cost effective, many side effects limit its use. The side effects associated with lithium are generally dose related [5]; therefore, the lowest effective dose should be used. Possible side effects include fine tremor of the hands, nystagmus, nausea, diarrhea, headache, weight gain, hypercholesterolemia, thyroid dysfunction, hypercalcemia/hyperparathyroidism, NDI, and renal injury [5]. In addition, the chronic use of lithium or acute high doses of the drug may cause neurological effects, such as coarse tremor, confusion, lethargy, seizures, coma, and cardiac, ophthalmological, and dermatological effects [5]. Close follow-up and clinical supervision are important for the early diagnosis and treatment of these side effects, due to the narrow therapeutic index and obscure clinical signs and symptoms of lithium toxicity.\n\nOur patient was admitted with lithium-associated complaints, including symptomatic sinus bradycardia, hypercalcemia, hyperparathyroidism, NDI, and thyroid dysfunction, although she stopped using lithium a short time before her admission. A lithium level at the time of admission may be more helpful for obtaining a clear clinical picture. However, we also think that this patient's condition was due to chronic exposure more than to acute toxicity. No additional stress factors could be determined (infection, ischemic heart disease, cardiovascular event (CVE), etc.). Upon the evaluation of the patient, our opinion was that the presence of chronic DI was relatively compensated by thirst and oral fluid intake; however, hypovolemia, resulting from the loss of consciousness due to cardiac problems, made the symptoms obvious. All of these side effects could have been prevented if standard treatment would have been administered and follow-up had been provided. However, in this patient, possible symptoms of chronic DI may have been overlooked. The problems caused by lithium may aggravate each other, such as aggravated bradycardia, NDI, and dehydration by hypercalcemia and vice versa; and all of these problems may cause euthyroid sick syndrome (ESS). Thus, the clinical assessment might become more complicated. Supporting these complicated pathophysiological occurrence mechanisms, an appropriate treatment modality, such as rehydration, may resolve the complicated clinical issue more than expected. We think that, in the present case, an undetectable stress factor might have started a vicious circle and caused the clinical signs and symptoms manifested in this patient.\n\nCardiac effects associated with the use of lithium are observed in 20–30% of patients [6, 7]. These include chronic T-wave and ST-segment depression, conduction abnormalities, arrhythmias, and sinoatrial (SA) and atrioventricular (AV) node abnormalities that may lead to sinus bradycardia and SA blockage [5]. Among patients taking lithium, sinoatrial pathology generally occurs in the elderly population, and it usually manifests with syncope [8]. Although ECG changes are relatively common, serious cardiac toxicity signs are rare. Serious toxicity is usually related to advanced age, renal disease, existing cardiac disease, the use of nephrotoxic agents, and the agent's actions on the AV node [5, 6]. In this case study, no findings that caused sinus bradycardia, such as myocardial infarction or ischemia, were determined. There was not a drug use history associated with sinus bradycardia, other than lithium. There was no electrolyte imbalance, except hypercalcemia, and increased intracranial pressure and other etiologic pathologies, such as hypothermia, could not be determined. Hypercalcemia was associated with the patient's chronic lithium use. In the present case, after a cardiologist excluded other reasons for sinus bradycardia, lithium exposure was considered to be the reason for the sinus bradycardia with associated problems, such as thyroid dysfunction, hypercalcemia, and NDI.\n\nIn the chronic use of lithium, due to the increase in the set point of the calcium sensing receptor, hyperparathyroidism is observed with an absolute risk of 10% (versus 0.1% of the general population) [3, 4]. Additionally, hyperparathyroidism increases the renal tubular absorption of calcium, contributing to hypercalcemia. Lithium-associated hyperparathyroidism is frequently observed four times more often in women than in men. With the discontinuation of lithium treatment, hyperparathyroidism usually resolves spontaneously, but it can also continue to be high. In this condition, possible adenoma or hyperplasia may be the causative factors, and parathyroid surgery or medication with calcimimetic agents may be required [3].\n\nNDI is defined as the inability of the kidneys to concentrate urine due to renal dysfunction, although normal levels of the antidiuretic hormone exist. Acquired NDI is diagnosed using a water deprivation test, and the urine osmolality of these patients is less than 300 mOsm/kg H2O, despite water deprivation and vasopressin treatment. Generally, an aquaporin-2 distribution problem caused by the G protein-coupled pathway disorder underscores the molecular basis of acquired DI [4].\n\nLithium causes NDI by accumulating in the distal tubular cells at a concentration that is 10–20 times higher than the serum concentration, leading to degenerative changes, necrosis, and a reduction in the aquaporin expression in the renal collecting ducts [9]. Lithium is the most common cause of acquired NDI and, in chronic lithium use, NDI can be observed in 20–40% of patients [3, 9, 10]. Although lithium may cause a decline in the glomerular filtration rate (GFR), in most patients it does so without clinical significance. Renal functions generally improve after the discontinuation of the drug; however, in some cases, it may take months or years to regain renal functions [3]. In addition, long-term use of lithium may cause irreversible injury due to interstitial nephropathy [3, 10]. Treatment consists of either addressing the causal disease or discontinuing the drug. Other probable useful treatment options are thiazide diuretics, NSAIDs, and low solute intake in food [11, 12]. Thiazide diuretics and NSAIDs have the potential to increase lithium toxicity and deterioration of renal function, so these drugs should be used with caution in these cases. Amiloride is the preferred diuretic, because, in addition to natriuresis, it prevents the entry of lithium into the tubular cells [11]; additionally, high doses of desmopressin have been observed to be effective in some NDI cases [11]. Our patient responded to high doses of desmopressin; however, the hypercalcemia detected in our case might be another reason for the acquired NDI, and the treatment for this high calcium level might have contributed to her recovery from NDI.\n\nThyroid dysfunctions may be observed in patients taking lithium medication, and goiter is the most common thyroid-associated clinical disorder. The prevalence of lithium-associated goiter differs according to geographic region, duration of lithium use, and diagnostic methods [13]. In patients using lithium, hypothyroidism and subclinical hypothyroidism have been reported at a rate of occurrence that is six times higher than the rate of occurrence in the normal population [4, 13]. Thyrotoxicosis associated with lithium may also be seen but less frequently than goiter and hypothyroidism. Lithium has been reported to increase the titer of the existing thyroid antibodies, disrupt the structure of thyroglobulin, reduce hepatic deiodination and the clearance of free thyroxin, competitively inhibit iodine transport in the thyroid gland, and, in some cases, reverse the increase in iodine uptake [13]. In our patient, the thyroid dysfunction was considered to be ESS. In the present case, lithium use and other conditions associated with lithium toxicity may, together, have led to thyroid dysfunction. The recovery of thyroid functions after treatment of other pathologies supported this conclusion.\n\n4. Conclusion\nLithium is an indispensable agent in the treatment of psychiatric disorders because of its efficacy and cost effectiveness; however, side effects can have insidious and serious consequences. The risk-benefit ratio of chronic lithium use must be evaluated in each individual case. Moreover, to avoid toxicity, lithium should be used at the lowest effective dose, serum lithium levels should be closely monitored, and patients should be evaluated for toxicity and side effects. In the literature, there are a limited number of case reports of lithium-induced multiple clinical conditions. The case presented in this paper is important because it required a multidisciplinary approach to address the multiple clinical manifestations. Additionally, clinicians should keep in mind that lithium-related side effects might trigger or exacerbate each other.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Sinus bradycardia without signs of ischemia on ECG.\n==== Refs\n1 Geddes J. R. Miklowitz D. J. Treatment of bipolar disorder The Lancet 2013 381 9878 1672 1682 10.1016/s0140-6736(13)60857-0 2-s2.0-84877709911 \n2 Cipriani A. Hawton K. Stockton S. Geddes J. R. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis British Medical Journal 2013 346 f3646 2-s2.0-84883245123 \n3 Giusti C. F. Amorim S. R. Guerra R. A. Portes E. S. Endocrine disturbances related to the use of lithium Arquivos Brasileiros de Endocrinologia & Metabologia 2012 56 3 153 158 10.1590/s0004-27302012000300001 2-s2.0-84862679934 22666729 \n4 McKnight R. F. Adida M. Budge K. Stockton S. Goodwin G. M. Geddes J. R. Lithium toxicity profile: a systematic review and meta-analysis The Lancet 2012 379 9817 721 728 10.1016/s0140-6736(11)61516-x 2-s2.0-84857643018 \n5 Oruch R. Elderbi M. A. Khattab H. A. Pryme I. F. Lund A. Lithium: a review of pharmacology, clinical uses, and toxicity European Journal of Pharmacology 2014 740 464 473 10.1016/j.ejphar.2014.06.042 2-s2.0-84919442509 24991789 \n6 Serinken M. Karcioglu O. Korkmaz A. Rarely seen cardiotoxicity of lithium overdose: complete heart block International Journal of Cardiology 2009 132 2 276 278 10.1016/j.ijcard.2007.08.058 2-s2.0-59249083377 18068832 \n7 Schneider S. Cobaugh D. J. Tintinalli J. Kelen G. D. Stapczynski J. S. Lithium Emergency Medicine: A Comprehensive Study Guide 2004 6th New York, NY, USA McGraw-Hill 1049 1051 \n8 Luby E. D. Singareddy R. K. Long-term therapy with lithium in a private practice clinic: a naturalistic study Bipolar Disorders 2003 5 1 62 68 10.1034/j.1399-5618.2003.01206.x 2-s2.0-0038445320 12656941 \n9 Li Y. Shaw S. Kamsteeg E.-J. Vandewalle A. Deen P. M. T. Development of lithium-induced nephrogenic diabetes insipidus is dissociated from adenylyl cyclase activity Journal of the American Society of Nephrology 2006 17 4 1063 1072 10.1681/asn.2005080884 2-s2.0-33645468796 16495377 \n10 Le Roy V. Delmas Y. Verdoux H. Chronic renal complications induced by lithium Encephale 2009 35 6 605 610 10.1016/j.encep.2008.12.007 2-s2.0-77449135723 20004292 \n11 Erden A. Karagöz H. Başak M. Lithium intoxication and nephrogenic diabetes insipidus: a case report and review of literature International Journal of General Medicine 2013 6 535 539 10.2147/IJGM.S46383 23861592 \n12 Khanna A. Acquired nephrogenic diabetes insipidus Seminars in Nephrology 2006 26 3 244 248 10.1016/j.semnephrol.2006.03.004 2-s2.0-33646533732 16713497 \n13 Kibirige D. Luzinda K. Ssekitoleko R. Spectrum of lithium induced thyroid abnormalities: a current perspective Thyroid Research 2013 6, article 3 10.1186/1756-6614-6-3 2-s2.0-84873631274\n\n",
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"title": "Multisystemic Side Effects of an Indispensable Old Drug: A Case Report of Chronic Lithium Use (A Patient with Multiple Side Effects of Lithium).",
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"abstract": "BACKGROUND\nHypnosis, despite its effectiveness, has been neglected. The aim of this study is to show the effectiveness and manageability of hypnosis as a stand-alone technique in dentistry.\n\n\nMETHODS\nThree patients underwent 6 oral surgery procedures (surgical third-molar removal, implant surgery, maxillary bone augmentation, and mucogingival surgery) with hypnosis as the only anesthetic. Two of the 3 patients had difficulties: 1 was sensitive to multiple chemicals, had Addison disease, and had previously experienced anaphylactic reactions to local anesthetics; the other was allergic to lidocaine and had undergone a paradoxical reaction to pharmacologic sedation in the past. All 3 patients had 2 preoperative sessions each to assess their perioperative risk, level of anxiety, hypnotic susceptibility, and capacity to develop full hypnotic analgesia. On a surgery day, hypnosis was induced and hypnotic analgesia was obtained according to a standard protocol, a procedure taking no more than 9 minutes in each case. Each surgical procedure was then completed successfully with the patient in a painless condition of full relaxation and sense of well-being, with stable cardiovascular parameters. None of the patients required postoperative analgesics, which were prescribed for use as needed.\nHypnosis is a valuable tool in dentistry, enabling the safe and rapid relief of anxiety and phobia and raising patient pain thresholds to the level of surgical analgesia. Unlike drugs and equipment, it is always readily available, cost-free, and has no adverse effects when administered by competent professionals. Hypnosis can be used for sedation in most patients and as a stand-alone technique in those with appropriate hypnotic susceptibility, improving the well-being and safety of patients.",
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"title": "Hypnosis as sole anesthesia for oral surgery: The egg of Columbus.",
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"abstract": "OBJECTIVE\nThe aim of this study was to study the angiopathic findings of ranibizumab-resistant polypoidal choroidal vasculopathy after switching to a treat-and-extend regimen with intravitreal aflibercept.\n\n\nMETHODS\nThe authors retrospectively reviewed 17 eyes of 17 Japanese patients with polypoidal choroidal vasculopathy (10 men and 7 women, age: 73.8 ± 7.4 years) who were treated with intravitreal aflibercept (2 mg/0.05 mL) injections from February 2013 to August 2014 at Tokyo University Hospital. All patients had switched to aflibercept because their polypoidal choroidal vasculopathy had been refractory to ranibizumab.\n\n\nRESULTS\nThe mean logMAR best-corrected visual acuity at baseline and after 12 months of therapy was 0.30 ± 0.29 (Snellen equivalent: 20/40) and 0.17 ± 0.26 (20/30) (paired t-test P < 0.001). Visual acuity remained stable in 5 cases (29%), deteriorated in 3 (18%), and improved in 9 (53%). Branching vascular networks persisted in all 17 eyes but shrank in 15 (88%). The mean lesion diameter was 3329 ± 1261 μm at baseline and 3180 ± 1247 μm after 12 months (P = 0.0002).\n\n\nCONCLUSIONS\nA treat-and-extend regimen with intravitreal aflibercept for ranibizumab-resistant patients resulted in branching vascular network shrinkage over a 1-year period.",
"affiliations": "*Department of Ophthalmology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; †Department of Ophthalmology, Jichi Medical University, Tochigi, Japan; ‡Singapore National Eye Centre, Singapore; §Singapore Eye Research Institute, Singapore; and ¶Duke-NUS (National University of Singapore) Graduate Medical School, Singapore.",
"authors": "Azuma|Keiko|K|;Obata|Ryo|R|;Nomura|Yoko|Y|;Tan|Xue|X|;Takahashi|Hidenori|H|;Yanagi|Yasuo|Y|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/IAE.0000000000001047",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0275-004X",
"issue": "36(11)",
"journal": "Retina (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Retina",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D020256:Choroidal Neovascularization; D004351:Drug Resistance; D057915:Drug Substitution; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D011127:Polyps; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D012189:Retrospective Studies; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity",
"nlm_unique_id": "8309919",
"other_id": null,
"pages": "2158-2165",
"pmc": null,
"pmid": "27258669",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "ANGIOGRAPHIC FINDINGS OF RANIBIZUMAB-RESISTANT POLYPOIDAL CHOROIDAL VASCULOPATHY AFTER SWITCHING TO A TREAT-AND-EXTEND REGIMEN WITH INTRAVITREAL AFLIBERCEPT.",
"title_normalized": "angiographic findings of ranibizumab resistant polypoidal choroidal vasculopathy after switching to a treat and extend regimen with intravitreal aflibercept"
} | [
{
"companynumb": "JP-ROCHE-1869826",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nDematiaceous, or dark-pigmented, fungi are known to cause infections such as phaeohyphomycosis, chromoblastomycosis, and mycetoma. These fungi are becoming increasingly important opportunistic pathogens in solid organ transplant recipients (SOTR). We present a retrospective chart review of 27 SOTR who developed phaeohyphomycosis infections post transplant from 1988 to 2009.\n\n\nMETHODS\nCases were reviewed for fungal species isolated, date and source of culture, immunosuppressive and fungal therapy used, and outcome. The majority of isolates obtained were from the skin and soft tissue, with 3 pulmonary and brain abscesses.\n\n\nRESULTS\nThe time from transplantation to onset of infection ranged from 2 months to 11 years. The species isolated were Exophiala (11), Ochroconis (3), Alternaria (2), Phoma (2), Wangiella (1), Cladosporium (1), Aureobasidium (1), Chaetomium (1), Coniothyrium (1), and non-sporulating fungi (2). An additional 4 patients had infections confirmed by pathology, but no cultures were done. Most of the affected skin lesions were surgically debrided and treated with itraconazole; 2 patients were treated with voriconazole and 2 with amphotericin D. Death from fungal disease occurred only in patients with pulmonary and brain abscesses.\n\n\nCONCLUSIONS\nAs the number of SOTR increases, so does the incidence of fungal infections in that population. Surgery, along with antifungal therapy and a reduction in immunosuppression, are the cornerstones of treatment.",
"affiliations": "Department of Internal Medicine, Section of Infectious Diseases, Tulane University School of Medicine, New Orleans, Louisiana, USA.",
"authors": "Schieffelin|J S|JS|;Garcia-Diaz|J B|JB|;Loss|G E|GE|;Beckman|E N|EN|;Keller|R A|RA|;Staffeld-Coit|C|C|;Garces|J C|JC|;Pankey|G A|GA|",
"chemical_list": "D000935:Antifungal Agents; D017964:Itraconazole; D000666:Amphotericin B; D065819:Voriconazole",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12197",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "16(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "dematiaceous fungi; phaeohyphomycosis; transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000666:Amphotericin B; D000935:Antifungal Agents; D001922:Brain Abscess; D003646:Debridement; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D017964:Itraconazole; D008169:Lung Abscess; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D016377:Organ Transplantation; D060446:Phaeohyphomycosis; D012189:Retrospective Studies; D013997:Time Factors; D065819:Voriconazole; D055815:Young Adult",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "270-8",
"pmc": null,
"pmid": "24628809",
"pubdate": "2014-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Phaeohyphomycosis fungal infections in solid organ transplant recipients: clinical presentation, pathology, and treatment.",
"title_normalized": "phaeohyphomycosis fungal infections in solid organ transplant recipients clinical presentation pathology and treatment"
} | [
{
"companynumb": "US-PFIZER INC-2015090704",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": nu... |
{
"abstract": "We present the case of an 80-year old man taking rivaroxaban for atrial fibrillation who sustained massive intra-abdominal bleeding in the setting of acute cholecystitis. CT scan on admission revealed evidence of active bleeding into the gallbladder lumen and gallbladder perforation. Immediate resuscitation was commenced with intravenous fluids, antibiotics and blood products. Despite attempts to correct coagulopathy, the patient's haemodynamic status deteriorated and an emergency laparotomy was performed, with open cholecystectomy, washout and haemostasis. The patient had a largely uneventful recovery and was discharged on day 11 of admission. Patients with coagulopathies, whether pharmacological or due to underlying disease processes, are at very high risk of severe haemorrhagic complications and subsequent morbidity. As such, prompt recognition and operative management of haemorrhagic perforated cholecystitis is of crucial importance.",
"affiliations": "Department of Surgery, Wollongong Hospital, South Coast Mail Centre, New South Wales, Australia.;St George Hospital, Kogarah, Australia.;Department of Surgery, Wollongong Hospital, South Coast Mail Centre, New South Wales, Australia.",
"authors": "Kwok|Allan|A|http://orcid.org/0000-0002-8742-6236;Chern|Tien Yew|TY|http://orcid.org/0000-0001-8320-0101;Winn|Robert|R|",
"chemical_list": "D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-226870",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "contraindications and precautions; gastrointestinal surgery; general surgery; haematology (drugs and medicines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D001281:Atrial Fibrillation; D002763:Cholecystectomy; D041881:Cholecystitis, Acute; D065427:Factor Xa Inhibitors; D005704:Gallbladder; D005705:Gallbladder Diseases; D006465:Hemoperitoneum; D006801:Humans; D007813:Laparotomy; D008297:Male; D000069552:Rivaroxaban; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30373899",
"pubdate": "2018-10-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27987134;24673623;9149210;21161216;17907301;15609706;26271278;20225785;18629579;22778467;6861782;20601855;17522906;25935908",
"title": "Acute cholecystitis and gallbladder perforation leading to massive haemoperitoneum in a patient taking rivaroxaban.",
"title_normalized": "acute cholecystitis and gallbladder perforation leading to massive haemoperitoneum in a patient taking rivaroxaban"
} | [
{
"companynumb": "AU-SA-2018SA325440",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ANTITHROMBIN III HUMAN\\COAGULATION FACTOR IX HUMAN\\COAGULATION FACTOR ... |
{
"abstract": "Nebivolol is a third-generation beta blocker that exerts selective antagonistic activity on β1 receptors. It has vasodilating properties that result from direct stimulation of endothelial nitric oxide synthase. Nebivolol is indicated for the treatment of hypertension and heart failure, and is generally well tolerated. In this article, we report a case of an infant who was admitted to the Pediatrics and Neonatology Unit of the Moscati Hospital (Aversa, Italy) about 24 hours after birth. The reason for hospitalization was persistent severe hypoglycemia (blood glucose = 30 mg/dL) and jaundice (total bilirubin = 12.5 mg/dL, indirect bilirubin 11.75 mg/dL). He was born by spontaneous delivery after a normal term pregnancy. Birth weight was 3040 g and the Apgar score was 6-9. The mother reported taking nebivolol 5 mg/day for unspecified tachycardia in the last 4 months of pregnancy. Clinical and instrumental investigations carried out during hospitalization did not reveal any congenital or perinatal abnormalities. After treatment for metabolic and electrolyte imbalance, he was discharged on the 10(th) day of hospitalization, in good clinical condition and with normalization of clinical and laboratory parameters. Currently, there are no specific studies on nebivolol tolerability during pregnancy. Our data suggest that the risk profile of nebivolol during pregnancy is the same as that of other β-blockers. Therefore, further studies are required to determine the safety of β-blockers during pregnancy and the risks to the unborn child.",
"affiliations": "Department of Experimental Medicine, Section of Pharmacology, Pharmacoepidemiology and Pharmacovigilance Centre of the Campania Region, Second University of Naples, Naples, Italy.;Department of Pediatric, Moscati Hospital, Aversa, Italy.;Department of Pediatric, Moscati Hospital, Aversa, Italy.;Department of Experimental Medicine, Section of Pharmacology, Pharmacoepidemiology and Pharmacovigilance Centre of the Campania Region, Second University of Naples, Naples, Italy.;Azienda Sanitaria Locale Di Caserta, Caserta, Italy.;Department of Experimental Medicine, Section of Pharmacology, Pharmacoepidemiology and Pharmacovigilance Centre of the Campania Region, Second University of Naples, Naples, Italy.;Department of Experimental Medicine, Section of Pharmacology, Pharmacoepidemiology and Pharmacovigilance Centre of the Campania Region, Second University of Naples, Naples, Italy.",
"authors": "Sullo|Maria Giuseppa|MG|;Perri|Domenico|D|;Sibilio|Michelina|M|;Rafaniello|Concetta|C|;Fucile|Annamaria|A|;Rossi|Francesco|F|;Capuano|Annalisa|A|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0976-500X.149148",
"fulltext": "\n==== Front\nJ Pharmacol PharmacotherJ Pharmacol PharmacotherJPPJournal of Pharmacology & Pharmacotherapeutics0976-500X0976-5018Medknow Publications & Media Pvt Ltd India JPP-6-4510.4103/0976-500X.149148Case ReportHypoglycemia, polycythemia and hyponatremia in a newborn exposed to nebivolol during pregnancy Sullo Maria Giuseppa Perri Domenico 1Sibilio Michelina 1Rafaniello Concetta Fucile Annamaria 2Rossi Francesco Capuano Annalisa Department of Experimental Medicine, Section of Pharmacology, Pharmacoepidemiology and Pharmacovigilance Centre of the Campania Region, Second University of Naples, Naples, Italy1 Department of Pediatric, Moscati Hospital, Aversa, Italy2 Azienda Sanitaria Locale Di Caserta, Caserta, ItalyAddress for correspondence: Maria Giuseppa Sullo, Department of Experimental Medicine, Section of Pharmacology, Pharmacoepidemiology and Pharmacovigilance Centre of the Campania Region, Second University of Naples, Via Costantinopoli 16, Naples - 80138, Italy. E-mail: mariagiuseppa.sullo@unina2.itJan-Mar 2015 6 1 45 48 04 2 2014 15 3 2014 28 6 2014 Copyright: © Journal of Pharmacology and Pharmacotherapeutics2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Nebivolol is a third-generation beta blocker that exerts selective antagonistic activity on β1 receptors. It has vasodilating properties that result from direct stimulation of endothelial nitric oxide synthase. Nebivolol is indicated for the treatment of hypertension and heart failure, and is generally well tolerated. In this article, we report a case of an infant who was admitted to the Pediatrics and Neonatology Unit of the Moscati Hospital (Aversa, Italy) about 24 hours after birth. The reason for hospitalization was persistent severe hypoglycemia (blood glucose = 30 mg/dL) and jaundice (total bilirubin = 12.5 mg/dL, indirect bilirubin 11.75 mg/dL). He was born by spontaneous delivery after a normal term pregnancy. Birth weight was 3040 g and the Apgar score was 6-9. The mother reported taking nebivolol 5 mg/day for unspecified tachycardia in the last 4 months of pregnancy. Clinical and instrumental investigations carried out during hospitalization did not reveal any congenital or perinatal abnormalities. After treatment for metabolic and electrolyte imbalance, he was discharged on the 10th day of hospitalization, in good clinical condition and with normalization of clinical and laboratory parameters. Currently, there are no specific studies on nebivolol tolerability during pregnancy. Our data suggest that the risk profile of nebivolol during pregnancy is the same as that of other β-blockers. Therefore, further studies are required to determine the safety of β-blockers during pregnancy and the risks to the unborn child.\n\nAdverse drug reactionsnebivololnewbornpregnancy\n==== Body\nINTRODUCTION\nNebivolol is a third-generation β1 - selectiveblocker that is indicated for the treatment of hypertension and heart failure.[1] It has vasodilatory properties mediated by direct stimulation of the endothelial nitric oxide synthase (eNOS).[2] Nebivolol is a racemic mixture of two enantiomers in a 1:1 ratio,[3] namely a d-and an l-isomer. The D-isomer selectively blocks the β1 receptor and has mild vasodilatory properties, while the L-isomer stimulates eNOS, thereby resulting in vasodilatation.[4] The hemodynamic changes induced by nebivolol may lead to a negative chronotropic effect, inhibition of sympathetic outflow from cerebral vasomotor centers, inhibition of peripheral β1-adrenoceptors,[5] suppression of renin activity, and decreased peripheral vascular resistance. The very high selectivity of the nebivolol D-isomer for β1 - versus β2-adrenergic receptors involves the limited effects on airway reactivity, insulin sensitivity[67] and the lesser negative inotropic effect of nebivolol in patients with heart failure.[89] Although nebivolol has no intrinsic sympathomimetic activity, it exerts an agonistic effect on β3-receptors, which may partially explain its effects on the endothelium.[5]\n\nNebivolol is well tolerated. The most frequently occurring adverse events (AEs) associated with nebivolol reported in clinical trials are fatigue (4-79%), headache (2-24%), paresthesia (7-13%), bradycardia (6-11%), rhinitis (1-7%), and dizziness (2-5%). Other commonly reported (>1%) nebivolol-associated AEs are diarrhea (2-3%) and nausea (1-3%), both of which are consistent with AEs reported for other β-blockers. Adverse events reported in <1% of patients are insomnia, asthenia, hypercholesterolemia, and hyperuricemia.[2] The following AEs were communicated to the manufacturer after nebivolol became commercially available: abnormal hepatic function, acute pulmonary edema, acute renal failure, atrioventricular block, bronchospasm, erectile dysfunction, hypersensitivity, myocardial infarction, pruritus, psoriasis, Raynaud's phenomenon, intermittent claudication, somnolence, syncope, and thrombocytopenia.[2] Nebivolol is contraindicated in patients with severe bradycardia, atroventricular nodal block greater than first degree, cardiogenic shock, decompensated heart failure, and severe liver disease. Like the use of other β-blockers, abrupt cessation of nebivolol therapy is not recommended because it may lead to a rebound effect and to the precipitation of severe angina, myocardial infarction, and ventricular arrhythmias.[2]\n\nLike most antihypertensive agents used in pregnancy, nebivolol is designated a pregnancy category C medication (no human data supporting safety or toxicity during pregnancy). Category C includes drugs for which human studies are lacking but animal studies showing a fetal risk. Category C drugs should be administrated only if the potential benefits outweigh the potential risks to the fetus. This category is difficult to interpret because there is no evidence of risk and it is so broad to be preclude usefulness in practice.[10]\n\nCASE REPORT\nHere we report the case of an infant who was admitted to the Pediatrics and Neonatology Unit of the Moscati Hospital (Aversa, Italy) about 24 hours after birth. The reason for hospitalization was persistent severe hypoglycemia (blood glucose = 30 mg/dL) and jaundice (total bilirubin = 12.5 mg/dL, indirect bilirubin 11.75 mgl/dL). He was born at term by spontaneous delivery after a normal pregnancy. Birth weight was 3040 g and the Apgar score was 6-9. The mother reported taking nebivolol 5 mg/day for unspecified tachycardia in the last 4 months of pregnancy. Because of jaundice and hypoglycemia, the infant immediately underwent phototherapy and intravenous administration of 10% glucose solution. The laboratory tests carried out at admission revealed polycythemia with hematocrit 63.7%, red blood cells count of 6,230,000/mm3, mild hyponatremia (132 mEq/L) and mild thrombocytopenia (platelets = 99,000/mm3) with prolongation of prothrombin time and activated partial thromboplastin time. Tests during hospitalization showed blood glucose level within normal limits, despite treatment with intravenous glucose solution, and coagulation remained deranged without overt clinical manifestations, and hyponatremia became more pronounced.\n\nUrinary electrolytes were below normal, hence it was decided to reduce fluid intake and increase the administration of sodium chloride. Abdominal ultrasonography, cardiology consultation, electrocardiography, echocardiography, and brain CT scan were unremarkable. Serial C-reactive protein, urinalysis, urine cultures and blood cultures were also unremarkable.\n\nThe clinical condition of the newborn gradually improved and coagulation test and the levels of blood glucose, bilirubin and serum sodium normalized. Consequently, the patient was discharged on the 10th day, in a good clinical condition and with normalization of clinical and laboratory parameters.\n\nDISCUSSION\nThe detection of adverse drug events (ADEs) is crucial to improving the quality of health care system both in adults and, especially in pediatrics. To date, pharmacovigilance studies on vaccine and drug safety are still not enough in pediatric population.[11121314] Moreover, pregnant women are often excluded from clinical studies, and this could induce an inadequate pharmacological treatment which could compromise both fetal and maternal well-being.\n\nIn this scenario, we report the first case, to our knowledge, of nebivolol induced a hypoglycemia, polycythemia and hyponatremia in a newborn after a spontaneous at-term delivery. During pregnancy, the mother received an off-label prescription of nebivolol for unspecified tachycardia. The consequences of β-blocker treatment during pregnancy are debated. Some studies found an association between β-blocker treatment and small for-gestational-age (SGA) newborns and preterm births,[1516171819] but not others.[2021] A study conducted in a cohort of all births in Denmark between 1995 and 2008 revealed an association between exposure to β-blockers and preterm birth and perinatal mortality. When the analysis was adjusted for maternal comorbidity, co-medication and smoking, only labetalol was found to be associated with perinatal mortality.[22] However, other studies show that labetalol is safer than other β-blockers during pregnancy,[1023] thus this drug is becoming the first-line choice for hypertension and other chronic conditions during pregnancy. In any event, the risk of SGA, preterm birth and perinatal mortality following exposure to β-blockers could be a class effect.[22]\n\nOur patient was affected by hypoglycemia, polycythemia and hyponatremia after being exposed to nebivolol during the last 4 months of pregnancy. There are numerous reports of hypotension, bradycardia and hypoglycemia in infants after administration of β-blockers, particularly labetalol, during pregnancy.[24] In particular, a cohort study showed that exposure to β-blockers in the last trimester of pregnancy is associated with an increased risk of hypoglycemia in infants. In fact, β-blockers spread through the placenta, and can increase insulin levels and decrease glucagon levels in the fetus, thereby resulting in hypoglycemia in the newborn.[25] However, hypoglycemia is common in neonates and usually occurs in the first 48 hours after birth. The risk of hypoglycemia in newborns is increased by prematurity, perinatal stress or asphyxia, small size for gestational age and being born to diabetic mothers.[26] Hypoglycemia can be transient or persistent. The persistent form may be due to metabolic diseases, such as hyperinsulinism and hypopituitarism, or hereditary hepatic enzyme deficiencies.[27] Instead, the transient hypoglycemia could represent a metabolic mechanism of adaptation to extrauterine life[28] and is commonly observed in at-risk infants.[29] Moreover, transient low blood glucose concentrations are frequently observed in healthy newborns[30] and, unlike in our case, it is a transient phenomenon.[28] Therefore, it is conceivable that exposure to nebivolol has favored the onset and persistence of hypoglycemia in our patient.\n\nThere are no reports of hyponatremia or polycythemia consequent to exposure to nebivolol. In our case, polycythemia may have resulted from placental insufficiency induced by nebivolol. In fact, β-blockers reduce placental perfusion.[24] The effects on placental hemodynamics have been observed in both human and animal studies. It has been suggested that β-blockers without intrinsic sympathomimetic activity cause selective vasoconstriction of placental vessels.[31] Placental insufficiency can lead to chronic or acute fetal hypoxia with birth asphyxia and hypothermia, neonatal hypoglycemia, polycythemia and coagulopathy.[32] Hyponatremia could be the consequence of increased blood viscosity resulting from polycythemia and thus it would be a pseudohypontremia.\n\nCONCLUSION\nTo our knowledge, this is the first case of hypoglycemia, polycythemia and hyponatremia in a newborn exposed to nebivolol during the last 4 months of pregnancy.\n\nThe safety profile of beta blockers (β-blockers) used in pregnancy is still unclear and controversial. There is a lack of studies on the tolerability and safety of nebivolol during pregnancy. However, it appears that the risk profile of nebivolol for pregnancies is the same as that of other β-blockers. Therefore, there is a need for studies designed to assess the tolerability profile of this class of drugs when used in pregnancy in order to minimize risks both for the unborn that for pregnant women. For this reason pharmacovigilance post-marketing studies are key elements to monitor the safety and effectiveness of approved drugs,[3334353637] especially when used in special conditions such as pregnancy.\n\nACKNOWLEDGEMENT\nThe authors thank Jean Ann Gilder (Scientific Communication srl., Naples, Italy) for text editing.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Cheng JW Nebivolol: A third-generation beta-blocker for hypertension Clin Ther 2009 31 447 62 19393838 \n2 Münzel T Gori T Nebivolol: The somewhat-different beta-adrenergic receptor blocker J Am Coll Cardiol 2009 54 1491 9 19815121 \n3 Mangrella M Rossi F Fici F Rossi F Pharmacology of nebivolol Pharmacol Res 1998 38 419 31 9990650 \n4 Van Nueten L De Crée J Nebivolol: Comparison of the effects of dl-nebivolol, d-nebivolol, l-nebivolol, atenolol, and placebo on exercise-induced increases in heart rate and systolic blood pressure Cardiovasc Drugs Ther 1998 12 339 44 9825177 \n5 Rozec B Quang TT Noireaud J Gauthier C Mixed beta3-adrenoceptor agonist and alpha1-adrenoceptor antagonist properties of nebivolol in rat thoracic aorta Br J Pharmacol 2006 147 699 706 16474420 \n6 Cazzola M Matera MG Ruggeri P Sanduzzi A Spicuzza L Vatrella A Comparative effects of a two-week treatment with nebivolol and nifedipine in hypertensive patients suffering from COPD Respiration 2004 71 159 64 15031571 \n7 D’Agostino B Gallelli L Falciani M Fici F Mangrella M Rossi F Nebivolol and airway responsiveness in the rabbit Life Sci 2001 68 2159 68 11324721 \n8 Brixius K Bundkirchen A Bölck B Mehlhorn U Schwinger RH Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium Br J Pharmacol 2001 133 1330 8 11498519 \n9 Bundkirchen A Brixius K Bölck B Mehlhorn U Bloch W Schwinger RH Nebivolol, carvedilol and metoprolol do not influence cardiac Ca(2+) sensitivity Eur J Pharmacol 2001 422 175 80 11430928 \n10 Podymow T August P Update on the use of antihypertensive drugs in pregnancy Hypertension 2008 51 960 9 18259046 \n11 Ferrajolo C Capuano A Verhamme KM Schuemie M Rossi F Stricker BH Drug-induced hepatic injury in children: A case/non-case study of suspected adverse drug reactions in VigiBase Br J Clin Pharmacol 2010 70 721 8 21039766 \n12 Bertuola F Morando C Menniti-Ippolito F Da Cas R Capuano A Perilongo G Association between drug and vaccine use and acute immune thrombocytopenia in childhood: A case-control study in Italy Drug Saf 2010 33 65 72 20000868 \n13 Bianciotto M Chiappini E Raffaldi I Gabiano C Tovo PA Sollai S Italian Multicenter Study Group for Drugand Vaccine Safety in Children. Drug use and upper gastrointestinal complications in children: A case-control study Arch Dis Child 2013 98 218 21 23264432 \n14 Gallo M Clavenna A Bonati M Siani P Irpino A Rossi F Active surveillance of adverse drug reactions in children in five Italian paediatric wards Open J Pediatr 2012 2 111 7 \n15 Magee LA Duley L Oral beta-blockers for mild to moderate hypertension during pregnancy Cochrane Database Syst Rev 2003 CD002863 12917933 \n16 Sibai BM Gonzalez AR Mabie WC Moretti M A comparison of labetalol plus hospitalization versus hospitalization alone in the management of preeclampsia remote from term Obstet Gynecol 1987 70 323 7 3627579 \n17 Magee LA Elran E Bull SB Logan A Koren G Risks and benefits of beta-receptor blockers for pregnancy hypertension: Overview of the randomized trials Eur J Obstet Gynecol Reprod Biol 2000 88 15 26 10659912 \n18 Nakhai-Pour HR Rey E Bérard A Antihypertensive medication use during pregnancy and the risk of major congenital malformations or small-for-gestational-age newborns Birth Defects Res B Dev Reprod Toxicol 2010 89 147 54 20437474 \n19 Lydakis C Lip GY Beevers M Beevers DG Atenolol and fetal growth in pregnancies complicated by hypertension Am J Hypertens 1999 12 541 7 10371362 \n20 Magee LA Ornstein MP von Dadelszen P Fortnightly review: Management of hypertension in pregnancy BMJ 1999 318 1332 6 10323823 \n21 Abalos E Duley L Steyn DW Henderson-Smart DJ Antihypertensive drug therapy for mild to moderate hypertension during pregnancy Cochrane Database Syst Rev 2007 CD002252 17253478 \n22 Meidahl Petersen K Jimenez-Solem E Andersen JT Petersen M Brødbæk K Køber L β-Blocker treatment during pregnancy and adversepregnancy outcomes: A nationwide population-based cohort study BMJ Open 2012 2 pii: e001185 \n23 Karthikeyan VJ Lip GY Hypertension in pregnancy: Pathophysiology and management strategies Curr Pharm Des 2007 13 2567 79 17897001 \n24 Heida KY Zeeman GG Van Veen TR Hulzebos CV Neonatal side effects of maternal labetalol treatment in severe preeclampsia Early Hum Dev 2012 88 503 7 22525036 \n25 Davis RL Eastman D McPhillips H Raebel MA Andrade SE Smith D Risks of congenital malformations and perinatal events among infants exposed to calcium channel and beta-blockers during pregnancy Pharmacoepidemiol Drug Saf 2011 20 138 45 21254284 \n26 Sweet CB Grayson S Polak M Management strategies for neonatal hypoglycemia J Pediatr Pharmacol Ther 2013 18 199 208 24052783 \n27 LaFranchi S Hypoglycemia of infancy and childhood Pediatr Clin North Am 1987 34 961 82 3302901 \n28 Hussain K Investigations for neonatal hypoglycaemia Clin Biochem 2011 44 465 6 22036328 \n29 Arya VB Senniappan S Guemes M Hussain K Neonatal hypoglycemia Indian J Pediatr 2014 81 58 65 23904063 \n30 Tin W Defining neonatal hypoglycaemia: A continuing debate Semin Fetal Neonatal Med 2014 19 27 32 24148999 \n31 Lennestål R Otterblad Olausson P Källén B Maternal use of antihypertensive drugs in early pregnancy and delivery outcome, notably the presence of congenital heart defects in the infants Eur J Clin Pharmacol 2009 65 615 25 19198819 \n32 Halliday HL Neonatal management and long-term sequelae Best Pract Res Clin Obstet Gynaecol 2009 23 871 80 19632899 \n33 Mazzitello C Esposito S De Francesco AE Capuano A Russo E De Sarro G Pharmacovigilance in Italy: An overview J Pharmacol Pharmacother 2013 4 Suppl 1 S20 8 24347976 \n34 Ruggiero S Rafaniello C Bravaccio C Grimaldi G Granato R Pascotto A Safety of attention-deficit/hyperactivity disorder medications in children: An intensive pharmacosurveillance monitoring study J Child Adolesc Psychopharmacol 2012 22 415 22 23234585 \n35 Rafaniello C Ianniello B De Vizia M Mercogliano A Lettieri B Rinaldi B Cardiorespiratory effects of change in posture after spinal anesthesia with hyperbaric bupivacaine Minerva Med 2011 102 501 4 22193381 \n36 Capuano A Irpino A Gallo M Ferrante L Illiano M L Rinaldi B Regional surveillance of emergency-department visits for outpatient adverse drug events Eur J Clin Pharmacol 2009 65 721 8 19294371 \n37 Capuano A Motola G Russo F Avolio A Filippelli A Rossi F Adverse drug events in two emergency departments in Naples, Italy: An observational study Pharmacol Res 2004 50 631 6 15501703\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0976-500X",
"issue": "6(1)",
"journal": "Journal of pharmacology & pharmacotherapeutics",
"keywords": "Adverse drug reactions; nebivolol; newborn; pregnancy",
"medline_ta": "J Pharmacol Pharmacother",
"mesh_terms": null,
"nlm_unique_id": "101552113",
"other_id": null,
"pages": "45-8",
"pmc": null,
"pmid": "25709355",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "20437474;22036328;22193381;23264432;10659912;19815121;11498519;19198819;19393838;24347976;9990650;24148999;22525036;22815467;10371362;16474420;20000868;11324721;23904063;19294371;12917933;24052783;21254284;3627579;23234585;9825177;21039766;17253478;15031571;18259046;10323823;19632899;3302901;17897001;11430928;15501703",
"title": "Hypoglycemia, polycythemia and hyponatremia in a newborn exposed to nebivolol during pregnancy.",
"title_normalized": "hypoglycemia polycythemia and hyponatremia in a newborn exposed to nebivolol during pregnancy"
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{
"companynumb": "IT-TEVA-546208ISR",
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"actiondrug": "5",
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"activesubstancename": "NEBIVOLOL"
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"abstract": "The National Institute on Drug Abuse has observed an increase in fentanyl deaths in the United States. One epidemic related to the abuse of fentanyl happened in Cook County in 2005-2007 (350 deaths). Another outbreak of fentanyl deaths occurred in 2015-2017 in the same area. The database of the Cook County Medical Examiner's Office was searched for cases of fentanyl deaths between 2015 and 2017: 1244 deaths were found. A comparison was performed with the previous data: an increase in the number of females was observed in 2015-2017. Also, in 2005-2007, the majority of deaths occurred among African American, while in 2015-2017, Caucasians were more involved. Within our population, some drug combinations were more common in specific demographic subgroups (male/females; Caucasian/African American; and certain age groups). The epidemiology and the most significant drug associations found at the toxicology are discussed, highlighting the usefulness of the knowledge about this outbreak for public health.",
"affiliations": "Department of Pathology, State University of New York Upstate Medical University, 750 E. Adams St., Syracuse, NY, 13210.;British Columbia Coroner's Service, 3649 Cambridge St., Vancouver, V5K1M5, BC, Canada.;Cook County Office of Medical Examiner, 2121 W Harrison St., Chicago, IL, 60612.;Department of Public Health and Preventive Medicine, State University of New York Upstate Medical University, 750 E. Adams St., Syracuse, NY, 13210.;Department of Pathology, State University of New York Upstate Medical University, 750 E. Adams St., Syracuse, NY, 13210.",
"authors": "Serinelli|Serenella|S|;White|Steven|S|;Arunkumar|Ponni|P|;Wang|Dongliang|D|;Gitto|Lorenzo|L|",
"chemical_list": "D000701:Analgesics, Opioid; D002492:Central Nervous System Depressants; D000431:Ethanol; D005283:Fentanyl",
"country": "United States",
"delete": false,
"doi": "10.1111/1556-4029.14114",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1198",
"issue": "64(6)",
"journal": "Journal of forensic sciences",
"keywords": "autopsy; drug overdose; fatal; fentanyl; fentanyl analogs; forensic science; public health; toxicology",
"medline_ta": "J Forensic Sci",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001741:African Americans; D000368:Aged; D000701:Analgesics, Opioid; D002492:Central Nervous System Depressants; D003334:Coroners and Medical Examiners; D062787:Drug Overdose; D000431:Ethanol; D005260:Female; D005283:Fentanyl; D006801:Humans; D007087:Illinois; D007668:Kidney; D008099:Liver; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal; D009293:Opioid-Related Disorders; D012189:Retrospective Studies; D017678:Sex Distribution; D044465:Whites; D055815:Young Adult",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "1735-1742",
"pmc": null,
"pmid": "31216059",
"pubdate": "2019-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "The Outbreak of Fentanyl-Related Deaths in Cook County, Illinois, Between October 2015 and December 2017: A Retrospective Study and a Comparison with Previous Data.",
"title_normalized": "the outbreak of fentanyl related deaths in cook county illinois between october 2015 and december 2017 a retrospective study and a comparison with previous data"
} | [
{
"companynumb": "US-JNJFOC-20191141536",
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"activesubstance": {
"activesubstancename": "ALCOHOL"
},
"drugadditional": null,
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{
"abstract": "BACKGROUND\nAnecdotal observation suggests that older patients in medical intensive care units receive higher doses of psychoactive medications during evening shifts than day and night shifts.\n\n\nOBJECTIVE\nTo determine the dosing patterns and total doses of fentanyl, lorazepam, and haloperidol according to nursing shift in a cohort of older patients in a medical intensive care unit.\n\n\nMETHODS\nThe sample consisted of 309 patients 60 years and older admitted to the medical intensive care unit at Yale-New Haven Hospital, New Haven, Connecticut. Data on time, dosage, and route of administration of the drugs were collected. Data were analyzed by using a Bayesian random effects Poisson model adjusted for individual heterogeneity, excess zero doses, and important clinical covariates.\n\n\nRESULTS\nMean age of the patients was 75 years; 58% received fentanyl, 55% received lorazepam, and 32% received haloperidol. Although dosing with fentanyl did not differ according to shift, doses of both lorazepam and haloperidol were higher during the evening shifts (4 pm to midnight) than during the day or night shifts. Compared with women, men received higher doses of both haloperidol and lorazepam and variability between shifts was greater.\n\n\nCONCLUSIONS\nIn this longitudinal, observational sample of older patients, data indicated a positive association between dose levels of lorazepam and haloperidol during the evening nursing shifts relative to other shifts. Further investigation is needed to determine potential causes and to evaluate the impact on outcomes of sleep deprivation and delirium.",
"affiliations": "Department of Medicine, Yale University School of Medicine, New Haven, CT 06511, USA.",
"authors": "Pisani|Margaret A|MA|;Bramley|Kyle|K|;Vest|Michael T|MT|;Akgün|Kathleen M|KM|;Araujo|Katy L B|KL|;Murphy|Terrence E|TE|",
"chemical_list": "D000701:Analgesics, Opioid; D014150:Antipsychotic Agents; D006993:Hypnotics and Sedatives; D001569:Benzodiazepines; D006220:Haloperidol; D008140:Lorazepam; D005283:Fentanyl",
"country": "United States",
"delete": false,
"doi": "10.4037/ajcc2013835",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1062-3264",
"issue": "22(5)",
"journal": "American journal of critical care : an official publication, American Association of Critical-Care Nurses",
"keywords": null,
"medline_ta": "Am J Crit Care",
"mesh_terms": "D000368:Aged; D000701:Analgesics, Opioid; D014150:Antipsychotic Agents; D001499:Bayes Theorem; D001569:Benzodiazepines; D015331:Cohort Studies; D003237:Connecticut; D003693:Delirium; D005260:Female; D005283:Fentanyl; D006220:Haloperidol; D006801:Humans; D006993:Hypnotics and Sedatives; D007362:Intensive Care Units; D008140:Lorazepam; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "9211547",
"other_id": null,
"pages": "e62-9",
"pmc": null,
"pmid": "23996429",
"pubdate": "2013-09",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "17239755;14982491;23269131;5349366;16394685;18929945;19237884;19945879;15640638;22851806;17698685;12421743;17102966;16919169;15071384;14044222;7620257;22991132;16236951;8208879;11797025;18416789;15082703;3558716;20116842;19745202;3928249;22025357;11511942",
"title": "Patterns of opiate, benzodiazepine, and antipsychotic drug dosing in older patients in a medical intensive care unit.",
"title_normalized": "patterns of opiate benzodiazepine and antipsychotic drug dosing in older patients in a medical intensive care unit"
} | [
{
"companynumb": "US-JNJFOC-20140421077",
"fulfillexpeditecriteria": "2",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": null,
... |
{
"abstract": "Immunomodulatory antibodies that enhance the immune system to fight cancer are revolutionizing the treatment of patients with an expanding variety of malignancies. There is a unique spectrum of side effects associated with immunomodulatory antibodies, termed immune-related adverse events (irAEs), which include colitis and hepatitis among others. The treatment of refractory or severe irAEs can occasionally require significant immunosuppression, involving steroids or tumor necrosis factor-alpha antagonists, placing these patients at risk for infections. We present the first reported case to our knowledge of an opportunistic infection in a patient treated with an immunomodulatory antibody. As the use of immunomodulatory antibodies expands and more patients develop irAEs that require treatment with immunosuppression, recognition of the potential for opportunistic infections in this emerging patient population will be critical. Prospective trials are needed to define the optimal immunosuppressive management of irAEs and determine whether prophylactic antiviral, antibacterial, or antifungal therapies are beneficial in this unique population.",
"affiliations": "New York-Presbyterian Hospital, Weill Cornell Medical College, 525 East 68th Street, New York, NY 10065, USA.;Memorial Sloan-Kettering Cancer Center, Melanoma and Immunotherapeutics Oncology Service, 300 East 66th Street, New York, NY 10065, USA.;Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.;Memorial Sloan-Kettering Cancer Center, Melanoma and Immunotherapeutics Oncology Service, 300 East 66th Street, New York, NY 10065, USA.;Memorial Sloan-Kettering Cancer Center, Melanoma and Immunotherapeutics Oncology Service, 300 East 66th Street, New York, NY 10065, USA.",
"authors": "Kyi|Chrisann|C|;Hellmann|Matthew D|MD|;Wolchok|Jedd D|JD|;Chapman|Paul B|PB|;Postow|Michael A|MA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/2051-1426-2-19",
"fulltext": "\n==== Front\nJ Immunother CancerJ Immunother CancerJournal for Immunotherapy of Cancer2051-1426BioMed Central 2051-1426-2-192499141310.1186/2051-1426-2-19Case ReportOpportunistic infections in patients treated with immunotherapy for cancer Kyi Chrisann 1chk9065@nyp.orgHellmann Matthew D 2hellmanm@mskcc.orgWolchok Jedd D 3wolchokj@mskcc.orgChapman Paul B 2chapmanp@mskcc.orgPostow Michael A 2postowm@mskcc.org1 New York-Presbyterian Hospital, Weill Cornell Medical College, 525 East 68th Street, New York, NY 10065, USA2 Memorial Sloan-Kettering Cancer Center, Melanoma and Immunotherapeutics Oncology Service, 300 East 66th Street, New York, NY 10065, USA3 Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA2014 18 6 2014 2 19 19 24 3 2014 14 4 2014 Copyright © 2014 Kyi et al.; licensee BioMed Central Ltd.2014Kyi et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (\nhttp://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (\nhttp://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Immunomodulatory antibodies that enhance the immune system to fight cancer are revolutionizing the treatment of patients with an expanding variety of malignancies. There is a unique spectrum of side effects associated with immunomodulatory antibodies, termed immune-related adverse events (irAEs), which include colitis and hepatitis among others. The treatment of refractory or severe irAEs can occasionally require significant immunosuppression, involving steroids or tumor necrosis factor-alpha antagonists, placing these patients at risk for infections. We present the first reported case to our knowledge of an opportunistic infection in a patient treated with an immunomodulatory antibody. As the use of immunomodulatory antibodies expands and more patients develop irAEs that require treatment with immunosuppression, recognition of the potential for opportunistic infections in this emerging patient population will be critical. Prospective trials are needed to define the optimal immunosuppressive management of irAEs and determine whether prophylactic antiviral, antibacterial, or antifungal therapies are beneficial in this unique population.\n\nImmunotherapyImmune-related adverse events (irAEs)Opportunistic infectionsMalignancyMelanomaIpilimumab\n==== Body\nBackground\nT-cell checkpoint blockade is one of the most active areas of cancer research and has demonstrated dramatic results in patients with a variety of cancers\n[1-5]. Ipilimumab, an antibody against cytotoxic T-lymphocyte-associated antigen 4, was the first immunomodulatory checkpoint inhibitor approved by the US Food and Drug Administration for patients with advanced melanoma\n[1]. Programmed cell death-1 (PD-1) receptor, another immunologic checkpoint, has also shown great promise as a therapeutic target in a variety of malignancies\n[4-6].\n\nT-cell checkpoint blockade can result in side effects called immune-related adverse events (irAEs), most commonly involving the skin (rash) and, particularly with ipilimumab, gastrointestinal tract (diarrhea, hepatitis). Refractory or severe irAEs often require treatment with prolonged immunosuppression including high-dose steroids and sometimes the addition of tumor necrosis factor-alpha blockade or other immunosuppressants\n[7]. We report a case of a patient with metastatic melanoma who was treated with ipilimumab, developed immune-mediated colitis requiring treatment with steroids and infliximab, and later developed an opportunistic infection with Aspergillus. This is the first case to be reported to our knowledge that specifically highlights the potential for developing opportunistic infections in this emerging patient population.\n\nCase presentation\nA 48-year-old Caucasian man was diagnosed with primary cutaneous melanoma in 1991 when he was noted to have a pigmented lesion on his posterior right neck. Subsequent biopsy showed Breslow depth 2 mm melanoma. No information about the presence or absence of ulceration was available. He underwent wide local excision with pathology demonstrating no residual disease. A sentinel lymph node biopsy was not pursued.\n\nThe patient remained free of disease for 20 years until the age of 68 when he developed new hypertension, prompting a renal ultrasound that showed normal kidneys. Two hepatic lesions were incidentally noted. A subsequent positron emission tomography (PET) scan demonstrated bilobar hepatic metastases and multiple pulmonary metastases concerning for metastatic disease. Core biopsy of a lesion in the right hepatic lobe confirmed metastatic melanoma. Mass-spectrometry genotyping (Sequenom) revealed no known mutations that affect the gene encoding serine-threonine protein kinase BRAF (e.g., the BRAF V600E mutation).\n\nThree weeks later, the patient began treatment with ipilimumab (3 mg/kg). After three doses of ipilimumab (approximately two months of therapy), he developed significant diarrhea. Colonoscopy with biopsy showed active colitis. He received two doses of infliximab (5 mg/kg, separated by 9 days) and high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day for one day, followed by prednisone 1 mg/kg/day tapered over one month) with ultimate resolution of his diarrhea.\n\nA computerized tomography (CT) scan three months after starting ipilimumab demonstrated response of pulmonary and hepatic metastases. However, new bilateral cavitary pulmonary consolidations were noted concerning for fungal pneumonia (Figure \n1a-b). At this time, the patient had no cough, fever, shortness of breath, or other pulmonary symptoms. Bronchoscopy was performed and bronchoalveolar lavage revealed Aspergillus fumigatus pneumonia with a lavage fluid also positive for galactomannan. Voriconazole and liposomal amphotericin B treatment for a 14-day course resulted in ultimate radiographic improvement (Figure \n1c). Although his response to ipilimumab lasted approximately six months, he later had disease progression and unfortunately passed away due to metastatic disease.\n\nFigure 1 Images and timeline of Aspergillus infection in patient treated with steroids for management of an immune-related adverse event. (a) Baseline chest CT scan prior to ipilimumab. (b) Three weeks after receiving high-dose immunosuppression for immune-related colitis, CT scans showed cavitary pulmonary consolidations (white arrow). Subsequent bronchoalveolar lavage was consistent with Aspergillus fumigatus pneumonia. (c) After a 14-day treatment with antifungals, repeat CT scan showed radiographic improvement in cavitary consolidations, but increased bilateral pleural effusions. (d) Timeline of described events (not to scale).\n\nConclusions\nAs the use of immunomodulatory antibodies that block T-cell checkpoints expands, so too may the complications associated with this treatment. The unique spectrum of immune-mediated toxicities from these agents has been well characterized and algorithms for suggested immunosuppression regimens have been developed. However, the potential for opportunistic infections to arise as a result of the immunosuppression necessary to treat an irAE has not previously been highlighted. Though we have chosen to describe this one illustrative case, we have observed additional cases at our institution, including patients with Fournier’s gangrene and cytomegalovirus viremia. Clinicians across the spectrum of internal medicine must have a high degree of suspicion for the development of these rare infections as early recognition, diagnosis, and treatment are essential to achieve favorable clinical outcomes.\n\nConsensus guidelines instruct clinicians on the prophylaxis and treatment of opportunistic infections arising in patients following hematopoietic stem cell transplantation\n[8]. As we learn more from patients treated with these novel immunomodulatory antibodies, similar guidelines may be necessary to define the optimal management strategies for irAEs while also minimizing infectious complications in this unique patient population. Ultimately, prospective trials may be needed to optimize the management of irAEs, taking into account the associated secondary infectious risks.\n\nConsent\nWritten informed consent was obtained from the patient’s next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nCTLA-4: Cytotoxic T-lymphocyte-associated antigen 4; PD-1: Programmed cell death-1; irAE: Immune-related adverse event.\n\nCompeting interests\nJDW and MP receive research support from Bristol-Myers Squibb and have served on advisory councils. CK, MDH, and PBC have no competing interests to disclose.\n\nAuthors’ contributions\nCK and MAP conceived of this study report, collected the data, wrote and revised the manuscript. MH conceived this study report concept and reviewed the manuscript. JDW and PBC reviewed the manuscript. All authors read and approved the final manuscript.\n==== Refs\nHodi FS O'Day SJ McDermott DF Weber RW Sosman JA Haanen JB Gonzalez R Robert C Schadendorf D Hassel JC Akerley W van den Eertwegh AJ Lutzky J Lorigan P Vaubel JM Linette GP Hogg D Ottensmeier CH Lebbe C Peschel C Quirt I Clark JI Wolchok JD Weber JS Tian J Yellin MJ Nichol GM Hoos A Urba WJ Improved survival with ipilimumab in patients with metastatic melanoma N Engl J Med 2010 363 711 723 10.1056/NEJMoa1003466 20525992 \nRobert C Thomas L Bondarenko I O'Day S DJ M Garbe C Lebbe C Baurain JF Testori A Grob JJ Davidson N Richards J Maio M Hauschild A Miller WH JrGascon P Lotem M Harmankaya K Ibrahim R Francis S Chen TT Humphrey R Hoos A Wolchok JD Ipilimumab plus dacarbazine for previously untreated metastatic melanoma N Engl J Med 2011 364 2517 2526 10.1056/NEJMoa1104621 21639810 \nHamid O Robert C Daud A Hodi FS Hwu WJ Kefford R Wolchok JD Hersey P Joseph RW Weber JS Dronca R Gangadhar TC Patnaik A Zarour H Joshua AM Gergich K Elassaiss-Schaap J Algazi A Mateus C Boasberg P Tumeh PC Chmielowski B Ebbinghaus SW Li XN Kang SP Ribas A Safety and Tumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma New Engl J Med 2013 369 134 144 10.1056/NEJMoa1305133 23724846 \nTopalian SL Hodi FS Brahmer JR Gettinger SN Smith DC McDermott DF Powderly JD Carvajal RD Sosman JA Atkins MB Leming PD Spigel DR Antonia SJ Horn L Drake CG Pardoll DM Chen L Sharfman WH Anders RA Taube JM McMiller TL Xu H Korman AJ Jure-Kunkel M Agrawal S McDonald D Kollia GD Gupta A Wigginton JM Sznol M Safety, activity, and immune correlates of anti-PD-1 antibody in cancer N Engl J Med 2012 366 2443 2454 10.1056/NEJMoa1200690 22658127 \nTopalian SL Sznol M McDermott DF Kluger HM Carvajal RD Sharfman WH Brahmer JR Lawrence DP Atkins MB Powderly JD Leming PD Lipson EJ Puzanov I Smith DC Taube JM Wigginton JM Kollia GD Gupta A Pardoll DM Sosman JA Hodi FS Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab J Clin Oncol 2014 32 10 1020 1030 10.1200/JCO.2013.53.0105 24590637 \nWeber JS Kudchadkar RR Yu B Gallenstein D Horak CE Inzunza HD Zhao X Martinez AJ Wang W Gibney G Kroeger J Eysmans C Sarnaik AA Chen YA Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma J Clin Oncol 2013 31 4311 4318 10.1200/JCO.2013.51.4802 24145345 \nWeber JS Kahler KC Hauschild A Management of immune-related adverse events and kinetics of response with ipilimumab J Clin Oncol 2012 30 2691 2697 10.1200/JCO.2012.41.6750 22614989 \nTomblyn M Chiller T Einsele H Gress R Sepkowitz K Storek J Wingard JR Young JA Boeckh MJ Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective Biol Blood Marrow Transplant 2009 15 10 1143 1238 10.1016/j.bbmt.2009.06.019 19747629\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2051-1426",
"issue": "2()",
"journal": "Journal for immunotherapy of cancer",
"keywords": "Immune-related adverse events (irAEs); Immunotherapy; Ipilimumab; Malignancy; Melanoma; Opportunistic infections",
"medline_ta": "J Immunother Cancer",
"mesh_terms": null,
"nlm_unique_id": "101620585",
"other_id": null,
"pages": "19",
"pmc": null,
"pmid": "24991413",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "20525992;24145345;22658127;21639810;22614989;23724846;24590637;19747629",
"title": "Opportunistic infections in patients treated with immunotherapy for cancer.",
"title_normalized": "opportunistic infections in patients treated with immunotherapy for cancer"
} | [
{
"companynumb": "US-PFIZER INC-2015150956",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "PREDNISONE"
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{
"abstract": "BACKGROUND\nThe incidence of antibody (Ab)-mediated pure red-cell aplasia (PRCA) in patients with chronic kidney disease (CKD) has increased between 1998 and 2002. After initially responding to treatment with recombinant human erythropoietic agents for CKD-associated anemia, patients became treatment-refractory and severely anemic. Although most PRCA cases have occurred in Europe, the varying epidemiologies among individual countries have not been well characterized.\n\n\nMETHODS\nWe investigated Ab-mediated PRCA in 12 Spanish patients treated with epoetin alfa alone or prior to treatment with epoetin beta (n=1) or darbepoetin alfa (n=1). Serum Abs against epoetin alfa were detected by radioimmunoprecipitation (RIP) assay or bioassay. Following diagnosis of PRCA, erythropoietic treatment was stopped and patients received immunosuppressive therapy alone (n=11) or in combination with renal transplant (n=1).\n\n\nRESULTS\nTreatments were administered for 16 months (average) before diagnosis of PRCA in bone marrow aspirates (n=8) or biopsies (n=4). At diagnosis, patients had an average of 0.68% blood reticulocytes and blood hemoglobin (Hb) level of 7.13 g/dL. Eight patients had anti-epoetin Abs detected by RIP, and 5 had neutralizing Abs measured in the bioassay. As of December 2003, 4 patients had died, 3 had no recovery, and 5 had recovered from anemia (blood Hb level, 9.9 g/dL). All 5 recovering patients received corticosteroid therapy alone, and 1 received a renal transplant as well as corticosteroids.\n\n\nCONCLUSIONS\nSudden onset of treatment-refractory anemia in CKD patients suggests a course of treatment cessation followed by diagnostic procedures for Ab-mediated PRCA, and immunosuppressive therapy. This study may serve as a model for a centralized global PRCA registry.",
"affiliations": "Renal Unit, University Hospital Reina Sofia, Cordoba - Spain.",
"authors": "Carracedo|J|J|;Madueño|J A|JA|;Ramirez|R|R|;Martin-Malo|A|A|;de Francisco|A L M|AL|;Aljama|P|P|;|||",
"chemical_list": "D000906:Antibodies; D006397:Hematinics; D007166:Immunosuppressive Agents; D011994:Recombinant Proteins; C103998:epoetin beta; D004921:Erythropoietin; D000068256:Darbepoetin alfa; D000068817:Epoetin Alfa",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1121-8428",
"issue": "18(4)",
"journal": "Journal of nephrology",
"keywords": null,
"medline_ta": "J Nephrol",
"mesh_terms": "D000906:Antibodies; D001706:Biopsy; D001853:Bone Marrow; D000068256:Darbepoetin alfa; D004359:Drug Therapy, Combination; D000068817:Epoetin Alfa; D004921:Erythropoietin; D005260:Female; D005500:Follow-Up Studies; D006397:Hematinics; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D008297:Male; D008875:Middle Aged; D015531:Radioimmunoprecipitation Assay; D011994:Recombinant Proteins; D012010:Red-Cell Aplasia, Pure; D012189:Retrospective Studies; D013030:Spain",
"nlm_unique_id": "9012268",
"other_id": null,
"pages": "382-7",
"pmc": null,
"pmid": "16245241",
"pubdate": "2005",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Antibody-mediated pure red-cell aplasia (PRCA): the Spanish experience.",
"title_normalized": "antibody mediated pure red cell aplasia prca the spanish experience"
} | [
{
"companynumb": "ES-AMGEN-ESPSP2020031953",
"fulfillexpeditecriteria": "2",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DARBEPOETIN ALFA"
},
"drugadditional": null,
... |
{
"abstract": "Ischemic stroke is the most common complication of atrial fibrillation (AF). Anticoagulation therapy reduces the risk of systemic embolization in almost all patients with AF irrespective of the type of AF (paroxysmal, persistent or permanent). But, all patients are not suitable candidates for systemic anticoagulation mainly due to the risk of bleeding. Left atrial appendage closure (LAAC) devices have been found to be very effective non-pharmacologic alternative therapy for such patients. There are various types of LAAC devices but United States Food and Drug Administration (US-FDA) have approved only Watchman device. Initially, bigger medical centers in the US had started the insertion of Watchman device but with improving procedural techniques and exciting outcomes, even the community-based hospitals have started to embrace this therapy. We have presented the first three cases of Watchman device placement performed in our hospital and discussed about the indications for placement of LAAC devices. We have also reviewed their efficacy individually.",
"affiliations": "Department of Internal Medicine, Easton Hospital , Easton, PA.;Department of Cardiology, Easton Hospital and Clinical Medicine, Drexel University College of Medicine , Easton, PA, USA.",
"authors": "Sharma|Munish|M|;Khalighi|Koroush|K|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.4081/cp.2017.898",
"fulltext": "\n==== Front\nClin PractClin PractCPClinics and Practice2039-72752039-7283PAGEPress Publications, Pavia, Italy 2824342810.4081/cp.2017.898Case ReportNon-Pharmacologic Approach to Prevent Embolization in Patients with Atrial Fibrillation in Whom Anticoagulation is Contraindicated Sharma Munish 1Khalighi Koroush 21 Department of Internal Medicine, Easton Hospital, Easton, PA2 Department of Cardiology, Easton Hospital and Clinical Medicine, Drexel University College of Medicine, Easton, PA, USA2040 Lehigh Street, apt 506, Easton, PA, USA, 18042. 610.250.4000 (office). munishs1@hotmail.com18 1 2017 11 1 2017 7 1 89819 9 2016 09 12 2016 28 12 2016 ©Copyright M. Sharma and K. Khalighi2017Licensee PAGEPress, ItalyThis work is licensed under a Creative Commons Attribution NonCommercial 4.0 License (CC BY-NC 4.0).Ischemic stroke is the most common complication of atrial fibrillation (AF). Anticoagulation therapy reduces the risk of systemic embolization in almost all patients with AF irrespective of the type of AF (paroxysmal, persistent or permanent). But, all patients are not suitable candidates for systemic anticoagulation mainly due to the risk of bleeding. Left atrial appendage closure (LAAC) devices have been found to be very effective non-pharmacologic alternative therapy for such patients. There are various types of LAAC devices but United States Food and Drug Administration (US-FDA) have approved only Watchman device. Initially, bigger medical centers in the US had started the insertion of Watchman device but with improving procedural techniques and exciting outcomes, even the community-based hospitals have started to embrace this therapy. We have presented the first three cases of Watchman device placement performed in our hospital and discussed about the indications for placement of LAAC devices. We have also reviewed their efficacy individually.\n\nKey words\nNon-valvular atrial fibrillationwarfarinWatchman deviceischemic strokenovel oral anticoagulants\n==== Body\nIntroduction\nArterial thromboembolism is the most common complication of AF. It consists of both peripheral embolization and stroke. Ischemic stroke is the most common embolic complication of AF while peripheral embolization constitute of less than 10 percent of such cases. Fifteen percent of all strokes originate from cardio embolic source and up to 30 % of all strokes in patients older than 80 years are due to AF.1 Anticoagulation therapy reduces the risk of systemic embolization in almost all patients with AF irrespective of the type of AF (paroxysmal, persistent or permanent). But, not all individuals are ideal candidates for anticoagulation due to varying degrees of associated bleeding risk. There are no clear strategies to reduce the risk of embolization in patients with AF for whom long-term anticoagulation is contraindicated. Novel non-pharmacologic strategies like radiofrequency catheter ablation have not been proven to reduce the risk of embolic stroke.2 In this context, we present three cases of percutaneous LAAC device placement done for an alternative embolization risk reduction strategy for non-valvular atrial fibrillation (NVAF) patients who were eligible for warfarin or novel oral anticoagulants (NOACS), but had reasons to seek another long-term therapeutic option. We will also review the indications for the use of the LAAC device, types of such devices and will analyze their efficacy.\n\nCase Reports\nCase #1\nA 74-year-old woman with history of recurrent symptomatic permanent NVAF due to hypertension presented with worsening shortness of breath, melena and a drop in hemoglobin requiring hospitalization. Patient had been on anticoagulation with warfarin, however due to severe symptomatic anemia manifested as shortness of breath and dizziness secondary to bleeding duodenal ulcer it was stopped. She also had risk of fall due to severe degenerative joint disease (DJD). Patient had a CHA2DS2-VASc score of 4 (age more than 65, female gender, coronary artery disease status post angioplasty and hypertension). She had HAS BLED score of 3 (age more than 65, bleeding from duodenal ulcer, hypertension). In the view of recurrent symptomatic AF and high CHA2DS2-VASc score, secondary prevention of arterial embolization was deemed necessary. After the discussion with patient and her family members a non-pharmacologic approach with implantation of LAAC device was considered. A pre-operative transesophageal echocardiogram (TEE) and Transthoracic echocardiogram (TTE) were done. Left atrial appendage (LAA) was well visualized with no evidence of thrombus (Figure 1). LAA measurements were done at the standard views. Right atrium was normal in size. Right ventricle was normal in size. Left ventricle was normal in size with well-preserved systolic function (60-65 percent). No regional wall motion abnormalities were noted in both TTE and TEE pre-operatively. There was no evidence of left ventricular thrombus. We used M mode 2D and 3D TEE.\n\nPatient underwent successful insertion of a 27 mm Watchman LAAC device under fluoroscopy and TEE guidance. Patient was discharged on aspirin 81 mg daily and warfarin for 45 days. A follow up TEE done postoperatively on 45th day showed no new changes and was consistent with the immediate postoperative TEE findings (Figure 2). Patient has shown no features of embolization on 1 year follow up so far. No flow was seen in LAA after device placement.\n\nCase #2\nAn 89-year-old woman with history of persistent NVAF due to long standing hypertensive cardiovascular disease presented with shortness of breath and weakness associated with severe anemia due to gastrointestinal (GI) bleeding secondary to arteriovenos malformation (AVM). Her hemoglobin level dropped from 11.5 to 6.0 mg/dl. Her CHA2DS2-VASc score was 5 (age more than 75, female gender, hypertension and Diabetes mellitus). Her HAS BLED score was 3 (hypertension, age more than 65 and previous bleeding episode). Due to high risk for recurrent GI bleeding, she was evaluated for a LAAC device placement. Her pre-operative TEE showed moderately dilated Left Atrium (LA) with at least 5 cm diameter. LAA was free of any intra-cavitary thrombi. There was a small remnant of patent foramen ovale with minimal degree of right-to-left shunting with Valsalva maneuvers. There was no significant pericardial effusion.\n\nThus, she underwent successful implantation of 21 mm Watchman device. Postoperative TEE showed a well-seated LAAC device (Figure 3). There was no evidence of thrombus in the LAA or on the closure device. There was a very small hemodynamically insignificant central leak in the middle of the device (0.1 centimeter in diameter with a jet of less than 0.1 centimeter in diameter)\n\nPatient was started on aspirin 81 mg daily and warfarin after the procedure and INR was maintained around 2 to 2.5. However within 45 days of the procedure, she was readmitted with severe GI bleeding, requiring immediate blood transfusion and re-endoscopy and subsequent cauterization of a new duodenal AVM. A repeat TEE did not show any new changes. Her warfarin was discontinued, and she was discharged on aspirin 81 mg daily and clopidogrel 75 mg daily. She presented again within 3 months due to another episode of GI bleed. Thus, clopidogrel was also stopped and only aspirin 81 mg daily was continued. Patient has shown no features of embolization on 6 months follow up so far.\n\nCase #3\nThis was an 87-year-old man with history of hypertensive cardiovascular disease, COPD, permanent AF and tachycardia bradycardia syndrome requiring permanent pacemaker in past. He also had history of advanced DJD, ambulatory dysfunction, chronic back pain and acute traumatic multiple rib fractures due to fall incident prior to Watchman procedure. He had a high CHA2DS2-VASc score of 5 (advanced age, history of diastolic heart failure, TIA, hypertensive cardiovascular disease), and HAS-BLED risk score of 4 (Elderly, bleeding tendency, hypertension, labile INR) and thus he was considered for LAAC device procedure for secondary stroke prevention.\n\nHis perioperative TEE showed no evidence for LAA thrombi or mass. His LA was moderately dilated measuring 5.0 cm in diameter. His right atrium and ventricle were in the upper limits of normal in size and function. His left ventricle was normal in size with a well-preserved systolic function (60-65%), with no regional wall motion abnormalities, moderate concentric left ventricular hypertrophy and no evidence of left ventricular thrombus.\n\nHe underwent a successful implantation of a 24 mm Watchman device under fluoroscopy and TEE guidance. He was discharged on low dose aspirin (81 mg daily) and warfarin to maintain an INR of about 2 for 45 days, and then a follow-up TEE showed no evidence for LA thrombus. The LAAC device was well seated with no echocardiographic evidence for device thrombus with leak or shunts on the Watchman device (Figure 4). Therefore, as per US-FDA protocol, warfarin therapy was discontinued and he is currently on dual antiplatelet therapy with aspirin 81 mg daily and clopidogrel 75 mg daily for six months post-operative period, after which only a low dose aspirin will be continued. He has remained asymptomatic for 5 months postoperatively so far.\n\nDiscussion\nAF is the most commonly encountered cardiac dysrhythmia. According to Framingham heart study, lifetime risk of developing AF from age 40 to 95 was 26 percent for men and 23 percent for women.3 North America has highest age adjusted prevalence rate of 700-775 per 100,000 population compared to relatively lower rate in countries like China, Japan and South Korea.4 In ATRIA study, around 2.3 million adults in United States had AF in 1996 and 1997. This number was expected to increase to 5.6 million by the year 2050.5,6 AF was associated with a 1.5 to 1.9-fold mortality risk after adjustment for the preexisting cardiovascular conditions with which AF was related.3 Several studies have indicated that most common cardiovascular event associated with mortality in AF is heart failure followed by stroke/systemic embolization (3 and 6). If we analyze embolic events in AF, which is by far the most common complication, data reveal that there is 4-5 fold increase in risk of stroke in patients with NVAF. CHA2DS2-VASc score of 1 represents annual risk of stroke of around 1 percent. While the score of 2 or greater represents an annual stroke risk of 2-15 percent. Thus, AF poses a significant mortality and morbidity burden and effective therapeutic and preventative strategies are imperative to minimize the effect of this health catastrophe.\n\nLeft atrial appendage as a source of emboli in atrial fibrillation\nNormally, left atrial appendage (LAA) plays a role in atrial contractility and contributes to the atrial kick contributing to up to 25% of Ejection fraction. However, fibrosis and inflammation leading to remodeling of the LAA in patients with long standing AF predisposes to thrombus formation and loss of contribution to filling of ventricle.7 LAA acts as the source of emboli in around 90 % of cases.8 Generally, patients with CHA2DS2-VASc score of 1 can be managed with aspirin or warfarin for prevention of embolization while score of 2 or more requires anticoagulation with warfarin or NOACS in NVAF. For patients who cannot be placed on anticoagulants due to unacceptable risk of bleeding or other reasons cited below ligation, amputation or occlusion of the LAA definitely provide a feasible option.\n\nIndications for left atrial appendage closure device placement\nFor patients undergoing cardiac surgery for other indications like Mitral valve or Maze surgery, surgical amputation or ligation of the LAA can be performed. The ligation or amputation may be incomplete posing the patient to continuous risk of LAA thrombus. This incidence was as high as 22 % in two series.9,10\n\nFor patients who are not undergoing cardiac surgery following may be the indications for LAAO: i) history of recurrent falls especially prior fall episodes resulting in injury; ii) recurrent GI bleeding; iii) thrombocytopenia or bleeding diathesis; iv) dual antiplatelet and anticoagulation therapy like in cases of Coronary artery disease with stent placement with concomitant AF; v) poor compliance with anticoagulation.\n\nTypes of devices\nThe only one device which is US-FDA approved is Watchman device.11 It has shown to have comparable efficacy and safety to long-term oral anticoagulation. There are other devices also which have European CE Mark approval but they lack randomized control trial to justify their benefit. Historical data suggest that catheter based LAA occlusion was performed in 200112 but this device was not used further.13\n\nWatchman device is a self-expanding nitinol device with fixation barbs and covered by permeable polyethylene terephthalate (PTFE) membrane. It comes in 5 different sizes and is placed through 14-French sheaths. There are 3 access sheaths namely double curve, single curve and anterior curve. Mostly, double curve sheath is preferred as it allows easier access.\n\nAmplatzer cardiac plug (St Jude Medical) is another device for LAA closure. Globally it is the second most commonly used LAA closure endovascular device after Watchman but it has not yet received US FDA approval. But, it received its CE Mark approval in Europe in 2008. There is a second generation of this device available named as Amplatzer Cardiac plug (Amulet) which received CE Mark approval in 2013. Basically, these devices consist of nitinol mesh and a proximal left atrial disk and a distal LAA lobe. Interestingly, both the lobe and the disk consist of Dacron mesh sewn by hand. Second generation device (Amulet) is more stable due to larger lobe and is also more useful in patients with larger left atrial appendage.\n\nTrans catheter patch (Custom medical devices, Greece) consists of a bio absorbable balloon that is originally used for the occlusion of the heart defects. Adjustment in shape and size allows it to be used as LAA closure device.\n\nLARIAT system is a percutaneous device placed non-surgically. It is not approved for LAA occlusion to prevent thromboembolism but soft tissue approximation is approved by US-FDA. It has 3 components consisting of occlusion balloon catheter, magnet tipped guide wires and suture delivery device.\n\nWavecrest device is an alternative to the Watchman if LAA is very small to accommodate other devices. Its advantage is due to the fact that a foam layer covers it on the LAA side and PTFE on the side facing left atrium. Again, it has not received US-FDA approval but did receive CE approval in 2013.\n\nManagement after device placement\nGenerally patients receive warfarin and aspirin for 45 days after Watchman device implantation. This is followed by replacing warfarin with clopidogrel and aspirin for up to 6 months after which clopidogrel is discontinued and patient is continued indefinitely on Aspirin.\n\nIn patients who cannot tolerate oral anticoagulation, aspirin and clopidogrel is used for 6 months post procedure.\n\nHowever, it is imperative to detect any evidence of leak around the LAA occlusion device or thrombus associated with device. Thus, a TEE must be ordered between one and six months of the procedure. Generally there is a trend to order TEE at 45 days after the procedure.\n\nOutcomes of left atrial appendage closure device: Watchman device\nThere are two major left atrial appendage closure (LAAC) randomized clinical trials that have been performed: PROTECT AF and PREVAIL trials. Both these trials were performed in patients with NVAF eligible for oral anticoagulation.14 PROTECT AF included 707 patients who were randomly assigned to either the device or to long-term anticoagulation in an almost 2:1 ratio. Patients with paroxysmal, persistent or permanent AF and CHADS2 score > 1 were included. 91 patients underwent device implantation. Patients were continued on warfarin and aspirin for 45 days followed by clopidogrel and aspirin for up to six months and finally aspirin alone for indefinite period. After a mean follow-up of 18 months, the primary efficacy event rate was similar in the intervention control groups (3.0 versus 4.9 events per 100 patient years, respectively; rate ratio 0.62, 95% Bayesian credible interval 0.35-1.25). After a mean follow-up of 2.3 years, the primary efficacy event rates were 3.0 and 4.3 percent, respectively. These results allowed for a finding of non-inferiority of the device with its specific antithrombotic protocol compared to warfarin.15 There was also a 60 % relative risk reduction of cardiovascular death in patients receiving Watchman device.\n\nMeta-analysis of 2 randomized clinical trials and 2 registries with Watchman device also revealed that patients had significantly fewer hemorrhagic strokes (hazard ratio 0.22, P=0.004). Patients also had a significant reduction in cardiovascular or unexplained death (hazard ratio 0.48, P=0.004). There was also significant reduction in nonprocedural bleeding with the device (hazard ratio 0.51, P=0.006).\n\nIn another study,16 where registry data of LAAC from two centers were prospectively collected from 110 patients with NVAF at risk of stroke, suitable and unsuitable for long-term anticoagulation showed significantly lower bleeding rates than PROTECT AF trials. There was mean absolute difference of stroke, 0.89 % (P=0.02) and major bleeding, 5.48 % (P<0.001). There was also significant cost effectiveness with LAAC device in a short period of time (cost saving against all therapies being 1162-7194 pounds).\n\nOutcome of other left atrial appendage closure devices\nAmplatzer cardiac plug has so far been evaluated in observational studies only. Globally this is the second most commonly used LAAC device but it has not received US-FDA approval. This device showed 59 percent risk reduction compared with the expected rate based upon the CHA2DS2-VASc score in a large pooled study from 22 European and Canadian centers. This study included 1047 patients.17 Asymptomatic migration and dislocation have been reported with this device though which is concerning.18,19\n\nLARIAT system evaluated in a retrospective series of 154 patients reported by the United States Trans catheter LAA Ligation Consortium showed 9.1 percent major bleeds while death, stroke or myocardial infarction occurred in 2.9 percent.20,21 But, complications such as laceration or perforation of the heart or complete LAA detachment from the heart have been reported.22 For Coherex WaveCrest device there currently are no peer-reviewed data published. They have encouraging results in animal studies though.\n\nCurrently, the main challenges for placement of Watchman device are cost of the device, easy availability of well-trained and experienced operators and ancillary staff and well equipped electrophysiology (EP) or interventional lab. These drawbacks are more prominient at a level of a community hospital than tertiary centers in the USA. With availability of advanced newer fluroscopic devices and 3D image guidance in a new hybrid EP, we were able to initiate the Watchman procedure at our instituition. Due to serious potential intraoperative complications such as cardiac tamponade and perforation, immediate availability of cardiothoracic surgeon in the EP lab is mandatory in our institution. Hybrid EP lab provides the option to convert it into a fully equipped operating room for surgeons in case of complications.\n\nConclusions\nIn patients with NVAF, LAA acts as the major site for thrombi formation and this forms the rationale for occlusion, ligation or amputation of the LAA. Patients who have NVAF and are not eligible for cardiac surgeries but have reasons to avoid long-term oral anticoagulation can definitely benefit from LAAC devices. According to the initial outcomes, Watchman device carries a great potential in prevention of stroke in NVAF but some of its benefits are obscured by procedure related complications. Thus, improvement in implantation techniques and devices will probably result in better procedural safety in the future and enhance the popularity and effectiveness of this device even in the community hospital settings. There is a glaring need to obtain results of well-structured comparative studies between LAAC and NOACS as they are more frequently used now (19). Currently, Watchman device is the only US-FDA approved device for the LAAC procedure but other devices like Amplatzer cardiac plug, Amulet, LARIAT system, Wavecrest device have also proven to be beneficial. Results of randomized control trials are needed in the USA to justify their benefit.\n\nFigure 1. Pre-operative left atrial appendage dimension at 45 degrees.\n\nFigure 2. Watchman device (arrow) in left atrial appendage at 54 degrees on follow up transesophageal echocardiogram.\n\nFigure 3. Watchman device, shown by the bracket, is well seated at the ostium of the left atrial appendage.\n\nFigure 4. Post-insertion of Watchman device seen at 91 degrees.\n==== Refs\nReferences\n1. Iskandar S Vacek J Lavu M Lakkireddy D. \nLeft atrial appendage closure for stroke prevention: devices, techniques, and efficacy . Cardiol Clin \n2016 ;34 :329 -51 .27150181 \n2. DeSimone CV Madhavan M Ebrille E \nAtrial fibrillation and stroke - increasing stroke risk with intervention . J Atrial Fibrillation \n2014 ;6 :87 -94 .\n3. Benjamin EJ Wolf PA D’Agostino RB \nImpact of atrial fibrillation on the risk of death: the Framingham Heart Study . Circulation \n1998 ;98 :946 .9737513 \n4. Chugh SS Havmoeller R Narayanan K \nWorldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study . Circulation \n2014 ;129 :837 .24345399 \n5. Lip GY Brechin CM Lane DA \nThe global burden of atrial fibrillation and stroke: a systematic review of the epidemiology of atrial fibrillation in regions outside North America and Europe . Chest \n2012 ;142 :1489 .22459778 \n6. Fauchier L Samson A Chaize G \nCause of death in patients with atrial fibrillation admitted to French hospitals in 2012: a nationwide database study . Open Heart \n2015 ;2 :e000290 .26688739 \n7. Kanderian AS Gillinov AM Pettersson GB \nSuccess of surgical left atrial appendage closure:assessment by transesophageal echocardiography . J Am Coll Cardiol \n2008 ;52 :924 .18772063 \n8. García-Fernández MA Pérez-David E Quiles J \nRole of left atrial appendage obliteration in stroke reduction in patients with mitral valve prosthesis: a transesophageal echocardiographic study . J Am Coll Cardiol \n2003 ;42 :1253 .14522491 \n9. Katz ES Tsiamtsiouris T Applebaum RM \nSurgical left atrial appendage ligation is frequently incomplete: a transesophagealechocardiograhic study . J Am Coll Cardiol \n2000 ;36 :468 .10933359 \n10. Holmes DR JrReddy VY \nLeft atrial appendage and closure: who, when, and how . Circ Cardiovasc Interv \n2016 ;9 :e002942 27139910 \n11. Sievert H Lesh MD Trepels T \nPercutaneous left atrial appendage transcatheter occlusion to prevent stroke in high-risk patients with atrial fibrillation: early clinical experience . Circulation \n2002 ;105 :1887 .11997272 \n12. Block PC Burstein S Casale PN \nPercutaneous left atrial appendage occlusion for patients in atrial fibrillation suboptimal for warfarin therapy: 5-year results of the PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) Study . JACC Cardiovasc Interv \n2009 ;2 :594 .19628179 \n13. Holmes DR Reddy VY Turi ZG \nPercutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial . Lancet \n2009 ;374 :534 .19683639 \n14. Reddy VY Doshi SK Sievert H \nPercutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-Year Follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) Trial . Circulation \n2013 ;127 :720 .23325525 \n15. Panikker S Lord J Jarman JW \nOutcomes and costs of left atrial appendage closure from randomized controlled trial and real-world experience relative to oral anticoagulation . Eur Heart J \n2016 [Epub ahead of print].\n16. Bartus K Han FT Bednarek J \nPercutaneous left atrial appendage suture ligation using the LARIAT device in patients with atrial fibrillation: initial clinical experience . J Am Coll Cardiol \n2013 ;62 :108 .23062528 \n17. Mester P Dompnier A Belle L. \nAsymptomatic migration of an AMPLATZER™ Amulet™ left atrial appendage occluder through the mitral valve . Catheter Cardiovasc Interv \n2016 [Epub ahead of print].\n18. Dendramis G Paleologo C Piraino D Augugliaro S. \nVery late dislocation of an AMPLATZER septal occluder device suspected thanks to a recent onset of right-axis deviation . JACC \n2016 ;9 :859 -60 .27101912 \n19. Afzal Sohaib SM Fox KF \nA meta-analysis of left atrial appendage closure for stroke prevention in atrial fibrillation-adding to the debate but elements remain unresolved . J Thorac Dis \n2015 ;7 :8 .\n20. Price MJ Gibson DN Yakubov SJ \nEarly safety and efficacy of percutaneous left atrial appendage suture ligation: results from the U.S. transcatheter LAA ligation consortium . J Am Coll Cardiol \n2014 ;64 :565 .25104525 \n21. Tzikas A Gafoor S Meerkin D \nLeft atrial appendage occlusion with the AMPLATZER Amulet device: an expert consensus step-by-step approach . Euro Intervent \n2016 ;11 :1512 -21 .\n22. Srivastava MC See VY Dawood MY Price MJ \nA review of the LARIAT device: insights from the cumulative clinical experience . Springerplus \n2015 ;4 :522 .26405642\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2039-7275",
"issue": "7(1)",
"journal": "Clinics and practice",
"keywords": "Non-valvular atrial fibrillation; Watchman device; ischemic stroke; novel oral anticoagulants; warfarin",
"medline_ta": "Clin Pract",
"mesh_terms": null,
"nlm_unique_id": "101563282",
"other_id": null,
"pages": "898",
"pmc": null,
"pmid": "28243428",
"pubdate": "2017-01-11",
"publication_types": "D002363:Case Reports",
"references": "27101912;26405642;27143657;27150181;27063823;19628179;10933359;27107315;18772063;26935273;25104525;19683639;11997272;14522491;9737513;23325525;23062528;22459778;27139910;24345399;26688739;26380784",
"title": "Non-Pharmacologic Approach to Prevent Embolization in Patients with Atrial Fibrillation in Whom Anticoagulation is Contraindicated.",
"title_normalized": "non pharmacologic approach to prevent embolization in patients with atrial fibrillation in whom anticoagulation is contraindicated"
} | [
{
"companynumb": "US-IPCA LABORATORIES LIMITED-IPC201702-000065",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditio... |
{
"abstract": "Carbapenem resistance, most notably in Klebsiella pneumonia (KPC), results in infections associated with significant morbidity and mortality. Here we report 2 cases of adolescent patients with KPC infection after high-risk bone marrow transplantation, who eventually succumbed from other causes and review the epidemiology and treatment options for KPC infections in this vulnerable population.",
"affiliations": "Stem Cell Transplant Unit, \"Agia Sofia Children's Hospital\" Infectious Diseases Unit, Department of Pathophysiology, Laikon General Hospital and Medical School, National and Kapodistrian University of Athens, Athens, Greece.",
"authors": "Komitopoulou|Anna|A|;Paisiou|Anna|A|;Oikonomopoulou|Christina|C|;Kaisari|Katerina|K|;Ioannidou|Eleni D|ED|;Tzannou|Ifigeneia|I|;Sipsas|Nikolaos V|NV|;Vessalas|George|G|;Peristeri|Ioulia|I|;Goussetis|Evgenios|E|;Kitra|Vasiliki|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000002142",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": null,
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "9505928",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33710116",
"pubdate": "2021-03-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Is Carbapenem-resistant Klebsiella pneumoniae Infection in Pediatric Bone Marrow Transplantation Recipients Inevitably Fatal?",
"title_normalized": "is carbapenem resistant klebsiella pneumoniae infection in pediatric bone marrow transplantation recipients inevitably fatal"
} | [
{
"companynumb": "GR-TEVA-2022-GR-2029985",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to determine whether proton pump inhibitors other than lansoprazole might be associated with microscopic colitis.\n\n\nBACKGROUND\nLansoprazole exposure has been associated with diarrhea and microscopic colitis, but this relationship has not been described with other proton pump inhibitors.\n\n\nMETHODS\nCases of microscopic colitis from a consultative gastroenterology practice were collected and reviewed for proton pump inhibitor exposure. Standard clinical, endoscopic, and biopsy findings were analyzed.\n\n\nRESULTS\nA case series of 4 patients is described in which subjects developed classic symptoms of lymphocytic-collagenous colitis with typical mucosal histopathology during treatment with omeprazole/esomeprazole. Symptoms promptly stopped and mucosal biopsies returned to normal with drug withdrawal. Disease quickly recurred in 2 patients who were reexposed to the drugs, one with biopsy documented recurrent collagenous colitis.\n\n\nCONCLUSIONS\nSome cases of microscopic colitis seem to be associated with omeprazole/esomaprazole exposure. These results have epidemiologic, diagnostic, and therapeutic ramifications, which are discussed.",
"affiliations": "Department of Gastroenterology, Maine Medical Center, Portland, ME, USA. gwilcox1@maine.rr.com",
"authors": "Wilcox|Gilbert M|GM|;Mattia|Anthony R|AR|",
"chemical_list": "D000897:Anti-Ulcer Agents; D009853:Omeprazole; D064098:Esomeprazole",
"country": "United States",
"delete": false,
"doi": "10.1097/MCG.0b013e31817d3fa1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0192-0790",
"issue": "43(6)",
"journal": "Journal of clinical gastroenterology",
"keywords": null,
"medline_ta": "J Clin Gastroenterol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000897:Anti-Ulcer Agents; D046728:Colitis, Microscopic; D004305:Dose-Response Relationship, Drug; D064098:Esomeprazole; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009853:Omeprazole",
"nlm_unique_id": "7910017",
"other_id": null,
"pages": "551-3",
"pmc": null,
"pmid": "19142168",
"pubdate": "2009-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Microscopic colitis associated with omeprazole and esomeprazole exposure.",
"title_normalized": "microscopic colitis associated with omeprazole and esomeprazole exposure"
} | [
{
"companynumb": "US-ASTRAZENECA-2009AC01411",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ESOMEPRAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "Mucormycosis is a relatively rare but extremely aggressive fungal infection that commonly affects patients who are compromised hosts. These infections typically come in various patterns: pulmonary, sinus, rhinocerebral, cerebral, cutaneous, or disseminated forms. Treatment usually consists of a combination of antifungal agents and surgical debridement, although morbidity and mortality are high. In this case report, we describe the course of a patient with a disseminated Mucor infection, primarily involving the upper extremities, who was successfully treated with topical and systemic antifungal agents without the need for surgical intervention.",
"affiliations": "Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY. Electronic address: mk3294@cumc.columbia.edu.;Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY.;Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY.",
"authors": "Konigsberg|Matthew W|MW|;Wu|Chia H|CH|;Strauch|Robert J|RJ|",
"chemical_list": "D000935:Antifungal Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jhsa.2020.01.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0363-5023",
"issue": "45(12)",
"journal": "The Journal of hand surgery",
"keywords": "Infection; mucormycosis; upper extremity",
"medline_ta": "J Hand Surg Am",
"mesh_terms": "D000935:Antifungal Agents; D003646:Debridement; D006801:Humans; D009091:Mucormycosis; D034941:Upper Extremity",
"nlm_unique_id": "7609631",
"other_id": null,
"pages": "1189.e1-1189.e5",
"pmc": null,
"pmid": "32216989",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Topical Treatment for Cutaneous Mucormycosis of the Upper Extremity.",
"title_normalized": "topical treatment for cutaneous mucormycosis of the upper extremity"
} | [
{
"companynumb": "US-009507513-2103USA008192",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ISAVUCONAZONIUM"
},
"drugadditional": null,... |
{
"abstract": "SCN3A was recently recognized as a gene associated with neurodevelopmental disorder and epilepsy. We present two additional patients with a novel de novo SCN3A pathogenic variant, and a review of all published cases of de novo variants. In one of our patients brain magnetic resonance imaging (MRI) disclosed a severe polymicrogyria and in the other it was normal. The clinical phenotype was characterized by a severe developmental delay and refractory epilepsy in the patient with polymicrogyria and intellectual disability with autistic features and pharmacoresponsive epilepsy in the subject with normal MRI. Polymicrogyria, a disorder of progenitor cells proliferation and migration, is an unanticipated finding for an ion channel dysfunction.",
"affiliations": "Epilepsy Clinic, Hospital Sírio-Libanês, São Paulo, Brazil; Department of Neurology, University of São Paulo School of Medicine, Brazil. Electronic address: luciana.minakaharada@hsl.org.br.;Department of Neurology, University of São Paulo School of Medicine, Brazil. Electronic address: ines.genetica@gmail.com.;Department of Neurology, University of São Paulo School of Medicine, Brazil. Electronic address: bruno.dellaripa@inisp.com.br.;Department of Neurology, University of São Paulo School of Medicine, Brazil. Electronic address: kate_souza@yahoo.com.br.;Mendelics Genomic Analysis, São Paulo, Brazil. Electronic address: fabiola.monteiro@mendelics.com.br.;Mendelics Genomic Analysis, São Paulo, Brazil. Electronic address: joao.kitajima@mendelics.com.br.;Radiology Department, Hospital Sírio-Libanês, São Paulo, Brazil. Electronic address: fil.godoy@gmail.com.;Radiology Department, Hospital Sírio-Libanês, São Paulo, Brazil. Electronic address: ds.delgado64@gmail.com.;Mendelics Genomic Analysis, São Paulo, Brazil; Department of Neurology, University of São Paulo School of Medicine, Brazil. Electronic address: fernando.kok@mendelics.com.br.;Epilepsy Clinic, Hospital Sírio-Libanês, São Paulo, Brazil; Department of Neurology, University of São Paulo School of Medicine, Brazil. Electronic address: eliana.garzon@inisp.com.br.",
"authors": "Inuzuka|Luciana Midori|LM|;Macedo-Souza|Lúcia Inês|LI|;Della-Ripa|Bruno|B|;Cabral|Katiane S S|KSS|;Monteiro|Fabiola|F|;Kitajima|João Paulo|JP|;de Souza Godoy|Luis Filipe|LF|;de Souza Delgado|Daniel|D|;Kok|Fernando|F|;Garzon|Eliana|E|",
"chemical_list": "D062552:NAV1.3 Voltage-Gated Sodium Channel; C424715:SCN3A protein, human; D015222:Sodium Channels",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.braindev.2019.09.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0387-7604",
"issue": "42(2)",
"journal": "Brain & development",
"keywords": "Epilepsy; Epileptic encephalopathy; Polymicrogyria; SCN3A",
"medline_ta": "Brain Dev",
"mesh_terms": "D002675:Child, Preschool; D004827:Epilepsy; D005260:Female; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D062552:NAV1.3 Voltage-Gated Sodium Channel; D065886:Neurodevelopmental Disorders; D010641:Phenotype; D065706:Polymicrogyria; D015222:Sodium Channels",
"nlm_unique_id": "7909235",
"other_id": null,
"pages": "211-216",
"pmc": null,
"pmid": "31677917",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Neurodevelopmental disorder associated with de novo SCN3A pathogenic variants: two new cases and review of the literature.",
"title_normalized": "neurodevelopmental disorder associated with de novo scn3a pathogenic variants two new cases and review of the literature"
} | [
{
"companynumb": "BR-MICRO LABS LIMITED-ML2020-01149",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": ... |
{
"abstract": "Sciatic nerve injury after inadvertent intramuscular gluteal injection is a well-described entity. We have presented a case of a rare and probably underdiagnosed pathological entity, Nicolau syndrome, which can be confused with injection palsy.\n\n\n\nWe report the case of a 13-year-old boy who had presented with foot drop and urinary and fecal incontinence after an intramuscular injection of benzathine penicillin in the left gluteal region. On examination, the patient had multiple ecchymoses over the left gluteal region and back of the thigh, mild swelling of the left lower limb, and left foot drop. Meticulous examination also revealed a subtle weakness of the opposite limb. Nerve conduction studies revealed axonopathy involving multiple bilateral lower limb nerves. These unusual neurological-dermatological signs and electrophysiological findings raised the concern for an alternative pathology, which was later diagnosed as Nicolau syndrome. The patient experienced clinical and electrophysiological recovery after a course of oral steroids and physiotherapy during the next few months.\n\n\n\nBefore diagnosing injection sciatic nerve injury, the possibility of medically treatable Nicolau syndrome should be considered. Neurosurgeons' familiarity with this pathology and a timely diagnosis is essential to plan appropriate treatment strategies.",
"affiliations": "Department of Neurosurgery, Rutgers Robert Wood Johnson Medical School and University Hospital, New Brunswick, New Jersey, USA; Department of Neurosurgery, Kempegowda Institute of Medical Sciences and Research Institute, Bengaluru, India. Electronic address: br439@rwjms.rutgers.edu.;Department of Neurosurgery, Rutgers Robert Wood Johnson Medical School and University Hospital, New Brunswick, New Jersey, USA.;Department of Neurosurgery, Rutgers Robert Wood Johnson Medical School and University Hospital, New Brunswick, New Jersey, USA.;Department of Neurosurgery, Kempegowda Institute of Medical Sciences and Research Institute, Bengaluru, India.;Department of Neurosurgery, Rutgers Robert Wood Johnson Medical School and University Hospital, New Brunswick, New Jersey, USA.;Department of Neurosurgery, Rutgers Robert Wood Johnson Medical School and University Hospital, New Brunswick, New Jersey, USA.;Department of Neurosurgery, Rutgers Robert Wood Johnson Medical School and University Hospital, New Brunswick, New Jersey, USA.",
"authors": "Raju|Bharath|B|;Ashraf|Omar|O|;Jumah|Fareed|F|;Appaji Gowda|Naveen Mandya|NM|;Gupta|Gaurav|G|;Sun|Hai|H|;Nanda|Anil|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005938:Glucocorticoids; D010401:Penicillin G Benzathine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2020.07.029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "143()",
"journal": "World neurosurgery",
"keywords": "Ecchymosis; Injection palsy; Lower limb weakness; Nicolau syndrome; Sciatic nerve injury",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D002081:Buttocks; D003937:Diagnosis, Differential; D004568:Electrodiagnosis; D005242:Fecal Incontinence; D005938:Glucocorticoids; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D009431:Neural Conduction; D065148:Nicolau Syndrome; D010401:Penicillin G Benzathine; D059348:Peripheral Nerve Injuries; D020427:Peroneal Neuropathies; D026741:Physical Therapy Modalities; D012584:Sciatic Nerve; D014549:Urinary Incontinence",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "51-55",
"pmc": null,
"pmid": "32679363",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review; D059040:Video-Audio Media",
"references": null,
"title": "Nicolau Syndrome, Masquerader of Postinjection Sciatic Nerve Injury: Case Report and Review of Literature.",
"title_normalized": "nicolau syndrome masquerader of postinjection sciatic nerve injury case report and review of literature"
} | [
{
"companynumb": "US-PFIZER INC-2021500778",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PENICILLIN G BENZATHINE"
},
"drugadditional": ... |
{
"abstract": "CLL is an aging-associated neoplasm with median age at diagnosis > 65 years. Little is known about safety and efficacy of FC/FCR regimens in elderly CLL patients with multiple comorbidities. We retrospectively revised medical records of 90 patients treated with FC/FCR regimens in our clinic. Data on demographic and biological characteristics, comorbidities, response to therapy, and treatment-associated adverse events were analyzed. Compared to FC, FCR yielded higher rates of OR (93.6 vs. 81.4%, p = .109) and CR (72.3 vs. 46.5%, p = .018). This translated in longer EFS (median 52 vs. 19 months, p = <.001) and OS (median 89 vs. 45 months, p = .001). Elderly patients (≥ 65 years) had more comorbidities and higher median CIRS-G score (7 vs. 4, p < .001). However, no association was found between CIRS-G score and survival. Decreased renal function was associated with dismal prognosis in patients treated with FCR.",
"affiliations": "Institute of Hematology, Almazov National Medical Research Centre, Akkuratova Street 2, Saint Petersburg, 197341, Russia. strugov@almazovcentre.ru.;Institute of Hematology, Almazov National Medical Research Centre, Akkuratova Street 2, Saint Petersburg, 197341, Russia.;Institute of Hematology, Almazov National Medical Research Centre, Akkuratova Street 2, Saint Petersburg, 197341, Russia.;Institute of Hematology, Almazov National Medical Research Centre, Akkuratova Street 2, Saint Petersburg, 197341, Russia.;Institute of Hematology, Almazov National Medical Research Centre, Akkuratova Street 2, Saint Petersburg, 197341, Russia.",
"authors": "Strugov|Vladimir|V|http://orcid.org/0000-0003-1059-3762;Stadnik|Elena|E|;Virts|Yulia|Y|;Andreeva|Tatyana|T|;Zaritskey|Andrey|A|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-018-3409-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "97(11)",
"journal": "Annals of hematology",
"keywords": "CIRS-G; CLL; Chronic lymphocytic leukemia; Comorbidities; FCR",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D015897:Comorbidity; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "2153-2161",
"pmc": null,
"pmid": "29946909",
"pubdate": "2018-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Impact of age and comorbidities on the efficacy of FC and FCR regimens in chronic lymphocytic leukemia.",
"title_normalized": "impact of age and comorbidities on the efficacy of fc and fcr regimens in chronic lymphocytic leukemia"
} | [
{
"companynumb": "PHHY2018RU146155",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": null,
... |
{
"abstract": "Intermittent treatment could improve the convenience, tolerability and cost of ART, as well as patients' quality of life. We conducted a 48 week multicentre study of a 4-days-a-week antiretroviral regimen in adults with controlled HIV-1-RNA plasma viral load (VL).\n\n\n\nEligible patients were adults with VL < 50 copies/mL for at least 1 year on triple therapy with a ritonavir-boosted PI (PI/r) or an NNRTI. The study protocol consisted of the same regimen taken on four consecutive days per week followed by a 3 day drug interruption. The primary outcome was the proportion of participants remaining in the strategy with VL < 50 copies/mL up to week 48. The study was designed to show an observed success rate of > 90%, with a power of 87% and a 5% type 1 error. The study was registered with ClinicalTrials.gov (NCT02157311) and EudraCT (2014-000146-29).\n\n\n\nOne hundred patients (82 men), median age 47 years (IQR 40-53), were included. They had been receiving ART for a median of 5.1 (IQR 2.9-9.3) years and had a median CD4 cell count of 665 (IQR 543-829) cells/mm3. The ongoing regimen included PI/r in 29 cases and NNRTI in 71 cases. At 48 weeks, 96% of participants (95% CI 90%-98%) had no failure while remaining on the 4-days-a-week regimen. Virological failure occurred in three participants, who all resumed daily treatment and became resuppressed. One participant stopped the strategy. No severe treatment-related events occurred.\n\n\n\nAntiretroviral maintenance therapy 4 days a week was effective for 48 weeks in 96% of patients, leading to potential reduction of long-term toxicities, high adherence to the antiretroviral regimen and drug cost saving.",
"affiliations": "Hôpitaux Universitaires Paris-Ile de France-Ouest, Hôpital Raymond Poincaré APHP, Garches, Université Versailles-Saint-Quentin, France.;Sorbonne Universités, INSERM, UPMC Université Paris 06, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France.;Institut de Médecine et Epidémiologie Appliquée, Hôpital Bichat, Université Paris 7, Paris, France.;Hôpitaux Universitaires Paris-Ile de France-Ouest, Hôpital Raymond Poincaré APHP, Garches, Université Versailles-Saint-Quentin, France.;Hôpitaux Universitaires Paris-Ile de France-Ouest, Hôpital Raymond Poincaré APHP, Garches, Université Versailles-Saint-Quentin, France.;Sorbonne Universités, INSERM, UPMC Université Paris 06, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France.;Institut de Médecine et Epidémiologie Appliquée, Hôpital Bichat, Université Paris 7, Paris, France.;Sorbonne Universités, INSERM, UPMC Université Paris 06, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France.;Centre Hospitalier Universitaire Bretonneau, Tours, France.;APHP, Centre Hospitalier Universitaire Avicenne, APHP, Bobigny 93, France.;Université Paris Sorbonne-Diderot, EA 7334, APHP Hotel-Dieu, URC-ECO, Paris, France.;APHP Hôpital R Poincaré, Département de Pharmacologie, Inserm U-1173, Université Paris-Ile de France Ouest, Garches 92, France.;APHP Hôpital R Poincaré, Département de Pharmacologie, Inserm U-1173, Université Paris-Ile de France Ouest, Garches 92, France.;INSERM U1043/CNRS5282, Université de Toulouse, CHU Purpan, Toulouse, France.;INSERM-ANRS, Agence Nationale pour la Recherche sur le Sida et les Hépatites, Paris, France.;Hôpitaux Universitaires Paris-Ile de France-Ouest, Hôpital Raymond Poincaré APHP, Garches, Université Versailles-Saint-Quentin, France.;Hôpitaux Universitaires Paris-Ile de France-Ouest, Hôpital Raymond Poincaré APHP, Garches, Université Versailles-Saint-Quentin, France.;Sorbonne Universités, INSERM, UPMC Université Paris 06, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France.;Sorbonne Universités, INSERM, UPMC Université Paris 06, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France.;Hôpitaux Universitaires Paris-Ile de France-Ouest, Hôpital Raymond Poincaré APHP, Garches, Université Versailles-Saint-Quentin, France.",
"authors": "de Truchis|Pierre|P|;Assoumou|Lambert|L|;Landman|Roland|R|;Mathez|Dominique|D|;Le Dû|Damien|D|;Bellet|Jonathan|J|;Amat|Karine|K|;Katlama|Christine|C|;Gras|Guillaume|G|;Bouchaud|Olivier|O|;Duracinsky|Martin|M|;Abe|Emuri|E|;Alvarez|Jean-Claude|JC|;Izopet|Jacques|J|;Saillard|Juliette|J|;Melchior|Jean-Claude|JC|;Leibowitch|Jacques|J|;Costagliola|Dominique|D|;Girard|Pierre-Marie|PM|;Perronne|Christian|C|;|||",
"chemical_list": "D044966:Anti-Retroviral Agents; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkx434",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "73(3)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D018791:CD4 Lymphocyte Count; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "738-747",
"pmc": null,
"pmid": "29186458",
"pubdate": "2018-03-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Four-days-a-week antiretroviral maintenance therapy in virologically controlled HIV-1-infected adults: the ANRS 162-4D trial.",
"title_normalized": "four days a week antiretroviral maintenance therapy in virologically controlled hiv 1 infected adults the anrs 162 4d trial"
} | [
{
"companynumb": "FR-GLAXOSMITHKLINE-FR2018046307",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LOPINAVIR\\RITONAVIR"
},
"drugadditiona... |
{
"abstract": "A smouldering adult T-cell leukaemia/lymphoma (ATLL) patient was admitted because of multiple erosions in the colon, which were infiltrated by a mixed population of lymphocytes. PET/CT demonstrated diffuse 18F-Fluorodeoxyglucose accumulation in the whole colon accompanied by multiple lymph node swelling. Histological examinations of lymph node suggested aggressive transformation to lymphoma type of ATLL. However, the general condition worsened with extremely elevated LDH, cytomegalovirus pp65 and sIL-2R after the administration of prednisolone. By contrast, subsequent administration of ganciclovir with tapered prednisolone ameliorated the laboratory findings. Differential diagnosis for aggressive ATLL and serious cytomegalovirus infection is needed.",
"affiliations": "Department of Hematology and Rheumatology, Saiseikai-Noe Hospital, Osaka, Japan.;Cancer Center, Hyogo College of Medicine, Hyogo, Japan.;Department of Pathology, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan.",
"authors": "Tabata|Rie|R|;Tabata|Chiharu|C|;Yasumizu|Ryoji|R|",
"chemical_list": "D015375:Receptors, Interleukin-2; D019788:Fluorodeoxyglucose F18",
"country": "England",
"delete": false,
"doi": "10.3851/IMP3050",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1359-6535",
"issue": "21(7)",
"journal": "Antiviral therapy",
"keywords": null,
"medline_ta": "Antivir Ther",
"mesh_terms": "D000368:Aged; D003092:Colitis; D003586:Cytomegalovirus Infections; D003937:Diagnosis, Differential; D019788:Fluorodeoxyglucose F18; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell; D008198:Lymph Nodes; D000072078:Positron Emission Tomography Computed Tomography; D015375:Receptors, Interleukin-2",
"nlm_unique_id": "9815705",
"other_id": null,
"pages": "641-645",
"pmc": null,
"pmid": "27058178",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Severe cytomegalovirus colitis with highly elevated sIL-2R mimicking aggressive transformation of adult T-cell lymphoma.",
"title_normalized": "severe cytomegalovirus colitis with highly elevated sil 2r mimicking aggressive transformation of adult t cell lymphoma"
} | [
{
"companynumb": "JP-ENDO PHARMACEUTICALS INC-2017-000417",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditiona... |
{
"abstract": "We report on two prepubescent girls with visual loss due to idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, both treated with recombinant human growth hormone for growth failure. The interval from starting hormone therapy to diagnosis of IIH was 3 and 18 months, respectively. Both girls did not complain of headache and nausea. They were neither obese nor did they suffer from renal insufficiency. In both patients, we observed bilateral optic disc edema with visual loss and elevated cerebrospinal fluid (CSF) pressures. Other causes of IIH were excluded with neuroimaging and CSF examination. Cessation of drug administration is often sufficient for symptom resolution in cases of hormone therapy-associated IIH. However, visual field defects in one girl remained unchanged during follow-up of 8 months. In children with IIH, the spectrum of neurologic and visual manifestations might be variable and unspecific. Diagnosis and management of IIH can be difficult in the absence of headache. Blurred or double vision due to cranial nerve palsy might be the only symptom rather than complaints about reduced visual acuity. Therefore, regular clinical monitoring of visual function and fundus appearance is essential for early diagnosis, efficient management, and improvement of visual outcome in children receiving recombinant human growth hormone.",
"affiliations": "Department of Ophthalmology, Centre for Ophthalmology, University Eye Hospital, Tuebingen, Germany. dorothea.besch@med.uni-tuebingen.de",
"authors": "Besch|Dorothea|D|;Makowski|Christine|C|;Steinborn|Marc-Matthias|MM|;Bonfig|Walter|W|;Sadowski|Bettina|B|",
"chemical_list": "D013006:Growth Hormone",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0032-1330855",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0174-304X",
"issue": "44(4)",
"journal": "Neuropediatrics",
"keywords": null,
"medline_ta": "Neuropediatrics",
"mesh_terms": "D001766:Blindness; D002648:Child; D005260:Female; D013006:Growth Hormone; D006801:Humans; D008279:Magnetic Resonance Imaging; D009898:Optic Disk; D009900:Optic Nerve; D010468:Perceptual Disorders; D011559:Pseudotumor Cerebri; D058609:Visual Field Tests",
"nlm_unique_id": "8101187",
"other_id": null,
"pages": "203-7",
"pmc": null,
"pmid": "23275258",
"pubdate": "2013-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Visual loss without headache in children with pseudotumor cerebri and growth hormone treatment.",
"title_normalized": "visual loss without headache in children with pseudotumor cerebri and growth hormone treatment"
} | [
{
"companynumb": "DE-EMD SERONO-E2B_90031646",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SOMATROPIN"
},
"drugadditional": "3",
... |
{
"abstract": "Renal cell carcinoma (RCC) metastasis to the bladder is rare. We report two cases that occurred metachronously during pazopanib treatment for other metastases. To our knowledge, this is the first report to demonstrate bladder metastasis from RCC during molecular targeted therapy with pazopanib. (Case 1) A woman in her 60s was referred to our department for evaluation of an incidental right renal tumor. Dynamic CT showed a 6 cm renal cell carcinoma. In February 201X she underwent laparoscopic right radical nephrectomy, revealing clear cell carcinoma (grade 1>2), stage pT3aN0M0. In February 201X+1 she complained of left pelvic pain. She was found to have metastasis to two iliac bones and an occipital bone. She received pazopanib, in addition to a bone modifying agent and radiotherapy for the iliac bones. After 8 months, she complained of asymptomatic gross hematuria in spite of having stable disease for bone metastasis. Cystoscopy showed a 1 cm solitary sessile nonpapillary tumor on the posterior wall. She underwent transurethral resection of bladder tumor (TUR-BT). Histological examination showed metastatic RCC. Thereafter she received sequential therapies (axitinib, sunitinib, nivolumab). She remains alive without recurrence in the bladder 51 months after TUR-BT. (Case 2) A woman in her 60s presented to our department with a complaint of painless gross hematuria. A dynamic CT showed an 8.5 cm renal cell carcinoma and multiple lung metastases. In March 201Y she underwent right radical nephrectomy, revealing clear cell carcinoma (grade 2>3), stage pT2aN0M1. In June 201Y she started pazopanib. After 9 months CT showed a bladder tumor in addition to progression of lung metastases. Cystoscopy showed a 1 cm solitary sessile nonpapillary tumor at dome. She underwent TUR-BT. Histological examination showed metastatic RCC. She had no recurrence in the bladder during follow-up although she died of RCC.",
"affiliations": "The Department of Urology, Hakodate Goryokaku Hospital.;The Department of Urology, Hakodate Goryokaku Hospital.;The Department of Urology, Hakodate Goryokaku Hospital.;The Department of Urology, Hakodate Goryokaku Hospital.;The Department of Urology, Hakodate Goryokaku Hospital.",
"authors": "Maruo|Kazutaka|K|;Takahashi|Atsushi|A|;Tabata|Hidetoshi|H|;Takayanagi|Akio|A|;Takagi|Yoshio|Y|",
"chemical_list": "D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib",
"country": "Japan",
"delete": false,
"doi": "10.5980/jpnjurol.111.58",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-5287",
"issue": "111(2)",
"journal": "Nihon Hinyokika Gakkai zasshi. The japanese journal of urology",
"keywords": "Implantation; Metastatic renal cell carcinoma to bladder; Pazopanib",
"medline_ta": "Nihon Hinyokika Gakkai Zasshi",
"mesh_terms": "D000368:Aged; D002292:Carcinoma, Renal Cell; D003131:Combined Modality Therapy; D015653:Cystectomy; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007191:Indazoles; D007680:Kidney Neoplasms; D008175:Lung Neoplasms; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D009392:Nephrectomy; D011743:Pyrimidines; D013449:Sulfonamides; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "2984841R",
"other_id": null,
"pages": "58-61",
"pmc": null,
"pmid": "33883361",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "RENAL CELL CARCINOMA METASTASIS TO BLADDER DURING MOLECULAR TARGETED THERAPY WITH PAZOPANIB: REPORT OF TWO CASES.",
"title_normalized": "renal cell carcinoma metastasis to bladder during molecular targeted therapy with pazopanib report of two cases"
} | [
{
"companynumb": "JP-AMGEN-JPNSP2020083835",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Since the development of combination antiretroviral therapy (cART), the incidence and mortality associated with Kaposi sarcoma (KS) have been reduced, although not eliminated. Clinical presentations of KS range from simple skin involvement to disseminated disease, including involvement of the oral cavity and viscera, which portends a more ominous prognosis. Multiple case reports and data from clinical trials indicate that administration of systemic corticosteroids may aggravate KS. We present a case of disseminated KS following administration of prednisone for presumed immune reconstitution inflammatory syndrome (IRIS) associated with fungal pneumonia in an HIV-infected individual. The discussion that follows outlines the pathophysiology and clinical presentations associated with KS and existing data for the role of corticosteroids in promoting KS progression.",
"affiliations": "Chief Resident of the Louisiana State University Health Sciences Center Internal Medicine Residency Program.;Assistant Professor of Medicine at Louisiana State University Health Sciences Center in New Orleans in the section of Infectious Diseases.;Associate Professor of Medicine and Microbiology and Director of the HIV Cancer Care Program at Louisiana State University Health Sciences Center in New Orleans.;former Chief Resident of Louisiana State University Health Sciences Center in New Orleans Internal Medicine Residency Program.;Resident in the Tulane University Pathology and Laboratory Medicine Program.;Richard Vial Professor and Vice Chair for Education in the Department of Medicine at LSUHSC-New Orleans.",
"authors": "Englert|Daniel|D|;Seal|Paula|P|;Parsons|Chris|C|;Arbour|Adrienne|A|;Roberts|Evans|E|;Lopez|Fred A|FA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0024-6921",
"issue": "166(5)",
"journal": "The Journal of the Louisiana State Medical Society : official organ of the Louisiana State Medical Society",
"keywords": null,
"medline_ta": "J La State Med Soc",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D000328:Adult; D006801:Humans; D008172:Lung Diseases, Fungal; D008297:Male; D009062:Mouth Neoplasms; D011014:Pneumonia; D012514:Sarcoma, Kaposi",
"nlm_unique_id": "7505618",
"other_id": null,
"pages": "224-30",
"pmc": null,
"pmid": "25369228",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Clinical case of the month: a 22-year-old man with AIDS presenting with shortness of breath and an oral lesion.",
"title_normalized": "clinical case of the month a 22 year old man with aids presenting with shortness of breath and an oral lesion"
} | [
{
"companynumb": "US-JUBILANT CADISTA PHARMACEUTICALS-2017JUB00222",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugad... |
{
"abstract": "Granulosa cell ovarian tumors are known to secrete estrogen. Herein we report a patient presenting with primary amenorrhea and virilization with markedly high androgen levels, all thought to be disproportional to be attributed to polycystic ovary syndrome (PCOS) alone. Bilateral oophorectomy revealed a rare androgen-secreting granulosa cell ovarian tumor and bilateral cysts (PCOS) both contributing to manifestations.\nDescription of a case and discussion of the literature.\nA 25-year-old female presented with primary amenorrhea, male pattern baldness and hirsutism of the face and chest, clitoral hypertrophy, cystic acne on the chest and shoulders, and type 2 diabetes. Diagnosis of PCOS was made at age 13 years. The concurrent presence of congenital adrenal hyperplasia was also considered. She was receiving metformin, oral contraceptives, and/or spironolactone with no improvement in manifestations at presentation to the endocrine clinic. She reported several elevated serum testosterone and androstenedione levels. Diagnosis of PCOS was established by the presence of enlarged cystic ovaries on ultrasound examination. The patient reported worsening manifestations including progression of diabetes despite therapy with metformin. She shaved her face, chest, and breasts daily for cosmetic reasons. Laboratory testing demonstrated markedly elevated total testosterone level (234 ng/dL), and normal cortisol and adrenocorticotropic hormone levels. Dexamethasone suppression and human chorionic gonadotropin stimulation indicated ovaries as a probable source of excessive circulating androgen levels. A computed tomography scan of the abdomen and pelvis showed multiple cysts in both ovaries, the largest being 1.9 cm in the right ovary. Due to the severity of manifestations, the patient was counseled to undergo fluoroscopically guided blood sampling of bilateral adrenal and ovarian veins, which confirmed both ovaries to be the source of the excess androgen production with a greater contribution by the right ovary. The patient underwent bilateral oophorectomy. Pathologic examination confirmed the presence of bilateral polycystic ovaries as well as an androgen-secreting granulosa cell tumor in the right ovary which apparently contributed to greater androgen levels in a right ovarian venous blood sample. Peripheral venous androgen levels normalized promptly after bilateral oophorectomy. Gradual resolution of clinical manifestations followed.\nA unique presentation of granulosa cell ovarian tumor with concurrent PCOS contributing to the extremely excessive production of androgens in a young woman manifesting primary amenorrhea and masculinization at the onset of puberty with marked gradual resolution of manifestations following bilateral oophorectomy.",
"affiliations": null,
"authors": "Harris|Ashley A|AA|;Kabadi|Udaya M|UM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4158/ACCR-2019-0576",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2376-0605",
"issue": "6(4)",
"journal": "AACE clinical case reports",
"keywords": null,
"medline_ta": "AACE Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101670593",
"other_id": null,
"pages": "e170-e173",
"pmc": null,
"pmid": "32734001",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "31657237;28850273;10907176;29995717;31499493;16957416;17624097;16515626;30033227;26642102;14711538;25098035;30376853",
"title": "MORE THAN MEETS THE EYE IN A PATIENT WITH PCOS: ANDROGEN-SECRETING GRANULOSA CELL OVARIAN TUMOR IN A VIRILIZED WOMAN WITH POLYCYSTIC OVARIAN SYNDROME (PCOS).",
"title_normalized": "more than meets the eye in a patient with pcos androgen secreting granulosa cell ovarian tumor in a virilized woman with polycystic ovarian syndrome pcos"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS-2018GMK036929",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"... |
{
"abstract": "Invasive pulmonary aspergillosis (IPA) is a life-threatening complication of microwave ablation (MWA) during the treatment of primary or metastatic lung tumors. The purpose of this study was to investigate the clinical, radiological and demographic characteristics and treatment responses of patients with IPA after MWA.\n\n\n\nFrom January 2011 to January 2016, all patients who were treated by MWA of their lung tumors from six health institutions were enrolled in this study. Patients with IPA secondary to MWA were identified and retrospectively evaluated for predisposing factors, clinical treatment, and outcome.\n\n\n\nThe incidence of IPA secondary to lung MWA was 1.44% (23/1596). Of the 23 patients who developed IPA, six died as a consequence, resulting in a high mortality rate of 26.1%. Using computed tomography (CT), pulmonary cavitation was the most common finding and occurred in 87.0% (20/23) of the patients. Sudden massive hemoptysis was responsible for one-third of the deaths (2/6). Most patients (22/23) received voriconazole as an initial treatment, and six patients with huge cavities underwent intracavitary lavage. Finally, 17 patients (73.9%) achieved treatment success.\n\n\n\nLung MWA may be an additional host risk factor for IPA, particularly in elderly patients with underlying diseases and in patients who have recently undergone chemotherapy. Early and accurate diagnosis of IPA after MWA is critical for patient prognosis. Voriconazole should be given as the first-line treatment as early as possible. Bronchial artery embolization or intracavitary lavage may be required in some patients.",
"affiliations": "a Department of Oncology , Shandong Provincial Hospital Affiliated to Shandong University , Jinan, Shandong Province , China.;a Department of Oncology , Shandong Provincial Hospital Affiliated to Shandong University , Jinan, Shandong Province , China.;a Department of Oncology , Shandong Provincial Hospital Affiliated to Shandong University , Jinan, Shandong Province , China.;b Department of Oncology , Second People Hospital of Dezhou , Dezhou, Shandong Province , China.;c Department of Oncology , 88 Hospital of Chinese People's Liberation Army , Taian, Shandong Province , China.;d Department of Oncology , Taishan Hospital of Shangdong Province , Taian, Shandong Province , China.;e Department of Oncology , Teng Zhou Central People's Hospital Affiliated to Jining Medical College , Tengzhou, Shandong Province , China.;f Department of Oncology , Affiliated Hospital of Jining Medical University , Jining, Shandong Province , China.;a Department of Oncology , Shandong Provincial Hospital Affiliated to Shandong University , Jinan, Shandong Province , China.;a Department of Oncology , Shandong Provincial Hospital Affiliated to Shandong University , Jinan, Shandong Province , China.;a Department of Oncology , Shandong Provincial Hospital Affiliated to Shandong University , Jinan, Shandong Province , China.;a Department of Oncology , Shandong Provincial Hospital Affiliated to Shandong University , Jinan, Shandong Province , China.;a Department of Oncology , Shandong Provincial Hospital Affiliated to Shandong University , Jinan, Shandong Province , China.;a Department of Oncology , Shandong Provincial Hospital Affiliated to Shandong University , Jinan, Shandong Province , China.;a Department of Oncology , Shandong Provincial Hospital Affiliated to Shandong University , Jinan, Shandong Province , China.",
"authors": "Huang|Guanghui|G|;Ye|Xin|X|;Yang|Xia|X|;Wang|Chuntang|C|;Zhang|Licheng|L|;Ji|Guangdong|G|;Zhang|Kaixian|K|;Wang|Huili|H|;Zheng|Aimin|A|;Li|Wenhong|W|;Wang|Jiao|J|;Han|Xiaoying|X|;Wei|Zhigang|Z|;Meng|Min|M|;Ni|Yang|Y|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/02656736.2018.1476738",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0265-6736",
"issue": "35(1)",
"journal": "International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group",
"keywords": "Complication; invasive pulmonary aspergillosis; lung tumors; microwave ablation",
"medline_ta": "Int J Hyperthermia",
"mesh_terms": "D055011:Ablation Techniques; D000368:Aged; D005260:Female; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8508395",
"other_id": null,
"pages": "71-78",
"pmc": null,
"pmid": "29874934",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Invasive pulmonary aspergillosis secondary to microwave ablation: a multicenter retrospective study.",
"title_normalized": "invasive pulmonary aspergillosis secondary to microwave ablation a multicenter retrospective study"
} | [
{
"companynumb": "CN-MYLANLABS-2019M1005313",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "We report a severe adverse event occurring in the course of a cohort study (ISRCTN13784335) aimed at measuring the efficacy and safety of venous stenting in the treatment of patients with medically refractory idiopathic intracranial hypertension (IIH). The patient was a 41-year-old woman who was not overweight, who presented with severe headache, grade 1 bilateral papilledema and transient tinnitus, refractory to medical treatment. Right transverse sinus stenting was successfully performed. Following surgery, the patient's state of consciousness decreased acutely with rapid and progressive loss of brainstem reflex. CT scan revealed acute cerebellar and intraventricular hemorrhage with obstructive hydrocephalus. Angioscan revealed normal venous sinus patency and cerebral MRI showed acute mesencephalic ischemia. Mechanical impairment of cerebellar venous drainage by the stent or venous perforation with the large guidewire used in this technique are two logical ways to explain the cerebellar hemorrhage seen in our patient. The risk of such a complication could probably be reduced using alternative tools and technique. However, given the low level of evidence around the safety of transverse sinus stenting in IIH, its formal assessment in clinical trials is required.",
"affiliations": "1 Research Center of the Centre Hospitalier Universitaire 36896 (CHU) de Québec , Axe Neurosciences (Neurosciences Unit), Department of Neurological Sciences, 36896 (CHU) de Québec (Hôpital de l'Enfant-Jésus), Université Laval, Quebec City, Quebec, Canada.;2 Research Center of the Centre Hospitalier Universitaire 36896 (CHU) de Québec , Axe Neurosciences (Neurosciences Unit), Department of Medical Imaging, 36896 (CHU) de Québec (Hôpital de l'Enfant-Jésus), Université Laval, Quebec City, Quebec, Canada.;2 Research Center of the Centre Hospitalier Universitaire 36896 (CHU) de Québec , Axe Neurosciences (Neurosciences Unit), Department of Medical Imaging, 36896 (CHU) de Québec (Hôpital de l'Enfant-Jésus), Université Laval, Quebec City, Quebec, Canada.;1 Research Center of the Centre Hospitalier Universitaire 36896 (CHU) de Québec , Axe Neurosciences (Neurosciences Unit), Department of Neurological Sciences, 36896 (CHU) de Québec (Hôpital de l'Enfant-Jésus), Université Laval, Quebec City, Quebec, Canada.;1 Research Center of the Centre Hospitalier Universitaire 36896 (CHU) de Québec , Axe Neurosciences (Neurosciences Unit), Department of Neurological Sciences, 36896 (CHU) de Québec (Hôpital de l'Enfant-Jésus), Université Laval, Quebec City, Quebec, Canada.;3 Department of Ophthalmology, 36896 (CHU) de Québec (Hôpital de l'Enfant-Jésus), Université Laval, Quebec City, Quebec, Canada.;1 Research Center of the Centre Hospitalier Universitaire 36896 (CHU) de Québec , Axe Neurosciences (Neurosciences Unit), Department of Neurological Sciences, 36896 (CHU) de Québec (Hôpital de l'Enfant-Jésus), Université Laval, Quebec City, Quebec, Canada.;1 Research Center of the Centre Hospitalier Universitaire 36896 (CHU) de Québec , Axe Neurosciences (Neurosciences Unit), Department of Neurological Sciences, 36896 (CHU) de Québec (Hôpital de l'Enfant-Jésus), Université Laval, Quebec City, Quebec, Canada.",
"authors": "Lavoie|Pascale|P|;Audet|Marie-Ève|MÈ|;Gariepy|Jean-Luc|JL|;Savard|Martin|M|;Verreault|Steve|S|;Gourdeau|Alain|A|;Milot|Geneviève|G|;Carrondo Cottin|Sylvine|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1591019917734389",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1591-0199",
"issue": "24(1)",
"journal": "Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences",
"keywords": "Idiopathic intracranial hypertension; hemorrhage; stenting",
"medline_ta": "Interv Neuroradiol",
"mesh_terms": "D000328:Adult; D002533:Cerebral Angiography; D002543:Cerebral Hemorrhage; D005260:Female; D006801:Humans; D019586:Intracranial Hypertension; D008279:Magnetic Resonance Imaging; D015607:Stents; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9602695",
"other_id": null,
"pages": "100-105",
"pmc": null,
"pmid": "28992723",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15159514;19517058;11812561;21704931;12743224;14872049;15881764;27556959;15111701;14638886;15026510;16107086;22089501;11781401;28073989;22146571;12744365;25579238;8559374;8848197;27830325;12093133;10983304;16091520;14756490;17214924",
"title": "Severe cerebellar hemorrhage following transverse sinus stenting for idiopathic intracranial hypertension.",
"title_normalized": "severe cerebellar hemorrhage following transverse sinus stenting for idiopathic intracranial hypertension"
} | [
{
"companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-334915",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
... |
{
"abstract": "We present a previously healthy man in his 30s who presented with typical viral prodrome symptoms and worsening abdominal pain. He was found to have portal vein thrombosis, with extensive hypercoagulability workup performed. It was determined that the aetiology of thrombus was secondary to acute cytomegalovirus infection. The patient was started on anticoagulation therapy, with later clot resolution demonstrated on abdominal Doppler ultrasound and abdominal CT scan. Given the atypical presentation of this common virus, we performed a literature review of cytomegalovirus-associated portal vein thrombosis in healthy individuals; we found that most patients present with non-specific symptoms of fever and abdominal pain in the setting of a viral prodrome. This case and literature review suggest physicians must consider cytomegalovirus-associated portal vein thrombosis as a potential diagnosis when patients present with abdominal pain and viral symptoms. The literature highlights the need for a consensus on anticoagulation and antiviral therapy.",
"affiliations": "Medical Education, Greenwich Hospital, Greenwich, Connecticut, USA.;Internal Medicine, Greenwich Hospital, Greenwich, Connecticut, USA.;Internal Medicine, Greenwich Hospital, Greenwich, Connecticut, USA khalil.hussein@ynhh.org.;Infectious Disease, Greenwich Hospital, Greenwich, Connecticut, USA.",
"authors": "Burkey|Caroline|C|;Teng|Catherine|C|;Hussein|Khalil Ian|KI|http://orcid.org/0000-0001-9095-0103;Sabetta|James|J|",
"chemical_list": "D000925:Anticoagulants",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-238645",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(12)",
"journal": "BMJ case reports",
"keywords": "infections; portal vein; venous thromboembolism",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D015746:Abdominal Pain; D000328:Adult; D000925:Anticoagulants; D001778:Blood Coagulation Disorders; D000072226:Computed Tomography Angiography; D003586:Cytomegalovirus Infections; D006801:Humans; D007121:Immunocompetence; D008297:Male; D011169:Portal Vein; D018608:Ultrasonography, Doppler; D020246:Venous Thrombosis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33372022",
"pubdate": "2020-12-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cytomegalovirus (CMV)-associated portal vein thrombosis in a healthy, immunocompetent man.",
"title_normalized": "cytomegalovirus cmv associated portal vein thrombosis in a healthy immunocompetent man"
} | [
{
"companynumb": "US-ROCHE-2814500",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALGANCICLOVIR"
},
"drugadditional": null,
"... |
{
"abstract": "Baking soda (sodium bicarbonate) is a common household item that has gained popularity as an alternative cancer treatment. Some have speculated that alkali therapy neutralizes the extracellular acidity of tumor cells that promotes metastases. Internet blogs have touted alkali as a safe and natural alternative to chemotherapy that targets cancer cells without systemic effects. Sodium bicarbonate overdose is uncommon, with few reports of toxic effects in humans. The case described here is the first reported case of severe metabolic alkalosis related to topical use of sodium bicarbonate as a treatment for cancer. This case highlights how a seemingly benign and readily available product can have potentially lethal consequences.",
"affiliations": "Laura B. Galinko is an anesthesiology resident at New York Presbyterian Hospital/Weill Cornell Medical College, New York, New York. At the time of this case report, Steven H. Hsu was a critical care medicine fellow and Michael L. Fingerhood was a pulmonary medicine fellow at Memorial Sloan Kettering Cancer Center, New York, New York. Cosmin Gauran is an assistant attending, Stephen M. Pastores is the critical care fellowship director, and Neil A. Halpern is the director of the Critical Care Center, and Sanjay Chawla is an associate attending in the Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center.;Laura B. Galinko is an anesthesiology resident at New York Presbyterian Hospital/Weill Cornell Medical College, New York, New York. At the time of this case report, Steven H. Hsu was a critical care medicine fellow and Michael L. Fingerhood was a pulmonary medicine fellow at Memorial Sloan Kettering Cancer Center, New York, New York. Cosmin Gauran is an assistant attending, Stephen M. Pastores is the critical care fellowship director, and Neil A. Halpern is the director of the Critical Care Center, and Sanjay Chawla is an associate attending in the Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center. shhsu@houstonmethodist.org.;Laura B. Galinko is an anesthesiology resident at New York Presbyterian Hospital/Weill Cornell Medical College, New York, New York. At the time of this case report, Steven H. Hsu was a critical care medicine fellow and Michael L. Fingerhood was a pulmonary medicine fellow at Memorial Sloan Kettering Cancer Center, New York, New York. Cosmin Gauran is an assistant attending, Stephen M. Pastores is the critical care fellowship director, and Neil A. Halpern is the director of the Critical Care Center, and Sanjay Chawla is an associate attending in the Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center.;Laura B. Galinko is an anesthesiology resident at New York Presbyterian Hospital/Weill Cornell Medical College, New York, New York. At the time of this case report, Steven H. Hsu was a critical care medicine fellow and Michael L. Fingerhood was a pulmonary medicine fellow at Memorial Sloan Kettering Cancer Center, New York, New York. Cosmin Gauran is an assistant attending, Stephen M. Pastores is the critical care fellowship director, and Neil A. Halpern is the director of the Critical Care Center, and Sanjay Chawla is an associate attending in the Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center.;Laura B. Galinko is an anesthesiology resident at New York Presbyterian Hospital/Weill Cornell Medical College, New York, New York. At the time of this case report, Steven H. Hsu was a critical care medicine fellow and Michael L. Fingerhood was a pulmonary medicine fellow at Memorial Sloan Kettering Cancer Center, New York, New York. Cosmin Gauran is an assistant attending, Stephen M. Pastores is the critical care fellowship director, and Neil A. Halpern is the director of the Critical Care Center, and Sanjay Chawla is an associate attending in the Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center.;Laura B. Galinko is an anesthesiology resident at New York Presbyterian Hospital/Weill Cornell Medical College, New York, New York. At the time of this case report, Steven H. Hsu was a critical care medicine fellow and Michael L. Fingerhood was a pulmonary medicine fellow at Memorial Sloan Kettering Cancer Center, New York, New York. Cosmin Gauran is an assistant attending, Stephen M. Pastores is the critical care fellowship director, and Neil A. Halpern is the director of the Critical Care Center, and Sanjay Chawla is an associate attending in the Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center.;Laura B. Galinko is an anesthesiology resident at New York Presbyterian Hospital/Weill Cornell Medical College, New York, New York. At the time of this case report, Steven H. Hsu was a critical care medicine fellow and Michael L. Fingerhood was a pulmonary medicine fellow at Memorial Sloan Kettering Cancer Center, New York, New York. Cosmin Gauran is an assistant attending, Stephen M. Pastores is the critical care fellowship director, and Neil A. Halpern is the director of the Critical Care Center, and Sanjay Chawla is an associate attending in the Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center.",
"authors": "Galinko|Laura B|LB|;Hsu|Steven H|SH|;Gauran|Cosmin|C|;Fingerhood|Michael L|ML|;Pastores|Stephen M|SM|;Halpern|Neil A|NA|;Chawla|Sanjay|S|",
"chemical_list": "D000468:Alkalies; D017693:Sodium Bicarbonate",
"country": "United States",
"delete": false,
"doi": "10.4037/ajcc2017278",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1062-3264",
"issue": "26(6)",
"journal": "American journal of critical care : an official publication, American Association of Critical-Care Nurses",
"keywords": null,
"medline_ta": "Am J Crit Care",
"mesh_terms": "D000287:Administration, Topical; D000368:Aged; D000468:Alkalies; D000471:Alkalosis; D005260:Female; D005440:Fluid Therapy; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007008:Hypokalemia; D009369:Neoplasms; D017693:Sodium Bicarbonate; D016896:Treatment Outcome",
"nlm_unique_id": "9211547",
"other_id": null,
"pages": "491-494",
"pmc": null,
"pmid": "29092872",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Basic Therapy Gone Awry.",
"title_normalized": "a basic therapy gone awry"
} | [
{
"companynumb": "US-PFIZER INC-2016575422",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SODIUM BICARBONATE"
},
"drugadditional": "3",
... |
{
"abstract": "Pulmonary venoocclusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) predominantly characterized by pulmonary vein and capillary involvement. An association between chemotherapy, in particular mitomycin C (MMC), and PVOD has been reported.\n\n\n\nWhat are the characteristics of MMC-induced PVOD, and what is the prognosis for patients with MMC-induced PVOD?\n\n\n\nWe report the clinical, functional, radiologic, and hemodynamic characteristics at diagnosis and outcomes of patients with PVOD from the French PH Registry after exposure to MMC. The results are expressed as the median (minimum-maximum).\n\n\n\nFrom June 2011 to December 2018, 17 incident cases of MMC-induced PVOD were identified. At diagnosis, these patients had severe clinical and functional impairment, with 12 patients having a New York Heart Association (NYHA) functional class of III or IV and a 6-min walk distance of 220 (0-465) m. Right heart catheterization confirmed severe precapillary PH with a mean pulmonary artery pressure of 38 (30-52) mm Hg, a cardiac index of 2.2 (1.5-4) L/(min × m2), and pulmonary vascular resistance of 8.3 (5.1-14.5) Wood units. The diffusing capacity of the lungs for carbon monoxide was markedly decreased at 31% (20%-51%) of the theoretical values associated with severe hypoxemia. MMC was withdrawn for all patients, and 14 patients received specific pulmonary arterial hypertension (PAH) therapies. Among these patients, mild but statistically insignificant improvements were observed in NYHA functional class (P = .10), 6-min walk distance (P = .09), and pulmonary vascular resistance (-4.7 Wood units; P = .052) at reassessment (median delay of 4.8 months). Three patients experienced pulmonary edema requiring the cessation or reduction of PAH treatment. The median overall survival was 20 months, and the 6-, 12-, and 24-month survival rates were 76%, 58%, and 18%, respectively.\n\n\n\nPVOD after MMC treatment is a rare but life-threatening complication associated with a poor prognosis despite MMC withdrawal and PAH-specific therapy.",
"affiliations": "Department of Respiratory and Intensive Care Medicine, National French Reference Constitutive Center for Rare Pulmonary Diseases, Hôpital François Mitterrand, Burgundy University Hospital, Dijon, France.;INSERM UMR_S 999 \"Pulmonary Hypertension: Pathophysiology and Novel Therapies\", Hôpital Marie Lannelongue, Le Plessis-Robinson, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Pharmacy, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; University of Paris-Saclay, Faculty of Pharmacy, Châtenay Malabry, France.;INSERM UMR_S 999 \"Pulmonary Hypertension: Pathophysiology and Novel Therapies\", Hôpital Marie Lannelongue, Le Plessis-Robinson, France; AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; University of Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France.;INSERM UMR_S 999 \"Pulmonary Hypertension: Pathophysiology and Novel Therapies\", Hôpital Marie Lannelongue, Le Plessis-Robinson, France; AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; University of Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France.;AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.;AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.;Department of Respiratory and Intensive Care Medicine, National French Reference Constitutive Center for Rare Pulmonary Diseases, Hôpital François Mitterrand, Burgundy University Hospital, Dijon, France; University of Bourgogne Franche-Comté, School of Medicine, Dijon, France; INSERM UMR 123-1, LNC Faculty of Medicine and Pharmacy, Dijon, France.;Department of Respiratory and Intensive Care Medicine, National French Reference Constitutive Center for Rare Pulmonary Diseases, Hôpital François Mitterrand, Burgundy University Hospital, Dijon, France.;Department of Respiratory Diseases, Hôpital Arnaud de Villeneuve, Montpellier University Hospitals, Montpellier, France; University of Montpellier, School of Medicine, Montpellier, France; INSERM U1046, Montpellier, France.;Department of Respiratory Diseases, Hôpital Arnaud de Villeneuve, Montpellier University Hospitals, Montpellier, France.;Department of Respiratory Medicine, National Coordinating Reference Center for Rare Pulmonary Diseases, Hôpital Louis Pradel, Lyon, France; Claude-Bernard Lyon 1 University, University of Lyon, INRA, UMR754, Lyon, France; UMR 754, Lyon, France.;Department of Respiratory Medicine, National Coordinating Reference Center for Rare Pulmonary Diseases, Hôpital Louis Pradel, Lyon, France.;Department of Cardiology, Assistance Publique-Hôpitaux de Marseille (AP-HM), Hôpital de la Timone, Aix-Marseille University, Marseille, France.;Internal Medicine Department, Hôpital Robert-Debré, Reims, France.;Department of Cardiology, University Hospital of Bordeaux, Bordeaux, France.;INSERM UMR_S 999 \"Pulmonary Hypertension: Pathophysiology and Novel Therapies\", Hôpital Marie Lannelongue, Le Plessis-Robinson, France; AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; University of Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France.;Department of Pathology, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.;INSERM UMR_S 999 \"Pulmonary Hypertension: Pathophysiology and Novel Therapies\", Hôpital Marie Lannelongue, Le Plessis-Robinson, France.;INSERM UMR_S 999 \"Pulmonary Hypertension: Pathophysiology and Novel Therapies\", Hôpital Marie Lannelongue, Le Plessis-Robinson, France; AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; University of Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France.;Department of Respiratory and Intensive Care Medicine, National French Reference Constitutive Center for Rare Pulmonary Diseases, Hôpital François Mitterrand, Burgundy University Hospital, Dijon, France; University of Bourgogne Franche-Comté, School of Medicine, Dijon, France; INSERM UMR 123-1, LNC Faculty of Medicine and Pharmacy, Dijon, France.;INSERM UMR_S 999 \"Pulmonary Hypertension: Pathophysiology and Novel Therapies\", Hôpital Marie Lannelongue, Le Plessis-Robinson, France; AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; University of Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France.;INSERM UMR_S 999 \"Pulmonary Hypertension: Pathophysiology and Novel Therapies\", Hôpital Marie Lannelongue, Le Plessis-Robinson, France; AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; University of Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France. Electronic address: david.montani@aphp.fr.",
"authors": "Certain|Marie-Caroline|MC|;Chaumais|Marie-Camille|MC|;Jaïs|Xavier|X|;Savale|Laurent|L|;Seferian|Andrei|A|;Parent|Florence|F|;Georges|Marjolaine|M|;Favrolt|Nicolas|N|;Bourdin|Arnaud|A|;Boissin|Clément|C|;Cottin|Vincent|V|;Traclet|Julie|J|;Renard|Sébastien|S|;Noel|Violaine|V|;Picard|François|F|;Girerd|Barbara|B|;Ghigna|Maria-Rosa|MR|;Perros|Frédéric|F|;Sitbon|Olivier|O|;Bonniaud|Philippe|P|;Humbert|Marc|M|;Montani|David|D|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D016685:Mitomycin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.chest.2020.09.238",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "159(3)",
"journal": "Chest",
"keywords": "mitomycin C; pharmacovigilance; pulmonary hypertension; pulmonary venoocclusive disease",
"medline_ta": "Chest",
"mesh_terms": "D000903:Antibiotics, Antineoplastic; D006328:Cardiac Catheterization; D005260:Female; D005602:France; D000085542:Functional Status; D006801:Humans; D006976:Hypertension, Pulmonary; D008168:Lung; D008297:Male; D008875:Middle Aged; D016685:Mitomycin; D010346:Patient Care Management; D060735:Pharmacovigilance; D011379:Prognosis; D011652:Pulmonary Circulation; D011668:Pulmonary Veno-Occlusive Disease; D011669:Pulmonary Wedge Pressure; D012042:Registries; D016019:Survival Analysis; D028761:Withholding Treatment",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "1197-1207",
"pmc": null,
"pmid": "32979348",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Characteristics and Long-term Outcomes of Pulmonary Venoocclusive Disease Induced by Mitomycin C.",
"title_normalized": "characteristics and long term outcomes of pulmonary venoocclusive disease induced by mitomycin c"
} | [
{
"companynumb": "FR-ACCORD-238082",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MITOMYCIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "OBJECTIVE\nAcetaminophen (APAP) is available over-the-counter and widely regarded as safe for use in pregnancy. APAP has been used to close a persistently patent ductus arteriosus. Fetal constriction/closure of the ductus arteriosus (FCCDA), of public health interest given the drug's widespread use during pregnancy, is being monitored globally, including by the European Medicines Agency Pharmacovigilance Risk Assessment Committee. Our objective was to share a comprehensive signal evaluation of FCCDA with in utero APAP exposure to determine if the totality of evidence is sufficiently more consistent with one of the following two possibilities: (1) APAP never contributes to FCCDA (null hypothesis or HO) versus (2) APAP may in some cases be at least a contributory cause of in utero DA narrowing (alternative hypothesis or HA) to justify risk communication.\n\n\nMETHODS\nTo assess the relative support for HO versus HA, we synthesize and interpret within an Austin Bradford Hill criteria framework a comprehensive, cross-disciplinary set of published information and de novo analysis, including toxicology, epidemiology, clinical pharmacology, and clinical and quantitative pharmacovigilance analysis of spontaneous reports.\n\n\nRESULTS\nWhile residual uncertainty remains, the totality of information is more compatible with HA than H0, to the extent that it is reasonably possible that APAP may sometimes be at least a contributory cause of FCCDA.\n\n\nCONCLUSIONS\nIt is reasonably possible that APAP may sometimes be at least a contributory cause of FCCDA, and this should therefore be communicated to stakeholders.\n\n\nBACKGROUND\nCLINICALTRIALS.\nNOT APPLICABLE.",
"affiliations": "Worldwide Safety and Regulatory, Pfizer Inc., 235 E 42nd St, New York, NY, 10017, USA. manfred.hauben@Pfizer.com.;Clinical Pharmacology, Pfizer Inc., 235 E 42nd St, New York, NY, 10017, USA.;Worldwide Safety and Regulatory, Pfizer Inc., 235 E 42nd St, New York, NY, 10017, USA.;Safety Surveillance and Risk Management, Pfizer Inc., 235 E 42nd St, New York, NY, 10017, USA.;Safety Surveillance and Risk Management, Pfizer Inc., 235 E 42nd St, New York, NY, 10017, USA.;Safety Surveillance and Risk Management, Pfizer Inc., 235 E 42nd St, New York, NY, 10017, USA.",
"authors": "Hauben|Manfred|M|https://orcid.org/0000-0002-3365-1374;Bai|Stephen|S|;Hung|Eric|E|;Lobello|Kasia|K|;Tressler|Charles|C|;Zucal|Vincent P|VP|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-020-03039-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-6970",
"issue": "77(7)",
"journal": "European journal of clinical pharmacology",
"keywords": "Acetaminophen; Drug exposure; Fetal ductus arteriosus closure; In utero; Signal evaluation",
"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D003250:Constriction; D004373:Ductus Arteriosus; D005260:Female; D006801:Humans; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects",
"nlm_unique_id": "1256165",
"other_id": null,
"pages": "1019-1028",
"pmc": null,
"pmid": "33410971",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": "19389789;22368623;25781500;29584842;29105147;27146832;25352038;23258386;24460433;22065264;22837295;24363755;30300944;25708490;2335261;9290437;15133806;29343586;28847300;28705177;19705407;22052330;29778098;20644061;29396682;17408310;12071785;27074377;32378285;19187799;19236117;23571771;28277341;6522619;2140240;21317433;2621359;27806383;14648334;28745124;18779991;27371685;31310697;23055849;25793044;8618179;28579716;14528470;23466189;28191193;30651828;26690325;24243665;23673817;17536881;30772861;29129700;834226;12755814",
"title": "Maternal paracetamol intake and fetal ductus arteriosus constriction/closure: comprehensive signal evaluation using the Austin Bradford Hill criteria.",
"title_normalized": "maternal paracetamol intake and fetal ductus arteriosus constriction closure comprehensive signal evaluation using the austin bradford hill criteria"
} | [
{
"companynumb": "US-JNJFOC-20210119861",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "The optimal management of patients with follicular lymphoma Grade 3 (FLG3) is controversial.\n\n\n\nThis is a case series of 45 patients with FLG3 treated with first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and observed for an extended time interval.\n\n\n\nThe overall response rate was 100% and the median progression-free survival (PFS) has not been reached, with a 3-year PFS of 70%; 14 (31%) patients relapsed, nearly all within 3 years. The baseline characteristic more strongly associated with a shorter PFS were lymph >4 node sites and presence of B symptoms. Three patients later progressed to diffuse large B cell lymphoma, all had baseline elevated serum lactate dehydrogenase level and high International Prognostic Index score. Median overall survival has not been reached. All 4 patients who later developed acute myeloid leukemia were older than 60 years at the time of start of therapy.\n\n\n\nR-CHOP is an effective first-line treatment for patients with FLG3, and might provide extended PFS, comparable with outcomes observed in diffuse large B-cell lymphoma, particularly in subgroups with limited nodal disease.",
"affiliations": "Department of Cancer Medicine, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.;Department of Hematopathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.;Department of Hematopathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.;Department of Gastrointestinal Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.;Department of Lymphoma and Myeloma, The University of Texas, M.D. Anderson Cancer Center, Houston, TX. Electronic address: lefayad@mdanderson.org.",
"authors": "Strati|Paolo|P|;Fowler|Nathan|N|;Pina-Oviedo|Sergio|S|;Medeiros|L Jeffrey|LJ|;Overman|Michael J|MJ|;Romaguera|Jorge E|JE|;Nastoupil|Loretta|L|;Wang|Michael|M|;Hagemeister|Fredrick B|FB|;Rodriguez|Alma|A|;Oki|Yasuhiro|Y|;Westin|Jason|J|;Turturro|Francesco|F|;Neelapu|Sattva S|SS|;Fayad|Luis|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2017.11.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "18(1)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "FLG3; Prognosis; R-CHOP; Survival; Treatment",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D008224:Lymphoma, Follicular; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "e103-e108",
"pmc": null,
"pmid": "29196178",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-Term Remissions of Patients With Follicular Lymphoma Grade 3 Treated With R-CHOP.",
"title_normalized": "long term remissions of patients with follicular lymphoma grade 3 treated with r chop"
} | [
{
"companynumb": "US-PFIZER INC-2018029178",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
"drugadditional": "3",... |
{
"abstract": "BACKGROUND\nChronic non-bacterial osteomyelitis (CNO) represents an autoinflammatory bone disorder. Currently there are no standardized diagnostic or treatment guidelines. The objective of the study is to describe our experience with biological therapy in children with the disease.\n\n\nMETHODS\nRetrospective chart review of patients with CNO treated with biological therapy followed at two tertiary hospitals from January 2007 to April 2020. Biologicals were started in most patients due to persistent disease activity after receiving standard therapy with at least 2 drugs (NSAIDs and corticosteroids and/or pamidronate).\n\n\nRESULTS\nTwenty-five patients were diagnosed with CNO. Out of those, 19 patients (15 females) failed conventional therapy. The mean age at diagnosis was 8.8±2.9 years and the mean diagnostic delay was 6.9±8.3 months. All patients presented with bone pain and 6/19 also had fever. The most frequently affected bones were femur (9 patients), followed by clavicle, tibia and vertebrae (6, 6 and 5 patients respectively). Nine children had skin lesions. C-reactive protein was elevated in 13/19 patients (mean 20.2mg/L±11.7) and ESR in 16/19 (mean 48mm/h±29). All patients received nonsteroidal anti-inflammatory drugs, 15/19 pamidronate, 10/19 corticosteroids and 19 anti-TNF-therapy. At the last follow-up visit, 10/19 patients were still on biological therapy (8 adalimumab, 2 infliximab) and 18 out of 19 remained asymptomatic. In regards to adverse effects, one patient receiving infliximab developed S. aureus osteomyelitis and another cutaneous leishmaniosis.\n\n\nCONCLUSIONS\nThis research emphasizes that anti-TNF-therapy represents an effective and safe alternative for patients with CNO refractory to conventional treatments.",
"affiliations": "Department of General Paediatrics and Infectious and Tropical Diseases, Hospital La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain.;Department of Pediatric Rheumatology, Hospital La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain. Electronic address: sarapepo@yahoo.es.;Department of Pediatric Rheumatology, University Hospital 12 de Octubre, Av Cordoba s/n, 28041 Madrid, Spain.;Department of Pediatric Rheumatology, Hospital La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain.;Department of Pediatric Rheumatology, Hospital La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain.;Department of Pediatric Rheumatology, University Hospital 12 de Octubre, Av Cordoba s/n, 28041 Madrid, Spain; Department of Public Health & Maternal and Child Health, Complutense University of Madrid, Plaza de Ramón y Cajal s/n, 28040 Madrid, Spain.",
"authors": "Bustamante|Jorge|J|;Murias|Sara|S|;Enriquez|Eugenia|E|;Alcobendas|Rosa|R|;Remesal|Agustín|A|;De Inocencio|Jaime|J|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000079424:Tumor Necrosis Factor Inhibitors",
"country": "France",
"delete": false,
"doi": "10.1016/j.jbspin.2020.105120",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1297-319X",
"issue": "88(2)",
"journal": "Joint bone spine",
"keywords": "Anti-TNF-therapy; Biological therapy; Children; Chronic non-bacterial osteomyelitis; Chronic recurrent multifocal osteomyelitis; Paediatrics",
"medline_ta": "Joint Bone Spine",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D001691:Biological Therapy; D002648:Child; D002908:Chronic Disease; D057210:Delayed Diagnosis; D005260:Female; D006801:Humans; D010019:Osteomyelitis; D012189:Retrospective Studies; D013211:Staphylococcus aureus; D016896:Treatment Outcome; D000079424:Tumor Necrosis Factor Inhibitors",
"nlm_unique_id": "100938016",
"other_id": null,
"pages": "105120",
"pmc": null,
"pmid": "33346110",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Biological therapy in refractory chronic nonbacterial osteomyelitis: A case series of 19 patients.",
"title_normalized": "biological therapy in refractory chronic nonbacterial osteomyelitis a case series of 19 patients"
} | [
{
"companynumb": "ES-JNJFOC-20201253032",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
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"actiondrug": "4",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
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"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThis post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from India.\n\n\nMETHODS\nChanges from baseline in HbA1c, fasting plasma glucose (FPG), body weight, and blood pressure (BP) with canagliflozin 100 and 300 mg were evaluated in a subgroup of patients from India (n = 124) from 4 randomized, double-blind, placebo- and active-controlled, Phase 3 studies (N = 2313; Population 1). Safety was assessed based on adverse event (AE) reports in these patients and in a broader subgroup of patients from India (n = 1038) from 8 randomized, double-blind, placebo- and active-controlled, Phase 3 studies (N = 9439; Population 2).\n\n\nRESULTS\nReductions in HbA1c with canagliflozin 100 and 300 mg were -0.74% and -0.88%, respectively, in patients from India, and -0.81% and -1.00%, respectively, in the 4 pooled Phase 3 studies. In the Indian subgroup, both canagliflozin doses provided reductions in FPG, body weight, and BP that were consistent with findings in the overall population. The incidence of overall AEs in patients from India was generally similar with canagliflozin 100 and 300 mg and noncanagliflozin. The AE profile in patients from India was generally similar to the overall population, with higher rates of genital mycotic infections and osmotic diuresis-related and volume depletion-related AEs with canagliflozin versus noncanagliflozin.\n\n\nCONCLUSIONS\nCanagliflozin provided glycemic control, body weight reduction, and was generally well tolerated in patients with T2DM from India.",
"affiliations": "Bangalore Diabetes Hospital, Bengaluru, Karnataka, India.;Dr. Mohan's Diabetes Specialties Centre and Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India.;CARE Hospitals, Hyderabad, Telangana, India.;Gandhi Research Institute, Nagpur, Maharashtra, India.;Department of Endocrinology, St. John's Medical College and Hospital, Bengaluru, Karnataka, India.;Janssen Research and Development, LLC, Raritan, NJ, USA.;Janssen Research and Development, LLC, Raritan, NJ, USA.;Janssen Research and Development, LLC, Raritan, NJ, USA.",
"authors": "Prasanna Kumar|K M|KM|;Mohan|Viswanathan|V|;Sethi|Bipin|B|;Gandhi|Pramod|P|;Bantwal|Ganapathi|G|;Xie|John|J|;Meininger|Gary|G|;Qiu|Rong|R|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/2230-8210.179996",
"fulltext": "\n==== Front\nIndian J Endocrinol MetabIndian J Endocrinol MetabIJEMIndian Journal of Endocrinology and Metabolism2230-82102230-9500Medknow Publications & Media Pvt Ltd India IJEM-20-37210.4103/2230-8210.179996Original ArticleEfficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from India Prasanna Kumar K. M. Mohan Viswanathan 1Sethi Bipin 2Gandhi Pramod 3Bantwal Ganapathi 4Xie John 5Meininger Gary 5Qiu Rong 5Bangalore Diabetes Hospital, Bengaluru, Karnataka, India1 Dr. Mohan's Diabetes Specialties Centre and Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India2 CARE Hospitals, Hyderabad, Telangana, India3 Gandhi Research Institute, Nagpur, Maharashtra, India4 Department of Endocrinology, St. John's Medical College and Hospital, Bengaluru, Karnataka, India5 Janssen Research and Development, LLC, Raritan, NJ, USACorresponding Author: Dr. K. M. Prasanna Kumar, Bangalore Diabetes Hospital, 16/M, Thimmaiah Road, Bengaluru - 560 052, Karnataka, India. E-mail: dr.kmpk@gmail.comMay-Jun 2016 20 3 372 380 Copyright: © 2016 Indian Journal of Endocrinology and Metabolism2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background:\nThis post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from India.\n\nMethods:\nChanges from baseline in HbA1c, fasting plasma glucose (FPG), body weight, and blood pressure (BP) with canagliflozin 100 and 300 mg were evaluated in a subgroup of patients from India (n = 124) from 4 randomized, double-blind, placebo- and active-controlled, Phase 3 studies (N = 2313; Population 1). Safety was assessed based on adverse event (AE) reports in these patients and in a broader subgroup of patients from India (n = 1038) from 8 randomized, double-blind, placebo- and active-controlled, Phase 3 studies (N = 9439; Population 2).\n\nResults:\nReductions in HbA1c with canagliflozin 100 and 300 mg were −0.74% and −0.88%, respectively, in patients from India, and −0.81% and −1.00%, respectively, in the 4 pooled Phase 3 studies. In the Indian subgroup, both canagliflozin doses provided reductions in FPG, body weight, and BP that were consistent with findings in the overall population. The incidence of overall AEs in patients from India was generally similar with canagliflozin 100 and 300 mg and noncanagliflozin. The AE profile in patients from India was generally similar to the overall population, with higher rates of genital mycotic infections and osmotic diuresis–related and volume depletion–related AEs with canagliflozin versus noncanagliflozin.\n\nConclusion:\nCanagliflozin provided glycemic control, body weight reduction, and was generally well tolerated in patients with T2DM from India.\n\nFasting blood glucoseHbA1chyperglycemiaoral medicationstype 2 diabetes\n==== Body\nINTRODUCTION\nThe prevalence of type 2 diabetes mellitus (T2DM) is increasing globally, particularly in developing countries.[12] In India, it is estimated that over 65 million people have T2DM, making it the country with the second highest number of cases, behind only China.[23] It is projected that nearly 110 million people in India will have T2DM by 2035.[2] Thus, T2DM poses a significant economic and health care burden in India.\n\nMany Indian patients have been shown to exhibit clinical and biochemical characteristics that predispose them to T2DM, including increased insulin resistance and abdominal obesity despite having lower body weight and body mass index (BMI).[4567] These characteristics are collectively referred to as the “Asian Indian Phenotype” and, along with lifestyle changes resulting from increased urbanization, contribute to the rising rates of T2DM in India.[457] Patients with T2DM in India generally develop the disease at a younger age than those in other parts of the world (i.e., 45–64 years vs. ≥65 years in developed countries).[67] The younger age of onset of T2DM increases the chances that patients will develop microvascular and macrovascular complications and comorbidities.[456]\n\nCanagliflozin is a sodium glucose co-transporter 2 (SGLT2) inhibitor developed for the treatment of adults with T2DM.[891011121314151617181920] Canagliflozin lowers plasma glucose via an insulin-independent mechanism by lowering the renal threshold for glucose and promoting urinary glucose excretion (~80–120 g/day), which leads to a mild osmotic diuresis and net caloric loss.[821222324] Across Phase 3 studies, canagliflozin improved glycemic control and reduced body weight and blood pressure (BP) and was generally well tolerated in a broad range of patients with T2DM inadequately controlled by their current treatment regimens.[91011121314151617181920] In a preliminary post hoc analysis, canagliflozin was shown to reduce HbA1c, body weight, and BP in patients with T2DM from India using pooled data from 6 placebo-controlled studies, including the CANagliflozin cardioVascular Assessment Study (CANVAS) add-on to insulin and add-on to sulfonylurea substudies.[25] An additional post hoc analysis was performed excluding the CANVAS substudies, which had a different design and patient population compared with the other studies, such as a shorter duration (18 weeks vs. 26 weeks) and a population of patients with T2DM who had a history or high risk of cardiovascular (CV) disease. This manuscript describes the efficacy findings from this analysis in subgroups of patients with T2DM from India based on pooled data from 4 placebo-controlled studies, as well as an assessment of the safety of canagliflozin based on pooled data from a broader population of patients with T2DM.\n\nMETHODS\nStudy design, patient populations, and treatments\nThis post hoc analysis for efficacy was based on pooled data from patients with T2DM (N = 2313; Population 1) enrolled in four 52-week, double-blind, placebo- and active-controlled, Phase 3 studies, including canagliflozin as monotherapy,[13] add-on to metformin,[15] add-on to metformin plus sulfonylurea,[17] and add-on to metformin plus pioglitazone.[18] In each study, patients were randomized to receive canagliflozin 100 or 300 mg or placebo once daily. The add-on to metformin study included a sitagliptin treatment arm that was not included in this analysis. In the monotherapy, add-on to metformin, and add-on to metformin plus pioglitazone studies, patients in the placebo group were switched to sitagliptin 100 mg after 26 weeks. The safety and tolerability of canagliflozin 100 and 300 mg were assessed in Population 1 and in a broader population of patients with T2DM enrolled in 8 double-blind, placebo- and active-controlled, Phase 3 studies (N = 9439; Population 2). Population 2 included 26-week data from the studies described above, as well as the 52-week study of canagliflozin as add-on to metformin versus glimepiride,[14] the 26-week study in older patients aged ≥55–≤80 years,[20] the 26-week study in patients with moderate renal impairment (baseline estimated glomerular filtration rate ≥30–<50 mL/min/1.73 m2),[12] and CANVAS.[26] Safety analyses for CANVAS, an ongoing event-driven study, were performed using data up to a cut-off date of September 15, 2011.\n\nAt screening, eligible patients must have had inadequately controlled T2DM with diet and exercise (monotherapy study) or while on the protocol-designated background antihyperglycemic agent (AHA) therapy. Key inclusion criteria for most studies included HbA1c ≥7.0% and ≤10.5% at screening and repeated fasting plasma glucose (FPG) <15.0 mmol/L during the pretreatment phase. The age range for most studies was ≥18–≤80 years; exceptions include the study in older patients aged ≥55–≤80 years; CANVAS, which enrolled patients aged ≥30 years (with CV history) or ≥50 years (with presence of CV risk factors) and had no upper age limit; and the study in patients with moderate renal impairment, which enrolled patients aged ≥25 years with no specified upper age limit. Common exclusion criteria included a history of diabetic ketoacidosis or type 1 diabetes; severe renal impairment; history of myocardial infarction, unstable angina, revascularization procedure, or a cerebrovascular accident within 3 months of screening; uncontrolled hypertension; and alanine aminotransferase level >2 times the upper limit of normal (ULN) or total bilirubin >1.5 times the ULN at screening. Details of the study design, including randomization, blinding, and glycemic rescue therapy, have previously been reported for the individual studies included in these pooled datasets.[1213141517182026]\n\nAll studies included in this analysis were conducted in accordance with ethical principles that comply with the Declaration of Helsinki and were consistent with Good Clinical Practices and applicable regulatory requirements. Study protocols and amendments were approved by the Institutional Review Boards and Independent Ethics Committees. All patients provided written informed consent prior to participation in the studies.\n\nStudy endpoints and assessments\nThis post hoc analysis evaluated changes from baseline in HbA1c, FPG, body weight, and systolic and diastolic BP at week 52 in Population 1 (N = 2313) and in a subgroup of patients from India (n = 124); safety and tolerability were assessed in these patients based on adverse event (AE) reports through week 52. Since therapy with canagliflozin and sitagliptin were not concurrently initiated in Population 1 (i.e., patients in the placebo groups of the monotherapy, add-on to metformin, and add-on to metformin plus pioglitazone studies switched to sitagliptin 100 mg after 26 weeks), direct comparisons for efficacy parameters at week 52 cannot be made as the placebo/sitagliptin group served as a control group for safety purposes only. Therefore, efficacy findings are reported for canagliflozin 100 and 300 mg, while safety findings are reported for canagliflozin 100 and 300 mg and placebo/sitagliptin. Safety and tolerability were also assessed in Population 2 (N = 9439) and in a subgroup of patients from India (n = 1038) through the primary time point of studies (i.e., week 26 or 52, or the cut-off date of September 15, 2011 for CANVAS). Documented hypoglycemia episodes, including biochemically documented episodes (≤3.9 mmol/L) and severe episodes (i.e., requiring the assistance of another individual or resulting in seizure or loss of consciousness), were also evaluated separately in patients from India in Population 2 in the pooled placebo-controlled studies by baseline use of AHAs associated with hypoglycemia, and in the individual add-on to metformin versus glimepiride study.\n\nStatistical analyses\nEfficacy analyses were conducted using the modified intent-to-treat population, which included all randomized patients who received ≥1 dose of double-blind study drug. The last observation carried forward approach was used to impute missing data; for patients who received glycemic rescue therapy, the last postbaseline value prior to initiation of rescue was used for analysis. An analysis of covariance model, with treatment and stratification factors as fixed effects and the corresponding baseline value for each endpoint as a covariate, was used to assess primary endpoints. The least squares (LS) mean changes from baseline were estimated. Safety analyses included all reported AEs, regardless of rescue therapy, and included all randomized patients who received ≥1 dose of double-blind study drug.\n\nRESULTS\nPatient disposition and baseline characteristics\nBaseline demographic and disease characteristics were generally similar across treatment groups within each population [Tables 1 and 2]. Patients from India were younger and tended to have a lower baseline body weight and BMI compared with patients in the overall populations. In Population 1, 23.9% of patients in the overall population discontinued the study compared with 16.9% of patients from India; rates of discontinuation with canagliflozin 100 and 300 mg and noncanagliflozin were 21.4%, 20.4%, and 31.7%, respectively, in the overall population and 14.3%, 15.9%, and 22.6%, respectively, in patients from India. In Population 2, rates of discontinuation were similar in the overall population and Indian subgroup (15.3% and 14.2%, respectively).\n\nTable 1 Baseline demographic and disease characteristics in the overall population and in the Indian subgroup (Population 1)\n\nTable 2 Baseline demographic and disease characteristics in the overall population and in the Indian subgroup (Population 2)\n\nEfficacy\nGlycemic parameters\nEfficacy parameters were assessed in a pooled population of patients from 4 Phase 3 studies (N = 2313; Population 1) and in a subgroup of patients from India (n = 124). Canagliflozin 100 and 300 mg provided clinically meaningful reductions in HbA1c in the overall population and in the Indian subgroup [Figure 1a]. In the overall population, LS mean reductions in HbA1c with canagliflozin 100 and 300 mg were −0.81% and −1.00%, respectively. In patients from India, reductions in HbA1c with canagliflozin 100 and 300 mg were −0.74% and −0.88%, respectively. Canagliflozin 100 and 300 mg also provided reductions in FPG in the overall population and in the Indian subgroup [Figure 1b]. In the overall population, LS mean reductions in FPG with canagliflozin 100 and 300 mg were −1.4 mmol/L and −1.8 mmol/L, respectively. In patients from India, reductions in FPG with canagliflozin 100 and 300 mg were −1.0 mmol/L and −1.8 mmol/L, respectively.\n\nFigure 1 Changes from baseline in (a) HbA1c, (b) FPG, (c) body weight, (d) systolic BP, and (e) diastolic BP in the overall population and in the Indian subgroup at week 52 (Population 1). FPG: Fasting plasma glucose, BP: Blood pressure, CANA: Canagliflozin, LS: Least squares, SE: Standard error\n\nBody weight and blood pressure\nBoth canagliflozin doses were associated with reductions in body weight in the overall population and in the Indian subgroup [Figure 1c]. In the overall population, LS mean percent reductions in body weight with canagliflozin 100 and 300 mg were −2.9% and −3.6%, respectively. In patients from India, mean percent reductions in body weight with canagliflozin 100 and 300 mg were −2.5% and −3.2%, respectively. Both canagliflozin doses also provided reductions in BP in the overall population and in the Indian subgroup [Figure 1d and e]. In the overall population, LS mean reductions in systolic BP with canagliflozin 100 and 300 mg were −3.4 mmHg and −4.1 mmHg, respectively. In patients from India, reductions with canagliflozin 100 and 300 mg were −3.4 mmHg and −4.4 mmHg, respectively. Reductions in diastolic BP with canagliflozin 100 and 300 mg were −1.9 mmHg and −1.9 mmHg, respectively, in the overall population, and −0.5 mmHg and −0.7 mmHg, respectively, in the Indian subgroup.\n\nSafety and tolerability\nIn Population 1, the overall incidence of AEs at week 52 was similar across treatment groups in the overall population and in the Indian subgroup [Table 3]. In the overall population, the incidence of AEs leading to discontinuation with canagliflozin 100 and 300 mg and noncanagliflozin was 4.6%, 4.0%, and 3.7%, respectively; the incidence of serious AEs was 4.9%, 3.8%, and 5.7%, respectively. In the Indian subgroup, 1 patient in the noncanagliflozin group and no patients treated with canagliflozin experienced AEs that led to discontinuation; 4 patients in the canagliflozin 100 mg group and no patients in the canagliflozin 300 mg and noncanagliflozin groups reported serious AEs.\n\nTable 3 Summary of overall adverse events and selected adverse events in the overall population and in the Indian subgroup at week 52 (Population 1)\n\nIn Population 2, the overall incidence of AEs was higher with canagliflozin 300 mg compared with canagliflozin 100 mg and noncanagliflozin in both the overall population and in the Indian subgroup; the incidence of AEs was lower overall in patients from India [Table 4]. In the overall population, the incidence of AEs leading to discontinuation was 4.2%, 5.6%, and 3.7% with canagliflozin 100 and 300 mg and noncanagliflozin, respectively; the incidence of serious AEs was 7.7%, 8.1%, and 8.3%, respectively. In the Indian subgroup, the incidence of AEs leading to discontinuation was 1.8%, 4.0%, and 1.4% with canagliflozin 100 and 300 mg and noncanagliflozin, respectively; the incidence of serious AEs was 7.0%, 4.6%, and 6.9%, respectively.\n\nTable 4 Summary of overall adverse events and selected adverse events in the overall population and in the Indian subgroup (Population 2)\n\nIn Populations 1 and 2, incidences of genital mycotic infections in men and women were higher with canagliflozin compared with noncanagliflozin in the overall populations and in the Indian subgroups; these AEs were mild to moderate in intensity, and few led to study discontinuation. In Population 2, the incidence of genital mycotic infections was lower across treatment groups in patients from India than in the overall population. Rates of urinary tract infections (UTIs) were generally similar across treatment groups in the overall population of Population 1; in patients from India in Population 1 (n = 124), UTI rates were lower with canagliflozin 300 mg (2.3%) versus canagliflozin 100 mg (14.3%) and noncanagliflozin (12.9%). In Population 2, UTI rates were higher with canagliflozin versus noncanagliflozin in both the overall population and in the Indian subgroup. The incidence of osmotic diuresis–related and volume depletion–related AEs was higher with canagliflozin versus noncanagliflozin in the overall population of Populations 1 and 2 and in the Indian subgroup of Population 2; in the Indian subgroup of Population 1, osmotic diuresis–related and volume depletion–related AEs were each reported by only 1 patient with canagliflozin 100 mg.\n\nAmong patients from India in the placebo-controlled studies of Population 2 not on a background AHA associated with hypoglycemia (n = 200), 4 patients experienced a documented hypoglycemia episode with canagliflozin 100 mg over 26 weeks; no documented hypoglycemia episodes were reported with canagliflozin 300 mg or placebo, and no severe episodes of hypoglycemia were reported in any treatment group [Supplemental Table 1]. Among those on a background AHA associated with hypoglycemia (n = 650), higher rates of documented hypoglycemia were seen with canagliflozin 100 and 300 mg versus placebo over 26 weeks (16.5%, 20.5%, and 11.8%, respectively); the incidence of severe hypoglycemia was 1.4%, 1.9%, and 0%, respectively. In patients from India in the study of canagliflozin as add-on to metformin (n = 109), the incidence of documented hypoglycemia was lower with canagliflozin 100 and 300 mg versus glimepiride over 52 weeks (5.9%, 2.9%, and 24.4%, respectively), despite HbA1c reductions of 0.71%, 0.65%, and 0.50%, respectively; the incidence of severe hypoglycemia was low and similar across treatment groups.\n\nSupplemental Table 1 Summary of documented hypoglycemia episodes in the Indian subgroup (Population 2)*, †\n\nClick here for additional data file.\n\n DISCUSSION\nFindings from this post hoc analysis of pooled Phase 3 studies demonstrated that canagliflozin provided glycemic improvements and reductions in body weight and BP in patients with T2DM from India. In contrast to what was seen in the initial analysis that included the CANVAS substudies,[25] canagliflozin provided dose-dependent reductions in HbA1c in patients from India, which is consistent with findings across Phase 3 studies of canagliflozin.[91011121314151617181920] Similar to what has been reported in studies of canagliflozin in other Asian populations,[27282930] canagliflozin was associated with reductions in body weight in patients from India, despite the relatively lower baseline body weight and BMI of these patients. The reductions in body weight were consistent with those observed with canagliflozin in the overall population and in other Phase 3 studies of canagliflozin in broader populations.[91011121314151617181920]\n\nBecause canagliflozin lowers blood glucose through an insulin-independent mechanism, the glycemic improvements and reductions in body weight and BP provided by canagliflozin may be particularly beneficial in treating Asian patient populations that generally have a higher prevalence of insulin resistance and beta-cell dysfunction.[31] As canagliflozin does not directly affect insulin secretion or insulin sensitivity, it is expected that canagliflozin would be similarly efficacious in Asian patients compared with a broader population of patients with T2DM, as demonstrated in this analysis. Incretin-based therapies, such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, may lose effectiveness over time as insulin resistance worsens and beta cells deteriorate.[32] Canagliflozin provides reductions in HbA1c comparable to what has been reported with DPP-4 and GLP-1 agonists in Asian patients with T2DM[3334353637] and has been shown to improve model-based indices of insulin sensitivity and beta-cell function with sustained treatment.[38]\n\nCanagliflozin was generally well tolerated in patients with T2DM from India with a safety profile similar to that seen in previous Phase 3 studies and in the overall populations reported in the current manuscript.[91011121314151617181920] In the broader safety population (Population 2), the incidence of male and female genital mycotic infections was lower in patients from India compared with the overall population and other Phase 3 studies of canagliflozin.[91011121314151617181920] A similar pattern of genital mycotic infections has been reported in studies of canagliflozin in other Asian populations,[27282930] as well as in studies of other SGLT2 inhibitors in Asian patients.[394041] The incidence of osmotic diuresis–related and volume depletion–related AEs was also lower across treatment groups in patients from India than in the overall Population 2.\n\nIn Population 2, the incidence of documented hypoglycemia among patients from India not on background AHAs associated with hypoglycemia was low across treatment groups. Among patients from India on a background AHA associated with hypoglycemia (i.e., insulin and/or sulfonylurea), the incidence of documented hypoglycemia was higher with both canagliflozin doses compared with placebo; the incidence of severe hypoglycemia episodes was low across groups. These findings are consistent with the overall population and other Phase 3 studies of canagliflozin, in which the incidence of hypoglycemia was low when canagliflozin was used in conjunction with background therapies that are not associated with hypoglycemia, and higher with background therapies associated with hypoglycemia.[9101314151617181920]\n\nLimitations of this study include the relatively small sample size of patients from India, the lack of a control group for week 52 efficacy data, and the post hoc analysis of data. Longer-term prospective studies would provide a better assessment of the durability of canagliflozin in patients with T2DM from India and would confirm that the efficacy and safety findings from studies of canagliflozin in broader patient populations also apply to these patients.\n\nCONCLUSIONS\nIn summary, canagliflozin provided glycemic improvements and reductions in body weight and BP and was generally well-tolerated in patients with T2DM from India on a range of background therapies.\n\nFinancial support and sponsorship\nThis study was sponsored by Janssen Research and Development, LLC. Editorial support was provided by Kimberly Fuller, Ph.D., of MedErgy, and was funded by Janssen Global Services, LLC.\n\nConflicts of interest\nK.M.P.K., V.M., B.S., P.G., and G.B. have no competing financial interests. J.X., G.M., and R.Q. are full-time employees of Janssen Research and Development, LLC.\n\nAcknowledgments\nCanagliflozin has been developed by Janssen Research and Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation.\n\nThis study was previously presented, in part, in abstract form at the 10th International Diabetes Federation-Western Pacific Region Congress; 21–24 November 2014; Suntec, Singapore.\n==== Refs\nREFERENCES\n1 Rawal LB Tapp RJ Williams ED Chan C Yasin S Oldenburg B Prevention of type 2 diabetes and its complications in developing countries: A review Int J Behav Med 2012 19 121 33 21590464 \n2 Guariguata L Whiting DR Hambleton I Beagley J Linnenkamp U Shaw JE Global estimates of diabetes prevalence for 2013 and projections for 2035 Diabetes Res Clin Pract 2014 103 137 49 24630390 \n3 Anjana RM Pradeepa R Deepa M Datta M Sudha V Unnikrishnan R Prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) in urban and rural India: Phase I results of the Indian Council of Medical Research-INdia DIABetes (ICMR-INDIAB) study Diabetologia 2011 54 3022 7 21959957 \n4 Ramachandran A Snehalatha C Viswanathan V Burden of type 2 diabetes and its complications – The Indian scenario Curr Sci 2002 83 1471 6 \n5 Mohan V Sandeep S Deepa R Shah B Varghese C Epidemiology of type 2 diabetes: Indian scenario Indian J Med Res 2007 125 217 30 17496352 \n6 Sosale A Prasanna Kumar KM Sadikot SM Nigam A Bajaj S Zargar AH Chronic complications in newly diagnosed patients with type 2 diabetes mellitus in India Indian J Endocrinol Metab 2014 18 355 60 24944931 \n7 Unnikrishnan R Anjana RM Mohan V Diabetes in South Asians: Is the phenotype different? Diabetes 2014 63 53 5 24357697 \n8 Rosenstock J Aggarwal N Polidori D Zhao Y Arbit D Usiskin K Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes Diabetes Care 2012 35 1232 8 22492586 \n9 Bode B Stenlöf K Harris S Sullivan D Fung A Usiskin K Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes Diabetes Obes Metab 2015 17 294 303 25495720 \n10 Stenlöf K Cefalu WT Kim KA Jodar E Alba M Edwards R Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: Findings from the 52-week CANTATA-M study Curr Med Res Opin 2014 30 163 75 24073995 \n11 Leiter LA Yoon KH Arias P Langslet G Xie J Balis DA Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: A randomized, double-blind, phase 3 study Diabetes Care 2015 38 355 64 25205142 \n12 Yale JF Bakris G Cariou B Nieto J David-Neto E Yue D Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease Diabetes Obes Metab 2014 16 1016 27 24965700 \n13 Stenlöf K Cefalu WT Kim KA Alba M Usiskin K Tong C Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise Diabetes Obes Metab 2013 15 372 82 23279307 \n14 Cefalu WT Leiter LA Yoon KH Arias P Niskanen L Xie J Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial Lancet 2013 382 941 50 23850055 \n15 Lavalle-González FJ Januszewicz A Davidson J Tong C Qiu R Canovatchel W Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: A randomised trial Diabetologia 2013 56 2582 92 24026211 \n16 Schernthaner G Gross JL Rosenstock J Guarisco M Fu M Yee J Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: A 52-week randomized trial Diabetes Care 2013 36 2508 15 23564919 \n17 Wilding JP Charpentier G Hollander P González-Gálvez G Mathieu C Vercruysse F Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: A randomised trial Int J Clin Pract 2013 67 1267 82 24118688 \n18 Forst T Guthrie R Goldenberg R Yee J Vijapurkar U Meininger G Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone Diabetes Obes Metab 2014 16 467 77 24528605 \n19 Yale JF Bakris G Cariou B Yue D David-Neto E Xi L Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease Diabetes Obes Metab 2013 15 463 73 23464594 \n20 Bode B Stenlöf K Sullivan D Fung A Usiskin K Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: A randomized trial Hosp Pract (1995) 2013 41 72 84 23680739 \n21 Sha S Devineni D Ghosh A Polidori D Hompesch M Arnolds S Pharmacodynamic effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, from a randomized study in patients with type 2 diabetes PLoS One 2014 9 e105638 25166023 \n22 Devineni D Curtin CR Polidori D Gutierrez MJ Murphy J Rusch S Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus J Clin Pharmacol 2013 53 601 10 23670707 \n23 Polidori D Sha S Ghosh A Plum-Mörschel L Heise T Rothenberg P Validation of a novel method for determining the renal threshold for glucose excretion in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus J Clin Endocrinol Metab 2013 98 E867 71 23585665 \n24 Devineni D Morrow L Hompesch M Skee D Vandebosch A Murphy J Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin Diabetes Obes Metab 2012 14 539 45 22226086 \n25 Kumar KM Mohan V Sethi B Gandhi P Bantwal G Xie J Efficacy and Safety of Canagliflozin in Patients with Type 2 Diabetes Mellitus from India. Poster Presented at: The 10th International Diabetes Federation Western Pacific Region (IDF-WPR) Congress; 21-24 November 2014 Singapore Suntec \n26 Neal B Perkovic V de Zeeuw D Mahaffey KW Fulcher G Stein P Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS) – A randomized placebo-controlled trial Am Heart J 2013 166 217 223.e11 23895803 \n27 Ji L Han P Liu Y Yang G Dieu Van NK Vijapurkar U Canagliflozin in Asian patients with type 2 diabetes on metformin alone or metformin in combination with sulphonylurea Diabetes Obes Metab 2015 17 23 31 25175734 \n28 Inagaki N Kondo K Yoshinari T Maruyama N Susuta Y Kuki H Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, 12-week study Diabetes Obes Metab 2013 15 1136 45 23782594 \n29 Inagaki N Kondo K Yoshinari T Takahashi N Susuta Y Kuki H Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: A 24-week, randomized, double-blind, placebo-controlled, phase III study Expert Opin Pharmacother 2014 15 1501 15 25010793 \n30 Inagaki N Kondo K Yoshinari T Kuki H Efficacy and safety of canagliflozin alone or as add-on to other oral antihyperglycemic drugs in Japanese patients with type 2 diabetes: A 52-week open-label study J Diabetes Investig 2015 6 210 8 \n31 Ma RC Chan JC Type 2 diabetes in East Asians: Similarities and differences with populations in Europe and the United States Ann N Y Acad Sci 2013 1281 64 91 23551121 \n32 Campbell RK Cobble ME Reid TS Shomali ME Distinguishing among incretin-based therapies. Pathophysiology of type 2 diabetes mellitus: Potential role of incretin-based therapies J Fam Pract 2010 59 9 Suppl 1 S5 9 20824239 \n33 Mohan V Yang W Son HY Xu L Noble L Langdon RB Efficacy and safety of sitagliptin in the treatment of patients with type 2 diabetes in China, India, and Korea Diabetes Res Clin Pract 2009 83 106 16 19097665 \n34 Pan C Xing X Han P Zheng S Ma J Liu J Efficacy and tolerability of vildagliptin as add-on therapy to metformin in Chinese patients with type 2 diabetes mellitus Diabetes Obes Metab 2012 14 737 44 22369287 \n35 Pan CY Yang W Tou C Gause-Nilsson I Zhao J Efficacy and safety of saxagliptin in drug-naïve Asian patients with type 2 diabetes mellitus: A randomized controlled trial Diabetes Metab Res Rev 2012 28 268 75 22081481 \n36 Yang W Pan CY Tou C Zhao J Gause-Nilsson I Efficacy and safety of saxagliptin added to metformin in Asian people with type 2 diabetes mellitus: A randomized controlled trial Diabetes Res Clin Pract 2011 94 217 24 21871686 \n37 Yang W Guan Y Shentu Y Li Z Johnson-Levonas AO Engel SS The addition of sitagliptin to ongoing metformin therapy significantly improves glycemic control in Chinese patients with type 2 diabetes J Diabetes 2012 4 227 37 22672586 \n38 Polidori D Mari A Ferrannini E Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes Diabetologia 2014 57 891 901 24585202 \n39 Ji L Ma J Li H Mansfield TA T’joen CL Iqbal N Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus: A randomized, blinded, prospective phase III study Clin Ther 2014 36 84 100.e9 24378206 \n40 Kaku K Inoue S Matsuoka O Kiyosue A Azuma H Hayashi N Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: A phase II multicentre, randomized, double-blind, placebo-controlled trial Diabetes Obes Metab 2013 15 432 40 23194084 \n41 Kaku K Watada H Iwamoto Y Utsunomiya K Terauchi Y Tobe K Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter-2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: A combined phase 2 and 3 randomized, placebo-controlled, double-blind, parallel-group comparative study Cardiovasc Diabetol 2014 13 65 24678906\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2230-9500",
"issue": "20(3)",
"journal": "Indian journal of endocrinology and metabolism",
"keywords": "Fasting blood glucose; HbA1c; hyperglycemia; oral medications; type 2 diabetes",
"medline_ta": "Indian J Endocrinol Metab",
"mesh_terms": null,
"nlm_unique_id": "101555690",
"other_id": null,
"pages": "372-80",
"pmc": null,
"pmid": "27186557",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "24678906;23895803;21959957;23194084;22226086;24026211;23680739;23782594;20824239;25802729;24528605;24357697;23464594;25166023;22081481;24585202;23279307;19097665;22672586;23850055;23564919;17496352;25175734;23585665;21871686;24630390;21590464;22492586;24118688;24378206;24965700;25205142;22369287;24073995;24944931;25010793;23670707;23551121;25495720",
"title": "Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from India.",
"title_normalized": "efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from india"
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"activesubstancename": "CANAGLIFLOZIN"
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{
"abstract": "A 77-year-old man with a complaint of impaired consciousness was brought to our emergency department. The patient was referred to our department because of a huge retroperitoneal tumor and multiple pulmonary nodules detected on computed tomography. Owning to an abnormally high level of dehydroepiandrosterone sulfate, right adrenal cancer was suspected. Pathological examination of the retroperitoneal tumor by echo-guided pericutaneous biopsy revealed an adrenocortical carcinoma. Under the diagnosis of stage IV adrenocortical carcinoma, mitotane therapy was started in May 2013. We adjusted the mitotane dose on the basis of the clinical evidence and the adrenocorticotropic hormone and cortisol levels.The tumors had increased in size after 2 months of the mitotane therapy. However, 2 months later, the tumor had significantly decreased in size. The treatment was continued for 53 months until he could no longer take medications orally, because of his advanced age, worse condition, and disuse syndrome.",
"affiliations": "Department of Urology, Saiseikai Yokohamashi Nanbu Hospital.;Department of Urology, Saiseikai Yokohamashi Nanbu Hospital.;Department of Urology, Saiseikai Yokohamashi Nanbu Hospital.;Department of Urology, Saiseikai Yokohamashi Nanbu Hospital.;Department of Pathology, Saiseikai Yokohamashi Nanbu Hospital.",
"authors": "Yamashita|Daisuke|D|;Hanai|Takahiro|T|;Onuki|Tatsuaki|T|;Suzuki|Kotaro|K|;Nakayama|Takashi|T|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D008939:Mitotane",
"country": "Japan",
"delete": false,
"doi": "10.5980/jpnjurol.110.12",
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"issn_linking": "0021-5287",
"issue": "110(1)",
"journal": "Nihon Hinyokika Gakkai zasshi. The japanese journal of urology",
"keywords": "adrenocortical carcinoma; mitotane",
"medline_ta": "Nihon Hinyokika Gakkai Zasshi",
"mesh_terms": "D000306:Adrenal Cortex Neoplasms; D018268:Adrenocortical Carcinoma; D000368:Aged; D018931:Antineoplastic Agents, Hormonal; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008939:Mitotane; D016896:Treatment Outcome",
"nlm_unique_id": "2984841R",
"other_id": null,
"pages": "12-17",
"pmc": null,
"pmid": "31956212",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A CASE REPORT: A PATIENT WITH METASTATIC ADRENOCORTICAL CARCINOMA EXCLUSIVELY TREATED WITH MITOTANE WITH LONG-TERM FOLLOW-UP.",
"title_normalized": "a case report a patient with metastatic adrenocortical carcinoma exclusively treated with mitotane with long term follow up"
} | [
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"activesubstancename": "HYDROCORTISONE"
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"abstract": "BACKGROUND\nFoscarnet (trisodium phosphonoformate hexahydrate) is standard treatment for ganciclovir-resistant cytomegalovirus (CMV) infections. In the kidney, foscarnet-induced injury may be attributed to reversible tubulointerstitial lesions, but foscarnet crystals have also been observed within glomerular capillaries, suggesting that foscarnet can lead to glomerular lesions such as crescentic glomerulonephritis. We present biopsy and autopsy findings of foscarnet induced nephropathy in a transplanted kidney, with a particular emphasis on the histopathology and electron micrographic peculiarities of drug crystal deposits.\n\n\nMETHODS\nA 72-year-old Caucasian male patient with a deceased donor kidney was treated with several foscarnet applications due to ganciclovir-resistant CMV infection. Transplant kidney biopsy revealed massive glomerular crystalline precipitates, resulting in crescentic glomerulonephritis and tubular damage. The last foscarnet application was complicated with several infections and kidney graft failure. Autopsy revealed multi-organ damage due to foscarnet crystal precipitations associated with systemic CMV and fungal infection. On autopsy of kidney specimens, we succeeded in preserving the rectangular flat plate-like foscarnet crystals in stacks detected by transmission electron microscopy (TEM) after 100% alcohol fixation. The chemical composition of the crystals was confirmed by attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy.\n\n\nCONCLUSIONS\nTransplant kidney biopsy remains the gold standard in distinguishing between foscarnet crystalline glomerular and/or tubulointerstitial lesions, and various forms of rejection and other causes of impaired renal function in transplant kidney.",
"affiliations": null,
"authors": "Pleško|Jerica|J|;Kovač|Damjan|D|;Arsov|Zoran|Z|;Lindič|Jelka|J|;Škoberne|Andrej|A|;Ferluga|Dušan|D|;Kojc|Nika|N|",
"chemical_list": "D000998:Antiviral Agents; D017245:Foscarnet; D015774:Ganciclovir",
"country": "Germany",
"delete": false,
"doi": "10.5414/CNP96S23",
"fulltext": null,
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"issn_linking": "0301-0430",
"issue": "96(1)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D000368:Aged; D064591:Allografts; D000998:Antiviral Agents; D017245:Foscarnet; D015774:Ganciclovir; D006801:Humans; D007668:Kidney; D016030:Kidney Transplantation; D008297:Male; D009395:Nephritis, Interstitial",
"nlm_unique_id": "0364441",
"other_id": null,
"pages": "127-132",
"pmc": null,
"pmid": "34643504",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Glomerular and tubulointerstitial foscarnet nephropathy of kidney allograft with emphasis on ultrastructural findings: A case report.",
"title_normalized": "glomerular and tubulointerstitial foscarnet nephropathy of kidney allograft with emphasis on ultrastructural findings a case report"
} | [
{
"companynumb": "SI-NOVARTISPH-NVSC2021SI293353",
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"activesubstancename": "CYCLOSPORINE"
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... |
{
"abstract": "Cutaneous metastasis is considered as a hazardous condition depending on the mean survival around 9 months, which usually originates from cancers of the breast, lung, ovary, colon, and rarely from the cervix. The crucial prognostic factor of cutaneous metastasis depends on the period between the primary malignancy and cutaneous metastasis. We report two cases of the unusual presentation of squamous cell cancer of the cervix that developed vulvar and umbilical metastasis in the 5th month of primary treatment. Both of our patients survived for 11 months following the primary treatment. In addition, our first case is the earliest vulvar recurrence of cervical carcinoma in the English literature following appropriate medical and surgical management.",
"affiliations": "Gaziantep University Faculty of Medicine, Department of Obstetrics and Gynecology, Gaziantep, Turkey.;Gaziantep University Faculty of Medicine, Department of Obstetrics and Gynecology, Gaziantep, Turkey.;Gaziantep University Faculty of Medicine, Department of Pathology, Gaziantep, Turkey.;Gaziantep University Faculty of Medicine, Department of Obstetrics and Gynecology, Gaziantep, Turkey.;Gaziantep University Faculty of Medicine, Department of Obstetrics and Gynecology, Gaziantep, Turkey.;Gaziantep University Faculty of Medicine, Department of Obstetrics and Gynecology, Gaziantep, Turkey.",
"authors": "Özcan|Hüseyin Çağlayan|HÇ|;Mustafa|Aynur|A|;Bozdağ|Zehra|Z|;Sucu|Seyhun|S|;Uğur|Mete Gürol|MG|;Balat|Özcan|Ö|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.4274/tjod.40225",
"fulltext": "\n==== Front\nTurk J Obstet GynecolTurk J Obstet GynecolTJODTurkish Journal of Obstetrics and Gynecology2149-93222149-9330Galenos Publishing 10.4274/tjod.402252272Case ReportEarly vulvar and umbilical incisional scar recurrence of cervical squamous cell carcinoma: Earlier than usually expected Özcan Hüseyin Çağlayan 1*Mustafa Aynur 1Bozdağ Zehra 2Sucu Seyhun 1Uğur Mete Gürol 1Balat Özcan 1\n1 \nGaziantep University Faculty of Medicine, Department of Obstetrics and Gynecology, Gaziantep, Turkey\n\n2 \nGaziantep University Faculty of Medicine, Department of Pathology, Gaziantep, Turkey\n* Address for Correspondence: Gaziantep University Faculty of Medicine, Department of Obstetrics and Gynecology, Gaziantep, Turkey Phone: +90 342 360 60 60 E-mail: ozcan.caglayan8@hotmail.com6 2017 15 6 2017 14 2 141 144 13 2 2017 27 4 2017 ©Turkish Journal of Obstetrics and Gynecology published by Galenos Publishing.2017This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Cutaneous metastasis is considered as a hazardous condition depending on the mean survival around 9 months, which usually originates from cancers of the breast, lung, ovary, colon, and rarely from the cervix. The crucial prognostic factor of cutaneous metastasis depends on the period between the primary malignancy and cutaneous metastasis. We report two cases of the unusual presentation of squamous cell cancer of the cervix that developed vulvar and umbilical metastasis in the 5th month of primary treatment. Both of our patients survived for 11 months following the primary treatment. In addition, our first case is the earliest vulvar recurrence of cervical carcinoma in the English literature following appropriate medical and surgical management.\n\nSquamous cell cervical cancerumbilical metastasisvulvar metastasis\n==== Body\nINTRODUCTION\nCervical cancer recurrence depends on the cancer’s clinical stage and may manifest as local or distant metastasis in different organs. Recurrence occurs most commonly in the pelvis, which includes the parametrium or lymph nodes, and in the vagina. Recurrence can rarely occur in the skin, ranging between 0.1-1.3%. In most cases, they manifest as an asymptomatic dermal/subcutaneous plaque, ulcer or nodule(1).\n\nWe report two unusual presentations of cervical squamous cell carcinoma with early vulvar and umbilical metastasis.\n\nCASE REPORTS\nCase 1\nA woman aged 41 years was admitted to a state hospital with pelvic pain, urinary burning, and vaginal bleeding. The patient was referred to our hospital after a cervical biopsy revealed cervical squamous cell carcinoma. On our physical examination, we observed an exophytic necrotic mass measuring 8x9 cm confined to the cervix with no parametrial invasion. According to the International Federation of Gynecology and Obstetrics classification, we established the diagnosis as stage 1b-2 cervical cancer. We excised the mass through the vagina route and performed a type 3 radical hysterectomy (Wertheim) with pelvic-paraaortic lymph node dissection followed by radiotherapy. In the fifth month after surgical treatment, we observed a 2x3-cm ulcerated nodular vulvar lesion (Figure 1). The lesion in the vulva was excised following abdominopelvic computerized tomography (CT) imaging, which revealed no significant pathology. The biopsy specimen showed squamous cell carcinoma (Figure 2). A paclitaxel and carboplatin combined chemotherapy protocol was used. Following 2 cycles of chemotherapy, positron emission tomography-CT revealed diffuse metastases in the abdominopelvic site. Despite and alternative protocol (gemcitabine and bevacizumab) administration, there was no response. The patient died in the 11th month of the postoperative period.\n\nCase 2\nA woman aged 54 years who was post-menopausal presented with vaginal bleeding that had persisted for 3 months. A vaginal examination revealed a cervical mass measuring 1x1.5 cm. Histologic examination of the mass showed cervical squamous cell carcinoma. A Wertheim operation was performed and there was no lymph node involvement and the mass had negative surgical borders (stage 1b-1). A Papanicolaou smear was obtained from the vaginal cuff 3 months later and the result was negative. The patient presented with severe abdominal pain, which was localized along the incisional scar region of her umbilicus five months after the primary surgical treatment. Abdominal CT revealed an umbilical mass measuring 4x4.5 cm in diameter (Figure 3). We considered that the fixed mass was inoperable; it included all layers of the umbilical wall and extended from umbilicus to the upper anterior abdominal wall with massive adhesions. We performed a partial resection of the mass and pathologic examination revealed metastatic squamous cell carcinoma. Two cycles of chemotherapy, including paclitaxel-carboplatin in the first cycle and bevacizumab-gemcitabine in the second cycle, and radiotherapy was administered. The patient died in the 11th month of her medication.\n\nDISCUSSION\nCutaneous metastasis usually originates from cancers of the breast, lung, ovary, colon, and rarely from the cervix. Cervical carcinoma metastases frequently occur in the vulva and anterior abdominal wall or scalp, extremities, and the umbilical surgical scar can be affected, albeit rarely(1). Invasive interventions, including paracentesis, laparoscopy, and laparotomy can also play a role in metastases of the cervix(2). In addition, cutaneous metastases have an incidence of 0.8% in treated cervical cancers(3). Adenocarcinoma and undifferentiated carcinoma of the cervix are the primary histopathologic types that contribute to cutaneous metastasis. However, there is no correlation between its prevalence and clinical stages(4).\n\nCervical carcinoma can spread either locally or through lymphatic vessels. The lymphatic route usually follows pelvic, paraaortic and/or supraclavicular nodes, respectively. Cervical lymphatics are drained through pre-ureteral, post-ureteral, and uterosacral nodes, but these routes cannot clarify vulvar involvement. Vaginal-vulvar pathways and hematogenous invasion could be the possible routes of vulvar and umbilical incisional scar invasions, respectively. These theories have not been proven by either histologic or imaging methods. Tumor invasion to pelvic organs and the vulva can be explained by the close anatomic relationship(5). Patients with cervical cancer metastasis can present with different symptoms. In our cases, painless skin lesions and severe abdominal pain localized in the umbilicus were the first signs of metastases during follow-up. It is very rare to detect cutaneous vulvar metastasis originating from cervical cancer before between 3.5 and 6 years after surgery(2,4). However, this is the earliest vulvar metastasis (in the 5th month of primary treatment) of cervical cancer in the English literature. A review of the relevant literature concerning vulvar metastasis is summarized in Table 1. In contrary, there are some reports regarding early umbilical recurrence of cervical cancer in the 4th, 5th, and 6th months of primary treatment(2,8,9). There are approximately 17 reports regarding umbilical metastasis of cervical cancer in the literature(2,10,11,12,13,14).\n\nCutaneous metastasis is considered as a hazardous condition; the mean life span is around 9 months. Regarding one study that included 1190 patients with cervical carcinoma, the incidence skin metastasis was 1.3%, which increased with advanced clinical stage as follows: 0.8% in stage 1, 1.2% in stages 2 and 3, and increasing to 4.8% in stage 4. The presence of such metastasis is associated with a high mortality rate within 2 years, regardless of the treatment procedure(15). Therefore, the crucial prognostic factor depends on the period between the primary malignancy and cutaneous metastasis. In other words, earlier metastasis means poorer prognosis. Survival was 11 months in both of our cases, most probably due to the short recurrence period (5th month) following the primary surgical treatment.\n\nPalliative surgery, chemotherapy, radiation therapy alone and/or in combination with cisplatin-based chemotherapy are well-known treatment modalities in managing advanced recurrent disease(16). Based on that, we applied platinum-based chemotherapy in both cases and concurrent radiotherapy after detecting vulvar and umbilical scar extensions, respectively. Nevertheless, there was no response and we administered an alternative protocol (gemcitabine and bevacizumab) in both cases, which may have prolonged survival to up to approximately one year.\n\nIn conclusion, cervical cancer rarely leads to vulvar and umbilical incisional scar metastasis, which can be accepted as a poor prognostic factor accompanied with short life span. Physicians should always keep in mind the likelihood of recurrence at these locations during follow-up in cases of cervical cancer. To the best of our knowledge, our first case is the earliest vulvar recurrence and our second case is one of the earliest recurrences of cervical carcinoma in the English literature following appropriate surgical and medical management.\n\nEthics\n\nInformed Consent: Consent forms were filled out by our two patients.\n\nPeer-review: Externally peer-reviewed.\n\nAuthorship Contributions\n\nConcept: A.M., Ö.B., Design: Z.B., Data Collection or Processing: A.M., S.S., Analysis or Interpretation: M.G.U., H.Ç.Ö., Literature Search: H.Ç.Ö., S.S., Writing: H.Ç.Ö., M.G.U.\n\nConflict of Interest: No conflict of interest was declared by the authors.\n\nFinancial Disclosure: The authors declared that this study has received no financial support.\n\nTable 1 Reported cases of vulvar metastasis in cervical cancer\nFigure 1 A 2x3-cm ulcerated fragile, firm, nodular lesion with irregular boundaries on the right labium majus with focal central hemorrhage\nFigure 2 Infiltrating tumor nests consisting of atypical squamous cells with large abundant eosinophilic cytoplasm and a large vesicular nucleus with prominent nucleoli\nFigure 3 Computerized tomography image of metastatic umbilical mass\n==== Refs\nReferences\n1 Kim WJ Park HJ Kim HS Kim SH Ko HC Kim BS et al Vulvar metastasis from squamous cell carcinoma of the cervix clinically presenting as lymphangioma circumcriptum Ann Dermatol 2011 23 64 7 21738365 \n2 Deka D Gupta N Bahadur A Dadhwal V Mittal S Umbilical Surgical and Vulvar Metastases Secondary to advanced cervical Squamous cell carcinoma: a report of two cases Arch Gynecol Obstet 2010 281 761 4 19789888 \n3 Bolli JA Doering DL Bosscher JR Day TG Jr Rao CV Owens K et al Squamous cell carcinoma antigen: clinical utility in squamous cell carcinoma of uterine cervix Gynecol Oncol 1994 55 169 73 7959279 \n4 Srivastava K Singh S Srivastava M Srivastava AN Incisional skin metastasis of a squamous cell cervical carcinoma 3.5 years after radical treatment-a case report Int J Gynecol Cancer 2005 15 1183 6 16343209 \n5 Quinn MA Benedet JL Odicino F Maisonneuve P Beller U Creasman WT et al Carcinoma of the cervix uteri. FIGO 6th Annual Report on the Results of Treatment in Gynecological Cancer Int J Gynaecol Obstet 2006 95(Suppl 1) S43 103 17161167 \n6 Grabiec M Walentowicz M Marszałek A Multiple skin metastases to vulva from carcinoma of the cervical stump Ginekol Pol 2010 81 140 3 20232714 \n7 Richmond NA Viera MH Velazquez-Vega J Kerdel FA Cutaneous Metastasis of Cervical Adenocarcinoma to the Vulva Dermatol Online J 2013 19 18172 24011272 \n8 Naumann RW Spencer S An umbilical metastasis after laparoscopy for squamous cell carcinoma of the cervix Gynecol Oncol 1997 64 507 9 9062161 \n9 Liro M Kobierski J Brzoska B Isolated metastasis of cervical cancer to the abdominal wall: a case report Ginekol Pol 2002 73 704 8 12369298 \n10 Martinez-Palones JM Gil-Moreno A Perez-Benavente MA Garcia-Gimenez A Xercavins J Umbilical metastasis after laparoscopic retroperitoneal paraaortic lymphadenectomy for cervical cancer: a true port-site metastasis? Gynecol Oncol 2005 97 292 5 15790481 \n11 Agostini A Carcopino X Franchi F Cravello L Lecuru F Blanc B Port site metastasis after laparoscopy for uterine cervical carcinoma Surg Endosc 2003 17 1663 5 12915964 \n12 Tun NM Yoe L Sister Mary Joseph Nodule: A Rare Presentation of Squamous Cell Carcinoma of the Cervix Ochsner J 2015 15 256 8 26412998 \n13 Samaila MO Adesiyun AG Waziri GD Koledade KA Kolawole AO Cutaneous umbilical metastases in post-menopausal females with gynaecological malignancies J Turk Ger Gynecol Assoc 2012 13 204 7 24592039 \n14 Tseng MJ Ho KC Lin G Yen TC Tsai CS Lai CH Peritoneal metastasis in primary cervical cancer: a case report Eu J Gynaecol Oncol 2007 28 225 8 \n15 Imachi M Tsukamoto N Kinoshita S Nakano H Skin metastasis from carcinoma of the uterine cervix Gynecol Oncol 1993 48 349 54 8462901 \n16 Behtash N Ghaemmaghami F Yarandi F Ardalan FA Khanafshar N Cutaneous metastasis from carcinoma cervix at the drain site: a case report Gynecol Oncol 2002 85 209 11 11925148\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2149-9330",
"issue": "14(2)",
"journal": "Turkish journal of obstetrics and gynecology",
"keywords": "Squamous cell cervical cancer; umbilical metastasis; vulvar metastasis",
"medline_ta": "Turk J Obstet Gynecol",
"mesh_terms": null,
"nlm_unique_id": "101656661",
"other_id": null,
"pages": "141-144",
"pmc": null,
"pmid": "28913152",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports",
"references": "9062161;17624093;8462901;17161167;15790481;7959279;22028576;16343209;24592039;24011272;11925148;19789888;12915964;26412998;12369298;20232714",
"title": "Early vulvar and umbilical incisional scar recurrence of cervical squamous cell carcinoma: Earlier than usually expected.",
"title_normalized": "early vulvar and umbilical incisional scar recurrence of cervical squamous cell carcinoma earlier than usually expected"
} | [
{
"companynumb": "TR-ACCORD-055991",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "There are very few cases of nondiverticulitis episodes of colonic perforation in the acute postoperative period following kidney transplantation described in the literature. Various nondiverticular causes of colonic perforations include ischemia, malignancy, cytomegalovirus (CMV) enterocolitis, and nonobstructive colonic dilatation. Immunosuppressive medication can contribute to colonic perforation, placing kidney recipients at risk for these complications. Since 2011, there have been 2 cases of transverse colonic perforation in the early postoperative period following renal transplantation at our institution. Both patients underwent urgent exploratory laparotomy with resection of perforated transverse colon and creation of a proximal colostomy. The aim of this study is to review the cases of colonic perforation following renal transplantation to gain a greater understanding of this rare occurrence. Despite the lack of a clear cause of perforation, it is imperative to have a high index of suspicion for colonic perforations in these immunocompromised patients to provide prompt surgical management and improved outcomes.",
"affiliations": "Division of General Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, NE. Electronic address: emily.zurbuchen@unmc.edu.;Division of Transplantation Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, NE.;Division of Transplantation Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, NE.",
"authors": "Zurbuchen|Emily A|EA|;Sela|Nathalie|N|;Maskin|Alexander|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2021.01.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "53(3)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000368:Aged; D003082:Colectomy; D044684:Colon, Transverse; D003108:Colonic Diseases; D003125:Colostomy; D005260:Female; D006801:Humans; D007416:Intestinal Perforation; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1070-1074",
"pmc": null,
"pmid": "33573821",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transverse Colonic Perforation in Renal Transplant Recipients During the Early Postoperative Period: A Case Series.",
"title_normalized": "transverse colonic perforation in renal transplant recipients during the early postoperative period a case series"
} | [
{
"companynumb": "US-MYLANLABS-2021M1027868",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "... |
{
"abstract": "Longitudinal electronic healthcare data hold great potential for drug safety surveillance. The tree-based scan statistic (TBSS), as implemented by the TreeScan® software, allows for hypothesis-free signal detection in longitudinal data by grouping safety events according to branching, hierarchical data coding systems, and then identifying signals of disproportionate recording (SDRs) among the singular events or event groups.\n\n\n\nThe objective of this analysis was to identify and visualize SDRs with the TBSS in historical data from patients using two antifungal drugs, itraconazole or terbinafine. By examining patients who used either itraconazole or terbinafine, we provide a conceptual replication of a previous TBSS analyses by varying methodological choices and using a data source that had not been previously used with the TBSS, i.e., the Optum Clinformatics™ claims database. With this analysis, we aimed to test a parsimonious design that could be the basis of a broadly applicable method for multiple drug and safety event pairs.\n\n\n\nThe TBSS analysis was used to examine incident events and any itraconazole or terbinafine use among US-based patients from 2002 through 2007. Event frequencies before and after the first day of drug exposure were compared over 14- and 56-day periods of observation in a Bernoulli model with a self-controlled design. Safety events were classified into a hierarchical tree structure using the Clinical Classifications Software (CCS) which mapped International Classification of Diseases, 9th Revision (ICD-9) codes to 879 diagnostic groups. Using the TBSS, the log likelihood ratio of observed versus expected events in all groups along the CCS hierarchy were compared, and groups of events that occurred at disproportionally high frequencies were identified as potential SDRs; p-values for the potential SDRs were estimated with Monte-Carlo permutation based methods. Output from TreeScan® was visualized and plotted as a network which followed the CCS tree structure.\n\n\n\nTerbinafine use (n = 223,968) was associated with SDRs for diseases of the circulatory system (14- and 56-day p = 0.001) and heart (14-day p = 0.026 and 56-day p = 0.001) as well as coronary atherosclerosis and other heart disease (14-day p = 0.003 and 56-day p = 0.004). For itraconazole use (n = 36,025), the TBSS identified SDRs for coronary atherosclerosis and other heart disease (p = 0.002) and complications of an implanted or grafted device (14-day p = 0.001 and 56-day p < 0.05). Use of both drugs was associated with SDRs for diseases of the digestive system at 14 days (p < 0.05) and this SDR had been observed among terbinafine users in a previous TBSS analysis with a different data source. The TreeScan® visualization facilitated the identification of the atherosclerosis and other heart disease SDRs as well as highlighting the consistency of the SDR for diseases of the digestive system across drugs and data sources.\n\n\n\nWith the TBSS, we identified potential SDRs related to the circulatory system that may reflect the cardiac risk that was described in the itraconazole product label. SDRs for diseases of the digestive system among terbinafine users were also reported in a previous signal detection analysis, although other SDRs from the previous publications were not replicated. The TBSS visualizations aided in the understanding and interpretation of the TBSS output, including the comparisons to the previous publications. In this conceptual replication, differences in the results observed in our analysis and the previous analyses could be attributable to variation in modeling and design choices as well as factors that were intrinsic to the underlying data sources. The broad consistency, but far from perfect concordance, of our results with the known safety profile of these antifungals including the risks from the itraconazole product label supports the rationale for continued investigations of signal detection methods across differing data sources and populations.",
"affiliations": "Worldwide Safety and Regulatory, Pfizer Inc., 219 E. 42nd St, New York, NY, 10017, USA. Stephen.Schachterle@pfizer.com.;Worldwide Safety and Regulatory, Pfizer Inc., 219 E. 42nd St, New York, NY, 10017, USA.;Worldwide Safety and Regulatory, Pfizer Inc., 219 E. 42nd St, New York, NY, 10017, USA.;Worldwide Safety and Regulatory, Pfizer Inc., 219 E. 42nd St, New York, NY, 10017, USA.;Worldwide Safety and Regulatory, Pfizer Inc., 219 E. 42nd St, New York, NY, 10017, USA.",
"authors": "Schachterle|Stephen E|SE|0000-0001-6017-2670;Hurley|Sharon|S|;Liu|Qing|Q|;Petronis|Kenneth R|KR|;Bate|Andrew|A|",
"chemical_list": "D000935:Antifungal Agents; D017964:Itraconazole; D000077291:Terbinafine",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40264-018-00784-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0114-5916",
"issue": "42(6)",
"journal": "Drug safety",
"keywords": null,
"medline_ta": "Drug Saf",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D000935:Antifungal Agents; D003201:Computers; D016208:Databases, Factual; D006801:Humans; D017964:Itraconazole; D012984:Software; D000077291:Terbinafine",
"nlm_unique_id": "9002928",
"other_id": null,
"pages": "727-741",
"pmc": null,
"pmid": "30617498",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": "23023988;19282026;23512870;22315152;28913963;9674627;21935385;22136184;29446176;16013091;23867812;27835661;20049851;28490262;26951233;24700557;15183243;17510856;15084500;24300404;30074538;26954351;19757412;12926717;23790544",
"title": "An Implementation and Visualization of the Tree-Based Scan Statistic for Safety Event Monitoring in Longitudinal Electronic Health Data.",
"title_normalized": "an implementation and visualization of the tree based scan statistic for safety event monitoring in longitudinal electronic health data"
} | [
{
"companynumb": "US-JNJFOC-20170913951",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TERBINAFINE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report two cases of young diabetic patients with intractable neovascular glaucoma (NVG) who were successfully managed with bevacizumab and mitomycin C-augmented trabeculectomy.\n\n\nRESULTS\nTwo young patients present with severe NVG secondary to diabetic proliferative retinopathy. The glaucoma was unresponsive to conventional medical therapy and complete panretinal photocoagulation. Both patients underwent augmented trabeculectomy with MMC and intravitreal injection of bevacizumab. Iris rubeosis resolved within 48 h. Both patients have a follow-up period of 6 months and the intraocular pressure (IOP) remain between 10-15 mmHg.\n\n\nCONCLUSIONS\nControlling IOP due to NVG in young diabetic patients is difficult and augmented trabeculectomy has a very high failure rate. The addition of intravitreal bevacizumab in the management of NVG particularly in young diabetic patients may improve the success rate of IOP control. It is known that bevacizumab retards neovascularisation. It may also be modulating wound-healing response as well. Bevacizumab may have a potential role in the surgical management of NVG.",
"affiliations": "Department of Ophthalmology, Tennent Institute of Ophthalmology, Gartnavel General Hospital, Glasgow, Scotland. kurtsc01@yahoo.co.uk",
"authors": "Cornish|K Spiteri|KS|;Ramamurthi|S|S|;Saidkasimova|S|S|;Ramaesh|K|K|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab",
"country": "England",
"delete": false,
"doi": "10.1038/eye.2008.113",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0950-222X",
"issue": "23(4)",
"journal": "Eye (London, England)",
"keywords": null,
"medline_ta": "Eye (Lond)",
"mesh_terms": "D000328:Adult; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D003922:Diabetes Mellitus, Type 1; D005260:Female; D015355:Glaucoma, Neovascular; D006801:Humans; D007429:Intraocular Pressure; D058449:Intravitreal Injections; D014130:Trabeculectomy; D016896:Treatment Outcome; D014792:Visual Acuity; D055815:Young Adult",
"nlm_unique_id": "8703986",
"other_id": null,
"pages": "979-81",
"pmc": null,
"pmid": "18451875",
"pubdate": "2009-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intravitreal bevacizumab and augmented trabeculectomy for neovascular glaucoma in young diabetic patients.",
"title_normalized": "intravitreal bevacizumab and augmented trabeculectomy for neovascular glaucoma in young diabetic patients"
} | [
{
"companynumb": "GB-MYLANLABS-2008S1010852",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BRIMONIDINE TARTRATE"
},
"drugadditional": "3... |
{
"abstract": "BACKGROUND\nOrthopedic trauma patients with Gustilo grade III injuries to the distal third of lower extremity present challenges to optimum reconstructive management. There is no consensus on the ideal autologous tissue for transfer in large lower extremity defect reconstruction. We present a large case series utilizing the vastus lateralis (VL) free flap for lower extremity Gustilo grade III reconstruction.\n\n\nMETHODS\nThis is a case series of patients who underwent VL free tissue transfer for Gustilo grade III injuries. A total of 38 free tissue transfers were performed for lower extremity reconstruction, 19 of which were VL flaps. Mean interval between injury and reconstruction was 46 days (range 7-240 days).\n\n\nRESULTS\nThe mean wound size was 11.37 cm x 11.42 cm and all cases underwent delayed reconstruction. Seven day flap viability was 100% and 30-day flap viability was 17/19 (89%). There were six complications: two hematomas requiring drainage, one flap dehiscence, one distal flap loss requiring a reverse saphenous vein graft extension, and two complete flap losses. Of the two failed flaps, one was attributed to heparin-induced thrombocytopenia and the other to venous congestion complicated by methicillin-resistant Staphylococcus aureus infection.\n\n\nCONCLUSIONS\nThe VL free flap is a reliable and versatile flap that can be tailored and tangentially thinned to match the shape and size of a defect, and the long pedicle allows the surgeon to stay away from the zone of injury. This flap should be strongly considered for lower extremity reconstruction, especially in salvage operations for large defects. © 2015 Wiley Periodicals, Inc. Microsurgery 37:212-217, 2017.",
"affiliations": "Department of Surgery, Inova Fairfax, Falls Church, VA.;School of Medicine, Virginia Commonwealth University, Richmond, VA.;Department of Surgery, Inova Fairfax, Falls Church, VA.;Private Practice, Plastic Surgery & Dermatology Associates, Fairfax, VA.",
"authors": "Kaminsky|Alexander J|AJ|;Li|Sean S|SS|;Copeland-Halperin|Libby R|LR|;Miraliakbari|Reza|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/micr.22526",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0738-1085",
"issue": "37(3)",
"journal": "Microsurgery",
"keywords": null,
"medline_ta": "Microsurgery",
"mesh_terms": "D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D058752:Free Tissue Flaps; D006085:Graft Survival; D006801:Humans; D015601:Injury Severity Score; D007869:Leg Injuries; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D052097:Quadriceps Muscle; D019651:Reconstructive Surgical Procedures; D018570:Risk Assessment; D017695:Soft Tissue Injuries; D016896:Treatment Outcome; D014945:Wound Healing; D055815:Young Adult",
"nlm_unique_id": "8309230",
"other_id": null,
"pages": "212-217",
"pmc": null,
"pmid": "26559177",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The vastus lateralis free flap for lower extremity gustilo grade III reconstruction.",
"title_normalized": "the vastus lateralis free flap for lower extremity gustilo grade iii reconstruction"
} | [
{
"companynumb": "PHHY2017US063962",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",
"d... |
{
"abstract": "Social factors may affect the available sources of toxic substances and causes of poisoning; and these factors may change over time. Additionally, understanding the characteristics of patients with acute toxic poisoning is important for treating such patients. Therefore, this study investigated the characteristics of patients with toxic poisoning. Patients visiting one of 3 hospitals in 2003 and 2011 were included in this study. Data on all patients who were admitted to the emergency departments with acute toxic poisoning were retrospectively obtained from medical records. Total 939 patients were analyzed. The average age of patients was 40.0 ± 20 yr, and 335 (36.9%) patients were men. Among the elements that did not change over time were the facts that suicide was the most common cause, that alcohol consumption was involved in roughly 1 of 4 cases, and that there were more women than men. Furthermore, acetaminophen and doxylamine remained the most common poisoning agents. In conclusion, the average patient age and psychotic drug poisoning has increased over time, and the use of lavage treatment has decreased.",
"affiliations": "Department of Emergency Medicine, Korea University Medical Center, Seoul, Korea.",
"authors": "Jang|Hak-Soo|HS|;Kim|Jung-Youn|JY|;Choi|Sung-Hyuk|SH|;Yoon|Young-Hoon|YH|;Moon|Sung-Woo|SW|;Hong|Yun-Sik|YS|;Lee|Sung-Woo|SW|",
"chemical_list": "D000082:Acetaminophen; D004319:Doxylamine",
"country": "Korea (South)",
"delete": false,
"doi": "10.3346/jkms.2013.28.10.1424",
"fulltext": "\n==== Front\nJ Korean Med SciJ. Korean Med. SciJKMSJournal of Korean Medical Science1011-89341598-6357The Korean Academy of Medical Sciences 2413334410.3346/jkms.2013.28.10.1424Original ArticlePharmacology, Drug Therapy & ToxicologyComparative Analysis of Acute Toxic Poisoning in 2003 and 2011: Analysis of 3 Academic Hospitals Jang Hak-Soo Kim Jung-Youn Choi Sung-Hyuk Yoon Young-Hoon Moon Sung-Woo Hong Yun-Sik Lee Sung-Woo Department of Emergency Medicine, Korea University Medical Center, Seoul, Korea.\nAddress for Correspondence: Jung-Youn Kim, MD. Department of Emergency Medicine, Korea University Medical Center, Guro Hospital, 148 Gurodong-gil, Guro-gu, Seoul 152-703, Korea. Tel: +82.2-2626-1561, Fax: +82.2-2626-1562, yellowwizard@hanmail.net10 2013 25 9 2013 28 10 1424 1430 12 4 2013 19 8 2013 © 2013 The Korean Academy of Medical Sciences.2013This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Social factors may affect the available sources of toxic substances and causes of poisoning; and these factors may change over time. Additionally, understanding the characteristics of patients with acute toxic poisoning is important for treating such patients. Therefore, this study investigated the characteristics of patients with toxic poisoning. Patients visiting one of 3 hospitals in 2003 and 2011 were included in this study. Data on all patients who were admitted to the emergency departments with acute toxic poisoning were retrospectively obtained from medical records. Total 939 patients were analyzed. The average age of patients was 40.0 ± 20 yr, and 335 (36.9%) patients were men. Among the elements that did not change over time were the facts that suicide was the most common cause, that alcohol consumption was involved in roughly 1 of 4 cases, and that there were more women than men. Furthermore, acetaminophen and doxylamine remained the most common poisoning agents. In conclusion, the average patient age and psychotic drug poisoning has increased over time, and the use of lavage treatment has decreased.\n\nPoisoningEpidemiologyEmergency Service, Hospital\n==== Body\nINTRODUCTION\nMany patients in emergency departments are admitted due to toxic poisoning. According to domestic research, patients admitted to emergency departments due to toxic poisoning represent between 0.68% and 5.5% of total visiting patients (1). Patients with poisoning may have been exposed to the toxic materials voluntarily or involuntarily, and the sources of the substances and reasons for poisonings are diverse. Various social factors can affect poisoning, and the characteristics of poisoning can change over time (2).\n\nExcluding patients with chronic addiction, most patients with symptomatic acute toxic poisoning requiring medical care are treated in emergency departments. Thus, it is necessary to understand the characteristics of patients with acute toxic poisoning admitted to emergency departments in order to develop a better approach for treating such patients.\n\nNationwide data on toxic poisoning have not been collected in Korea. Moreover, much of the existing research is limited to singe-center studies. Recently, multi-center studies were carried out, and some reports attempted to standardize data-collection systems (3, 4). Still, most studies used only data that were limited in scope and scale. However, the need for a regular data collection has increased due to the fact that epidemiologic data, regarding toxic poisoning, requires consistent monitoring. Therefore, the authors hypothesized that the characteristics of poisoning cases would change over time. And an epidemiological study of poisoning cases in the year 2003 and 2011 was conducted to compare the differences over time, with the ultimate goal of developing data that could potentially help in the treatment of poisoned patients.\n\nMATERIALS AND METHODS\nStudy subjects\nFor this investigation, the year from January 1 to December 31, 2003 was set, and the year from January 1 to December 31, 2011 was set. Data from patients visiting the emergency department at one of 3 university hospitals in Korea (1 in Gangnam and 1 in Gangbuk, Seoul, and 1 in Gyeonggi-do) who were admitted due to toxic poisoning were evaluated. As there are three hospitals affiliated with the one medical center at which the study was conducted, data were collected through a unified protocol from the emergency departments of all three hospitals. Electronic record-keeping at the medical center began in 2003, and thus 2003 was chosen as the first year of study, and 2011 was chosen for its most recent data.\n\nStudy design\nThe clinical history, symptoms, and laboratory data were extracted about all patients who visited the emergency department because of toxic poisoning. Data on patients with poisoning due to any category of toxic substance, including caustic agents, irritants, natural plant and animal poisons, chemical agents, and medications were analysed.\n\nIn 2003, total 370 patients were admitted, and in 2011, total 569 patients were admitted respectively. The epidemiological characteristics of all 939 patients were investigated. Data on gender, age, cause of exposure to toxic material, purchase route, type of toxic material, admission details, and mortality rates were retrospectively investigated using patients' clinical histories. Patients thought to have been poisoned by a single intake of alcohol or by food poisoning were excluded.\n\nStatistical analyses\nThe chi-square test and one-way ANOVA were used for frequency analysis. All statistical calculations were performed using SPSS 14.0 (SPSS, Inc, Chicago, IL, USA). The level of significance was set at P < 0.05. Data are expressed as mean ± SD. The characteristics of patients admitted in 2003 and those admitted in 2011 were compared.\n\nEthics statement\nThis research was carried out after receiving approval from the institutional review board of the Korea University Ansan Hospital (No. AS12174). Informed consent was waived by the board.\n\nRESULTS\nA total of 939 patients including, 370 patients from the 2003 and 569 patients from the 2011 were included in the analysis. The mean ± standard deviation of age of all patients was 40.0 ± 20.0 yr, (37.03 ± 18.7 yr in 2003, and 41.65 ± 20.5 yr in 2011); the age of patients with acute toxic poisoning significantly increased over time (P < 0.001). The male-to-female ratio was 1:1.57 in 2003 (144 male and 226 female patients) and 1:1.86 in the 2011 (199 male and 370 female patients); however, the sex ratio was not significantly different between 2003 and 2011. Most cases of toxic poisoning were due to suicidal committing in both 2003 (74.9%) and 2011 (72.0%); accidental poisoning was the next most common cause of poisoning. The toxic substances were most often obtained from pharmacies (i.e., as over-the-counter medications) and other stores in 2003; however, in 2011, the most common routes of purchse changed to hospital-prescribed drugs followed by over-the-counter medications. Patients visiting the emergency department for acute toxic poisoning represented 0.39% of all patients in both 2003 and 2011. The proportion of cases accompanied by alcohol consumption did not change significantly from the 2003 to the 2011 (25.7% and 26.7%, respectively) (Table 1).\n\nOf the 307 patients admitted in 2003, 92 were aged in their 30s, 83 in their 20s, and 68 in their 40s. Among the 569 patients admitted in 2011, 124 patients were aged in their 30s, 90 in their 40s, and 88 in their 20s. Although, most of the patients were aged 20-40 yr in both year, the age distribution had significantly statistical difference between the 2 yr (P = 0.03) (Fig. 1).\n\nMost admissions in both 2003 and 2011 occurred during the night rather than during the day (Fig. 2). Further, admissions were most common in May and August in 2003, and in April, September, and October in 2011; however, there were no meaningful differences between the 2003 and 2011 (Fig. 3).\n\nIn 2003, substances that were the most common cause of poisoning were over-the-counter drugs, acetaminophen and doxylamine, followed by household items and chemical substances. In 2011, although the percentage of poisonings caused by over-the-counter drugs decreased, they remained the most common causative agents, followed by psychiatric drugs (Table 2).\n\nFifty percent of patients returned to their home in 2003, whereas only 36.2% of patients in 2011 returned to their homes. Among poisoned patients, 6 and 9 patients died in 2003 and 2011, respectively. Lavage was conducted in 45.9% of patients in 2003 but was done only in 5.4% in 2011 Table 3, Fig. 4. Additionally, charcoal administration increased in 2011. These changes between the 2 yr were all statistically significant (Table 3). Among the patients who died in both years, paraquat was the most common toxic substances: paraquat poisoning was responsible for 5 of the 6 deaths in 2003 and 5 of the 9 deaths in 2011 (Table 4).\n\nComparing the characteristics of poisoning cases between hospitals revealed that the Gangbuk hospital had a total of 32,606 Emergency Department patients in 2003, and 47,597 in 2011. The Gangnam hospital had 24,344 Emergency Department patients in 2003, and 54,545 in 2011. Finally, The Ansan hospital had 36,877 Emergency Department patients in 2003 and 44,763 in 2011.\n\nThe characteristics of three hospitals are shown in the Table 5. There was no difference in sex or age of poisoning patients among the three hospitals. In 2003, the Gangnam hospital showed a relatively lower rate of poisoning by prescription drugs, with a higher rate of use of over-the-counter drugs. The Gyunggido hospital continued to have the highest rate of accidental exposure among the three hospitals in both years.\n\nDISCUSSION\nIn emergency departments, the proportion of patients with toxic poisoning differs depending on which substances are defined as toxic and classification of these toxic materials. Toxic poisoning may be broadly or narrowly defined, and its definition may differ in different countries and societies, and over time (2). In addition, collection and analysis of nationwide data on poisoning plays a key role in informing policies for toxic substances, including the production and sales management of toxic substances as well as, placement of poison control centers and stores of rare antidotes (4, 5). Therefore, relying on treatment data from other countries is problematic. In USA for example, nationwide toxic poisoning centers participate in the Toxic Poisoning Surveillance System (TESS), and data are stored in a database operated by the American Association of Poison Control Centers (AAPCC) (6). However, there are no standardized nationwide guidelines for such classifications in Korea (3).\n\nOur study focused on determining the changes over time of the characteristics of Korean patients with toxic poisoning who were admitted to emergency departments. Comparative research was conducted on data from patients attending 3 university hospitals in Korea in 2003 and in 2011.\n\nThe average age of patients with toxic poisoning increased from 37.03 ± 18.7 yr in 2003 to 41.65 ± 20.5 yr in 2011. Among the 370 patients assessed in 2003, 90 (24.3%), 82 (22.2%) and 68 (18.4%) patients were aged in their 30s, 20s, and 40s; among the 569 patients assessed in 2011, 122 (21.4%), 90 (18.8%), and 88 (18.5%) patients were in their 30s, 40s, and 20s. The most common age range for patients with poisoning seemed to increase after a decade from patients in their 20s-30s to those in their 30s-40s. In 1992, Song et al. (1) reported that patients in their 20s were the highest proportion (35.7%) of patients with toxic poisoning. In addition, Lee et al. (7) also found that the most common age group with poisoning patients were in their 20s (46.8%) in 1996. Kang et al. (8) also reported that 23.7% of patients with toxic poisoning were in their 20s in 1999. On the other hand, the mean age of patients with toxic poisoning was 47.8 yr according to data reported by Park et al. (3) in 2004, and So et al., (4) reported that the mean age was 46.02 ± 20.12 yr, with patients in their 40s representing the most common age group (20.4%) in 2008. In other countries, Burillo-Putze et al. (9) reported that the average age of patients with toxic poisoning in Spain in 2003 was 33 yr. Xiang et al. (10) reported that most patients with toxic poisoning admitted to emergency departments in USA were aged 35-44 yr. In Korea, the highest portions of poisoning to toxic substances were found in young and socially active people in their 30s and 40s, and the average age appears to be increasing slightly.\n\nIn this study, toxic poisoning was more common in women than men during both years. In 2003, the male-to-female ratio was 1:1.57 (144 males to 226 females), and in 2011, the ratio was 1:1.86 (199 males to 370 females). In other data from Korea, Lee et al. (7) reported a male-to-female ratio of 1:1.73 for patients with poisoning. Likewise, the proportion of females among poisoning patients was reported to be 52.1% by So et al. (4), 53.3% by Kang et al. (8), and 68.4% by Song et al. (1). Park et al. (3) reported a male-to-female ratio of 1:1.14. Given that female patients are exposed to toxic substances at a higher rate than male patients, and the main cause of poisoning being consumption of toxic material while committing suicide, this finding is most likely related to the high rate of suicidal attempts among women (14). According to Xiang et al. (10), 56.7% of all suicide attempts are made by women. In contrast to that reported in Korea, Burillo-Putze et al. (9) reported that 56% of suicides are committed by men in Spain.\n\nMost cases of toxic poisoning are due to consumption of toxic substances for committing suicide, while accidental poisoning are the second most common cause. Burillo-Putze et al. (9) reported that 77.7% of patients admitted to emergency departments with acute toxic poisoning had attempted suicide, which are similar to our study findings: 74.9% and 72.0% of admissions in 2003 and 2011, respectively, were due to suicide attempts. Similar rates were reported by Song et al. (67.2% in 1992) (1), Lee et al. (86.8% in 1996) (7), Kang et al. (72.6% in 1998) (8), Park et al. (89.2% in 2004) (3), and So et al. (61.0% in 2008) (4).\n\nThe proportion of toxic poisoning cases due to prescribed drugs tended to increase over time. In 2003, pharmacies were the most common source of toxic materials followed by other types of stores. However, in 2011, substances most commonly source causing poisoning were hospital prescriptions, followed by over-the-counter drugs. Lee et al. (7) reported that in 1996, 47.8% of toxic poisonings were due to pharmacy-purchased drugs, which is similar to our results for the year 2003.\n\nIn our study, in both 2003 and 2011, patients with toxic poisoning represented 0.39% of all patients admitted to emergency departments. Meanwhile, Burillo-Putze et al. (9), reported this percentage as 0.66% in Spain. In the Korean study by Song et al. (1) in 1992, the rate was 0.68%. These rates are somewhat lower than that reported in the 1980s, in which the proportions were between 3.2% and 5.5% (2).\n\nThere was little change in the proportion of toxic poisoning cases that were accompanied by alcohol consumption (25.7% in 2003 and 26.7% in 2011). According to the report by Kang et al. (8) in 1996, 44.4% of male and 27.8% of female patients admitted with toxic poisoning involved alcohol consumption, and Burillo-Putze et al. (9) reported 26.3% of toxic poisonings were accompanied by alcohol consumption.\n\nMost cases of toxic poisoning occur during the night rather than during the day, and no temporal change was observed in the present study. Kang et al. (8) reported that in 1998, most patients with toxic poisoning visited emergency departments between 8 p.m. and 12 p.m., whereas the least number of patients were admitted between 4 a.m. and 8 a.m. (5.2%). In 2003, most patients with toxic poisoning were admitted to emergency departments in May and August, whereas in 2011, most were admitted in April, September, and October; however, this difference was not significant. Kang et al. (8) reported that in 1998, 33.3% of cases of toxic poisoning occurred in September, October, and November, which is similar to the incidence observed in 2011 in the present study and Shin et al. (15).\n\nThe most important factor to consider in the treatment of acute toxic poisoning is the causative substance. Decontamination and treatment methods as well as antidotes used are different according to toxic substances. Therefore, access to data on substances commonly associated with toxic poisoning is very important for doctors dealing with patients in emergency departments. The substances most commonly causing poisoning vary depending on the patient's society, for example, the ease of purchase and acquisition of toxic substances; changes over time may also be affected. In our research, over-the-counter drugs and household toxic materials were the most common causative agents in 2003. Meanwhile, the percentage of poisonings due to over-the-counter drugs decreased in 2011; however, these drugs remained the most common causative substances, followed by psychiatric drugs. The subject of psychiatric treatment has traditionally been taboo in Korea. Therefore, the treatment of such conditions has historically been rare. The growing number of patients receiving psychiatric treatment in recent years may have facilitated the acquisition and use of psychiatric drugs, especially antipsychotics.\n\nIn 2003 and 2011, 50% and 36.2% of patients with toxic poisoning returned to their homes, respectively. Compared to the 2003, the proportion of discharged patients decreased and the proportion of self-discharged patients increased in the 2011. This may be because many poisonings were due to consumption of toxic substances while committing suicide. Although poisoning itself may not be life threatening, the ratio of patients for whom hospital transfers or hospitalization would have been recommended increased because of reattempted suicides. Nevertheless, many patients do not want to be hospitalized, and increased awareness of a doctor's obligation to obtain informed consent is thought to be one of the reasons for the increased rates of self-discharge.\n\nSix patients in the 2003 and 9 patients in the 2011 expired from toxic poisoning. Among them, 5 of 6 patients in 2003 and 6 of 9 patients in 2011 died due to paraquat poisoning. In Korea, the sale and production of paraquat are forbidden by law since 2012. Accordingly, we expect a decrease in mortality due to paraquat poisoning.\n\nIn terms of treatment, the most remarkable change over time was observed in the procedure of gastric lavage. In 2003, 45.92% of patients received lavage treatment, whereas in 2011 only 5.4% received lavage. In addition, the administration of charcoal increased significantly in 2011 (Table 3). Lavage was previously used indiscriminately for gastrointestinal decontamination in cases of acute poisoning. However, it is now thought that the advantages of lavage do not justify the risk of complications, such as aspiration. The study by Benson et al. (11) emphasized that gastric lavage should only be performed under correct indications. Even though the rate of unnecessary use of gastric lavage has decreased, the rate is still high according to a domestic study (12). In addition, a recent study in Denmark regarding gastric lavage revealed that the procedure was still overused (13). This study is important as it is the first to report the decrease in use of gastric lavage in Korea, and as such, is in accordance with the international trend.\n\nComparing the characteristics of poisoning cases between hospitals revealed that the Gangnam hospital experienced more cases that involved the consumption of alcohol. The Gangbuk hospital had a higher proportion of poisoning cases out of the total patients admitted to the emergency department. The Gyeonggi-do hospital had more cases of accidental exposure and gastric lavage in comparison to the other hospitals.\n\nOne of the limitations of this study is that the use of antidotes besides lavage and charcoal was not investigated. Because we focused mainly on temporal changes, not all therapeutic information was verified. However, because antidotes are specific to each toxic substance and the toxic substances were verified, it can be assumed that antidotes were used appropriately in each case. Another limitation of this study is that although it was a multi-center study, data from only three centers were included. Because drug poisoning is affected by time, social factors, and regional factors, national data would be of great interest and allow meaningful regional comparisons. Lastly, this study was initially designed to have a 10-yr interval. However, due to electronic difficulties in data collection, the authors chose to study year 2003 and 2011. We believe the additional future studies monitoring changes over one or two decades would be greatly beneficial to gain a deeper understanding.\n\nIn conclusion, this multi-center study compared the characteristics of patients admitted to the emergency department with toxic poisoning in 2003 and 2011. Among the elements that did not change over time were the facts that suicide was the most common cause of toxic exposure, that alcohol consumption was involved in roughly one out of four cases, and that there were more female than male cases. Furthermore, acetaminophen and doxylamine remained the most common poisoning agents. On the other hand, increases in average poisoning patient age, exposure to psychiatric drugs and a decrease in gastric lavage cases were the most salient features that had changed over time. Understanding the characteristics of patients with acute toxic poisoning is important for providing optimal care. Our study results suggest that it is necessary to continuously collect data of patients admitted to emergency departments with toxic poisoning at multiple centers.\n\nThe authors have no conflicts of interest to disclose.\n\nFig. 1 Age group. Rate of emergency department visits for poisoning by age group, 2003 and 2011.\n\nFig. 2 Times to visit hospital. Rate of emergency department visits for poisoning by year and visiting time.\n\nFig. 3 Monthly distribution. Rates of emergency department visits for poisoning by month, 2003 and 2011.\n\nFig. 4 Patients treated by lavage in 2003 and 2011 (2003, 45.9%; 2011, 5.4%).\n\nTable 1 General characteristics of the subjects\n\nSD, standard deviation; ED, emergency department.\n\nTable 2 Substances of poisoning\n\nDM, diabetes mellitus.\n\nTable 3 Disposition comparison of 2003 vs 2011\n\nED, emergency department; ICU, intensive care unit.\n\nTable 4 Characteristics of expired patients in 2003 vs 2011\n\nTable 5 Characteristics of patients by 3 hospitals\n==== Refs\n1 Song KJ Cho KH Lee HS Drug intoxication patients in the emergency department J Korean Soc Emerg Med 1992 3 38 45 \n2 Han ST Lee JH Comparative analysis of acute drug intoxication between 1980s and 1990s J Korean Soc Emerg Med 1999 10 441 446 \n3 Park JK Jeong SP Kim SH Yoo IS Park JS Yoo JH Jeong SK The toxic exposure patients of Daejon province by modifiied TESS style J Korean Soc Clin Toxicol 2004 2 1 6 \n4 So BH Lee MJ Kim H Moon JM Park KH Sung AJ Yeom SR Oh SB You JY Lee KW 2008 database of Korean toxic exposures: a preliminary study J Korean Soc Clin Toxicol 2010 8 51 60 \n5 Andrew E Tellerup M Termälä AM Jacobsen P Gudjonsdottir GA Poisonings in the Nordic countries in 2007: a 5-year epidemiological follow-up Clin Toxicol (Phila) 2012 50 210 214 22372789 \n6 Litovitz T The TESS database: use in product safety assessment Drug Saf 1998 18 9 19 9466085 \n7 Lee SW Jeon JM Hong YS Analysis of self-poisoning patients J Korean Soc Emerg Med 1996 7 390 397 \n8 Kang JH Lee HN Jin YH Lee JB A clinical analysis of acute drug intoxication in emergency department setting J Korean Soc Emerg Med 1999 10 431 440 \n9 Burillo-Putze G Munne P Dueñas A Pinillos MA Naveiro JM Cobo J Alonso J Clinical Toxicology Working Group, Spanish Society of Emergency Medicine (SEMESTOX) National multicentre study of acute intoxication in emergency departments of Spain Eur J Emerg Med 2003 10 101 104 12789064 \n10 Xiang Y Zhao W Xiang H Smith GA ED visits for drug-related poisoning in the United States, 2007 Am J Emerg Med 2012 30 293 301 21367556 \n11 Benson BE Hoppu K Troutman WG Bedry R Erdman A Höjer J Mégarbane B Thanacoody R Caravati EM American Academy of Clinical Toxicology European Association of Poisons Centres and Clinical Toxicologists Position paper update: gastric lavage for gastrointestinal decontamination Clin Toxicol (Phila) 2013 51 140 146 23418938 \n12 Ok TG Cho JH Park CW Cheon SW Lee SY Kim SE Choi KH Bae JH Seo JY Ahn HC The clinical investigation of gastric lavage in patiernts with acute poisoning J Korean Soc Clin Toxicol 2005 3 22 26 \n13 Westergaard B Hoegberg LC Groenlykke TB Adherence to international recommendations for gastric lavage in medical drug poisonings in Denmark 2007-2010 Clin Toxicol (Phila) 2012 50 129 135 22292974 \n14 Lee CA Choi SC Jung KY Cho SH Lim KY Pai KS Cho JP Characteristics of patients who visit the emergency department with self-inflicted injury J Korean Med Sci 2012 27 307 312 22379343 \n15 Shin SD Suh GJ Rhee JE Sung J Kim J Epidemiologic characteristics of death by poisoning in 1991-2001 in Korea J Korean Med Sci 2004 19 186 194 15082889\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1011-8934",
"issue": "28(10)",
"journal": "Journal of Korean medical science",
"keywords": "Emergency Service, Hospital; Epidemiology; Poisoning",
"medline_ta": "J Korean Med Sci",
"mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000428:Alcohol Drinking; D002648:Child; D002675:Child, Preschool; D004319:Doxylamine; D004636:Emergency Service, Hospital; D005260:Female; D006785:Hospitals, University; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D011041:Poisoning; D012189:Retrospective Studies; D012737:Sex Factors; D013406:Suicide, Attempted; D055815:Young Adult",
"nlm_unique_id": "8703518",
"other_id": null,
"pages": "1424-30",
"pmc": null,
"pmid": "24133344",
"pubdate": "2013-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study",
"references": "22292974;23418938;22379343;9466085;12789064;21367556;22372789;15082889",
"title": "Comparative analysis of acute toxic poisoning in 2003 and 2011: analysis of 3 academic hospitals.",
"title_normalized": "comparative analysis of acute toxic poisoning in 2003 and 2011 analysis of 3 academic hospitals"
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"activesubstance": {
"activesubstancename": "ASPIRIN"
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"abstract": "Patients with common variable immunodeficiency (CVID) can develop granulomatous-lymphocytic interstitial lung disease (GLILD), which is associated with increased morbidity and mortality. Treating GLILD is a significant challenge because it is rare and can be pathologically heterogeneous. Here we describe two cases of patients with CVID-associated GLILD with biopsies demonstrating loosely organized tertiary lymphoid structures (TLSs). Based on the pivotal role that B cells play in TLS initiation and maintenance, we hypothesized that using rituximab monotherapy for B-cell depletion alone would be sufficient for the disruption of the pathologic process underlying GLILD. These two cases demonstrate that adapting a strategy of B cell depletion monotherapy may be effective in TLS-associated conditions such as GLILD.",
"affiliations": "Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.;Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.;Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.;Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.;Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. Electronic address: dwesemann@bwh.harvard.edu.",
"authors": "Ng|Julie|J|;Wright|Kyle|K|;Alvarez|Maura|M|;Hunninghake|Gary M|GM|;Wesemann|Duane R|DR|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.chest.2019.01.034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "155(5)",
"journal": "Chest",
"keywords": "B cells; common variable immunodeficiency; granulomatous lymphocytic interstitial lung disease; rituximab; tertiary lymphoid tissue",
"medline_ta": "Chest",
"mesh_terms": "D000328:Adult; D000074322:Antineoplastic Agents, Immunological; D001402:B-Lymphocytes; D001707:Biopsy, Needle; D017074:Common Variable Immunodeficiency; D005260:Female; D005500:Follow-Up Studies; D006099:Granuloma; D006801:Humans; D007150:Immunohistochemistry; D017563:Lung Diseases, Interstitial; D008297:Male; D011013:Pneumonectomy; D000069283:Rituximab; D012494:Sampling Studies; D003074:Solitary Pulmonary Nodule; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "e117-e121",
"pmc": null,
"pmid": "31060706",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "24131823;27607895;15316526;17143328;27446088;23102069;27441396;15843574;25552357;19900842;21926237;28444364;26091728;22930256;29218052",
"title": "Rituximab Monotherapy for Common Variable Immune Deficiency-Associated Granulomatous-Lymphocytic Interstitial Lung Disease.",
"title_normalized": "rituximab monotherapy for common variable immune deficiency associated granulomatous lymphocytic interstitial lung disease"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-19-03239",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "RITUXIMAB"
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{
"abstract": "Background: Erotomania, also known as de Clerambault's syndrome, is characterized by the delusion that a person has fallen in love with the patient. It occasionally appears secondary to psychiatric disorders and organic brain diseases. However, there have been no reports on cases secondary to dementia with Lewy bodies (DLB). Case Presentation: The patient was an 83-year-old woman who lived alone. Mild cognitive impairment appeared at the age of 82 years. Soon after, she had the delusional conviction that her family doctor was in love with her. Her symptoms, such as gradually progressive cognitive impairment, cognitive fluctuations, and parkinsonism, indicated DLB. She was treated with a small dose of antipsychotic agents. Conclusions: This case report suggests the possibility of de Clerambault's syndrome during the early stages of DLB. Further investigations are required to clarify the mechanism and treatment of de Clerambault's syndrome in patients with DLB.",
"affiliations": "Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Japan.",
"authors": "Suehiro|Takashi|T|;Satake|Yuto|Y|;Hashimoto|Mamoru|M|;Ikeda|Manabu|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fpsyt.2021.665868",
"fulltext": "\n==== Front\nFront Psychiatry\nFront Psychiatry\nFront. Psychiatry\nFrontiers in Psychiatry\n1664-0640\nFrontiers Media S.A.\n\n10.3389/fpsyt.2021.665868\nPsychiatry\nCase Report\nCase Report: De Clerambault's Syndrome in Dementia With Lewy Bodies\nSuehiro Takashi\n\nSatake Yuto\n\nHashimoto Mamoru\n\nIkeda Manabu *\n\nDepartment of Psychiatry, Osaka University Graduate School of Medicine, Suita, Japan\nEdited by: Breno Satler Diniz, University of Connecticut Health Center, United States\n\nReviewed by: Madia Lozupone, University of Bari Aldo Moro, Italy; Hiroshige Fujishiro, Nagoya University, Japan\n\n*Correspondence: Manabu Ikeda mikeda@psy.med.osaka-u.ac.jp\nThis article was submitted to Aging Psychiatry, a section of the journal Frontiers in Psychiatry\n\n10 6 2021\n2021\n12 66586809 2 2021\n19 5 2021\nCopyright © 2021 Suehiro, Satake, Hashimoto and Ikeda.\n2021\nSuehiro, Satake, Hashimoto and Ikeda\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBackground: Erotomania, also known as de Clerambault's syndrome, is characterized by the delusion that a person has fallen in love with the patient. It occasionally appears secondary to psychiatric disorders and organic brain diseases. However, there have been no reports on cases secondary to dementia with Lewy bodies (DLB).\n\nCase Presentation: The patient was an 83-year-old woman who lived alone. Mild cognitive impairment appeared at the age of 82 years. Soon after, she had the delusional conviction that her family doctor was in love with her. Her symptoms, such as gradually progressive cognitive impairment, cognitive fluctuations, and parkinsonism, indicated DLB. She was treated with a small dose of antipsychotic agents.\n\nConclusions: This case report suggests the possibility of de Clerambault's syndrome during the early stages of DLB. Further investigations are required to clarify the mechanism and treatment of de Clerambault's syndrome in patients with DLB.\n\nde Clerambault's syndrome\nerotomania\ndementia\ndementia with Lewy bodies\ndelusion\n==== Body\nIntroduction\n\nErotomania (de Clerambault's syndrome) is a relatively rare disorder, characterized by the delusion that a person is in love with the patient (1). The object of the delusion commonly has a higher social status than the patient and usually remains unchanged (1). The epidemiology of the disorder is unclear (2). The pure form of de Clerambault's syndrome cannot be explained by any other psychiatric disorders and a pre-existing psychiatric disorder is associated with the onset of the syndrome in its secondary form (3). Schizophrenia is reportedly the most frequent psychiatric comorbidity in the secondary form (4). Moreover, there are few reports on de Clerambault's syndrome in the clinical course of dementia (5), such as Alzheimer's disease (AD) (2, 6, 7), vascular dementia (8), and frontotemporal dementia (9).\n\nDementia with Lewy bodies (DLB) is the second most common form of degenerative dementia after AD (10). While delusions, such as delusion of theft and misidentification, are highly prevalent in patients with dementia, they are more frequent in patients with DLB (4). In addition, delusions in such patients are relatively various. For instance, delusional jealousy is observed most frequently in patients with DLB (11). However, there are no reports on de Clerambault's syndrome in patients with DLB. Herein, we report a case of de Clerambault's syndrome that appeared in the early stages of DLB.\n\nCase Description\n\nThe patient was an 83-year-old woman. She had been receiving treatment for hypertension and constipation for more than 20 years. However, she had no other medical history, including psychiatric disorders. There was no family history of psychiatric disorders or neurodegenerative disorders. Following graduation from high school, she began working in a nightclub. She got married in her twenties and had a daughter. She divorced a few years later. Following her daughter gaining employment, she started living alone. She was on public income support during her visit to our clinic. She gradually felt a lack of motivation for outdoor activities at the age of 82 years. Simultaneously, she started facing difficulty with housework and complained of mild amnesia. A few months later, she informed her daughter about the delusional thought that the family doctor drew her blood to kill her. Despite the delusion of persecution, she continued visiting the clinic. Her daughter pointed out that her thought was delusional as it was impossible. Despite all evidence to the contrary, it remained unchanged. However, the delusion suddenly changed a month later, without any specific cause. She believed that her family doctor had fallen in love with her and proposed marriage to her. The delusional conviction seemingly strengthened with time. Moreover, she gradually made up her mind to accept the proposal. Considering the gradual progression of cognitive impairment and apathy, her daughter proposed living together. She refused her daughter's proposal and continued living alone because she was convinced that she would live with her family doctor in the near future. Her daughter recommended that she visit a memory clinic. Although she did not have any insight into her delusional beliefs, she was aware of her cognitive impairment. Therefore, she visited our memory clinic and was admitted to our hospital for examination and treatment at the age of 83 years.\n\nOn her first visit to our hospital, we did not observe any apparent depressive or manic symptoms. Neurological examinations revealed mild bradykinesia, mild rigidity of the left upper and lower limbs, and chronic constipation. The results of her cognitive assessment were as follows: Mini-Mental State Examination score was 20/30, a Japanese version of the Alzheimer's Disease Assessment Scale-cognitive subscale score was 10/70, the index of subtests of the digit span of Wechsler Adult Intelligence Scale-III was 5, and Mayo Fluctuation Questionnaire score was 5 out of 8, which indicated mild recent memory impairment, attention deficit, and cognitive fluctuation (Table 1). We conducted the Neuropsychiatric Inventory 12 to assess her neuropsychiatric symptoms. She scored 20 points, involving the categories of delusion (12/12) and apathy (8/12) (Table 1). Blood test results, including vitamins, thyroid function, and infections, were all normal. Brain magnetic resonance imaging revealed mild diffuse cortical atrophy and mild bilateral hippocampal atrophy, compatible with her age (Figure 1). Perfusion single photon emission computed tomography revealed mild hypoperfusion in the bilateral parietal lobe. Myocardial accumulation of metaiodobenzylguanidine (123I-MIBG) was low (H/M = early: 1.72, delayed: 1.34) (Figure 2). The aforementioned results indicated a probable diagnosis of DLB (12).\n\nTable 1 The results of neuropsychological tests and the Neuropsychiatric Inventory (NPI).\n\n\tScore\t\nMini-Mental State Examination\t20/30\t\nJapanese version of the Alzheimer's Disease Assessment Scale-cognitive subscale score\t10/70\t\nDigit span of Wechsler Adult Intelligence Scale-III (index)\t5\t\nMayo Fluctuation Questionnaire\t5/8\t\nNeuropsychiatric Inventory 12\t\t\n Delusions\t12/12\t\n Hallucinations\t0\t\n Agitation/aggression\t0\t\n Depression\t0\t\n Anxiety\t0\t\n Euphoria\t0\t\n Apathy\t8/12\t\n Disinhibition\t0\t\n Irritability/lability\t0\t\n Aberrant motor behavior\t0\t\n Sleep disturbances\t0\t\n Eating abnormalities\t0\t\n\nFigure 1 Brain MRI of the patient showing mild diffuse atrophy, compatible with her age. (A–C) Axial sections of T1 weighted images; (D) A coronal section.\n\nFigure 2 Myocardial accumulation of metaiodobenzylguanidine (123I-MIBG) is low [H/M = early: 1.72 (A), delayed: 1.34 (B)]. The circled areas indicate heart.\n\nFollowing the examinations, she was prescribed 3 mg of donepezil, the dose of which was gradually increased to 10 mg. She was simultaneously prescribed 25 mg of quetiapine (at night) for the treatment of delusions. However, we soon discontinued quetiapine because of its adverse reactions, such as drowsiness and dizziness. We also prescribed brexpiprazole (1 mg/day) and risperidone (0.5 mg/day). However, their side effects, such as drowsiness, were extremely severe, without any amelioration of her delusion. While she did not refuse the medications, she still had no insight to her delusion. Moreover, she occasionally claimed to visit her family doctor following her discharge. We then prescribed blonanserin (4 mg/day) and continued it, with extremely mild side effects. After 2 weeks, her attitude to the delusional beliefs began to change. She gradually lost passion for her family doctor. Based on our suggestions, she changed her family doctor and was discharged from our hospital. During follow-up, she rarely talked about the previous doctor, who had been the subject of her delusion. She still lives alone, and her delusion has not recurred. She is currently on donepezil (10 mg/day) and a small amount of an antipsychotic agent, with coordination of the circumstances (non-pharmacotherapy).\n\nDiscussion\n\nDe Clerambautlt's syndrome is based on the concept of erotomania proposed by de Clerambault in 1942 (13). He considered erotomania to manifest in the following two forms: (i) pure type and (ii) secondary type. Ellie et al. proposed the diagnostic criteria of the secondary form of de Clerambault's syndrome in 1985 as follows (14): (a) a delusional conviction of being in amorous communication with another person, (b) the other person being of a relatively higher rank, (c) the other person was the first to fall in love, (d) the other person was the first to make advances, (e) sudden onset, (f) the object of the amorous delusion remains unchanged, (g) the patient provides an explanation for the paradoxical behavior of the loved one, (h) chronic course, and (i) no hallucinations. The aforementioned case history and symptoms fulfilled all criteria.\n\nClinical features of the patient, such as gradually progressive cognitive deficit, fluctuating cognition, rigidity, hypersensitivity to antipsychotics, and low uptake in 123I-MIBG myocardial scintigraphy, indicated probable DLB (12). She experienced mild cognitive impairment, as revealed by several neuropsychological tests. Moreover, her activities of daily living were relatively preserved. Therefore, de Clerambault's syndrome supposedly appeared during the early stages of DLB. Psychiatric-onset DLB has increasingly gained attention in recent years. Some studies have reported sufficiently severe delusion requiring hospitalization during the early stages of DLB (15).\n\nSudden onset is one of the features of de Clerambault's syndrome. However, the above-mentioned case was unique in that the object of the delusion was also that of persecutory delusion, immediately before the manifestation of de Clerambault's syndrome. De Clerambault reported the possible association between the emotional state, including hypomania and the occurrence of the pure type of the syndrome. In addition, cases of the syndrome secondary to affective disorders were described more frequently in the manic state than in the depressive state (16). Our examinations failed to detect any emotional problems in the patient, including the results of NPI (Table 1). However, an emotional change, such as a very mild manic episode, might have existed around the emergence of the delusion. In contrast, the patients with de Clerambault's syndrome have been often reported to interpret usual situations, behaviors, or attitudes as proof of delusional love during the initial stages of the syndrome (17). The attitude of her family doctor toward her persecutory delusion might have been interpreted in the delusional context and become the cue for the appearance of the erotomanic delusion.\n\nSchizophrenia is the most frequent disease that induces the secondary form of de Clerambault's syndrome. Nonetheless, other psychiatric disorders or conditions can also be the underlying causes. Of those diseases, only a few case reports have described de Clerambault's syndrome in patients with dementia (5). In each such report, cognitive impairment was relatively mild. Moreover, some studies have reported the association between a deficit of frontal lobe function and the appearance of delusions (5). The profile of cognitive impairment in the aforementioned case was compatible with the features suggested in previous reports. According to Kraepelin, patients suffering from erotomania usually have preserved intellectual function (17). Similarly, the occurrence of de Clerambault's syndrome may require relatively preserved cognitive function in patients with dementia. In addition, the neural correlates of the other delusions in dementia have been investigated in previous studies, some of which established the association between delusions and hypoperfusion or a functional deficit in the frontal lobe (18, 19). The same could be true of de Clerambault's syndrome in patients with dementia. This necessitates further investigations of the neural correlates of de Clerambault's syndrome.\n\nIn patients with dementia, the use of antihypertensives has been reported to be a risk of delusions. Since the present patient lived alone for a long time, her detailed medication history was uncertain. Although she seemed to have been prescribed medications for hypertension and constipation nearly 20 years according to information from herself and her daughter, we could not rule out the possibility that some medication influenced the appearance of the erotomanic delusion.\n\nApproximately 60% of patients with DLB have delusions (5). More than 50% of these patients develop delusions in the mild stages (clinical dementia rating, 0.5) (20). There have been some reports on patients with DLB and unusual delusions, such as Othello syndrome (11), delusional parasitosis (21, 22) and delusion of duplication (23). In particular, Othello syndrome, characterized by delusional beliefs of infidelity of a partner, was known to be found in as much as 26.3% of DLB (11). Although De Clerambault's syndrome and Othello syndrome have a common “sexual” theme, few reports of De Clerambault's syndrome have been reported in DLB. Inappropriate sexual behavior is relatively common in people with dementia (24, 25), and the dysfunction of frontal lobes, cortico-striatal circuit and dopaminergic pathway are known to be the bases of inappropriate sexual behavior (26, 27). However, de Clerambault's syndrome has been more associated to manic state than to depressive state (16) and depressive state is known to be more common in patients with neurodegenerative dementias including DLB (20). On the other hand, Othello Syndrome has been reported to be more associated with depression than bipolar disorder (25). The relevance to mood disturbances may account for the rare occurrence of de Clerambault's syndrome in patients with neurodegenerative dementias including DLB. Further studies are needed to prospectively investigate the association between senile onset delusions, particularly unusual delusions and DLB diagnosis. This can be attributed to previous reports on delusions being the initial symptoms in the prodromal stage of DLB (15) and their development during the mild stages of DLB (20, 28).\n\nThe treatment of de Clerambault's syndrome is relatively difficult (17). Most reports on its pharmacological treatment have suggested the usefulness of antipsychotic agents, including pimozide (12, 18), risperidone (29), and olanzapine (30). Quetiapine (50 mg/day) failed to remit the delusion in a patient with AD (6). In this case, quetiapine, risperidone, and brexpiprazole failed to exert their effectiveness because of adverse reactions. However, the impact of these agents on de Clerambault's syndrome in such patients is unclear, because the duration of administration was not long enough to judge their actual usefulness. In this case, blonanserin did not produce severe side effects and was effective against delusions in low dosage. Considering the hypersensitivity to antipsychotic drugs in patients with DLB (13), a small dosage might be recommended initially and, if necessary, the dose can be gradually increased, with a careful observation of the side effects. Further studies are required to investigate the pharmacological treatment of patients with DLB and de Clerambault's syndrome.\n\nThe aforementioned case report revealed that de Clerambault's syndrome could appear during the early stages of disease in patients with DLB. Previous studies have reported the occurrence of relatively rare delusions during the early stages of DLB. This necessitates further accumulation of knowledge about delusions in patients with DLB for an early diagnosis.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nWritten informed consent was obtained from the patient and her family for the publication of any potentially identifiable images or data included in this study.\n\nAuthor Contributions\n\nTS conducted treated the patient during admission, collected the data, and wrote the initial draft of this article. MI and YS conducted the outpatient treatment. MI, MH, and YS offered advice for the treatment and participated in the discussion of the results. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nThe authors would like to thank Dr. Masao Iwase, Kenji Yoshiyama, Tamiki Wada, Hideki Kanemoto, Kyosuke Kakeda, Sumiyo Umeda, Hirotaka Nakatani, Fuyuki Koizumi, and Maki Yamakawa for their useful comments on the study data.\n\nFunding. This study was supported by a health and labor sciences research grant (no. 20GB01001) for MI.\n==== Refs\nReferences\n\n1. Rudden M Sweeny J Frances A . Diagnosis and clinical course of erotomanic and other delusional patients. Am J Psychiatry. (1995) 147 :625–8. 10.1176/ajp.147.5.625 2327490\n2. Carrier L . Erotomania and senile dementia. Am J Psychiatry. (1987) 147 :1092. 10.1176/ajp.147.8.1092a\n3. Munro A . Delusional Disorder – Paranoia and Related Illness. Cambridge: Cambridge University Press (1999). 10.1017/CBO9780511544095\n4. Gillet T Emison SR Hassayeh F . Primary and secondary erotomania: clinical characteristics and follow-up. Acta Psychiatr Scand. (1990) 82 :65–9. 10.1111/j.1600-0447.1990.tb01357.x 2399821\n5. Cipriani G Danti S Vedovello M Nuti A Lucetti C . Understanding delusion in dementia: a review. Geriatr Gerontol Int. (2014) 14 :32–9. 10.1111/ggi.12105 23879399\n6. Brüne M Schröder SG . Erotomania variants in dementia. J Geriatr Psychiatry Neurol. (2003) 16 :232–4. 10.1177/0891988703258323 14653432\n7. Cobb JP Marks IM . Morbid jealousy featuring as obsessive–compulsive neurosis: treatment by behavioural psychotherapy. Br J Psychiatry. (1979) 134 :301–5. 10.1192/bjp.134.3.301 509011\n8. Heinik J Aharon-Peretz J Hes JP . De Clérambault's syndrome in multi-infarct dementia. Psychiatr Fenn. (1991) 22 :23–6.\n9. Olojugba C de Silva R Kartsounis LD Royan L Carter J . De Clerambault's syndrome (erotomania) as a presenting feature of fronto-temporal dementia and motor neuron disease (FTD-MND). Behav Neurol. (2007) 18 :193–5. 10.1155/2007/274156 17726249\n10. Vann Jones SA O'Brien JT . The prevalence and incidence of dementia with Lewy bodies: a systematic review of population and clinical studies. Psychol Med. (2014) 44 :673–83. 10.1017/S0033291713000494 23521899\n11. Hashimoto M . Sakamoto S, Ikeda M. Clinical features of delusional jealousy in elderly patients with dementia. J Clin Psychiatry. (2015) 76 :691–5. 10.4088/JCP.14m09018 25939090\n12. McKeith IG Boeve BF Dickson DW Halliday G Taylor JP Weintraub D . Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology. (2017) 89 :88–100. 10.1212/WNL.0000000000004058 28592453\n13. de Clérambault GG . Les psychoses passionnelles [Psychoses of passion]. In: Fretet J , editor. Oewve Pshiatrique. Paris: Presses Universitaires de France. (1942). Vol. 1 . p. 311–451.\n14. Drevets WC Rubin EH . Erotomania and senile dementia of Alzheimer type. Br J Psychiatry. (1987) 151 :400–2. 10.1192/bjp.151.3.400 3427297\n15. McKeith IG Ferman TJ Thomas AJ Blank F Boeve BF Fujishiro H . Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology. (2020) 94 :743–55. 10.1212/WNL.0000000000009323 32241955\n16. Stephen FS . “Les psychoses passionnelles” reconsidered: a review of de Clérambault's cases and syndrome with respect to mood disorders. J Psychiatry Neurosci. (1991) 16 :81–90.1911738\n17. Sampogna G Zinno F Giallonardo V Luciano M Vecchio VD Fiorillo A . The de Clérambault syndrome: more than just a delusional disorder? Int Rev Psychiatry. (2020) 32 :385–90. 10.1080/09540261.2020.1744536 32286086\n18. Nagahama Y Okina T Suzuki N Matsuda M . Neural correlates of psychotic symptoms in dementia with Lewy bodies. Brain. (2010) 133 :557–67. 10.1093/brain/awp295 19920063\n19. Reeves SJ Gould RL Powell JF Howard RJ . Origins of delusions in Alzheimer's disease. Neurosci Biobehav Rev. (2012) 36 :2274–87. 10.1016/j.neubiorev.2012.08.001 22910677\n20. Kazui H Yoshiyama K Kanemoto H Suzuki Y Sato S Hashimoto M . Differences of behavioral and psychological symptoms of dementia in disease severity in four major dementias. PLoS ONE. (2016) 11 :e0161092. 10.1371/journal.pone.0161092 27536962\n21. Magierski R Magierska J Kloszewska I Sobow T . Dementia with Lewy bodies manifested as delusional parasitosis (Ekbom's syndrome). Alzheimers Dement. (2015) 11 :781–2. 10.1016/j.jalz.2015.06.1746\n22. Ochiai S Sugawara H Kajio Y Tanaka H Ishikawa T Fukuhara R . Delusional parasitosis in dementia with Lewy bodies: a case report. Ann Gen Psychiatry. (2019) 18 :29. 10.1186/s12991-019-0253-3 31892935\n23. Solla P Mura G Cannas A Floris G Fonti D Orofino G . An unusual delusion of duplication in a patient affected by Dementia with Lewy bodies. BMC Neurol. (2017) 17 :78. 10.1186/s12883-017-0842-1 28424054\n24. Burns A Jacoby R Levy R . Psychiatric phenomena in Alzheimer's disease. IV: disorders of behaviour. Brit J Psychol. (1990) 157 :86–94. 10.1192/bjp.157.1.86 2397368\n25. Szasz G . Sexual incidents in an extended care unit for aged men. J Am Geriatr Soc. (1983) 31 :407–11. 10.1111/j.1532-5415.1983.tb03715.x 6863791\n26. Black B Muralee S Tampi RR . Inappropriate sexual behaviors in dementia. J Geriatr Psychiatry Neurol. (2005) 18 :155–62. 10.1177/0891988705277541 16100105\n27. Santa Rosa Malcher CM Roberto da Silva Gonçalves Oliveira K Fernandes Caldato MC Lopes Dos Santos Lobato B da Silva Pedroso J de Tubino Scanavino M . Sexual disorders and quality of life in Parkinson's disease. Sex Med. (2021) 9 :100280. 10.1016/j.esxm.2020.10.008 33429240\n28. Hashimoto M Yatabe Y Ishikawa T Fukuhara R Kaneda K Honda K . Relationship between dementia severity and behavioral and psychological symptoms of dementia in dementia with Lewy bodies and Alzheimer's disease patients. Geriatr Cogn Dis Extra. (2015) 5 :244–52. 10.1159/000381800 26195980\n29. Kelly BD Kennedy N Shanley D . Delusion and desire: erotomania revisited. Acta Psychiatr Scand. (2000) 102 :74–5. 10.1034/j.1600-0447.2000.102001074.x 10892614\n30. Alao AO Armenta W Yolles JC . de Clerambault syndrome successfully treated with olanzapine. Ann Pharmacother. (2000) 34 :266–9. 10.1345/aph.19123 10676840\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-0640",
"issue": "12()",
"journal": "Frontiers in psychiatry",
"keywords": "de Clerambault's syndrome; delusion; dementia; dementia with Lewy bodies; erotomania",
"medline_ta": "Front Psychiatry",
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"nlm_unique_id": "101545006",
"other_id": null,
"pages": "665868",
"pmc": null,
"pmid": "34177653",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "10676840;22910677;6863791;3427297;2375449;10892614;17726249;25939090;33429240;19920063;1911738;26195980;28592453;32286086;31892935;16100105;2327490;23521899;14653432;32241955;2399821;509011;28424054;2397368;23879399;27536962",
"title": "Case Report: De Clerambault's Syndrome in Dementia With Lewy Bodies.",
"title_normalized": "case report de clerambault s syndrome in dementia with lewy bodies"
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"abstract": "BACKGROUND\nHypoparathyroidism is characterised by hypocalcaemia, and standard management is with an active vitamin D analogue and adequate oral calcium intake (dietary and/or supplements). Little is described in the literature about the impact of intercurrent illnesses on calcium homeostasis in children with hypoparathyroidism.\n\n\nMETHODS\nWe describe three children with hypoparathyroidism in whom intercurrent illnesses led to hypocalcaemia and escalation of treatment with alfacalcidol (1-hydroxycholecalciferol) and calcium supplements.\n\n\nRESULTS\nThree infants managed with standard treatment for hypoparathyroidism (two with homozygous mutations in GCMB2 gene and one with Sanjad-Sakati syndrome) developed symptomatic hypocalcaemia (two infants developed seizures) following respiratory or gastrointestinal illnesses. Substantial increases in alfacalcidol doses (up to three times their pre-illness doses) and calcium supplementation were required to achieve acceptable serum calcium concentrations. However, following resolution of illness, these children developed an increase in serum calcium and hypercalciuria, necessitating rapid reduction to pre-illness dosages of alfacalcidol and oral calcium supplementation.\n\n\nCONCLUSIONS\nIntercurrent illness may precipitate symptomatic hypocalcaemia in children with hypoparathyroidism, necessitating increase in dosages of alfacalcidol and calcium supplements. Close monitoring is required on resolution of the intercurrent illness, with timely reduction of dosages of active analogues of vitamin D and calcium supplements to prevent hypercalcaemia, hypercalciuria and nephrocalcinosis.",
"affiliations": "Royal Manchester Children's HospitalManchester, UK.;Royal Manchester Children's HospitalManchester, UK.;King Abdullah Specialized Children's HospitalRiyadh, Saudi Arabia.;Royal Preston HospitalPreston, UK.;Royal Manchester Children's HospitalManchester, UK.;Royal Manchester Children's HospitalManchester, UK Raja.Padidela@cmft.nhs.uk.",
"authors": "Chinoy|A|A|;Skae|M|M|;Babiker|A|A|;Kendall|D|D|;Mughal|M Z|MZ|;Padidela|R|R|",
"chemical_list": null,
"country": "England",
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"doi": "10.1530/EC-17-0234",
"fulltext": "\n==== Front\nEndocr ConnectEndocr ConnectECEndocrine Connections2049-3614Bioscientifica Ltd Bristol 10.1530/EC-17-0234EC170234ResearchImpact of intercurrent illness on calcium homeostasis in children with hypoparathyroidism: a case series A Chinoy et al.Intercurrent illness in hypoparathyroidismChinoy A 1Skae M 1Babiker A 2Kendall D 3Mughal M Z 1Padidela R 11 Royal Manchester Children’s HospitalManchester, UK\n2 King Abdullah Specialized Children’s HospitalRiyadh, Saudi Arabia\n3 Royal Preston HospitalPreston, UK\nCorrespondence should be addressed to R Padidela; Email: Raja.Padidela@cmft.nhs.uk11 2017 06 9 2017 6 8 589 594 4 9 2017 6 9 2017 © 2017 The authors2017The authors This work is licensed under a Creative Commons Attribution 4.0 International License.Background\nHypoparathyroidism is characterised by hypocalcaemia, and standard management is with an active vitamin D analogue and adequate oral calcium intake (dietary and/or supplements). Little is described in the literature about the impact of intercurrent illnesses on calcium homeostasis in children with hypoparathyroidism.\n\nMethods\nWe describe three children with hypoparathyroidism in whom intercurrent illnesses led to hypocalcaemia and escalation of treatment with alfacalcidol (1-hydroxycholecalciferol) and calcium supplements.\n\nResults\nThree infants managed with standard treatment for hypoparathyroidism (two with homozygous mutations in GCMB2 gene and one with Sanjad-Sakati syndrome) developed symptomatic hypocalcaemia (two infants developed seizures) following respiratory or gastrointestinal illnesses. Substantial increases in alfacalcidol doses (up to three times their pre-illness doses) and calcium supplementation were required to achieve acceptable serum calcium concentrations. However, following resolution of illness, these children developed an increase in serum calcium and hypercalciuria, necessitating rapid reduction to pre-illness dosages of alfacalcidol and oral calcium supplementation.\n\nConclusion\nIntercurrent illness may precipitate symptomatic hypocalcaemia in children with hypoparathyroidism, necessitating increase in dosages of alfacalcidol and calcium supplements. Close monitoring is required on resolution of the intercurrent illness, with timely reduction of dosages of active analogues of vitamin D and calcium supplements to prevent hypercalcaemia, hypercalciuria and nephrocalcinosis.\n\nKeywords\nhypoparathyroidismhypocalcaemiaintercurrent illnessalfacalcidol\n==== Body\nIntroduction\nHypoparathyroidism (HPT) is the partial or complete reduction of parathyroid hormone (PTH) secretion from the parathyroid glands. PTH stimulates 1-alpha-hydroxylase enzyme to produce 1,25(OH)2-vitamin D, which facilitates active absorption of oral calcium (Ca) from the intestine. PTH also mobilises Ca from the bone (by increasing the number and activity of osteoclasts to encourage bone resorption) to maintain serum Ca concentration. PTH also regulates serum phosphate. HPT is therefore characterised by hypocalcaemia and hyperphosphatemia.\n\nThe standard treatment for HPT is with active vitamin D (calcitriol (1,25(OH2)D)) or its analogue (alfacalcidol (ACD; 1-hydroxycholecalciferol)) and ensuring adequate oral Ca intake (through diet and supplements if necessary) (1). PTH in addition stimulates renal Ca reabsorption in the distal nephron and therefore in severe HPT increased urinary Ca excretion may occur when serum corrected calcium (cCa) is at the upper end of the reference range. Therefore, historically it has been important to maintain the cCa of these patients below the normal range (between 1.9 and 2.2 mmol/L), and frequently monitor cCa and urinary calcium creatinine ratio (Ur Ca:Cr), along with responsive dose changes to prevent both under-treatment (resulting in symptomatic hypocalcaemia) and over-treatment (resulting in potential for hypercalciuria and nephrocalcinosis) (1). However, we do recognise that the optimal cCa for each patient with HPT often depends on the specific aetiology and genetic mutations.\n\nThere is scanty information in the medical literature, which describes the impact that intercurrent illness may have on serum cCa concentration in children with HPT. We describe a case series of three children with genetic causes of HPT in whom intercurrent illnesses led to escalation of treatment with ACD along with Ca supplements. We provide specific advice on management of HPT during intercurrent illnesses.\n\nMethods\nEthics statement\nThis case series did not need approval from an ethical committee, as it simply involved a retrospective review of case notes with no intervention or other investigation.\n\nConsent statement\nConsent has been obtained from each patient or subject after full explanation of the purpose and nature of all procedures used.\n\nCase series description and results\nCase 1\nA two-month-old male with HPT due to homozygous GCMB2 (glial cell missing b 2) mutation had cCa, which was maintained within the normal range for infants with HPT by ACD 400 ng (80 ng/kg) daily and Ca supplements (initial PTH at diagnosis <0.6 pmol/L, normal range 1.6–6.9 pmol/L). He developed bronchiolitis caused by rhinovirus and parainfluenzae virus type 2. On day four of illness, his serum cCa dropped from 1.90 mmol/L at the start of illness to 1.53 mmol/L, which was associated with a hypocalcaemic seizure. This was managed with intravenous calcium gluconate – initially as boluses (0.11 mmol/kg), but thereafter with an infusion (1–2 mmol/kg/day) in view of persistent hypocalcaemia. Over the following 12 days, ACD dose was increased up to 1500 ng (300 ng/kg) daily and Ca supplements increased from 12 mmol (2.5 mmol/kg, 100 mg/kg) daily to 48 mmol (10 mmol/kg, 400 mg/kg) daily. Despite these substantial doses, and tolerance of full enteral milk feeds, control of cCa concentration remained suboptimal (largely 1.6–1.9 mmol/L), with hypercalcuria (Ur Ca:Cr 2.05 mmol/mmol, mean value for children <12 months: 1.50 mmol/mmol (2)) demonstrated with cCa >1.9 mmol/L. Given these challenges, subcutaneous injections of teriparatide – recombinant human PTH(1–34) (rhPTH(1–34) was initiated on an off-licence basis (dose 0.4 μg/kg twice-daily)). This established acceptable cCa for a child with severe HPT (mainly 1.9–2.3 mmol/L) over the following days, allowing discontinuation of ACD and oral Ca supplements within 7 days and discharge within 12 days. Furthermore, hypercalciuria that had been demonstrated whilst on ACD improved (Ur Ca:Cr 0.74 mmol/mmol). Figure 1 displays his cCa during illness, along with interventions instigated. He subsequently has remained on rhPTH(1–34), as it has provided better control of cCa whilst avoiding hypercalciuria.\nFigure 1 Presentation and progress of case 1 during bronchiolitic illness, demonstrating fluctuations in serum corrected calcium during admission and management needed. NPA – nasopharyngeal aspirate. Dotted lines indicate the range of optimal serum corrected calcium concentration for children with severe hypoparathyroidism (1.9–2.2 mmol/L).\n\n\n\n\nCase 2\nA two-month-old male with HPT secondary to GCMB2 mutation was stable on ACD 400 ng (110 ng/kg) daily (initial PTH at diagnosis <0.6 pmol/L). He presented with bronchiolitis due to respiratory syncytial virus and rhinovirus. Despite normal feeding, his cCa dropped to 1.44 mmol/L with resulting hypocalcaemic seizures. He required intravenous Ca infusion and his dose of ACD was increased to 1500 ng (400 ng/kg) daily along with oral Ca supplementation (5 mmol/day, 1.3 mmol/kg/day, 50 mg/kgday). After 11 days of admission, his bronchiolitis resolved, his cCa improved to 2.0–2.2 mmol/L and he was discharged home on ACD 1200 ng and oral Ca supplementation of 5 mmol daily.\n\nDuring a two-week period of frequent cCa monitoring, his cCa was stable between 2.0 and 2.2 mmol/L. After one month, his investigations revealed hypercalcaemia (cCa 2.74 mmol/L) and hypercalciuria (Ur Ca:Cr ratio 1.40 mmol/mmol). Although this might only be borderline hypercalcaemia in a healthy infant, it is considered significantly elevated in a child with severe HPT due to the risks associated with hypercalciuria. This necessitated discontinuation of oral Ca supplementation and a rapid reduction in ACD doses to 200 ng (55 ng/kg) daily. Figure 2 displays his cCa during and after this illness, along with alterations in management.\nFigure 2 Presentation and progress of case 2 during bronchiolitis illness, demonstrating changes in serum corrected calcium during admission and management needed. NPA – nasopharyngeal aspirate; RSV – respiratory syncitial virus; Ur Ca:Cr – urinary calcium:creatinine ratio. Dotted lines indicate the range of optimal serum corrected calcium concentration for children with severe hypoparathyroidism (1.9–2.2 mmol/L).\n\n\n\n\nCase 3\nA six-month-old male with Sanjad-Sakati syndrome, confirmed by genetic mutation in TBCE (tubulin-specific chaperone E) gene, had HPT (PTH <0.6 pmol/L) and was stable on standard doses of ACD, though had already developed signs of nephrocalcinosis. He presented to a tertiary hospital in Saudi Arabia with viral gastroenteritis and subsequent hypocalcaemic seizures. This necessitated increase in doses of ACD up to 3000 ng per day to maintain his cCa within an acceptable range.\n\nUnfortunately, due to distance of tertiary paediatric services, he was lost to follow-up for 18 months on 3000 ng of ACD per day. He represented at 2 years of age with symptomatic hypercalcaemia (cCa >3 mmol/L) and severe bilateral nephrocalcinosis.\n\nAchieving optimal cCa (1.9–2.2 mmol/L) on reduction of ACD proved challenging and he was therefore transferred to our tertiary unit in the UK. Standard doses of ACD were unable to achieve normocalcaemia without worsening hypercalciuria (Ur Ca:Cr 0.7–3.9 mmol/mmol). He was therefore commenced on teriparatide (dose 0.4 µg/kg twice-daily) on which he has been able to maintain his cCa between 2.0 and 2.2 mmol/L with no further progression of nephrocalcinosis (Ur Ca:Cr mainly <0.5 mmol/mmol).\n\nDiscussion\nWe have reported three cases of HPT where intercurrent illness required escalation in treatment doses of active analogues of vitamin D and oral Ca supplements to maintain adequate cCa levels. There are few reports in the medical literature, which describes loss of control in Ca concentration in patients with HPT during intercurrent illness. Bhadada and coworkers (3) described two adult cases – a 30-year-old female and an 18-year-old male – with HPT who developed an upper respiratory infection and viral gastroenteritis respectively, resulting in hypocalcaemia necessitating increased Ca supplements, with or without increased calcitriol or ACD therapy. To our knowledge, there are no such reports in the paediatric literature.\n\nThis case series demonstrates that infants with HPT are susceptible to sudden, severe and symptomatic hypocalcaemia during times of intercurrent illness, despite prior adequate control. This was particularly observed in cases 1 and 2, both of whom suffered hypocalcaemic seizures as a result of their bronchiolitic illness and required marked increase in doses of ACD and oral Ca to achieve optimal cCa concentration. We would therefore recommend vigilance for periods of illness, and to urgently attend health care services if mild symptoms of hypocalcaemia (irritability, lethargy, muscle spasms tremors) or risk factors for deterioration (such as vomiting or poor feeding) are identified. Even without such features, measurement of cCa is strongly advised to ensure no impending hypocalcaemia, which could be corrected with increased intake of oral Ca and ACD or infusion of intravenous Ca. Doing so in a timely manner may prevent more profound symptomatic hypocalcaemia. Parental education regarding the above is crucial to identifying affected children early.\n\nFurthermore, cases 2 and 3 demonstrate that close monitoring of cCa is also needed on resolution of illness in children with HPT. It appears that resistance to standard management resolves on resolution of the illness, necessitating a reduction in active vitamin D and oral Ca doses. Failure to reduce doses will increase the risk of hypercalciuria and nephrocalcinosis as was seen in case 3. Parental education regarding this risk will facilitate frequent monitoring of this complication and weaning regime as appropriate.\n\nAll three patients had severe HPT due to genetic causes – two infants had GCMB2 mutations, which causes severe HPT due to lack of the Gcmb2 transcription factor that is vital for parathyroid gland development (4) and one infant had Sanjad-Sakati syndrome, which also manifests with severe HPT (5). In our experience, this loss of control is less likely to occur in children with partial HPT, for example, due to 22q11.2 deletion syndrome (despite their immunodeficiency as part of this syndrome making them more prone to severe illness) (6), where the resistance to treatment may not be as marked.\n\nOur case series suggests a greater affect on infants with HPT. Although the cause for this can only be hypothesised, a combination of poorer reserves and a greater impact of feed intolerance would seem contributory.\n\nThe cause for this transient deterioration in control of children with HPT during intercurrent illness, despite adequate prior control on oral active vitamin D analogues and Ca supplements, remains unknown. Further research would be warranted to elucidate the exact mechanisms. It could be simply that these illnesses influence intake and absorption of dietary Ca and medications, as suggested by Bhadada and coworkers (3). On this point, it is worth mentioning that infants with severe HPT who are kept fasted for prolonged periods may also suffer hypocalcaemia due to inadequate dietary Ca intake.\n\nHowever, our cases were tolerating feeds during their illness (barring case 1 during early phase of illness). We postulate that this phenomenon may involve cortisol-driven effects on 1,25(OH)2-vitamin D. It is recognised that the stress of intercurrent illness is associated with a physiological increase in cortisol secretion. There is evidence to support that cortisol reduces Ca absorption from the gut (7, 8). Furthermore, it has also been demonstrated that this cortisol-induced reduction in Ca absorption is resistant to administration of 1,25(OH)2-vitamin D (9). In vitro studies in animal models have also suggested that cortisol stimulation may cause PTH release (10). Thus, in an unaffected person and those with partial HPT, cortisol released during intercurrent illness would reduce gut absorption of Ca, but this would be balanced by PTH release, which maintains normocalcaemia. However, in subjects with severe HPT, there is complete lack of PTH release to counter reduced gut Ca absorption, resulting in hypocalcaemia. Perhaps, 'sick day' rules, akin to those well established for children with cortisol deficiency, might need to be applied to ACD and rhPTH doses in children with severe HPT. In the absence of firm evidence to support any specific rules, we advise an individualised case-by-case approach. Our pragmatic practice is to increase ACD dose by approximately 50% and rhPTH dose by approximately 10% at the onset of illness. Thereafter, 6–12 hourly monitoring, either of cCa or ionised Ca, along with Ur Ca:Cr, is essential to adjust doses accordingly to maintain cCa within the optimal range. Furthermore, monitoring of biochemistry on resolution of illness (and rapid reduction of doses to baseline) is equally important, to avoid over-treatment.\n\nInflammatory cytokines may also have a role in this phenomenon. Interleukin (IL)-1β and IL-6 are both pro-inflammatory cytokines whose levels have been shown to increase within hours of infection in crticially ill patients and are inversely related to serum Ca concentrations (11). Animal models have demonstrated that both of these cytokines upregulate calcium-sensing receptor expression, suppress PTH secretion, are associated with significantly decreased 1,25(OH)2-vitamin D levels and appear to drive PTH resistance by downregulating target-organ PTH receptors (11). Therefore, one could postulate that, in children in whom PTH production is already severely affected, further impact on PTH secretion and resistance may explain the significant hypocalcaemia observed in this cohort during intercurrent illness.\n\nrhPTH(1–34) is the active fragment of PTH and is a recognised treatment for HPT in adults, although its original licence is for management of post-menopausal osteoporosis. However, it is unlicensed and very rarely used in children following a report of osteosarcoma risk in growing rat studies (12). Notably, these findings were not substantiated in primate studies (13). All reports to date in human children have not replicated the concerns identified in rat studies and have been shown to be safe (in the short term thus far) and effective in managing HPT, albeit with small case numbers (14, 15). Therefore, rhPTH(1–34) is more recently increasingly being used on an off-license individual basis. In case 1, where the HPT was resistant to management with large doses of ACD and oral Ca, subcutaneous rhPTH(1–34) was shown to be effective in normalising cCa whilst reducing hypercalciuria. We would suggest consideration of rhPTH(1–34) in severe cases of Ca imbalance in children with HPT during intercurrent illness that are refractory to escalation in ACD doses. However, counselling of parents about the possible long-term risks based on animal studies need to be conveyed. Similar to our cases, others have also used rhPTH(1–34) in infants with HPT refractory to standard doses of oral active vitamin D analogues and Ca supplementation (16, 17, 18). We employ a subcutaneous twice-daily dosing regime, which has been shown to be more effective than once-daily regimes (19, 20), although there is evidence emerging to suggest continuous subcutaneous infusion of rhPTH(1–34) via pumps may confer even greater efficacy in terms of steady cCa concentration (21).\n\nIn conclusion, we have demonstrated through our case series the potential for sudden, profound and symptomatic hypocalcaemia in infants with HPT during intercurrent illness, requiring vigilance, regular monitoring and timely escalation of ACD and oral Ca dosage. At the same time, resolution of intercurrent illness results in normalisation of cCa, such that close monitoring and dose reduction to baseline is needed to prevent hypercalcaemia and hypercalciuria. rhPTH(1–34) may have a role in these situations. The mechanisms underlying this phenomenon remain unclear, although we speculate whether excess cortisol secretion during intercurrent illness may play a role. Further research is warranted to elucidate the exact mechanisms.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis report did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nAuthor contribution statement\nA Chinoy – Writing and revising manuscript. M Skae, A Babiker, D Kendall, MZ Mughal – Revising manuscript. R Padidela – Revising manuscript and corresponding author.\n==== Refs\nReferences\n1 De Sanctis V Soliman A Fiscina B. \nHypoparathyroidism: from diagnosis to treatment . Current Opinion in Endocrinology, Diabetes and Obesity \n2012 \n19 \n435 –442 . (10.1097/MED.0b013e3283591502 )\n2 Metz MP. \nDetermining urinary calcium/creatinine cut-offs for the paediatric population using published data . Annals of Clinical Biochemistry \n2006 \n43 \n398 –401 . (10.1258/000456306778520106 )17022882 \n3 Bhadada SK Bhansali A Sridhar S Singh R Rao S. \nDo we need sick-day guidelines for hypoparathyroidism? \nIndian Journal of Endocrinology and Metabolism \n2012 \n16 \n489 –491 . (10.4103/2230-8210.95763 )22629541 \n4 Doyle D Kirwin SM Sol-Church K Levine MA. \nA novel mutation in the GCM2 gene causing severe congenital isolated hypoparathyroidism . Journal of Pediatric Endocrinology and Metabolism \n2012 \n25 \n741 –746 . (10.1515/jpem-2012-0080 )23155703 \n5 Rafique B Al-Yaarubi S. \nSanjad-Sakati syndrome in Omani children . Oman Medical Journal \n2010 \n25 \n227 –229 . (10.5001/omj.2010.63 )22043344 \n6 Weinzimer SA. \nEndocrine aspects of the 22q11.2 deletion syndrome . Genetics in Medicine \n2001 \n3 \n19 –22 . (10.1097/00125817-200101000-00005 )11339371 \n7 Feher JJ Wasserman RH. \nIntestinal calcium-binding protein and calcium absorption in cortisol-treated chicks: effects of vitamin D3 and 1,25-dihydroxyvitamin D3 . Endocrinology \n1979 \n104 \n547 –551 . (10.1210/endo-104-2-547 )221183 \n8 Shultz TD Bollman S Kumar R. \nDecreased intestinal calcium absorption in vivo and normal brush border membrane vesicle calcium uptake in cortisol-treated chickens: evidence for dissociation of calcium absorption from brush border vesicle uptake . PNAS \n1982 \n79 \n3542 –3546 . (10.1073/pnas.79.11.3542 )6954501 \n9 Favus MJ Walling MW Kimberg DV. \nEffects of 1,25-dihydroxycholecalciferol on intestinal calcium transport in cortisone-treated rats . Journal of Clinical Investigation \n1973 \n52 \n1680 –1685 . (10.1172/JCI107349 )4718960 \n10 Au WY. \nCortisol stimulation of parathyroid hormone secretion by rat parathyroid glands in organ culture . Science \n1976 \n193 \n1015 –1017 . (10.1126/science.948759 )948759 \n11 Hendy GN Canaff L. \nCalcium-sensing receptor, proinflammatory cytokines and calcium homeostasis . Seminars in Cell and Developmental Biology \n2016 \n49 \n37 –43 . (10.1016/j.semcdb.2015.11.006 )26612442 \n12 Vahle JL Sato M Long GG Young JK Francis PC Engelhardt JA Westmore MS Linda Y Nold JB. \nSkeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1–34) for 2 years and relevance to human safety . Toxicologic Pathology \n2002 \n30 \n312 –321 . (10.1080/01926230252929882 )12051548 \n13 Vahle JL Zuehlke U Schmidt A Westmore M Chen P Sato M. \nLack of bone neoplasms and persistence of bone efficacy in cynomolgus macaques after long-term treatment with teriparatide [rhPTH(1–34)] . Journal of Bone and Mineral Research \n2008 \n23 \n2033 –2039 . (10.1359/jbmr.080807 )18684088 \n14 Rejnmark L Underbjerg L Sikjaer T \nHypoparathyroidism. Replacement therapy with parathyroid hormone. \nEndocrinology and Metabolism \n2015 \n30 \n436 –442 . (10.3803/EnM.2015.30.4.436 )26394728 \n15 Cusano NE Rubin MR Irani D Sliney J JrBilezikian JP. \nUse of parathyroid hormone in hypoparathyroidism . Journal of Endocrinological Investigation \n2013 \n36 \n1121 –1127 . (10.1007/BF03346763 )24445125 \n16 Cho YH Tchan M Roy B Halliday R Wilson M Dutt S Siew S Munns C Howard N. \nRecombinant parathyroid hormone therapy for severe neonatal hypoparathyroidism . Journal of Pediatrics \n2012 \n160 \n345 –348 . (10.1016/j.jpeds.2011.09.022 )22048054 \n17 Newfield RS. \nRecombinant PTH for initial management of neonatal hypocalcemia . New England Journal of Medicine \n2007 \n356 \n1687 –1688 . (10.1056/NEJMbib63043 )17442918 \n18 Linglart A Rothenbuhler A Gueorgieva I Lucchini P Silve C Bougnères P. \nLong-term results of continuous subcutaneous recombinant PTH (1–34) infusion in children with refractory hypoparathyroidism . Journal of Clinical Endocrinology and Metabolism \n2011 \n96 \n3308 –3312 . (10.1210/jc.2011-1359 )21865375 \n19 Winer KK Sinaii N Reynolds J Peterson D Dowdy K Cutler GB Jr \nLong-term treatment of 12 children with chronic hypoparathyroidism: a randomized trial comparing synthetic human parathyroid hormone 1–34 versus calcitriol and calcium . Journal of Clinical Endocrinology and Metabolism \n2010 \n95 \n2680 –2688 . (10.1210/jc.2009-2464 )20392870 \n20 Winer KK Sinaii N Peterson D Sainz B JrCutler GB Jr \nEffects of once versus twice-daily parathyroid hormone 1–34 therapy in children with hypoparathyroidism . Journal of Clinical Endocrinology and Metabolism \n2008 \n93 \n3389 –3395 . (10.1210/jc.2007-2552 )18492754 \n21 Winer KK Fulton KA Albert PS Cutler GB Jr \nEffects of pump versus twice-daily injection delivery of synthetic parathyroid hormone 1–34 in children with severe congenital hypoparathyroidism . Journal of Pediatrics \n2014 \n165 \n556 –563 . (10.1016/j.jpeds.2014.04.060 )24948345\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2049-3614",
"issue": "6(8)",
"journal": "Endocrine connections",
"keywords": "alfacalcidol; hypocalcaemia; hypoparathyroidism; intercurrent illness",
"medline_ta": "Endocr Connect",
"mesh_terms": null,
"nlm_unique_id": "101598413",
"other_id": null,
"pages": "589-594",
"pmc": null,
"pmid": "28993435",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article",
"references": "12051548;24445125;221183;23128574;20392870;23155703;17442918;21865375;22048054;18684088;11339371;24948345;4718960;17022882;26394728;6954501;22043344;948759;18492754;26612442;22629541",
"title": "Impact of intercurrent illness on calcium homeostasis in children with hypoparathyroidism: a case series.",
"title_normalized": "impact of intercurrent illness on calcium homeostasis in children with hypoparathyroidism a case series"
} | [
{
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"activesubstancename": "ALFACALCIDOL"
},
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{
"abstract": "Nivolumab is widely used to treat several late-stage malignancies such as melanoma and non-small-cell lung cancer by inhibiting the interaction between the programmed cell death protein-1 and its ligand. By stimulating an antitumor immune response, it also leads to immune adverse events. Here. we report two cases of subacute cutaneous lupus erythematosus (SCLE) induced by nivolumab. Case 1: a 72-year-old woman with a stage IV melanoma. Two months after nivolumab discontinuation because of autoimmune hepatitis, the patient was in complete remission and pruritic nummular erythematous plaques appeared on the back and arms. Case 2: a 43-year-old man put under nivolumab for a metastatic non-small-cell lung cancer. After two cycles, an annular erythematous eruption appeared on the hands, arms, and chest. The hypothesis of SCLE was confirmed by biopsies showing lymphoid perivascular inflammatory infiltrates, with scarce C3 deposits along the basal layer of the epidermis in patient 2. Both patients tested positive for antinuclear antibodies and anti-SSA antibodies. Lesions were regressive under topical corticosteroids and hydroxychloroquine for the first patient and oral prednisone for the second patient. No systemic involvement was observed. The occurrence of SCLE 2 months after nivolumab discontinuation is evidence that the drug effect is prolonged because of the maintenance of programmed cell death protein-1 reception saturation for months. A causal relationship between SCLE and nivolumab is suggested by (i) the occurrence of SCLE after at least two cycles, (ii) the regression of lesions following treatment with corticosteroids and hydroxychloroquine, and (iii) the fact that it appeared after remission in our first patient.",
"affiliations": "Departments of Dermatology.;Departments of Dermatology.;Departments of Dermatology.;Pathology, Amiens University Hospital, Amiens, France.;Departments of Dermatology.;Departments of Dermatology.",
"authors": "Zitouni|Nesrine B|NB|;Arnault|Jean-Philippe|JP|;Dadban|Ali|A|;Attencourt|Christophe|C|;Lok|Catherine C|CC|;Chaby|Guillaume|G|",
"chemical_list": "D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.1097/CMR.0000000000000536",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-8931",
"issue": "29(2)",
"journal": "Melanoma research",
"keywords": null,
"medline_ta": "Melanoma Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008178:Lupus Erythematosus, Cutaneous; D008297:Male; D000077594:Nivolumab",
"nlm_unique_id": "9109623",
"other_id": null,
"pages": "212-215",
"pmc": null,
"pmid": "30489484",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Subacute cutaneous lupus erythematosus induced by nivolumab: two case reports and a literature review.",
"title_normalized": "subacute cutaneous lupus erythematosus induced by nivolumab two case reports and a literature review"
} | [
{
"companynumb": "FR-009507513-1903FRA011412",
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"patient": {
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{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE SULFATE"
},
"drugaddition... |
{
"abstract": "We present a case of a 55-year-old man post right lung transplantation receiving ECMO for treatment of respiratory failure secondary to methicillin-resistant Staphylococcus aureus (MRSA) pneumonia.\n\n\n\nExtracorporeal membrane oxygenation (ECMO) is a frequently utilized support therapy for patients with cardiac and/or respiratory failure. Dosing of medications during ECMO can be challenging due to several factors, including sequestration of medications within ECMO circuits, alterations in volume of distribution, and changes in drug clearance. The patient was initiated on empiric antibiotics, then switched to linezolid at a dose of 600 mg every 8 hours. Linezolid plasma concentrations were collected 30 minutes prior to the sixth administered dose and 30 minutes following the 1-hour infusion of the sixth dose, which resulted in values of 0.4 and 1.7 μg/mL, respectively. The ratio of 24-hour area under the curve (AUC0-24) to minimum inhibitory concentration (MIC), assuming a MIC of 2 μg/mL, was calculated using the extrapolated maximum concentration (1.9 μg/mL) and minimum concentration (0.35 μg/mL), resulting in an AUC0-24/MIC value of 10.8. Due to subtherapeutic linezolid plasma concentrations, ceftaroline was initiated and continued for a total of 18 days. To our knowledge, this is the second report to describe inadequate plasma concentrations of linezolid during ECMO.\n\n\n\nIn the case described here, linezolid at a dose of 600 mg every 8 hours did not achieve target plasma concentrations in a patient receiving concomitant venovenous ECMO support.",
"affiliations": "Arnold and Marie Schwartz College of Pharmacy and Health Sciences (LIU Pharmacy), Brooklyn, NY, and New York-Presbyterian/Weill Cornell Medical Center, New York, NY.;Department of Pharmacy, Ohio State University Wexner Medical Center, Columbus, OH.;BCPS, Department of Pharmacy, Temple University Hospital, Philadelphia, PA.;BCCCP, Department of Pharmacy Practice, Temple University School of Pharmacy, Philadelphia, PA.",
"authors": "Nikolos|Peter|P|;Osorio|Justin|J|;Mohrien|Kerry|K|;Rose|Christina|C|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000069349:Linezolid",
"country": "England",
"delete": false,
"doi": "10.1093/ajhp/zxaa066",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "77(11)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": "critical care; infectious diseases; pharmacokinetics",
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000900:Anti-Bacterial Agents; D019540:Area Under Curve; D015199:Extracorporeal Membrane Oxygenation; D006801:Humans; D000069349:Linezolid; D008297:Male; D008657:Metabolic Clearance Rate; D055624:Methicillin-Resistant Staphylococcus aureus; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D018410:Pneumonia, Bacterial; D012131:Respiratory Insufficiency; D013203:Staphylococcal Infections",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "877-881",
"pmc": null,
"pmid": "32426841",
"pubdate": "2020-05-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pharmacokinetics of linezolid for methicillin-resistant Staphylococcus aureus pneumonia in an adult receiving extracorporeal membrane oxygenation.",
"title_normalized": "pharmacokinetics of linezolid for methicillin resistant staphylococcus aureus pneumonia in an adult receiving extracorporeal membrane oxygenation"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2020-02471",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugad... |
{
"abstract": "Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening hypersensitivity reactions mainly caused by drugs. Data on incubation period, hospital stay, and outcome for HIV-positive patients are sparse. Role of corticosteroids in their management is still controversial.\n\n\n\nIndoor cases of SJS, SJS-TEN overlap, and TEN were analyzed for causative drugs, incubation period, a severity-of-illness score for toxic epidermal necrolysis (SCORTEN) score, HIV status, treatment, and outcome. Comparison of parameters between HIV and non-HIV cases was done. Utilization pattern of corticosteroids and their role in outcome were evaluated.\n\n\n\nFour SJS, 15 SJS-TEN overlap, and 21 TEN cases were evaluated. Antimicrobials (27.1%), antiviral (23%), antiseizure drugs (8.4%), and analgesics (8.4%) were commonly associated drugs. Among 12 (30%) HIV-reactive cases, nevirapine (97.6%) and cotrimoxazole (41.6%) were common causative drugs. Males (75%) were affected more than females (25%) among HIV-positive individuals. Incubation period was significantly higher in HIV-reactive patients. Total 30 (75%) patients were treated with corticosteroids. Dexamethasone (90%) and prednisolone (26.6%) were most commonly used. No significant difference was found among cases treated with or without corticosteroids.\n\n\n\nAntimicrobial drugs are common to cause SJS/TEN. Among HIV-reactive patients, male have more risk, incubation period is more and severity of reaction is less. Effectiveness of corticosteroids for treatment of SJS/TEN is inconclusive.",
"affiliations": "Department of Pharmacology, GMERS Medical College, Junagadh, Gujarat, India.;Department of Pharmacology, GMERS Medical College, Gotri, Vadodara, Gujarat, India.;Department of Pharmacology, Govt. Medical College, Bhavnagar, Gujarat, India.;Department of Pharmacology, Govt. Medical College, Bhavnagar, Gujarat, India.",
"authors": "Hirapara|H N|HN|;Patel|T K|TK|;Barvaliya|M J|MJ|;Tripathi|C|C|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000700:Analgesics; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D000998:Antiviral Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D019829:Nevirapine",
"country": "India",
"delete": false,
"doi": "10.4103/njcp.njcp_122_16",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "20(8)",
"journal": "Nigerian journal of clinical practice",
"keywords": null,
"medline_ta": "Niger J Clin Pract",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D000700:Analgesics; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D000998:Antiviral Agents; D044466:Asians; D002648:Child; D005260:Female; D006679:HIV Seropositivity; D006801:Humans; D007194:India; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D019829:Nevirapine; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013262:Stevens-Johnson Syndrome; D013997:Time Factors; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D055815:Young Adult",
"nlm_unique_id": "101150032",
"other_id": null,
"pages": "978-983",
"pmc": null,
"pmid": "28891542",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Drug-induced Stevens-Johnson syndrome in Indian population: A multicentric retrospective analysis.",
"title_normalized": "drug induced stevens johnson syndrome in indian population a multicentric retrospective analysis"
} | [
{
"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-281300",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"d... |
{
"abstract": "Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease caused by reactivation of a latent JC polyoma virus. The first cases of PML were described 50 years ago in patients with lymphoma. PML typically occurs in immunocompromised individuals, particularly those infected with HIV. We present a 52-year-old male with lymphoma who was treated with R-CHOP (R: Rituximab; C: Cyclophosphamide; H: Doxorubicin; O: Vincristine; P: Prednisone). After six cycles of therapy, the patients developed tonic-clonic seizure. MRI of the brain showed multiple brain lesions. The pathology of a brain biopsy was diagnostic for PML. We review radiographic and histopathological features of the disease. The literature on PML and its association with immunosuppressant agents is reviewed, and the impact of rituximab and other biological agents in the setting is highlighted.",
"affiliations": "Specialty Internal Medicine Unit, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia. Electronic address: jaffar.tawfiq@jhah.com.;Specialty Internal Medicine Unit, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia.;Specialty Internal Medicine Unit, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia.;Pathology Services Division, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia.",
"authors": "Al-Tawfiq|Jaffar A|JA|;Banda|Ramzi W|RW|;Daabil|Riyadh A|RA|;Dawamneh|M F|MF|",
"chemical_list": "D000970:Antineoplastic Agents; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-0341",
"issue": "8(5)",
"journal": "Journal of infection and public health",
"keywords": "Lymphoma; PML; R-CHOP; Rituximab",
"medline_ta": "J Infect Public Health",
"mesh_terms": "D000970:Antineoplastic Agents; D001706:Biopsy; D001921:Brain; D006651:Histocytochemistry; D006801:Humans; D007150:Immunohistochemistry; D007968:Leukoencephalopathy, Progressive Multifocal; D008223:Lymphoma; D008279:Magnetic Resonance Imaging; D008297:Male; D008853:Microscopy; D008875:Middle Aged; D011859:Radiography; D000069283:Rituximab",
"nlm_unique_id": "101487384",
"other_id": null,
"pages": "493-7",
"pmc": null,
"pmid": "25666327",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Progressive multifocal leukoencephalopathy (PML) in a patient with lymphoma treated with rituximab: A case report and literature review.",
"title_normalized": "progressive multifocal leukoencephalopathy pml in a patient with lymphoma treated with rituximab a case report and literature review"
} | [
{
"companynumb": "PHHY2015SA108910",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
"dru... |
{
"abstract": "Background Superselective ophthalmic artery chemotherapy (SOAC) is a proven therapy for the treatment of retinoblastomas. We describe the technique, results and complications of SOAC performed in our hospital. Objective The aim of this article is to demonstrate that a seemingly complex technique can be carried out with a low morbidity rate. Methods A retrospective analysis of patients receiving SOAC in our department from November 2014 to April 2017 was performed. Data collected were age, gender, number of procedures, arteries approached, bilaterality of treatment, and complications. The procedure was performed using a 3F sheath and a flow-dependent 1.5F microcatheter that was navigated from the femoral artery to the ostium of the ophthalmic artery (OA). When the OA was too small or a stable position could not be achieved, the microcatheter was navigated in the external carotid artery to reach an anastomotic ramus (AR) of the middle meningeal artery (MMA) to the OA. The drugs were then injected through the microcatheter in a pulsatile way. Results Forty-one patients underwent SOAC. A total of 248 procedures were performed in 45 eyes, and 248 arteries were approached (205 OAs and 43 MMAs). Four patients underwent tandem therapy (both eyes treated in the same procedure). Complications were: hypotension and bradycardia during the procedure (five cases), transient thrombosis of the femoral artery (two cases), retinal hemorrhage (one case), alopecia (one case), and anaphylactic shock to carboplatin (one case). No patient showed adverse effects of radiation or ischemic stroke. Conclusion SOAC is a safe technique with a very low complication rate.",
"affiliations": "1 Department of Interventional Radiology, 36947 Hospital Nacional de Pediatria JP Garrahan , Buenos Aires, Argentina.;1 Department of Interventional Radiology, 36947 Hospital Nacional de Pediatria JP Garrahan , Buenos Aires, Argentina.;2 Department of Neurosurgery, 36947 Hospital Nacional de Pediatria JP Garrahan , Buenos Aires, Argentina.;3 Department of Oncology, 36947 Hospital Nacional de Pediatria JP Garrahan , Buenos Aires, Argentina.;3 Department of Oncology, 36947 Hospital Nacional de Pediatria JP Garrahan , Buenos Aires, Argentina.",
"authors": "Requejo|Flavio|F|;Marelli|Juan|J|;Ruiz Johnson|Agustin|A|;Sampor|Claudia|C|;Chantada|Guillermo|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1591019917738962",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1591-0199",
"issue": "24(1)",
"journal": "Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences",
"keywords": "Superselective ophthalmic artery; femoral artery; middle meningeal artery; ophthalmic artery; retinoblastoma",
"medline_ta": "Interv Neuroradiol",
"mesh_terms": "D015901:Angiography, Digital Subtraction; D002404:Catheterization; D002533:Cerebral Angiography; D002675:Child, Preschool; D005260:Female; D005263:Femoral Artery; D006801:Humans; D007223:Infant; D007261:Infusions, Intra-Arterial; D008297:Male; D008576:Meningeal Arteries; D009880:Ophthalmic Artery; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "9602695",
"other_id": null,
"pages": "93-99",
"pmc": null,
"pmid": "29119878",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article",
"references": "27258771;24422571;18342944;27189421;21670326;25742925;21225909;12817038;11230646;26198114;16155131;21060044;26378747;24729462;21320950;18978345;15108036;24157736;24243706;20381868;14360881",
"title": "The technique of superselective ophthalmic artery chemotherapy for retinoblastoma: The Garrahan Hospital experience.",
"title_normalized": "the technique of superselective ophthalmic artery chemotherapy for retinoblastoma the garrahan hospital experience"
} | [
{
"companynumb": "AR-TEVA-2018-AR-863942",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MELPHALAN HYDROCHLORIDE"
},
"drugadditional": "3... |
{
"abstract": "BACKGROUND\nChronic lymphoproliferative disorder of NK-cells (CLPD-NK) manifests as a persistent increase (≥2 × 109 /L, for > 6 months) of mature NK-cells in peripheral blood with an indolent clinical course. The disease is rare, and only limited case series have been published.\n\n\nMETHODS\nWe retrospectively studied 11 patients with CLPD-NK diagnosed at our institution between 2005 and 2017.\n\n\nRESULTS\nPatients included 7 men and 4 women with a median age of 60 years (range, 25-89 years). Ten patients (91%) had cytopenias. Bone marrow involvement by CLPD-NK ranged from 5-15%. The most commonly detected antigenic aberrancies by low cytometry immunophenotyping were as follows: CD7decreased/dim (30%), CD8uniform+ (36%), CD56-/partial (73%), CD94bright (55%), and KIR restriction (100%). JAK/STAT pathway mutations were detected in 8 of 10 (80%) patients and involved STAT3 (n = 7) and JAK3 (n = 1). The presence of mutations tended to correlate with the occurrence of other cytopenias (anemia/thrombocytopenia) and requirement for treatment. Seven patients received single-agent therapy, with amelioration of symptoms; 4 patients were observed. There were no disease-associated deaths or progression to more aggressive disease during the follow-up interval (median, 17 months).\n\n\nCONCLUSIONS\nPatients with CLPD-NK have an indolent clinical course and frequent hematologic manifestations that are responsive to single-agent therapy. Mutations in STAT3 are common and portend more pronounced clinical manifestations.",
"affiliations": "Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"authors": "Kurt|Habibe|H|http://orcid.org/0000-0002-4579-3003;Jorgensen|Jeffrey L|JL|;Amin|Hesham M|HM|;Patel|Keyur P|KP|;Wang|Sa A|SA|;Lin|Pei|P|;Kanagal-Shamanna|Rashmi|R|;Loghavi|Sanam|S|;Thakral|Beenu|B|http://orcid.org/0000-0001-5140-3633;Khogeer|Haitham A|HA|;Jabbour|Elias J|EJ|;Li|Shaoying|S|;Yin|C Cameron|CC|;Medeiros|L Jeffrey|LJ|;Khoury|Joseph D|JD|http://orcid.org/0000-0003-2621-3584",
"chemical_list": "D015415:Biomarkers; D053612:Janus Kinases",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13038",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "100(5)",
"journal": "European journal of haematology",
"keywords": "\nJAK3\n; \nSTAT3\n; chronic lymphoproliferative disorder of NK-cells",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D001706:Biopsy; D001853:Bone Marrow; D002908:Chronic Disease; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D053612:Janus Kinases; D007694:Killer Cells, Natural; D054066:Leukemia, Large Granular Lymphocytic; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "444-454",
"pmc": null,
"pmid": "29385279",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Chronic lymphoproliferative disorder of NK-cells: A single-institution review with emphasis on relative utility of multimodality diagnostic tools.",
"title_normalized": "chronic lymphoproliferative disorder of nk cells a single institution review with emphasis on relative utility of multimodality diagnostic tools"
} | [
{
"companynumb": "US-ACCORD-067399",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "OBJECTIVE\nVarious population-based cohort studies have shown that antimicrobial agents increase the risk of overanticoagulation in patients using coumarins. In this study, we assessed this association in hospitalized patients.\n\n\nMETHODS\nWe included all patients hospitalized in the Spaarne Gasthuis (Haarlem/Hoofddorp, the Netherlands), who started using an antimicrobial agent during acenocoumarol treatment or vice versa between 1 January 2015 and 1 July 2019. Patients were followed from start of concomitant therapy until 48 h after termination of the concomitant therapy or discharge, whichever came first. We analyzed the association between the antimicrobial agents and the risk of overanticoagulation, defined as an interpolated INR above 6, using Cox regression analysis. We corrected for multiple testing with the Bonferroni correction. Patients who started using acenocoumarol and amoxicillin/clavulanic acid were used as reference group.\n\n\nRESULTS\nIn the study population, sixteen antimicrobial agents were started frequently concomitantly with acenocoumarol treatment. We included 2157 interaction episodes in 1172 patients. Patients who started using the combination of co-trimoxazole (HR 3.76; 95% CI 1.47-9.62; p = 0.006), metronidazole (HR 2.55; 95% CI 1.37-4.76; p = 0.003), or itraconazole (HR 4.11; 95% CI 1.79-9.45; p = 0.001) concomitantly with acenocoumarol treatment had an increased risk of overanticoagulation compared with patients using acenocoumarol and amoxicillin/clavulanic acid concomitantly. The associations for metronidazole (p = 0.045) and itraconazole (p = 0.015) remained statistically significant after correction for multiple testing.\n\n\nCONCLUSIONS\nCo-trimoxazole, metronidazole, and itraconazole increase the risk of overanticoagulation in patients using acenocoumarol. These combinations should be avoided if possible or otherwise acenocoumarol doses should be reduced and INR measured more frequently.",
"affiliations": "Pharmacy Foundation of Haarlem Hospitals, Boerhaavelaan 24, 2035 RC, Haarlem, The Netherlands. mbecker@sahz.nl.;Pharmacy Foundation of Haarlem Hospitals, Boerhaavelaan 24, 2035 RC, Haarlem, The Netherlands.;Pharmacy Foundation of Haarlem Hospitals, Boerhaavelaan 24, 2035 RC, Haarlem, The Netherlands.;Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.;Department of Internal Medicine, Spaarne Gasthuis, Haarlem / Hoofddorp, The Netherlands.;Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.",
"authors": "Becker|Matthijs L|ML|https://orcid.org/0000-0003-0054-7498;van Uden|Renate C A E|RCAE|;Giezen|Thijs J|TJ|;Meijer|Karina|K|https://orcid.org/0000-0001-9447-0465;Houtenbos|Ilse|I|;van den Bemt|Patricia M L A|PMLA|https://orcid.org/0000-0003-1418-5520",
"chemical_list": "D000890:Anti-Infective Agents; D000925:Anticoagulants; D008795:Metronidazole; D017964:Itraconazole; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D000074:Acenocoumarol",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-020-02930-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-6970",
"issue": "76(10)",
"journal": "European journal of clinical pharmacology",
"keywords": "Acenocoumarol; Adverse effects; Anticoagulants; Antimicrobial drugs; Drug interactions",
"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D000074:Acenocoumarol; D000368:Aged; D000369:Aged, 80 and over; D000890:Anti-Infective Agents; D000925:Anticoagulants; D004347:Drug Interactions; D005260:Female; D006760:Hospitalization; D006801:Humans; D019934:International Normalized Ratio; D017964:Itraconazole; D008297:Male; D008795:Metronidazole; D009426:Netherlands; D012189:Retrospective Studies; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "1256165",
"other_id": null,
"pages": "1457-1464",
"pmc": null,
"pmid": "32524154",
"pubdate": "2020-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "7776988;8819244;19578179;7383081;378674;8792056;8037888;25456000;11406743;12428081;24429904;21452031;15947920;18031295;8470047;12087353;25470432;934223;17269842;24657899;9663807;2171705;21771587;17318526",
"title": "Drug-drug interactions with metronidazole and itraconazole in patients using acenocoumarol.",
"title_normalized": "drug drug interactions with metronidazole and itraconazole in patients using acenocoumarol"
} | [
{
"companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2020-03162",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
... |
{
"abstract": "We present the case of a 55-year-old female patient with metamizole-induced agranulocytosis after total knee arthroplasty, leading to septic periprosthetic joint infections (PJIs). Owing to metamizole-induced agranulocytosis, the synovial leukocyte count was negative. Here, we discuss the diagnostic challenges evolving from sepsis and neutropenia in patients with suspected PJIs. We suggest an urgent surgical approach, mainly focusing on the clinical presentation preoperatively. Later, our patient developed candidemia and periprosthetic tissue samples were positive for Candida albicans. For fungal PJIs, long-term follow-up studies are lacking and therapeutic recommendations differ. Here, we present our therapeutic approach, including staged revision and 12 weeks of systemic antifungal therapy, and discuss recent findings regarding the therapy of fungal PJIs.",
"affiliations": "Department of General Orthopedics and Tumor Orthopedics, Muenster University Hospital, Muenster, North Rhine-Westphalia, Germany.;Department of General Orthopedics and Tumor Orthopedics, Muenster University Hospital, Muenster, North Rhine-Westphalia, Germany.;Department of General Orthopedics and Tumor Orthopedics, Muenster University Hospital, Muenster, North Rhine-Westphalia, Germany.;Department of General Orthopedics and Tumor Orthopedics, Muenster University Hospital, Muenster, North Rhine-Westphalia, Germany.;Department of General Orthopedics and Tumor Orthopedics, Muenster University Hospital, Muenster, North Rhine-Westphalia, Germany.;Department of General Orthopedics and Tumor Orthopedics, Muenster University Hospital, Muenster, North Rhine-Westphalia, Germany.;Department of General Orthopedics and Tumor Orthopedics, Muenster University Hospital, Muenster, North Rhine-Westphalia, Germany.;Department of General Orthopedics and Tumor Orthopedics, Muenster University Hospital, Muenster, North Rhine-Westphalia, Germany.",
"authors": "Oenning|Sebastian|S|;Moellenbeck|Burkhard|B|;Gosheger|Georg|G|;Schmidt-Bräkling|Tom|T|;Schwarze|Jan|J|;Ackmann|Thomas|T|;Schneider|Kristian Nikolaus|KN|;Theil|Christoph|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.artd.2020.07.040",
"fulltext": "\n==== Front\nArthroplast Today\nArthroplast Today\nArthroplasty Today\n2352-3441 Elsevier \n\nS2352-3441(20)30159-X\n10.1016/j.artd.2020.07.040\nCase Report\nFungal Periprosthetic Knee Joint Infection in a Patient with Metamizole-Induced Agranulocytosis\nOenning Sebastian Cand Medoenningsebastian@gmail.comsebastian.oenning@gmx.net∗ Moellenbeck Burkhard MD Gosheger Georg MD Schmidt-Bräkling Tom MD Schwarze Jan MD Ackmann Thomas MD Schneider Kristian Nikolaus MD Theil Christoph MD Department of General Orthopedics and Tumor Orthopedics, Muenster University Hospital, Muenster, North Rhine-Westphalia, Germany\n∗ Corresponding author. Muenster University Hospital, 48149 Muenster, North Rhine-Westphalia, Germany. Tel.: +4915772023995. oenningsebastian@gmail.comsebastian.oenning@gmx.net\n27 8 2020 \n12 2020 \n27 8 2020 \n6 4 726 730\n24 6 2020 17 7 2020 25 7 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/).We present the case of a 55-year-old female patient with metamizole-induced agranulocytosis after total knee arthroplasty, leading to septic periprosthetic joint infections (PJIs). Owing to metamizole-induced agranulocytosis, the synovial leukocyte count was negative. Here, we discuss the diagnostic challenges evolving from sepsis and neutropenia in patients with suspected PJIs. We suggest an urgent surgical approach, mainly focusing on the clinical presentation preoperatively. Later, our patient developed candidemia and periprosthetic tissue samples were positive for Candida albicans. For fungal PJIs, long-term follow-up studies are lacking and therapeutic recommendations differ. Here, we present our therapeutic approach, including staged revision and 12 weeks of systemic antifungal therapy, and discuss recent findings regarding the therapy of fungal PJIs.\n\nKeywords\nPeriprosthetic infectionAgranulocytosisFungal infectionCandida infectionTotal knee arthroplastyRevision arthroplasty\n==== Body\nIntroduction\nPeriprosthetic joint infection (PJI) is a severe complication after joint arthroplasty that can be associated with multiple revision surgeries, prolonged hospitalization, and poor functional outcome [1]. PJI occurs in about 2% of primary total knee arthroplasty (TKA) [2]. In 50%-60%, PJIs are caused by Staphylococcus aureus or coagulase-negative staphylococci, such as Staphylococcus epidermidis [3], whereas fungal PJIs are rare, accounting for only 1% of all PJIs [4]. Patients who are immunocompromised or severely comorbid are considered at particular risk for fungal PJIs.\n\nMetamizole is a potent nonopioid analgesic drug, which is widely used for postoperative analgesia after TKA. However, very rarely, patients develop a metamizole-induced agranulocytosis (MIA) as a severe side effect, leading to immune deficiency and making them susceptible to systemic infection. Recent studies among patients treated with metamizole showed an incidence of less than one case of MIA per one million patients per year [5].\n\nThe presented case deals with a patient developing fungal PJIs in the context of an MIA after TKA.\n\nCase history\nWe present the case of a 55-year-old woman with degenerative joint disease who underwent a complex primary TKA, performed in 2017 at an outside hospital using a constrained TKA for varus osteoarthritis. Her comorbidities include asthma and atopic dermatitis. After TKA, she was prescribed metamizole as pain medication and was discharged home. Five weeks after TKA, the patient was readmitted to an external hospital and presented in an acute septic state with pancytopenia, phlegmonous soft-tissue inflammation in both arms, and atrial fibrillation. Bone marrow puncture showed a most likely MIA. In blood cultures, Staphylococcus epidermidis was detected, whereas wound swabs from both hands were positive for Serratia marcescens. Antibiotic treatment with meropenem and linezolid was established at the outside facility.\n\nOwing to progressive sepsis, the patient was referred to our institution’s intensive care unit. At admission, the patient presented with progredient, warm, and erythematous soft-tissue swellings in both arms and a massively swollen and warm knee, which had undergone TKA as mentioned. She had an elevated serum C-reactive protein (CRP) of 26 mg/dL, elevated ferritin of 188 μg/L, and a white blood cell (WBC) count of 0.38 × 10³/μL. Blood differential count revealed a polymorphonuclear leukocyte percentage (PMN%) of 2.6%.\n\nOrthopaedic consultation was urgent because an acute PJI with systemic sepsis was suspected. Joint aspiration from the swollen knee was performed. The synovial WBC count was 0.085 × 10³/μL with PMN% of 14%. Radiograph imaging showed no signs of prosthetic loosening (Fig. 1). However, owing to the massively swollen, heated, and red knee, explantation of the implant and insertion of a polymethylmethacrylate cement spacer, loaded with gentamicin, clindamycin, and 2 g of vancomycin per 40 g cement, was performed on the same day. Synovial fluid and tissue samples obtained intraoperatively both showed neither bacterial nor fungal growth; however, the patient had positive blood cultures for Escherichia coli.Figure 1 Anteroposterior (a) and lateral (b) radiographs of the right knee at admission. No signs of prosthetic loosening were found.\n\n\n\nOwing to the suspected fasciitis with both arms being at risk of developing an acute compartment syndrome, we also performed an exploration of the upper extremities and fasciotomy with subsequent application of a vacuum-assisted closure device.\n\nThe postoperative antibiotic treatment included meropenem, daptomycin, and clindamycin. Within the following days, blood culture samples were negative. Repeated bone marrow puncture confirmed a most likely sepsis-triggered pancytopenia, developing from MIA. Magnetic resonance imaging of the patient’s left forearm showed contrast medium enhancement in both deep and superficial fasciae, falling in line with the phlegmonous clinical appearance. Other infectious foci such as endocarditis and respiratory or urinary tract infections were excluded.\n\nSix days after spacer implantation, Candida albicans was first detected in a peripherally obtained blood culture, so that micafungin (100 mg/d) was added to the systemic treatment. Subsequently, the phlegmons in arms and axillae improved clinically, whereas now we observed continuous purulent secretion from the affected knee, as the serum WBC count slowly recovered. Ten days after spacer implantation, Candida albicans was detected in central blood cultures and in wound swabs from the phlegmons in both arms.\n\nThus, the intensive care unit performed an F18-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) to identify a potential focus and assess the extent of the patient’s infectious lesions. It showed severe soft-tissue infections, mainly in the left forearm and the right knee (Fig. 2), with septic emboli in the soft tissue and spleen. In addition, there were signs of pneumonia with reactive lymphadenopathy. A bronchoalveolar lavage, which was positive for Candida albicans, confirmed pulmonary involvement.Figure 2 FDG-PET/CT showed increased metabolism in the periprosthetic soft tissues of the right knee.\n\n\n\nAs there was persistent wound drainage from the operated knee after spacer implantation and fungal systemic infection was present, we revised the patient’s knee and exchanged the spacer (Fig. 3). The new spacer was loaded with gentamicin, clindamycin, and 600 mg of voriconazole per 40 g of cement. Tissue samples and joint aspirate were positive for fluconazole-sensitive Candida albicans. Postoperatively, we adjusted the antifungal treatment, which now included voriconazole (2 × 200 mg/d) and micafungin (100 mg/d).Figure 3 Anteroposterior (a) and lateral (b) radiographs of the spacer impregnated with gentamicin, clindamycin, and voriconazole.\n\n\n\nFrom now on, clinical signs of joint and soft-tissue infections were regressive. A week after spacer exchange, our patient left the intensive care unit with a WBC count within the physiological range and continuously decreasing serum CRP levels. A computed tomography scan of the thorax showed regressive pulmonary lesions, and magnetic resonance imaging of the cranium ruled out mycotic cerebral infestation. Two months after admission, the skin lesion of the left forearm was covered by an autologous split skin graft. We discharged the patient under strict immobilization of the affected knee and continuous antimycotic therapy including oral fluconazole (400 mg/d) to complete 12 weeks of antifungal treatment.\n\nFollow-ups after completed antifungal therapy showed continuous clinical improvements with regressive pain, healed surgical wounds, and no signs of persistent infection. Serum interleukin-6 (IL-6) was 8 pg/mL, and serum CRP came down to 0.5 mg/dL. Four months after completion of antifungal therapy, we reimplanted a rotating-hinge revision TKA (Fig. 4). Micafungin (100 mg/d) was given intravenously for 3 weeks after reimplantation until the final long-term cultures obtained intraoperatively remained negative. Eventually, all wounds healed uneventfully and there is an event-free follow-up of 2 years after reimplantation. Currently, flexion of the affected knee is limited to 60°, while full active extension is possible with mild pain. The patient shows no signs of reinfection.Figure 4 Anteroposterior (a) and lateral (b) radiographs of the right knee after reimplantation of a rotating-hinge revision TKA.\n\n\n\nDiscussion\nThe preoperative diagnosis of PJI can be a challenge and is based on multiple parameters. The European Bone and Joint Infection Society and Musculoskeletal Infection Society both have published reliable criteria that can be considered a diagnostic standard [6,7]. Although serum parameters such as CRP, D-dimers, and the erythrocyte sedimentation rate can be used as a first diagnostic step, their sensitivity and specificity are quite low. Despite serum CRP being the most important serum marker for PJIs [6], it was shown that serum CRP levels alone do not allow an accurate diagnosis because of a high rate of false-negative results [8]. In recent studies, serum IL-6 levels in PJIs were analyzed and a cutoff value of 13 pg/mL indicating PJIs was suggested [9]. However, further studies with a higher number of cases are needed to assess the diagnostic value of IL-6.\n\nTo diagnose PJIs, preoperative joint aspiration is usually necessary. As per the Musculoskeletal Infection Society, positive periprosthetic microbiological cultures are a major criterion confirming PJIs [6]. However, cultures from joint aspirate were shown to have high rates of false-negative results so that their sensitivity is limited [10]. In addition, culture results are sensitive to previous antibiotic treatment [11,12]. Because in septic patients such as the one mentioned previously it is inevitable to immediately initiate broad antimicrobial therapy [13], the risk of false-negative cultures is further increased. Based on this, several studies showed high rates of culture-negative PJIs, ranging from 5% to 42% [12].\n\nLeukocyte and neutrophil counts from joint aspirates have been shown to have the highest sensitivity preoperatively [6,12]. However, in a state of agranulocytosis, such as that in the presented case, both synovial WBC count and synovial PMN% show false-negative results so that PJIs cannot be ruled out by joint aspiration. This diagnostic challenge can occur in all neutropenic patients. Although MIA is rare, neutropenia or functional impairment of neutrophils can be both the cause and consequence of sepsis [14,15]. Septic patients with prosthetic joints are at high risk of developing a hematogenic microbial contamination of their implants, with that risk being further increased by neutropenia. At the same time, the number of patients with prosthetic joints rises continuously [16]. Thus, diagnostic challenges in patients with suspected PJIs and coexisting sepsis and neutropenia will become more relevant in future clinical practice and, as described, we can expect interference with serological, synovial, and microbiological parameters. In this case, we therefore suggest focusing on clinical findings preoperatively. If there is any doubt regarding a possible PJI, we recommend a fast surgical approach to confirm the diagnosis and to remove the infected implant [17].\n\nLater, the patient developed candidemia, possibly originating from pneumonia and secondary infection of the spacer. In retrospect, it remains unclear whether the fungal organism was present at the beginning, as the culturing of fungal organisms from joints can be difficult [18,19]. Because fungal PJIs only account for 1%-2% of all PJIs, it is debatable to what degree the established diagnostic criteria can be used [4]. In our orthopaedic department, we treat around 70 cases of PJIs per year, with about 1-2 of those being caused by fungal organisms.\n\nBased on the few studies published on this issue, staged revision using a spacer and long-term antifungal systemic treatment is the most promising approach [20]. Local antifungal treatment must be considered to ensure high antifungal doses at the site of infection. Based on this, we immediately started intravenous antimycotic therapy with micafungin and implanted a voriconazole-impregnated polymethylmethacrylate spacer. However, some Candida strains are azole resistant, so that in those cases, spacers impregnated with amphotericin, ideally in liposomal formulations for optimal release properties, can be used [21]. Although liposomal amphotericin was shown to have local antifungal efficacy, our case supports the suggestion of voriconazole also having high local antifungal potency [[22], [23], [24]].\n\nPostoperatively, we covered the patient with a dual systemic antimycotic therapy including voriconazole and micafungin, according to the microbiological resistance testing. At discharge, antifungal treatment was switched to oral fluconazole, so that antifungal therapy after spacer exchange lasted for 12 weeks. While the optimal period of systemic antifungal therapy after spacer implantation is still unclear, some studies discussed a prolonged treatment with recommendations ranging from at least 6 weeks to 12 weeks [20,25].\n\nBecause therapeutic algorithms and large groups of patients with fungal PJIs are lacking, treatment success rates after 2 years vary from 50% [25] to 100%, with the latter only including staged revisions after fungal PJIs after TKA [23]. In general, the outcome in fungal PJIs is worse and complication rates are higher than those in bacterial PJIs [20]. In studies by Brown et al. [26], the reinfection rate was 24% after 2 years. Possible explanations include high rates of polymicrobial infections among fungal PJIs and high-risk comorbidities making patients susceptible to fungal PJIs [24]. However, risk factors for fungal PJIs have hardly been investigated. Although long-term follow-up studies have not been published yet, our patient has been treated successfully with the aforementioned therapeutic protocol.\n\nSummary\nDiagnostic challenges in patients with suspected PJIs will become more relevant. Coexisting sepsis and neutropenia can interfere with serological, synovial, and microbiological parameters. In this case, we suggest focusing on clinical findings preoperatively, and if there is any doubt, we recommend an urgent surgical approach and removal of the implant whenever possible.\n\nFungal PJIs were successfully treated with staged revision arthroplasty, implanting a voriconazole-impregnated spacer followed by 12 weeks of antifungal therapy. Long-term follow-up studies are needed to establish therapeutic algorithms and improve patients’ outcome.\n\nConflict of interests\nThe authors declare there are no conflicts of interest.\n\nAppendix A Supplementary data\nConflict of Interest Statement for All the Authors\n \n\nAcknowledgments\nThe authors acknowledge funding from the Open Access Publication Fund of the Westphalia Wilhelm University, Muenster, for paying the publication fee.\n==== Refs\nReferences\n1 Kurtz S.M. Lau E.C. Son M.S. Chang E.T. Zimmerli W. Parvizi J. Are we winning or losing the battle with periprosthetic joint infection: trends in periprosthetic joint infection and mortality risk for the medicare population J Arthroplasty 33 10 2018 3238 29914821 \n2 Koh C.K. Zeng I. Ravi S. Zhu M. Vince K.G. Young S.W. Periprosthetic joint infection is the main cause of failure for modern knee arthroplasty: an analysis of 11,134 knees Clin Orthop Relat Res 475 9 2017 2194 28573549 \n3 Papalia R. Vespasiani-Gentilucci U. Longo U.G. Advances in management of periprosthetic joint infections: an historical prospective study Eur Rev Med Pharmacol Sci 23 2 2019 129 30977879 \n4 Nace J. Siddiqi A. Talmo C.T. Chen A.F. Diagnosis and management of fungal periprosthetic joint infections J Am Acad Orthop Surg 27 18 2019 e804 30520804 \n5 Huber M. Andersohn F. Sarganas G. Metamizole-induced agranulocytosis revisited: results from the prospective berlin case-control surveillance study Eur J Clin Pharmacol 71 2 2015 219 25378038 \n6 Parvizi J. Tan T.L. Goswami K. The 2018 definition of periprosthetic hip and knee infection: an evidence-based and validated criteria J Arthroplasty 33 5 2018 1309 29551303 \n7 Renz N. Yermak K. Perka C. Trampuz A. Alpha defensin lateral flow test for diagnosis of periprosthetic joint infection J Bone Joint Surg Am 100 9 2018 742 29715222 \n8 Akgün D. Müller M. Perka C. Winkler T. The serum level of C-reactive protein alone cannot be used for the diagnosis of prosthetic joint infections, especially in those caused by organisms of low virulence Bone Joint J 100-B 11 2018 1482 30418061 \n9 Hoell S. Borgers L. Gosheger G. Interleukin-6 in two-stage revision arthroplasty Bone Joint J 97–B 1 2015 71 \n10 Karczewski D. Winkler T. Perka C. Müller M. The preoperative microbial detection is no prerequisite for the indication of septic revision in cases of suspected periprosthetic joint infection Biomed Res Int 2018 2018 1729605 30035117 \n11 Al-Mayahi M. Cian A. Lipsky B.A. Administration of antibiotic agents before intraoperative sampling in orthopedic infections alters culture results J Infect 71 5 2015 518 26283328 \n12 Abdel Karim M. Andrawis J. Bengoa F. Hip and knee section, diagnosis, algorithm: proceedings of international consensus on orthopedic infections J Arthroplasty 34 2 2019 S339 30348566 \n13 Rhodes A. Evans L.E. Alhazzani W. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016 Intensive Care Med 45 3 2017 304 \n14 Hotchkiss R.S. Monneret G. Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy Nat Rev Immunol 13 12 2013 862 24232462 \n15 Singer M. Deutschman C.S. Seymour C. The third international consensus definitions for sepsis and septic shock (sepsis-3) JAMA 315 8 2016 801 26903338 \n16 Sloan M. Premkumar A. Sheth N.P. Projected volume of primary total joint arthroplasty in the u.s., 2014 to 2030 J Bone Joint Surg Am 100 17 2018 1455 30180053 \n17 Strony J. Brown S. Choong P. Ghert M. Jeys L. O’Donnell R.J. Musculoskeletal infection in orthopaedic oncology J Bone Joint Surg Am 101 20 2019 e107 31626015 \n18 Jakobs O. Schoof B. Klatte T.O. Fungal periprosthetic joint infection in total knee arthroplasty: a systematic review Orthop Rev (Pavia) 7 1 2015 1 \n19 Yoon H.-K. Cho S.-H. Lee D.-Y. A review of the literature on culture-negative periprosthetic joint infection: epidemiology, diagnosis and treatment Knee Surg Relat Res 29 3 2017 155 28854760 \n20 Kuiper J.W.P. Van Den Bekerom M.P.J. Van Der Stappen J. Nolte P.A. Colen S. 2-Stage revision recommended for treatment of fungal hip and knee prosthetic joint infections Acta Orthop 84 6 2013 517 24171675 \n21 Cunningham B. McLaren A.C. Pauken C. McLemore R. Liposomal formulation increases local delivery of amphotericin from bone cement: a pilot study infection Clin Orthop Relat Res 470 10 2012 2671 22467417 \n22 Miller R.B. McLaren A.C. Pauken C. Clarke H.D. McLemore R. Voriconazole is delivered from antifungal-loaded bone cement Clin Orthop Relat Res 471 1 2013 195 22782573 \n23 Kim J.K. Lee D.Y. Kang D.W. Ro D.H. Lee M.C. Han H.S. Efficacy of antifungal-impregnated cement spacer against chronic fungal periprosthetic joint infections after total knee arthroplasty Knee 25 4 2018 631 29778657 \n24 Theil C. Schmidt-Braekling T. Gosheger G. Moellenbeck B. Dieckmann R. Idelevich E.A. Fungal prosthetic joint infection in total hip or knee arthroplasty Bone Joint J 101 B 5 2019 589 31038988 \n25 Ueng S.W.N. Lee C.Y. Hu C.C. Hsieh P.H. Chang Y. What is the success of treatment of hip and knee candidal periprosthetic joint infection? Clin Orthop Relat Res 471 9 2013 3002 23633184 \n26 Brown T.S. Petis S.M. Osmon D.R. Periprosthetic joint infection with fungal pathogens J Arthroplasty 33 8 2018 2605 29636249\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-3441",
"issue": "6(4)",
"journal": "Arthroplasty today",
"keywords": "Agranulocytosis; Candida infection; Fungal infection; Periprosthetic infection; Revision arthroplasty; Total knee arthroplasty",
"medline_ta": "Arthroplast Today",
"mesh_terms": null,
"nlm_unique_id": "101681808",
"other_id": null,
"pages": "726-730",
"pmc": null,
"pmid": "32923558",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "26903338;24171675;28573549;30348566;28854760;25874061;22782573;29778657;22467417;29914821;23633184;26283328;25568416;24232462;29551303;30180053;29636249;30035117;25378038;31038988;30520804;28101605;30418061;31626015;29715222;30977879",
"title": "Fungal Periprosthetic Knee Joint Infection in a Patient with Metamizole-Induced Agranulocytosis.",
"title_normalized": "fungal periprosthetic knee joint infection in a patient with metamizole induced agranulocytosis"
} | [
{
"companynumb": "DE-MYLANLABS-2020M1080180",
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"activesubstancename": "LINEZOLID"
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{
"abstract": "OBJECTIVE\nLedipasvir/Sofosbuvir (LDV/SOF) with or without Ribavirin (RBV) has shown good results in terms of efficacy and safety in clinical trials in advanced liver cirrhosis, but real-life data are still needed in order to confirm this profile. We investigated the efficacy and safety of LDV/SOF in a large Romanian population with liver cirrhosis and genotype 1b hepatitis C virus (HCV).\n\n\nMETHODS\nWe analyzed a multicentric retrospective cohort enrolling 349 patients with decompensated liver cirrhosis due to HCV who received LDV/SOF±RBV 12/24 weeks (301/48). Patients were included between 2017-2018, all with genotype 1b. Main inclusion criteria were liver cirrhosis and detectable HCV RNA. The cases were followed-up monthly during therapy and 12 weeks after the end of therapy.\n\n\nRESULTS\nThe cohort included 60% females with a median age of 61, 16% interferon (IFN) pre-treated, 53% with comorbidities, 40/53/7 % with Child Pugh A/B/C, 4% with virus B co-infection and 8% with previously treated hepatocellular carcinoma. Mean initial MELD score was 11.92 (6.82÷ 24.5). Six patients were lost during follow-up. Sustained virologic response (SVR) in intention-to-treat was reported in 85.1%. Predictive factors of SVR in decompensated cirrhosis were female gender (p=0.01), advanced age (p<0.001), lower bilirubin levels (p=0.002) and lower CTP score (p=0.02). In patients with CTP score B or C low bilirubin levels (p=0.003), low INR (p<0.001), increased platelet count (p=0.04), low CTP score (p<0.001), lack of encephalopathy (p=0.02), serum albumin >3.5g/dl (p=0.002) predicted improvement of liver function. Serious adverse events were reported in 16/349 (4.6%), most of them due to severe liver decompensation (9/16).\n\n\nCONCLUSIONS\nLDV/SOF±RBV proved to be highly efficient in our difficult to treat population with 85.1% SVR.",
"affiliations": "Carol Davila University of Medicine and Pharmacy, Gastroenterol and Hepatol Depart, Clinic Fundeni Institute, Bucharest, Romania. . drlgheorghe@gmail.com.;Carol Davila University of Medicine and Pharmacy, Gastroenterol and Hepatol Depart, Clinic Fundeni Institute, Bucharest, Romania. . preda_monicaa@yahoo.com.;Carol Davila University of Medicine and Pharmacy, Internal Medicine Depart, Clinic Fundeni Institute, Bucharest, Romania. laura_ate@yahoo.com.;Gastroenterol and Hepatol Depart, Clinic Fundeni Institute, Bucharest; 4) Carol Davila University of Medicine and Pharmacy, Internal Medicine Depart, Emergency Universitary Hospital, Bucharest, Romania. doina.proca08@gmail.com.;Gastroenterol and Hepatol Depart, Clinic Fundeni Institute, Bucharest; 4) Carol Davila University of Medicine and Pharmacy, Internal Medicine Depart, Emergency Universitary Hospital, Bucharest, Romania. andreea.grigore92@yahoo.com.;UMF \"Carol Davila\" Internal Medicine Department, Emergency Universitary Hospital, Bucharest, Romania. cora.pop@gmail.com.;Gr. T. Popa University of Medicine and Pharmacy, Gastroenterol and Hepatol Depart, Gastroenterol and Hepatol Institute, Iasi, Romania. ancatrifan@yahoo.com.;Gr. T. Popa University of Medicine and Pharmacy, Gastroenterol and Hepatol Depart, Gastroenterol and Hepatol Institute, Iasi, Romania. stanciucarol@yahoo.com.;Carol Davila University of Medicine and Pharmacy, Gastroenterol and Hepatol Depart, Clinic Fundeni Institute, Bucharest, Romania. mmdiculescu@yahoo.com.;Carol Davila University of Medicine and Pharmacy, Internal Medicine Depart, Colentina Hospital, Bucharest, Romania. theodor.voiosu@gmail.com.;Carol Davila University of Medicine and Pharmacy, Internal Medicine Depart, Colentina Hospital, Bucharest, Romania. cbaicus@gmail.com.;Gastroenterology and Hepatology Department, Clinic Fundeni Institute, Bucharest, Romania. letitiatugui@yahoo.com.;Carol Davila University of Medicine and Pharmacy, Gastroenterol and Hepatol Depart, Clinic Fundeni Institute, Bucharest, Romania. msiacob@gmail.com.;Carol Davila University of Medicine and Pharmacy, Gastroenterol and Hepatol Depart, Elias Emergency Hospital, Bucharest, Romania. tieranucristian@gmail.com.;Carol Davila University of Medicine and Pharmacy, Gastroenterol and Hepatol Depart, Clinic Fundeni Institute, Bucharest, Romania.;Carol Davila University of Medicine and Pharmacy, Gastroenterol and Hepatol Depart, Clinic Fundeni Institute, Bucharest, Romania. m_manuc@yahoo.com.",
"authors": "Gheorghe|Liliana Simona|LS|;Preda|Carmen|C|;Iliescu|Laura|L|;Istratescu|Doina|D|;Chifulescu|Andreea Elena|AE|;Pop|Corina Silvia|CS|;Trifan|Anca|A|;Stanciu|Carol|C|;Diculescu|Mircea|M|;Voiosu|Theodor|T|;Baicus|Cristian|C|;Tugui|Letitia|L|;Iacob|Speranta|S|;Tieranu|Cristian|C|;Meianu|Corina|C|;Manuc|Mircea|M|",
"chemical_list": "D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; C000595958:ledipasvir, sofosbuvir drug combination; D012254:Ribavirin; D000069474:Sofosbuvir",
"country": "Romania",
"delete": false,
"doi": "10.15403/jgld-2448",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1841-8724",
"issue": "29(3)",
"journal": "Journal of gastrointestinal and liver diseases : JGLD",
"keywords": null,
"medline_ta": "J Gastrointestin Liver Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents; D001562:Benzimidazoles; D005260:Female; D005449:Fluorenes; D005838:Genotype; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012254:Ribavirin; D012383:Romania; D000069474:Sofosbuvir; D000072230:Sustained Virologic Response; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "101272825",
"other_id": null,
"pages": "385-390",
"pmc": null,
"pmid": "32919421",
"pubdate": "2020-09-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Efficacy and Safety of Ledispavir/Sofosbuvir with or without Ribavirin in patients with Decompensated Liver Cirrhosis and Hepatitis C Infection: a Cohort Study.",
"title_normalized": "efficacy and safety of ledispavir sofosbuvir with or without ribavirin in patients with decompensated liver cirrhosis and hepatitis c infection a cohort study"
} | [
{
"companynumb": "RO-GILEAD-2020-0495381",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEDIPASVIR\\SOFOSBUVIR"
},
"drugadditional": nul... |
{
"abstract": "Pathogenic missense and truncating variants in the GABRG2 gene cause a spectrum of epilepsies, from Dravet syndrome to milder simple febrile seizures. In most cases, pathogenic missense variants in the GABRG2 gene segregate with a febrile seizure phenotype. In this case series, we report a recurrent, de novo missense variant (c0.316 G > A; p.A106T) in the GABRG2 gene that was identified in five unrelated individuals. These patients were described to have a more severe phenotype than previously reported for GABRG2 missense variants. Common features include variable early-onset seizures, significant motor and speech delays, intellectual disability, hypotonia, movement disorder, dysmorphic features and vision/ocular issues. Our report further explores a recurrent pathogenic missense variant within the GABRG2 variant family and broadens the spectrum of associated phenotypes for GABRG2-associated disorders.",
"affiliations": "a GeneDx, Inc , Gaithersburg , MD , USA.;a GeneDx, Inc , Gaithersburg , MD , USA.;a GeneDx, Inc , Gaithersburg , MD , USA.;a GeneDx, Inc , Gaithersburg , MD , USA.;b Division of Genetics and Genomics , Boston Children's Hospital , Boston , MA , USA.;b Division of Genetics and Genomics , Boston Children's Hospital , Boston , MA , USA.;c NIH Common Fund , Undiagnosed Diseases Network , Bethesda , MD , USA.;c NIH Common Fund , Undiagnosed Diseases Network , Bethesda , MD , USA.;e Division of Neurophysiology , Boston Children's Hospital , Boston , MA , USA.;c NIH Common Fund , Undiagnosed Diseases Network , Bethesda , MD , USA.;f Division of Child Neurology, Departments of Neurology and Pediatrics , Children's Hospital of Philadelphia , Philadelphia , PA , USA.;g Individualized Medical Genetics Center, Division of Human Genetics, Division of Neurology , The Children's Hospital of Philadelphia , Philadelphia , PA , USA.;h Division of Metabolic Disorders , CHOC Children's Hospital , Orange , CA , USA.;h Division of Metabolic Disorders , CHOC Children's Hospital , Orange , CA , USA.;i Neurology , CHOC Children's Hospital , Orange , CA , USA.;j Wilhelmina Children's Hospital/University Medical Center , Utrecht , the Netherlands.;j Wilhelmina Children's Hospital/University Medical Center , Utrecht , the Netherlands.;k Department of Genetics , University Medical Center Utrecht , Utrecht , the Netherlands.;k Department of Genetics , University Medical Center Utrecht , Utrecht , the Netherlands.;l University of North Carolina at Chapel Hill , Chapel Hill , NC , USA.;m University of North Carolina at Chapel Hill , Chapel Hill , NC , USA.;a GeneDx, Inc , Gaithersburg , MD , USA.;a GeneDx, Inc , Gaithersburg , MD , USA.;a GeneDx, Inc , Gaithersburg , MD , USA.;a GeneDx, Inc , Gaithersburg , MD , USA.",
"authors": "Zou|Fanggeng|F|;McWalter|Kirsty|K|;Schmidt|Lindsay|L|;Decker|Amy|A|;Picker|Jonathan D|JD|;Lincoln|Sharyn|S|;Sweetser|David A|DA|;Briere|Lauren C|LC|;Harini|Chellamani|C|;|||;Marsh|Eric|E|;Medne|Livija|L|;Wang|Raymond Y|RY|;Leydiker|Karen|K|;Mower|Andrew|A|;Visser|Gepke|G|;Cuppen|Inge|I|;van Gassen|Koen L|KL|;van der Smagt|Jasper|J|;Yousaf|Adeel|A|;Tennison|Michael|M|;Shanmugham|Anita|A|;Butler|Elizabeth|E|;Richard|Gabriele|G|;McKnight|Dianalee|D|",
"chemical_list": "C546279:GABRG2 protein, human; D011963:Receptors, GABA-A",
"country": "England",
"delete": false,
"doi": "10.1080/01677063.2017.1315417",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-7063",
"issue": "31(1-2)",
"journal": "Journal of neurogenetics",
"keywords": "Epilepsy; GABRG2; genetics; missense; phenotype; seizures",
"medline_ta": "J Neurogenet",
"mesh_terms": "D000015:Abnormalities, Multiple; D000293:Adolescent; D002648:Child; D004827:Epilepsy; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability; D008297:Male; D000068079:Motor Disorders; D009069:Movement Disorders; D009123:Muscle Hypotonia; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011963:Receptors, GABA-A; D012720:Severity of Illness Index; D013064:Speech Disorders",
"nlm_unique_id": "8406473",
"other_id": null,
"pages": "30-36",
"pmc": null,
"pmid": "28460589",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18446616;16452673;27367160;9647870;24798517;16924025;12117362;23720301;12097483;23069679;19505943;22569178;21714819;18566737;19261880;15201329;20354512;11326274;18414213;20308251;11748509;21478889;26005849;25741868;17175814;21425109;24061200;20485450;24407264;11326275;19561590;27864268;23708187;19451168;25356966;27066572;25726841;9771735;16860540",
"title": "Expanding the phenotypic spectrum of GABRG2 variants: a recurrent GABRG2 missense variant associated with a severe phenotype.",
"title_normalized": "expanding the phenotypic spectrum of gabrg2 variants a recurrent gabrg2 missense variant associated with a severe phenotype"
} | [
{
"companynumb": "US-UCBSA-2017024732",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXCARBAZEPINE"
},
"drugadditional": "3",
... |
{
"abstract": "Serious bacterial infections in immunocompromised patients require highly effective antibacterial therapy for cure, and thus, this setting may reveal novel mechanisms by which bacteria circumvent antibiotics in the absence of immune pressure. Here, an infant with leukemia developed vancomycin-resistant Enterococcus faecium (VRE) bacteremia that persisted for 26 days despite appropriate antibiotic therapy. Sequencing of 22 consecutive VRE isolates identified the emergence of a single missense mutation (L152F) in relA, which constitutively activated the stringent response, resulting in elevated baseline levels of the alarmone guanosine tetraphosphate (ppGpp). Although the mutant remained susceptible to both linezolid and daptomycin in clinical MIC testing and during planktonic growth, it demonstrated tolerance to high doses of both antibiotics when growing in a biofilm. This biofilm-specific gain in resistance was reflected in the broad shift in transcript levels caused by the mutation. Only an experimental biofilm-targeting ClpP-activating antibiotic was able to kill the mutant strain in an established biofilm. The relA mutation was associated with a fitness trade-off, forming smaller and less-well-populated biofilms on biological surfaces. We conclude that clinically relevant relA mutations can emerge during prolonged VRE infection, causing baseline activation of the stringent response, subsequent antibiotic tolerance, and delayed eradication in an immunocompromised state.\n\n\n\nThe increasing prevalence of antibiotic-resistant bacterial pathogens is a major challenge currently facing the medical community. Such pathogens are of particular importance in immunocompromised patients as these individuals may favor emergence of novel resistance determinants due to lack of innate immune defenses and intensive antibiotic exposure. During the course of chemotherapy, a patient developed prolonged bacteremia with vancomycin-resistant Enterococcus faecium that failed to clear despite multiple front-line antibiotics. The consecutive bloodstream isolates were sequenced, and a single missense mutation identified in the relA gene, the mediator of the stringent response. Strains harboring the mutation had elevated baseline levels of the alarmone and displayed heightened resistance to the bactericidal activity of multiple antibiotics, particularly in a biofilm. Using a new class of compounds that modulate ClpP activity, the biofilms were successfully eradicated. These data represent the first clinical emergence of mutations in the stringent response in vancomycin-resistant entereococci.",
"affiliations": "Department of Infectious Diseases, St. Jude Children's Hospital, Memphis, Tennessee, USA.;Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.;Department of Infectious Diseases, St. Jude Children's Hospital, Memphis, Tennessee, USA.;Department of Infectious Diseases, St. Jude Children's Hospital, Memphis, Tennessee, USA.;Department of Infectious Diseases, St. Jude Children's Hospital, Memphis, Tennessee, USA.;Department of Infectious Diseases, St. Jude Children's Hospital, Memphis, Tennessee, USA.;Department of Oncology, St. Jude Children's Hospital, Memphis, Tennessee, USA.;Department of Pathology, St. Jude Children's Hospital, Memphis, Tennessee, USA.;Department of Chemical Biology and Therapeutics, St. Jude Children's Hospital, Memphis, Tennessee, USA.;Department of Infectious Diseases, St. Jude Children's Hospital, Memphis, Tennessee, USA.;Department of Infectious Diseases, St. Jude Children's Hospital, Memphis, Tennessee, USA.;Department of Infectious Diseases, St. Jude Children's Hospital, Memphis, Tennessee, USA Joshua.wolf@stjude.org jason.rosch@stjude.org.;Department of Infectious Diseases, St. Jude Children's Hospital, Memphis, Tennessee, USA Joshua.wolf@stjude.org jason.rosch@stjude.org.",
"authors": "Honsa|Erin S|ES|;Cooper|Vaughn S|VS|0000-0001-7726-0765;Mhaissen|Mohammed N|MN|;Frank|Matthew|M|;Shaker|Jessica|J|;Iverson|Amy|A|;Rubnitz|Jeffrey|J|;Hayden|Randall T|RT|;Lee|Richard E|RE|;Rock|Charles O|CO|;Tuomanen|Elaine I|EI|;Wolf|Joshua|J|;Rosch|Jason W|JW|",
"chemical_list": "D000900:Anti-Bacterial Agents; D050505:Mutant Proteins; D006159:Guanosine Tetraphosphate; D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases",
"country": "United States",
"delete": false,
"doi": "10.1128/mBio.02124-16",
"fulltext": "\n==== Front\nmBioMBiombiombiomBiomBio2150-7511American Society for Microbiology 1752 N St., N.W., Washington, DC 28049149mBio02124-1610.1128/mBio.02124-16Research ArticleRelA Mutant Enterococcus faecium with Multiantibiotic Tolerance Arising in an Immunocompromised Host Stringent Response Mutant Is Antibiotic TolerantHonsa et al.Honsa Erin S. ahttp://orcid.org/0000-0001-7726-0765Cooper Vaughn S. bMhaissen Mohammed N. aFrank Matthew aShaker Jessica aIverson Amy aRubnitz Jeffrey cHayden Randall T. dLee Richard E. eRock Charles O. aTuomanen Elaine I. aWolf Joshua afRosch Jason W. aa Department of Infectious Diseases, St. Jude Children’s Hospital, Memphis, Tennessee, USAb Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USAc Department of Oncology, St. Jude Children’s Hospital, Memphis, Tennessee, USAd Department of Pathology, St. Jude Children’s Hospital, Memphis, Tennessee, USAe Department of Chemical Biology and Therapeutics, St. Jude Children’s Hospital, Memphis, Tennessee, USAf Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USAGilmore Michael S. EditorHarvard Medical SchoolAddress correspondence to Joshua Wolf, Joshua.wolf@stjude.org, or Jason W. Rosch, jason.rosch@stjude.org.E.S.H. and V.S.C. contributed equally to this article.\n\n3 1 2017 Jan-Feb 2017 8 1 e02124-1622 11 2016 28 11 2016 Copyright © 2017 Honsa et al.2017Honsa et al.This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.ABSTRACT\nSerious bacterial infections in immunocompromised patients require highly effective antibacterial therapy for cure, and thus, this setting may reveal novel mechanisms by which bacteria circumvent antibiotics in the absence of immune pressure. Here, an infant with leukemia developed vancomycin-resistant Enterococcus faecium (VRE) bacteremia that persisted for 26 days despite appropriate antibiotic therapy. Sequencing of 22 consecutive VRE isolates identified the emergence of a single missense mutation (L152F) in relA, which constitutively activated the stringent response, resulting in elevated baseline levels of the alarmone guanosine tetraphosphate (ppGpp). Although the mutant remained susceptible to both linezolid and daptomycin in clinical MIC testing and during planktonic growth, it demonstrated tolerance to high doses of both antibiotics when growing in a biofilm. This biofilm-specific gain in resistance was reflected in the broad shift in transcript levels caused by the mutation. Only an experimental biofilm-targeting ClpP-activating antibiotic was able to kill the mutant strain in an established biofilm. The relA mutation was associated with a fitness trade-off, forming smaller and less-well-populated biofilms on biological surfaces. We conclude that clinically relevant relA mutations can emerge during prolonged VRE infection, causing baseline activation of the stringent response, subsequent antibiotic tolerance, and delayed eradication in an immunocompromised state.\n\nIMPORTANCE\nThe increasing prevalence of antibiotic-resistant bacterial pathogens is a major challenge currently facing the medical community. Such pathogens are of particular importance in immunocompromised patients as these individuals may favor emergence of novel resistance determinants due to lack of innate immune defenses and intensive antibiotic exposure. During the course of chemotherapy, a patient developed prolonged bacteremia with vancomycin-resistant Enterococcus faecium that failed to clear despite multiple front-line antibiotics. The consecutive bloodstream isolates were sequenced, and a single missense mutation identified in the relA gene, the mediator of the stringent response. Strains harboring the mutation had elevated baseline levels of the alarmone and displayed heightened resistance to the bactericidal activity of multiple antibiotics, particularly in a biofilm. Using a new class of compounds that modulate ClpP activity, the biofilms were successfully eradicated. These data represent the first clinical emergence of mutations in the stringent response in vancomycin-resistant entereococci.\n\nHHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)\nhttps://doi.org/10.13039/1000000601U01AI124302Jason W. RoschHHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)\nhttps://doi.org/10.13039/1000000601RO1AI110618Jason W. RoschHHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)\nhttps://doi.org/10.13039/100000060R01AI111449Richard LeeHHS | NIH | National Institute of General Medical Sciences (NIGMS)\nhttps://doi.org/10.13039/100000057R01GM034496Charles O. RockHHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)AI27913AI2111585Elaine I. Tuomanen cover-dateJanuary/February 2017\n==== Body\nINTRODUCTION\nCurrent challenges in treatment of infections are focused on the marked reduction of new candidates in the antibacterial discovery pipeline at a time of increasing rates of antimicrobial resistance, including emergence of methicillin-resistant Staphylococcus aureus (MRSA), β-lactam- and macrolide-resistant Streptococcus pneumoniae, and vancomycin-resistant enterococci (VRE) (1–4). VRE species are especially problematic clinically, as these bacteria are resistant to all first-line antibiotics and infection is associated with a marked increase in risk of mortality (5–8). However, other challenges to therapeutic success are also emerging, particularly in the immuncompromised host, where refractory bacteremia and prolonged antibiotic therapy increase the opportunity to select for alternative bacterial survival traits by mutation or genetic exchange (9–12). Once mutations arise, the permissive nature of the compromised immune system may allow for the development of secondary mutations that compensate for any associated fitness trade-offs (13). As such, hosts more permissive for infection have been postulated to represent an important reservoir for the emergence of novel problematic pathogens (14).\n\nIn the absence of host defenses, bacterial killing by antibiotics is required for cure. Commonly this is ensured by administering drugs with the aim of ensuring that concentrations at the site of infection are above the MIC as reported by the clinical laboratory. This assumes the bactericidal concentration is close to the MIC. However, bacteria can persist when the MIC and minimal bactericidal concentration (MBC) dissociate such that antibiotics inhibit growth but fail to kill, a property called “tolerance” (15–17). As genome sequencing technologies improve, it has become evident that mutations—particularly those involved in stress responses—can impact efficacy of antibiotics (18). The bacterial stringent response, which slows metabolism under low-nutrient or stress conditions, can decrease the response to antibiotic therapy, allowing quiescent bacteria to survive and tolerate antibiotics, without a change in MIC (19). In S. aureus, induction of the stringent response increases tolerance to β-lactam antibiotics (20–22), and in Gram-negative bacteria, activation contributes to the production of biofilm persister cells (23, 24). Also, a report on Enterococcus faecalis demonstrated that treatment of cells with mupirocin induced expression of transport and stress-related genes, and strong repression of genes involved DNA, RNA, and protein synthesis, similar to a stringent response (25). Despite the importance of the stringent response, there are few reports of clinical emergence of mutations in this pathway, none demonstrating reduced antibiotic efficacy (22), and no studies focusing on antibiotic tolerance and stringent response in E. faecium. For Enterococcus species, although the stringent response pathway is well characterized and antibiotic resistance is widespread, we report the first example of mutation in the stringent response pathway causing increased baseline alarmone levels, which was responsible for antibiotic tolerance within a biofilm.\n\nRESULTS\nClinical setting.\nThe patient was a 6-week-old African-American girl born by normal vaginal delivery at term. Acute myeloid leukemia was diagnosed at 4 weeks of age, after she presented with fever and marked leukocytosis. A double-lumen central venous catheter (CVC) was placed (7.0 French-scale Hickman catheter; Bard Access Systems, Salt Lake City, UT), and chemotherapy was initiated, resulting in prolonged profound neutropenia. Induction chemotherapy comprised systemic cytarabine, daunorubicin, etoposide, and methylprednisolone plus intrathecal methotrexate, hydrocortisone, and cytarabine. The patient received intravenous cefepime as antibacterial prophylaxis. After 2 weeks of chemotherapy, during profound neutropenia, routine microscopic examination of a peripheral blood smear revealed bacterial organisms, although the patient had no signs or symptoms of infection. Blood cultures were obtained from both lumens of the CVC, and empirical combination therapy with vancomycin and meropenem was initiated. After blood cultures grew vancomycin-resistant Enterococcus faecium, the antibiotic regimen was changed to linezolid, which was eventually supplemented with daptomycin, gentamicin, and quinupristin-dalfopristin (Table 1).\n\nTABLE 1 Summary of patient parameters and antimicrobial therapya\n\na ANC, absolute neutrophil count; CVC, central venous catheter; CSF, cerebrospinal fluid.\n\nInitial paired blood cultures drawn from the two CVC lumens showed a differential time to positivity of 4.0 h, and culture of the explanted device at the time of CVC removal (day 9) was positive for E. faecium, suggesting that the infection was initially related to biofilm on the surface of the CVC (26). However, over the 28 days, the bacteremia failed to clear despite targeted antibiotic therapy, as well as CVC removal and replacement on two occasions, both allowing for CVC-free periods. Antibiotic therapy was chosen in accordance with expert opinion and in vitro susceptibility testing that indicated the strain remained sensitive to all antibiotics administered except the initial vancomycin and meropenem (27). During the persistent bacteremia, there was no significant change in the reported antimicrobial susceptibility pattern according to testing performed in our clinical microbiology laboratory. Every strain was susceptible to linezolid (MIC, 1 to 2 µg/ml), quinupristin-dalfopristin (MIC, 0.5 µg/ml), and daptomycin (MIC, 3 to 4 µg/ml). High-level resistance to gentamicin was not detected (MIC, <500 µg/ml).\n\nA comprehensive diagnostic evaluation, including Doppler ultrasonography of the upper and lower extremities to detect intravascular thrombosis, ultrasound of head and abdomen, and magnetic resonance imaging (MRI) of the entire body failed, to identify any additional source of persistent infection. Analysis of cerebrospinal fluid (CSF) obtained through lumbar puncture on day 2 of infection was within normal limits, and bacterial culture was sterile. Transthoracic echocardiography performed on days 11 and 22 showed mild preexisting aortic regurgitation without clear evidence of vegetations. The initial source for the bloodstream infection is thought to have been luminal colonization and biofilm formation within the CVC, and after device removal, the bloodstream infection persisted. Based on this history, we believe that the most likely focus of persistent infection was occult endocarditis or septic thrombophlebitis.\n\nThe patient’s absolute neutrophil count (ANC) remained at 0 cells/mm3 until day 20, when donor granulocyte transfusion was initiated. Granulocyte transfusion was repeated again on days 22, 23, 24, 25, 26, and 27 until neutropenia resolved. Daily ANC values are shown in Table 1. On day 27, the bacteremia cleared, and the patient received an additional 6 weeks of linezolid treatment for possible endocarditis with full clinical recovery.\n\nGenetic characterization.\nThe initial VRE isolate was sequenced and completely assembled to obtain a closed genome comprising one 2.93-Mbp chromosome and three plasmids of 171, 78.6, and 59.2 kbp, containing a total of approximately 3,208 open reading frames (see Table S1 in the supplemental material). Analysis of the functional roles of predicted coding regions revealed multiple antibiotic resistance systems, including the vanB gene cluster for vancomycin, fluoroquinolones, aminoglycosides, β-lactams, and multiple putative drug efflux pumps (Table 2) (28, 29). All 22 isolates were completely sequenced at high depth (mean coverage of 256.6×) and aligned to the closed reference genome of the initial VRE isolate. In total, all genomes differed by only five single nucleotide polymorphisms (SNPs), and no insertions or deletions were detected, indicating that a single strain was responsible for the prolonged bacteremia. Four of the five mutations were identified only once in single isolates: therefore, we concluded these mutations were not clinically relevant. These mutations included Y175C missense mutation in rnz (RNase Z), the A221D missense mutation in ptsI (phosphoenolpyruvate phosphotransferase enzyme I), the P640H missense mutation in recF (recombination protein F), and a silent mutation in a hypothetical plasmid protein (Table 1). However, one missense mutation in the relA gene, predicted to encode an RelA(L152F) variant, was found in eight isolates. The relA mutation was first detected 3 days after starting antibiotic therapy and persisted through the clinical course until the infection eventually resolved (Table 1). The observation that the mutation was intermittently identified indicated that both the initial strain and the relA mutant strain coexisted until the later stages of the infection. As will be discussed, there may have been initial sampling bias during collection of a representative isolate from each day listed in Table 1; however, we believe this may have underestimated the true presence and persistence of the relA variant subpopulation.\n\n10.1128/mBio.02124-16.3Table S1 Genomic characterization of the VRE isolate. Download Table S1, XLS file, 2.1 MB.\n\nCopyright © 2017 Honsa et al.2017Honsa et al.This content is distributed under the terms of the Creative Commons Attribution 4.0 International license. TABLE 2 VRE isolates possessed multiple antibiotic resistance genes\n\nResistance function\tAntibiotic\tResistance gene(s)\t\nAlter cell wall charge\tPolymyxin\tpmrE\t\nAntibiotic-altering enzyme\tMacrolide\termB, msrC\t\nAntibiotic efflux\tFluoroquinolone\tarlR\t\nAntibiotic efflux\tTetracycline\tadeC, tetK, tetC\t\nAntibiotic efflux\tWide range\tlmrCD\t\nAntibiotic efflux\tLincosamide\tlsaE\t\nAntibiotic efflux\tStreptogramin\tmsrC, isaA\t\nAntibiotic inactivation enzyme\tLincosamide\tlnuB\t\nAminoglycoside-modifying enzymes\tAminoglycoside\taac(6′)-Ii, aac(6′)-Ie–aph(2′′)-Ia\t\nAminoglycoside-modifying enzymes\tAminoglycoside\taph(3′)-IIIa, aad(6′)\t\nAntibiotic target protection protein\tTetracycline\ttet32, tetO\t\nAntibiotic target replacement proteins\tβ-Lactams\tpbp1b, pbp2x, pbp2b, pbp1a, mecC\t\nMolecular bypass\tGlycopeptide\tvanB cassette\t\nTarget Mutation\tTrimethoprim\tdfrE, dfrF\t\nTarget mutation\tRifampin\trpoB\t\nTarget mutation\tFluoroquinolone\tgyrB\t\nRelA is a critical mediator of the bacterial stringent response via production of the alarmone guanosine tetraphosphate (ppGpp) and has been implicated in resistance or tolerance to antibiotic stress in several bacterial pathogens (30). In our RelA mutants, the altered residue (L152F) is immediately adjacent to residues essential for the hydrolase activity of the RelA enzyme (31). Modeling of the structural consequences of this mutation indicated that the native leucine is buried in the structure; however, replacement of this residue with a phenylalanine would not allow for such tight packing, potentially causing a local change in the active site. This mutation was initially detected on the fourth day of the bloodstream infection and appeared to become more prevalent later in the course of therapy, particularly once daptomycin was included in the antibiotic regimen (Table 1). Previous studies have also identified mutations in relA in response to daptomycin exposure in vitro, although no impact on antibiotic efficacy has been demonstrated (32). These data indicate that the VRE population remained mostly homogeneous, except for a single-point mutation in the stringent response pathway. This relA mutation arose during the course of the infection and persisted throughout the course of therapy despite treatment with antibiotics to which the bacterium retained apparent susceptibility based on MIC testing. It is worth noting that the VRE strains analyzed in this paper were genetically identical (isogenic), except for the relA missense mutation, and they all possessed multiple antibiotic resistance genes as shown in Table 2. Furthermore, no growth defects were identified between the wild type (WT) and the isogenic relA mutants in the absence of stressors (see Fig. S1A in the supplemental material).\n\n10.1128/mBio.02124-16.1Figure S1 No planktonic growth defects were detected in either the WT or isogenic relA mutant. Download Figure S1, DOCX file, 0.1 MB.\n\nCopyright © 2017 Honsa et al.2017Honsa et al.This content is distributed under the terms of the Creative Commons Attribution 4.0 International license. Effects of RelA mutation.\nThe missense mutation in a highly conserved domain essential for RelA hydrolase activity led us to ascertain whether the identified mutation in relA conferred any discernible differences in levels of (p)ppGpp, the alarmone that mediates the downstream stringent response pathways. Strains that were genetically identical with the exception of the single-base-pair relA mutation were allowed to incorporate 32P, and the baseline levels of (p)ppGpp were measured. Strains carrying the mutation in relA demonstrated approximately 3× greater basal levels of ppGpp than the WT controls (Fig. 1A, thin-layer chromatography [TLC] blot, and B, quantification [P < 0.001, Mann-Whitney test]). This observation suggested inappropriate activation of the alarmone at baseline in the absence of an external stimulus, potentially priming the cells to more rapidly adapt to adverse conditions such as antibiotic exposure. While we attempted to monitor differences in (p)ppGpp and GTP levels in linezolid-stressed relA WT and mutant strains, we could not detect any induction of the stringent response (Fig. 1C). It should be noted that both WT and relA mutant bacteria stressed with mupirocin did not show a difference in activated stringent response alarmone levels (WT shown in Fig. 1C [mutant identical to WT]). However, as will be discussed, we suggest the fitness benefit of the relA mutation is to provide a higher resting level of alarmone, which allowed these strains to better adapt and respond to antibiotic stress during therapy (tolerance).\n\nFIG 1 Basal levels of ppGpp are increased in VRE strains harboring mutant relA alleles. (A) Multiple relA WT or mutant (isogenic) strains were grown in low-phosphate media, followed by incubation with 32P, and levels of resting (p)ppGpp were measured by densitometry. (B) Data for ppGpp levels are quantified, and means and standard deviations are shown. Levels were normalized relative to the wild-type strain (100%). *, P = 0.0079 by Mann-Whitney testing. (C) Controls: negative control without any stressor (Cont.), positive-control mupirocin, as well as linezolid.\n\nThe most likely initial focus of infection in this case, the CVC, is associated with the development of surface-associated bacterial biofilm (33–35). This was possibly followed by biofilm formation on the heart valves; however, this could not be conclusively diagnosed. As mutations in relA have been implicated in alterations in biofilm formation, we next determined the effect of this mutation on the capacity of these strains to form biofilm. Since traditional growth curves (see Fig. S1B in the supplemental material) and time-kill assays (see Fig. S2 in the supplemental material) did not detect differences in the survival of the relA mutant compared to an isogenic relA WT strain (planktonic growth) in the presence of daptomycin or linezolid, we hypothesized that the mutation may demonstrate a more pronounced phenotype in a biofilm population. To explore a possible fitness trade-off in biofilm formation, we grew biofilms on fibronectin-coated 24-well plates for 24 h. After removal of any planktonic cells and staining with crystal violet, absorbance at 595 nm was determined as a quantification of biofilm size and thickness. Parallel to this analysis, we resuspended non-crystal violet-treated biofilms in phosphate-buffered saline (PBS) and serially diluted and plated for CFU-per-milliliter counts. As shown in Fig. 2A, the relA mutant consistently had significantly smaller biofilms than the isogenic WT strain when grown on these fibronectin-coated surfaces. Concurrently, identically grown biofilms identified at least a log decrease of relA mutant biofilm growth compared to the WT isogenic strain (109 versus 108 CFU after 24 h of growth in fibronectin-coated plates). Each strain was grown under identical conditions, as well as inoculated from titrated stocks, indicating that the missense mutation in relA conferred a defect in biofilm formation and bacterial survival within a biofilm.\n\n10.1128/mBio.02124-16.2Figure S2 Time-kill assays of the WT and relA mutant. Download Figure S2, DOCX file, 0.1 MB.\n\nCopyright © 2017 Honsa et al.2017Honsa et al.This content is distributed under the terms of the Creative Commons Attribution 4.0 International license. FIG 2 Biofilm size and live cell number are decreased in VRE strains harboring mutant relA alleles. (A) Biofilms of the VRE WT and relA mutant were formed in 24-well plates coated with bovine fibronectin. Quantification of biofilm was performed with crystal violet staining. Absorbance at 595 nm was measured for each sample. Three independent experiments were performed and combined to determine the mean average (with error bars). *, P = 0.0074 by two-tailed t test. The relA WT consistently grew to 109 CFU/ml, while the relA mutant grew to 108 CFU/ml per 24-h biofilm. (B and C) Biofilms were formed on multichambered glass slides. After 48 h, biofilms were stained with the Live/Dead BacLight bacterial viability kit and analyzed by confocal microscopy. (B) Representative images of a single segment. (C) The ratio of green to red (fluorescein isothiocyanate [FITC] to tetramethyl rhodamine isothiocyanate [TRITC]) signal was calculated from the average of each section, and ratios were combined for the final average (n = 8). **, P = 0.002.\n\nTo further investigate defects in biofilm formation of our relA mutant, we performed confocal fluorescence microscopy. Here, biofilms of relA WT and mutant isogenic strains were allowed to form on an abiotic surface (microscope slide chamber) for 48 h. Live/dead staining was then performed, and confocal microscopy was used to measure fluorescein isothiocyanate (FITC) and tetramethyl rhodamine isothiocyanate (TRITC) fluorescence of z-stack 16-µm sections of each biofilm. To remove bias from biofilm sampling, each chamber for each strain was randomly analyzed in four separate sections, and each strain was analyzed in two separate chambers on multiple days, allowing an n value of 8 for each strain. Figure 2B shows that the WT strain had consistently brighter fluorescence in each section, compared to the relA mutant on the right. Furthermore, when the green and red signals were quantified and a ratio determined (Fig. 2C), there was a consistently higher fluorescent intensity for live cells for the WT strains. This suggests that the biofilm of the mutant harbors less total live cells, which correlates back to the CFU/ml data of established cells. Together, our biofilm analysis suggests that the ability to form thicker, more robust biofilms is compromised in the relA mutant.\n\nA mutation such as relA(L152F) that primes cells to enter the stringent response by increasing ppGpp levels is expected to affect expression of many genes. Likewise, the phenotypic differences between planktonic and biofilm growth of these strains should be related to transcriptome changes. We tested these predictions by performing RNA sequencing on these strains grown either in the liquid planktonic phase or as biofilms on a biotic surface. This experiment revealed broad changes in expression in as much as 15% of the ~2,940 genes in the genome in the relA mutant compared to the WT and during the shift from planktonic to biofilm growth. The interactions between genotype and growth environment were most telling. Not only did this single relA mutation affect expression (mostly by downregulation) of a broad array of genes in both conditions, it also changed how certain genes responded during the shift from planktonic to biofilm growth. In fact, 35 genes responded in opposite directions in the shift to biofilm growth for the WT and the mutant (i.e., expression was up for the WT, down for the mutant, or vice versa), and 25 genes were divergently expressed for the relA mutant under biofilm and planktonic growth conditions. Some of these genes with divergent expression provide potential mechanistic explanations for the biofilm-dependent resistance observed, including liaS, a major target of mutations causing resistance to daptomycin (36), which was upregulated in the WT biofilm relative to WT planktonic culture, but downregulated in the relA biofilm relative to planktonic relA cells. A small group of genes were uniquely upregulated in the relA biofilm, including genes with chaperone functions, such as greA (EFAU004_01358) and cspA (EFAU004_01491), which would presumably enhance stress tolerance. However, the overwhelming signature of the relA mutant was that it downregulated far more genes during biofilm growth than the WT strain (480 genes in comparison with 214 genes), and the direct comparison of the WT biofilm and the relA biofilm also revealed 433 genes downregulated by the mutant. In summary, this single mutation not only suppressed expression of many genes, it did so in a biofilm-dependent manner that actually reversed the tendency of some genes to be upregulated under this condition by the WT.\n\nGiven these biofilm-dependent changes in expression, it was somewhat surprising to observe a fitness trade-off for the relA mutant in forming biofilms in standard media. However, in the patient, the bacteria would have been constantly exposed to various antibiotic stresses during therapy. We therefore investigated whether the relA mutation conferred enhanced tolerance to antibiotic-mediated killing in a biofilm model. Since no resistance was detected against linezolid and daptomycin (MIC clinical data and Table 2), we hypothesized that the relA mutation was not responsible for a detectable rise in antibiotic resistance, but rather allowed the mutants to respond faster to antibiotic stress in a biofilm, thus becoming tolerant to multiple antibiotics. Biofilms of the two isogenic strains (WT or relA mutant) were allowed to form on Nunc peg plates in the rich medium Todd-Hewitt broth supplemented with yeast extract, following previously published protocols (37, 38). As a control, the relA mutation conferred no discernible difference in the outgrowth of planktonic cells removed from biofilms in the absence of antibiotics (Fig. 3A), indicating the relA mutation did not affect outgrowth from a biofilm. However, when the biofilms were subjected to prolonged antibiotic exposure, high concentrations of vancomycin, linezolid, and daptomycin were successful in eradicating the WT strain but failed to eradicate strains harboring the relA mutation (Fig. 3B, C, and D). It should be noted that the subsequent outgrowth of each strain was in the absence of antibiotic, so no antibiotic carryover could be responsible for the difference in response to antibiotic stress. These data indicated that this mutation conferred a selective advantage to the in vitro survival of antibiotic-tolerant persister cells within a biofilm, in the absence of linezolid or daptomycin resistance using standard CLSI susceptibility testing. Despite the defect of biofilm formation on fibronectin-coated plates, the relA mutant still displayed enhanced tolerance to antibiotics in the biofilm state. Taken together, these data suggest that while the relA mutation led to increased alarmone resting levels and subsequent tolerance to multiple-antibiotic stressors, the mutant strain was deficient in the ability to form biofilms compared to its WT counterparts.\n\nFIG 3 The relA mutation contributes to tolerance to antibiotics in biofilms. Strains were grown and allowed to form biofilms by using a peg suspension system. Biofilms were then treated with the respective antibiotics (256 µg/ml vancomycin, 50 µg/ml linezolid, and 50 µg/ml daptomycin) for 24 h. After antibiotic treatment, biofilms were washed, collected by centrifugation, and allowed to outgrow in antibiotic-free medium to ascertain an approximation of bacterial killing. Data represent the mean of three replicates; error bars represent standard deviation. For clarity, 6 h to 14 h is shown, as there was no growth prior to 6 h for drug-treated VRE.\n\nEradication of bacterial biofilms is a major challenge during therapy due to their inherently greater tolerance to many antibiotics and their capacity to both resist antibiotic penetration and resist immune clearance (39). This phenomenon is especially confounded in immunocompromised patients. A new experimental approach to target such refractory bacterial communities has been the development of a class of compounds that cause unregulated activation of the housekeeping protease ClpP (40). We assayed the bactericidal activity of one such investigational compound, ADEP-4, against isogenic strains possessing either WT or relA mutant strains in the context of a biofilm. While the absence of antibiotic once again had no effect on the planktonic outgrowth of bacteria, treatment with ADEP-4 successfully eradicated biofilms of both strains (Fig. 4A and B). These data indicate that strains harboring the relA mutation that conferred enhanced tolerance to clinically approved antibiotics during biofilm growth remained susceptible to this investigational class of compounds.\n\nFIG 4 The ClpP activator successfully eradicates biofilm irrespective of the relA mutation. The wild type (A) and an isogenic mutant (B) harboring the relA missense mutation were allowed to form biofilms for 24 h. Following biofilm formation, cells were treated with either DMSO (black lines) or the ClpP activator ADEP-4 at 0.2 µM for 24 h (blue lines). After antibiotic treatment, biofilms were washed, collected by centrifugation, and allowed to outgrow in antibiotic-free medium to ascertain an approximation of bacterial killing. Data represent the mean from four replicates; error bars represent standard deviation.\n\nDISCUSSION\nThe stringent response is a highly conserved mechanism by which bacteria can control broad metabolic changes required for survival under adverse conditions and has been implicated in the virulence of several prominent pathogens (41). It has also been implicated in the ability to promote antibiotic “tolerance”: bacterial cells that are able to survive antibiotic concentrations much higher than the MIC and can replicate once antibiotic pressure is removed (15, 17, 19, 22, 24). It is hypothesized that this is due to the absence or inactivity of antibiotic targets: for example, tolerant persister cells may not be actively dividing, so the presence of linezolid would not affect protein synthesis and therefore would not cause bacterial cell death. As such, these tolerant cells can persist during prolonged antibiotic exposure, further complicating antibiotic treatment.\n\nIn Enterococcus, two enzymes are responsible for the production of the stringent response alarmone (p)ppGpp: the bifunctional RSH (i.e., Rel SpoT homolog [RelA for this study]) and the monofunctional RelQ alarmone synthase (42, 43). Recent studies have highlighted the importance of subtle alterations in the levels of basal ppGpp as opposed to the higher levels induced during the stringent response in mediating broad-range antibiotic tolerance (42). These data suggest that mutations in relA that alter basal ppGpp levels may confer antibiotic tolerance of significance in an immunocompromised setting.\n\nEmergence of a mutation in the relA gene has been observed during persistent infection with S. aureus, but not in Enterococcus (22). Furthermore, the identification of a clinical VRE isolate with tolerance to multiple antibiotics due to a relA mutation has not been previously reported. It is important to note that our antibiotic-tolerant relA VRE mutants could not be distinguished from their isogenic WT counterparts by standard in vitro clinical MIC testing or by traditional growth curves (Fig. S1A) and time-kill assays (Fig. S2) of exponentially replicating cells in liquid culture. While the fitness advantage of the relA mutation was not present in planktonic culture, we determined that it was significant in the biofilm elimination model, whereby the mutant survived exposure to several antibiotics used to treat infection, suggesting an increase in antibiotic tolerance (Fig. 5). This has previously been reported for multiple bacterial pathogens, but not for VRE (22, 44). Biofilms harboring the RelA missense mutation in the hydrolase domain had increased resting alarmone levels and were recalcitrant to elimination by conventional antibiotic treatment. This included both linezolid and daptomycin, of which no genetically encoded antibiotic resistance mechanisms existed (Table 2). However, both the WT and relA mutant were effectively eradicated by ADEP-4, which has been shown to constitutively activate the housekeeping protease ClpP. These data indicate that such unconventional antibiotic strategies may be extremely effective for eliminating tolerant, persistent infections in an immunocompromised host. The ClpP-sensitive, conventional antibiotic-tolerant biofilm population is reminiscent of the presumed clinical course, as the focus of infection is thought to have initially been the CVC followed by possible endocarditis, both infections typically thought to be caused by multicellular biofilm communities. Despite antibiotic therapy, bacterial clearance required host immune reconstitution; the infection only cleared upon neutrophil recovery. This is an important reminder that clinical response may not correlate with in vitro susceptibility testing, especially in immunocompromised hosts or biofilm-associated infections (34).\n\nFIG 5 Summary of significant differences in expression between the WT and the relA mutant, in both planktonic and biofilm growth, as revealed by RNA-seq. The numbers shown are the number of genes in which expression differs at a very stringent cutoff of q < 0.001; arrow direction should be read as “is less than.” Arrow thickness is proportionate to the number of differences. Boxes containing both arrows denote genes with divergent expression, as follows: 35 genes have reduced expression in the relA mutant biofilm that were increased in the WT biofilm, and 25 genes have reduced expression in the relA biofilm that were increased in the relA planktonic culture.\n\nThere exist a multitude of pathways by which bacteria can evolve greater antibiotic tolerance, as evidenced by in vitro selection; however, only a subset of the mutations observed in the laboratory are identified in clinical isolates (45). Mutations conferring tolerance provide an obvious advantage to bacteria in the presence of the antibiotic but may involve trade-offs in fitness (46). In order for new tolerance mechanisms to disseminate throughout a population, any fitness trade-off must be alleviated through compensatory mutations to allow the strain to compete with and outgrow nonresistant organisms in the absence of antibiotic selection. In immunocompromised hosts, bacterial pathogens may replicate and evolve novel antibiotic tolerance mechanisms free from the usual immune surveillance (47–49). This phenomenon is reflected in our study, whereby a mutation in the stringent response arose and was maintained under antibiotic pressure in the context of an ongoing, profoundly immunocompromised state (Fig. 6).\n\nFIG 6 Pathway of stringent response with relA hydrolase mutation. During stress response, RelA (RSH/SpoT homolog in VRE) and RelQ are responsible for the production of the alarmone (red circles). In the relA mutants, a missense mutation adjacent to an active site in the hydrolysis domain led to increased resting levels of ppGpp. Cells were “primed” to respond faster to stress in a biofilm, which included antibiotic stress in the patient’s case. We propose that the presence of ppGpp downregulated multiple nonessential pathways, as shown by the RNA-seq data, including biofilm components. Therefore, while the relA mutant was fit to survive in an immunocompromised patient, once the immune system was reconstituted, the fitness trade-off of a smaller, less robust biofilm would enhance susceptibility to neutrophil killing.\n\nWhile in vitro data suggested that the presence of the relA mutation rendered these strains more tolerant to antibiotic stress within a biofilm, we detected a fitness defect in the ability to form biofilms of the same size compared to the isogenic WT strain. In accordance with patient treatment (Table 1), while the immune system was suppressed, the relA mutants were more adapted to tolerate antibiotic stress during the multiantibiotic treatment phase, which we hypothesized was due to higher resting alarmone levels. Although they were able to persist within the bloodstream of the immunocompromised patient, these relA mutants were deficient in producing a larger biofilm, as shown in confocal microscopy results. It is well known that RelA activation and alarmone production are responsible for the downregulation of nonessential genes and proteins, including proteins and saccharides that form biofilm matrices (50).\n\nAs discussed, bacteremia finally resolved only upon neutrophil recovery. These findings indicate a “perfect storm” for antibiotic tolerance development: the compromised host immune system ameliorates the impact of any bacterial fitness loss and provides a permissive environment for replication coupled with continuous antibiotic selection pressure due to the empirical therapy required for treatment or prophylaxis. This specific set of requirements could be relevant in several other immunocompromised patient populations in which rates of bacterial colonization and infection are high, especially if they are biofilm mediated.\n\nThis study has some limitations. Although persistence of bacteremia clinically suggested an intravascular focus such as endocarditis, this was never proven. Similarly, the coexistence of both the mutant and parent strains throughout the course of infection might represent a mixed biofilm at one site or infection with different isolates at discrete anatomic locations. Population profiling might have improved the interpretation of these results, but only a single sample was saved by the clinical microbiology laboratory at each time point, making such profiling impossible to perform. Generation of a relA missense mutation in the WT VRE background could provide further weight to the conclusions of the study, but genetic manipulation of a multidrug-resistant enterococcal strain has the potential to introduce additional mutations arising during prolonged passaging. Hence we opted to compare strains that were isogenic, with the exception of the relA SNP, based on genome sequencing for all phenotypic comparisons.\n\nBased on our results, we conclude that during prolonged infection, bacterial populations may acquire evolutionarily advantageous mutations conferring antibiotic tolerance. This may be especially likely within the permissive environment of an immunocompromised host. This is the first clinical case showing in vivo development of a mutation in the enterococcal relA gene during prolonged infection that functionally conferred tolerance to clinically relevant antibiotics without a change in clinically tested MIC. The case expands our understanding of the role of the stringent response in susceptibility and tolerance to a wide range of antibiotics, especially in biofilms, and demonstrates that these mutations can occur during human infection. This mutation is especially clinically significant, as linezolid and daptomycin are the last line of defense against infection with VRE, an important and already highly resistant pathogen. Furthermore, ClpP activators retained bactericidal activity against the relA mutant within a biofilm, indicating a potential future therapeutic strategy for targeting such persistent infections.\n\nMATERIALS AND METHODS\nInitial growth and storage of VRE isolates.\nTwenty-two VRE bloodstream isolates, one from each day of collection, were received from the clinical microbiology laboratory at St. Jude Children’s Research Hospital. A loop of each strain was grown in Todd-Hewitt broth supplemented with 3% yeast extract (ThyB [Bacto BD]) at 37°C in 5% CO2. Glycerol stocks were generated for each strain and stored at −80°C until further analysis. Each glycerol stock was also grown on tryptic soy agar (21) containing 3% sheep blood (Merck, Darmstadt, Germany) to verify purity: colony morphology results indicated that all samples were pure.\n\nGenomic DNA extraction and sequencing.\nBacteria were grown in unshaken overnight cultures in ThyB medium and collected by centrifugation before genomic DNA was extracted by using the Purelink Genomic Extraction kit (Life Technologies, Inc.). Sequencing libraries were prepared and bar-coded by using the Nextera kit (Illumina) and pooled in one lane of an Illumina HiSeq2500, yielding a mean (standard deviation [SD]) of 6.6 × 106 (4.2 × 106) reads and 1.0 Gbp ± 637 Mbp. To obtain a more robust genome assembly, the initial bloodstream isolate was also subjected to PacBio sequencing with 5- to 10-kb fragment libraries loaded on one SMRTcell (Johns Hopkins Sequencing Center), producing 385.2 Mbp of sequence. Contiguous consensus sequences (contigs) were assembled by using the PacBio SMRTanalysis toolkit, resulting in a genome containing 3,242,672 Mbp in four circular contigs and 118.8× mean per-bp coverage. This polished genome served as a reference for the mapping of all subsequent Illumina short reads, at a mean per-base-pair coverage of 256.6× (SD, 138×). Reference mapping and the detection of SNPs, indels, and structural variants were conducted by using breseq software as described previously (51). Mutation calls were pooled by using a custom shell script, 23 of which were used to correct the PacBio genome assembly at sites that were mostly restricted to one plasmid. A preliminary set of nine putative unique calls were verified by manually inspecting the sequence pileups, which revealed 4 false mutations produced by poor alignments and 5 consensus mutations among the 22 bloodstream isolates, including one in the relA gene responsible for the stringent response.\n\nrelA sequencing.\nA single VRE isolate from each of infection days 1, 3, and 5 (wild type) and 4, 16, and 17 (mutant) was grown in 5 ml ThyB overnight at 37°C. Cultures were bead beaten with silica beads for 10 min to break open cells. An internal fragment of the relA gene of each isolate was PCR amplified by using forward primer 5′-GTGGACGGCGTAACCAAATTAGGG-3′ and reverse primer 5′-CCACTTACGTATTTTTCACGTTCTTCTC-3′. DreamTaq Green DNA polymerase (Thermo Scientific) was used with a 51°C annealing temperature and a 1-min extension period at 72°C for 30 cycles. PCRs were cleaned up by using Qiagen MinElute kits and sequenced by using the forward primer with Sanger sequencing to confirm the relA SNP.\n\nPlanktonic growth measurements.\nNinety-six-well plates (Costar) were inoculated with approximately 2 × 106 CFU/ml of either the relA WT or isogenic relA mutant per well. Two hundred microliters ThyB was used to measure the growth of each strain in the presence of linezolid (6.25 µg/ml) over 8 h. After 8 h, triplicates of each strain in either no drug or linezolid were serially diluted on ThyB agar and plates were incubated at 37°C overnight. The number of CFU per milliliter was calculated, and growth of each strain was compared to growth at 8 h in no drug. Two-tailed t test was used to calculate significant differences in the growth of each strain, of which there were no significant differences observed.\n\nTime-kill kinetics.\nVRE isolates corresponding to the WT (day 5) and relA mutant (day 17) were grown overnight in ThyB (pH 6.5) at 37°C. Cultures were back-diluted 1:100 or 1:1,000 to produce an approximate starting culture of 105 CFU/ml. To obtain the daptomycin kill kinetics, sterile-filtered (0.22-µm-pore filter) 1 mM CaCl2 was added to ThyB prior to the experiment. Aliquots (1 ml) of each culture were separately analyzed over time (in triplicate), and either dimethyl sulfoxide (DMSO)/PBS (no-compound control [Sigma/Lonza]), 50 µg/ml daptomycin (Cubist Pharmaceuticals), or 200 µg/ml linezolid (Sigma) was added. Each sample was analyzed by performing serial dilution to determine the number of CFU per milliliter over time. The limit of detection was 1 × 103 CFU/ml. Each time-kill assay was repeated three times, and a representative replicate is presented (see Fig. S2 in the supplemental material).\n\nBiofilm antibiotic tolerance assays.\nNunc plates with peg lids were used to grow VRE biofilms and analyze the biofilm eradication capabilities of linezolid, vancomycin, and daptomycin. A 200-µl aliquot of ThyB (+1 mM CaCl2 for daptomycin) was inoculated into single wells of the 96-well plates. Each condition was tested at least in triplicate for WT and the isogenic relA mutant. Frozen stocks of VRE from days 5 (22) and 17 (relA mutant) were inoculated into each well. Peg lids were seeded into the liquid culture, and the cells were allowed to grow overnight at 37°C. Peg lids were then washed in sterile water to remove planktonic cells, placed in new Nunc plates containing ThyB and under the appropriate drug/stress condition, and incubated at 37°C overnight. A second wash in sterile water was then performed, and the peg lid was placed into a new Nunc plate with 100 µl ThyB. Centrifugation at 800 × g for 20 min was performed to remove biofilms from the peg. After centrifugation, peg lids were discarded, and the plate was incubated at 37°C overnight in a Cytation 3 (BioTek) plate reader recording absorbance at 600 nm over 24 h. This method allowed quantification of the growth of any viable cells from the biofilms. The average of at least three independent readings is reported for each strain and condition.\n\nStringent response measurement.\nStrains were grown at 37°C in C+Y medium (53) without potassium phosphate until an optical density at 600 nm (OD600) measurement of 0.2 was obtained. To a 1-ml aliquot of culture, 500 μCi of [32P]orthophosphate (American Radiolabeled Chemicals) was added. After a 2.5-h incubation, a 100-μl aliquot of culture was added to 50 μl of 13 M formic acid and then exposed to two freeze/thaw cycles using dry ice. Samples were spotted onto a polyethyleneimine (PEI)-cellulose TLC plate (Analtech) and developed in a tank of 1.5 M KH2PO4 (pH 3.4). After the plate was dried, it was exposed to a phospho-imaging screen for 48 h; the signal intensity was read by using a Typhoon FLA 9500 (GE Healthcare Life Sciences) and quantified by using ImageQuant TL. Five replicates harboring a WT relA locus and five replicates harboring the point mutation of interest were included in these experiments. As a control, each VRE strain was incubated with 100 µg/ml mupirocin (Sigma) as a positive control for stringent response induction. In addition, strains were also incubated with 10 µg/ml linezolid to determine whether linezolid exposure induced the stringent response.\n\nBiofilm quantification assays.\nTwenty-four-well plates (Costar) were coated with bovine plasma fibronectin (Sigma) by an overnight incubation at 37°C. Each well was gently washed with 1 ml of 1× PBS, followed by addition of 1 ml fresh ThyB and inoculated from frozen titered stocks of the VRE WT or relA mutant. Biofilms were allowed to form by overnight growth without shaking at 37°C. Supernatant was removed, and each biofilm was gently washed twice with 1× PBS to remove planktonic bacteria. PBS was discarded, and wells were allowed to dry. Four hundred microliters of 1% (wt/vol) crystal violet was added to each well or 1 µl PBS to disrupt biofilms for determination of CFU per milliliter. After 20 min for staining, crystal violet was removed, and each well was washed multiple times with 1 × PBS until supernatant was clear. After drying, 1 ml 95% ethanol was added to each well, and the well was gently shaken for 10 min to allow complete solubilization of the crystal violet into solution. Absorbance at 595 nm was measured using a Cytation3 plate reader (BioTek) to quantify biofilm. At least three independent determinations for each experimental condition were performed. The number of CFU per milliliter for each biofilm was determined via serial dilution and plating on ThyB agar.\n\nFluorescence microscopy of VRE biofilms.\nμ-slide 8-chamber microscopy slides (IBIDI) were inoculated (each chamber) with 300 µl ThyB per well plus 3-µl frozen stocks of the VRE relA WT or mutant. Slides were incubated overnight at 37°C to allow biofilms to form. Two hundred microliters of medium was carefully removed from each chamber in order to not disrupt formed biofilms, 200 µl fresh ThyB was added, and slides were again incubated overnight at 37°C. One hour prior to confocal microscopy, components A and B of the Thermo Scientific Live/Dead BacLight bacterial viability kit were thawed and equally mixed according to the manufacturer’s instructions. One microliter of this mixture was then carefully added to wells at a staggered interval of 30 min, to allow comparable microscopy pictures of live/dead staining to occur. After a 30-min incubation at room temperature in the dark, the first chamber was analyzed in a confocal microscope (Nikon C2). For each chamber, four random segments were subject to z-stacking at a total height of 16 µm from the first fluorescent image corresponding to the bottom of the biofilm. Total green (fluorescein isothiocyanate [FITC]) and red (tetramethyl rhodamine isothiocyanate [TRITC]) filter sets from this volume (16 µm3) were analyzed for each segment, and each strain was analyzed in at least 2 separate chambers. This allowed an n value of 8, corresponding to four individual segments per chamber. The ratio of green to red signal was calculated from the average of each section, and results were combined for the final average value reported. Prism6 was used to analyze all data, and significance was calculated via two-tailed t test.\n\nRNA extraction, cDNA synthesis and qRT-PCR, rRNA depletion, and RNA sequencing.\nSeventy-five-square-centimeter flasks (Corning) were coated overnight at 37°C with fibronectin (Sigma). After 24 h, each flask was inoculated with 30 ml ThyB and either the relA WT or mutant. After 24 h, supernatant was removed, and biofilm cells were scraped off the flask, eluted in 10 ml RNAprotect, and pelleted by a 10-min spin at 10,000 × g. Planktonic cells were grown in 30 ml ThyB until mid-log phase (OD600 of 0.5), suspended in RNAprotect, and pelleted by a 10-min spin at 10,000 × g. Each biofilm sample was comprised of 3 flasks that were subsequently extracted and pooled to generate sufficient RNA for sequencing. All samples were run in triplicate for planktonic or biofilm pellets for each strain, and RNA extraction was performed immediately after collection of the cell pellets.\n\nRNA extraction was performed using the Qiagen RNeasy kit with slight modifications for initial cell lysis. Briefly, 250 µl silicon beads was added to each pellet containing RLT lysis buffer and 2-mercaptoethanol and bead beat (FastPrep MP Biomedicals) for one cycle of 45 s with a setting of 5.5. After cell lysis, the Qiagen RNeasy process was continued with a QiaShredder cleanup step and the RNeasy protocol was completed. Each RNA sample was eluted in a final volume of 30 µl of RNase-free water and stored at −20°C. rRNA was depleted using the RiboMinus kit (Thermo-Fisher) following the manufacturer’s guidelines. For each sample, 30 µg of RNA was utilized for the depletions. Following depletion, libraries were prepared for sequencing using the Illumina stranded mRNA protocol.\n\nRNA-seq analysis.\nFour replicates each of the relA WT and mutant strains were grown under planktonic and biofilm conditions, and RNA was extracted from bulk cultures. RNA libraries were prepared for sequencing and pooled on one lane of an Illumina HiSeq2000 at St. Jude Children’s Research Hospital. These produced an average of 82 million reads for the WT planktonic cultures, 91 million reads for the WT biofilm cultures, 82 million reads for the relA planktonic cultures, and 130 million reads for the relA biofilm cultures. Differences in expression were evaluated using Rockhopper version 2.03 (52), which compares strand-aware, normalized sequence counts found throughout the reference genome. We used the well-annotated E. faecalis Aus04 reference genome (PRJNA86649) for this purpose, which had high identity to the strains reported here. Resulting P values of differentially expressed genes were used to compute false discovery rate (q) values derived from a Benjamini-Hochberg correction with a false discovery rate of <1%. Only q values of <0.001 are reported here in Table S2 in the supplemental material, almost certainly underestimating the number of significant differences.\n\n10.1128/mBio.02124-16.4Table S2 RNA-seq expression analysis. Download Table S2, XLSX file, 1.4 MB.\n\nCopyright © 2017 Honsa et al.2017Honsa et al.This content is distributed under the terms of the Creative Commons Attribution 4.0 International license. Ethics statement.\nThis project was approved by the St. Jude Children’s Research Hospital Institutional Review Board before any research procedures were performed (XPD14-052). Consent was obtained in writing from the patient’s legal guardian for use of clinical samples and access to the medical record for research purposes.\n\nAccession number(s).\nThe chromosomal and plasmid sequences of the initial isolate are accessible at NCBI under GenBank accession no. CP018070, CP018071, CP018072, and CP018073.\n\nCitation Honsa ES, Cooper VS, Mhaissen MN, Frank M, Shaker J, Iverson A, Rubnitz J, Hayden RT, Lee RE, Rock CO, Tuomanen EI, Wolf J, Rosch JW. 2017. RelA mutant Enterococcus faecium with multiantibiotic tolerance arising in an immunocompromised host. mBio 8:e02124-16. https://doi.org/10.1128/mBio.02124-16.\n\nACKNOWLEDGMENTS\nJ.W.R. and V.C. are supported by 1U01AI124302. J.W.R. is supported by 1RO1AI110618. 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Hogg T , Mechold U , Malke H , Cashel M , Hilgenfeld R \n2004 \nConformational antagonism between opposing active sites in a bifunctional RelA/SpoT homolog modulates (p)ppGpp metabolism during the stringent response . Cell \n117 :57 –68 . doi:10.1016/S0092-8674(04)00260-0 .15066282 \n32. Hachmann AB , Sevim E , Gaballa A , Popham DL , Antelmann H , Helmann JD \n2011 \nReduction in membrane phosphatidylglycerol content leads to daptomycin resistance in Bacillus subtilis . Antimicrob Agents Chemother \n55 :4326 –4337 . doi:10.1128/AAC.01819-10 .21709092 \n33. Costerton JW , Stewart PS , Greenberg EP \n1999 \nBacterial biofilms: a common cause of persistent infections . Science \n284 :1318 –1322 . doi:10.1126/science.284.5418.1318 .10334980 \n34. Donlan RM , Costerton JW \n2002 \nBiofilms: survival mechanisms of clinically relevant microorganisms . Clin Microbiol Rev \n15 :167 –193 . doi:10.1128/CMR.15.2.167-193.2002 .11932229 \n35. Nallapareddy SR , Singh KV , Sillanpää J , Garsin DA , Höök M , Erlandsen SL , Murray BE \n2006 \nEndocarditis and biofilm-associated pili of Enterococcus faecalis . J Clin Invest \n116 :2799 –2807 . doi:10.1172/JCI29021 .17016560 \n36. Sinel C , Cosquer T , Auzou M , Goux D , Giard JC , Cattoir V \n2016 \nSequential steps of daptomycin resistance in Enterococcus faecium and reversion to hypersusceptibility through IS-mediated inactivation of the liaFSR operon . J Antimicrob Chemother \n71 :2793 –2797 . doi:10.1093/jac/dkw229 .27353469 \n37. Harrison JJ , Stremick CA , Turner RJ , Allan ND , Olson ME , Ceri H \n2010 \nMicrotiter susceptibility testing of microbes growing on peg lids: a miniaturized biofilm model for high-throughput screening . Nat Protoc \n5 :1236 –1254 . doi:10.1038/nprot.2010.71 .20595953 \n38. Kristich CJ , Li YH , Cvitkovitch DG , Dunny GM \n2004 \nEsp-independent biofilm formation by Enterococcus faecalis . J Bacteriol \n186 :154 –163 . doi:10.1128/JB.186.1.154-163.2004 .14679235 \n39. Høiby N , Bjarnsholt T , Givskov M , Molin S , Ciofu O \n2010 \nAntibiotic resistance of bacterial biofilms . Int J Antimicrob Agents \n35 :322 –332 . doi:10.1016/j.ijantimicag.2009.12.011 .20149602 \n40. Conlon BP , Nakayasu ES , Fleck LE , LaFleur MD , Isabella VM , Coleman K , Leonard SN , Smith RD , Adkins JN , Lewis K \n2013 \nActivated ClpP kills persisters and eradicates a chronic biofilm infection . Nature \n503 :365 –370 . doi:10.1038/nature12790 .24226776 \n41. Dalebroux ZD , Svensson SL , Gaynor EC , Swanson MS \n2010 \nppGpp conjures bacterial virulence . Microbiol Mol Biol Rev \n74 :171 –199 . doi:10.1128/MMBR.00046-09 .20508246 \n42. Gaca AO , Kajfasz JK , Miller JH , Liu K , Wang JD , Abranches J , Lemos JA \n2013 \nBasal levels of (p)ppGpp in Enterococcus faecalis: the magic beyond the stringent response . mBio \n4 :e00646-13. doi:10.1128/mBio.00646-13 .24065631 \n43. Gaca AO , Colomer-Winter C , Lemos JA \n2015 \nMany means to a common end: the intricacies of (p)ppGpp metabolism and its control of bacterial homeostasis . J Bacteriol \n197 :1146 –1156 . doi:10.1128/JB.02577-14 .25605304 \n44. Khakimova M , Ahlgren HG , Harrison JJ , English AM , Nguyen D \n2013 \nThe stringent response controls catalases in Pseudomonas aeruginosa and is required for hydrogen peroxide and antibiotic tolerance . J Bacteriol \n195 :2011 –2020 . doi:10.1128/JB.02061-12 .23457248 \n45. Beceiro A , Tomás M , Bou G \n2013 \nAntimicrobial resistance and virulence: a successful or deleterious association in the bacterial world? \nClin Microbiol Rev \n26 :185 –230 . doi:10.1128/CMR.00059-12 .23554414 \n46. Rozen DE , McGee L , Levin BR , Klugman KP \n2007 \nFitness costs of fluoroquinolone resistance in Streptococcus pneumoniae . Antimicrob Agents Chemother \n51 :412 –416 . doi:10.1128/AAC.01161-06 .17116668 \n47. Handel A , Regoes RR , Antia R \n2006 \nThe role of compensatory mutations in the emergence of drug resistance . PLoS Comput Biol \n2 :e137 . doi:10.1371/journal.pcbi.0020137 .17040124 \n48. Levin BR , Perrot V , Walker N \n2000 \nCompensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria . Genetics \n154 :985 –997 .10757748 \n49. Tanaka MM , Valckenborgh F \n2011 \nEscaping an evolutionary lobster trap: drug resistance and compensatory mutation in a fluctuating environment . Evolution \n65 :1376 –1387 . doi:10.1111/j.1558-5646.2011.01223.x .21521192 \n50. He H , Cooper JN , Mishra A , Raskin DM \n2012 \nStringent response regulation of biofilm formation in vibrio cholerae . J Bacteriol \n194 :2962 –2972 . doi:10.1128/JB.00014-12 .22467780 \n51. Deatherage DE , Barrick JE \n2014 \nIdentification of mutations in laboratory-evolved microbes from next-generation sequencing data using breseq . Methods Mol Biol \n1151 :165 –188 . doi:10.1007/978-1-4939-0554-6_12 .24838886 \n52. McClure R , Balasubramanian D , Sun Y , Bobrovskyy M , Sumby P , Genco CA , Vanderpool CK , Tjaden B \n2013 \nComputational analysis of bacterial RNA-seq data . Nucleic Acids Res \n41 :e140 . doi:10.1093/nar/gkt444 .23716638 \n53. Rosch JW , Sublett J , Gao G , Wang YD , Tuomanen EI \n2008 \nCalcium efflux is essential for bacterial survival in the eukaryotic host . Mol Microbiol \n70 (2 ):435 –444 . doi:10.1111/j.1365-2958.2008.06425.x .18761687\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "8(1)",
"journal": "mBio",
"keywords": null,
"medline_ta": "mBio",
"mesh_terms": "D000900:Anti-Bacterial Agents; D016470:Bacteremia; D018441:Biofilms; D004361:Drug Tolerance; D016984:Enterococcus faecium; D005260:Female; D016908:Gram-Positive Bacterial Infections; D006159:Guanosine Tetraphosphate; D006801:Humans; D016867:Immunocompromised Host; D007223:Infant; D008025:Ligases; D008826:Microbial Sensitivity Tests; D050505:Mutant Proteins; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D065507:Vancomycin-Resistant Enterococci",
"nlm_unique_id": "101519231",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28049149",
"pubdate": "2017-01-03",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "16447111;11181117;14679235;23554414;25135187;23806896;23457248;10334980;24642063;17116668;24226776;21379570;23300476;20595953;3534137;21521192;25605304;24065631;21099116;19514856;21709092;1982975;15066282;11932229;23716638;27607357;10757748;18761687;16007529;3895353;20548948;25275120;8678715;23650175;22653948;20149602;22467780;21572327;25787285;19766888;24767965;17016560;20508246;27353469;24832453;22096200;24838886;19929705;23659600;18847403;12905129;17040124;24713324",
"title": "RelA Mutant Enterococcus faecium with Multiantibiotic Tolerance Arising in an Immunocompromised Host.",
"title_normalized": "rela mutant enterococcus faecium with multiantibiotic tolerance arising in an immunocompromised host"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS-2017GMK026197",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE BUTYRATE"
},
"... |
{
"abstract": "OBJECTIVE\nHuman immunodeficiency virus (HIV) infection remains a major cause of morbidity and mortality worldwide. Many studies have found a higher prevalence of hearing impairment among HIV-positive individuals.\n\n\nOBJECTIVE\nTo investigate the effect of HIV and highly active antiretroviral treatment (HAART) on the hearing function in a Cameroonian population.\n\n\nMETHODS\nWe conducted a prospective case-control study from March 1, 2012, through January 31, 2013. The study took place at the National Social Insurance Fund Hospital in Yaoundé, Cameroon, a public health facility. We included 90 HIV-positive case patients and 90 HIV-negative control patients aged 15 to 49 years without any history of hearing loss or treatment with a known ototoxic drug. The case group was further divided into 3 subgroups: 30 HAART-naive patients, 30 patients receiving first-line HAART, and 30 patients receiving second-line HAART.\n\n\nMETHODS\nHearing function was assessed by pure-tone audiometry and classified according to the criteria of the Bureau International d'Audio-Phonologie.\n\n\nMETHODS\nHearing loss due to HIV and HAART.\n\n\nRESULTS\nThe HIV-positive patients had more otologic symptoms (hearing loss, dizziness, tinnitus, and otalgia) than HIV-negative patients (41 vs 13, P = .04). There were 49 cases (27.2%) of hearing loss in the HIV-positive group vs 10 (5.6%) in the HIV-negative group (P = .04). Compared with HIV-negative individuals, the odds of hearing loss were higher among HIV-infected HAART-naive patients (right ear: odds ratio [OR], 6.7; 95% CI, 4.3-9.7; P = .004; left ear: OR, 6.2; 95% CI, 3.5-8.3; P = .006), patients receiving first-line HAART (right ear: OR, 5.6; 95% CI, 1.9-10.5; P = .01; left ear: OR, 12.5; 95% CI, 8.5-15.4; P < .001), and patients receiving second-line HAART (right ear: OR, 6.7; 95% CI, 3.3-9.6; P = .004; left ear: OR, 3.7; 95% CI, 3.0-5.0; P = .08).\n\n\nCONCLUSIONS\nHearing loss is more frequent in HIV-infected patients compared with uninfected patients. Therefore, HIV-infected patients need special audiologic care. Further studies are needed because controversy remains regarding the factors that lead to ear damage.",
"affiliations": "Department of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon.;Department of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon2National Social Insurance Fund Hospital, Yaoundé, Cameroon.;Edéa Regional Hospital, Edéa, Cameroon4Medical Diagnostic Center, Yaoundé, Cameroon.;Department of Internal Medicine, University of British Columbia, Vancouver, British Columbia, Canada.;Department of Preventive and Social Medicine, Laval University, Québec City, Québec, Canada.;Douala General Hospital, Douala, Cameroon.;Yaoundé General Hospital, Yaoundé, Cameroon.;Geneva Teaching Hospital, Geneva, Switzerland.;Department of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon.;Department of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon3Edéa Regional Hospital, Edéa, Cameroon7Douala General Hospital, Douala, Cameroon.",
"authors": "Fokouo|Jean Valentin F|JV|;Vokwely|Jean Espoir E|JE|;Noubiap|Jean Jacques N|JJ|;Nouthe|Brice Enid|BE|;Zafack|Joseline|J|;Minka Ngom|Esthelle Stéphanie|ES|;Dalil|Asmaou Bouba|AB|;Ngo Nyeki|Adèle-Rose|AR|;Bengono|Géneviève|G|;Njock|Richard|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1001/jamaoto.2015.125",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6181",
"issue": "141(5)",
"journal": "JAMA otolaryngology-- head & neck surgery",
"keywords": null,
"medline_ta": "JAMA Otolaryngol Head Neck Surg",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D001301:Audiometry, Pure-Tone; D002163:Cameroon; D016022:Case-Control Studies; D004244:Dizziness; D004433:Earache; D005260:Female; D015658:HIV Infections; D034381:Hearing Loss; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D014012:Tinnitus",
"nlm_unique_id": "101589542",
"other_id": null,
"pages": "436-41",
"pmc": null,
"pmid": "25741887",
"pubdate": "2015-05-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effect of HIV Infection and Highly Active Antiretroviral Therapy on Hearing Function: A Prospective Case-Control Study From Cameroon.",
"title_normalized": "effect of hiv infection and highly active antiretroviral therapy on hearing function a prospective case control study from cameroon"
} | [
{
"companynumb": "CM-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-41832BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "CM",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
... |
{
"abstract": "Lenalidomide is an immunomodulatory drug administered orally in the treatment of multiple myeloma. Some elderly patients require a reduced lenalidomide dose because of comorbidities and/or adverse events. This study investigated the actual dose of lenalidomide in elderly patients, finding that most received reduced (5-10 mg) doses. The most common reasons for dose reduction were renal dysfunction (54% of patients), fatigue (grade ≥3; 20%), hematologic disorder (grade ≥3; 14%), and rash (grade ≥3; 9%). Their median time to progression was 11.8 months and their median overall survival was 39.2 months. The overall response rate was 73%, including 17% with a complete response, 19% with a very good partial response, and 37% with a partial response. These results showed that, contrary to western countries, most patients were treated with a reduced dose of lenalidomide in Japan. However, it is suggested that continued treatment with a tolerable dose may yield favorable outcomes.",
"affiliations": "First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan.",
"authors": "Nakaya|Aya|A|;Fujita|Shinya|S|;Satake|Atsushi|A|;Nakanishi|Takahisa|T|;Azuma|Yoshiko|Y|;Tsubokura|Yukie|Y|;Hotta|Masaaki|M|;Yoshimura|Hideaki|H|;Ishii|Kazuyoshi|K|;Ito|Tomoki|T|;Nomura|Shosaku|S|",
"chemical_list": "D007155:Immunologic Factors; D013792:Thalidomide; D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000477792",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5792",
"issue": "138(1)",
"journal": "Acta haematologica",
"keywords": "Elderly; Lenalidomide; Reduced dose; Relapsed/refractory multiple myeloma; Transplant ineligibility",
"medline_ta": "Acta Haematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D003907:Dexamethasone; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007564:Japan; D000077269:Lenalidomide; D008297:Male; D009101:Multiple Myeloma; D013792:Thalidomide",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "55-60",
"pmc": null,
"pmid": "28728162",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "23727684;25628469;27864218;27935580;22571200;18032763;25184863;21126632;16855634;21747400",
"title": "Realistic Lenalidomide Dose Adjustment Strategy for Transplant-Ineligible Elderly Patients with Relapsed/Refractory Multiple Myeloma: Japanese Real-World Experience.",
"title_normalized": "realistic lenalidomide dose adjustment strategy for transplant ineligible elderly patients with relapsed refractory multiple myeloma japanese real world experience"
} | [
{
"companynumb": "JP-CELGENEUS-JPN-20171000497",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE ACETATE"
},
"drugadditional"... |
{
"abstract": "Limited information is available on the urinary excretion of colistin in infected patients. This study aimed to investigate the pharmacokinetics of colistimethate sodium (CMS) and formed colistin in urine in patients with multidrug-resistant (MDR) Gram-negative bacterial infections. A pharmacokinetic study was conducted on 12 patients diagnosed with an infection caused by an extremely drug-resistant (XDR) P. aeruginosa strain and treated with intravenous CMS. Fresh urine samples were collected at 2-h intervals, and blood samples were collected predose (Cmin ss) and at the end of the CMS infusion (Cmax ss) for measurement of concentrations of CMS and formed colistin using high-performance liquid chromatography (HPLC). CMS urinary recovery was determined as the summed amount of CMS and formed colistin recovered in urine for each 2-h interval divided by the CMS dose. There were 12 enrolled patients, 9 of whom were male (75%). Data [median (range)] were as follows: age, 65.5 (37 to 86) years; colistimethate urinary recovery 0 to 6 h, 42.6% (2.9% to 72.8%); range of concentrations of colistin in urine, <0.1 to 95.4 mg/liter; Cmin ss and Cmax ss of colistin in plasma, 0.9 (<0.2 to 1.4) and 0.9 (<0.2 to 1.4) mg/liter, respectively. In 6/12 (50%) patients, more than 40% of the CMS dose was recovered in the urine within the first 6 h after CMS administration. This study demonstrated rapid urinary excretion of CMS in patients within the first 6 h after intravenous administration. In all but one patient, the concentrations of formed colistin in urine were above the MIC for the most predominant isolate of P. aeruginosa in our hospital. Future studies are warranted for optimizing CMS dosage regimens in urinary tract infection (UTI) patients.",
"affiliations": "Pharmacy Department, Hospital del Mar, Barcelona, Spain sluque@parcdesalutmar.cat.;Infectious Diseases Department, Hospital del Mar, Barcelona, Spain.;Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.;Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Victoria, Australia.;Pharmacy Department, Hospital del Mar, Barcelona, Spain.;Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.;Pharmacy Department, Hospital del Mar, Barcelona, Spain.;Pharmacy Department, Hospital del Mar, Barcelona, Spain.",
"authors": "Luque|Sonia|S|;Escaño|Carol|C|;Sorli|Luisa|L|;Li|Jian|J|;Campillo|Nuria|N|;Horcajada|Juan Pablo|JP|;Salas|Esther|E|;Grau|Santiago|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; C004691:colistinmethanesulfonic acid; D003091:Colistin",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.02595-16",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0066-4804",
"issue": "61(8)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": "Gram-negative bacteria; colistin; pharmacokinetics; urinary tract infections",
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D000151:Acinetobacter Infections; D040981:Acinetobacter baumannii; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D002851:Chromatography, High Pressure Liquid; D003091:Colistin; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa; D014552:Urinary Tract Infections",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28559275",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": "15044428;25698772;4903524;19433570;11587346;21555763;25267662;20176909;24189256;21544080;15312219;16931410;23957376;14585859;21208892;23769664;24550334;12234867;25267660;16396919;19797945",
"title": "Urinary Concentrations of Colistimethate and Formed Colistin after Intravenous Administration in Patients with Multidrug-Resistant Gram-Negative Bacterial Infections.",
"title_normalized": "urinary concentrations of colistimethate and formed colistin after intravenous administration in patients with multidrug resistant gram negative bacterial infections"
} | [
{
"companynumb": "ES-ACCORD-066636",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "BACKGROUND\nAnaphylaxis is a serious allergic reaction that may cause death. The signs and symptoms of anaphylaxis have not been examined in the Saudi population before.\n\n\nOBJECTIVE\nThe present study examined the signs, symptoms, triggers, and demographic patterns of patients treated for anaphylaxis at a large tertiary care hospital in Riyadh, Saudi Arabia.\n\n\nMETHODS\nAll the patients who were prescribed new prescriptions of adrenaline auto-injectors (AAs) between February 1, 2010 and December 31, 2011 were included in this study. Information was collected using a standardized form.\n\n\nRESULTS\nThere were 238 patients who were analyzed. The median age at the time of first AA prescription was 15.5 years. Female to male ratio was 52:48 and 54% of the subjects were more than 18 years of age. There were some differences in the presenting signs and symptoms observed in our study compared with similar studies from around the world. Urticaria and angioedema were the most common at about 70% across all ages, followed by shortness of breath at 28%. Some triggers were found to be more common in our region. Food was the commonest trigger for anaphylaxis including tree nuts, egg, and sesame. Drug allergy was also a common trigger, with penicillins and nonsteroidal anti-inflammatory drugs being the commonest. Regarding insect allergy, samsam ant was the commonest trigger in our study.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first study on anaphylaxis in Saudi Arabia. Some of the manifestations of anaphylaxis are significantly different in our population study compared to previously published data from other parts of the world. While managing anaphylaxis, we should be mindful of these differences. This improved understanding should help reduce the morbidity and mortality associated with anaphylaxis in our region.",
"affiliations": "Section of Allergy & Immunology, Department of Medicine, King Faisal Specialist Hospital & Research Center, Riyadh 3354, Saudi Arabia.;Medical and Critical Care Pharmacy, Department of Pharmaceutical Care, King Faisal Specialist Hospital & Research Center, Riyadh 3354, Saudi Arabia.;Section of Allergy & Immunology, Department of Medicine, King Faisal Specialist Hospital & Research Center, Riyadh 3354, Saudi Arabia.;Department of Medicine, King Faisal Specialist Hospital & Research Center, Riyadh 3354, Saudi Arabia.;Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital & Research Center, Riyadh 3354, Saudi Arabia.;Section of Allergy & Immunology, Department of Medicine, King Faisal Specialist Hospital & Research Center, Riyadh 3354, Saudi Arabia.",
"authors": "Sheikh|Farrukh|F|;Amin|Rashid|R|;Rehan Khaliq|Agha M|AM|;Al Otaibi|Talal|T|;Al Hashim|Samia|S|;Al Gazlan|Sulaiman|S|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5415/apallergy.2015.5.4.216",
"fulltext": "\n==== Front\nAsia Pac AllergyAsia Pac AllergyAPAAsia Pacific Allergy2233-82762233-8268Asia Pacific Association of Allergy, Asthma and Clinical Immunology 10.5415/apallergy.2015.5.4.216Original ArticleFirst study of pattern of anaphylaxis in a large tertiary care hospital in Saudi Arabia Sheikh Farrukh 1†Amin Rashid 2†Rehan Khaliq Agha M. 1Al Otaibi Talal 3Al Hashim Samia 4Al Gazlan Sulaiman 11 Section of Allergy & Immunology, Department of Medicine, King Faisal Specialist Hospital & Research Center, Riyadh 3354, Saudi Arabia.2 Medical and Critical Care Pharmacy, Department of Pharmaceutical Care, King Faisal Specialist Hospital & Research Center, Riyadh 3354, Saudi Arabia.3 Department of Medicine, King Faisal Specialist Hospital & Research Center, Riyadh 3354, Saudi Arabia.4 Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital & Research Center, Riyadh 3354, Saudi Arabia.\nCorrespondence: Farrukh Sheikh. Section of Allergy & Immunology, Department of Medicine, King Faisal Specialist Hospital & Research Center, Riyadh 3354, MBC 46, Saudi Arabia. Tel: +966-14427492, Fax: +966-14427499, fsheikh96@kfshrc.edu.sa†Farrukh Sheikh and Rashid Amin contributed equally to this article.\n\n10 2015 28 10 2015 5 4 216 221 19 3 2015 01 10 2015 Copyright © 2015. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nAnaphylaxis is a serious allergic reaction that may cause death. The signs and symptoms of anaphylaxis have not been examined in the Saudi population before.\n\nObjective\nThe present study examined the signs, symptoms, triggers, and demographic patterns of patients treated for anaphylaxis at a large tertiary care hospital in Riyadh, Saudi Arabia.\n\nMethods\nAll the patients who were prescribed new prescriptions of adrenaline auto-injectors (AAs) between February 1, 2010 and December 31, 2011 were included in this study. Information was collected using a standardized form.\n\nResults\nThere were 238 patients who were analyzed. The median age at the time of first AA prescription was 15.5 years. Female to male ratio was 52:48 and 54% of the subjects were more than 18 years of age. There were some differences in the presenting signs and symptoms observed in our study compared with similar studies from around the world. Urticaria and angioedema were the most common at about 70% across all ages, followed by shortness of breath at 28%. Some triggers were found to be more common in our region. Food was the commonest trigger for anaphylaxis including tree nuts, egg, and sesame. Drug allergy was also a common trigger, with penicillins and nonsteroidal anti-inflammatory drugs being the commonest. Regarding insect allergy, samsam ant was the commonest trigger in our study.\n\nConclusion\nTo our knowledge, this is the first study on anaphylaxis in Saudi Arabia. Some of the manifestations of anaphylaxis are significantly different in our population study compared to previously published data from other parts of the world. While managing anaphylaxis, we should be mindful of these differences. This improved understanding should help reduce the morbidity and mortality associated with anaphylaxis in our region.\n\nAdrenalineAnaphylaxisSaudi Arabia\n==== Body\nINTRODUCTION\nAnaphylaxis is a serious allergic reaction that is rapid in onset and may cause death [1]. Anaphylactic reactions can be triggered by allergic responses to a wide range of substances including food, medications, insect stings, and latex. Lifetime prevalence of anaphylaxis is up to 2% with the largest number of cases being reported among children and adolescents [2]. Anaphylaxis occurs in 30 per 100,000 people annually in the United States with a reported mortality of 1-2% [3]. The rate of occurrence is increasing in industrialized countries [4]. The incidence and prevalence of anaphylaxis in Saudi Arabia is unknown.\n\nCommon symptoms and signs of anaphylaxis include skin and respiratory manifestations in up to 90%, and 70% respectively. In addition, gastrointestinal and cardiovascular systems are involved up to 45% each [5678].\n\nPrompt assessment and treatment are critical in anaphylaxis, as respiratory or cardiac arrest and death can occur within minutes [9]. Prompt intramuscular injection of adrenaline is one of the cornerstones of treatment of anaphylaxis [10]. It is therefore important to study the dispensing of adrenaline in different geographical regions. This will help us understand the epidemiology of anaphylaxis and aid ongoing efforts to reduce morbidity and mortality associated with it and could provide important clues for its primary prevention. Global agenda for anaphylaxis research according to the World Allergy Organization anaphylaxis guidelines also stress the importance of epidemiologic research in anaphylaxis [11]. Similar work has already been published from other parts of the world [1213].\n\nThe aim of the study was to examine the frequency of signs, symptoms, triggers, and demographic patterns of anaphylaxis using the prescription pattern of AAs at a large tertiary care center in Riyadh, Saudi Arabia.\n\nMATERIALS AND METHODS\nAll patients given new prescriptions of AAs at our hospital between February 1, 2010 and December 31, 2011 were included in this study.\n\nPatients prescribed AAs were identified using hospital Pharmacy database and the case records of these patients were retrospectively reviewed. Clinical data was collected using a standardized form that included information on demographics and indications for AA prescriptions.\n\nThe data was subclassified by age, gender, nationality, triggers, signs and symptoms, as well as the geographical location within Saudi Arabia.\n\nStatistical analysis\nData analysis was performed using SPSS ver. 12.0 (SPSS Inc., Chicago, IL, USA)\n\nEthical considerations/consent documents\nThe protocol was approved by the Research Advisory Committee of the hospital. This was a retrospective review of our hospital records which did not require any intervention, device or patient interaction and presented no risk to the patients at all. All patients who had received AAs during the study period outlined above were reviewed for descriptive data such as age, gender, and indications. Patients were not contacted during the duration of the chart review. All the data collected was anonymous and patient identifiers such as medical record number, date of birth were deleted once data was analysed using the SPSS ver. 12.0. Only the principal investigator had access to the complete data and other coinvestigators did not store the data but passed it on to him for analyses and filing in the SPSS software.\n\nRESULTS\nDemographics\nThis study looked at 238 new patients who were prescribed AAs over a period of 2 years. There were 238 patients who were analyzed. The median age at the time of first AA prescription was 15.5 years. Female to male ratio was 52:48 and 54% of the subjects were more than 18 years of age. Most of these prescriptions were given to Saudi patients mainly from Riyadh area but also from most other parts of the Kingdom. However about 18% were given to Non Saudis living in the Riyadh region. Most of these were employees of the hospital or their dependents (Table 1).\n\nUrticaria and angioedema were the most common sign or symptom with about 70% across adults and children. The second most common symptom was shortness of breath which was about 33% in adults and 23% in children. Nausea and vomiting was reported in about 9% of our subjects. Itching without rash was noticed in about 8%. Other infrequent signs or symptoms are detailed (Table 2).\n\nTriggers\nFood was the commonest trigger for anaphylaxis, out of which tree nuts and egg were the most frequent, followed by sesame, milk, and peanut, respectively (Table 3). Dates are commonly consumed in this part of the world and were also reported as a trigger in a few individuals. As expected, overall food allergy was more common in children, but shrimp allergy was more frequently reported in adults.\n\nDrug allergy was also a common trigger, with penicillins and nonsteroidal anti-inflammatory drugs (NSAIDs) being the commonest (Table 4). Regarding insect allergy, samsam ant was the commonest trigger in our study population (Table 5).\n\nDISCUSSION\nAnaphylaxis signs and symptoms are being reported from many areas around the world. It is also observed that allergies and anaphylaxis incidence is on the rise. It is therefore important to understand more about this life threatening condition in our region.\n\nThe only approved indication for AAs is anaphylaxis. It is available only at a few centers in Saudi Arabia. In a large tertiary care hospital it should provide us with a good estimate of the anaphylaxis patterns in our population. However, as the AAs are also available at a few other hospitals in the country, our data may not reflect the complete burden of anaphylaxis in our region.\n\nThe observation regarding signs and symptoms again reiterates an important fact regarding anaphylaxis recognition and management. Not all patients with anaphylaxis would present with skin signs or symptoms. Although most of the signs and symptoms were similar to other published data, there were some differences observed in our study population [14] (Table 2).\n\nAs observed in many of the other populations, the commonest sign or symptom of anaphylaxis in our study population was also urticaria/angioedema. However it was slightly less common and was reported in about 71% of people. Shortness of breath was reported in 28% of the other studies. This was also less commonly observed compared to some of the other populations. Dizziness, syncope, and hypotension were seen equally (about 8% of the study population) and were significantly less compared with some of the other areas. In addition to ethnic differences that may be present, suboptimal recognition of patients with anaphylaxis may have resulted in the observed differences between reported signs and symptoms in our population. Further studies are needed from our part of the world to validate this finding.\n\nFood allergy was the commonest trigger for anaphylaxis in our study population (Table 3). The leading triggers were tree nut, egg, sesame, peanut, and milk, respectively. Another interesting fact was that sesame allergy was much more common in our region compared to peanut allergy. Ethnic differences in food exposures and consumptions may explain some of these differences.\n\nAmong the other triggers, penicillin, NSAIDs and sulfa were the most commonly encountered (Table 4). Cholinergic urticaria also known as generalized heat urticaria which is triggered by a rise in body temperature and can be complicated by bronchial hyperresponsiveness and anaphylaxis was found in about 6% of patients [14].\n\nLatex allergy was seen in 3.4% of our study subjects. Food allergy as a cause of anaphylaxis was observed more commonly in children, while other triggers for anaphylaxis were more commonly observed in adults (Fig. 1).\n\nAmong the insects (Table 5), samsam ant which is native to our region was the commonest insect allergy in our study population. There is no commercial extract available for testing or desensitization and there is an urgent need for its development for our population. There were no cases reported for hornet/yellow jacket or wasp allergy. The exact triggers for food dependent exercise-induced anaphylaxis were not identified.\n\nIn conclusion, this is the first study on anaphylaxis in Saudi Arabia. While there are many similarities to other published data, some of the presenting signs, symptoms, and triggers of anaphylaxis are significantly different in our study population. While managing anaphylaxis, we should be mindful of these differences. This improved understanding should help reduce the morbidity and mortality associated with anaphylaxis in our region.\n\nFig. 1 Common triggers. Comparison of triggers between children and adults. Incidence specified according to age. NSAID, nonsteroidal antiinflammatory drug.\nTable 1 Demographic characteristics\nTable 2 Signs and symptoms\nValues are presented as number (%).\n\nTable 3 Triggers of anaphylaxis (foods)\nValues are presented as number (%).\n\nTable 4 Other triggers\nValues are presented as number (%).\n\nNSAID, nonsteroidal anti-inflammatory drug.\n\nTable 5 Insects\nValues are presented as number (%).\n==== Refs\n1 Sampson HA Munoz-Furlong A Campbell RL Adkinson NF Jr Bock SA Branum A Brown SG Camargo CA Jr Cydulka R Galli SJ Gidudu J Gruchalla RS Harlor AD Jr Hepner DL Lewis LM Lieberman PL Metcalfe DD OConnor R Muraro A Rudman A Schmitt C Scherrer D Simons FE Thomas S Wood JP Decker WW Second symposium on the definition and management of anaphylaxis: summary report: Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium J Allergy Clin Immunol 2006 117 391 397 16461139 \n2 Lieberman P Camargo CA Jr Bohlke K Jick H Miller RL Sheikh A Simons FE Epidemiology of anaphylaxis: findings of the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group Ann Allergy Asthma Immunol 2006 97 596 602 17165265 \n3 Golden DB Patterns of anaphylaxis: acute and late phase features of allergic reactions Novartis Found Symp 2004 257 101 110 15025394 \n4 Liew WK Williamson E Tang ML Anaphylaxis fatalities and admissions in Australia J Allergy Clin Immunol 2009 123 434 442 19117599 \n5 Ewan PW Dugue P Mirakian R Dixon TA Harper JN Nasser SM BSACI BSACI guidelines for the investigation of suspected anaphylaxis during general anaesthesia Clin Exp Allergy 2010 40 15 31 20205694 \n6 Chacko T Ledford D Peri-anesthetic anaphylaxis Immunol Allergy Clin North Am 2007 27 213 230 17493499 \n7 Harboe T Benson MD Oi H Softeland E Bjorge L Guttormsen AB Cardiopulmonary distress during obstetrical anaesthesia: attempts to diagnose amniotic fluid embolism in a case series of suspected allergic anaphylaxis Acta Anaesthesiol Scand 2006 50 324 330 16480466 \n8 Ebo DG Bosmans JL Couttenye MM Stevens WJ Haemodialysisassociated anaphylactic and anaphylactoid reactions Allergy 2006 61 211 220 16409199 \n9 Pumphrey RS Lessons for management of anaphylaxis from a study of fatal reactions Clin Exp Allergy 2000 30 1144 1150 10931122 \n10 Simons FE First-aid treatment of anaphylaxis to food: focus on epinephrine J Allergy Clin Immunol 2004 113 837 844 15131564 \n11 Simons FE Ardusso LR Bilo MB El-Gamal YM Ledford DK Ring J Sanchez-Borges M Senna GE Sheikh A Thong BY World Allergy Organization World Allergy Organization anaphylaxis guidelines: summary J Allergy Clin Immunol 2011 127 587 593.e1-22 21377030 \n12 Mullins RJ Clark S Camargo CA Jr Regional variation in epinephrine autoinjector prescriptions in Australia: more evidence for the vitamin D-anaphylaxis hypothesis Ann Allergy Asthma Immunol 2009 103 488 495 20084842 \n13 Tham EH Tay SY Lim DL Shek LP Goh AE Giam YC Chng HH Lee BW Epinephrine auto-injector prescriptions as a reflection of the pattern of anaphylaxis in an Asian population Allergy Asthma Proc 2008 29 211 215 18430320 \n14 Handfield KS Dolan CK Kaplan M Cholinergic urticaria with anaphylaxis: hazardous duty of a deployed US marine Cutis 2015 95 241 243 25942027\n\n",
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"keywords": "Adrenaline; Anaphylaxis; Saudi Arabia",
"medline_ta": "Asia Pac Allergy",
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"title": "First study of pattern of anaphylaxis in a large tertiary care hospital in Saudi Arabia.",
"title_normalized": "first study of pattern of anaphylaxis in a large tertiary care hospital in saudi arabia"
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"abstract": "BACKGROUND\nCytomegalovirus (CMV) remains an important pathogen in transplant patients, and valacyclovir (VACV) prophylaxis 8 g/day has been used in high-risk CMV-seromismatched [D+/R-] renal transplant patients to decrease CMV disease. Neurotoxic adverse effects have limited its use, and the aim of the present study was to retrospectively evaluate low-dose VACV prophylaxis, 3 g/day for 90 days after transplantation, in 102 D+/R- renal transplant patients.\n\n\nMETHODS\nWe compared patient and graft survival rates up to 5 years after transplantation with the data from the Collaborative Transplant Study Group (CTS) database. The incidence of CMV disease, rejection and neurotoxic adverse effects was analyzed up to 1 year after transplantation.\n\n\nRESULTS\nThe patient and graft survival rates up to 5 years were comparable with those derived from the CTS. CMV disease was diagnosed in 25% of the patients and 2% developed tissue-invasive CMV disease. The rejection frequency was 22% and neurotoxic adverse effects were seen in 2% of the patients.\n\n\nCONCLUSIONS\nLow-dose VACV prophylaxis (3 g/day) for 90 days post-transplantation results in high patient and graft survival rates and reduces the incidence of CMV disease. Neurotoxic adverse effects are minimal. We believe that low-dose VACV prophylaxis should be considered to form one of the arms in future prospective comparison studies for the prevention of CMV disease in the high-risk D+/R- population of renal transplant patients.",
"affiliations": "Department of Medical Sciences, Uppsala University, Uppsala, Sweden. fredrik.sund@akademiska.se",
"authors": "Sund|Fredrik|F|;Tufveson|Gunnar|G|;Döhler|Bernd|B|;Opelz|Gerhard|G|;Eriksson|Britt-Marie|BM|",
"chemical_list": "D000998:Antiviral Agents; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir",
"country": "England",
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"doi": "10.1093/ndt/gfs531",
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"issue": "28(3)",
"journal": "Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association",
"keywords": null,
"medline_ta": "Nephrol Dial Transplant",
"mesh_terms": "D000212:Acyclovir; D000328:Adult; D019072:Antibiotic Prophylaxis; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011379:Prognosis; D051436:Renal Insufficiency, Chronic; D012189:Retrospective Studies; D015996:Survival Rate; D013997:Time Factors; D000077483:Valacyclovir; D014633:Valine",
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"pubdate": "2013-03",
"publication_types": "D016428:Journal Article",
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"title": "Clinical outcome with low-dose valacyclovir in high-risk renal transplant recipients: a 10-year experience.",
"title_normalized": "clinical outcome with low dose valacyclovir in high risk renal transplant recipients a 10 year experience"
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"companynumb": "SE-TEVA-496677ISR",
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"abstract": "OBJECTIVE\nTo investigate the clinical characteristics of patients with relapse-refractory acute myeloid leukemia(AML) with AML1-ETO+, and therapeutic effcacy and side effects of decitabine combined with modified CAG regimen.\n\n\nMETHODS\nClinical data of 8 cases of AML with AML1-ETO+ from June 2015 to January 2016 were analyzed retrospectively, including age, sex, initial symptoms, peripheral blood and bone marrow characteristics and so on. at the same time, the therapeutic effcacy and side effects of decitabine combined with modified CAG regimen were evaluated. The 8 patient were with median age of 44.5(16-59) years.\n\n\nRESULTS\nAmong these 8 patients, 1 patients were relapsed and other 7 patients were relapse/refractory patients, their median white blood cell count was 23.57(7.5-65.29)×109/L, median platelet count was 40(19-69)×109/L, median hemoglobin 1evel was 107(79-131) g/L, median lactate dehydrogenase level was 313.5(124.1-865.9) U/L at the initial diagnosis. The results showed that after treatment with decitabine combined with modified CAG, 7 patients achieved complete remission, 1 patient did not achieve remission, the overall remission rate was 87.5%(7/8). The main side effects of this regimen was myelosupp-ression, there were no new lung infection and other serious complications, 1 case without complete remission was treated with FLAG, and died of heart failure.\n\n\nCONCLUSIONS\nAccording to preliminary results of decitabine combined with modified CAG regimen for treatment of relapse/refractory AML patients with AMLl-ETO+ displays higer remission rate and lower side effects.",
"affiliations": "Jiangsu University, Zhenjiang 212013, Jiangsu Province, China; Department of Hematology, Changshu Municipal Second People's Hospital, Changshu 215500, Jiangsu Province, China.;Department of Hematology, The Affiliated Hospital of Jiangsu University (Zhenjiang Municipal Jiangbin Hospital), Zhenjiang 212008, Jiangsu Province, China. E-mail: feixiaomingujs@gmail.com.",
"authors": "Liu|Qiang|Q|;Fei|Xiao-Ming|XM|",
"chemical_list": "C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D015250:Aclarubicin; D000077209:Decitabine; D001374:Azacitidine",
"country": "China",
"delete": false,
"doi": "10.7534/j.issn.1009-2137.2016.05.009",
"fulltext": null,
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"issue": "24(5)",
"journal": "Zhongguo shi yan xue ye xue za zhi",
"keywords": null,
"medline_ta": "Zhongguo Shi Yan Xue Ye Xue Za Zhi",
"mesh_terms": "D015250:Aclarubicin; D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine; D050676:Core Binding Factor Alpha 2 Subunit; D003561:Cytarabine; D000077209:Decitabine; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D007958:Leukocyte Count; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101084424",
"other_id": null,
"pages": "1334-1338",
"pmc": null,
"pmid": "27784352",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Efficacy of Decitabine Combined with Modified CAG Regimen for Relapse/Refractory Acute Myeloid Leukemia with AML1-ETO.",
"title_normalized": "clinical efficacy of decitabine combined with modified cag regimen for relapse refractory acute myeloid leukemia with aml1 eto"
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"companynumb": "CN-MYLANLABS-2018M1038227",
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"occurcountry": "CN",
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"activesubstance": {
"activesubstancename": "ACLARUBICIN"
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"abstract": "BACKGROUND\nThere are few data regarding the utilization of opioids during pregnancy. The objective of this study was to define the prevalence and patterns of opioid use in a large cohort of pregnant women who were commercial insurance beneficiaries.\n\n\nMETHODS\nData for the study were derived from a deidentified research database of women from across the United States who had both medical and prescription benefits. By using diagnostic codes, the authors defined a cohort of 534,500 women with completed pregnancies who were enrolled in a commercial insurance plan from 6 months before pregnancy through delivery.\n\n\nRESULTS\nOverall, 76,742 women (14.4%) were dispensed an opioid at some point during pregnancy. There were 30,566 women (5.7%) dispensed an opioid during the first trimester, 30,434 women (5.7%) during the second trimester, and 34,906 women (6.5%) during the third trimester. Of these, 11,747 women (2.2%) were dispensed opioids three or more times during pregnancy. The most commonly dispensed opioids during pregnancy were hydrocodone (6.8%), codeine (6.1%), and oxycodone (2.0%). The prevalence of exposure at anytime during pregnancy decreased slightly during the study period from 14.9% for pregnancies that delivered in 2005 to 12.9% in 2011. The prevalence of exposure varied significantly by region and was lowest in the Northeast and highest in the South.\n\n\nCONCLUSIONS\nThis study demonstrates that opioids are very common exposures during pregnancy. Given the small and inconsistent body of literature on their safety in pregnancy, these findings suggest a need for research in this area.",
"affiliations": "From the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, and Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (B.T.B.); Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts (S.H.-D.); Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (J.P.R.); and Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (J.D.S., M.D., M.A.F., K.F.H.).",
"authors": "Bateman|Brian T|BT|;Hernandez-Diaz|Sonia|S|;Rathmell|James P|JP|;Seeger|John D|JD|;Doherty|Michael|M|;Fischer|Michael A|MA|;Huybrechts|Krista F|KF|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "United States",
"delete": false,
"doi": "10.1097/ALN.0000000000000172",
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"issn_linking": "0003-3022",
"issue": "120(5)",
"journal": "Anesthesiology",
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"medline_ta": "Anesthesiology",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D015331:Cohort Studies; D004363:Drug Utilization; D005260:Female; D006801:Humans; D007342:Insurance Benefits; D007348:Insurance, Health; D011247:Pregnancy; D015995:Prevalence; D014481:United States",
"nlm_unique_id": "1300217",
"other_id": null,
"pages": "1216-24",
"pmc": null,
"pmid": "24525628",
"pubdate": "2014-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "21514558;22227786;1426180;22550030;17063132;22156272;18342447;18294334;21484468;16687350;19718704;20927730;23462783;443241;17690963;20002323;21345403;23558845;3960086;24084542;1116890;21656212;20123184;4010751;15343213",
"title": "Patterns of opioid utilization in pregnancy in a large cohort of commercial insurance beneficiaries in the United States.",
"title_normalized": "patterns of opioid utilization in pregnancy in a large cohort of commercial insurance beneficiaries in the united states"
} | [
{
"companynumb": "US-JNJFOC-20140508401",
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"activesubstancename": "FENTANYL"
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"abstract": "To compare the total number of adverse events (AEs) before and after mesenchymal stromal cell (MSC) infusion in refractory JIA and to evaluate its effectiveness.\n\n\n\nSingle-centre Proof of Mechanism Phase Ib, open label intervention study in JIA patients previously failing all biologicals registered for their diagnosis. Six patients received 2 million/kg intravenous infusions of allogeneic bone-marrow derived MSC. In case of ACR-Ped30-response but subsequent loss of response one and maximal two repeated infusions are allowed.\n\n\n\nSix JIA patients with 9.2 years median disease duration, still active arthritis and damage were included. All had failed methotrexate, corticosteroids and median five different biologicals. MSC were administered twice in three patients. No acute infusion reactions were observed and a lower post-treatment than pre-treatment incidence in AEs was found. The one systemic onset JIA (sJIA) patient had again an evolving macrophage activation syndrome, 9 weeks after tocilizumab discontinuation and 7 weeks post-MSC infusion. Statistically significant decreases were found 8 weeks after one MSC infusion in VAS well-being (75-56), the JADAS-71 (24.5-11.0) and the cJADAS10 (18.0-10.6).\n\n\n\nMSC infusions in six refractory JIA patients were safe, although in sJIA stopping the 'failing' biologic treatment carries a risk of a MAS flare, as the drug might still suppress the systemic features.\n\n\n\nTrial register.nl, http://https://www.trialregister.nl, NTR4146.",
"affiliations": "Department of Pediatric Immunology and Rheumatology, UMC Utrecht, Wilhelmina Children's Hospital.;Department of Pediatric Immunology and Rheumatology, UMC Utrecht, Wilhelmina Children's Hospital.;Faculty of Medicine, Utrecht University.;Cell Therapy Facility, Division Laboratories and Pharmacy, UMC Utrecht, Utrecht, The Netherlands.;Department of Pediatric Immunology and Rheumatology, UMC Utrecht, Wilhelmina Children's Hospital.;Department of Pediatric Immunology and Rheumatology, UMC Utrecht, Wilhelmina Children's Hospital.",
"authors": "Swart|Joost F|JF|;de Roock|Sytze|S|;Nievelstein|Rutger A J|RAJ|;Slaper-Cortenbach|Ineke C M|ICM|;Boelens|Jaap J|JJ|;Wulffraat|Nico M|NM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/kez157",
"fulltext": "\n==== Front\nRheumatology (Oxford)Rheumatology (Oxford)brheumRheumatology (Oxford, England)1462-03241462-0332Oxford University Press 10.1093/rheumatology/kez157kez157Clinical ScienceBone-marrow derived mesenchymal stromal cells infusion in therapy refractory juvenile idiopathic arthritis patients Swart Joost F 12de Roock Sytze 12Nievelstein Rutger A J 23Slaper-Cortenbach Ineke C M 4Boelens Jaap J 12Wulffraat Nico M 121 Department of Pediatric Immunology and Rheumatology, UMC Utrecht, Wilhelmina Children's Hospital2 Faculty of Medicine, Utrecht University3 Department of Pediatric Radiology, Division Imaging, UMC Utrecht, Utrecht, The Netherlands4 Cell Therapy Facility, Division Laboratories and Pharmacy, UMC Utrecht, Utrecht, The NetherlandsCorrespondence to: Joost F. Swart, Department of Pediatric Immunology and Rheumatology, UMC Utrecht, Wilhelmina Children's Hospital, Intern mail address KC 03.063.0, PO Box 85090, 3508 AB Utrecht, The Netherlands. E-mail: jswart@umcutrecht.nl10 2019 27 4 2019 27 4 2019 58 10 1812 1817 7 1 2019 25 3 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nObjectives\nTo compare the total number of adverse events (AEs) before and after mesenchymal stromal cell (MSC) infusion in refractory JIA and to evaluate its effectiveness.\n\nMethods\nSingle-centre Proof of Mechanism Phase Ib, open label intervention study in JIA patients previously failing all biologicals registered for their diagnosis. Six patients received 2 million/kg intravenous infusions of allogeneic bone-marrow derived MSC. In case of ACR-Ped30-response but subsequent loss of response one and maximal two repeated infusions are allowed.\n\nResults\nSix JIA patients with 9.2 years median disease duration, still active arthritis and damage were included. All had failed methotrexate, corticosteroids and median five different biologicals. MSC were administered twice in three patients. No acute infusion reactions were observed and a lower post-treatment than pre-treatment incidence in AEs was found. The one systemic onset JIA (sJIA) patient had again an evolving macrophage activation syndrome, 9 weeks after tocilizumab discontinuation and 7 weeks post-MSC infusion. Statistically significant decreases were found 8 weeks after one MSC infusion in VAS well-being (75–56), the JADAS-71 (24.5–11.0) and the cJADAS10 (18.0–10.6).\n\nConclusion\nMSC infusions in six refractory JIA patients were safe, although in sJIA stopping the ‘failing’ biologic treatment carries a risk of a MAS flare, as the drug might still suppress the systemic features.\n\nTrial registration\nTrial register.nl, http://https://www.trialregister.nl, NTR4146.\n\nJuvenile arthritistherapeuticsmesenchymal stromal cellsstem cell transplantationNetherlands Organisation for Health Research and Development10.13039/501100001826Dutch Arthritis Foundation\n==== Body\nRheumatology key messages\n\nMesenchymal stromal cell infusions in 6 refractory JIA patients were safe.\n\nFor systemic JIA patients, there are risks from withdrawing current therapy prior to mesenchymal stromal cell.\n\nRefractory JIA is worth investigating further as an indication for mesenchymal stromal cell treatment.\n\n\n\n\n\n\n\nIntroduction\nJIA is not a single disorder, but consists of a heterogeneous group of inflammatory childhood diseases with a prevalence of 16–150 per 100 000 children [1]. Certain subtypes can only be found in children, while systemic onset JIA (sJIA) has the immunological signature of an auto-inflammatory rather than a classical auto-immune disease [2]. Although the introduction of biological agents has greatly improved the outcome, only 45–62% of JIA children on a biological reach an ACR-Ped 70% improvement at 12 months [3]. The patients remaining resistant to biological therapies might still suffer from a very severe, debilitating and potentially fatal disease. For such children, autologous haematopoietic stem cell transplantation has been performed since 1997 with a drug-free remission rate of 50–55%, but with considerable morbidity and even mortality [4]. Late relapses led to lower percentages for drug-free long-term outcome [5].\n\nCellular therapies are evolving and now include mesenchymal stromal cells (MSC). MSC are non-embryonic stromal cells present in bone marrow, fat, umbilical cord and many other tissues. MSC are widely studied for therapeutic purposes, because they are relatively easily harvested and expandable. MSC have strong immunosuppressive qualities in vitro inhibiting Th1-cells, B-cells, dendritic cells, NK-cells, and activating regulatory T cells [6]. Myelo-ablation may be omitted because MSC do not express MHC-class-II and only little MHC-class-I. Allogeneic MSC are thus valuable off-the-shelf third-party donor cells with only a small chance of in-vitro alloimmune reactions and low rates of treatment-related serious adverse events similar to autologous MSC [7]. In 2004, a patient with severe graft-vs-host disease received MSC from his mother with a striking clinical response [8]. Since then, over 1000 patients have been described treated with i.v. MSC for various diseases [9]. As far as we know, JIA patients were never before treated with allogeneic bone-marrow derived MSC. We hypothesized refractory JIA patients who failed registered biologics may profit from i.v. MSC and therefore conducted this small Proof of Mechanism phase Ib clinical trial.\n\nMethods\nStudy population\nThe study is conducted according to the Declaration of Helsinki, registered at EUDRACT (2012–002067-10) and approved by the Dutch Ministry of Health and The Central Committee on Research Involving Human Subjects (NL40454.000.13). The study is registered in the Dutch National Trial Register (NTR4146). All parents and patients consented to the study.\n\nSubjects eligible for this study needed to meet all of the following: patients (4–18 years of age) diagnosed with JIA according to ILAR-criteria with active arthritis resistant to intra-articular steroids and systemic use of methotrexate previously failing all biologicals registered for their JIA subtype. There were no biologicals yet registered for (extended) oligoarthritis JIA patients; however, the failure of two classes of biologicals was required for these patients. Patients are followed for moderate or worse adverse events via the Pharmachild pharmacovigilance database [10]. Exclusion criteria for participation in this study were refusal to withdraw from biologicals, concurrent infection, febrile illness, malignancy or pregnancy.\n\nUse of co-medication\nNSAIDs, paracetamol and tramadol could be used as escape medication during acute pain attacks and stable doses of systemic steroids and synthetic DMARDs were allowed in order to qualify for a next MSC infusion. Biologicals and additional IA steroid injections were reasons to disqualify for a next MSC infusion.\n\nSample size calculation\nUsing an 80% one-sided confidence interval, it was estimated by Cocks and Torgerson that a pilot trial should have at least 9% of the sample size of the main planned trial [11]. The number of biological-allocated patients in the randomized phase of the JIA-registration trial was 25 for etanercept, 68 for adalimumab and 60 for abatacept. If MSC were to be studied with an equal randomized controlled trial with six patients in this tolerability pilot study, we fulfilled the above-mentioned requirements.\n\nInvestigational product\nThe MSC used were isolated from bone marrow mononuclear cells obtained from healthy (consenting) donors by plastic adherence and expanded under GMP-conditions in our Cell Therapy Facility using human platelet lysate derived from five pooled platelets donations as source of growth factors as described before [12]. Density separated bone-marrow cells were seeded in two-layer CellStacks in αMEM with 5% platelet lysate and 2 IU/ml Heparin. After 7 days, non-adherent cells were depleted and when 80–100% confluency was reached, the cells were harvested using trypsin. The cells were put into new CellStacks for further expansion till passage 3, harvested and cryopreserved before infusion.\n\nThe MSC differentiated towards osteoblasts, adipocytes and chondrocytes. The release criteria (all needed) were >70% expresses the MSC phenotype (CD73+, CD90+ and CD105+); <10% haematopoietic cells (CD45+); <1% T cells (CD45+, CD3+ cells); Sterility testing (no bacteria, fungi or yeast); Mycoplasma tests <10 CFU/mL, and Endotoxins <1 IU/ml\n\nThe MSC were thawed, counted, tested for viability and 2 million living cells/kg bodyweight with a maximum of three doses were injected i.v. Repeated i.v. administrations with this dose (up to 2 million/kg) was already used in children for the HOVON-MSC-112 graft-vs-host disease study in our hospital. In case of repeated infusion, the MSC from the same donor was used.\n\nStudy design\nSingle centre Proof of Mechanism Phase Ib, open label, non-randomized study during 64 weeks per patient with continuous follow-up for adverse events (AEs).\n\nThe study consisted of nine visits (V) at week -12(V0), 0(V1), 4(V2), 8(V3), 12(V4), 16(V5), 26(V6), 39(V7), 52(V8). At V0, patients and physicians recorded the AEs on the current therapeutic regimen in the 12 weeks before the MSC-therapy. At V1, questionnaires, physical examination, venepuncture and a MRI of a clinically active large joint were performed with subsequently the first MSC infusion. At V2–8, questionnaires, physical examination and venepuncture were performed. The MSC infusion could be repeated at V3 and V5 if there is at least ACR Ped 30% improvement at V2 or V4 but weaning of the effect at the following visit. The patients were their own historic controls regarding both safety and efficacy.\n\nCollection of the study data\nThe visits encompassed complete medical history, medication use, Childhood Health Assessment Questionnaire, the Juvenile Arthritis Multidimensional Assessment Report, a complete physical examination including a physician global assessment. The ACR Ped-30 was only used to decide if another MSC-infusion was needed. A weighted joint score, a scoring system for JIA in which joints are weighted to reflect their relative importance to children's function [13] and Juvenile Arthritis Disease Activity Scores (JADAS) were calculated.\n\nEndpoints\nThe primary outcome was the number of AEs per 3 months after MSC infusion compared with 3 months prior to the MSC. Secondary objectives were the 8-week (before 2nd MSC) and end-of-study parameters: ESR (mm/h), CRP (mg/L), active joint count, tender joint count, limited joint count, weighted joint count, VAS well-being, VAS pain, physician global assessment, JADAS-71, cJADAS-10, Childhood Health Assessment Questionnaire, Quality of Life and Juvenile Arthritis Functionality Scale (derived from the Juvenile Arthritis Multidimensional Assessment Report).\n\nStatistical analysis\nFor the comparative pre- and post-MSC incidences of adverse events, the two-sided χ2 test (Fisher’s exact) for related samples was used. For the comparison of start- and end-of-study results the Wilcoxon signed Ranks test (2-tailed) for related samples was used. The significance level was set at P <0.05. We use SPSS version 21.0.0.0.\n\nResults\nPatients\nSix therapy-refractory JIA patients (four males) were included (see Table 1). All patients had articular joint damage and/or extra-articular damage at baseline. All had failed methotrexate, corticosteroids (intra-articular and/or systemic) and median 5 (2–7) different biologicals (see Table 1). All patients had stable persistent disease activity at study start and synovitis on a MRI-scan. Three patients referred from other centres also had follow-up visits elsewhere, unfortunately resulting in some missing data. For all patients, complete safety data was obtained.\n\n\nTable 1 Patient characteristics at baseline\n\n\t Patient number\t1\t2\t3\t4\t5\t6\tTotal (% or median)\t\n\nPatient characteristics\n\t\t\t\t\t\t\t\t\n\tSex (female%)\tF\tF\tM\tM\tM\tM\t\n33%\n\t\n\tAge at 1st MSC\t12.1\t15.9\t09.4\t14.0\t16.8\t16.2\t\n15.0 yrs\n\t\n\tDisease duration at 1st MSC\t4.4\t9.2\t6.7\t13.3\t9.3\t12.7\t\n9.2 yrs\n\t\n\tExtended oligo-articular\t✓\t\t\t✓\t\t\t\n33%\n\t\n\tPoly-articular RF-\t\t✓\t✓\t\t✓\t\t\n50%\n\t\n\tSystemic\t\t\t\t\t\t✓\t\n17%\n\t\n\tAntinuclear antibodies +\t-\t-\t-\t+\t+\t-\t\n33%\n\t\n\tUveitis ever\t-\t-\t-\t-\t-\t-\t\n0%\n\t\n\tJADI-Articular damage\t1\t7\t18\t1\t12\t0\t\n4\n\t\n\tJADI-Extra-articular damage\t1\t0\t1\t1\t3\t7\t\n1\n\t\n\nMedication history (duration in months)\n\t\t\t\t\t\t\t\t\n\tIA steroids (ever)\t✓\t\t\t✓\t✓\t✓\t\t\nCorticosteroids\tMP pulse i.v.\t\t\t\t\t3x\t7x\t\t\n\tOral steroids\t\t70\t67\t18\t15\t153\t\n43\n\t\n\tMTX\t43\t16\t59\t152\t81\t153\t\n70\n\t\n\tSulfasalazine\t\t6\t\t\t41\t\t\t\nsDMARDs\tLeflunomide\t\t\t\t\t22\t\t\t\n\tCiclosporine\t\t\t\t\t\t2\t\t\n\tThalidomide\t\t\t\t\t\t34\t\t\nAlkylating agents\tCyclophosphamide\t\t\t\t\t\t9\t\t\nKinase inhibitor\tTofacitinib\t\t\t\t\t\t3\t\t\n\tAbatacept\t\t5\t\t\n19\n\t3\t7\t\n4\n\t\n\tAnakinra\t\t\t\t\t\n1\n\t5\t\t\n\tAdalimumab\t30\t11\t1\t9\t46\t\t\n10\n\t\n\tCertolizumab\t\t\n4\n\t\t\t\t\t\t\nBiologicals\tCanakinumab\t\t\t2\t\t\t3\t\t\n\tEtanercept\t\t18\t8\t100\t15\t3\t\n12\n\t\n\tGolimumab\t\t\t23\t\t\t\t\t\n\tInfliximab\t\t\t\t\t\t3\t\t\n\tRituximab\t\t\t\t\t\t6\t\t\n\tTocilizumab\t\n6\n\t3\t\n3\n\t4\t2\t\n75\n\t\n4\n\t\n\taHSCT (CYC & ATG)\t\t\t\t\t✓\t\t\t\n\nLast time biological prior to MSC (weeks)\n\t5\t31\t12a\t5\t17\t2\t\n9\n\t\n\nConcurrent medication use\n\t\t\t\t\t\t\t\t\n\tMTX (mg/wk)\t25\t\t\t7.5\t\t25\t\t\n\tPrednisolone (mg/d)\t\t10\t13\t5\t14\t2\t\n8\n\t\nThe underlined biologicals are the ones last used by that specific patient.\n\na This patient used his last tocilizumab as 2-weekly subcutaneous injections.\n\naHSCT: autologous haematopoietic stem cell transplant; ATG: antithymocyte globulines; JADI: Juvenile Arthritis Damage Index; Mo: months; MP: methylprednisolone; MSC: mesenchymal stromal cells; sDMARDs: synthetic DMARDs.\n\nTreatment during the study\nAll patients had discontinued their biological therapy at median 9 weeks before MSC administration. MSC were administered at week 0 in all and again in week 8 (or ultimately delayed till week 11) in the three patients qualifying for a repeated infusion (see Table 2). None of these three patients qualified for the third MSC-infusion. Other anti-rheumatic therapy changes than the MSC were made in patients 2, 4, 5 and 6 at week 28, 22, 13 and 9, respectively (see Table 2).\n\n\nTable 2 Primary outcome: adverse events and the concomitant treatments per patient\n\nEpisodes (months)\t−3–0\t0–3\t3–6\t6–9\t9–12\tMonthly Incidence Pre-MSC\tMonthly Incidence Post-MSC\tIncidence /person/month Pre-MSC\tIncidence /person/month Post-MSC\t\nP-value\t\n\nSerious Adverse Events\n\t\t\t\t\t\nPt 1\t\nHematemesis faecal impaction\n\tFecal impaction\t-\tFecal impaction\t-\t0.67\t0.17\t0.111\t0.055\t0.60\t\nPt 2\t\t-\t-\t-\tBilateral pneumonia\t0\t0.08\t\nPt 3\t\n-\n\t-\t-\t-\t-\t0\t0\t\nPt 4\t\n-\n\t-\t-\t-\t-\t0\t0\t\nPt 5\t\n-\n\t-\t-\t-\t-\t0\t0\t\nPt 6\t\n-\n\t\n-\n\tEvolving MAS\t-\t-\t0\t0.08\t\n\nTotal\n\t\n2\n\t\n1\n\t1\t1\t1\t\n0.67\n\t\n0.33\n\t\n\nAdverse Events\n\t\t\t\t\t\nPt 1\t\n-\n\t-\t-\t-\t-\t0\t0\t0.055\t0.014\t0.36\t\nPt 2\t\n-\n\t-\t-\t-\t-\t0\t0\t\nPt 3\t\nFlu-like illness\n\t-\tURTI\t\t-\t0.33\t0.08\t\nPt 4\t\n-\n\t-\t-\t\t-\t0\t0\t\nPt 5\t\n-\n\t-\t-\t-\t-\t0\t0\t\nPt 6\t-\t-\t-\t-\t-\t0\t0\t\n\nTotal\n\t\n1\n\t0\t1\t0\t0\t\n0.33\n\t\n0.08\n\t\n\nAnti-rheumatic therapy\n\t\nPt 1\t\n(Wk -5 Toclilizumab)\n\nMTX 25mg/wk sc\n\n\n\t\nWk 0 & 11: MSC\n\nMTX 25mg/wk po\n\n\n\tMTX 25mg/wk po\tMTX 25mg/wk po\tMTX 25mg/wk po\t\t\t\t\t\t\nPt 2\t\nPred. 10 mg/d\n\t\nWk 0: MSC\n\nPred. 10 mg/d\n\n\n\tPred. 10 mg/d\t\nWk 28 & 30 Rituximab\n\nPred. 10 mg/d\n\n\n\tPred. 10 mg/d\t\t\t\t\t\t\nPt 3\t\n(Wk -10 Tocilizumaba)\n\nPred. 12.5 mg/d\n\n\n\t\nWk 0: MSC\n\nPred. 12.5 mg/d\n\n\n\tPred. 12.5 mg/d\tPred. 12.5 mg/d\tPred. 12.5 mg/d\t\t\t\t\t\t\nPt 4\t\n\n(Wk -5 Abatacept)\n\n\n\nPred. 5mg/d\n\n\n\nMTX 7.5 mg/wk po\n\n\n\n\t\nWk 0 & 10: MSC\n\nPred. 5mg/d\n\nMTX 7.5 mg/wk\n\n\n\t\nWk 23: Sirolimus 2mg/d\n\nPred. 7.5mg/d\n\nWk 22: MMF 1500mg/d\n\n\n\t\nWk 38: IA steroids (4)\n\nWk 38: Etanercept\n\nPred. 10mg/d\n\nMMF 1500mg/d\n\n\n\t\nEtanercept 50mg/10d\n\nPred. 7.5mg/d\n\nMMF 1500mg/d\n\n\n\t\t\t\t\t\t\nPt 5\t\nPred. 14 mg/d\n\t\nWk 0 & 8: MSC\n\nPred. 14 mg/d\n\n\n\t\nWk 13: IA steroidsb\n\nWk 16: Adalimumab\n\nPred. 10 mg/d\n\nWk 13: MTX 15mg/wk sc\n\n\n\t\nWk 32: MMF 1000mg/d\n\nAdalimumab 40mg/wk\n\nPred. 5 mg/d\n\nMTX 20 mg/wk sc\n\n\n\t\nMMF 1500mg/d\n\nAdalimumab 40mg/wk\n\nPred. 2.5 mg/d\n\nMTX 20 mg/wk sc\n\n\n\t\t\t\t\t\t\nPt 6\t\n\n(Wk-2 Tocilizumab)\n\n\n\nPred 2 mg/d\n\n\n\nMTX 25 mg/wk po\n\n\n\n\t\nWk 0: MSC\n\nWk 9: MP 3x pulse\n\nWk 9: Tocilizumab /e.o.w.\n\nWk 9: Pred. 60->30 mg/d\n\n\nMTX 25 mg/wk po\n\n\n\n\t\nTocilizumab / e.o.w.\n\nPred. 30->10 mg/d\n\nMTX 25mg/wk po\n\n\n\t\nTocilizumab / e.o.w.\n\nPred. 10->5 mg/d\n\nMTX 25mg/wk po\n\n\n\t\nWk 39: MMF 1440mg/d\n\nTocilizumab / e.o.w.\n\nPred. 2 mg/d\n\nMTX 25mg/wk po\n\n\n\t\t\t\t\t\t\nSerious and moderate-severe adverse events are shown for 3-month periods before and 12 months after the first MSC-infusion. Also, the anti-rheumatic medication given during the study is shown per patient; therapy changes are in bold. The biologics used prior to week 0 are between brackets with their last administrations displayed. Incidences are displayed per patient/month. The two-sided χ2 test (Fisher’s exact) for related samples was used for statistical analysis of the incidences of events per person per month comparing the Pre-MSC with the Post-MSC episode.\n\na subcutaneous.\n\nb 5 joints injected.\n\ne.o.w: every other week; MP: methylprednisolone; MSC: mesenchymal stromal cells; po: per os; Pred: prednisolone; URTI: upper respiratory tract infection; Wk: week.\n\nSafety\nNo acute infusion reactions were observed during any of the nine MSC administrations. Overall we found a non-significant (P =0.60) lower monthly incidence of serious adverse events and a non-significant (P =0.36) lower monthly incidence of moderate-severe AE post-MSC compared with pre-MSC (see Table 2).\n\nIn the 3 months pre-MSC, two serious adverse events were recorded in patient 1 with hospitalizations for (drug-induced) haematemesis and for faecal impaction. She needed to be readmitted for the latter condition twice in the year post-MSC.\n\nPatient 2 was admitted 50 weeks post-MSC for bilateral pneumonia and 20 weeks after her second rituximab infusion while still using 10 mg/day prednisolone.\n\nPatient 6, the only systemic JIA patient with a medical history of a macrophage activation syndrome (MAS) presented to the emergency room with significant headache and afebrile lethargy at week 7. Compared with the routine visit 2 days before, he now had a marked polyarthritic flare and a sharp drop in his white blood cell count (from 3.2 to 1.7×109/l), platelet count (from 170 to 89×109/l), rising ESR (from 40 to 82 mm/h), normal stable CRP (from 0.4 to 2.8 mg/l), normal ferritin level 41.2 µg/l (41.2 ng/ml), normal stable fibrinogen (from 3.8 to 3.4 g/l) and elevated rising triglycerides (from 1.2 to 2.8 mmol/l). Both clinical and laboratory features suggested an evolving MAS, although being afebrile with a normal ferritin he did not (yet) fulfil the criteria [14]. He was admitted and treated with 3 days i.v. methylprednisolone 1 g/day with a dramatic clinical improvement within 24 h. There was no intercurrent infection found and blood cultures stayed negative. He restarted tocilizumab on the second day of admission and was discharged a day later with normalization of all the aforementioned laboratory values.\n\nEfficacy\nFor efficacy we analysed the results at 8 weeks after the first MSC all patients received. Statistically significant decreases were found between baseline and the 8-week results in VAS well-being (75–56), the JADAS-71 (24.5–11.0) and the cJADAS10 (18.0–10.6) (see for more details Supplementary Table S1, available at Rheumatology online).\n\nAt the end of the study, three of six patients had clinically inactive disease with a fourth almost reaching this; however, two of these four also received additional treatments half way (see Supplementary Table S2 and Supplementary Fig. S1A-N, available at Rheumatology online, for the analysis of all end-of-study results and the individual graphs).\n\nDiscussion\nIn this study we did not see any acute infusional reactions after allogeneic MSC administration, which is in agreement with the meta-analysis of 13 studies [9]. We found a lower incidence for AEs post-treatment than pre-treatment, even though we ascribed all found AEs to the MSC infusions. Some of the AEs that we encountered post-treatment were, however, due to a chronic pre-existent problem (faecal impaction). The bilateral pneumonia in patient 2 was more likely due to the combination of corticosteroids and repeated rituximab infusions than resulting from the single MSC infusion 50 weeks earlier.\n\nThe one sJIA patient in our study with a history of both MAS and JIA flare 4 weeks after discontinuation of tocilizumab, did now suffer from an evolving MAS 9 weeks after the discontinuation of tocilizumab. This patient had neither clinical nor laboratory effect of the MSC, and already suffered from a JIA flare 3 weeks before the evolving MAS, which is also more likely due to an again unsuccessful discontinuation of tocilizumab. We can, however, not discern the role of the single infusion MSC 7 weeks earlier.\n\nIn our study four of six patients showed a decrease of clinically active joints 8 weeks after the first MSC administration, with a decrease of CRP and ESR in three of the four patients with an elevated value at the start. In the six study patients, only JADAS-71, cJADAS10 and the VAS well-being decreased significantly in that short period. The median scores of the patient reported outcome measures of VAS pain, Childhood Health Assessment Questionnaire and Quality of Life all improved non-significantly during that same episode. The only other study describing twice 40 million umbilical cord derived intravenously in 10 steroid-using JIA patients also found MSC to be safe and observed an improvement in DAS28, as well as a decrease of ESR and CRP and better functionality and growth [15]. The efficacy results of both that and our studies should, however, be interpreted with caution, as the non-blinded fashion induces bias. Furthermore, in a meta-analysis of randomized JIA trials, the placebo rate response found was already 35% on physician global assessment improvement [16]. The additional therapy changes in our study beyond week 9 in two out of four responders make it impossible to interpret the exact reason for their improvement at 1 year. In conclusion, from the findings in our study we believe that MSC are safe in JIA patients, but one should be aware of (evolving) MAS in sJIA patients and therefore consider adding MSC to the failing biologic treatment, as it might still unknowingly suppress the systemic features.\n\nSupplementary Material\nkez157_Supplementary_Data Click here for additional data file.\n\n Acknowledgements\nJ.F.S., I.C.M.S.-C. and N.M.W. planned the study. J.J.B. helped J.F.S. in the preparation for ethical approval. J.F.S. informed all patients. J.F.S. and N.M.W. evaluated all patients. J.F.S. checked the completeness of the data. J.F.S. analysed the clinical data. R.A.J.N. analysed all MRI data. S.dR. analysed the immunological data. J.F.S. wrote the manuscript. S.dR., R.A.J.N., I.C.M.S.-C., J.J.B. and N.M.W. critically reviewed and edited the manuscript before submission. All authors contributed substantially to discussion of content. We thank Bianca Lang, Tamás Constantin and Simone Gorter for their help from a distance. We thank Patrick van de Torre for his involvement and physiotherapeutic evaluation of the study patients. We thank Caroline Lindemans for her involvement in the administration of the MSC and Kasper Westinga for the deliverance of the MSC.\n\n\nFunding: This study was sponsored by The Netherlands Organisation for Health Research and Development (ZonMw) and the Dutch Arthritis Foundation (Reumafonds) grant RF 901.\n\n\nDisclosure statement: The authors have declared no conflicts of interest.\n==== Refs\nReferences\n1 \nRavelli A , Martini A. Juvenile idiopathic arthritis. Lancet 2007 ;369:767–78.\n2 \nPascual V , Allantaz F , Arce E , Punaro M , Banchereau J. \nRole of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade . J Exp Med 2005 ;201 :1479 –86 .15851489 \n3 \nHorneff G , De Bock F , Foeldvari I \net al\nSafety and efficacy of combination of etanercept and methotrexate compared to treatment with etanercept only in patients with juvenile idiopathic arthritis (JIA): preliminary data from the German JIA Registry . Ann Rheum Dis 2009 ;68 :519 –25 .18413440 \n4 \nSwart JF , Delemarre EM , van Wijk F \net al\nHaematopoietic stem cell transplantation for autoimmune diseases . Nat Rev Rheumatol 2017 ;13 :244 –56 .28228650 \n5 \nBrinkman DMC , de Kleer IM , ten Cate R \net al\nAutologous stem cell transplantation in children with severe progressive systemic or polyarticular juvenile idiopathic arthritis: long-term followup of a prospective clinical trial . Arthritis Rheum 2007 ;56 :2410 –21 .17599770 \n6 \nKrampera M , Pasini A , Pizzolo G \net al\nRegenerative and immunomodulatory potential of mesenchymal stem cells . Curr Opin Pharmacol 2006 ;6 :435 –41 .16777484 \n7 \nHare JM , Fishman JE , Gerstenblith G \net al\nComparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial . JAMA 2012 ;308 :2369 –79 .23117550 \n8 \nLe Blanc K , Rasmusson I , Sundberg B \net al\nTreatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells . Lancet 2004 ;363 :1439 –41 .15121408 \n9 \nLalu MM , McIntyre L , Pugliese C \net al\nSafety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials . PLoS One 2012 ;7 :e47559 .23133515 \n10 \nSwart J , Giancane G , Horneff G \net al\nPharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15, 000 patients from Pharmachild and national registries . Arthritis Res Ther 2018 ;20 :285 .30587248 \n11 \nCocks K , Torgerson DJ. \nSample size calculations for pilot randomized trials: a confidence interval approach . J Clin Epidemiol 2013 ;66 :197 –201 .23195919 \n12 \nDonega V , Nijboer CH , Braccioli L \net al\nIntranasal administration of human MSC for ischemic brain injury in the mouse: in vitro and in vivo neuroregenerative functions . PLoS One 2014 ;9 :e112339 .25396420 \n13 \nBandeira M , Falcone A , Pistorio A \net al\nWeighting improves the information provided by joint counts on the severity of arthritis and its impact on patients’ well-being in juvenile idiopathic arthritis . Rheumatology 2006 ;45 :343 –7 .16234273 \n14 \nRavelli A , Minoia F , Davì S \net al\n2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborat . Arthritis Rheumatol 2016 ;68 :566 –76 .26314788 \n15 \nWang L , Zhang Y , Li H \net al\nClinical observation of employment of umbilical cord derived mesenchymal stem cell for juvenile idiopathic arthritis therapy . Stem Cells Int 2016 ;2016 :9165267 .26770214 \n16 \nDemirkaya E , Lanni S , Bovis F \net al\nA meta-analysis to estimate the placebo effect in randomized controlled trials in juvenile idiopathic arthritis . Arthritis Rheumatol 2016 ;68 :1540 –50 .26749157\n\n",
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"issue": "58(10)",
"journal": "Rheumatology (Oxford, England)",
"keywords": "Juvenile arthritis; mesenchymal stromal cells; stem cell transplantation; therapeutics",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": "D000293:Adolescent; D001171:Arthritis, Juvenile; D001854:Bone Marrow Cells; D002648:Child; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells; D010865:Pilot Projects; D000075082:Proof of Concept Study; D016896:Treatment Outcome",
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"pages": "1812-1817",
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"pubdate": "2019-10-01",
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"title": "Bone-marrow derived mesenchymal stromal cells infusion in therapy refractory juvenile idiopathic arthritis patients.",
"title_normalized": "bone marrow derived mesenchymal stromal cells infusion in therapy refractory juvenile idiopathic arthritis patients"
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"abstract": "The occurrences of hyperuricemia and acute kidney injury after antithymocyte globulin treatment are unusual in kidney transplant recipients. Here, we report a unique case of acute kidney injury with extreme hyperuricemia after antithymocyte globulin treatment in a kidney transplant recipient with underlying aplastic anemia.\n\n\n\nA 40-year-old woman with aplastic anemia who received a kidney transplant 5 years 6 months before presented to our emergency department with complaints of oliguria, generalized edema, and general weakness 6 days after receiving antithymocyte globulin treatment for acute T-cell-mediated rejection. Urinalysis revealed 100 uric acid crystal particles. The blood chemistry test results showed rapid increases in serum creatinine (from 2.86 mg/dL to 5.58 mg/dL) and uric acid levels (from 10.2 mg/dL to 32.7 mg/dL), which suggested acute uric acid nephropathy. Tumor lysis syndrome was suspected to be the cause of the acute uric acid nephropathy; hence, the patient was reevaluated for aplastic anemia. Human leukocyte antigen-DR15 was positive, and flow cytometry revealed a low percentage of glycophosphatidyl inositol-deficient granulocytes (2.9%), which suggested paroxysmal nocturnal hemoglobinuria clones. These findings indicate that the previously diagnosed aplastic anemia had either originally been hypocellular myelodysplastic syndrome (MDS) or later transformed into hypocellular MDS, which is a type of bone marrow failure syndrome.\n\n\n\nClinicians should consider unexpected tumor lysis syndrome to be the cause of complications after antithymocyte globulin treatment in kidney transplant recipients with underlying bone marrow failure syndrome.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea.;Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea.;Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea.;Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea.;Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea. yangch@catholic.ac.kr.",
"authors": "Park|Yohan|Y|;Chung|Byung Ha|BH|;Park|Cheol Whee|CW|;Kim|Yong-Soo|YS|;Yang|Chul Woo|CW|0000-0001-9796-636X",
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"fulltext": "\n==== Front\nBMC Nephrol\nBMC Nephrol\nBMC Nephrology\n1471-2369 BioMed Central London \n\n1903\n10.1186/s12882-020-01903-9\nCase Report\nAcute kidney injury with extreme hyperuricemia after antithymocyte globulin treatment in a kidney transplant recipient with underlying aplastic anemia: a case report\nPark Yohan Chung Byung Ha Park Cheol Whee Kim Yong-Soo http://orcid.org/0000-0001-9796-636XYang Chul Woo yangch@catholic.ac.kr grid.411947.e0000 0004 0470 4224Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591 South Korea \n2 7 2020 \n2 7 2020 \n2020 \n21 25111 9 2019 22 6 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nThe occurrences of hyperuricemia and acute kidney injury after antithymocyte globulin treatment are unusual in kidney transplant recipients. Here, we report a unique case of acute kidney injury with extreme hyperuricemia after antithymocyte globulin treatment in a kidney transplant recipient with underlying aplastic anemia.\n\nCase presentation\nA 40-year-old woman with aplastic anemia who received a kidney transplant 5 years 6 months before presented to our emergency department with complaints of oliguria, generalized edema, and general weakness 6 days after receiving antithymocyte globulin treatment for acute T-cell-mediated rejection. Urinalysis revealed 100 uric acid crystal particles. The blood chemistry test results showed rapid increases in serum creatinine (from 2.86 mg/dL to 5.58 mg/dL) and uric acid levels (from 10.2 mg/dL to 32.7 mg/dL), which suggested acute uric acid nephropathy. Tumor lysis syndrome was suspected to be the cause of the acute uric acid nephropathy; hence, the patient was reevaluated for aplastic anemia. Human leukocyte antigen-DR15 was positive, and flow cytometry revealed a low percentage of glycophosphatidyl inositol-deficient granulocytes (2.9%), which suggested paroxysmal nocturnal hemoglobinuria clones. These findings indicate that the previously diagnosed aplastic anemia had either originally been hypocellular myelodysplastic syndrome (MDS) or later transformed into hypocellular MDS, which is a type of bone marrow failure syndrome.\n\nConclusions\nClinicians should consider unexpected tumor lysis syndrome to be the cause of complications after antithymocyte globulin treatment in kidney transplant recipients with underlying bone marrow failure syndrome.\n\nKeywords\nTumor lysis syndromeAntithymocyte globulinAplastic anemiaMyelodysplastic syndromeKidney transplantationKorean Health Technology R&D Project, Ministry for Health & Welfare, Republic of KoreaHI14C3417Yang Chul Woo issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nAcute uric acid nephropathy is one of the causes of acute kidney injury (AKI). Acute uric acid nephropathy is most commonly caused by tumor lysis syndrome (TLS); however, it may also occur from rhabdomyolysis or other conditions [1, 2]. When significant cell lysis occurs, large quantities of nucleotides are quickly released and metabolized in the liver, causing an increase in the serum uric acid level to > 12 mg/dL. Increased renal excretion of uric acid causes supersaturation in the urine, while the formation of uric acid crystals leads to the obstruction of the tubule lumen [3, 4].\n\nTLS is usually caused by treatment of hematologic malignancies with high turnover rates, such as acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), or lymphoma [5], and is relatively rare in bone marrow failure syndromes, which shows the hypocellularity of the bone marrow [6, 7]. Moreover, TLS caused by antithymocyte globulin (ATG) administration has not been reported in kidney transplant (KT) recipients to date. Here, we report a unique case of acute uric acid nephropathy presumably caused by ATG treatment-related TLS in a KT recipient with acute rejection who was previously diagnosed with aplastic anemia (AA).\n\nCase presentation\nA 40-year-old woman who underwent kidney transplantation 5 years 6 months before presented to our emergency department with complaints of oliguria, generalized edema, and general weakness 6 days after receiving ATG treatment for acute T-cell-mediated rejection.\n\nShe was diagnosed with severe AA 8 years before on the basis of a bone marrow biopsy that revealed < 5% cellularity without cytogenetic abnormalities and with an inadequate response to ATG. Thus, she was managed conservatively with intermittent red blood cell and platelet transfusions without cyclosporine owing to concomitant chronic kidney disease. End-stage renal disease developed 7 years before, for which the patient had been receiving peritoneal dialysis (PD) for 1 year. She was transferred to our hospital for simultaneous kidney and hematopoietic stem cell transplantation. At that time, we planned a sequential transplantation (kidney transplantation followed by hematopoietic stem cell transplantation) with her mother as the donor. The ABO blood type was compatible, and two mismatched human leukocyte antigen (HLA) types were found. Panel reactive antibodies were 75% positive for class II. The donor-specific antibody was DR04, and the median fluorescence intensity was 1865. Rituximab (375 mg/m2) and basiliximab (20 mg) were administered as induction therapies. Tacrolimus, mycophenolate mofetil (MMF), and glucocorticoids were used for maintenance immunosuppression. However, MMF was changed to mizoribine after the patient experienced severe diarrhea and dyspepsia 3 years 6 months after receiving the KT.\n\nAfter kidney transplantation, the AA improved gradually without a hematopoietic stem cell transplantation. The complete blood cell count (CBC) improved with a hemoglobin (Hb) level of > 9 g/dL and platelet (PLT) count of > 50,000/μL, indicating that blood transfusion was unnecessary. The bone marrow biopsy findings improved 16 months after the kidney transplantation (Fig. 1). Graft function was also well-maintained; however, the serum creatinine (Cr) level increased gradually 5 years after kidney transplantation, reaching 2.41 mg/dL 5 years 5 months after transplantation. The graft biopsy revealed acute T-cell-mediated rejection type IA. We initially managed the patient with methylprednisolone pulse therapy (125 mg twice daily) for 5 days; however, her renal function deteriorated further after 1 month (Fig. 2). Thus, we administered ATG 1.5 mg/(kg·day) for 5 days. At that time, we pre-medicated the patient with methylprednisolone for 5 days, with 500 mg once and subsequently with 125 mg twice daily for the following 4 days.\nFig. 1 Bone marrow biopsy findings before and after the kidney transplantation. a Bone marrow biopsy findings before and (b) 16 months after kidney transplantation. The bone marrow cellularity of < 5% before the transplantation increased to 20% with normal hematopoietic differentiation. c Bone marrow biopsy karyotyping before and (d) 16 months after the kidney transplantation. Note the lack of cytogenetic abnormalities\n\nFig. 2 Laboratory findings before and after ATG administration and upon discharge. The uric acid level was remarkably increased after the ATG treatment for acute rejection, which suggests tumor lysis syndrome. Abbreviations: MP, methylprednisolone; ATG, antithymocyte globulin; Cr, creatinine; Ca, calcium; P, inorganic phosphorus; K, potassium\n\n\n\nOn the day of admission, the patient complained of general weakness and generalized edema and showed a pretibial pitting edema. Blood testing revealed high serum blood urea nitrogen and Cr levels with hyperuricemia, hyperphosphatemia, and hyperkalemia, consistent with TLS. Urinalysis revealed > 100 uric acid crystal particles, and the uric acid-to-Cr ratio was 1.06, which was consistent with acute uric acid nephropathy [8] (Table 1).\nTable 1 Laboratory findings at the emergency department at 6 days after antithymocyte globulin administration\n\nThe complete blood cell count and serum chemistry test findings\t\n WBC (× 103/μL)\t13.4\t\n Hb (g/dL)\t7.6\t\n PLT (×103/μL)\t38\t\n BUN (mg/dL)\t73.1\t\n Cr (mg/dL)\t5.58\t\n Uric acid (mg/dL)\t32.7\t\n Calcium (mg/dL)\t8.3\t\n Phosphorus (mg/dL)\t7.1\t\n Potassium (mEq/L)\t6.1\t\n Albumin (g/dL)\t2.6\t\n LDH (U/L)\t556\t\n CPK (U/L)\t8\t\nThe dipstick urinalysis and urine chemistry test findings\t\n Hematuria\t1+\t\n Proteinuria\t1+\t\n Uric acid crystal (/HPF)\t> 100\t\n Uric acid (mg/dL)\t46.4\t\n Cr (mg/dL)\t43.6\t\n Uric acid / Cr ratio\t1.06\t\nAbbreviations: WBC, white blood cell; Hb Hemoglobin; PLT Platelet; BUN Blood urea nitrogen; Cr Creatinine; LDH Lactate dehydrogenase; CPK Creatine phosphokinase; HPF High power field\n\n\n\nTwo hemodialysis sessions were completed because of oliguria (urine output, < 200 mL/day). After hemodialysis, the patient’s serum uric acid and Cr levels remained at 3.3 and 3.96 mg/dL, respectively, with a daily urine output of > 1500 mL, and she was discharged (Fig. 2). TLS was suspected to be the cause of the acute uric acid nephropathy; therefore, post-transplantation lymphoproliferative disorder was considered a possibility. Epstein-Barr virus was not detected, and the imaging studies showed no findings indicative of lymphoma. Thus, the patient was reevaluated for the underlying hematologic disease. Flow cytometry of the paroxysmal nocturnal hemoglobinuria (PNH) clones revealed a 2.9% glycophosphatidyl inositol (GPI)-deficient granulocyte and a 2.9% CD24-deficient granulocyte expansion, which suggest that either the AA transformed into myelodysplastic syndrome (MDS) or the original underlying disease was MDS. Unfortunately, the patient progressed to graft failure 2 months after discharge and resumed PD.\n\nDiscussion and conclusions\nThe present case demonstrates the occurrence of an extremely high increase in serum uric acid level (> 30 mg/dL) and AKI after ATG treatment in a KT recipient with underlying AA. We diagnosed the case as TLS based on the criteria for hyperuricemia, hyperphosphatemia, hyperkalemia, and AKI [9]. TLS usually presents within 7 days of cytotoxic chemotherapy [5] and most often occurs in hematologic malignancies with high turnover rates, such as AML and ALL, but is rarely reported in bone marrow failure syndromes such as AA and MDS [7, 9]. This is the first report of acute uric acid nephropathy presumably caused by ATG treatment-related TLS in a KT recipient with a previous diagnosis of AA.\n\nTLS development after ATG treatment is unusual. This case was characterized by a long, 8-year history of AA with gradual improvement after kidney transplantation. Thus, the underlying AA was considered the cause of the TLS. A case review revealed two interesting findings. First, the patient was HLA-DR15 positive. In previous studies, AA patients with HLA-DR15 positivity showed 8.53 times higher hematologic improvement with immunosuppressants and higher coexisting PNH and MDS rates than the negative group [10, 11]. Second, the patient had PNH clones (2.9% GPI- and 2.9% CD24-deficient granulocytes), which suggested subclinical PNH. These features were consistent with those of a previous report that subclinical PNH in MDS patients showed a high HLA-DR15 positivity rate (90.5%) and bone marrow hypocellularity (64.3%). In addition, these patients often have normal karyotypic morphologies (95.2%) and respond well to immunosuppressants (77.8%) [12], as observed in the bone marrow biopsy findings from our case (Fig. 1). All the findings showed the possibility that the patient in this report either originally had hypocellular MDS or a previously diagnosed AA that had transformed into another type of bone marrow failure syndrome owing to clonal evolution [13, 14].\n\nOne may argue that high-dose methylprednisolone rather than ATG is responsible for the TLS in this case. Indeed, the development of TLS after high-dose methylprednisolone administration in MDS was previously reported [7]. In the review of our case, the patient was administered high-dose methylprednisolone two times with a 1-month interval (acute rejection treatment and premedication for ATG). If the high-dose methylprednisolone administration was responsible for the TLS in our case, TLS should have occurred during the first administration of methylprednisolone for acute rejection treatment. Thus, we suggest ATG, rather than methylprednisolone, to be the cause of the TLS, and that the possible pathophysiology of the ATG therapy-related TLS in MDS is the presence of potentially chemosensitive hematologic malignant cells. This presumption may be supported by a previous report of rapid tumor cell lysis occurring after ATG therapy for Sezary syndrome (cutaneous T-cell lymphoma) [15].\n\nIn this case, mizoribine was used as a maintenance immunosuppressant. Previous studies reported that mizoribine might cause hyperuricemia in patients with renal dysfunction [16, 17]. Mizoribine use may have contributed to the extreme hyperuricemia in this case; however, despite continuing the mizoribine therapy after TLS event, hyperuricemia was not observed anymore. Thus, mizoribine was unlikely to be the main cause of acute uric acid nephropathy in this patient.\n\nThis report has some limitations. First, we could not confirm the hematologic disease because the patient was reluctant to undergo bone marrow biopsy after developing TLS. Therefore, whether the patient’s underlying hematologic disease was MDS or AML was unclear. However, the patient’s CBC over the next 2 years after TLS event showed no evidence of blasts in peripheral blood that suggested AML. Second, whether the initial diagnosis of AA should have been hypocellular MDS is uncertain. However, our findings suggest that AA is a type of bone marrow failure syndrome that may overlap with other diseases or transform into another disease via clonal evolution during the disease course.\n\nIn conclusion, this was a unique case of ATG treatment-related TLS in a KT recipient previously diagnosed with AA. Thus, transplant clinicians should be cautious of the fact that the clinical course of AA may be more diverse than once thought and it can cause TLS in KT recipients receiving ATG treatment.\n\nAbbreviations\nAAAplastic anemia\n\nAKIAcute kidney injury\n\nALLAcute lymphoid leukemia\n\nAMLAcute myeloid leukemia\n\nATGAntithymocyte globulin\n\nCBCComplete blood cell count\n\nCrCreatinine\n\nGPIGlycophosphatidyl inositol\n\nHbHemoglobin\n\nHLAHuman leukocyte antigen\n\nKTKidney transplant\n\nMDSMyelodysplastic syndrome\n\nMMFmycophenolate mofetil\n\nPDPeritoneal dialysis\n\nPLTPlatelet\n\nPNHParoxysmal nocturnal hemoglobinuria\n\nTLSTumor lysis syndrome\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nBHC and CWY cared the patient; YP collected data and drafted the manuscript with CWY. CWP and YSK discussed the case together. All authors read and approved the final manuscript.\n\nFunding\nThis research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT(2018M3A9E802151). This manuscript is a case report, researchers-led paper, with no specific participation by funders.\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nEthics approval and consent to participate\nThis case report was reviewed by the Institutional Review Board of Seoul St. Mary’s Hospital and it was approved by an ethics committee (KC19ZESE0576).\n\nConsent for publication\nWritten consent was obtained from the patient’s mother for publication of the study because the patient died at the time of writing the manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Ejaz AA Mu W Kang DH Roncal C Sautin YY Henderson G Could uric acid have a role in acute renal failure? Clin J Am Soc Nephrol 2007 2 1 16 21 10.2215/CJN.00350106 17699382 \n2. Moreau D Pharmacological treatment of acute renal failure in intensive care unit patients Contrib Nephrol 2005 147 161 173 15604615 \n3. Kim YG Huang XR Suga S Mazzali M Tang D Metz C Involvement of macrophage migration inhibitory factor (MIF) in experimental uric acid nephropathy Mol Med 2000 6 10 837 848 10.1007/BF03401822 11126199 \n4. Shimada M Johnson RJ May WS Jr Lingegowda V Sood P Nakagawa T A novel role for uric acid in acute kidney injury associated with tumour lysis syndrome Nephrol Dial Transplant 2009 24 10 2960 2964 10.1093/ndt/gfp330 19581334 \n5. Howard SC Jones DP Pui CH The tumor lysis syndrome N Engl J Med 2011 364 19 1844 1854 10.1056/NEJMra0904569 21561350 \n6. Feng Y Jiang T Wang L Hyperuricemia and acute kidney injury secondary to spontaneous tumor lysis syndrome in low risk myelodysplastic syndrome BMC Nephrol 2014 15 164 10.1186/1471-2369-15-164 25304761 \n7. Yang SS Chau T Dai MS Lin SH Steroid-induced tumor lysis syndrome in a patient with preleukemia Clin Nephrol 2003 59 3 201 205 10.5414/CNP59201 12653264 \n8. Kelton J Kelley WN Holmes EW A rapid method for the diagnosis of acute uric acid nephropathy Arch Intern Med 1978 138 4 612 615 10.1001/archinte.1978.03630280074023 637642 \n9. Cairo MS Bishop M Tumour lysis syndrome: new therapeutic strategies and classification Br J Haematol 2004 127 1 3 11 10.1111/j.1365-2141.2004.05094.x 15384972 \n10. Song EY Kang HJ Shin HY Ahn HS Kim I Yoon SS Association of human leukocyte antigen class II alleles with response to immunosuppressive therapy in Korean aplastic anemia patients Hum Immunol 2010 71 1 88 92 10.1016/j.humimm.2009.10.002 19819281 \n11. Saunthararajah Y Nakamura R Nam JM Robyn J Loberiza F Maciejewski JP HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome Blood 2002 100 5 1570 1574 10.1182/blood.V100.5.1570.h81702001570_1570_1574 12176872 \n12. Wang H Chuhjo T Yasue S Omine M Nakao S Clinical significance of a minor population of paroxysmal nocturnal hemoglobinuria-type cells in bone marrow failure syndrome Blood. 2002 100 12 3897 3902 10.1182/blood-2002-03-0799 12393738 \n13. Maciejewski JP Balasubramanian SK Clinical implications of somatic mutations in aplastic anemia and myelodysplastic syndrome in genomic age Hematology Am Soc Hematol Educ Program 2017 2017 1 66 72 10.1182/asheducation-2017.1.66 29222238 \n14. Afable MG 2nd Tiu RV Maciejewski JP Clonal evolution in aplastic anemia Hematology Am Soc Hematol Educ Program. 2011 2011 90 95 10.1182/asheducation-2011.1.90 22160018 \n15. Fisher RI Kubota TT Mandell GL Broder S Young RC Regression of a T-cell lymphoma after administration of antithymocyte globulin Ann Intern Med 1978 88 6 799 800 10.7326/0003-4819-88-6-799 149512 \n16. Shi Y Liu H Chen XG Shen ZY Hyperuricemia in living donor kidney transplantation patients during Mizoribine administration caused mainly by changes in kidney function Transplant Proc 2019 51 5 1392 1396 10.1016/j.transproceed.2019.01.133 31155176 \n17. Chen P Xu X Liu L Wu J Li J Fu Q Prediction of mizoribine pharmacokinetic parameters by serum creatinine in renal transplant recipients Eur J Clin Pharmacol 2019 75 3 363 369 10.1007/s00228-018-2584-4 30386911\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "21(1)",
"journal": "BMC nephrology",
"keywords": "Antithymocyte globulin; Aplastic anemia; Kidney transplantation; Myelodysplastic syndrome; Tumor lysis syndrome",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000741:Anemia, Aplastic; D000961:Antilymphocyte Serum; D000080983:Bone Marrow Failure Disorders; D005260:Female; D006084:Graft Rejection; D006801:Humans; D033461:Hyperuricemia; D007155:Immunologic Factors; D016030:Kidney Transplantation; D009190:Myelodysplastic Syndromes; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "251",
"pmc": null,
"pmid": "32615929",
"pubdate": "2020-07-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Acute kidney injury with extreme hyperuricemia after antithymocyte globulin treatment in a kidney transplant recipient with underlying aplastic anemia: a case report.",
"title_normalized": "acute kidney injury with extreme hyperuricemia after antithymocyte globulin treatment in a kidney transplant recipient with underlying aplastic anemia a case report"
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"abstract": "Considering the role played by the heat shock protein of 70 kDa (HSP70) in cancer, we characterized this protein and its major regulator, the heat shock factor 1 (HSF1), in chronic lymphocytic leukemia (CLL). We found both HSP70 and HSF1 overexpressed in CLL patients, correlated to poor prognosis and abnormally localized in the nucleus of leukemic B cells. The two proteins were strictly correlated each other and their levels decreased consensually in those patients responding to in vivo therapeutic regimens. HSP70 and HSF1 inhibition was proved to be effective in inducing a dose-dependent in vitro apoptosis of CLL B cells. Considering that HSF1 is finely regulated by kinases belonging to pathways triggered by rat sarcoma (RAS), we benefited from a previous proteomic study performed in CLL patients aiming to assess the activation/expression of key signaling proteins. We found that patients showing high levels of HSP70 also expressed high Akt-Ser473, thus activating HSF1. Inhibition of PI3K, which activates AKT, reduced the expression of HSF1 and HSP70. By contrast, HSP70-low patients displayed high activation of MEK1/2 and ERK1/2, known to negatively regulate HSF1. These data demonstrate that the HSP70 expression is regulated by the modulation of HSF1 activity through the activation of RAS-regulated pathways and suggest the HSP70/HSF1 interplay as an interesting target for antileukemic therapies. Finally, inhibition of PI3K, that activates AKT, reduced the expression of HSF1 and HSP70.",
"affiliations": "Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.;Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.;Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.;Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.;Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.;Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.;Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.;Department of Woman's and Child's Health, University of Padua, Padua, Italy.;Department of Woman's and Child's Health, University of Padua, Padua, Italy.;Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.;Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.;Department of Woman's and Child's Health, University of Padua, Padua, Italy.;Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.;Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.",
"authors": "Frezzato|Federica|F|0000-0001-7093-2493;Raggi|Flavia|F|;Martini|Veronica|V|;Severin|Filippo|F|0000-0001-8712-9656;Trimarco|Valentina|V|;Visentin|Andrea|A|;Scomazzon|Edoardo|E|;Accordi|Benedetta|B|;Bresolin|Silvia|S|;Piazza|Francesco|F|;Facco|Monica|M|;Basso|Giuseppe|G|;Semenzato|Gianpietro|G|;Trentin|Livio|L|",
"chemical_list": "D005419:Flavonoids; D044948:Flavonols; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D051057:Proto-Oncogene Proteins c-akt; D000225:Adenine; C017875:fisetin",
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"issue": "145(11)",
"journal": "International journal of cancer",
"keywords": "HSF1; HSP70; chronic lymphocytic leukemia; inhibition; signal transduction",
"medline_ta": "Int J Cancer",
"mesh_terms": "D000225:Adenine; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002467:Cell Nucleus; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids; D044948:Flavonols; D015972:Gene Expression Regulation, Neoplastic; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases; D010880:Piperidines; D011379:Prognosis; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D011743:Pyrimidines; D015398:Signal Transduction; D015854:Up-Regulation",
"nlm_unique_id": "0042124",
"other_id": null,
"pages": "3089-3100",
"pmc": null,
"pmid": "31044428",
"pubdate": "2019-12-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "HSP70/HSF1 axis, regulated via a PI3K/AKT pathway, is a druggable target in chronic lymphocytic leukemia.",
"title_normalized": "hsp70 hsf1 axis regulated via a pi3k akt pathway is a druggable target in chronic lymphocytic leukemia"
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"abstract": "BACKGROUND Cefepime-induced neurotoxicity has been described in intensive care units (ICUs) and neuro ICU settings, occurring in patients started on cefepime for management of severe infections and sepsis. Most cases occur within 1 to 10 days after starting the drug. We publish a case that occurred on the general medical ward of a patient who had been on cefepime therapy for 4 weeks prior to admission. The aim of this study was to improve the knowledge of this serious condition to general internists as our patient was being managed on the general medical ward. CASE REPORT A 72-year-old female on prolonged intravenous antibiotics for sacral and pelvic osteomyelitis presented with acute encephalopathy and aphasia in the setting of an acute kidney injury. Due to the acute focal neurologic deficit, she was initially admitted as a stroke alert. After a negative magnetic resonance imaging (MRI) of the brain, an electroencephalogram (EEG) was pursued and showed nonconvulsive status epilepticus (NCSE). NCSE was likely a result of cefepime therapy in the setting of an acute kidney injury. CONCLUSIONS Cefepime-induced neurotoxicity should be suspected in any patient on cefepime therapy who develops acute changes in mental status, myoclonus, or evidence of seizures. Risk factors for the disease include older age, renal dysfunction, critical illness, and inappropriate dosing based upon renal function. A high index of suspicion is required and delays in diagnosis are common as there are frequently multiple possible causes for altered mental status in systemically ill patients requiring treatment with broad-spectrum antibiotics.",
"affiliations": "Division of Hospital Medicine, Department of Medicine, Denver Health Medical Center, Denver, CO, USA.;Division of Hospital Medicine, Department of Medicine, Denver Health Medical Center, Denver, CO, USA.;Division of Hospital Medicine, Department of Medicine, Denver Health Medical Center, Denver, CO, USA.",
"authors": "Cunningham|John M|JM|;Sachs|Katherine V|KV|;Allyn|Rebecca|R|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D000077287:Levetiracetam; D000077723:Cefepime; D008140:Lorazepam",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.921643",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32147665\n10.12659/AJCR.921643\n921643\nArticles\nCefepime-Induced Neurotoxicity Presenting with Nonconvulsive Status Epilepticus Admitted as a Stroke Alert\nCunningham John M. EF12 Sachs Katherine V. EF12 Allyn Rebecca EF12 \n1 Division of Hospital Medicine, Department of Medicine, Denver Health MedicalCenter, Denver, CO, U.S.A.\n\n2 University of Colorado School of Medicine, Denver, CO, U.S.A.\nCorresponding Author: John M. Cunningham, e-mail: John.cunningham@dhha.orgAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n09 3 2020 \n21 e921643-1 e921643-5\n23 11 2019 06 1 2020 27 1 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 72-year-old\n\nFinal Diagnosis: Cefepime-induced neurotoxicity\n\nSymptoms: Aphasia\n\nMedication:—\n\nClinical Procedure: —\n\nSpecialty: General and Internal Medicine\n\nObjective:\nUnusual or unexpected effect of treatment\n\nBackground:\nCefepime-induced neurotoxicity has been described in intensive care units (ICUs) and neuro ICU settings, occurring in patients started on ce fepime for management of severe infections and sepsis. Most cases occur within 1 to 10 days after starting the drug. We publish a case that occurred on the general medical ward of a patient who had been on cefepime therapy for 4 weeks prior to admission. The aim of this study was to improve the knowledge of this serious condition to general internists as our patient was being managed on the general medical ward.\n\nCase Report:\nA 72-year-old female on prolonged intravenous antibiotics for sacral and pelvic osteomyelitis presented with acute encephalopathy and aphasia in the setting of an acute kidney injury. Due to the acute focal neurologic deficit, she was initially admitted as a stroke alert. After a negative magnetic resonance imaging (MRI) of the brain, an electroencephalogram (EEG) was pursued and showed nonconvulsive status epilepticus (NCSE). NCSE was likely a result of cefepime therapy in the setting of an acute kidney injury.\n\nConclusions:\nCefepime-induced neurotoxicity should be suspected in any patient on cefepime therapy who develops acute changes in mental status, myoclonus, or evidence of seizures. Risk factors for the disease include older age, renal dysfunction, critical illness, and inappropriate dosing based upon renal function. A high index of suspicion is required and delays in diagnosis are common as there are frequently multiple possible causes for altered mental status in systemically ill patients requiring treatment with broad-spectrum antibiotics.\n\nMeSH Keywords:\nAphasiaCephalosporinsEpilepsy, GeneralizedNeurotoxicity Syndromes\n==== Body\nBackground\nInitial use of broad-spectrum antibiotics has well documented uses in the Emergency Department and critical care setting in patients with severe sepsis and septic shock [1]. However, continuation of broad-spectrum antibiotics without appropriate antimicrobial stewardship can have severe consequences including antimicrobial resistance, nosocomial infections, increased costs, and severe side effects [2]. Neurologic complications of antibiotics are overall rare but well documented [3]. Challenges can include separating neurologic sequelae of the antibiotic from delirium due to worsening of the infection, metabolic abnormalities that develop due to the underlying illness, or other medications started during hospitalization. While using a prolonged course of antibiotics, it is important to both closely monitor renal and liver function which may affect drug pharmacokinetics and dosing. In addition, clinicians should be aware of the rare and dangerous complications of the drugs being prescribed.\n\nWe present a case of cefepime-induced neurotoxicity that was unique in our review of the literature. Most cases of cefepime-induced neurotoxicity begin within 1 to 10 days of starting the drug [4]. Our case started after 4 weeks of receiving intravenous cefepime for pelvic osteomyelitis. As a result, the initial sepsis and critical illness from the infection had already resolved. This patient presented with an acute encephalopathy and aphasia leading to an initial stroke evaluation in the emergency department. The negative stroke evaluation led to admission to the general medicine service for management of delirium and a possible urinary tract infection (UTI) based upon a positive urinalysis (UA). This resulted in delayed recognition of this serious condition. We aim to both describe characteristics of cefepime-induced neurotoxicity and to also describe clinical characteristics of nonconvulsive status epilepticus (NCSE) that the internist should be aware as a potential clue to cefepime toxicity.\n\nCase Report\nA 72-year-old female with a history of a stage IV sacral wound and pelvic osteomyelitis, insulin dependent diabetes, and a chronic indwelling Foley catheter presented to the emergency department with confusion and aphasia. She was sent from a nursing home with the report that she was no longer communicating verbally and was having difficulty following commands compared to an earlier assessment. It had been more than 4 hours since she had been observed at her baseline. The patient was staying in a nursing facility to receive intravenous antibiotics and rehabilitation for her osteomyelitis. Previously, she had been living independently in the community, completing her activities of daily living (ADLs) independently and had no prior history of dementia. Her blood glucose was 61 mg/dL prior to arrival and her mental status did not improve with dextrose. Her other past medical and surgical history included diabetes, hypertension, Roux-en-Y gastric bypass, and a prior history of coronary artery disease. Her medications included cefepime 2 grams intravenous every 8 hours and daptomycin 400 mg intravenous every 24 hours for ongoing treatment of pelvic osteomyelitis, insulin via an insulin pump, aspirin, prasugrel, pantoprazole, lisinopril, and metoprolol succinate.\n\nOn emergency department arrival, the patient was afebrile, pulse was 72 beats per minute, respiratory rate was 18 breaths per minute, blood pressure was 175/67 mmHg and oxygen saturation was 97% breathing on 2 L/minute by nasal cannula. Body weight was 77.2 kg. She was awake and moving all extremities spontaneously but was non-verbal. She would open and move her eyes spontaneously and to voice but could not consistently follow commands. Glasgow Coma Scale was 10 on admission (eye 4, verbal 2, motor 4). Neurologic examination was limited by cooperation which made it difficult to assess for motor strength, presence of pronator drift, and asterixis. The examination was positive for receptive and expressive aphasia. The patient was able to withdraw to painful stimuli in all extremities, reflexes were symmetric throughout, there was no clonus or Babinski’s sign, pupils were equally reactive and there was no facial droop. No convulsions or myoclonic jerks were noted. The cardiovascular and pulmonary examinations were normal. Abdominal examination revealed multiple well healed surgical scars but was otherwise benign.\n\nLaboratory tests on arrival were notable for an elevated serum creatinine of 1.2 mg/dL with a blood urea nitrogen (BUN) of 53 mg/dL when compared to baseline of 0.8 mg/dL. Using a modified Cockcroft-Gault equation to account for weight, the creatinine clearance was 45 mL/minute, however the true glomerular filtration rate (GFR) was likely lower given the presence of an acute kidney injury. Sodium, glucose, and other electrolytes were within normal limits. Complete blood count showed a normal white count 7.2 k/uL, chronic anemia with a hemoglobin of 11.2 g/dL and elevated platelets 541 k/uL. Urinalysis showed 3+ leukocytes. Aspartate aminotransferase (AST) was 75 U/L and alanine aminotransferase (ALT) was 90 U/L but the remainder of the liver function tests were normal. Thyroid function testing was normal, and a urine drug screen was negative. Given the presence of acute aphasia, we were concerned for a left hemispheric transient ischemic attack (TIA) or stroke. Computed tomography (CT) of the brain with angiography was normal and follow-up magnetic resonance imaging (MRI) did not show any evidence of acute stroke or abnormalities in the left frontal or temporal lobes. Lumbar puncture to evaluate for infectious encephalitis was not performed on admission due to patient’s inability to follow commands and need for procedural sedation to be coordinated with anesthesia.\n\nAt this time, the presumed diagnosis was acute delirium; however, the precipitating factor was unclear. Despite the abnormal urinalysis, acute infection became less likely given that the patient was afebrile with a normal white blood cell count and was already receiving broad spectrum antibiotics. Common metabolic abnormalities such as hypoglycemia and hyponatremia were ruled out. The patient was not on any sedating medications and there was no history of toxic ingestions or trauma. Cultures of the blood and urine were obtained, the patient was placed on delirium precautions and broad-spectrum antibiotics. After 24 hours of observation, the patient had made no improvement in her condition. She had been unable to take any oral food or fluids and her serum creatinine had increased to 1.9 mg/dL despite intravenous fluids and supportive care.\n\nAfter the standard workup for common metabolic and infectious etiologies of encephalopathy had been unrevealing, alternate etiologies for her condition were considered. The presentation of persistent aphasia and delirium in a patient being treated with cefepime in the setting of an acute kidney injury prompted consideration of cefepime-induced neurotoxicity. Cefepime was discontinued and additional testing with an EEG to evaluate for nonconvulsive status epilepticus (NCSE) was performed. EEG (Figure 1) revealed a bi-frontal predominant, 1.5 to 2.5 Hz rhythmic spike and wave pattern that occurred in the absence of observable tonic, clonic, or automotor behaviors. The patient received 2 doses of 2 mg intravenous lorazepam and a 1000 mg loading dose of intravenous levetiracetam. On continuous EEG monitoring, evidence of NCSE resolved within minutes of initial lorazepam administration subsequently showing intermittent normalization of the EEG. The initial EEG finding combined with both the EEG and clinical improvement after anticonvulsant administration met the Salzburg criteria for “definite NCSE” [5]. After resolution of NCSE, the patient had a GCS score of 15. She regained verbal function, was speaking in complete sentences and following commands. Her only deficit at this point was mild confusion and she was amnestic for how she presented to the hospital. Repeat EEG done the following morning showed bi-hemispheric slowing but with no further evidence of seizure. Following discontinuation of cefepime, there was no recurrence of NCSE or clinical seizures.\n\nDiscussion\nCefepime-induced neurotoxicity was first described in 1999 [6]. The most common clinical presentation is delirium (80%) but there is a spectrum of neurologic presentations with 40% presenting with myoclonus, 31% in NCSE, 11% with seizures, and 9% with aphasia [7]. Symptoms typically begin 1 to 10 days after starting cefepime [4]. The most common risk factors for development of this disorder include renal dysfunction (87%), older age, critical illness, and dosing not adjusted for renal function (50%) [6,7]. The pathophysiology is not well defined but is thought to be due to concentration dependent competitive gamma aminobutyric acid (GABA) antagonism induced by cefepime accumulation in the central nervous system (CNS) [6]. Diagnosis of cefepime-induced neurotoxicity requires either the temporal association of compatible neurologic symptoms after cefepime administration or if patients have clinical or EEG improvements after discontinuation of cefepime without another identified cause [8]. Prior reviews show that delays in diagnosis are common [9]. In our case, this was likely due to anchoring on more commonly seen diagnoses on the general medicine service.\n\nNonconvulsive status epilepticus is defined as a continuous state of seizures without convulsions, or multiple nonconvulsive seizures for more than 30 minutes without interictal full recovery. NCSE can present with multiple symptoms, none of which are specific to the disorder including: altered mental status (82%), lethargy or coma (22%), speech disturbances (15%), myoclonus (13%), and hallucinations (6%) [10]. However, the rapid onset of any of these without another explanation should lead to additional testing, including an EEG. In one study of patients admitted to an acute geriatric ward, 8 patients who were initially diagnosed as having a UTI causing altered mental status and who had not returned to their prior neurologic status were found to have NCSE on EEG [11]. In critically ill patients, the etiology of nonconvulsive seizures can be broad and include traumatic brain injury, CNS infection, anoxic brain injury, subarachnoid hemorrhage, toxic-metabolic disturbances, and sepsis [10,12]. History and physical, laboratory evaluation, and imaging did not reveal any of these alternate causes of NCSE in our patient. Cefepime concentrations that result in toxicity are not well defined, but the available literature suggests avoiding trough levels greater than 20 mg/L or steady state levels greater than 35 mg/L [13]. However, there is not a set level at which toxicity is diagnosed and levels are not required to make the diagnosis and therefore were not checked in this case.\n\nThe most critical component in management is early recognition that cefepime could be contributing to progressive confusion and delirium and to promptly discontinue the drug. Cessation of the drug alone results in clinical improvement in the majority of patients after a median of 2 days [6–8]. Those presenting with NCSE are likely to need additional anticonvulsant treatment. As for generalized convulsive status epilepticus, intravenous lorazepam is the first-line treatment. Second-line agents include phenytoin, valproic acid, and levetiracetam but these are less well studied in NCSE compared to other forms of seizure and epilepsy [10]. In some instances, dialysis may be needed to reduce cefepime concentrations [7]. In one review of cefepime-induced neurotoxicity, earlier recognition and diagnosis resulted in improved prognosis and neurologic recovery [8].\n\nConclusions\nWe presented a case of a 72-year-old female with a history of pelvic osteomyelitis treated with cefepime who presented with a developing acute kidney injury and acute encephalopathy with aphasia and was ultimately found to be in NCSE attributed to cefepime. Her acute kidney injury occurring during the 4th week of therapy was likely the precipitating factor that led to decreased renal clearance and incorrect cefepime dosing. Most literature on this topic is in critical care, infectious disease, and neurology journals. Due to the fact that this patient had chronic osteomyelitis and had a negative stroke evaluation in the Emergency Department, she was primarily being managed by the general medicine service. In many respects, this is a classic case with a rare presentation lurking amidst much more commonly seen diagnosis on general medical wards. Knowing the various and sometimes subtle manifestations of NCSE (i.e., altered mental status) combined with the common usage of cefepime, make having an understanding of this drug’s neurologic complications critical for the general internist. Patients on cefepime who experience progressive delirium, myoclonus, or speech disturbances without an alternative cause should promptly be considered for discontinuation of the drug and further evaluation with EEG.\n\nDepartment and Institution where work was done\n\nDenver Health Medical Center, Denver, CO, U.S.A.\n\nConflict of interests\n\nNone.\n\nFigure 1. Electroencephalogram (EEG). Continuous EEG monitoring was performed using video monitoring. The following (A–C) are 17 second frames. Electrodes were placed using the International 10–20 system of electrode placement. Low frequency filter 1 Hz, high frequency filter 70 Hz, sensitivity 7 uV. (A) Shows nonconvulsive status epilepticus (NCSE) characterized by 1.5–2.5 Hz rhythmic spike-wave pattern that was bifrontal predominant. (B) Continuous electroencephalogram (EEG) monitoring minutes after lorazepam showing interruption of the previous rhythmic spike-wave pattern. (C) Continuous electroencephalogram (EEG) monitoring after the second dose of lorazepam showing resolution of the epileptic discharges with now diffuse intermixed slowing.\n==== Refs\nReferences:\n1. Levy MM Evans LE Rhodes A The surviving sepsis campaign bundle: 2018 update Crit Care Med 2018 46 6 997 1000 29767636 \n2. Karanika S Paudel S Grigoras C Systematic review and meta-analysis of clinical and economic outcomes from the implementation of hospital-based antimicrobial stewardship programs Antimicrob Agents Chemother 2016 60 8 4840 52 27246783 \n3. Mattappalil A Mergenhagen KA Neurotoxicity with antimicrobials in the elderly: A review Clin Ther 2014 36 11 1489 511 25450476 \n4. Dakdouki GK Al-Awar GN Cefepime-induced encephalopathy Int J Infect Dis 2004 8 1 59 61 14690782 \n5. Krogstad MH Høgenhaven H Beier CP Krøigård T Nonconvulsive status epilepticus: Validating the Salzburg criteria against an expert EEG examiner J Clin Neurophysiol 2019 36 2 141 45 30585889 \n6. Payne LE Gagnon DJ Riker RR Cefepime-induced neurotoxicity: A systemic review Crit Care 2017 21 1 276 29137682 \n7. Appa AA Jain R Rakita RM Hakimian S Pottinger PS Characterizing cefepime neurotoxicity: A systematic review Open Forum Infect Dis 2017 4 4 oxf170 \n8. Li HT Lee CH Wu T Clinical, electroencephalographic features and prognosis factors of cefepime-induced neurotoxicity: A retrospective study Neurocrit Care 2019 31 2 329 37 30756319 \n9. Thabet F Al Maghrabi M Al Barraq A Tabarki B Cefepime-induced nonconvulsive status epilepticus: Case report and review Neurocrit Care 2009 10 3 347 51 19034700 \n10. Sutter R Semmlack S Kaplan PW Nonconvulsive status epilepticus in adults – insights into the invisible Nat Rev Neurol 2016 12 5 281 93 27063108 \n11. Shavit L Grenader T Galperin I Nonconvulsive status epilepticus in elderly a possible diagnostic pitfall Eur J Intern Med 2012 23 8 701 4 22884408 \n12. Oddo M Carrera E Claassen J Continuous electroencephalography in the Medical Intensive Crit Care Med 2009 37 6 2051 56 19384197 \n13. Huwyler T Lenggenhager L Abbas M Cefepime plasma concentrations and clinical toxicity: A retrospective cohort study Clin Microbiol Infect 2017 23 7 454 59 28111294\n\n",
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"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D001037:Aphasia; D001927:Brain Diseases; D000077723:Cefepime; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D008140:Lorazepam; D010019:Osteomyelitis; D013226:Status Epilepticus",
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"pubdate": "2020-03-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Cefepime-Induced Neurotoxicity Presenting with Nonconvulsive Status Epilepticus Admitted as a Stroke Alert.",
"title_normalized": "cefepime induced neurotoxicity presenting with nonconvulsive status epilepticus admitted as a stroke alert"
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"abstract": "We report a case of a 62-year-old man treated for Streptococcus pneumoniae meningitis by ceftriaxone and dexamethasone. After neurological improvement, neurological degradation by vasculitis occurred, despite effective concentrations of ceftriaxone in the serum and cerebrospinal fluid (CSF). S. pneumoniae with increased MICs to third-generation-cephalosporins (3GC) was isolated from the ventricular fluid 10 days after the isolation of the first strain. Isolate analysis showed that a mutation in the penicillin-binding protein 2X (PBP2X) has occurred under treatment.",
"affiliations": "Laboratoire de Microbiologie Clinique, Groupe Hospitalier Paris Saint-Joseph, Paris, France amizrahi@hpsj.fr.;EA 4043 Unité Bactéries Pathogènes et Santé, Université Paris-Saclay, Université Paris-Sud, Paris, France.;EA 4043 Unité Bactéries Pathogènes et Santé, Université Paris-Saclay, Université Paris-Sud, Paris, France.;Laboratoire de Microbiologie Clinique, Groupe Hospitalier Paris Saint-Joseph, Paris, France.;Equipe Mobile de Microbiologie Clinique, Groupe Hospitalier Paris Saint-Joseph, Paris, France.;Réanimation Polyvalente, Groupe Hospitalier Paris Saint-Joseph, Paris, France.;Réanimation NeuroChirurgicale, Fondation Ophtalmologique Adolphe de Rothschild, Paris, France.;Laboratoire de Microbiologie Clinique, Groupe Hospitalier Paris Saint-Joseph, Paris, France.;Laboratoire de Microbiologie Clinique, Groupe Hospitalier Paris Saint-Joseph, Paris, France.",
"authors": "Mizrahi|A|A|0000-0003-3135-5093;Marvaud|J C|JC|0000-0002-5490-0720;Pilmis|B|B|;Nguyen Van|J C|JC|;Couzigou|C|C|;Bruel|C|C|;Engrand|N|N|;Le Monnier|A|A|;Lambert|T|T|",
"chemical_list": "D002511:Cephalosporins; D046915:Penicillin-Binding Proteins; C072223:PBP 2x protein, Streptococcus; D002443:Ceftriaxone; D003907:Dexamethasone",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.01958-19",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0066-4804",
"issue": "64(3)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": "3GC resistance; Streptococcus pneumoniae; meningitis; meningitis-related delayed cerebral injury; penicillin-binding protein; treatment failure",
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D002443:Ceftriaxone; D002511:Cephalosporins; D003907:Dexamethasone; D006801:Humans; D008297:Male; D008586:Meningitis, Pneumococcal; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D046915:Penicillin-Binding Proteins; D013296:Streptococcus pneumoniae",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31712218",
"pubdate": "2020-02-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8161625;9767060;28203777;27062097;7425601;22103652;1406283;16426988;29746358",
"title": "Emergence of Ceftriaxone Resistance during a Case of Pneumococcal Meningitis with Fatal Evolution.",
"title_normalized": "emergence of ceftriaxone resistance during a case of pneumococcal meningitis with fatal evolution"
} | [
{
"companynumb": "FR-MYLANLABS-2020M1042172",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nPhase 3 trials have demonstrated a survival advantage for patients with optimally debulked epithelial ovarian cancer who received intravenous (IV) and intraperitoneal (IP) chemotherapy compared with IV therapy alone. This was despite a significant proportion of patients in the IV/IP arms not completing all 6 planned cycles. Our objective was to evaluate the prognostic significance of the number of IV/IP cycles administered.\n\n\nMETHODS\nData were analyzed for all patients with stage III to IV epithelial ovarian cancer who underwent optimal primary cytoreduction followed by 1 or more cycles of IV/IP chemotherapy from January 2005 to July 2011 at our institution. A landmark analysis was performed to associate progression-free survival (PFS) and overall survival (OS) with the number of IV/IP cycles given.\n\n\nRESULTS\nWe identified 201 patients; 26 (13%) received 1 to 2 cycles of IV/IP chemotherapy, 41 (20%) received 3 to 4 cycles, and 134 (67%) received 5 to 6 cycles. The 5-year PFS for patients who received 1 to 2, 3 to 4, and 5 to 6 cycles was 18%, 29%, and 17%, respectively. The 5-year OS for patients who received 1 to 2, 3 to 4, and 5 to 6 cycles was 44%, 54%, and 57%, respectively. There was no significant difference in PFS (P = 0.31) or OS (P = 0.14) between the 3 groups. The most common reason for discontinuing IV/IP therapy was treatment-related toxicity (77%). Postoperative complications were the most common reason for not initiating IV/IP therapy (42%) in patients who subsequently transitioned to it.\n\n\nCONCLUSIONS\nWe did not detect a significant survival difference between patients who received 1 to 2, 3 to 4, or 5 to 6 IV/IP chemotherapy cycles. Women may still derive a survival benefit if they receive fewer than 6 IV/IP cycles.",
"affiliations": "*Gynecology Service, Department of Surgery, †Department of Epidemiology and Biostatistics, and ‡Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; and §Weill Cornell Medical College, New York, NY.",
"authors": "Suidan|Rudy S|RS|;Zhou|Qin|Q|;Iasonos|Alexia|A|;O'Cearbhaill|Roisin E|RE|;Chi|Dennis S|DS|;Long Roche|Kara C|KC|;Tanner|Edward J|EJ|;Denesopolis|John|J|;Barakat|Richard R|RR|;Zivanovic|Oliver|O|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1097/IGC.0000000000000389",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1048-891X",
"issue": "25(4)",
"journal": "International journal of gynecological cancer : official journal of the International Gynecological Cancer Society",
"keywords": null,
"medline_ta": "Int J Gynecol Cancer",
"mesh_terms": "D018262:Adenocarcinoma, Clear Cell; D002288:Adenocarcinoma, Mucinous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D018284:Cystadenocarcinoma, Serous; D016889:Endometrial Neoplasms; D005185:Fallopian Tube Neoplasms; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms; D010534:Peritoneal Neoplasms; D011182:Postoperative Care; D011379:Prognosis; D015996:Survival Rate",
"nlm_unique_id": "9111626",
"other_id": null,
"pages": "599-606",
"pmc": null,
"pmid": "25664437",
"pubdate": "2015-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "18234300;17704411;19959211;22067389;22204724;22204725;22446622;23507546;23578540;24399786;10655437;11181662;11600607;11870167;12860964;16368440;8960474;15350354;16394300;19577277",
"title": "Prognostic significance of the number of postoperative intraperitoneal chemotherapy cycles for patients with advanced epithelial ovarian cancer.",
"title_normalized": "prognostic significance of the number of postoperative intraperitoneal chemotherapy cycles for patients with advanced epithelial ovarian cancer"
} | [
{
"companynumb": "US-ROCHE-1586526",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
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"drugadditional": null,
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{
"abstract": "Fibrous dysplasia (FD) is a skeletal disease caused by somatic activating mutations of the cyclic adenosine monophosphate (cAMP)-regulating protein, α-subunit of the Gs stimulatory protein (G(s) α). These mutations lead to replacement of normal bone by proliferative osteogenic precursors, resulting in deformity, fracture, and pain. Medical treatment has been ineffective in altering the disease course. Receptor activator of NF-κB ligand (RANKL) is a cell-surface protein involved in many cellular processes, including osteoclastogenesis, and is reported to be overexpressed in FD-like bone cells. Denosumab is a humanized monoclonal antibody to RANKL approved for treatment of osteoporosis and prevention of skeletal-related events from bone metastases. We present the case of a 9-year-old boy with severe FD who was treated with denosumab for a rapidly expanding femoral lesion. Immunohistochemical staining on a pretreatment bone biopsy specimen revealed marked RANKL expression. He was started on monthly denosumab, with an initial starting dose of 1 mg/kg and planned 0.25 mg/kg dose escalations every 3 months. Over 7 months of treatment he showed marked reduction in pain, bone turnover markers (BTMs), and tumor growth rate. Denosumab did not appear to impair healing of a femoral fracture that occurred while on treatment. With initiation of treatment he developed hypophosphatemia and secondary hyperparathyroidism, necessitating supplementation with phosphorus, calcium, and calcitriol. BTMs showed rapid and sustained suppression. With discontinuation there was rapid and dramatic rebound of BTMs with cross-linked C-telopeptide (reflecting osteoclast activity) exceeding pretreatment levels, accompanied by severe hypercalcemia. In this child, denosumab lead to dramatic reduction of FD expansion and FD-related bone pain. Denosumab was associated with clinically significant disturbances of mineral metabolism both while on treatment and after discontinuation. Denosumab treatment of FD warrants further study to confirm efficacy and determine potential morbidity, as well as to determine the mechanism of RANKL in the pathogenesis of FD and related bone marrow stromal cell diseases.",
"affiliations": "Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.",
"authors": "Boyce|Alison M|AM|;Chong|William H|WH|;Yao|Jack|J|;Gafni|Rachel I|RI|;Kelly|Marilyn H|MH|;Chamberlain|Christine E|CE|;Bassim|Carol|C|;Cherman|Natasha|N|;Ellsworth|Michelle|M|;Kasa-Vubu|Josephine Z|JZ|;Farley|Frances A|FA|;Molinolo|Alfredo A|AA|;Bhattacharyya|Nisan|N|;Collins|Michael T|MT|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053245:RANK Ligand; D000069448:Denosumab",
"country": "United States",
"delete": false,
"doi": "10.1002/jbmr.1603",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0884-0431",
"issue": "27(7)",
"journal": "Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research",
"keywords": null,
"medline_ta": "J Bone Miner Res",
"mesh_terms": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001706:Biopsy; D001859:Bone Neoplasms; D001842:Bone and Bones; D002462:Cell Membrane; D049109:Cell Proliferation; D002648:Child; D000069448:Denosumab; D005357:Fibrous Dysplasia of Bone; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D009362:Neoplasm Metastasis; D010024:Osteoporosis; D053245:RANK Ligand",
"nlm_unique_id": "8610640",
"other_id": null,
"pages": "1462-70",
"pmc": null,
"pmid": "22431375",
"pubdate": "2012-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "14557424;3720010;19874199;18489744;1609087;7375958;1944469;20881962;20697156;19524963;19455604;9950424;20841428;20493982;9403710;21289258;21353695;21060033;20533525;12952917;16495394;14647989;19016594;1594625;15647815;8352377;17228997;15177003;17229001;14555262;20881963;11341325;17964729;17195907;10365102;20149736;9541505",
"title": "Denosumab treatment for fibrous dysplasia.",
"title_normalized": "denosumab treatment for fibrous dysplasia"
} | [
{
"companynumb": "US-AMGEN-USASP2011045041",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Prone positioning has been used for decades to improve oxygenation in patients with acute respiratory distress syndrome. With the COVID-19 pandemic there has been a growing emphasis on the utilization of prone positioning for non-intubated patients as a means of preventing invasive ventilation and improving outcomes. In this case report, a patient is presented with acute hypoxemic respiratory failure in late pregnancy who experienced significant improvements in oxygenation with prone positioning. Additionally, the physiology of prone positioning is reviewed, as well as its mechanism and safety in pregnancy.",
"affiliations": "Department of Obstetrics and Gynecology, Rush University Medical Center, 1620 West Harrison Street, Chicago, IL 60612, United States of America.;Department of Obstetrics and Gynecology, Rush University Medical Center, 1620 West Harrison Street, Chicago, IL 60612, United States of America.;Chair of Maternal Fetal Medicine, Rush University Medical Center, 1620 West Harrison Street, Chicago, IL 60612, United States of America.;Department of Maternal Fetal Medicine, Rush University Medical Center, 1620 West Harrison Street, Chicago, IL 60612, United States of America.",
"authors": "Testani|Erica|E|;Twiehaus|Sara|S|;Waters|Thaddeus|T|;Pombar|Xavier|X|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.crwh.2021.e00339",
"fulltext": "\n==== Front\nCase Rep Womens Health\nCase Rep Womens Health\nCase Reports in Women's Health\n2214-9112\nElsevier\n\nS2214-9112(21)00057-6\n10.1016/j.crwh.2021.e00339\ne00339\nArticle\nConscious prone positioning in a pregnant patient with COVID-19 respiratory distress: A case report and review\nTestani Erica Erica_Testani@rush.edu\na⁎\nTwiehaus Sara Sara_J_Twiehaus@rush.edu\na\nWaters Thaddeus Thaddeus_Waters@rush.edu\nb\nPombar Xavier Xavier_Pombar@rush.edu\nc\na Department of Obstetrics and Gynecology, Rush University Medical Center, 1620 West Harrison Street, Chicago, IL 60612, United States of America\nb Chair of Maternal Fetal Medicine, Rush University Medical Center, 1620 West Harrison Street, Chicago, IL 60612, United States of America\nc Department of Maternal Fetal Medicine, Rush University Medical Center, 1620 West Harrison Street, Chicago, IL 60612, United States of America\n⁎ Corresponding author. Erica_Testani@rush.edu\n29 6 2021\n7 2021\n29 6 2021\n31 e0033910 6 2021\n24 6 2021\n25 6 2021\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/).\nProne positioning has been used for decades to improve oxygenation in patients with acute respiratory distress syndrome. With the COVID-19 pandemic there has been a growing emphasis on the utilization of prone positioning for non-intubated patients as a means of preventing invasive ventilation and improving outcomes. In this case report, a patient is presented with acute hypoxemic respiratory failure in late pregnancy who experienced significant improvements in oxygenation with prone positioning. Additionally, the physiology of prone positioning is reviewed, as well as its mechanism and safety in pregnancy.\n\nHighlights\n\n• Prone positioning is effective in improving oxygenation in non-intubated, gravid women with COVID-19 respiratory distress.\n\n• Patients may benefit from prone positioning if they require > 2 L/min O2 to maintain SaO2 ≥ 95%.\n\n• Prone positioning should be maintained for as long as tolerated but should be discontinued if there is no improvement within 15min.\n\nKeywords\n\nCOVID-19\nProne positioning\nPregnancy\n==== Body\n1 Introduction\n\nProne positioning has been utilized since the 1970s to treat severe hypoxia in patients with acute respiratory distress syndrome (ARDS) [1]. In 2011, Guérin et al. reported a significant decrease in 28-day and 90-day mortality with early application of prolonged prone positioning sessions in patients with severe ARDS [2]. More recently, 40 observational studies have demonstrated mild to dramatic improvements in oxygenation in patients placed in the prone position [3]. With the advent of the COVID-19 pandemic, a new focus has been placed on prone positioning as a method of improving oxygenation in a wide range of patients, from those intubated in the intensive care unit to conscious patients in the emergency department. In the case reported here, prone positioning was used in a non-intubated pregnant woman with hypoxic respiratory distress secondary to COVID-19 infection. The mechanism of prone positioning and its efficacy and safety in pregnancy are also reviewed.\n\n2 Case presentation\n\nA 25-year-old gravid woman (G1P0) at 28 6/7 weeks of gestation was transferred from a local hospital to the intensive care unit of a tertiary-care referral center for worsening hypoxic respiratory failure secondary to known COVID-19 pulmonary infection. The patient had a previous history of Graves' disease.\n\nOn admission the patient reported worsening nonproductive cough, exertional dyspnea, nausea and emesis for one week. Admission vitals were as follows: heart rate 115 beats per min, blood pressure 111/77 mmHg, temperature 105.2 °F, respiratory rate 20/min and spO2 95% on 10 L high-flow nasal canula. Chest radiography demonstrated bilateral patchy opacities worse in the right lower lobe. The admission ultrasound demonstrated a single, live fetus with an estimated fetal weight of 1271 g. A computed tomography scan was negative for pulmonary embolism. A transthoracic echocardiogram was within normal limits. Her laboratory results were significant for an elevated CRP, LDH, and d-dimer (Table 1). An arterial blood gas test was significant for hypoxemia (pH 7.47, PaCO2 24 mmHg, PaO2 67 mmHg, HCO3 17.7 mmol/L). Monitoring of the fetal heart rate demonstrated intermittent spontaneous decelerations. The obstetrical team decided to administer a 2-day course of betamethasone because of concerns for a premature delivery. Due to the severity of the findings, the patient received therapeutic heparin for anticoagulation and a 5-day course of remdesivir.Table 1 Maternal clinical laboratory values during hospital admission.\n\nTable 1\tReference Range\tHD1\tHD2\tHD3\tHD4\tHD5\tHD6\tHD7\t\nD-dimer (mg/L)\t0–0.6\t0.84\tNA\tNA\t0.45\t0.72\t1.94\t1.51\t\nCRP (mg/L)\t0–8.0\t114.6\t160.4\t93.6\t37.7\t14.8\t13.8\t11.5\t\nLDH (U/L)\t110–240\t291\t349\t287\t291\t384\t309\t267\t\nFerritin (ng/mL)\t12–260\t94\t119\t151\t132\tNA\tNA\tNA\t\nCPK (U/L)\t10–205\t113\t95\t52\t40\t44\t37\t33\t\nTroponin (ng/mL)\t0–0.4\t0.003\tNA\tNA\tNA\tNA\tNA\tNA\t\nWBC (x 109/L)\t3.4–10.0\t12.5\t12.8\t9.2\t7.7\t5.1\t6.0\t6.4\t\nHgb (g/dL)\t12.0–15.5\t10.0\t11.1\t11.9\t10.4\t10.3\t10.7\t9.9\t\nLymphocyte count (x 109/L)\t0.7–5.2\t0.97\t0.81\t1.05\t0.87\t1.36\t1.53\t1.99\t\nPLT (x 109/L)\t140–450\t244\t268\t272\t355\t375\t374\t321\t\nALT (U/L)\t10–40\t25\t26\t20\t19\t34\t66\t77\t\nAST (U/L)\t10–40\t37\t39\t29\t31\t57\t81\t82\t\nAbbreviations: NA, not assessed.\n\nOn hospital day 2, the patient made minimal improvements in oxygenation, with persistent exertional dyspnea, a respiratory rate of 30–38/min and an spO2 of 95%. She was weaned to 8 L/min high-flow nasal canula. On hospital day 3 the decision was made to place the patient in the prone position due to continued O2 requirement of 8 L/min high-flow nasal canula despite attempts to wean to a lower supplemental oxygen rate. Once in the prone position, the patient experienced an immediate rise of spO2 from 95% to 100%. The patient remained in the prone position for approximately 4 h, during which time she was weaned from 8 L/min to 3 L/min nasal canula with an spO2 of 98–100%.\n\nOn hospital day 4 the patient was again placed in the prone position due to continued dyspnea and intermittent desaturation to low 90s with exertion. She remained in the prone position for approximately 6 h, during which time she maintained an spO2 > 95% on 3 L/min of oxygen by nasal canula. By mid-day, the patient was deemed stable and transferred from the ICU to labor and delivery. There she remained in the prone position for an additional 6 h and eventually weaned to 2 L/min of oxygen by nasal canula. By hospital day 6 the patient was transitioned to room air and she was ultimately discharged on hospital day 7.\n\nThe patient's prenatal course following discharge from hospital was unremarkable. Ultimately, she underwent a spontaneous, term vaginal delivery of a healthy male infant with APGAR scores of 9/9. The infant was COVID-19 negative at the time of delivery.\n\nInformed consent was obtained for the publication of this case report.\n\n3 Discussion\n\nThis case demonstrates rapid improvement of oxygenation in a gravid woman with COVID-19 pneumonia after being placed in the prone position. Recently the Society for Maternal-Fetal Medicine has included prone positioning as a method for managing intubated and non-intubated pregnant patients with COVID-19 [4]. However, few studies have documented the safety and efficacy of placing pregnant patients in the prone position. Samanta et al. documented the case of a gravid woman at 31 weeks of gestation with hypoxic respiratory failure secondary to H1N1 infection who was intubated. The patient demonstrated significant improvement in oxygenation when she was placed in the prone position [5].\n\nThere have been recent reports assessing the feasibility and effectiveness of prone positioning in awake, non-intubated patients with COVID-19 [[6], [7], [8]]. The institution where this patient was cared for has developed guidelines on the implementation of prone positioning in the treatment of symptomatic, non-intubated pregnant patients (Table 2). The use of pregnancy-specific mattress or combination of pillows and sheets can be used to accommodate the gravid uterus.Table 2 Guideline for prone positioning.\n\nTable 2Timing\t\n1. Consider placing patient in a prone position if they require more than 2 L/min of O2 by nasal cannula to maintain SaO2 ≥ 95 and/or respiratory rate is >30 per minute for significant portion of time.\t\nDetermine Following Prior to Repositioning\t\n1. Ability to move independently in bed.\n2. Mental status\n3. Contraindications to placing in prone position.\t\nMonitoring and Positioning of the Patient\t\n1. EKG leads are placed if clinically indicated.\n2. SpO2 probe (continuous) should be placed on patient if not already in use.\n3. Place FHR straps in non-pressure point areas once the patient is in the prone position.\n4. Verify that oxygen supply tubing is unobstructed.\n5. Pillows may be placed under the hips, or under the legs, as needed, for comfort.\n6. Place call bell and phone within reach\n7. Consider rotating position every 4 h. However, the patient may remain in the prone position for as long as they can tolerate it if the patient desires.\n8. Increase O2 supply to patient whenever repositioning of the patient is performed.\t\nDocumentation\t\n1. SpO2\n\n2. Oxygen device and oxygen rate (L/min of O2)\n\n3. Respiratory rate\n\n4. Presence of dyspnea should be assessed before and after placing patient in the prone position.\n\n\t\nDiscontinuation of Prone Position\t\n1. No improvement within 10–15 min of being placed in the prone position.\n2. Worsening of hemodynamic decompensation once in the prone position\n3. If FHR is unable to me monitored, continue discontinuation on case-by-case basis.\n4. Significant improvement is maintained when placed back in the supine position.\t\nConsider Transfer to ICU\t\n1. Inability to maintain oxygen saturation ≥ 95% (PaSO2) with supplemental oxygen or rapidly escalating supplemental oxygen need.\n\n2. Hypotension (MAP <65) despite appropriate fluid resuscitation (~1000 mL bolus of crystalloid fluids).\n\n3. Evidence of new end-organ dysfunction (eg, altered mental status, renal insufficiency, hepatic insufficiency, cardiac dysfunction, etc.)\n\n\t\n\nPrior to prone positioning, assessment must be performed to determine if patients are appropriate candidates. Indications for this population include a requirement for more than 2 L/min O2 to maintain SaO2 ≥ 95% or a respiratory rate over 30 breaths per minute. Absolute contraindications are few but include spinal instability, facial or pelvic fractures, and an open abdominal wound. Relative contraindications include confusion or inability to independently change position. The patient should be positioned such that she is lying on the upper chest and pelvis, supported by their arms. Pillows and foam should be placed at pressure points to maximize patient comfort and avoid significant pressure on the gravid uterus. Continuous maternal and fetal monitoring, including EKG, continuous spO2 and fetal heart rate are required to identify any deterioration in clinical status. The goal is to maintain the patient in the prone position for as long as can be tolerated. Prone positioning should be discontinued if there is no improvement within 10–15 min of onset, worsening hemodynamic decompensation, if fetal heart rate is unable to be continuously monitored or if significant improvement is maintained when the patient is placed back in the supine position.\n\nProne positioning improves oxygenation by three principal mechanisms. The first is increased uniformity of ventilation. The prone position allows for more even distribution of ventilation and perfusion when compared to the supine position, leading to improved oxygenation throughout the entire lung. This theory has been corroborated by CT, nuclear, and inert gas experiments which measured aeration and ventilation in the prone position and demonstrated improved homogeneity [6,9,10].\n\nThe second mechanism relates to the alteration of lung mass. Lung shape is conical with more mass and alveoli located in the dorsal lung. In the supine position the dorsal lung is compressed by the weight of the abdominal cavity and mediastinum. In ARDS the increased edema and lung mass result in compression atelectasis of the dependent lung fields, i.e., the dorsal lung when supine. The prone position relieves the compression, resulting in recruitment of more alveoli in the dorsal lung for increased gas exchange [6,10,11].\n\nThe final mechanism relates to modifications of chest wall compliance. In normal thoracic anatomy, the dorsal chest wall is less compliant than the ventral chest. In the supine position, the chest wall compliance is determined by the relative elasticity of the ventral chest wall and the diaphragm since the dorsal thoracic cage is in contact with the bed and therefore restricted. In the prone position, overall chest compliance is decreased because it is dependent on the dorsal chest for many of its movements. Paradoxically this leads to improved distribution of gases toward the ventral and para-diaphragmatic lung, resulting in higher recruitment of these areas [7,11,12].\n\nPatients with ARDS respond differently to the prone position in terms of degree and timing of improvement. Oxygen response is typically measured by improvements in PaO2/FIO2. Observational studies have shown that the prevalence of improved oxygenation response varies from 54% to 100%, with 20% of studies reporting an improvement in less than 70% of patients [3]. Prone positioning is most effective in improving oxygenation when initiated early (i.e., less than 4 days from onset of ARDS) during the exudative phase, when congestive and compressive atelectasis are predominant features. Additionally, the time required for oxygenation to improve during prone positioning is highly variable. Typically, patients experience a rapid initial improvement (<30 min), followed by a period of slower improvement over a variable amount of time. Several studies have demonstrated a plateau in improvement at 2–4 h, while others observed that subjects required up to 24–48 h before oxygenation improved. Despite initial improvements, many studies have noted that this is often transient and diminishes over a variable amount of time when the patient is returned to the supine position [3].\n\nPlacing patients in the prone position for a long period is highly recommended in cases of severe ARDS, as characterized by a PaO2/FIO2 of 100 mmHg according to the Berlin criteria [6,10,11]. This recommendation is based on 5 major studies, including the 2013 PROSEVA trial, which demonstrated an absolute mortality risk reduction of 17% and a relative risk reduction of 50% in patients placed in the prone position for 17 h for approximately 4 days [2]. In moderate ARDS the pattern of response is less clear. However, previous meta-analyses suggest that prone positioning should be strongly considered in patients with moderate ARDS with an PaO2/FIO2 lower than 150 mmHg. Alternatively, long-term prone positioning has historically been discouraged in patients with mild ARDS (PaO2/FIO2 between 200 and 300 mmHg) as research fails to demonstrate any survival benefit [6,10,11].\n\nResearch on placing patients in the prone position has focused on intubated patients in the setting of an intensive care unit. However, amidst the COVID-19 pandemic new studies have examined the benefits of the prone position in non-intubated patients. Elharrar et al. examined 24 patients with acute hypoxemic respiratory failure. Of the 15 patients who tolerated the prone position, six demonstrated a mean increase in PaO2 of more than 20% from baseline. Three of the patients returned to baseline PaO2 after supination [7]. Sartini et al. performed a 1-day cross-sectional study that included 15 awake patients with mild or moderate ARDS. Patients received noninvasive ventilation with sessions of prone positioning. The patients had a median of 2 sessions of prone positioning for approximately 3 h. Oxygenation and respiratory rate improved while the patient was in the prone position. These improvements persisted for 1 h after each session in most patients [8].\n\nThis case report has demonstrated the success and safety of implementing prone positioning in non-intubated pregnant women. There have been case reports of using the prone position in pregnancy as well as position papers supporting its use in the management of pregnant patients infected with COVID-19 [4,[13], [14], [15], [16]]. However, evidence that placing patients with COVID-19 infections in the prone position reduces overall morbidity is lacking. Studies evaluating the potential impact of placing these patients in the prone position on maternal and fetal outcomes are needed.\n\nContributors\n\nErica Testani was involved in patient care and drafting the manuscript.\n\nSara Twiehaus was involved in patient care and drafting the manuscript.\n\nThaddeus Waters was involved in patient care and drafting the manuscript.\n\nXavier Pombar assisted in topic research and writing the manuscript.\n\nConflict of interest\n\nThe authors declare that they have no conflict of interest regarding the publication of this case report.\n\nFunding\n\nNo funding from an external source supported the publication of this case report.\n\nPatient consent\n\nObtained.\n\nProvenance and peer review\n\nThis case report was peer reviewed.\n==== Refs\nReferences\n\n1 Bryan A.C. Conference on the scientific basis of respiratory therapy. Pulmonary physiotherapy in the pediatric age group. Comments of a devil’s advocate Am. Rev. Respir. Dis. 110 6 Pt 2 1974 143 144 4440945\n2 Guérin C. Reignier J. Richard J.C. Prone positioning in severe acute respiratory distress syndrome N. Engl. J. Med. 368 23 2013 2159 2168 23688302\n3 Kallet R.H. A comprehensive review of prone position in ARDS Respir. Care 60 11 2015 1660 1687 26493592\n4 Society for Maternal Fetal Medicine Management Considerations for Pregnant Patients With COVID-19 January 7th, 2021\n5 Samanta S. Samanta S. Wig J. Baronia A.K. How safe is the prone position in acute respiratory distress syndrome at late pregnancy? Am. J. Emerg. Med. 32 6 2014 687.e1–687.e6873\n6 Coppo A. Bellani G. Winterton D. Feasibility and physiological effects of prone positioning in non-intubated patients with acute respiratory failure due to COVID-19 (PRON-COVID): a prospective cohort study Lancet Respir. Med. 8 2020 744 765 S2213–2600(20)30268-X 32569584\n7 Elharrar X. Trigui Y. Dols A.M. Use of prone positioning in nonintubated patients with COVID-19 and hypoxemic acute respiratory failure JAMA. 323 22 2020 2336 2338 32412581\n8 Sartini C. Tresoldi M. Scarpellini P. Respiratory parameters in patients with COVID-19 after using noninvasive ventilation in the prone position outside the intensive care unit JAMA. 323 22 2020 2338 2340 32412606\n9 Scholten E.L. Beitler J.R. Prisk G.K. Malhotra A. Treatment of ARDS with prone positioning Chest. 151 1 2017 215 224 27400909\n10 Gattinoni L. Taccone P. Carlesso E. Marini J.J. Prone position in acute respiratory distress syndrome. Rationale, indications, and limits Am. J. Respir. Crit. Care Med. 188 11 2013 1286 1293 24134414\n11 Gattinoni L. Busana M. Giosa L. Prone positioning in acute respiratory distress syndrome Semin. Respir. Crit. Care Med. 40 1 2019 94 100 31060091\n12 Malbouisson L.M. Busch C.J. Puybasset L. Lu Q. Cluzel P. Rouby J.J. Role of the heart in the loss of aeration characterizing lower lobes in acute respiratory distress syndrome. CT Scan ARDS Study Group Am. J. Respir. Crit. Care Med. 161 6 2000 2005 2012 10852781\n13 Schnettler W.T. Al Ahwel Y. Suhag A. Severe acute respiratory distress syndrome in coronavirus disease 2019-infected pregnancy: obstetric and intensive care considerations Am. J. Obstet. Gynecol. MFM 2 3 2020 100120 32363337\n14 Pierce-Williams R.A.M. Burd J. Felder L. Clinical course of severe and critical coronavirus disease 2019 in hospitalized pregnancies: a United States cohort study Am. J. Obstet. Gynecol. MFM 2 3 2020 100134 32391519\n15 Tolcher M.C. McKinney J.R. Eppes C.S. Prone positioning for pregnant women with hypoxemia due to coronavirus disease 2019 (COVID-19) Obstet. Gynecol. 136 2 2020 259 261 32516274\n16 Vogel J.P. Tendal B. Giles M. Clinical care of pregnant and postpartum women with COVID19: living recommendations from the National COVID-19 Clinical Evidence Taskforce Aust. N. Z. J. Obstet. Gynaecol. 60 6 2020 840 851 33119139\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-9112",
"issue": "31()",
"journal": "Case reports in women's health",
"keywords": "COVID-19; Pregnancy; Prone positioning",
"medline_ta": "Case Rep Womens Health",
"mesh_terms": null,
"nlm_unique_id": "101682122",
"other_id": null,
"pages": "e00339",
"pmc": null,
"pmid": "34221902",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "10852781;26493592;23688302;32412606;32516274;31060091;24412021;4440945;24134414;32363337;27400909;32412581;32569585;32391519;33119139",
"title": "Conscious prone positioning in a pregnant patient with COVID-19 respiratory distress: A case report and review.",
"title_normalized": "conscious prone positioning in a pregnant patient with covid 19 respiratory distress a case report and review"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2022-05773",
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BETAMETHASONE"
},
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{
"abstract": "BACKGROUND\nPsoriasis is a chronic inflammatory skin disorder that may be initiated or exacerbated by some drug intakes. Some of the most common medications known to trigger or worsen existing psoriasis include lithium, gold salts, beta blockers and antimalarials.\n\n\nCONCLUSIONS\nWe report an exceptional case of plantar psoriasis in a woman who was treated by olmesartan for 3 years.",
"affiliations": "National Center Chalbi Belkahia of Pharmacovigilance, 9 Avenue du Dr Zouhaier Essafi 1006, Tunis, Tunisia.;Faculty of Medicine, Research Unit: UR17ES12, University of Tunis El Manar, 15 Rue Djebel Lakhdhar, La Rabta, 1007, Tunis, Tunisia.;National Center Chalbi Belkahia of Pharmacovigilance, 9 Avenue du Dr Zouhaier Essafi 1006, Tunis, Tunisia.;National Center Chalbi Belkahia of Pharmacovigilance, 9 Avenue du Dr Zouhaier Essafi 1006, Tunis, Tunisia.;National Center Chalbi Belkahia of Pharmacovigilance, 9 Avenue du Dr Zouhaier Essafi 1006, Tunis, Tunisia.;National Center Chalbi Belkahia of Pharmacovigilance, 9 Avenue du Dr Zouhaier Essafi 1006, Tunis, Tunisia.",
"authors": "Charfi|Ons|O|;Badri|Talel|T|;Lakhoua|Ghozlane|G|;Kastalli|Sarrah|S|;El Aidli|Sihem|S|;Zaïem|Ahmed|A|",
"chemical_list": "D000959:Antihypertensive Agents; D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574886313666181017120629",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8863",
"issue": "14(1)",
"journal": "Current drug safety",
"keywords": "Psoriasis; antagonist receptors of angiotensin II; interleukin; olmesartan; sartans; side effect.",
"medline_ta": "Curr Drug Saf",
"mesh_terms": "D000959:Antihypertensive Agents; D005260:Female; D005528:Foot; D006801:Humans; D006973:Hypertension; D007093:Imidazoles; D008875:Middle Aged; D011565:Psoriasis; D013777:Tetrazoles",
"nlm_unique_id": "101270895",
"other_id": null,
"pages": "77-79",
"pmc": null,
"pmid": "30332975",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Plantar Psoriasis Associated with Olmesartan.",
"title_normalized": "plantar psoriasis associated with olmesartan"
} | [
{
"companynumb": "TN-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-114204",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE\\OLMESARTAN MEDOXOMI... |
{
"abstract": "Salmeterol, a long-acting β2-adrenergic receptor agonist used for the treatment of asthma and chronic obstructive pulmonary disease, has an adverse effects profile that is similar to that of salbutamol and other β2-agonists. We report a sympathomimetic syndrome with metabolic acidosis and hyperlactatemia after intentional inhalation of salmeterol in a suicide attempt. A 16-year-old female patient was admitted to the emergency department approximately 2 hours after having inhaled 60 puffs of a combination of salmeterol xinafoate 25 μg and fluticasone propionate 50 μg. She presented in an anxious state with complaints of palpitations and chest pain. The electrocardiogram demonstrated sinus tachycardia and ST-segment depression in the inferior and anterolateral leads. Laboratory findings showed hypokalemia, hypophosphatemia, and lactic acidosis. Cardiac troponin I and creatine kinase MB remained within the normal range. Treatment was supportive and included intravenous fluids and cautious potassium supplementation. The next day, electrocardiographic and laboratory findings returned to normal. We hypothesize that stimulation of β2-adrenergic receptors by inhalation of salmeterol caused this patient's lactic acidosis. This observation is consistent with the hypothesis that the hyperlactatemia observed during asthma attacks is due in part to the administration of high doses of β2-agonists. Salmeterol overdose by inhalation appears to be sufficient to cause lactic acidosis.",
"affiliations": "Departments of Emergency Medicine and 3Intensive Care, Universite´ Catholique de Louvain, Cliniques Universitaires St-Luc, Brussels, Belgium. alessandro.manara@uclouvain.be",
"authors": "Manara|Alessandro|A|;Hantson|Philippe|P|;Vanpee|Dominique|D|;Thys|Frédéric|F|",
"chemical_list": "D058666:Adrenergic beta-2 Receptor Agonists; D000730:Androstadienes; D001993:Bronchodilator Agents; D019344:Lactic Acid; D000068299:Salmeterol Xinafoate; D000068298:Fluticasone; D000420:Albuterol; D011188:Potassium",
"country": "England",
"delete": false,
"doi": "10.2310/8000.2012.110581",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1481-8035",
"issue": "14(6)",
"journal": "CJEM",
"keywords": null,
"medline_ta": "CJEM",
"mesh_terms": "D000140:Acidosis, Lactic; D000280:Administration, Inhalation; D000293:Adolescent; D058666:Adrenergic beta-2 Receptor Agonists; D000420:Albuterol; D000730:Androstadienes; D001249:Asthma; D001993:Bronchodilator Agents; D004334:Drug Administration Schedule; D062787:Drug Overdose; D004359:Drug Therapy, Combination; D005260:Female; D005440:Fluid Therapy; D000068298:Fluticasone; D006801:Humans; D033182:Intention; D019344:Lactic Acid; D011188:Potassium; D000068299:Salmeterol Xinafoate",
"nlm_unique_id": "100893237",
"other_id": null,
"pages": "378-81",
"pmc": null,
"pmid": "23131487",
"pubdate": "2012-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lactic acidosis following intentional overdose by inhalation of salmeterol and fluticasone.",
"title_normalized": "lactic acidosis following intentional overdose by inhalation of salmeterol and fluticasone"
} | [
{
"companynumb": "BE-GLAXOSMITHKLINE-B0848543A",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MONTELUKAST SODIUM"
},
"drugadditional": n... |
{
"abstract": "The case of a 58-year old female patient with epidermal growth factor-positive pulmonary adenocarcinoma treated with the tyrosine kinase inhibitor afatinib is reported. After several months of first-line therapy the patient developed severe hyponatremia and tumor reassessment revealed a progressive course of the lung cancer. Rebiopsy showed transformation of the tumor into small-cell lung cancer. Therapy with afatinib was stopped immediately and platin-based chemotherapy was started. This case shows that tumor transformation under tyrosine kinase inhibitor therapy from non-small-cell into small-cell lung cancer can occur in rare cases.",
"affiliations": "Klinik und Poliklinik für Innere Medizin II (Kardiologie, Pneumologie und Internistische Intensivmedizin), Universitätsklinikum Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Deutschland. myriam.koch@klinik.uni-regensburg.de.;Institut für Pathologie, Universitätsklinikum Regensburg, Regensburg, Deutschland.;Klinik und Poliklinik für Innere Medizin II (Kardiologie, Pneumologie und Internistische Intensivmedizin), Universitätsklinikum Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Deutschland.",
"authors": "Koch|M|M|;Utpatel|K|K|;Schulz|C|C|",
"chemical_list": "D004268:DNA-Binding Proteins; C504003:TTF1 protein, human; D014157:Transcription Factors; D000077602:Tolvaptan; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00108-017-0321-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-9554",
"issue": "59(4)",
"journal": "Der Internist",
"keywords": "Afatinib; Biopsy; Non-small-cell lung cancer; Small-cell lung cancer; Tyrosine kinase inhibitor",
"medline_ta": "Internist (Berl)",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000077716:Afatinib; D001706:Biopsy; D001999:Bronchoscopy; D002471:Cell Transformation, Neoplastic; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D018450:Disease Progression; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D007010:Hyponatremia; D008168:Lung; D008175:Lung Neoplasms; D008875:Middle Aged; D009367:Neoplasm Staging; D016609:Neoplasms, Second Primary; D010257:Paraneoplastic Syndromes; D055752:Small Cell Lung Carcinoma; D000077602:Tolvaptan; D014057:Tomography, X-Ray Computed; D014157:Transcription Factors",
"nlm_unique_id": "0264620",
"other_id": null,
"pages": "384-387",
"pmc": null,
"pmid": "28980030",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25846096;26070531;27652204",
"title": "Hyponatremia in a 58-year-old female patient with EGFR-positive lung adenocarcinoma.",
"title_normalized": "hyponatremia in a 58 year old female patient with egfr positive lung adenocarcinoma"
} | [
{
"companynumb": "DE-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-056227",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"dr... |
{
"abstract": "Carfilzomib, lenalidomide, and dexamethasone (KRd) have been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) based on ASPIRE clinical trial. However, its effectiveness and safety profile in real clinical practice should be further assessed. We retrospectively evaluated 130 consecutive RRMM patients treated with KRd between December 2015 and August 2018, in 9 Hematology Departments of Rete Ematologica Pugliese (REP). The overall response rate (ORR) was 79%, with 37% complete response (CR). Treatment with KRd led to an improvement in response regardless of age, refractory disease, and number and type of previous therapies. After a median follow-up of 18 months, median PFS was 24 months and 2y-PFS was 54%. PFS was longer in patients achieving a very good partial response (VGPR) with median PFS of 32.4 months. The relapses after prior autologous transplant (ASCT) positively impact median PFS. Several baseline disease characteristics, such as III ISS scoring or elevated LDH, and prior exposure to lenalidomide were found to negatively impact PFS. Primary refractory or relapsed myeloma patients have been treated with KRd as bridge to ASCT with a great benefit. Thirty-four (83%) reached at least a partial response after KRd and 21 (61%) performed ASCT. In transplanted patients, median PFS was not reached and 2y-PFS was 100%. The treatment discontinuation rate due to adverse events (AEs) was 18%, most commonly for lenalidomide (11%). Overall, in 10% of patients, a KRd dose reduction was necessary at least once (2.5% for carfilzomib and 8% for lenalidomide). The most frequent AE was neutropenia (44%) and anemia (41%). Infections occurred in 14% of patients. Cardiovascular events occurred in 11% of patients. Elderly patients have tolerated therapy very well, without additional side effects compared to younger patients, except for cardiac impairment. Our analysis confirmed that KRd is effective in RRMM patients. It is well tolerated and applicable to the majority of patients outside clinical trials. A longer PFS was shown in patients achieving VGPR, in those lenalidomide naïve and in patients relapsing after previous ASCT. Previous ASCT should not hamper the option for KRd therapy. Accordingly, KRd should be used as bridge regimen to ASCT with remarkable improvement in response and PFS rates. Further clinical studies are needed.",
"affiliations": "Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Via San Pio X, 73039, Tricase (LE), Italy. trialematologia@piafondazionepanico.it.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Via San Pio X, 73039, Tricase (LE), Italy.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Via San Pio X, 73039, Tricase (LE), Italy.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Via San Pio X, 73039, Tricase (LE), Italy.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Via San Pio X, 73039, Tricase (LE), Italy.;Department of Hematology and Bone Marrow Transplant, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.;Department of Hematology and Bone Marrow Transplant, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.;Department of Hematology, Hospital Perrino, Brindisi, Italy.;Department of Hematology, Hospital Perrino, Brindisi, Italy.;Department of Hematology, Hospital Vito Fazzi, Lecce, Italy.;Department of Hematology, Hospital Vito Fazzi, Lecce, Italy.;Department of Hematology and Bone Marrow Transplant, Hospital G.Moscati, Taranto, Italy.;Department of Hematology and Bone Marrow Transplant, Hospital G.Moscati, Taranto, Italy.;Department of Hematology, ASL BT, Barletta, Italy.;Department of Hematology, ASL BT, Barletta, Italy.;Department of Hematology and Bone Marrow Transplant, Policlinico, University of Bari, Bari, Italy.;Department of Hematology, Hospital University Riuniti, Foggia, Italy.;Department of Hematology and Bone Marrow Transplant, Osp Riuniti Ancona, University of Ancona, Ancona, Italy.;Department of Hematology and Bone Marrow Transplant, Policlinico, University of Bari, Bari, Italy.;Department of Hematology and Bone Marrow Transplant, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.;Department of Hematology, Hospital Perrino, Brindisi, Italy.;Department of Hematology, Hospital Vito Fazzi, Lecce, Italy.;Department of Hematology and Bone Marrow Transplant, Hospital G.Moscati, Taranto, Italy.;Department of Hematology, ASL BT, Barletta, Italy.;Department of Hematology, Hospital IRCCS Oncologico, Bari, Italy.;Department of Hematology, Hospital University Riuniti, Foggia, Italy.;Department of Hematology and Bone Marrow Transplant, Policlinico, University of Bari, Bari, Italy.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Via San Pio X, 73039, Tricase (LE), Italy.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Via San Pio X, 73039, Tricase (LE), Italy.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Via San Pio X, 73039, Tricase (LE), Italy.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Via San Pio X, 73039, Tricase (LE), Italy.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Via San Pio X, 73039, Tricase (LE), Italy.;Department of Hematology and Bone Marrow Transplant, Hospital Card. G. Panico, Via San Pio X, 73039, Tricase (LE), Italy.",
"authors": "Mele|Anna|A|http://orcid.org/0000-0003-1630-2495;Prete|Eleonora|E|;De Risi|Clara|C|;Citiso|Stefania|S|;Greco|Giuseppina|G|;Falcone|Antonietta Pia|AP|;Sanpaolo|Grazia|G|;Mele|Giuseppe|G|;Giannotta|Angela|A|;Vergine|Carolina|C|;Reddiconto|Giovanni|G|;Palazzo|Giulia|G|;Sabatelli|Sabrina|S|;Germano|Candida|C|;Miccolis|Rosanna|R|;Curci|Paola|P|;Palumbo|Gaetano|G|;Offidani|Massimo|M|;Rizzi|Rita|R|;Cascavilla|Nicola|N|;Pastore|Domenico|D|;Di Renzo|Nicola|N|;Mazza|Patrizio|P|;Tarantini|Giuseppe|G|;Guarini|Attilio|A|;Capalbo|Silvana|S|;Specchia|Giorgina|G|;Greco|Antonino|A|;De Francesco|Rosa|R|;Sibilla|Silvia|S|;Tonialini|Lorenzo|L|;Morciano|Maria Rosaria|MR|;Pavone|Vincenzo|V|",
"chemical_list": "D009842:Oligopeptides; C524865:carfilzomib; D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-020-04329-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "100(2)",
"journal": "Annals of hematology",
"keywords": "Autologous transplant and carfilzomib; Carfilzomib plus lenalidomide and dexamethasone (KRd); KRd as bridge therapy; Real-life experience; Relapsed/refractory multiple myeloma",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003907:Dexamethasone; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009842:Oligopeptides; D012008:Recurrence; D015996:Survival Rate",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "429-436",
"pmc": null,
"pmid": "33161453",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": "28125372",
"title": "Carfilzomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma patients: the real-life experience of Rete Ematologica Pugliese (REP).",
"title_normalized": "carfilzomib lenalidomide and dexamethasone in relapsed refractory multiple myeloma patients the real life experience of rete ematologica pugliese rep"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-286136",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARFILZOMIB"
},
"dru... |
{
"abstract": "Oral calcium salts are recommended for the treatment of chronic hypoparathyroidism (HypoPT), although dosimetry is variable between individual patients and clinicians. However, patient feedback on calcium salts can be negative, particularly due to gastrointestinal side effects and hypercalciuria-related complications. We begin with a clinical case of a HypoPT patient taking oral calcium salts following thyroid surgery, who requested support in reducing her dose of these with a view to stopping entirely. To evaluate her request, we first describe the usual treatment of HypoPT according to current guidance and then present data from (a) a case note review of a cohort of 24 HypoPT patients managed with a \"no calcium\" treatment regimen by single physician (b) a comprehensive online survey of HypoPT patients' treatment and experiences (n = 330). The case note review found that target range serum calcium levels were successfully achieved in all 24 patients since transitioning to a \"no calcium\" regimen, without any breakthrough hypocalcaemia-related symptoms, the development of new renal stones, the occurrence of calcium-related hospital admissions or the finding of significant hypercalciuria. The online survey identified 36% of HypoPT patients who continued to take activated vitamin D, but had discontinued calcium supplements. HypoPT patients not currently taking calcium reported a significantly lower prevalence of adverse effects and outcomes, both compared with their previous experiences whilst taking calcium and also compared with the 64% of patients who continued to take oral calcium. We conclude that, subject to methodological limitations, there are significant issues of tolerability arising from conventional calcium-based treatment regimens for patients with chronic HypoPT. For selected patients, it may be reasonable to facilitate a managed therapeutic transition to \"no calcium\" regimen, and we also propose that calcium-based regimes be prospectively evaluated against calcium-free (or calcium-low) alternatives.",
"affiliations": "Sunderland Royal Hospital, City Hospitals Sunderland NHS Foundation Trust, Sunderland, UK.;HypoPara UK, East Grinstead, West Sussex, UK.;The Royal Victoria Infirmary, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.;The Royal Victoria Infirmary, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.",
"authors": "Al-Sharefi|Ahmed|A|0000-0002-9777-5317;Glenister|Elizabeth|E|;Morris|Margaret|M|;Quinton|Richard|R|0000-0002-4842-8095",
"chemical_list": "D002136:Calcium, Dietary; D014807:Vitamin D",
"country": "England",
"delete": false,
"doi": "10.1111/cen.13955",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-0664",
"issue": "90(6)",
"journal": "Clinical endocrinology",
"keywords": "Calcium; Hypoparathyroidism; dyspepsia; hospitalization; patient survey; vitamin D",
"medline_ta": "Clin Endocrinol (Oxf)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002136:Calcium, Dietary; D015331:Cohort Studies; D019587:Dietary Supplements; D005260:Female; D006111:Graves Disease; D006801:Humans; D053565:Hypercalciuria; D006996:Hypocalcemia; D007011:Hypoparathyroidism; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011795:Surveys and Questionnaires; D006113:United Kingdom; D014807:Vitamin D",
"nlm_unique_id": "0346653",
"other_id": null,
"pages": "775-780",
"pmc": null,
"pmid": "30801749",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Is calcium supplementation always needed in patients with hypoparathyroidism?",
"title_normalized": "is calcium supplementation always needed in patients with hypoparathyroidism"
} | [
{
"companynumb": "GB-TEVA-2019-GB-1061125",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CALCIUM CARBONATE\\CALCIUM GLUBIONATE\\SODIUM BICARBONATE"
... |
{
"abstract": "BACKGROUND\nThe combination of a platinum agent and anthracycline has shown activity in pediatric solid tumors. This trial evaluated the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of oxaliplatin combined with doxorubicin in pediatric patients with recurrent solid tumors.\n\n\nMETHODS\nOxaliplatin was administered on day 1 and Doxorubicin on days 1-3 of each 21 day course. The study utilized a standard 3 + 3 dose escalation design. Three dose levels were evaluated: (1) oxaliplatin 105 mg/m(2) and doxorubicin 20 mg/m(2); (2) oxaliplatin 130 mg/m(2) and doxorubicin 20 mg/m(2); and (3) oxaliplatin 130 mg/m(2) and doxorubicin 25 mg/m(2). Dexrazoxane was administered at 10 times the doxorubicin dose prior to doxorubicin infusion.\n\n\nRESULTS\nSeventeen patients were enrolled. Dose level 1 was the determined MTD. Grade 2 cardiac DLT was seen in one of six patients on dose level 1, grade 4 thrombocytopenia in two of five patients on dose level 2, and one each of grade 2 cardiac and grade 4 thrombocytopenia in five patients on dose level 3. Cardiac DLT was only noted in patients with prior exposure to both anthracycline and chest radiation. No grade 3 or 4 neurotoxicity or mucositis was seen. Objective responses were noted in two patients with neuroblastoma and one each of mixed germ cell tumor, thymic neuroendocrine carcinoma, and nasopharyngeal carcinoma.\n\n\nCONCLUSIONS\nOxaliplatin 105 mg/m(2) on day 1 combined with doxorubicin 20 mg/m(2) days 1-3 was the MTD. This combination shows sufficient activity to justify further studies in select pediatric tumors.",
"affiliations": "Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California 90027, USA. lmascarenhas@chla.usc.edu",
"authors": "Mascarenhas|Leo|L|;Malogolowkin|Marcio|M|;Armenian|Saro H|SH|;Sposto|Richard|R|;Venkatramani|Rajkumar|R|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D004317:Doxorubicin",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.24471",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "60(7)",
"journal": "Pediatric blood & cancer",
"keywords": null,
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local; D009369:Neoplasms; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "1103-7",
"pmc": null,
"pmid": "23335436",
"pubdate": "2013-07",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "18726098;10944126;20658614;20308874;4362485;7763011;10519894;16314621;8951344;18467729;16239023;18802151;15774791;9193323;9220289;19117350;8261411;9609103;19170226;9541691;9647613;17538173;22473161;17019740;23024067;14501385;3335002;4371948",
"title": "A phase I study of oxaliplatin and doxorubicin in pediatric patients with relapsed or refractory extracranial non-hematopoietic solid tumors.",
"title_normalized": "a phase i study of oxaliplatin and doxorubicin in pediatric patients with relapsed or refractory extracranial non hematopoietic solid tumors"
} | [
{
"companynumb": "US-JNJFOC-20130607273",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "We report here the successful treatment of hepatitis C virus (HCV) transmitted from a nucleic acid testing (NAT)-negative donor to three HCV-negative recipients-two renal transplants and one liver. Both renal recipients underwent standard deceased-donor renal transplantation with immediate graft function. The liver recipient underwent standard orthotopic liver transplantation and recovered uneventfully. The donor was a 39-year-old woman with a terminal serum creatinine of 0.7 mg/dL. She was high risk for bloodborne pathogens, based upon a history of sexual contact with an HCV-infected male partner. Recipient 1 was a 45-year-old man with a history of end-stage renal disease from systemic lupus erythematosus. Recipient 2 was a 62-year-old woman with a history of end-stage renal disease caused by hypertension and insulin-dependent diabetes. Recipient 3 was a 42-year-old man with acute liver failure from acetaminophen ingestion. All recipients became HCV polymerase chain reaction positive on post-transplant follow-up. Both kidney recipients were treated with ledipasvir/sofosbuvir combination therapy for 12 weeks without side effects or rejection episodes. Recipient 3 was treated with ledipasvir/sofosbuvir in combination with ribavirin for 12 weeks without side effects. All patients achieved a sustained viral response at 12 weeks and are considered cured of HCV. The kidney recipients maintained good allograft function with a serum creatinine of 1.4 mg/dL and 1.0 mg/dL, respectively. Both renal recipients maintained normal liver function post treatment and did not develop any evidence of fibrosis. The liver recipient's liver function tests returned to normal without further incident. This case report provides evidence for the successful treatment of donor-derived HCV in transplant recipients.",
"affiliations": "Transplant Division, Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA.;Department of Surgery, Johns Hopkins University, Baltimore, MD, USA.;Division of Nephrology, Thomas Jefferson University, Philadelphia, PA, USA.;Transplant Division, Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA.;Division of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia, PA, USA.",
"authors": "Shah|Ashesh P|AP|;Cameron|Andrew|A|;Singh|Pooja|P|http://orcid.org/0000-0002-0253-2970;Frank|Adam M|AM|;Fenkel|Jonathan M|JM|",
"chemical_list": "D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; D012367:RNA, Viral; C586541:ledipasvir; D000082:Acetaminophen; D012254:Ribavirin; D000069474:Sofosbuvir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12660",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "19(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nDAA\n; \nHCV\n; PHS increased risk; donor-derived infections",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D064591:Allografts; D000998:Antiviral Agents; D001562:Benzimidazoles; D017848:Blood-Borne Pathogens; D056486:Chemical and Drug Induced Liver Injury; D018562:Disease Transmission, Infectious; D004359:Drug Therapy, Combination; D005260:Female; D005449:Fluorenes; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012367:RNA, Viral; D012254:Ribavirin; D000069474:Sofosbuvir; D066027:Transplant Recipients; D019562:Viral Load",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28060446",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of donor-derived hepatitis C viral infection in three transplant recipients from a donor at increased risk for bloodborne pathogens.",
"title_normalized": "successful treatment of donor derived hepatitis c viral infection in three transplant recipients from a donor at increased risk for bloodborne pathogens"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201704068",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMedication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of bisphosphonates and anti-resorptive drugs prescribed for treatment of severe osteoporosis, Paget's disease, and bone malignancies. The aim of this study was to evaluate the clinical outcome of a combined pharmacological and surgical management strategy on patients affected by MRONJ.\n\n\nMETHODS\nMedical records of patients with MRONJ were retrospectively examined to collect clinical history data. Conservative management included an initial pharmacological phase with antibiotics and antiseptic agents, followed by surgical intervention to remove bone sequestrum. Primary outcomes were healing from MRONJ at short term (1 month after surgery) and at longer term (3 months after surgery). Secondary outcome was assessment of recurrences at longer-term follow-up.\n\n\nRESULTS\nThirty-five patients were included in the study with mean follow-up of 23.86 ± 18.14 months. Seven cases showed spontaneous exfoliation of necrotic bone during pharmacological therapy, which in one case did not require any further intervention. At 1-month posttreatment, 31 out of 35 (88.5%) patients showed complete healing. The 25 patients who were followed for at least 3 months revealed a healing rate of 92% (23/25). Recurrences occurred in 7 patients out 23 who showed the long-term healing, after a mean period of 7.29 ± 3.45 months. The prognostic score (University of Connecticut Osteonecrosis Numerical Scale-UCONNS) was significantly higher (p = 0.01) in patients with poor healing as compared to complete healing, both at 1 and 3 months posttreatment.\n\n\nCONCLUSIONS\nA MRONJ treatment approach based on a combined pharmacological and surgical treatment strategy showed a high rate of healing and few recurrences.",
"affiliations": "Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, Università degli Studi di Milano, Via Beldiletto 1, 20142 Milan, Italy.;Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, Università degli Studi di Milano, Via Beldiletto 1, 20142 Milan, Italy.;Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, Università degli Studi di Milano, Via Beldiletto 1, 20142 Milan, Italy.;Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, Università degli Studi di Milano, Via Beldiletto 1, 20142 Milan, Italy.;Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, Università degli Studi di Milano, Via Beldiletto 1, 20142 Milan, Italy.;Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, Università degli Studi di Milano, Via Beldiletto 1, 20142 Milan, Italy.",
"authors": "Varoni|Elena M|EM|0000-0002-7287-2188;Lombardi|Niccolò|N|0000-0001-8261-1179;Villa|Giulio|G|;Pispero|Alberto|A|;Sardella|Andrea|A|0000-0003-4491-4640;Lodi|Giovanni|G|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/antibiotics10020195",
"fulltext": "\n==== Front\nAntibiotics (Basel)\nAntibiotics (Basel)\nantibiotics\nAntibiotics\n2079-6382\nMDPI\n\n10.3390/antibiotics10020195\nantibiotics-10-00195\nArticle\nConservative Management of Medication-Related Osteonecrosis of the Jaws (MRONJ): A Retrospective Cohort Study\nhttps://orcid.org/0000-0002-7287-2188\nVaroni Elena M. *\nhttps://orcid.org/0000-0001-8261-1179\nLombardi Niccolò\nVilla Giulio\nPispero Alberto\nhttps://orcid.org/0000-0003-4491-4640\nSardella Andrea\nLodi Giovanni\nRams Thomas E. Academic Editor\nDipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, Università degli Studi di Milano, Via Beldiletto 1, 20142 Milan, Italy; niccolo.lombardi@unimi.it (N.L.); giulio@tuilik.com (G.V.); pispero.alberto@gmail.com (A.P.); andrea.sardella@unimi.it (A.S.); giovanni.lodi@unimi.it (G.L.)\n* Correspondence: elena.varoni@unimi.it; Tel.: +39-0250319017\n17 2 2021\n2 2021\n10 2 19507 1 2021\n12 2 2021\n© 2021 by the authors.\n2021\nLicensee 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/).\nBackground: Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of bisphosphonates and anti-resorptive drugs prescribed for treatment of severe osteoporosis, Paget’s disease, and bone malignancies. The aim of this study was to evaluate the clinical outcome of a combined pharmacological and surgical management strategy on patients affected by MRONJ. Materials and methods: Medical records of patients with MRONJ were retrospectively examined to collect clinical history data. Conservative management included an initial pharmacological phase with antibiotics and antiseptic agents, followed by surgical intervention to remove bone sequestrum. Primary outcomes were healing from MRONJ at short term (1 month after surgery) and at longer term (3 months after surgery). Secondary outcome was assessment of recurrences at longer-term follow-up. Results: Thirty-five patients were included in the study with mean follow-up of 23.86 ± 18.14 months. Seven cases showed spontaneous exfoliation of necrotic bone during pharmacological therapy, which in one case did not require any further intervention. At 1-month posttreatment, 31 out of 35 (88.5%) patients showed complete healing. The 25 patients who were followed for at least 3 months revealed a healing rate of 92% (23/25). Recurrences occurred in 7 patients out 23 who showed the long-term healing, after a mean period of 7.29 ± 3.45 months. The prognostic score (University of Connecticut Osteonecrosis Numerical Scale—UCONNS) was significantly higher (p = 0.01) in patients with poor healing as compared to complete healing, both at 1 and 3 months posttreatment. Conclusions: A MRONJ treatment approach based on a combined pharmacological and surgical treatment strategy showed a high rate of healing and few recurrences.\n\nantibiotics\npentoxifylline\ntocopherol\nsequestrectomy\nosteonecrosis\n==== Body\n1. Introduction\n\nAs defined in 2014 by the American Association of Oral and Maxillofacial Surgeons (AAOMS), medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of bisphosphonates and of certain anti-resorptive drugs, such as denosumab [1], commonly prescribed for controlling severe osteoporosis, Paget’s disease, and bone malignancies, including multiple myeloma and bone metastases [1]. Bisphosphonates (BPs) are analogues of inorganic pyrophosphate, inhibiting the pyrophosphate-dependent enzymes mediating bone resorption [2]. Denosumab is a human monoclonal immunoglobulin G2 subclass (IgG2) that mimics the function of the endogenous molecule osteoprotegerin (OPG), reducing bone metabolism [3]. Even if the potential of BPs and denosumab to increase the survival in cancer patients remains uncertain, they significantly improve the quality of life, reducing bone pain in cases of advanced bone metastases [4].\n\nMRONJ pathogenesis is still largely unknown. A multi-factorial mechanism has been advocated, involving inhibition of angiogenesis and remodeling in bone tissue, presence of continuous micro-trauma within the oral cavity during eating and speaking, as well as a potential role and impact from oral mucosal inflammation or odontogenic infection [5,6].\n\nA recognized risk factor for MRONJ is high concentration and long duration of BP intake [7]. The frequency of MRONJ in cancer patients has been estimated, ranging from 1% to 15%, while the frequency in patients with osteoporosis, receiving much lower BP doses, is estimated around 0.001% to 0.01% [8,9]. Antiangiogenic agents, tyrosine kinase inhibitors, and monoclonal antibody-targeting Vascular-Endothelial Growth Factor (VEGF)—such as sunitimib, sorafefenib, bevacizumab—worsen the risk of MRONJ from 5- to 10-fold [1,10]. Since MRONJ negatively impacts patient quality of life [11], preventive dental treatment is strongly recommended [12].\n\nDespite no international consensus for treating MRONJ, a decisional tree to manage these patients requires consideration of the staging of MRONJ, patient age, gender, and systemic health [9]. The primary objective of treatment is to control symptoms, mainly pain, and to avoid progression of MRONJ to a more advanced stage [13]. Recent studies suggest a need for early surgical management to ensure complete removal of the necrotic bone following implementation of a first-line conservative nonsurgical approach with antibiotics, antimicrobials, and analgesics [13,14,15,16,17]. Surgery, in particular, is recommended in the presence of well-defined bone sequestra; in these cases, sequestrectomy or surgical debridement is needed. In patients with advanced stages who show a progression of the disease, or in cases of persistent pain and infection despite the medical therapy, an extensive resection is required [1,18,19]. Medical therapy itself appears to control pain and infection in about 50% of patients. A risk of sepsis, mainly in immunocompromised cancer patients, further justifies surgical intervention [19]. To date, MRONJ surgical therapy has been associated with variable percentages of success due to high heterogeneity among published studies [18,20,21].\n\nThe aim of this study was to retrospectively assess the success and recurrence rates in a cohort of MRONJ patients treated with a first pharmacological phase, intended for isolating gradually necrotic bone tissue and promoting sequestration, followed by a surgical intervention limiting the need for extensive resections.\n\n2. Materials and Methods\n\n2.1. Patients\n\n2.1.1. Study Design and Patient Population\n\nThis cohort study retrospectively analyzed clinical records of MRONJ patients referred to the Oral Medicine Unit (ASST Santi Paolo e Carlo) at University of Milan, from October 2008 to December 2017. MRONJ staging of affected patients was defined according to 2014 AAOMS criteria [1].\n\n2.1.2. Eligibility Criteria\n\nThe inclusion criteria included patients with MRONJ diagnosis at stage I–III, according to AAOMS criteria [1,21]. All patients were treated first with a pharmacological phase and then a surgical phase for bone sequestration removal [1,13,14,15,16,17]. The exclusion criteria were [1]: history of radiation therapy to the jaws or obvious metastatic disease to the jaws, no history of pharmacological therapy for MRONJ, and no history of surgical removal or spontaneous exfoliation of bone sequestra.\n\n2.1.3. Treatment Intervention\n\nEach patient received two phases of management, i.e., a pharmacological phase and a surgical phase. Based on previous literature [1,13,14,15,16,17], the protocol first used a medical management approach with antibiotics and local measures and followed the patients until there was evidence of bone sequester formation. At that point, surgical treatment of the MRONJ lesion site was performed with the goal of removing the sequestered bone and debridement of the site. In recurrent cases, the patients were referred to maxillofacial surgeons for major surgical procedures, i.e., bone resection.\n\nBased on previous studies [1,9,21,22], systemic antibiotics were prescribed to all study patients as follows: amoxicillin 3 g/day or clindamycin 1800 mg/day in cases of allergy to the penicillin; for the cases scarcely responsive to single-antibiotic therapy, metronidazole 500 mg/day for a maximum 14 days. Topical antiseptic therapy with 0.2% chlorhexidine mouthwash and 1% chlorhexidine gel, applied onto exposed necrotic bone, was also prescribed [17].\n\nSurgical intervention (sequestrectomy) was performed when sequestered bone was clinically or radiographically evident and not spontaneously exfoliated, following a MRONJ protocol previously recommended [23]. Briefly, one week before surgical intervention, each patient received the dental scaling, topical antiseptic therapy (0.2% chlorhexidine mouthwash, twice/day), and the prescription of antibiotic therapy started three days before the surgery (amoxicillin 3 g/day, or clindamycin 1800 mg/day in case of allergy to penicillin) [23]. On the day of surgical intervention, under local anesthesia, necrotic bone was removed via full-thickness mucoperiosteal flap, with minimal trauma to the cortical plates. Teeth involved in the necrotic area were extracted and a meticulous bone curettage and osteoplasty were performed until clear bleeding and white vital bone were clinically evident. The flap was closed with an absorbable suture via periosteal releasing incisions to achieve primary closure and in order to maximize the vascular supply to the area as well as to reduce risk of infection at the surgical site. Post-surgery, patients continued for two weeks the systemic antibiotic therapy and antiseptic mouthwash and also applied 1% chlorhexidine gel onto the surgical wound twice/day for at least 14 days. On the basis of the promising results obtained in previous studies [24,25,26], and under approval of the patient’s oncologist, pentoxifylline and tocopherol were also prescribed per os (pentoxifylline 800 mg/day + tocopherol 800 U.I./day), before and/or after surgical intervention, according to clinical case.\n\n2.2. Data Collection\n\nClinical and demographic data collected for each patient included, age, gender, systemic conditions, MRONJ stage [1], bisphosphonate, anti-resorptive, or anti-angiogenetic therapy (dosage, suspension, and duration), formation of bone sequestra, area of exposed bone (localization and size), date of surgical intervention(s), number of recurrences, and length of follow-up. The duration of therapy was determined as the period from the start of treatment to the first visit to our clinical unit. The prognostic score (University of Connecticut Osteonecrosis Numerical Scale—UCONNS) described by Landesberg was applied to find possible correlation between outcomes and patient systemic conditions [27]. UCONNS scores assess the individual prognosis based on known risk factors for MRONJ management failure, including systemic health conditions, comorbidities, type, and duration of bisphosphonate therapy and type of intervention performed. UCONNS scores were categorized as follow: 0–8, 9–16, 17–24, 25–32.\n\n2.3. Outcomes\n\n2.3.1. Primary Outcomes: Clinical Healing\n\nThe following criteria for clinical healing were used (adapted from [28]):Short-term healing—A patient was defined as “healed at short-term”, if presenting, for at least 1 month after sequestrectomy or spontaneous exfoliation of necrotic bone, the following clinical picture: absence of exposed necrotic bone or bone that can be probed through a fistula; absence of purulent drainage; absence of edema and stimulated pain; complete mucosal coverage of the surgical site.\n\nLong-term healing—A patient was defined as “healed at long-term”, if presenting the same clinical picture described above but lasting for at least 3 months after sequestrectomy or spontaneous exfoliation of bone sequestration.\n\nStable MRONJ clinical picture—A patient was “stable” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with the same stage seen during the first visit.\n\nWorsened MRONJ clinical picture—A patient was “worsened” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with a worse stage than found at first diagnosis.\n\nImproved MRONJ clinical picture—A patient was “improved” when, at the last available follow-up visit, showing clinical evidence of MRONJ, with a better stage than the one of the first diagnosis.\n\n2.3.2. Secondary Outcomes: Rate of MRONJ Recurrence\n\nRecurrence\n\nRecurrence was defined as the appearance of exposed necrotic bone or bone that could be probed through a fistula, in association or not with radiographic evidence of architectural bone changes persisting for more than 8 weeks in an area that had already demonstrated a long-term healing.\n\nAdverse Effects\n\nAny adverse events due to pharmacological and/or surgical phases were recorded when specified in the medical record.\n\n2.4. Statistical Analysis\n\nMeans and standard deviations were calculated for continuous variables; Kolmogorov–Smirnov test of normality was applied, and data were normally distributed. A t-test was used to compare means between two unpaired samples. For categorical variables, extracted data were expressed as percentages, and statistical analyses to identify significant differences were performed by applying the χ2 test using the online Graphpad statistical software (GraphPad Software®, San Diego, CA, USA). Statistical significance was set at p ≤ 0.05. Odds ratios were also calculated using the online MedCalc Software Ltd statistical software (MedCalc Software Ltd., Ostend, Belgium).\n\n2.5. Ethical Approval\n\nThe study was performed under ethical approval obtained from the Ethic Committee of the AO San Paolo (ID study approval: ONM-BF-Gene, 2016). Opt-out patient consent was obtained.\n\n2.6. STROBE Statement\n\nThe Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement was used to prepare this report.\n\n3. Results\n\nFrom an initial cohort of 45 patients with MRONJ, 35 subjects were included in the study. Ten patients were excluded for the following reasons: positive anamnesis for head and neck radiotherapy (n = 2), or insufficient clinical data (n = 8). Figure 1 provides a flow-chart of enrolled study patients, while patient demographic and clinical data are summarized in Table 1.\n\nMost of patients were women (χ2; p = 0.02); the mean age of study participants at the first examination was 73.46 ± 9.29 years (range 51–93 years) (Table 1). Six patients out thirty-five were undergoing anticancer chemotherapy at the moment of surgical intervention. Eight patients were receiving intravenous steroid treatment, which in four cases was associated with the chemotherapeutic regimen (Table 1). Six patients were also affected by diabetes.\n\nMost patients were treated with zoledronate and showed stage II MRONJ lesions (Table 1).\n\nThe mean follow-up of patients, from the first visit up to the last one available, was 23.86 ± 18.14 months (range: 1–74 months). The mean therapy with zoledronate lasted 34.29 ± 33.42 months; in some cases, the drug was suspended for a mean period of 8.53 ± 20.21 months. The mean duration of alendronate therapy was longer (79.42 ± 63.33 months), with a mean suspension period, when occurring, of 13.15 ± 19.58 months. The mean duration of the therapy with denosumab was shorter, lasting 15 ± 7.94 months, with a mean suspension time of 0.8 ± 1.1 months (Table 2).\n\nThe pharmacological phase involved the use of topical chlorhexidine and systemic amoxicillin, with 11 patients also receiving metronidazole. In nine patients (25.71%), the supportive pharmacological therapy for MRONJ included also pentoxifylline and tocopherol (mean period of administration 3.81 ± 2.46 months).\n\nSeven cases showed spontaneous exfoliation of necrotic bone. In four cases, the exfoliation occurred during the pharmacological phase: in one case, the sequestrum was completely exfoliated not requiring any further intervention, while in three patients the sequestra were partially exfoliated, requiring the further surgical intervention at the same site. In the other three patients, a spontaneous exfoliation of an additional bone sequestrum followed sequestrectomy.\n\nFifty-seven interventions of sequestrectomy were performed. Eighteen patients received a single surgical intervention, while four patients underwent two interventions in two different sites affected by MRONJ. In five subjects, the interventions were more than two; one patient required five interventions at the same site.\n\nFigure 2 describes a clinical case where antibiotic administration gradually resulted in the isolation of bone sequestrum from the surrounding healthy bone.\n\nFigure 3A–F describes the surgical intervention for bone sequestrum removal in a patient who developed MRONJ after zolendronate intake for oncological reasons (metastases of breast carcinoma).\n\n3.1. Primary Outcomes\n\n3.1.1. Short-Term Healing\n\nAt 1-month post-surgery, 31 out 35 (88.57%) patients showed complete healing. The four not-healed cases were MRONJ stage II: in two cases the picture was stable at last follow-up, while the other two demonstrated a worsening of their conditions. These four patients received zolendronate (in one case alternating to denosumab) for oncological reasons for a mean period of 18.66 ± 4.72 months (range 17–60 months). Two of them had suspended the drug for 10 and 13 months. The mean UCONNS prognostic score was 15.83 ± 7.24 in healed patients, 25 ± 4.08 in not-healed patients (t-test, p = 0.01). Figure 4 describes the short-term healing outcomes depending on UCONNS score.\n\n3.1.2. Long-Term Healing\n\nTwenty-five patients had long-term follow-up (at least 3 months), while the other ten patients, including two patients who did not heal at short-term, were lost prior to further follow-up. In the 25 patients, the mean follow-up was 27.28 ± 15.37 months from the first visit. Twenty-three out 25 (92%) showed complete healing of the surgical site for at least 3 months after surgery (Figure 5). Two patients were not healed at either short-term or long-term follow-up. One of them showed a stable MRONJ lesion in the posterior maxilla, while the other patient with MRONJ at the mandible showed a worsening clinical picture. This patient was referred to maxillofacial surgeons for major surgery. Both not-healed patients had MRONJ stage II and received zoledronate for oncological reasons, respectively for 24 and 17 months. One of the patients was under current zoledronate treatment (in addition to chemotherapy), while the other patient had suspended the drug 13 months before. The mean UCONNS prognostic score was 16.56 ± 7.63 in healed patients, as compared to 22.5 ± 0.7 in not-healed patients (t-test, p = 0.001).\n\nTable 3 reports healing outcomes at long term in patients who received also pentoxifylline and tocopherol therapy.\n\n3.2. Secondary Outcomes\n\n3.2.1. Recurrences\n\nRecurrences were recorded in seven patients out 23 (30.4%) who showed long-term healing: two were stage I, four at stage II, and one was at stage III. The recurrences occurred on average 7.29 ± 3.45 months after surgical intervention. Five out of seven patients who showed recurrences were receiving zoledronate for a mean period of 37.2 ± 24.47 months, while the remaining two patients were under therapy with alendronate for a mean period of 84 ± 16.97 months (Odds Ratio—OR:1.81; 95% CI: 0.27 to 11.86; p = 0.53). Recurrence in the oncological group occurred in five out 15 healed patients, while considering the osteoporotic group in 2 out 8 healed patients (OR 1. 50; 95% CI: 0.21 to 10.30; p = 0.68) (Figure 6).\n\n3.2.2. Adverse Events\n\nNo adverse events were reported, except for one case of spontaneous bleeding from the exposed necrotic bone, which occurred soon after the start of pentoxifylline and tocopherol therapy.\n\n4. Discussion\n\nMRONJ is a debilitating condition that more frequently affects females, the elderly, and persons treated for oncological reasons [18,20,28]. Although this complication has important clinical implications for dental practitioners—who need to know the correct management of a patient under anti-resorptive therapy—recent studies highlighted a lack of knowledge among dentists and dental students [29,30,31].\n\nThese findings support that, following a combined pharmacological and surgical conservative approach, most patients experience a complete healing. The UCONNS prognostic score was significantly higher in patients with poor healing as compared to those with complete healing in lesions. This conservative approach of MRONJ management was based on previous study outcomes [1,9,21,22] and included systemic antibiotics as well as antiseptic therapy with 0.2% chlorhexidine mouthwash and 1% chlorhexidine gel applied onto exposed necrotic bone [17].\n\nTreatment of MRONJ patients remains challenging, and therapeutic options vary from pharmacological supportive approach with antibiotics and antiseptics to extensive surgical resection of necrotic bone. According to previous studies [14,18,20,32,33], an early surgical approach with appropriate resection margins and primary wound closure can ensure a better surgical outcome (mucosal healing without signs of infection) stage improvement at 6 months, with mucosal and radiographic healing evident at one-year posttreatment. Since pharmacological therapy alone rarely leads to lesion healing even at stage I [16], Khan and colleagues [9], in their systematic review, recommended surgical resection with tension-free primary closure.\n\nIn our experience, pharmacological management of MRONJ lesions seems to promote progressive isolation of the bone sequestrum, enabling minimally invasive surgical intervention, with a potentially higher rate of long-term success than major surgical resection. Progressive isolation of necrotic bone throughout the preliminary pharmacologic phase allows removal of necrotic tissue without undue sacrifice of healthy bone.\n\nConsistent with previous research findings on conservative management of MRONJ [16,17,21], a high healing rate was achieved in the present study, although the study sample size was small. Importantly, UCONNS scores were confirmed to play a significant role in influencing treatment outcomes. Indeed, similar to a proposed cut-off value of UCONNS scores ≥ 15 to identify a higher rate of therapeutic failure [34], we found that all non-healed (both stable and worse) patients had a UCONNS score beyond 17.\n\nThe rate of recurrence after 3-month healing (30.4%), in the present study, appeared similar to that reported by Mucke and colleagues (28.7%), although they performed only surgical debridement in most of their patients [32]. However, due to methodological heterogeneity, a direct comparison among studies remains still complicated, considering that recurrence may occur after several months and that a too short follow-up period may bias the findings.\n\nThe additional use of pentoxifylline and tocopherol in treatment of MRONJ lesions is worth further investigation. In this study, most patients healed without major adverse side effects. Only one patient experienced bleeding at the start of pentoxifylline and tocopherol therapy. The Italian drug agency (AIFA) [35] warned of excessive bleeding among patients receiving anticoagulants, thrombolytic agents, and inhibitors of platelet aggregation who simultaneously are administered pentoxifylline and tocopherol. In our study the patient who developed spontaneous bleeding was not under treatment with any of these drugs.\n\nThe main limitation of this retrospective study is the use of medical records not specifically designed for the aim of the study. Thus, collected data might be limited in scope, making identification of potential confounding factors difficult, and making patient inclusion into the study prone to selection bias. Further limitations include varying lengths of follow-up of patients and varying patient compliance with the pharmacological protocol, along with the lack of calibration among the oral surgeons who performed the interventions and a lack of standardization in data collection. The retrospective design also predisposes the study to numerous threats to external validity, which limits interpretation and generalizability of the results (such as single-group threat, i.e., the lack of a comparison and/or control groups, and historical threat, where other events, different from the intervention under investigation, can affect the outcomes) [36].\n\n5. Conclusions\n\nAn initial pharmacological phase based on antibiotic and antiseptic agents is useful to gradually isolate bone sequestration in MRONJ patients and facilitate a subsequent surgical phase. This approach is particularly advisable for treatment of stages I and II of MRONJ. UCONNS-related prognostic factors play a relevant role in determining the success of MRONJ therapy.\n\nAuthor Contributions\n\nConceptualization, G.L. and E.M.V.; methodology, E.M.V., G.L. and N.L.; validation, G.L. and A.S.; formal analysis, G.L. and E.M.V.; investigation, N.L., A.P. and G.V.; data curation, N.L., G.V. and A.P.; writing—original draft preparation, G.V. and E.M.V.; writing—review and editing, N.L. and G.L.; supervision, G.L. and A.S. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of AO San Paolo (ID protocol approval: ONM-BF-Gene, 2016).\n\nInformed Consent Statement\n\nThis study is retrospective study. Opt-out patient consent was obtained.\n\nData Availability Statement\n\nThe data presented in this study are available on request from the corresponding author.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 Flow diagram of enrolled patients.\n\nFigure 2 Clinical case of MRONJ localized in left mandible. (A) Cone beam computed tomography (CBCT) images, sagittal and frontal views, showing isolation of mandibular bone sequestration following antibiotic and topical antiseptic therapy (red arrows indicate the bone sequestrum). (B) Necrotic bone sequestration, resulting from the surgical intervention.\n\nFigure 3 Clinical case of MRONJ localized in the upper maxilla. (A) Cone beam computed tomography (CBCT) images, frontal and sagittal views, showing maxillary bone sequestration (red arrows indicate the bone sequestrum). (B) Intraoral clinical view showing the presence of fistula, which demonstrates the presence of infection. (C) Necrotic bone sequestrum removal, after the opening of the surgical flap (mid-crestal incision on the alveolar crest of the edentulous area). (D) The necrotic bone was completely removed until reaching the healthy bone tissue; bone curettage and osteoplasty were performed until vital bone was clinically observed. (E) Primary closure via periosteal releasing incisions using absorbable suture. (F) Follow-up after 3 months from the surgical intervention showing a complete tissue healing.\n\nFigure 4 Comparison of the short-term healing outcomes depending on University of Connecticut Osteonecrosis Numerical Scale (UCONNS) score.\n\nFigure 5 Comparison of the long-term healing outcomes depending on UCONNS score.\n\nFigure 6 Comparison of long-term healing and recurrence in oncological and osteoporotic group.\n\nantibiotics-10-00195-t001_Table 1 Table 1 Demographic and clinical data concerning patient gender, age, comorbidities, concomitant cancer therapies, stage, and localization of medication-related osteonecrosis of the jaw (MRONJ) (n = 35).\n\nDemographic and Clinical Data\tNumber of Patients (%)\t\nGender\t\t\n-Male\t11 (31.4%)\t\n-Female\t24 (68.6%) *\t\nAge, years\tYears\t\nRange\t51–93\t\nMean, SD\t73.46 ± 9.29\t\nConcomitant cancer therapies\t\t\n-Steroids\t4 (11.4%)\t\n-Chemotherapy\t6 (17.1%)\t\n-Steroids and Chemotherapy\t4 (11.4%)\t\n-No steroids, No Chemotherapy\t21 (60%)\t\nPrimary disease requiring anti-resorptive drugs\t\t\n-Breast cancer\t10 (28.6%)\t\n-Prostate cancer\t4 (11.4%)\t\n-Multiple myeloma\t7 (20%)\t\n-Osteoporosis\t14 (40%)\t\nType of drug associated with MRONJ\t\t\nZolendronate\t17 (48.5%) *\t\nAlendronate\t9 (25.7%)\t\nDenosumab\t2 (5.7%)\t\nAlendronate + Denosumab\t2 (5.7%)\t\nAlendronate + Risendronate\t1(2.9%)\t\nAlendronate + Zolendronate\t1(2.9%)\t\nAlendronate + Ibandronate\t1(2.9%)\t\nIbandronate + Clodronate\t1 (2.9%)\t\nZolendronate + Denosumab\t1 (2.9%)\t\nStage of MRONJ\t\t\n-Stage I\t6 (17.1%)\t\n-Stage II\t28 (80%)\t\n-Stage III\t1 (2.9%) *\t\nMRONJ localization\t\t\nMaxilla\t12 (34.2%)\t\nMandible\t24 (68.5%) * ψ\t\n* χ2 test, significance: p ≤ 0.05. ψ One patient had both mandibular and maxillary lesions.\n\nantibiotics-10-00195-t002_Table 2 Table 2 Clinical data concerning MRONJ-related therapy.\n\nMRONJ-Related Therapy\tMonths\t\nDuration of therapy\t\t\n-Zoledronate\t34.29 ± 33.42\t\n-Alendronate\t79.42 ± 63.33\t\n-Denosumab\t15 ± 7.94\t\nSuspension of drug\t\t\n-Zoledronate\t8.53 ± 20.21\t\n-Alendronate\t13.15 ± 19.58\t\n-Denosumab\t0.8 ± 1.1\t\n\nantibiotics-10-00195-t003_Table 3 Table 3 Clinical outcomes of patients who received pentoxifylline and tocopherol therapy for management of MRONJ.\n\nAge (Years)\tCause of Anti-Resorptive Treatment\tGender\tType of MRONJ-Related Drug\tUCONNS Score\tStage of MRONJ\tSite of MRONJ\tOutcomes\t\n68\tCancer\tFemale\tAlendronate\t12\tStage II\tMandible\tHealed\t\n65\tCancer\tFemale\tZoledronate\t23\tStage II\tMandible\tWorsened\t\n53\tCancer\tFemale\tZoledronate\t31\tStage II\tMandible\tStable\t\n51\tCancer\tFemale\tZoledronate-Denosumab\t24\tStage II\tMaxilla\tWorsened\t\n93\tOsteoporosis\tFemale\tAlendronate-Denosumab\t13\tStage II\tMaxilla/Mandible\tHealed\t\n85\tCancer\tFemale\tZoledronate\t26\tStage II\tMaxilla\tHealed\t\n65\tCancer\tMale\tDenosumab\t22\tStage II\tMandible\tHealed\t\n90\tOsteoporosis\tFemale\tAlendronate\t8\tStage II\tMaxilla\tHealed\t\n77\tCancer\tMale\tZoledronate\t21\tStage II\tMandible\tHealed\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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"fulltext_license": "CC BY",
"issn_linking": "2079-6382",
"issue": "10(2)",
"journal": "Antibiotics (Basel, Switzerland)",
"keywords": "antibiotics; osteonecrosis; pentoxifylline; sequestrectomy; tocopherol",
"medline_ta": "Antibiotics (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101637404",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33671429",
"pubdate": "2021-02-17",
"publication_types": "D016428:Journal Article",
"references": "20955948;28838836;25240948;25031944;21907470;22967310;30155844;26321065;32016175;20006163;28527518;25234529;28703840;18775204;28760314;25414052;30642734;27984770;31106139;27651287;26659615;23891014;21291478;30220314;29279671;28963584;22883322;32760820;30325561;31054989;20927569;30218655;19371819;29932939;27956123",
"title": "Conservative Management of Medication-Related Osteonecrosis of the Jaws (MRONJ): A Retrospective Cohort Study.",
"title_normalized": "conservative management of medication related osteonecrosis of the jaws mronj a retrospective cohort study"
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"companynumb": "IT-THERAMEX-2021000249",
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"abstract": "OBJECTIVE\nGranulocyte colony-stimulating factor (G-CSF) acts on reproductive function at different stages, but its effects on the early stages of embryo development are unknown. The aim of this study was to assess the effect of G-CSF administration during treatment with assisted reproductive technologies (ART) and early pregnancy on newborns.\n\n\nMETHODS\nRetrospective study in women undergoing egg donation, with a study group including 33 live-born children from a pregnancy in which G-CSF was administered, and a control group of 3798 children in which this medication was not ordered during pregnancy. The analysis was of perinatal outcomes resulting from G-CSF treatment administered off-label compared with a control group.\n\n\nRESULTS\nNo significant differences were found in maternal age (40.9 ± 0.1 versus 38.9 ± 1.8, P = 0.055), body mass index (23.2 ± 0.2 versus 22.6 ± 1.5, P = 0.503), infant birthweight (2952 ± 200 versus 3145 ± 270 g, P = 0.184), gestational age (38 ± 1 versus 37 ± 1 weeks, P = 0.926) or length (50.2 ± 1.5 versus 48.7 ± 2.7 cm, P = 0.678) (between the control group and women treated with G-CSF, respectively). The prematurity rates of births before week 36 (10.0% versus 9.5%, P = 0.783) or week 32 (2.2% versus 0.0%, P = 0.585) were similar in the control and study groups, respectively. The incidence of low birthweight (<2500 g; 19.6% versus 11.8%, P = 0.570) or very low birthweight (1500 g; 2.5% versus 0.0%, P = 0.454) was not significantly different between non-treated and G-CSF-treated women, respectively.\n\n\nCONCLUSIONS\nAdministration of G-CSF at embryo transfer and during early pregnancy in recurrent miscarriage patients with KIR-HLA-C mismatch undergoing egg donation ART treatment does not convey a higher risk of perinatal complications.",
"affiliations": "IVI Madrid, Madrid, Spain.;IVI Madrid, Madrid, Spain.;IVI Madrid, Madrid, Spain.;IVI Madrid, Madrid, Spain. Electronic address: Antonio.Requena@ivirma.com.",
"authors": "Cruz|María|M|;Alecsandru|Diana|D|;García-Velasco|Juan Antonio|JA|;Requena|Antonio|A|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.rbmo.2019.09.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1472-6483",
"issue": "39(6)",
"journal": "Reproductive biomedicine online",
"keywords": "GM-CSF; IVF; KIR-HLA-C mismatch; Perinatal outcomes; Recurrent miscarriage",
"medline_ta": "Reprod Biomed Online",
"mesh_terms": "D000328:Adult; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007231:Infant, Newborn; D018587:Oocyte Donation; D011247:Pregnancy; D012189:Retrospective Studies",
"nlm_unique_id": "101122473",
"other_id": null,
"pages": "976-980",
"pmc": null,
"pmid": "31680063",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Use of granulocyte colony-stimulating factor in ART treatment does not increase the risk of adverse perinatal outcomes.",
"title_normalized": "use of granulocyte colony stimulating factor in art treatment does not increase the risk of adverse perinatal outcomes"
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"abstract": "G-CSF administration after high-dose chemotherapy and autologous stem cell transplantation (ASCT) has been shown to expedite neutrophil recovery. Several studies comparing filgrastim and pegfilgrastim in the post-ASCT setting concluded that the two are at least equally effective. Lipegfilgrastim (LIP) is a new long-acting, once-per-cycle G-CSF. This multicentric, prospective study aimed to describe the use of LIP in multiple myeloma patients receiving high-dose melphalan and autologous stem cell transplantation (ASCT) and compare LIP with historic controls of patients who received short-acting agent (filgrastim [FIL]). Overall, 125 patients with a median age of 60 years received G-CSF after ASCT (80 patients LIP on day 1 post-ASCT and 45 patients FIL on day 5 post-ASCT). The median duration of grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 10 [9]/L) was 5 days in both LIP and FIL groups, whereas the median number of days to reach ANC ≥ 0.5 × 10 [9]/L was 10% lower in the LIP than in the FIL group (10 vs 11 days), respectively. Male sex was significantly associated with a faster ANC ≥ 0.5 × 10 [9] L response (p = 0.015). The incidence of FN was significantly lower in the LIP than in the FIL group (29% vs 49%, respectively, p = 0.024). The days to discharge after ASCT infusion were greater in patients with FN (p < 0.001). The study indicates that LIP had a shorter time to ANC recovery and is more effective than FIL for the prevention of FN in the ASCT setting.",
"affiliations": "Stem Cell Transplant Program, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy. dr.massimomartino@gmail.com.;CNR-IFC, Rome, Italy. mercedes.gori@ifc.cnr.it.;CNR-IFC, Research Unit of Reggio Calabria, Reggio Calabria, Italy.;Department of Hematology, Unità di Ricerca Biotecnologica, Cosenza, Italy.;Hematology Unit, Azienda Ospedaliera Regionale S. Carlo - Ospedale San Carlo, Potenza, Italy.;Stem Cell Transplant Program, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.;Stem Cell Transplant Program, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.;Stem Cell Transplant Program, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.;Stem Cell Transplant Program, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.;Stem Cell Transplant Program, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.;Stem Cell Transplant Program, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.;Stem Cell Transplant Program, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.;Hematology Unit, Department of Hemato-Oncology, Ospedale Annunziata, Cosenza, Italy.;Division of Hematology, Department of Department of Human Pathology in Adulthood and Childhood \"Gaetano Barresi\", University of Messina, Messina, Italy.;Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy.;Pharmacy Unit, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.;Hematology Unit, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.;Hematology Unit, Azienda Ospedaliera, Papardo, Messina, Italy.;CNR-IFC, Rome, Italy.",
"authors": "Martino|Massimo|M|http://orcid.org/0000-0002-3987-419X;Gori|Mercedes|M|;Tripepi|Giovanni|G|;Recchia|Anna Grazia|AG|;Cimminiello|Michele|M|;Provenzano|Pasquale Fabio|PF|;Naso|Virginia|V|;Ferreri|Anna|A|;Moscato|Tiziana|T|;Console|Giuseppe|G|;Loteta|Barbara|B|;Gallo|Giuseppe Alberto|GA|;Gentile|Massimo|M|;Innao|Vanessa|V|;Rossi|Marco|M|;Morabito|Antonella|A|;Vincelli|Iolanda Donatella|ID|;Mannina|Donato|D|;Pitino|Annalisa|A|",
"chemical_list": "C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim; D008558:Melphalan",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-019-03901-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "99(2)",
"journal": "Annals of hematology",
"keywords": "Autologous stem cell transplant; Filgrastim; G-CSF; High dose melphalan; Lipegfilgrastim; Multiple myeloma",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000368:Aged; D064592:Autografts; D005260:Female; D000069585:Filgrastim; D006801:Humans; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009101:Multiple Myeloma; D011092:Polyethylene Glycols; D011446:Prospective Studies; D012737:Sex Factors; D033581:Stem Cell Transplantation",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "331-341",
"pmc": null,
"pmid": "31853703",
"pubdate": "2020-02",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study",
"references": "30470875;31130488;25184862;26596670;28379796;28606646;30728439;30653422;31171419;9432046;7538555;9579836;7512124;20015929;22248711;20007996;21323524;20706722;20045479;16930141;11252586;18628128;29198330;10023306;15678345;15961767;23788754;20511163;23945072;26092233;26024743;30827127;30839100;28614980;22788745;24913501",
"title": "A comparative effectiveness study of lipegfilgrastim in multiple myeloma patients after high dose melphalan and autologous stem cell transplant.",
"title_normalized": "a comparative effectiveness study of lipegfilgrastim in multiple myeloma patients after high dose melphalan and autologous stem cell transplant"
} | [
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"companynumb": "IT-AMGEN-ITASP2019214343",
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"activesubstancename": "MELPHALAN"
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"abstract": "BACKGROUND\nEctopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is caused by tumours releasing ACTH. Ectopic ACTH-producing tumour regression is rarely induced using steroidogenesis inhibitors. We presented a case of EAS in which ACTH production by a lung tumour was reduced by metyrapone (MTP) and also reviewed previous cases of ectopic ACTH production suppressed via steroidogenesis inhibition.\n\n\nMETHODS\nA 71-year-old female with general fatigue, central obesity and impaired glucose tolerance was diagnosed with Cushing's syndrome due to elevated ACTH (192.9 pg/mL; normal range, 7.2-63.3 pg/mL), cortisol (73.1 μg/dL; 6.4-21.0 μg/dL) and 24-h urinary free cortisol (UFC) (6160 μg/day; 11.2-80.3 μg/day) levels. Chest computed tomography identified a solid 26.6 × 22.9 × 30.0 mm tumour with a cavity in the upper lobe of the left lung. There was no adrenal gland enlargement. Tumour markers were not significantly elevated; ACTH levels were not suppressed by 8-mg dexamethasone. A corticotropin-releasing hormone stimulation test revealed blunted ACTH response (basal ACTH, 204.6 pg/mL; highest ACTH level during the 120-min stimulation test, 214.0 pg/mL). She was diagnosed with EAS due to a lung lesion. MTP treatment was started to reduce cortisol production. ACTH levels and cortisol and UFC levels were normalised and the ACTH-producing lung tumour was ablated after MTP treatment. In several reported cases, plasma ACTH levels reduced during steroidogenesis inhibitor treatment for EAS. Among the 10 patients, three cases of pheochromocytoma, one of thymic carcinoid and one of islet cell carcinoma were reported. In four cases, the tumour was not detected. In our case, the pathology of the lung tumour was unknown because of lack of tumour cells in biopsy. The patients were treated with ketoconazole (KTZ) and/or MTP and exhibited ACTH and cortisol/UFC suppression, but tumour regression was observed only in our case.\n\n\nCONCLUSIONS\nMTP and/or KTZ may reduce ACTH and cortisol production. The tumour spontaneously regressed after MTP treatment, indicating that MTP may reduce the tumour size without surgery. The mechanisms of therapeutic effects of steroidogenesis inhibitors and prognosis of spontaneous remission should be elucidated further via molecular biology studies.",
"affiliations": "Department of Paediatrics, Aichi Medical University, School of Medicine, Nagakute, Japan. iwahide1976@gmail.com.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Aichi Medical University, School of Medicine, Nagakute, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Aichi Medical University, School of Medicine, Nagakute, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Aichi Medical University, School of Medicine, Nagakute, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Aichi Medical University, School of Medicine, Nagakute, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Aichi Medical University, School of Medicine, Nagakute, Japan.;Department of Paediatrics, Aichi Medical University, School of Medicine, Nagakute, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Aichi Medical University, School of Medicine, Nagakute, Japan.",
"authors": "Iwayama|Hideyuki|H|http://orcid.org/0000-0002-5218-5815;Hirase|Sho|S|;Nomura|Yuka|Y|;Ito|Tatsuo|T|;Morita|Hiroyuki|H|;Otake|Kazuo|K|;Okumura|Akihisa|A|;Takagi|Junko|J|",
"chemical_list": "D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone; D008797:Metyrapone",
"country": "England",
"delete": false,
"doi": "10.1186/s12902-018-0246-2",
"fulltext": "\n==== Front\nBMC Endocr DisordBMC Endocr DisordBMC Endocrine Disorders1472-6823BioMed Central London 24610.1186/s12902-018-0246-2Case ReportSpontaneous adrenocorticotropic hormone (ACTH) normalisation due to tumour regression induced by metyrapone in a patient with ectopic ACTH syndrome: case report and literature review http://orcid.org/0000-0002-5218-5815Iwayama Hideyuki iwahide1976@gmail.com 1Hirase Sho shohirase0420cset@hotmail.co.jp 2Nomura Yuka nomura.yuka@aichi-med-u.ac.jp 2Ito Tatsuo itou.tatsuo.503@mail.aichi-med-u.ac.jp 2Morita Hiroyuki moritahi@aichi-med-u.ac.jp 2Otake Kazuo ezotogar@mac.com 2Okumura Akihisa okumura.akihisa.479@mail.aichi-med-u.ac.jp 1Takagi Junko jutakagi@icloud.com 21 0000 0001 0727 1557grid.411234.1Department of Paediatrics, Aichi Medical University, School of Medicine, Nagakute, Japan 2 0000 0001 0727 1557grid.411234.1Division of Endocrinology and Metabolism, Department of Internal Medicine, Aichi Medical University, School of Medicine, Nagakute, Japan 27 3 2018 27 3 2018 2018 18 1915 10 2017 20 3 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nEctopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is caused by tumours releasing ACTH. Ectopic ACTH-producing tumour regression is rarely induced using steroidogenesis inhibitors. We presented a case of EAS in which ACTH production by a lung tumour was reduced by metyrapone (MTP) and also reviewed previous cases of ectopic ACTH production suppressed via steroidogenesis inhibition.\n\nCase presentation\nA 71-year-old female with general fatigue, central obesity and impaired glucose tolerance was diagnosed with Cushing’s syndrome due to elevated ACTH (192.9 pg/mL; normal range, 7.2–63.3 pg/mL), cortisol (73.1 μg/dL; 6.4–21.0 μg/dL) and 24-h urinary free cortisol (UFC) (6160 μg/day; 11.2–80.3 μg/day) levels. Chest computed tomography identified a solid 26.6 × 22.9 × 30.0 mm tumour with a cavity in the upper lobe of the left lung. There was no adrenal gland enlargement. Tumour markers were not significantly elevated; ACTH levels were not suppressed by 8-mg dexamethasone. A corticotropin-releasing hormone stimulation test revealed blunted ACTH response (basal ACTH, 204.6 pg/mL; highest ACTH level during the 120-min stimulation test, 214.0 pg/mL). She was diagnosed with EAS due to a lung lesion. MTP treatment was started to reduce cortisol production. ACTH levels and cortisol and UFC levels were normalised and the ACTH-producing lung tumour was ablated after MTP treatment. In several reported cases, plasma ACTH levels reduced during steroidogenesis inhibitor treatment for EAS. Among the 10 patients, three cases of pheochromocytoma, one of thymic carcinoid and one of islet cell carcinoma were reported. In four cases, the tumour was not detected. In our case, the pathology of the lung tumour was unknown because of lack of tumour cells in biopsy. The patients were treated with ketoconazole (KTZ) and/or MTP and exhibited ACTH and cortisol/UFC suppression, but tumour regression was observed only in our case.\n\nConclusion\nMTP and/or KTZ may reduce ACTH and cortisol production. The tumour spontaneously regressed after MTP treatment, indicating that MTP may reduce the tumour size without surgery. The mechanisms of therapeutic effects of steroidogenesis inhibitors and prognosis of spontaneous remission should be elucidated further via molecular biology studies.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12902-018-0246-2) contains supplementary material, which is available to authorized users.\n\nKeywords\nCushing’s syndromeEctopic hormone syndromeSteroidogenesis inhibitorMetyraponeTumour regressionhttp://dx.doi.org/10.13039/501100001691Japan Society for the Promotion of Science16K19676Iwayama Hideyuki The Nitto FoundationAichi Medical University “Aikei-Kai” FoundationYoshiko & Seizo Foundationissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nCushing’s syndrome (CS) is associated with excess mortality and morbidity due to the long-term sequela of excessive cortisol levels [1]. Steroidogenesis enzyme inhibitors are the mainstay medical treatments for hypercortisolemia associated with CS [1], among which ketoconazole (KTZ) and metyrapone (MTP) are most commonly used. Both drugs act on the adrenal cortex to inhibit the steroid biosynthetic pathway and reversibly inhibit cortisol synthesis [1].\n\nEctopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is caused by tumours that release ACTH [2]. EAS accounts for approximately 10% of all cases of CS [2]. EAS occurs when ACTH is produced somewhere other than the pituitary gland [2]. KTZ and MTP are also used to treat EAS [1]. The loss of negative feedback due to low circulating cortisol levels may then lead to an increase in ACTH levels [1]. However, several cases in which ACTH over-production was reversed via treatment with steroidogenesis inhibitors without surgery have been reported [3–9].\n\nIn this study, we report a rare case of EAS in which ACTH levels, as well as those of cortisol and urinary free cortisol (UFC), are normalised by treatment with MTP. In addition, the lung tumour, which was considered the ACTH-producing tumour, was ablated after the administration of MTP. This is the first reported case of the regression of an ectopic ACTH-producing tumour upon treatment with a steroidogenesis inhibitor using functional imaging. Moreover, we reviewed reported cases of ectopic ACTH production that was suppressed by steroidogenesis inhibition.\n\nCase presentation\nA 71-year-old female presented with general fatigue, leg oedema and impaired glucose tolerance. Her medical history included Graves’ disease, colon polyp, sarcoidosis and uveitis following glucocorticoid treatment. Upon hospitalisation, she exhibited weight gain, central obesity, moon facies, proximal muscle weakness and elevated ACTH (192.9 pg/mL, normal range, 7.2–63.3 pg/mL), cortisol (73.1 μg/dL; normal range, 6.4–21.0 μg/dL) and 24-h UFC levels (6160 μg/day; normal range, 11.2–80.3 μg/day). Normal diurnal variation of cortisol was lost. Brain magnetic resonance imaging revealed an empty sella with no pituitary adenoma. Chest computed tomography (CT) identified a solid tumour of 26.6 mm × 22.9 mm × 30.0 mm in size with a cavity in the upper lobe of the left lung (Fig. 1a). There was no adrenal gland enlargement. Vanillylmandelic acid (7.9 ng/mL; normal range, 3.3–8.6 ng/mL) and homovanillic acid (10.5 ng/mL; normal range, 4.4–15.1 ng/mL) levels were not elevated. Tumour makers, including carcinoembryonic antigen (CEA), cancer antigen (CA) 19-9, CA 125, cytokeratin-19 fragments (CYFRA 21-1), sialyl Lewis X (SLX), squamous cell carcinoma antigen, pro-gastrin-releasing peptide and neuron-specific enolase, were not significantly elevated.Fig. 1 Imaging studies of the lung nodule at the time of hospitalisation (a, b) and 6 months after disease onset (c, d). a. Computed tomography (CT) at the time of hospitalisation. The white arrow indicates a nodule with a cavity in the upper lobe of the left lung. b. Gallium scintigraphy (67Ga-citrate) at the time of hospitalisation. The white arrow indicates high accumulation of gallium at the same location as the lung lesion. c. CT 6 months after disease onset. The lung lesion has disappeared, and a small scar remains. d. Somatostatin scintigraphy (111In-Pentetreotide) 6 months after disease onset. There is no accumulation in the left upper lobe (white arrow). The arrowhead indicates light accumulation of indium-111-radio-labelled octreotide in the mediastinum\n\n\n\nTo differentiate between Cushing disease and EAS, an overnight 8-mg dexamethasone suppression test was performed. ACTH and cortisol levels were 184.8 pg/mL and 76.5 μg/dL, respectively, before the administration of dexamethasone. ACTH and cortisol levels 12 h after suppression with 8-mg dexamethasone were 176.7 pg/mL and 67.2 μg/dL, respectively. Lack of suppression of ACTH and cortisol by 8-mg dexamethasone is consistent with that with EAS. A corticotropin-releasing hormone (CRH) stimulation test revealed a blunted response of ACTH (basal ACTH, 204.6 pg/mL; highest ACTH level during the 120-min stimulation test, 214.0 pg/mL). According to these findings, the patient was diagnosed with EAS due to a lung lesion. MTP treatment was started to reduce cortisol production on the first day of hospitalisation (day 1).\n\nOn day 3, because cortisol levels fell below the normal range (2.8 μg/dL), hydrocortisone treatment was started for supplementation. On the same day, the patient developed pneumonia and pleural effusion. C-reactive protein and beta-d-glucan levels were elevated to 23.85 and 69.6 mg/dL (normal range for beta-D-glucan, 0–20 mg/dL), respectively, whereas the patient’s white blood cell count was normal (8300/μL). Imipenem/cilastatin (1 g/day, days 3–12) and caspofungin acetate (50 mg/day, days 5–20) were administered as antimicrobial and antifungal treatments, respectively.\n\nOn day 14, CT detected enlargement of the lung tumour to a 5-cm-diameter mass (Additional file 1: Figure S1). Along with enlargement of the lung tumour, ACTH levels increased to 358.5 pg/mL, with no elevation of cortisol due to MTP treatment. Therefore, the nodular lesion was considered an ACTH-producing tumour. Surprisingly, on day 19, her serum ACTH level decreased to 62.4 pg/mL, concurrently with the decline of the serum cortisol content. On day 39, serum ACTH levels were temporarily elevated to 376.3 pg/mL; however, the levels returned to the normal range. Gallium scintigraphy (67Ga-citrate) revealed a positive signal in the same location as the lung lesion (Fig. 1b).\n\nBrush cytology using bronchoscopy showed only few neutrophils, dust cells, ciliated columnar cells, and squamous cells, and no malignant findings were found. Second, CT-guide biopsy was performed. Histological examination showed organising pneumonia-like reaction, thickening alveolar wall due to fibrosis, and accumulating histiocytes in the alveoli. Malignant findings were not found even at this time. Fungus were not found by Periodic acid-Schiff and Grocott staining. Subsequently, we tried CT-guided lung biopsy. However, the specimen did not include the lung tissue and only included pleura and muscles of the chest wall.\n\nSurgical treatment was considered, but ACTH levels remained normal (28.6–48.2 pg/mL) together with suppressed cortisol, regression of the lung nodule and disappearance of the pleural effusion. No tumour cells were revealed by bronchoscopy and CT-guided lung biopsy. Hypokalaemia and hyperglycaemia were also improved. Therefore, surgery was cancelled. She was discharged 6 weeks after admission. Six months after admission, CT revealed a small residual lesion in the lungs (Fig. 1c) and somatostatin scintigraphy (111In-Pentetreotide) identified no accumulation of the positive signal (Fig. 1d). She had good intervention adherence and tolerability with no adverse or unanticipated events. We have carefully observed the patient for the recurrence of CS.\n\nDiscussion\nWe have presented a unique case of ectopic ACTH production with ACTH normalisation upon shrinkage of a pulmonary lesion. It is rare that steroidogenesis inhibitors suppress ectopic ACTH production and induce tumour regression. The therapeutic effect of MTP or cyclic CS may explain the regression of ACTH-producing cells. This is the first reported case of the regression of an ectopic ACTH-producing tumour following treatment with a steroidogenesis inhibitor as confirmed using functional imaging.\n\nIn several reported cases, plasma ACTH levels were reduced during steroidogenesis inhibitor treatment for EAS (Table 1) [3–9]. Among the 10 patients, including our case, three cases of pheochromocytoma, one case of thymic carcinoid, and one case of islet cell carcinoma were reported. In four cases, the tumour was not detected. In our case, the pathology of the lung tumour was unknown because of the lack of tumour cells in the biopsy. The reported patients were treated with KTZ and/or MTP. In addition to steroidogenesis inhibitors, octreotide and phentolamine/landiolol were used in one case each. All patients exhibited ACTH and cortisol/UFC suppression, but tumour regression was observed only in our case. These data suggest that MTP and/or KTZ may reduce ACTH and cortisol production.Table 1 Reported cases of ectopic adrenocorticotropin production that was suppressed by steroidogenesis inhibitorsa\n\nCase\tAuthor\tPublication Year\tTumour Pathology\tDrug\tACTH Suppression\tACTH levels a (pg/mL)\t\tCortisol Suppression\tCortisol levels a (μg/dL)\t\tUFC Suppression\tUFC levels a (μg/24 h)\t\tTumour Regression\t\n\t\t\t\t\t\tBefore\tAfter\t\tBefore\tAfter\t\tBefore\tAfter\t\t\n1\tBeardwell [3]\t1981\tND\tMTP\t+\t450\t66\t+\t> 72.5\t6.8\tNA\tNA\t19.9\tND\t\n2\tBeardwell [3]\t1981\tND\tMTP\t+\t98\t62\t+\t51.5\t16.6\t+\t366\t26.2\tND\t\n3\tSteen [9]\t1991\tthymic carcinoid\tKTZ\t+ (partially)\t388\t120\t+\t> 72.5\t18.9\tNA\tNA\tNA\t- (operation)\t\n4\tLoh [5]\t1996\tpheochromocytoma\tKTZ\t+ (partially)\t105\t78\tNA\t51.9\tNA\t+\t189\t3.6\t- (operation)\t\n5\tDoi [4]\t2003\tislet cell carcinoma\toctreotide or MTP\t+\t735\t13\t+\t145\t1.9\tNA\tNA\tNA\t- (operation)\t\n6\tMizoguchi [6]\t2007\tpheochromocytoma\tKTZ\t+ (partially)\t360 c\t78\t+\t180 c\t< 1.0 c\tNA\tNA\tNA\t- (operation)\t\n7\tSharma [8]\t2012\tND\tKTZ/MTP\t+\t114\t44\tNA\tNA\tNA\t+\t455\t27\tND\t\n8\tSharma [8]\t2012\tND\tKTZ/MTP\t+\t108\t7\tNA\tNA\tNA\t+\t559\t4\tND\t\n9\tSakuma [7]\t2016\tpheochromocytoma\tphentolamine/landiolol/MTP\t+\t995\t18.4\t+\t85.6\t< 1.0\t+\t1250\treduced\t- (operation)\t\n10\tOur case\t2018\t(lung tumour) b\tMTP\t+\t192.9\t48.2\t+\t73.1\t7.6\t+\t6160\t35.5\t+\t\nND tumour was not detected, ACTH adrenocorticotropic hormone, UFC urinary free cortisol, KTZ ketoconazole, MTP metyrapone, NA the date was not available\n\naACTH, cortisol and UFC before and after the initiation of steroidogenesis inhibitor\n\nbtumour pathology was unknown because of the lack of tumour cells in the biopsy\n\ncas real numbers were not available in the literature, the numbers were read from the graph\n\n\n\nThe mechanisms by which steroidogenesis inhibitors suppress ectopic ACTH production are unclear. The primary mechanism by which KTZ inhibits steroidogenesis is the inhibition of 17-hydroxylase, 11β-hydroxylase and the cholesterol side-chain cleavage enzyme [10], versus the inhibition of 11β-hydroxylase for MTP [10]. Interestingly, two studies conducted in vivo and vitro illustrated that ACTH secretion by tumour cells obtained from patients with EAS was decreased by treatment with KTZ [9] or MTP [6]. Steen et al. reported that KTZ dose-dependently lowered ACTH secretion in vivo and in vitro in a patient with an ectopic ACTH-producing thymic carcinoid tumour and CS [9]. Mizuguchi et al. revealed that cortisol increased the expression of proopiomelanocortin (POMC) in primary cultured thymic carcinoid cells [6]. Cortisol also induced demethylation of the POMC promoter, which was considered the cause of ACTH elevation [6]. They concluded that the decline of serum cortisol levels was the cause of decreased ACTH levels. Unfortunately, they did not report the effect of MTP on ACTH production in vitro. Thus, the complete mechanism by which steroidogenesis inhibitors reduce ACTH production in patients with EAS remains to be elucidated.\n\nDirect impairment of ACTH biosynthesis by steroidogenesis inhibitors is also considered a cause of ACTH reduction. An in vitro study found that KTZ inhibited ACTH secretion at therapeutic doses by impairing adenylate cyclase activation in corticotrophs [11], which is the downstream of CRH and its receptor, generating cyclic AMP from ATP in pituitary corticotrophs [12]. However, the contribution of this effect to the action of KTZ in patients with EAS has not been demonstrated. In our patient, this mechanism may have reduced ACTH secretion from the lung tumour, but its contribution will be investigated in the future.\n\nTumour haemorrhage or infarction has been postulated as the cause of spontaneous remission of pituitary-dependent CS [5]. Although underlying mechanisms of pituitary-dependent CS and EAS are different, tumour haemorrhage or infarction can be the cause of remission in EAS. High or low intensity, indicating haemorrhage or infarction, respectively, had not been found in the lung tumour by consecutive CT. The lung tumour gradually shrunk without a mixed pattern suspected to have haemorrhage or infarction. There was no evidence of tumour haemorrhage or infarction in our patient. The cause of spontaneous remission in our patient remains unclear.\n\nAnother potential differential diagnosis of this patient was cyclic CS, which involves the fluctuating over-production of cortisol over months or years. In this patient, aberrant ACTH production occurred 1 month after the initiation of MTP, although it has since been suppressed for 1 year and 6 months. She has been observed carefully to determine whether hypercortisolemia will reappear. She is very pleased with the condition resolving itself without surgical intervention.\n\nConclusion\nWe presented a rare case of EAS in which ACTH production by a lung tumour was reduced by MTP. The tumour itself regressed spontaneously after the initiation of MTP, indicating that this drug may reduce tumour size without surgery. The mechanisms of the therapeutic effect of steroidogenesis inhibitors and the prognosis of spontaneous remission should be elucidated further via molecular biology studies.\n\nAdditional file\n\nAdditional file 1: Figure S1. Enlargement of the lung tumour on day 14. (TIFF 48 kb)\n\n \n\n\nAbbreviations\nACTHAdrenocorticotropic hormone\n\nCSCushing’s syndrome\n\nCTComputed tomography\n\nEASEctopic ACTH syndrome\n\nKTZKetoconazole\n\nMTPMetyrapone\n\nPOMCProopiomelanocortin\n\nUFCUrinary free cortisol\n\nElectronic supplementary material\n\nThe online version of this article (10.1186/s12902-018-0246-2) contains supplementary material, which is available to authorized users.\n\nAcknowledgements\nWe thank the patient for her participation in this study. We would also like to express our gratitude to the nursing staff at Aichi Medical University. We thank Hideaki Ito at Department of Pathology, Aichi Medical University for making a draft of pathological part. The research of HI was supported by JSPS KAKENHI Grant Number 16 K19676, The Nitto Foundation, Aichi Medical University “Aikei-Kai” Foundation and Yoshiko & Seizo Foundation.\n\nFunding\nThe authors declare that they have no funding for this research.\n\nAvailability of data and materials\nThe datasets during and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nHI contributed to the design of the research, the interpretation of data for the patient, and was a major contributor in writing the manuscript. SH, YN, TI, HM contributed to the acquisition and analysis of data from the patient. KO and AO revised the manuscript critically for important intellectual content. JT supervised clinical procedures, gave critical input to the manuscript, and contributed to the final approval of the version to be published. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThis case report was approved by the ethical committee at Aichi Medical University (2017-H212). Written informed consent was obtained from the participant included in the study. All study evaluations and procedures were performed in accordance with the Declaration of Helsinki.\n\nConsent for publication\nWritten informed consent for publication was obtained from the patient.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Daniel E Newell-Price JD Therapy of endocrine disease: steroidogenesis enzyme inhibitors in Cushing's syndrome Eur J Endocrinol 2015 172 6 R263 R280 10.1530/EJE-14-1014 25637072 \n2. Orth DN Cushing's syndrome N Engl J Med 1995 332 12 791 803 10.1056/NEJM199503233321207 7862184 \n3. Beardwell CG Adamson AR Shalet SM Prolonged remission in florid Cushing's syndrome following metyrapone treatment Clin Endocrinol 1981 14 5 485 492 10.1111/j.1365-2265.1981.tb00638.x \n4. Doi M Imai T Shichiri M Tateno T Fukai N Ozawa N Sato R Teramoto K Hirata Y Octreotide-sensitive ectopic ACTH production by islet cell carcinoma with multiple liver metastases Endocr J 2003 50 2 135 143 10.1507/endocrj.50.135 12803233 \n5. Loh KC Gupta R Shlossberg AH Spontaneous remission of ectopic Cushing's syndrome due to pheochromocytoma: a case report Eur J Endocrinol 1996 135 4 440 443 10.1530/eje.0.1350440 8921826 \n6. Mizoguchi Y Kajiume T Miyagawa S Okada S Nishi Y Kobayashi M Steroid-dependent ACTH-produced thymic carcinoid: regulation of POMC gene expression by cortisol via methylation of its promoter region Horm Res 2007 67 5 257 262 17220632 \n7. Sakuma I Higuchi S Fujimoto M Takiguchi T Nakayama A Tamura A Kohno T Komai E Shiga A Nagano H Cushing syndrome due to ACTH-secreting Pheochromocytoma, aggravated by glucocorticoid-driven positive-feedback loop J Clin Endocrinol Metab 2016 101 3 841 846 10.1210/jc.2015-2855 26700559 \n8. Sharma ST Nieman LK Prolonged remission after long-term treatment with steroidogenesis inhibitors in Cushing's syndrome caused by ectopic ACTH secretion Eur J Endocrinol 2012 166 3 531 536 10.1530/EJE-11-0949 22190002 \n9. Steen RE Kapelrud H Haug E Frey H In vivo and in vitro inhibition by ketoconazole of ACTH secretion from a human thymic carcinoid tumour Acta Endocrinol 1991 125 3 331 334 1659100 \n10. Schteingart DE Drugs in the medical treatment of Cushing's syndrome Expert Opin Emerg Drugs 2009 14 4 661 671 10.1517/14728210903413522 19939210 \n11. Stalla GK Stalla J Huber M Loeffler JP Hollt V von Werder K Muller OA Ketoconazole inhibits corticotropic cell function in vitro Endocrinology 1988 122 2 618 623 10.1210/endo-122-2-618 2448128 \n12. Asa SL Ezzat S The pathogenesis of pituitary tumours Nat Rev Cancer 2002 2 11 836 849 10.1038/nrc926 12415254\n\n",
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"issue": "18(1)",
"journal": "BMC endocrine disorders",
"keywords": "Cushing’s syndrome; Ectopic hormone syndrome; Metyrapone; Steroidogenesis inhibitor; Tumour regression",
"medline_ta": "BMC Endocr Disord",
"mesh_terms": "D000182:ACTH Syndrome, Ectopic; D000324:Adrenocorticotropic Hormone; D000368:Aged; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D008175:Lung Neoplasms; D008797:Metyrapone; D011379:Prognosis; D012074:Remission Induction",
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"title": "Spontaneous adrenocorticotropic hormone (ACTH) normalisation due to tumour regression induced by metyrapone in a patient with ectopic ACTH syndrome: case report and literature review.",
"title_normalized": "spontaneous adrenocorticotropic hormone acth normalisation due to tumour regression induced by metyrapone in a patient with ectopic acth syndrome case report and literature review"
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"abstract": "Rapidly growing mycobacteria have become increasingly recognized as pathogens implicated in surgical site infections that can be both difficult to diagnose and treat with an evolving understanding of both intrinsic and acquired resistance patterns. As common environmental commensal organisms that can colonize water supplies, they are of particular concern in the setting of a growing medical tourism industry. We present a case of a 49-year-old woman who acquired a highly multidrug-resistant Mycobacterium abscessus skin and soft-tissue infection after cosmetic abdominoplasty that required radical surgical debridement and 6 months of intravenous therapy to eradicate. This case highlights the challenges in the management of M. abscessus infections including delay to diagnosis and resistance patterns that are likely to become more common despite antibiotic stewardship efforts.",
"affiliations": "Beth Israel Deaconess Medical Center, Boston, Massachusetts, US.;Beth Israel Deaconess Medical Center, Boston, Massachusetts, US.",
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"fulltext": "\n==== Front\nJ Glob Infect DisJ Glob Infect DisJGIDJournal of Global Infectious Diseases0974-777X0974-8245Wolters Kluwer - Medknow India JGID-11-8310.4103/jgid.jgid_148_17Case ReportA Case of Lipotourism-associated Multidrug-resistant Mycobacterium abscessus Infection Lee Rose Anne Wigmore Robin Beth Israel Deaconess Medical Center, Boston, Massachusetts, USAddress for correspondence: Dr. Rose Anne Lee, Beth Israel Deaconess Medical Center, Boston, Massachusetts, US. E-mail: rose.lee@childrens.harvard.eduApr-Jun 2019 11 2 83 85 Copyright: © 2019 Journal of Global Infectious Diseases2019This 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.Rapidly growing mycobacteria have become increasingly recognized as pathogens implicated in surgical site infections that can be both difficult to diagnose and treat with an evolving understanding of both intrinsic and acquired resistance patterns. As common environmental commensal organisms that can colonize water supplies, they are of particular concern in the setting of a growing medical tourism industry. We present a case of a 49-year-old woman who acquired a highly multidrug-resistant Mycobacterium abscessus skin and soft-tissue infection after cosmetic abdominoplasty that required radical surgical debridement and 6 months of intravenous therapy to eradicate. This case highlights the challenges in the management of M. abscessus infections including delay to diagnosis and resistance patterns that are likely to become more common despite antibiotic stewardship efforts.\n\nKeywords:\nLipotourismmedical tourismmultidrug resistanceMycobacterium abscessus skin and soft-tissue infectionplastic surgery\n==== Body\nINTRODUCTION\nRapidly growing mycobacteria (RGM) are environmental organisms found worldwide and defined by their ability to grow in subculture within 1 week. Mycobacterium abscessus is known to be the most pathogenic of the RGM group and has been identified in recent outbreaks of wound infections related to medical tourism in the Caribbean islands. Reports of patients with M. abscessus infections from the Dominican Republic have been described since the early 2000s and recently culminated in a US Centers for Disease Control and Prevention outbreak investigation that identified 21 cases in six states from 2013 to 2014.[1] Despite a growing awareness of these infections, they nonetheless remain rare and there is often a delay in diagnosis. We present a case of lipotourism-related M. abscessus surgical site infection notable for significant multidrug resistance.\n\nCASE REPORT\nA 49-year-old woman underwent abdominoplasty with breast implant exchange, mastopexy, and upper back liposuction in the Dominican Republic in May 2016. She reportedly had significant seromas after these procedures that required daily aspirations for 2 weeks with drain placement. Three months postoperatively and after returning to the United States, she developed erythematous indurated areas over her abdomen, particularly near the former aspiration sites. She denied fevers, chills, night sweats, or gastrointestinal symptoms but did have progressive malaise and abdominal pain. She was evaluated by plastic surgery and multiple superficial subcutaneous abscesses were drained at bedside in clinic. The largest collection was 5.5 cm and cultures had no growth. Despite this, she was treated with cefadroxil for 10 days. She had a normal white blood cell count and C-reactive protein. She returned several times for bedside incision and drainage and culture data were frequently without growth, although one culture grew sensitive Klebsiella pneumoniae and another showed coagulase-negative Staphylococcus treated with 7-day courses of trimethoprim-sulfamethoxazole. After a month of procedures, a wound culture eventually isolated Mycobacterium abscessus. She was referred to the infectious disease clinic and empirically started on moxifloxacin and clarithromycin, pending sensitivity data on the isolate.\n\nAfter 3 weeks of therapy, she redeveloped openly draining superficial periumbilical abscesses. Her isolate's susceptibilities returned with resistance to all oral antibiotics tested including moxifloxacin (minimum inhibitory concentration [MIC] >8), clarithromycin (MIC >16), doxycycline, minocycline, trimethoprim-sulfamethoxazole, and ciprofloxacin as well as identification of clarithromycin-inducible resistance. Given the severity of infection, she eventually agreed to radical surgical debridement 4 months after commencement of care. Intraoperatively, a large amount of unhealthy granulation tissue with fat necrosis was observed, and 15–20 individual pockets of infection were addressed over an area of 25 cm × 25 cm [Figure 1]. The surgery team postulated that the liposuction cannula may have been contaminated as most of the infections were above Scarpa's layer with some involvement of deeper fat and fascia where the cannula may have passed.\n\nFigure 1 Initial radical surgical debridement\n\nPostoperatively, she was started on amikacin 15 mg/kg daily (MIC 16 sensitive) and imipenem-cilastatin 500 mg every 6 h (MIC 8 intermediate). She underwent baseline auditory testing and completed a 6-month course with good overall cosmesis [Figure 2] and without significant adverse side effects. While she managed to complete this course without a port (long-term central venous catheter), she did undergo three exchanges of her short-term peripherally inserted cutaneous catheter and faced significant financial instability including loss of home.\n\nFigure 2 After completion of both surgical and antibiotic therapy\n\nDISCUSSION\nThis case is notable in that it highlights two major challenges: (1) the growth of medical tourism and its possible complications and (2) the treatment of multidrug-resistant M. abscessus skin and soft-tissue infections (SSTIs).\n\nIn an era of globalization, there have been predictions of ten-fold increases in medical tourism from the United States growing from 750,000 individuals estimated to have traveled abroad in 2007.[2] While accurate estimates of medical tourists are sparse in current literature, there is an increasing number of reported cases of medical tourism-related mycobacterial complications.[3456] While care in low- and middle-income countries is not necessarily substandard, providers should be aware of associated infections that may be less commonly seen in the United States. RGMs are known environmental pathogens that can form tenacious biofilms in water systems due to their hydrophobic fatty acid cell wall that makes eradication difficult without rigorous disinfection.[7] RGM surgical site infections are often attributable to medical center tap water supplies and inadequate disinfection of surgical instruments and liposuction cannulas.[8]\n\nM. abscessus SSTIs are considered uncommon and frequently difficult-to-treat infections for which the American Thoracic Society/Infectious Diseases Society of America guideline on nontuberculous mycobacterial (NTM) infections offers minimal guidance beyond the recommendation to treat severe infections with a minimum of 4 months and consideration of combination therapy.[9] These recommendations are based on expert opinion and case series experience as there are no published randomized clinical trials. Much of our therapeutic strategies for mycobacterial SSTI are extrapolated from pulmonary infections that represent a separate clinical entity.\n\nThe discovery of an erythromycin methylase (erm) gene was a major development in this field which elucidated mechanisms of innate macrolide resistance that have important implications for treatment. Macrolides were described in NTM guidelines to be the only drug class with reliable in vitro activity; however, clinically had high rates of treatment failure despite predicted susceptibility. Nash et al. demonstrated that the presence of the erm gene conferred inducible macrolide resistance demonstrable by a rising clarithromycin MIC when isolates were held for an extended incubation period of 14 days.[10] As such, as in this case, M. abscessus infections continue to be a challenging clinical scenario with limited antibiotic options.\n\nCONCLUSION\nIt is important for clinicians to have a high index of suspicion for atypical surgical site infections including RGM in the setting of lipotourism. Especially, in areas of the world with evolving antibiotic stewardship, multidrug-resistant infections may become more common and is especially important for mycobacteria which already have significant innate resistance mechanisms.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgments\nThis work would not have been possible without the support of the Boston Children's Hospital and Beth Israel Deaconess Medical Center. I am especially indebted to Drs. Peter Weller, Chair of the Infectious Diseases Division at Beth Israel Deaconess Medical Center, and Dr. Michael Wessels, Chair of Infectious Diseases at Boston Children's Hospital. I am also indebted to the plastic surgeons involved in the care of this patient, in particular, Dr. Eugene Fukodome.\n==== Refs\nREFERENCES\n1 Schnabel D Esposito DH Gaines J Ridpath A Barry MA Feldman KA Multistate US outbreak of rapidly growing mycobacterial infections associated with medical tourism to the Dominican Republic, 2013-2014(1) Emerg Infect Dis 2016 22 1340 7 27434822 \n2 Keckley PH Underwood HR Medical Tourism: Consumers in Search of Value 2008 Last accessed on 2017 Nov 10 Washington Deloitte Center for Health Solutions Available from: http://www.medicaltourisminturkey.org/panel/Panel1/3Deloitte.pdfError! Hyperlink reference not valid \n3 Klein HJ Simic D Fuchs N Schweizer R Mehra T Giovanoli P Complications after cosmetic surgery tourism Aesthet Surg J 2017 37 474 82 28364525 \n4 Ross KM Moscoso AV Bayer LR Rosselli-Risal L Orgill DP Plastic surgery complications from medical tourism treated in a U.S. Academic medical center Plast Reconstr Surg 2018 141 517e 23e \n5 Cusumano LR Tran V Tlamsa A Chung P Grossberg R Weston G Rapidly growing Mycobacterium infections after cosmetic surgery in medical tourists: The Bronx experience and a review of the literature Int J Infect Dis 2017 63 1 6 28780185 \n6 Adabi K Stern CS Weichman KE Garfein ES Pothula A Draper L Population health implications of medical tourism Plast Reconstr Surg 2017 140 66 74 28654593 \n7 van Ingen J Blaak H de Beer J de Roda Husman AM van Soolingen D Rapidly growing nontuberculous mycobacteria cultured from home tap and shower water Appl Environ Microbiol 2010 76 6017 9 20639378 \n8 Centers for Disease Control and Prevention (CDC). Rapidly growing mycobacterial infection following liposuction and liposculpture – Caracas, Venezuela, 1996-1998 MMWR Morb Mortal Wkly Rep 1998 47 1065 7 9879630 \n9 Griffith DE Aksamit T Brown-Elliott BA Catanzaro A Daley C Gordin F An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases Am J Respir Crit Care Med 2007 175 367 416 17277290 \n10 Nash KA Brown-Elliott BA Wallace RJ Jr A novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae Antimicrob Agents Chemother 2009 53 1367 76 19171799\n\n",
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"keywords": "Lipotourism; Mycobacterium abscessus skin and soft-tissue infection; medical tourism; multidrug resistance; plastic surgery",
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"title": "A Case of Lipotourism-associated Multidrug-resistant Mycobacterium abscessus Infection.",
"title_normalized": "a case of lipotourism associated multidrug resistant mycobacterium abscessus infection"
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"abstract": "There is no established chemotherapy regimen in metastatic primary urethral cancer (mPUC). The efficacy of a cisplatin (CDDP)-based regimen has been reported, however, when the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) occurs, the chemotherapy regimen should be changed to another platinum compound. In this report, we describe a 66-year-old woman who was diagnosed as mPUC with, CDDP-induced SIADH. After switching her to CBDCA and careful managing her sodium balance, three courses of the chemotherapy regimen were completed.",
"affiliations": "Department of Pharmacy, Nagoya City University Hospital, Nagoya, Japan.;Department of Nephro-Urology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.;Department of Pharmacy, Nagoya City University Hospital, Nagoya, Japan.;Department of Nephro-Urology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.;Department of Pharmacy, Nagoya City University Hospital, Nagoya, Japan.;Department of Pharmacy, Nagoya City University Hospital, Nagoya, Japan.;Department of Clinical Pharmaceutics, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.;Department of Endocrinology and Diabetes, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.;Department of Nephro-Urology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.;Department of Pharmacy, Nagoya City University Hospital, Nagoya, Japan; Department of Clinical Pharmaceutics, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.",
"authors": "Sugiyama|Yosuke|Y|;Naiki|Taku|T|;Kondo|Masahiro|M|;Iida|Keitaro|K|;Kondo|Yuki|Y|;Tasaki|Yoshihiko|Y|;Kataoka|Tomoya|T|;Hotta|Asami|A|;Yasui|Takahiro|T|;Kimura|Kazunori|K|",
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"fulltext": "\n==== Front\nUrol Case RepUrol Case RepUrology Case Reports2214-4420Elsevier S2214-4420(17)30028-110.1016/j.eucr.2017.02.001OncologySyndrome of Inappropriate Secretion of Antidiuretic Hormone Caused by Carboplatin After Switching from Cisplatin in a Metastatic Urethral Cancer Patient Sugiyama Yosuke aNaiki Taku naiki@med.nagoya-cu.ac.jprx-nike@hotmail.co.jpb∗Kondo Masahiro aIida Keitaro bKondo Yuki aTasaki Yoshihiko aKataoka Tomoya cHotta Asami dYasui Takahiro bKimura Kazunori aca Department of Pharmacy, Nagoya City University Hospital, Nagoya, Japanb Department of Nephro-Urology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japanc Department of Clinical Pharmaceutics, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japand Department of Endocrinology and Diabetes, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan∗ Correspondence author. Department of Nephro-Urology, Nagoya City University, Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-cho, Mizuho-ku 467-8601, Nagoya, Japan. Fax: +81 52 852 3179.Department of Nephro-UrologyNagoya City UniversityGraduate School of Medical Sciences1, Kawasumi, Mizuho-choMizuho-kuNagoya467-8601Japan naiki@med.nagoya-cu.ac.jprx-nike@hotmail.co.jp01 3 2017 5 2017 01 3 2017 12 17 19 1 2 2017 6 2 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).There is no established chemotherapy regimen in metastatic primary urethral cancer (mPUC). The efficacy of a cisplatin (CDDP)-based regimen has been reported, however, when the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) occurs, the chemotherapy regimen should be changed to another platinum compound. In this report, we describe a 66-year-old woman who was diagnosed as mPUC with, CDDP-induced SIADH. After switching her to CBDCA and careful managing her sodium balance, three courses of the chemotherapy regimen were completed.\n\nKeywords\nSIADHUrethral carcinomaCarboplatinCisplatin\n==== Body\nIntroduction\nPrimary urethral carcinoma (PUC) is an extremely rare malignancy. Recent reports described an annual incidence of 4.3 million in men, according to a review of databases from 1973 to 2002. In women, the incidence was about one-third higher than that in men. There is no established treatment for metastatic PUC (mPUC). Recent NCCN guidelines recommend that chemotherapy should be done based on the histology,1 and in squamous cell carcinoma (SCC), which was most common in PUC, platinum-based chemotherapy should be performed in order to improve overall survival.2\n\nDuring cisplatin-based chemotherapy, electrolyte abnormalities are common adverse effects that manifest regardless of primary site, and hyponatremia is the most common of them. Severe hyponatremia affects not only quality of life but may also be life threatening SIADH, which is symptomized by severe hyponatremia, is characterized by water retention, central nervous system disorders, and pulmonary or endocrine disease. Cisplatin (CDDP) is associated with a higher incidence of SIADH than other platinum preparations, and some reports suggest that if CDDP-induced SIADH occurs, the regimen should be changed to another platinum compound.3 Nevertheless, no report has discussed the efficacy of switching from CDDP to carboplatin (CBDCA) after the emergence of SIADH. We report here on one case of severe CDDP-induced SIADH in a mPUC patient, in whom we managed the sodium balance and performed a total of 3 cycles of chemotherapy after switching to a CBDCA-based regimen.\n\nCase presentation\nA 66-year-old woman was admitted for investigation of continuous hematuria. Magnetic resonance imaging of the pelvis demonstrated a 40 × 36 mm multiseptated cystic mass replacing most of the pelvis (Fig. 1a, b), and transurethral biopsy of the vaginal mass revealed a squamous cell carcinoma. Computed tomography (CT) revealed bilateral inguinal lymph node metastases and multiple lung metastases, so the final diagnosis of the clinical stage was cT3N1M1. After informed consent, she received induction first-line chemotherapy, approved by the Institutional Review Board of Nagoya City University Hospital. The systemic chemotherapy regimen was based on penile cancer; CDDP (25 mg/m2 day 1–3), paclitaxel (PTX) (175 mg/m2 day 1) and ifosfamide (1200 mg/m2 day 1–3) were administered intravenously, and 4000 mL hydration per day was administered for 3 days in order to prevent toxicity. On day 4, she complained of moderate nausea and fatigue, and the symptoms worsened. On day 6, her serum sodium level was reduced to 101 mEq/L, the antidiuretic hormone (ADH) level was increased to 8.8 pg/mL (<4.2 pg/mL), and the plasma osmolality was 227 mOsm/kg, and urine osmolality was 492 mOsm/kg; the serum creatinine was 0.64 mg/dL, and the serum cortisol was 31.4 μg/dL (4.5–21.1 μg/dL) without edema or dehydration. She was diagnosed as CDDP-induced SIADH and treated with cautious hypertonic saline infusion. Her nausea was resolved and she recovered fully from fatigue. Her serum sodium level rose gradually to 133 mEq/L during 72 hours. She subsequently received 2 courses of a combination of PTX and ifosfamide without CDDP, which showed little efficacy against the metastatic lesions, supported by oral sodium and careful monitoring. SIADH did not recur, but the treatment was ineffective, and CT revealed progression of lung metastatic sites. She was received 3 courses of PTX and CBDCA as second-line chemotherapy, with continuous careful monitoring and sodium taken orally. After one complete cycle her serum sodium level had decreased, and the ADH was increased; she was diagnosed as a relapse of SIADH on day 5 of the second cycle (Fig. 2), but it was controllable. In addition, grade 2 anorexia appeared as an adverse event, but it improved within 2 days. After 2 cycles of the second-line treatment the metastatic sites were stable, so one more cycle of the same regimen was administered. After completion of a total of 3 cycles of the PTX and CBDCA combination, her performance status worsened because of progression, and she died of cancer after palliative therapy for 2 months.\n\nDiscussion\nSIADH is a disorder of impaired water excretion caused by an inability to suppress secretion of ADH. Some anticancer drugs may cause SIADH, in particular, CBDCA (Table 1) in combinations with PTX. In this case, SIADH occurred during first-line CDDP-based treatment, but the second and third cycles of treatment without CDDP did not cause hyponatremia. Uchida et al4 reported that CDDP induces SIADH by: (i) hyponatremia, which triggers increased renal salt reabsorption in order to reduce renal Na+ excretion in the loops of Henle, (ii) increased water re-absorption in the collecting ducts, which reduces the risk of nephrotoxicity, (iii) increased secretion of ADH induced by vomiting and pain. It was reported that CDDP-induced SIADH 4–6 days after start of treatment, and CBDCA caused SIADH within a similar time frame (Table 1). Therefore, during administration of the combination regimen, PTX and CBDCA, serum sodium levels should be monitored from the beginning treatment.\n\nThe pathogenesis of CBDCA-induced SIADH is unknown. Kagawa et al5 reported a successful completion of treatment with a combination of CBDCA and vindesine after switching from the regimen containing CDDP and vindesine in a lung cancer patient. The cases discussed here posed a high risk to the renal function partly because several of them needed a urinary diversion or a functioning solitary kidney. In urethral cancer, as in our case, it is not possible to switch from cisplatin even when electrolyte abnormalities occur, so switching to CBDCA from CDDP might be an option.\n\nConclusion\nWe experienced a case of severe SIADH caused by CDDP in a mPUC patient. Switching to a CBDCA-based regimen might be a feasible option in very rare urological malignancies.\n\nConflict of interest\nThere are no potential conflicts of interest.\n\nAcknowledgments\nNone.\n\nFunding: The authors received no financial support for the research, authorship, and/or publication of this article.\n\nFigure 1 Magnetic resonance imaging of the pelvis. Urethral tumor (white arrow) and bilateral inguinal lymph node metastases (white arrowhead).\n\nFigure 1Figure 2 Serum sodium and antidiuretic hormone (ADH) level Serum sodium level decreased to 101 mEq/L on day 6 of the first cycle of the initial chemotherapy. Serum ADH level was 8.8 pg/mL. Hyponatremia was improved by sodium supplementation, and then chemotherapy could be continued. During second-line chemotherapy, after completion of one cycle of the regimen, the patient's serum sodium level was again decreased and ADH increased, and she was diagnosed as relapse of SIADH on day 5 of the second cycle.\n\nFigure 2Table 1 Summary of articles on syndrome of inappropriate secretion of antidiuretic hormone (SIADH) caused by CBDCA\n\nTable 1Age/Sex\tTumor Type\tChemotherapy Regimen\tOnset of SIADH (Day After Injection of CBDCA)\tNadir Serum Sodium Level (mEq/mL)\tTreatment\t\n63/F\tAdenocarcinoma in ovary\tCBDCA + PTX\t5\t109\tUnknown\t\n60/F\tAdenocarcinoma in lung\tCBDCA + PTX\t6\t101\t3% saline infusion\t\n49/F\tBreast cancer\tCBDCA + DTX + trastuzumab\t6\t105\tFluid restriction\t\n71/F\tAdenocarcinoma in lung\tCBDCA + PEM\t7\t118\tSaline infusion (dose unknown)\t\nCurrent case\tSquamous cell carcinoma in urethra\tCBDCA + PTx + ifosfamide\t4\t101\t3% saline infusion\t\nCBDCA, carboplatin; DTX, docetaxel; PEM, pemetrexed; PTX, paclitaxel; SIADH, syndrome of inappropriate secretion of antidiuretic hormone.\n==== Refs\nReferences\n1 National Comprehensive Cancer Network, Inc. The NCCN Guidelines, Version 2 2016 https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf Accessed 12 September 2016 \n2 Dayyani F. Hoffman K. Eifel P. Management of advanced primary urethral carcinomas BJU Int 114 2014 25 31 24447439 \n3 Reyad D. Zekri J. Farag K. Hyponatremia and SIADH frequency in clinically euvolemic patients receiving chemotherapy: prospective study in unselected patients' cohort J Cancer Sci Ther 8 2016 3 \n4 Uchida Y. Kinoshita K. Tanaka T. Two cases of SIADH in patients with gastrointestinal cancer possibly induced by CDDP in FP chemotherapy Jpn J Gastroenterol Surg 37 2004 1588 1593 \n5 Kagawa K. Fujitaka K. Isobe T. Syndrome of inappropriate secretion of ADH (SIADH) following cisplatin administration in a pulmonary adenocarcinoma patient with a malignant pleural effusion Intern Med 40 2001 1020 1023 11688826\n\n",
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"keywords": "Carboplatin; Cisplatin; SIADH; Urethral carcinoma",
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"abstract": "BACKGROUND\nToxic shock syndrome (TSS) is a rare but serious, life-threatening medical condition and potentially lethal if not detected and treated early. It is mainly caused by a toxin called toxin-1 produced by Staphylococcus aureus, and characterized by fever, hypotension, rash, skin desquamation and multisystem involvement.\n\n\nMETHODS\nHerein, we describe a nine-month-old male patient who presented to the hospital complaining of fever, vomiting and hypoactivity on day one post-orchidopexy. During hospitalization, his condition began to deteriorate with signs and symptoms of multisystemic failure. Laboratory tests and radiological images were done, leading to the decision to reopen and drain the surgical wound. Wound and nasal swabs were cultured and showed S. aureus infection, and the diagnosis of toxic shock syndrome was confirmed.\n\n\nCONCLUSIONS\nTSS is a systemic illness resulting from overwhelming host response to bacterial exotoxins, that cause T cells activation and the release of pro-inflammatory cytokines (IL-1 and TNF-α causing fever, hypotension, and tissue injury). Also, it can present with CNS signs that may be misdiagnosed with meningitis in pediatrics. It requires early identification and treatment despite its rarity with mortality rate of 81% even with treatment. The patient's presentation, examination and laboratories tests with the blood and wound cultures were highly suggestive for this condition.\n\n\nCONCLUSIONS\nPhysicians must maintain a high index of suspicion for TSS, as early diagnosis and treatment make a difference. This condition shouldn't be excluded even in young age patients or after simple procedure as in our case in which TSS occurred after orchidopexy.",
"affiliations": "Al-Quds University, Faculty of Medicine, Jerusalem, State of Palestine. Electronic address: yo_usef97@hotmail.com.;Al-Quds University, Faculty of Medicine, Jerusalem, State of Palestine.;Al-Quds University, Faculty of Medicine, Jerusalem, State of Palestine.;Al-Quds University, Faculty of Medicine, Jerusalem, State of Palestine.;Al-Quds University, Faculty of Medicine, Jerusalem, State of Palestine.;Palestine Red Crescent Society Hospital, Hebron, State of Palestine.",
"authors": "Abuzneid|Yousef S|YS|;Rabee|Abdelrahman|A|;Alzeerelhouseini|Hussam I A|HIA|;Ghattass|Deema W S|DWS|;Shiebat|Nermeen|N|;Abukarsh|Radwan|R|",
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"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612\nElsevier\n\nS2210-2612(21)01089-0\n10.1016/j.ijscr.2021.106587\n106587\nCase Report\nPost-surgical staphylococcal toxic shock syndrome in pediatrics: A case report\nAbuzneid Yousef S. yo_usef97@hotmail.com\na⁎1\nRabee Abdelrahman a1\nAlzeerelhouseini Hussam I.A. a\nGhattass Deema W.S. a\nShiebat Nermeen a\nAbukarsh Radwan b\na Al-Quds University, Faculty of Medicine, Jerusalem, State of Palestine\nb Palestine Red Crescent Society Hospital, Hebron, State of Palestine\n⁎ Corresponding author at: Al-Quds University, Main Campus, Abu Dis, P.O. Box 89, State of Palestine. yo_usef97@hotmail.com\n1 Yousef S. Abuzneid and Abdelrahman Rabee contributed equally to this work.\n\n10 11 2021\n12 2021\n10 11 2021\n89 10658729 9 2021\n3 11 2021\n9 11 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nIntroduction\n\nToxic shock syndrome (TSS) is a rare but serious, life-threatening medical condition and potentially lethal if not detected and treated early. It is mainly caused by a toxin called toxin-1 produced by Staphylococcus aureus, and characterized by fever, hypotension, rash, skin desquamation and multisystem involvement.\n\nCase presentation\n\nHerein, we describe a nine-month-old male patient who presented to the hospital complaining of fever, vomiting and hypoactivity on day one post-orchidopexy. During hospitalization, his condition began to deteriorate with signs and symptoms of multisystemic failure. Laboratory tests and radiological images were done, leading to the decision to reopen and drain the surgical wound. Wound and nasal swabs were cultured and showed S. aureus infection, and the diagnosis of toxic shock syndrome was confirmed.\n\nDiscussion\n\nTSS is a systemic illness resulting from overwhelming host response to bacterial exotoxins, that cause T cells activation and the release of pro-inflammatory cytokines (IL-1 and TNF-α causing fever, hypotension, and tissue injury). Also, it can present with CNS signs that may be misdiagnosed with meningitis in pediatrics.\n\nIt requires early identification and treatment despite its rarity with mortality rate of 81% even with treatment.\n\nThe patient's presentation, examination and laboratories tests with the blood and wound cultures were highly suggestive for this condition.\n\nConclusion\n\nPhysicians must maintain a high index of suspicion for TSS, as early diagnosis and treatment make a difference. This condition shouldn't be excluded even in young age patients or after simple procedure as in our case in which TSS occurred after orchidopexy.\n\nHighlights\n\n• Toxic shock syndrome is a life-threatening condition that can be highly mortal even with treatment.\n\n• Post-surgical TSS is very rare and according to the literature this is the first reported case post-orchidopexy.\n\n• Broad spectrum antibiotics with debridement of the necrotic tissue as management are the best option to treat this condition.\n\nKeywords\n\nPost-surgical\nInfection\nToxic shock syndrome\nPediatric surgery\n==== Body\npmc1 Introduction\n\nToxic shock syndrome (TSS) is a toxin-mediated, acute, and potentially life-threatening condition that is usually precipitated by infection with either Staphylococcus aureus or group A Streptococcus (GAS), also called Streptococcus pyogenes [1]. And it mainly results from an overwhelming host response to bacterial superantigens that activates T lymphocytes with a massive release of proinflammatory cytokines responsible for fever, rash, septic shock, and multiple organ failures [2]. The mortality in pediatric patients approaches 5% for TSS secondary to S. aureus and up to 10% for TSS secondary to Streptococcus pyogenes [3].\n\nPostoperative TSS is a rare clinical entity occurring in only 0.003% of surgical cases [4]. Herein, we present a rare and interesting case of postoperative Staphylococcal TSS in a nine-month-old male which is, according to our literature, the first reported case of TSS occurring after orchidopexy.\n\nThe work has been reported in line with the SCARE 2020 criteria [17].\n\n2 Case presentation\n\nA nine-month male infant came to our ER (Palestine Red Crescent Society Hospital, Hebron, State of Palestine) complaining of high-grade fever with vomiting and hypoactivity after one day post-operation due to a left non-palpable undescended testis. The fever was registered as 39 °C axillary and the patient also manifested irritability and was found to be in severe dehydration, so he was admitted as a case of viral gastritis in another hospital.\n\nDuring the course of his hospitalization (thirteen days), he also developed watery diarrhea which was associated with poor feeding and abdominal distention. Moreover, his condition continued deteriorating, showing signs and symptoms of abdominal distention, rigidity, tenderness, high grade fever, decreased urine output, drowsiness, and bloody stool. After that, the infant was referred to our hospital for further investigations and management.\n\nOn arrival, laboratory tests and a detailed physical examination were performed. The patient looked ill, tachypneic and grunting with a blood pressure of 90/40 mmHg, abdominal distention, rigid abdomen (more on the left side where a left inguinal incision of 5 cm was present) and tenderness. He also was hypoactive and semiconscious with a GCS (Glasgow Coma Scale) of 8 [18].\n\nLaboratory findings showed that he had a low hemoglobin level of 7.5 g/dL, a high WBCs count of 15.5 × 103/μL and a low platelet count of 54 × 103/μL. He also had low potassium (2.7 mmol/L), high urea (33 mg/dL), high ammonia (80.5 μ/dL), high AST (192 U/L) and ALT (739 U/L), high PT (33 s) and INR (2.32) and low albumin (2 g/dL).\n\nBlood gases also showed metabolic acidosis with compensatory respiratory alkalosis in which the pH was 7.35 with a pCO2 level of 16 mmHg and a HCO3 level of 9 mEq/L.\n\nAfter few hours, the patient developed O2 desaturation, so he was connected to oxygen by nasal cannula (0.5–1 L) and transferred to the Pediatric Intensive Care Unit (PICU) in our hospital. Consequently, two peripheral cannulas were inserted, and blood cultures were taken. We also kept the patient NPO (nil per os) and gave an IV (intravenous) fluid expansion with dextrose saline (DS) 0.45 with 7% dehydration and maintenance and started him on meropenem (200 mg once every 8 h) and vancomycin (200 mg once every 8 h).\n\nDue to his low platelets levels and abnormal coagulation profile, packed RBCs, fresh frozen plasma (FPP) and vitamin K were given.\n\nAn abdominal ultrasound was executed and showed dilated aperistaltic bowel loops but with good vascularity and no intussusceptions or volvulus. It also showed hepatomegaly (10 cm). More radiological images were performed, and an abdominal and chest CT scan showed a congested groin in which the left inguinal as well as the left abdominal wall were extending to the lower chest fatty plane containing few air bubbles, suggesting fasciitis with turbid fluid. Diffuse bowel loop dilation mostly due to an ileus and an enlarged liver of 10 cm were also noticed and there was evidence of bilateral pulmonary lower lobe infiltrates with ground glass appearance and/or atelectasis. Skin desquamation on both feet was seen on post-operative day 10 (Fig. 1).Fig. 1 Skin desquamation seen in post-operative day 10.\n\nFig. 1\n\nAfterwards, the surgical wound was opened, which secreted dirty fluid and made another incision over the most indurated area which also secreted dirty fluid. We kept the wound and the incision opened with drains on them and took a wound swab for culture which, later on, showed Staphylococcus aureus infection. We also took a nasal swab and blood and urine cultures giving as positive results only in the nasal swab for Staphylococcus aureus as well.\n\nAfter an antibiotic sensitivity test for the bacteria, we started the patient on clindamycin and tazocin.\n\nNPS (nasopharyngeal swab) for COVID-19 was also taken and was positive, so the patient was started also on azithromycin and budecort nebulizer.\n\nOn the second day of admission, a central line was inserted under US guidance and the patient was sent to the OR (operating room) where we did a surgical debridement of the wound under general anesthesia because there was infected necrotic tissue in the left inguinal region extending to the loin but with a healthy fascia. During the surgery, a second swab culture from the wound was taken and showed no bacterial growth.\n\nAfter the surgery, the patient had an endotracheal tube (ETT) and was connected to a mechanical ventilator under sedation for four days, remaining hemodynamically stable and weaning gradually the sedation until extubation. Meanwhile, there was daily wound care and dressing (Fig. 2) until the wound became healthy and without discharge so we could close the wound over a drain.Fig. 2 A. Opened wound for drainage after debridement of infected necrotic tissue. B. Closed wound after the removal of the drainage showing the skin in good conditions with no discharge before going home.\n\nFig. 2\n\nWe started to feed him gradually until well tolerated and full feeding capacities once he was extubated and awake. After one-week post-operation, the patient was discharged home in good general conditions.\n\n3 Discussion\n\nToxic shock syndrome (TSS) is a systematic severe illness which is characterized by shock, pyrexia, gastrointestinal disturbances, an erythematous rash, and central nervous system signs including lethargy or irritability (which can be misdiagnosed with those signs of meningitis in pediatrics) [5].\n\nStreptococcus and staphylococcus bacteria can both cause this condition through the elaboration of toxins. Streptococcus pyogenes (specially the M1 and M3 serotypes) and Staphylococcus aureus are the most common microorganisms associated with TSS [6].\n\nThese organisms cause an overwhelming host response to bacterial superantigens through mitogenic exotoxins which bind to a major histocompatibility complex class-II (MHC-2), CD28 costimulatory receptors, and T-cell receptors which furthermore result in a constitutive activation of T-cells and proinflammatory cytokine release [7].\n\nDifferent strains of Staphylococcus aureus produce TSS toxin 1 and staphylococcal enterotoxin B and C, products that act as superantigens. These superantigens bind and activate T-cells indiscriminately, leading to the amplification of cytokines TNF-α and IL-1 (together, causing fever, hypotension, and tissue injury) [8].\n\nPostoperative TSS is extremely rare but going through the literature, it has been documented as a complication from a broad range of procedures. A contaminated product (i.e., napkin and tampon) as a cause of postoperative staphylococcal TSS was identified only in very few cases [9].\n\nAs mentioned in the introduction, only 0.003% of surgical cases has been identified as postoperative TSS [4].\n\nAs we can see in our case and as mentioned in the case presentation, our patient came complaining of high-grade fever, vomiting, hypoactivity, with a picture of gastritis and severe dehydration, which progressed to other signs and symptoms of shock. His laboratory results also indicated shock and the patient was deterioration fast, so we started the protocol for septic shock and gave the patient IV fluids and broad-spectrum of antibiotics as an initial treatment.\n\nHowever, it was not until the culture results and the physical manifestations of this condition (like the skin desquamation and the secretion of dirty fluid from the incision of the previous operation) that we realized the diagnosis.\n\nThis condition can be listed with other differential diagnosis such as Kawasaki disease, scarlet fever, Rocky Mountain Spotted fever and leptospirosis [13].\n\nMoreover, untreated TSS is fatal and mortality rates up to 81% have been reported even if the patients were treated. Herein, cases of TSS require a high index of suspicion, early antibiotic administration, and aggressive hemodynamic support [10] since hemodynamic instability and cardiovascular collapse are terminal manifestations of this condition and need treatment with aggressive fluid resuscitation and vasopressor support [6].\n\nBroad-spectrum antibiotics for the coverage of MRSA and streptococcus (i.e., vancomycin and linezolid) and gram-negative bacteria need to be initiated until antibiotic sensitivity lab results come (then switch to the appropriate antibiotic). Also, clindamycin should be used to counteract the systemic effects that the toxins will produce after their release [6].\n\nTherapy with corticosteroids for TSS is poorly studied, with few papers demonstrating a reduction in the duration of fever and severity of the illness [11], [12].\n\nThe administration of intravenous immune-globulin or also known as IVIG (usually 1–2 g/kg) has been proposed in many articles as a potential adjunct in the treatment of TSS due to the effect of immunoglobulins by blocking the activation of T-cells by both staphylococcal and streptococcal superantigens. They also contribute by improving bacterial opsonization, phagocytosis, and destruction [14], [15], [16].\n\nIn comparison to the case that we present, we indeed started with broad-spectrum antibiotics which were vancomycin and meropenem. However, we did not include corticosteroids nor IVIG to his treatment. Also, in was not until we received the laboratory and culture results about the incision that we diagnosed him and switched to more specific antibiotics (clindamycin and tazosin) after the sensitivity tests results were concluded.\n\nWe also had to re-open the incision, debride the necrotic tissue and let it open for wound care and dressing to a better control and better care, preventing another future complication.\n\nAfter full recovery and good food intake, we were able to discharge the patient to his house in good conditions.\n\nTo summarize, the infant that we present in this case report was referred to our hospital as a case of gastritis with severe dehydration. Thorough examination and laboratory testing, the patient was found to have high grade fever, hypotension and signs and symptoms of multisystemic involvement including diarrhea, decreased urine output, drowsiness, semi-consciousness, and bloody stool and desquamation of the skin. Thus, rising the suspicion for having TSS.\n\nHe had low platelets, low hemoglobin, high urea, high ammonia, high liver enzymes and PT and INR, and lot albumin. In addition, wound culture was done and returned positive for Staphylococcus aureus, making the diagnosis towards TSS clearer.\n\nHerein, we started his treatment with broad spectrum antibiotics, which we switched to a more specific one after the antibiotic sensitivity test came back.\n\nThis case report reflects and fulfils all the criteria for the diagnosis of TSS due to the correlating findings that we mention above.\n\n4 Conclusion\n\nWe describe a case of a nine-month-old infant who presented to our hospital as a picture of postoperative TSS.\n\nWe believe that this reported case (TSS post-orchidopexy) is one of its kind according to the literature review and it should be written so all the physicians can know about it and be aware.\n\nThe diagnosis was challenging perse, but full examination and laboratory tests were highly suggestive for the diagnosis. Blood and wound cultures were taken, and the patient was started on broad spectrum antibiotics which then were switched to more specific ones according to the antibiotic sensitivity tests.\n\nSurgical debridement of the wound was performed because due to this condition, necrosis of the skin was notices. After that, the patient was discharged in good conditions a week later.\n\nIt is very important that the physicians, especially the surgeons, know about this possible complication after post-orchidopexy because such condition, which is rare but fatal, can be well controlled and easily treated if discovered promptly.\n\nEthical approval\n\nThe study is exempt from ethical approval in our institution.\n\nSources of funding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nCRediT authorship contribution statement\n\nStudy concept or design: Radwan Abukarsh.\n\nData collection and data analysis: Yousef S. Abuzneid.\n\nWriting the manuscript: Yousef S. Abuzneid, Abdelrahman Rabee, Hussam I. A. Alzeerelhouseini, Deema W. S. Ghattass, Raed A. H. Jubran, Nermeen Shiebat.\n\nReview & editing the manuscript: Yousef S. Abuzneid, Abdelrahman Rabee.\n\nRegistration of research studies\n\nNot applicable.\n\nGuarantor\n\nDr. Yousef S. Abuzneid.\n\nConsent\n\nWritten informed consent was obtained from the patient's parents for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nDeclaration of competing interest\n\nThere is no conflict of interest.\n\nAcknowledgments\n\nThe authors are very thankful for the contribution of Dr. Raed A. Jubran who helped us in collecting the data and search the literature review of this case report.\n==== Refs\nReferences\n\n1 Silversides J.A. Lappin E. Ferguson A.J. Staphylococcal toxic shock syndrome: mechanisms and management Curr. Infect. Dis. Rep. 12 5 2010 392 400 10.1007/s11908-010-0119-y 21308522\n2 Ladhani S. Understanding the mechanism of action of the exfoliative toxins of Staphylococcus aureus FEMS Immunol. Med. Microbiol. 39 2 2003 181 189 10.1016/S0928-8244(03)00225-6 14625102\n3 Chuang Y.Y. Huang Y.C. Lin T.Y. Toxic shock syndrome in children: epidemiology, pathogenesis, and management Paediatr. Drugs 7 1 2005 11 25 10.2165/00148581-200507010-00002 15777108\n4 Graham D.R. O'Brien M. Hayes J.M. Raab M.G. Postoperative toxic shock syndrome Clin. Infect. Dis. 20 4 1995 895 899 7795091\n5 Slingluff C.L. Jr. Burns W.W. Cooperberg C. Toxic shock syndrome after inguinal hernia repair. Report of a case with patient survival Am. Surg. 56 10 1990 Oct 610 612 PMID: 2221610 2221610\n6 Chandra R. Gold S. Kohler C. Valladares J. Hennessy S.A. Bhat S.G. When all Else fails: a rare case of postoperative toxic shock syndrome arising from surgical site infection after decompressive neurectomy successfully treated with angiotensin-2 Case Rep. Crit. Care 10 2021 2021 Feb 6698218 PMID: 33628522; PMCID: PMC7889388\n7 Proft T. Fraser J.D. Streptococcal superantigens: biological properties and potential role in disease. Ferretti J.J. Stevens D.L. Fischetti V.A. Streptococcus pyogenes: Basic Biology to Clinical Manifestations [Internet] 2016 2016 Feb 10 University of Oklahoma Health Sciences Center Oklahoma City (OK) PMID: 26866236\n8 Schlievert P.M. Bohach G.A. Ohlendorf D.H. Stauffacher C.V. Leung D.Y. Murray D.L. Prasad G.S. Earhart C.A. Jablonski L.M. Hoffmann M.L. Chi Y.I. Molecular structure of staphylococcus and streptococcus superantigens J. Clin. Immunol. 15 6 Suppl 1995 Nov 4S 10S 10.1007/BF01540887 Erratum in: J Clin Immunol 1996 Mar;16(2):126. PMID: 8613491 8613491\n9 Bartlett P. Reingold A.L. Graham D.R. Dan B.B. Selinger D.S. Tank G.W. Wichterman K.A. Toxic shock syndrome associated with surgical wound infections JAMA 247 10 1982 Mar 12 1448 1450 PMID: 7057535 7057535\n10 Davies H.D. McGeer A. Schwartz B. Green K. Cann D. Simor A.E. Low D.E. Invasive group a streptococcal infections in Ontario, Canada. Ontario group a streptococcal study group N. Engl. J. Med. 335 8 1996 Aug 22 547 554 10.1056/NEJM199608223350803 PMID: 8684408 8684408\n11 Vergis N. Gorard D.A. Toxic shock syndrome responsive to steroids J. Med. Case Rep. 16 1 2007 Feb 5 PMID: 17411451; PMCID: PMC1839760\n12 Todd J.K. Ressman M. Caston S.A. Todd B.H. Wiesenthal A.M. Corticosteroid therapy for patients with toxic shock syndrome JAMA 252 24 1984 Dec 28 3399 3402 PMID: 6389917 6389917\n13 Raghavendra P. Kharidehal N. Staphylococcal toxic shock syndrome in a 3-year-old male child. The internet J. Infect. Dis. 5 2 2005\n14 Lappin E. Ferguson A.J. Gram-positive toxic shock syndromes Lancet Infect. Dis. 9 5 2009 May 281 290 10.1016/S1473-3099(09)70066-0 PMID: 19393958 19393958\n15 Schmitz M. Roux X. Huttner B. Streptococcal toxic shock syndrome in the intensive care unit Ann. Intensive Care 8 2018 88 10.1186/s13613-018-0438-y 30225523\n16 Mouthon L. Kaveri S.V. Spalter S.H. Lacroix-Desmazes S. Lefranc C. Desai R. Kazatchkine M.D. Mechanisms of action of intravenous immune globulin in immune-mediated diseases Clin. Exp. Immunol. 104 Suppl 1 1996 May 3 9 PMID: 8625540 8625540\n17 Agha R.A. Franchi T. Sohrabi C. Mathew G. Kerwan A. SCARE Group The SCARE 2020 guideline: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg. 84 2020 226 230 10.1016/j.ijsu.2020.10.034 33181358\n18 Adapted from: Advanced Trauma Life Support: Course for Physicians 1993 American College of Surgeons\n\n",
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"abstract": "The purpose of this study was to assess autoantibody incidence in patients treated with infliximab for various diseases, and the development of autoimmune diseases using a multicenter, longitudinal, open-label, phase IV observational study. All patients received anti-tumor necrosis factor (anti-TNF) according to local treatment guidelines. The autoantibodies assessed before and after infliximab treatment were ANA, anti-Sm, anti-dsDNA, anticardiolipin IgM/IgG, anti-Scl70, anti-centromere B, anti-chromatin, anti-ribosomal P, anti-Sm-RNP, anti-RNP A, anti-RNP 68 kD, anti-La/SSB, anti-Ro/SSA 52 kD and 60 kD, and anti-Jo1. ANA was determined by indirect immunofluorescence on HEp-2 cells (INOVA); the remaining was assessed using BioPlexTM 2200. The Fisher exact test, Wilcoxon test, and the McNemar were used when appropriate.Two hundred eighty-six patients were included (139 with rheumatoid arthritis, 77 with ankylosing spondylitis, 29 with inflammatory bowel disease, 27 with psoriatic arthritis, and 14 with psoriasis), 167 females and 119 males, with mean age of 46.3 years. Subjects received at least five infusions of infliximab (6-month treatment). A significant difference was observed in antinuclear antibody (ANA) detection between samplings (p = 0.001). Among patients that had ANA before treatment (n = 92), six became ANA-negative, 48 had increased titers, 29 maintained, and nine decreased titers after treatment; a total of 186 patients had a positive ANA after treatment. Fine speckled nuclear pattern was most commonly observed (both before and after infliximab treatment). The number of patients with anti-dsDNA had a statistically significant increase (p = 0.003). No significant differences were noted for anticardiolipin and the remaining autoantibodies tested. Among the 286 patients included in the study, only one (0.35 %) showed clinical signs of drug-induced lupus, presenting elevated ANA and anti-dsDNA titers that normalized once treatment was discontinued. Infliximab induced the formation of autoantibodies in the combined population (ANA and anti-dsDNA with no apparent clinical importance).",
"affiliations": "Departamento de Reumatologia, Universidade Federal do Estado Rio de Janeiro, Rio de Janeiro, Brazil.;Departamento de Reumatologia, Universidade de Cuiabá, Cuiabá, Brazil.;Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.;Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.;Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil. roger.a.levy@gmail.com.",
"authors": "Vaz|João Luiz Pereira|JL|;Fernandes|Vander|V|;Nogueira|Felipe|F|;Arnóbio|Adriano|A|;Levy|Roger A|RA|",
"chemical_list": "D018501:Antirheumatic Agents; D001323:Autoantibodies; D000069285:Infliximab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-015-3140-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "35(2)",
"journal": "Clinical rheumatology",
"keywords": "Autoantibodies; Biomarkers; Diagnostic tests; Infliximab; Pharmacovigilance",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D018501:Antirheumatic Agents; D001323:Autoantibodies; D005260:Female; D006801:Humans; D000069285:Infliximab; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "325-32",
"pmc": null,
"pmid": "26676808",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "23379516;15142273;16319094;24557776;7524507;16425572;18578960;15535831;16829990;15986349;16239844;15899041;25554102;24456934;24899660;19762393;19291351;21801160;15297281;24217668;21125159",
"title": "Infliximab-induced autoantibodies: a multicenter study.",
"title_normalized": "infliximab induced autoantibodies a multicenter study"
} | [
{
"companynumb": "BR-JNJFOC-20160223065",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Leukoencephalopathies have been reported after heroin inhalation or ingestion, and buprenorphine injection, but the physiopathology remains unclear. We report here the first case of leukoencephalopathy caused by buprenorphine ingestion in a 2-year-old child who was admitted for coma and fever. Due to technical problems, the toxicology screen was delayed, and infectious disease was first suspected. A brain MRI found bilateral and symmetric white matter damages in the cerebral hemispheres and the cerebellum. Rapid recovery and positive toxicology screen for buprenorphine on day 4 confirmed the diagnosis of acute intoxication.",
"affiliations": "Unité de Réanimation Pédiatrique et Néonatale et Brûlés Pédiatriques, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Nord, Chemin des Bourrely, 13915 Marseille, Cedex 20, France.",
"authors": "Bellot|Blandine|B|;Michel|Fabrice|F|;Thomachot|Laurent|L|;Chaumoitre|Kathia|K|;Battaglia|Fabrice|F|;Lagier|Pierre|P|",
"chemical_list": "D000701:Analgesics, Opioid; D002047:Buprenorphine",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejpn.2011.03.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1090-3798",
"issue": "15(4)",
"journal": "European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society",
"keywords": null,
"medline_ta": "Eur J Paediatr Neurol",
"mesh_terms": "D000208:Acute Disease; D000701:Analgesics, Opioid; D001925:Brain Damage, Chronic; D002047:Buprenorphine; D002675:Child, Preschool; D003128:Coma; D005334:Fever; D006801:Humans; D056784:Leukoencephalopathies; D008279:Magnetic Resonance Imaging; D008297:Male",
"nlm_unique_id": "9715169",
"other_id": null,
"pages": "368-71",
"pmc": null,
"pmid": "21450498",
"pubdate": "2011-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute leukoencephalopathy after buprenorphine intoxication in a 2-year-old child.",
"title_normalized": "acute leukoencephalopathy after buprenorphine intoxication in a 2 year old child"
} | [
{
"companynumb": "FR-RB-025150-11",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPRENORPHINE HYDROCHLORIDE"
},
"drugadditional": "4",
... |
{
"abstract": "The treatment of alcohol use disorder (AUD) with sodium oxybate (SMO) or gamma-hydroxybutyric acid (GHB) was introduced in Italy and Austria more than 20 years and 15 years ago, respectively, and it is now widely employed to treat alcohol withdrawal syndrome (AWS) and to maintain alcohol abstinence. These indications derive from its similar structure to the inhibitory neurotransmitter γ-amino-butyric acid (GABA), exerting an ethanol-mimicking effect, because it binds to GABAB receptors. Craving for, and abuse of, SMO remain a controversial issue; even though these unfavorable effects are evident in poly-drug addicted patients and in those with psychiatric diagnosis of borderline personality disorder. In addition, despite cases of severe intoxication and deaths being widely documented when GHB is used as \"street drug\"; its clinical use remains safe. Thus, the aim of the present review is to examine the role of SMO in the treatment of AUD, its possible implications in reducing alcohol consumption, and cases of abuse, and severe intoxication due to SMO during its clinical use in the treatment of AUD.",
"affiliations": "Department of Internal Medicine, SS Annunziata Hospital, Cento, Ferrara 44042, Italy. f.caputo@ausl.fe.it.;Unit for Addiction Treatment, Department of Mental Health, Lugo, Ravenna 48022, Italy. teo.vignoli@ausl.ra.it.;Alcohol Use Disorders Unit, Department of Internal Medicine, Catholic University of Rome, Rome 00168, Italy. claudia.tarli@gmail.com.;\"G. Fontana\" Centre for the Study and Multidisciplinary Treatment of Alcohol Addiction, Department of Clinical Medicine, University of Bologna, Bologna 40130, Italy. m.domenicali@unibo.it.;Department of Internal Medicine, SS Annunziata Hospital, Cento, Ferrara 44042, Italy. g.zoli@ausl.fe.it.;\"G. Fontana\" Centre for the Study and Multidisciplinary Treatment of Alcohol Addiction, Department of Clinical Medicine, University of Bologna, Bologna 40130, Italy. mauro.bernardi@unibo.it.;Alcohol Use Disorders Unit, Department of Internal Medicine, Catholic University of Rome, Rome 00168, Italy. addolorato@policlinicogemelli.it.",
"authors": "Caputo|Fabio|F|;Vignoli|Teo|T|;Tarli|Claudia|C|;Domenicali|Marco|M|;Zoli|Giorgio|G|;Bernardi|Mauro|M|;Addolorato|Giovanni|G|",
"chemical_list": "D006885:Hydroxybutyrates; D012978:Sodium Oxybate",
"country": "Switzerland",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nInt J Environ Res Public HealthInt J Environ Res Public HealthijerphInternational Journal of Environmental Research and Public Health1661-78271660-4601MDPI 10.3390/ijerph13030290ijerph-13-00290ReviewA Brief Up-Date of the Use of Sodium Oxybate for the Treatment of Alcohol Use Disorder Caputo Fabio 12*Vignoli Teo 3Tarli Claudia 4Domenicali Marco 2Zoli Giorgio 1Bernardi Mauro 2Addolorato Giovanni 4Maremmani Icro Academic Editor1 Department of Internal Medicine, SS Annunziata Hospital, Cento, Ferrara 44042, Italy; g.zoli@ausl.fe.it2 “G. Fontana” Centre for the Study and Multidisciplinary Treatment of Alcohol Addiction, Department of Clinical Medicine, University of Bologna, Bologna 40130, Italy; m.domenicali@unibo.it (M.D.); mauro.bernardi@unibo.it (M.B.)3 Unit for Addiction Treatment, Department of Mental Health, Lugo, Ravenna 48022, Italy; teo.vignoli@ausl.ra.it4 Alcohol Use Disorders Unit, Department of Internal Medicine, Catholic University of Rome, Rome 00168, Italy; claudia.tarli@gmail.com (C.T.); giovanni.addolorato@unicatt.it (G.A.)* Correspondence: f.caputo@ausl.fe.it; Tel.: +39-05-1683-835305 3 2016 3 2016 13 3 29022 12 2015 23 2 2016 © 2016 by the authors; licensee MDPI, Basel, Switzerland.2016This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).The treatment of alcohol use disorder (AUD) with sodium oxybate (SMO) or gamma-hydroxybutyric acid (GHB) was introduced in Italy and Austria more than 20 years and 15 years ago, respectively, and it is now widely employed to treat alcohol withdrawal syndrome (AWS) and to maintain alcohol abstinence. These indications derive from its similar structure to the inhibitory neurotransmitter γ-amino-butyric acid (GABA), exerting an ethanol-mimicking effect, because it binds to GABAB receptors. Craving for, and abuse of, SMO remain a controversial issue; even though these unfavorable effects are evident in poly-drug addicted patients and in those with psychiatric diagnosis of borderline personality disorder. In addition, despite cases of severe intoxication and deaths being widely documented when GHB is used as “street drug”; its clinical use remains safe. Thus, the aim of the present review is to examine the role of SMO in the treatment of AUD, its possible implications in reducing alcohol consumption, and cases of abuse, and severe intoxication due to SMO during its clinical use in the treatment of AUD.\n\nalcohol use disorderpharmacological treatmentsodium oxybate\n==== Body\n1. Introduction\nSodium oxybate (SMO) (gamma-hydroxybutyric acid (GHB), gamma hydroxybutyrate, or sodium salt of GHB), is a short-chain fatty acid that occurs naturally in the mammalian brain, in particular in the thalamus, hypothalamus, and basal ganglia [1]. SMO is structurally similar to the inhibitory neurotransmitter γ-amino-butyric acid (GABA) binding to GABAB receptors [1,2,3]. Its functions are as both a precursor and a metabolite of the GABA system. Irrespective of the brain SMO concentration, it is far from certain that SMO interacts directly with the GABAA receptor [4]. SMO is primarily eliminated by the liver by the enzyme GHB dehydrogenase, and by a still not fully ascertained process of beta-oxidation [1]. Only a modest quantity of SMO remains unmodified (2%–5%) and eliminated with urine with a relatively short window of detection (3–12 h) [2]. After exogenous ingestion of SMO, its maximum concentration occurs after 20–40 min, and its half-life is 30–50 min [5]. It is thought that the alcohol-mimicking effect of SMO is related to the effects of the dopamine increase mediated by GABAB receptors in the mesocorticolimbic circuitry [1,3,6]. This results in a decreasing GABA release with a consequent increase of dopamine within this system [1]. Indeed, the exact mechanism by which GABAB agonists exert their effect on alcohol craving is still a matter of research [7]. Most evidence suggests that mesolimbic dopaminergic neurons, originating in the ventral tegmental area and projecting their neurons into the nucleus accumbens, could play a pivotal role in the regulation of alcohol craving, being stimulated by alcohol consumption [7].\n\nIn the United States, the Food and Drug Administration approved SMO (Xyrem®) as a Schedule III Controlled Substance to treat cataplexy and excessive daytime sleepiness in patients with narcolepsy [8,9]. In Europe, SMO is used in Germany (Somsanit®) and in France (Gamma-OH®) for intravenous anesthesia, and has been used for the treatment of alcohol use disorder (AUD) in Italy (Alcover®) since 1992, and in Austria since 1999. Indeed, several studies have demonstrated that SMO is a safe and effective drug for treating AUD.\n\n2. SMO for the Treatment of Alcohol Withdrawal Syndrome\nAlcohol withdrawal syndrome (AWS) represents a clinical condition that usually develops in alcohol-dependent patients within 6–24 h after the abrupt discontinuation or decrease of alcohol consumption [10]. SMO was tested in preclinical and clinical settings for the treatment of AWS [11]. A meta-analysis performed in 2010 by the Cochrane Collaboration showed that SMO (50–100 mg/kg/day) is more effective than placebo in reducing the CIWA-Ar score with an equal efficacy to benzodiazepines and clomethiazole without any differences in the onset of side effects [12]. Recently, the GATE 1 study (phase IV, multicenter, multinational, randomized, double-blind, double-dummy, with parallel groups) showed that SMO presents a similar efficacy to oxazepam (one of the gold standard benzodiazepines) in the treatment of uncomplicated AWS [13].\n\n3. SMO as an Anti-Craving Drug to Treat Alcohol Use Disorder\nThanks to the ability of SMO to inhibit voluntary ethanol consumption, SMO is used for the treatment of AUD with very encouraging results in maintaining total alcohol abstinence.In particular, almost 50%–60% of treated patients achieve and maintain alcohol abstinence at the end of the first three months of treatment [14]; in addition, SMO is at least as effective as naltrexone (NTX) or disulfiram (DF) in the maintenance of abstinence in alcohol-dependent patients [12]. Concerns have been raised about the risk of developing addiction to, misuse, or abuse of SMO. However, clinical trials have shown that episodes of craving for, and abuse of, SMO in alcoholics are very limited (~10% of cases), and are mainly confined to patients with AUD associated with poly-drug addiction and psychiatric co-morbidity [3,11,12,15]. Moreover, cases of death related to SMO abuse have not been documented in clinical trials dedicated to the treatment of alcohol dependence [3,11] or narcolepsy [16]. However, “real-life trials” which would have improved the awareness of the negative impact of this phenomenon during the daily treatment of alcoholic patients with SMO have not been performed.\n\nIn addition, as reported recently by a survey among fifty Italian alcohologists [14], a consensus has been reached to prolong the treatment with SMO until a significant improvement in the motivation to abstain is achieved, to increase the dosages of SMO until the craving for alcohol is suppressed, and to not consider the treatment of SMO as being the “last chance” drug when no result has been achieved with other pharmacological and non-pharmacological treatments. From 50 to 100 mg/kg/day, fractioned into three to six daily administrations, could be considered a safe approach to use SMO [11,12,15]. About 30% of alcohol-dependent patients treated with SMO can develop side effects, represented by dizziness, sedation, and asthenia. These events do not, in general, require discontinuation of treatment, because the dizziness disappears spontaneously after the first doses, while sedation and asthenia disappear within 2–3 weeks. In addition, no side effects due to the combination of SMO 50 mg/kg and alcohol were observed in those SMO-treated alcoholics who were still drinking during the treatment [11,12,15]. This was also confirmed by a recent randomized, double-blind, double-dummy, cross-over trial in healthy volunteers aimed at exploring the pharmaco-dynamic interaction of the solid immediate release formulation of SMO and alcohol, which clearly showed that SMO and alcohol have separate adverse effect profiles, and that the objective effects of SMO are much less marked than those of alcohol, without any deleterious interaction [17]. However, larger clinical trials with alcohol dependent patients aimed at investigating a possible negative interaction during the concurrent intake of alcohol and SMO have not been performed, so that the suggestion not to drink during SMO administration represents a crucial message for physicians before prescribing this medication for AUD.\n\nSMO has also been evaluated in combination with other drugs. In particular, an open, randomized, comparative study evaluated the efficacy of SMO in combination with NTX in maintaining alcohol abstinence compared to SMO and NTX used singly [18]. These data confirm that the two drugs combine their different actions synergistically without suppressing the favorable effects of each other. In SMO treatment-resistant chronic alcoholics (30%–40%), the combination with DF was proposed. SMO-DF combines the adverse effect of DF with the anti-reward effect of SMO [19].\n\n4. Possible Role of SMO in Reducing Alcohol Consumption\nThe major outcome in the treatment of AUD remains total alcohol abstinence; this is because alcohol intake, even in low doses, continues to maintain the craving for alcohol and may also lead to abuse of alcohol [20]. Nevertheless, a reduction in alcohol intake, in particular for heavy drinkers, does lead to an improvement in physical and psychological health even if the patient does not achieve abstinence [21,22]. Moreover, a reduction of alcohol intake can represent a temporary step toward the achievement of complete abstinence [23,24]. In the light of these considerations, it has been demonstrated that all clinical studies testing the efficacy of SMO in maintaining abstinence from alcohol have recorded a number of patients who failed to achieve this primary end-point, but did reduce their alcohol intake [12]. In particular, SMO was shown to be significantly more effective than placebo in reducing the number of daily drinks (p < 0.00001) and in reducing relapses into heavy drinking (p < 0.00032) in a controlled clinical trial [25]. In a two-phase trial exploring the efficacy of dose-fractioning of SMO treatment, 17.4% of patients did not achieve complete abstinence but they significantly reduced their daily drinking (p < 0.05) at the end of the first three month phase [26]. An open multicenter study found a reduction of biomarkers of alcohol abuse after SMO treatment, and the group of patients who did not achieve complete abstinence, did reduce their average alcohol intake [27]. Maremmani et al. described a long term treatment with SMO in a population of treatment-resistant patients [28]; although the group was not so numerous, the partial responder group who reduced their alcohol intake for an average of 40% was larger than the total responders who achieved complete abstinence from alcohol (14.3% vs. 11.4%). More recent studies [29,30] investigating the efficacy of SMO in some particular population types (according to Lesch typology and with or without psychiatric co-morbidity) found that a relevant number of patients did not achieve complete abstinence, but they did not return to heavy drinking (41.7% of the total population) [29,30]. A recently published SMO trial [11] considered the cumulative days of abstinence (CAD) as the primary endpoint. This study demonstrated a borderline significance in favor of SMO in reducing CAD [11]. Considering SMO as a possible treatment option for reducing alcohol consumption, concerns remain about the side effects of the combination with alcohol.No additional sedative effects induced by drinking during SMO treatment were found in healthy subjects [17]. Moreover, considering that SMO is utilized both for treating AWS and to maintain abstinence, according to clinical practice, then complete abstinence from alcohol should not be considered an exclusion criterion for treatment with SMO [14].\n\nIn the light of these considerations, there is some preliminary evidence that SMO can be efficient in reducing alcohol intake in patients who fail to maintain total alcohol abstinence. It also seems that, for less motivated patients to achieve total alcohol abstinence immediately, the reduction in alcohol intake could be the primary end-point of SMO treatment, suggesting a role in harm reduction treatment. Unfortunately, the end points defined by published trials are varied and non-comparable: heavy drinking days, daily alcohol intake, total amount of alcohol intake, or cumulative days of abstinence. Thus, more studies to confirm these data and to explore the efficacy of SMO in patients considering alcohol reduction as their primary goal are warranted.\n\n5. Severe Intoxications Due to GHB: These Do not Refer to Its Clinical Use\nGHB as a “street drug”, sold for recreational use, is mostly reported in Anglo-Saxon countries [31]; however, experiences of this have also been reported in Italy [32,33]. “Street use” represents the first cause of GHB-related death [31]. Risk factors are unknown: dose/concentration, frequently combined use with other drugs, difficulties with dose titration [34], and narrow safety margins between a recreational dose and a fatal dose [35]. Cardiorespiratory depression is a documented dose-related effect of GHB [36], and it is likely to be the principal cause of death in GHB overdoses [31]. Whereas it is well known that a GHB blood concentration of 500 mg/L causes death due to cardiorespiratory depression, it is impossible to clearly define a “lethal” dose [4]. Reduced vigilance leading to trauma and driving impairment are other possible causes of GHB-related death [37]. Furthermore, considering that blood GHB levels increase substantially post mortem, even in persons in whom the cause of death excluded any possible exposure to GHB [38,39], a strictly causal relationship between GHB use and death is, sometimes, very difficult to clearly ascertain [4]. With regard to SMO treatment for AUD (Alcover®), there are no published data about related deaths [4]. In this regard, interestingly, only one case has been documented [40]; however, this was a heroin-dependent patient and the concomitant use of morphine would have played a crucial role as a cause of death.\n\n6. Conclusions\nAccording to many studies conducted to evaluate the pharmacological effects, SMO is efficient in the treatment of AWS and in achieving and maintaining total abstinence from alcohol.The pharmacological activity of this drug is well-known: thanks to its ethanol-mimicking effect binding GABAB receptors, SMO increases dopamine levels in the mesocorticolimbic circuitry and determines a craving reduction. None of the above-mentioned trials reported serious side effects during the treatment with SMO; craving for, and abuse of, SMO in alcohol-dependent patients represent a very limited phenomenon (~10%–15% of cases); particular caution in prescribing this drug in the case of alcoholics with poly-drug addiction and/or a borderline personality disorder is warranted. In addition, due to its very short half-life (30–50 min), the fractioning of the SMO doses from three to six daily administrations avoids the occurrence of further sedative effects in patients who voluntarily use alcohol during the treatment with this drug [3,11,14,15]. Moreover, since clinical trials aimed at investigating the efficacy of SMO in reducing alcohol consumption have not been performed, and since concerns remain about the side effects of the combination with alcohol, it is hard to prescribe SMO for this purpose. In order to amplify the effects of the drug, SMO can also be used in combination with another anti-craving drug (such as NTX) or adversive drug (such as DF). It seems that when SMO is combined with other drugs with different mechanisms of actions, they work without suppressing the favorable effects of each other.\n\nIn conclusion, we believe that SMO can be considered one of the most effective drugs in the treatment of AUD, with a good profile in safety [3,11]. However, all patients taking SMO should be closely monitored by specialists working in an Alcohol Addiction Center with the support of a family member in the administration of the drug.\n\nAcknowledgments\nNo funding sources, and no grants, have been received to perform this study. Authors thank Susan West for her English revision of the paper. \n\nAuthor Contributions\nFabio Caputo, Teo Vignoli, Claudia Tarli, Marco Domenicali, Giorgio Zoli, Mauro Bernardi, and Giovanni Addolorato conceived and designed the review; Fabio Caputo, Teo Vignoli, and Claudia Tarli analyzed the data; Fabio Caputo, Teo Vignoli, and Claudia Tarli wrote the paper. \n\nConflicts of Interest\nDuring the last two year, Fabio Caputo and Giovanni Addolorato, as consultants, received fees from Laboratorio Farmaceutico CT, Lundbeck Italia, and D&A Pharma. All other authors declare that they have no conflicts of interest\n==== Refs\nReferences\n1. Snead O.C. Gibson K.M. Gamma-hydroxybutyric acid N. Engl. J. Med. 2005 352 2721 2732 10.1056/NEJMra044047 15987921 \n2. Busardò F.P. Jones A.W. GHB pharmacology and toxicology: Acute intoxication, concentrations in blood and urine in forensic cases and treatment of the withdrawal syndrome Curr. Neuropharmacol. 2015 13 47 70 10.2174/1570159X13666141210215423 26074743 \n3. Keating G.M. Sodium oxybate: A review of its use in alcohol withdrawal syndrome and in the maintenance of abstinence in alcohol dependence Clin. Drug Investig. 2014 34 63 80 10.1007/s40261-013-0158-x 24307430 \n4. Carter L.P. Koek W. France C.P. Behavioural analysis of GHB: Receptor mechanisms Pharmacol. Ther. 2009 121 100 114 10.1016/j.pharmthera.2008.10.003 19010351 \n5. Palatini P. Tedeschi L. Frison G. Padrini R. Zordan R. Orlando R. Gallimberti L. Gessa G.L. Ferrara S.D. Dose-dependent absorption and elimination of gamma-hydroxybutyric acid in healthy volunteers Eur. J. Clin. Pharmacol. 1993 45 353 356 10.1007/BF00265954 8299669 \n6. Gessa G.L. Agabio R. Carai M. Lobina C. 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Identification and management of alcohol withdrawal syndrome Drugs 2015 75 353 365 10.1007/s40265-015-0358-1 25666543 \n11. Skala K. Caputo F. Mirijello A. Vassallo G. Antonelli M. Ferrulli A. Walter H. Lesh O. Addolorato G. Sodium oxybate in the treatment of alcohol dependence: From the alcohol withdrawal syndrome to the alcohol relapse prevention Expert Opin. Pharmacother. 2014 15 245 257 10.1517/14656566.2014.863278 24283802 \n12. Leone M.A. Vigna-Taglianti F. Avanzi G. Brambilla R. Faggiano F. Gamma-hydroxybutyrate (GHB) for treatment of alcohol withdrawal and prevention of relapses Cochrane Database Syst. Rev. 2010 2 10.1002/14651858.CD006266.pub2 \n13. Caputo F. Skala K. Mirijello A. Ferrulli A. Walter H. Lesh O. Addolorato G. Sodium oxybate in the treatment of alcohol withdrawal syndrome: A randomized double-blind comparative study versus oxazepam. The GATE 1 Trial CNS Drugs 2014 28 743 752 10.1007/s40263-014-0183-1 24996524 \n14. Caputo F. Mirijello A. Cibin M. Mosti A. Ceccanti M. Domenicali M. Bernardi M. Maremmani I. Addolorato G. Novel strategies to treat alcohol dependence with sodium oxybate according to clinical practice Eur. Rev. Med. Pharmacol. Sci. 2015 19 1315 1320 25912595 \n15. Caputo F. Vignoli T. Grignaschi A. Cibin M. Addolorato G. Bernardi M. Pharmacological management of alcohol dependence: From mono-therapy to pharmacogenetics and beyond Eur. Neuropsychopharmacol. 2014 24 181 191 10.1016/j.euroneuro.2013.10.004 24182622 \n16. Wang Y.G. Swick T.J. Carter L.P. Thorpy M.J. Benowitz N.L. Sodium oxybate: Updates and correction to previously published safety data J. Clin. Sleep Med. 2011 7 415 416 21897784 \n17. Pross N. Patat A. Vivet P. Bidaut M. Fauchoux N. Pharmacodynamic interactions of a solid formulation of sodium oxybate and ethanol in healthy volunteers Br. J. Clin. Pharmacol. 2015 80 480 492 10.1111/bcp.12632 25782469 \n18. Caputo F. Addolorato G. Stoppo M. Francini S. Vignoli T. Lorenzini F. del Re A. Comaschi C. Andreone P. Trevisani F. Comparing and combining gamma-hydroxybutyric acid (GHB) and naltrexone in maintaining abstinence from alcohol: An open randomised comparative study Eur. Neuropsychopharmacol. 2007 17 781 789 10.1016/j.euroneuro.2007.04.008 17611081 \n19. Maremmani A.G.I. Pani P.P. Rovai L. Pacini M. Dell’Osso L. Maremmani I. Long-term γ-Hydroxybutyric acid (GHB) and disulfiram combination therapy in GHB treatment-resistant chronic alcoholics Int. J. Environ. Res. Public Health 2011 8 2816 2827 10.3390/ijerph8072816 21845160 \n20. Connor J.P. Haber P.S. Hall W.D. Alcohol use disorders Lancet 2015 10.1016/S0140-6736(15)00122-1 \n21. Rehm J. Baliunas D. Borges G.L.G. Graham K. Irving H. Kehoe T. Parry C.D. Patra J. Popova S. Poznyak V. The relation between different dimensions of alcohol consumption and burden of disease: An overview Addiction 2010 105 817 843 10.1111/j.1360-0443.2010.02899.x 20331573 \n22. Testino G. Leone S. Borro P. Treatment of alcohol dependence: Recent progress and reduction of consumption Minerva Med. 2014 105 447 466 25392958 \n23. Gastfriend D.R. Garbutt J.C. Pettinati H.M. Forman R.F. Reduction in heavy drinking as a treatment outcome in alcohol dependence J. Subst. Abus. Treat. 2007 33 71 80 10.1016/j.jsat.2006.09.008 17588491 \n24. Van Amsterdam J. van den Brink W. Reduced-risk drinking as a viable treatment goal in problematic alcohol use and alcohol dependence J. Psychopharmacol. 2013 27 987 997 10.1177/0269881113495320 23824247 \n25. Gallimberti L. Ferri M. Ferrara S.D. Fadda F. Gessa G.L. Gamma-hydroxybutyric acid in the treatment of alcohol dependance: A double-blind study Alcohol. Clin. Exp. Res. 1992 16 673 676 10.1111/j.1530-0277.1992.tb00658.x 1326902 \n26. Addolorato G. Cibin M. Caputo F. Capristo E. Gessa G.L. Stefanini G.F. Gasbarrini G. Gamma-hydroxybutyric acid in the treatment of alcoholism: Dosage fractioning utility in non-responder alcoholic patients Drug Alcohol Depend. 1998 53 7 10 10.1016/S0376-8716(98)00094-5 10933335 \n27. Addolorato G. Castelli E. Stefanini G.F. Casella G. Caputo F. Marsigli L. Bernardi M. Gasbarrini G. An open multicentric study evaluating 4-hydroxybutyric acid sodium salt in the medium-term treatment of 179 alcohol dependent subjects. GHB Study Group Alcohol Alcohol. 1996 31 341 345 10.1093/oxfordjournals.alcalc.a008160 8879280 \n28. Maremmani I. la Manna F. Tagliamonte A. Long-term therapy using GHB (sodium gamma hydroxybutyrate) for treatment-resistant chronic alcoholics J. Psychoact. Drugs 2001 33 135 142 10.1080/02791072.2001.10400478 11476260 \n29. Caputo F. Francini S. Brambilla R. Vigna-Taglianti F. Stoppo M. del Re A. Leggio L. Addolorato G. Zoli G. Bernardi M. Sodium oxybate in maintaining alcohol abstinence in alcoholic patients with and without psychiatric comorbidity Eur. Neuropsychopharmacol. 2011 21 450 456 10.1016/j.euroneuro.2010.12.005 21276717 \n30. Caputo F. del Re A. Brambilla R. Grignaschi A. Vignoli T. Vigna-Taglianti F. Addolorato G. Zoli G. Cibin M. Bernardi M. Sodium oxybate in maintaining alcohol abstinence in alcoholic patients according to Lesch typologies: A pilot study J. Psychopharmacol. 2014 28 23 30 10.1177/0269881113504015 24045881 \n31. Zvosec D.L. Smith S.W. Quinn Strobl T.P.A. Dyer J.E. Case series of 226 g-hydroxybutyrate–associated deaths: Lethal toxicity and trauma Am. J. Emerg. Med. 2011 29 319 332 10.1016/j.ajem.2009.11.008 20825811 \n32. Martinotti G. Lupi M. Carlucci L. Cinosi E. Santacroce R. Acciavatti T. Chillemi E. Bonifaci L. Janiri L. Di Giannantonio M. Novel psychoactive substances: Use and knowledge among adolescents and young adults in urban and rural areas Hum. Psychopharmacol. Clin. Exp. 2015 30 295 301 10.1002/hup.2486 26216566 \n33. Vento A.E. Martinotti G. Cinosi E. Lupi M. Acciavatti T. Carrus D. Santacroce R. Chillemi E. Bonifaci L. di Giannantonio M. Substance use in the club scene of Rome: A pilot study BioMed. Res. Int. 2014 2014 10.1155/2014/617546 25243163 \n34. Degenhardt L. Darke S. Dillon P. GHB use among Australians: Characteristics, use patterns and associated harm Drug Alcohol Depend. 2002 67 89 94 10.1016/S0376-8716(02)00017-0 12062782 \n35. Schulz M. Iwersen-Bergmann S. Andresen H. Schmoldt A. Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics Crit. Care 2012 16 R136 10.1186/cc11441 22835221 \n36. Thai D. Dyer J.E. Jacob P. Haller C.A. Clinical pharmacology of 1,4-butanediol and gamma-hydroxybutyrate after oral 1,4-butanediol administration to healthy volunteers Clin. Pharmacol. Ther. 2007 81 178 184 10.1038/sj.clpt.6100037 17192771 \n37. Couper F.J. Logan B.K. GHB and driving impairment J. Forensic Sci. 2001 46 919 923 10.1520/JFS15070J 11451079 \n38. Fieier E.L. Coleman D.E. Baselt R.C. Gamma-hydroxybutyrate concentrations in pre- and postmortem blood and urine Clin. Chem. 1998 214 692 \n39. Elliott S.P. Further evidence for the presence of GHB in postmortem biological fluid: Implications for the interpretation offindings J. Anal. Toxicol. 2004 28 20 26 10.1093/jat/28.1.20 14987420 \n40. Ferrara S.D. Tedeschi L. Frison G. Rossi A. Fatality due to gamma-hydroxybutyric acid (GHB) and heroin intoxication J. Forensic Sci. 1995 40 501 504 10.1520/JFS13816J 7782758\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1660-4601",
"issue": "13(3)",
"journal": "International journal of environmental research and public health",
"keywords": "alcohol use disorder; pharmacological treatment; sodium oxybate",
"medline_ta": "Int J Environ Res Public Health",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000428:Alcohol Drinking; D019973:Alcohol-Related Disorders; D000437:Alcoholism; D001317:Austria; D005260:Female; D006801:Humans; D006885:Hydroxybutyrates; D007558:Italy; D008297:Male; D008875:Middle Aged; D012978:Sodium Oxybate; D013375:Substance Withdrawal Syndrome; D055815:Young Adult",
"nlm_unique_id": "101238455",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26959045",
"pubdate": "2016-03-05",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "20331573;20166080;21276717;21845160;21897784;22893778;23824247;24307430;24045881;24283802;24182622;24996524;22835221;25243163;25392958;25666543;25912595;26074743;26216566;26088121;25782469;10869869;10933335;11451079;11476260;12062782;14987420;1326902;8299669;7782758;8879280;9510892;15987921;17140279;17192771;17588491;17611081;19010351;20825811",
"title": "A Brief Up-Date of the Use of Sodium Oxybate for the Treatment of Alcohol Use Disorder.",
"title_normalized": "a brief up date of the use of sodium oxybate for the treatment of alcohol use disorder"
} | [
{
"companynumb": "IT-JAZZ-2016-IT-006117",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM OXYBATE"
},
"drugadditional": null,
... |
{
"abstract": "Tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR) have shown highly favourable outcomes in patients with advanced-stage non-small-cell lung cancer (NSCLC). The adverse effects of EGFR-TKIs are generally less severe than those of conventional cytotoxic therapies. We report a patient with NSCLC who presented with acute kidney injury associated with biopsy-proven acute tubular injury during osimertinib treatment and whose renal function recovered after reducing the osimertinib dose. A 61-year-old male smoker complained of dyspnoea on exertion for 1 month before his visit to the medical centre. He was diagnosed with lung adenocarcinoma of the left lower lobe (cT4N3M1a, stage IVA) and was positive for an EGFR mutation (exon 19 deletion). Osimertinib was initiated at 80 mg/day. At treatment initiation, the patient's serum creatinine level was 0.64 mg/dL, with microscopic haematuria; by day 83, this level had increased to 1.33 mg/dL, with proteinuria. On day 83, we reduced the osimertinib dose to 40 mg/day and performed a kidney biopsy on day 98. The histological diagnosis was tubular injury with IgA deposition. Based on the clinical course and histological findings, we speculated that the kidney injury was associated with osimertinib. After dose reduction, the patient's serum creatinine level decreased to 1.07 mg/dL, and proteinuria disappeared. He maintained a partial response for >6 months after osimertinib administration. We report the first case of biopsy-proven mild IgA deposition, crescent formation, and tubular injury probably caused by osimertinib and demonstrate how reducing the osimertinib dose could strike a balance between its anti-cancer efficacy and adverse effects.",
"affiliations": "Department of Respiratory Medicine, Osaka General Medical Center, Osaka, Japan.;Department of Kidney Disease and Hypertension, Osaka General Medical Center, Osaka, Japan.;Department of Respiratory Medicine, Osaka General Medical Center, Osaka, Japan.;Department of Respiratory Medicine, Osaka General Medical Center, Osaka, Japan.;Department of Respiratory Medicine, Osaka General Medical Center, Osaka, Japan.;Department of Respiratory Medicine, Osaka General Medical Center, Osaka, Japan.;Department of Respiratory Medicine, Osaka General Medical Center, Osaka, Japan.",
"authors": "Niitsu|Takayuki|T|;Hayashi|Terumasa|T|;Uchida|Junji|J|;Yanase|Takafumi|T|;Tanaka|Satoshi|S|;Kuroyama|Munenori|M|;Ueno|Kiyonobu|K|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000518774",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1660-8151",
"issue": null,
"journal": "Nephron",
"keywords": "Case report; Drug-induced kidney injury; Non-small-cell lung carcinoma; Osimertinib",
"medline_ta": "Nephron",
"mesh_terms": null,
"nlm_unique_id": "0331777",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "34569520",
"pubdate": "2021-09-17",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Drug-Induced Kidney Injury Caused by Osimertinib: Report of a Rare Case.",
"title_normalized": "drug induced kidney injury caused by osimertinib report of a rare case"
} | [
{
"companynumb": "2021A767421",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "OSIMERTINIB"
},
"drugadditional": "1",
"drugadmin... |
{
"abstract": "The aim of this study was to assess the use of the pathological response to neoadjuvant chemotherapy (NAC) for predicting disease prognosis in patients with advanced ovarian cancer who received neoadjuvant dose-dense weekly paclitaxel and carboplatin (dd-TC) therapy.\n\n\n\nWe retrospectively investigated patients with advanced epithelial ovarian, tubal, or peritoneal carcinoma treated at our hospital from July 2004 to October 2014. Patients received dd-TC therapy as NAC followed by interval debulking surgery (IDS). Specimens resected during IDS were divided into 4 groups based on pathological response: grade 1, most tumor cells appeared to be viable; grade 2a, most tumor cells had disappeared, whereas the remaining tumor cells were vacuolated or degenerated; grade 2b, small numbers of viable tumor cells were observed; and grade 3, small aggregations of macrophages were seen.\n\n\n\nSixty-eight patients were enrolled. The median number of NAC cycles was 3 (range, 2-6), and 51 patients (75.0%) achieved complete resection at IDS. Regarding pathological response, 7 (10.3%) patients were classified as grade 1, 11 (16.2%) as grade 2a, 46 (67.7%) as grade 2b, and 4 (5.9%) as grade 3. In univariate and multivariate analyses, grades 2b and 3 pathological responses were significant favorable prognostic factors for progression-free survival (P = 0.028; hazard ratio, 0.48; 95% confidence interval, 0.26-0.92).\n\n\n\nAlthough the pathological complete response rate to NAC was low in this study, both complete and good pathological responses to NAC might be favorable prognostic factors for PFS in patients with advanced ovarian cancer who receive dd-TC.",
"affiliations": "*Department of Medical Oncology, Chiba University, Chiba; and Departments of †Breast and Medical Oncology, ‡Pathology, §Pharmacy, and ∥Gynecology, National Cancer Center Hospital, Tokyo, Japan.",
"authors": "Ebata|Takahiro|T|;Yunokawa|Mayu|M|;Yoshida|Hiroshi|H|;Bun|Seiko|S|;Shimoi|Tatsunori|T|;Shimomura|Akihiko|A|;Kodaira|Makoto|M|;Yonemori|Kan|K|;Shimizu|Chikako|C|;Fujiwara|Yasuhiro|Y|;Kato|Tomoyasu|T|;Tamura|Kenji|K|",
"chemical_list": "D016190:Carboplatin; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1097/IGC.0000000000001107",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1048-891X",
"issue": "27(9)",
"journal": "International journal of gynecological cancer : official journal of the International Gynecological Cancer Society",
"keywords": null,
"medline_ta": "Int J Gynecol Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D000077216:Carcinoma, Ovarian Epithelial; D017024:Chemotherapy, Adjuvant; D005185:Fallopian Tube Neoplasms; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial; D010051:Ovarian Neoplasms; D017239:Paclitaxel; D010534:Peritoneal Neoplasms; D011379:Prognosis; D012189:Retrospective Studies",
"nlm_unique_id": "9111626",
"other_id": null,
"pages": "1850-1855",
"pmc": null,
"pmid": "29040183",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Prognostic Impact of the Pathological Response to Neoadjuvant Dose-Dense Therapy for Ovarian Carcinoma.",
"title_normalized": "the prognostic impact of the pathological response to neoadjuvant dose dense therapy for ovarian carcinoma"
} | [
{
"companynumb": "JP-CORDEN PHARMA LATINA S.P.A.-JP-2017COR000247",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugad... |
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